TW201524969A - Glucose transport inhibitors - Google Patents

Abstract

The present invention relates to chemical compounds that selectively inhibit glucose transporter 1 (GLUT1), to methods of preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds, to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, as well as to intermediate compounds useful in the preparation of said compounds.

Description

Glucose transport inhibitor

The present invention relates to a compound which selectively inhibits glucose transporter 1 (GLUT1), a method of preparing the same, a pharmaceutical composition and a combination comprising the same, and a pharmaceutical combination for use in the manufacture of a medicament for treating or preventing a disease Uses of the materials and intermediate compounds suitable for the preparation of such compounds.

Glucose is essential for metabolism in most cells. Because glucose is a polar molecule, specific transport proteins are required for transport across biofilms. The transport of glucose across the apical membrane of the intestinal and renal epithelial cells depends on the presence of the secondary active Na ⁺ /glucose symporters SGLT-1 and SGLT-2, which are used alongside the Na ⁺ ions The synergistic transport of the electrochemical gradient down provides the energy to enrich glucose inside the cell. The facilitated diffusion of glucose across the cell membrane is catalyzed by other means of glucose transport (protein symbol GLUT, gene symbol SLC2 representing solute carrier family 2) belonging to the transport facilitator superfamily (main facilitator superfamily), such glucose The carrier includes an organic anion and a cation transporter, a yeast hexose transporter, a plant hexose/proton symporter, and a bacterial sugar/proton symporter.

The basal glucose transporter (GLUT) acts as a glucose channel and is required for maintaining the essential glucose requirements of the cell. These GLUTs are constitutively and functioning in cells and are not regulated (or insensitive) by insulin. All cells use both glycolysis and oxidative phosphorylation in mitochondria, but when oxygen is abundant, most rely on oxidative phosphorylation; when oxygen is deficient (hypoxia), as it occurs in cancer, it switches to sugar Fermentation. In glycolysis, Portugal Glucose is converted to pyruvate and two ATP molecules are produced in the process. Cancer cells are mainly hypoxic (low oxygen) due to their faster proliferation rate. Therefore, cancer cells use glycolysis (lactate formation) as their main glucose metabolism pathway. Such glycolysis conversion not only confers higher metastatic and invasive potential to cancer, but also increases the vulnerability of cancer to external disturbances in glycolysis. A reduction in basal glucose transport may limit glucose supply to cancer cells, leading to glucose deficiency, forcing cancer cells to slow down or starve.

All known GLUT proteins contain 12 transmembrane domains and facilitate the diffusion of glucose by a non-energy dependent process. GLUT1 may transport glucose into cells by alternating its conformation. According to this model, GLUT1 exposes a single substrate binding site to the exterior or interior of the cell. The combination of glucose and a site triggers a conformational change that releases glucose to the other side of the membrane. The results of studies on transgenic genes and gene knockout animals support the important role of these transporters in controlling glucose utilization, glucose storage, and glucose sensing. The GLUT protein differs in its kinetics and is tailored to the needs of the cell type it serves. Although more than one GLUT protein can be expressed by a specific cell type, cancer often overexpresses GLUT1, which is a high-affinity glucose transporter, and its degree of expression is related to the invasion and metastasis potential of cancer, indicating that glucose transport is up-regulated in cancer cell growth and The importance of the severity of cancer malignancies. GLUT1 expression was also found to be significantly higher than that of any other glucose transporter.

Evidence suggests that cancer cells are less sensitive to glucose than normal cells. Numerous studies have strongly demonstrated that basal glucose transport inhibition induces apoptosis and blocks cancer cell growth. Anti-angiogenesis has been shown to be an extremely effective way to limit cancer growth and cause cancer resection.

It has been shown that GLUT1 expression is reduced after transfection of GLUT1 antisense cDNA into cancer cell lines, inhibiting in vitro cell growth and tumor growth in vivo, and reducing in vitro invasiveness of cells (Noguchi Y. et al. Cancer Lett 154(2), 2000 , 175-182; Ito S. et al. J Natl Cancer Inst 94 (14), 2002, 1080-1091).

GLUT1 has been shown to be the highest in ErbB2 and PyVMT-induced mouse breast cancer models. Degree of hexose transporter, and the use of shRNA or Cre/lox to reduce GLUT1 levels leads to a decrease in glucose use, decreased growth in plastics and in soft agar, and impaired tumor growth in nude mice (Christian D. Young) Et al., PLoS ONE, August 2011, Vol. 6, No. 8, e23205, 1-12).

Thus, inhibition of GLUT1 represents a promising approach for the treatment of proliferative disorders, including solid tumors such as carcinomas and sarcomas and leukemias and lymphoid malignancies or other disorders associated with uncontrolled cell proliferation.

Different compounds exhibiting inhibition of GLUT1 have been disclosed in the prior art. For example, WO 2011/119866 (A1) discloses compositions and methods for glucose transport inhibition; WO 2012/051117 (A2) and WO 2013/155338 (A2) disclose substituted benzamide as GLUT1 inhibitor.

The compounds disclosed in the prior art exhibit some structural similarity to the compounds of the invention. WO 97/36881 (A1) discloses compounds containing an arylheteroaryl group which inhibits farnesyl protein transferase. WO00/07996 (A2) discloses pyrazole estrogen receptor agonists and antagonist compounds. WO 01/21160 (A2) discloses that a methotrexate derivative is an inhibitor of the herpesvirus family. WO 03/037274 (A2) and WO 2004/099154 (A2) disclose pyrazole-guanamine as inhibitors of sodium channels. WO2004/098528 (A2) discloses pyrazole-derived compounds as inhibitors of p38 kinase. WO2006/132197 (A1) discloses heterocyclic compounds as inhibitors of type 1 11-hydroxysteroid dehydrogenases. WO2006/062249 (A1) discloses a compound for the prevention, treatment or amelioration of a disease in which activation of a thrombopoietin receptor is effective. WO 2008/126899 (A1) discloses a 5-membered heterocyclic compound as an inhibitor of xanthine oxidase. WO 2008/008286 (A2) discloses substituted pyrazoles as intragastric hormone receptor antagonists. WO 2009/025793 (A2) discloses compounds which act as bitter blockers. WO 2009/027393 (A2) and WO 2010/034737 (A1) disclose pyrazole compounds for controlling invertebrate pests. WO2009/099193 (A1) discloses compounds which have an inhibitory effect on melanin production. WO2009/119880 (A1) reveals androgen receptor antagonism Pyrazole derivatives. WO2011/050305 (A1) and WO2011/050316 (A1) disclose that a pyrazole compound acts as a stereoregulatory modulator of mGluR4 receptor activity. WO 2011/126903 (A2) discloses polysubstituted aromatic compounds, including substituted pyrazolyl groups, as thrombin inhibitors. WO2004/110350 (A2) discloses compounds that modulate beta-amyloid. WO 2009/055917 (A1) discloses inhibitors of histone deacetylase. WO 02/23986 (A1) discloses 4-nonylaminopyrazole derivatives which exhibit fungicidal activity. WO 03/051833 (A2) discloses heteroaryl substituted pyrazole compounds as mGluR5 modulators. WO 2009/076454 (A2) discloses compounds which modulate the activity of a calcium channel-operated calcium channel. WO 99/32454 (A1) discloses nitrogen-containing heteroaromatics containing an ortho-substituted P1 group as a factor Xa inhibitor. WO2004/037248 (A2) and WO2004/043951 (A1) disclose compounds which act as modulators of peroxisome proliferator-activated receptors. WO 2013/109991 (A1) discloses various heterocyclic compounds for the treatment of neurodegenerative diseases. WO 2014031936 (A2) discloses heteroaromatic compounds as α7β1 integrin modulators.

However, the above-mentioned current advanced techniques have not specifically disclosed the compound of the general formula (I) of the present invention, or a tautomer, a stereoisomer, an N-oxide, a hydrate, a solvate or a salt thereof, or a mixture thereof, such as As described and defined herein, and as hereinafter referred to as "the compound of the invention", or its pharmacological activity.

The invention encompasses compounds of the general formula (I): Wherein: R ¹ represents C ₁ -C ₃ alkyl-, halo-C ₁ -C ₃ alkyl-, cyano-, -C(=O)OR ¹⁰ or -C(=O)N(R ^10a ) R ^10b group; R ² represents C ₁ -C ₃ alkyl-, halo-C ₁ -C ₃ alkyl-, cyano-, -C(=O)OR ¹⁰ or -C(=O)N( R ^10a ) R ^10b group; R ³ represents a group selected from the group consisting of aryl-, heteroaryl-, C ₅ -C ₆ cycloalkyl- and 5- to 6-membered heterocycloalkyl-; The 5- to 6-membered heterocycloalkyl-group is optionally benzofused; wherein the aryl-, heteroaryl-, C ₅ -C ₆ cycloalkyl- and 5- to 6-membered heterocycloalkyl- The group is optionally substituted one or more times by -(L ² ) _p -R ⁷ ; and wherein two -(L ² ) _p -R ⁷ groups are present in the aryl- or heteroaryl group, if present - If the groups are ortho to each other, a bridge selected from the group consisting of *-C ₃ -C ₈ alkyl-*, *-O(CH ₂ ) ₂ O-*, *-O(CH) ₂ ) O-*, *-O(CF ₂ )O-*, *-CH ₂ C(R ^10a )(R ^10b )O-*, *-C(=O)N(R ^10a )CH ₂ -* , *-N(R ^10a )C(=O)CH ₂ O-*, *-NHC(=O)NH-*; wherein each * represents a point of attachment to the aryl- or heteroaryl- group; R ^4a represents a hydrogen atom or a halogen atom or a group selected from the group consisting of cyano-, hydroxy-, C ₁ -C _3- alkyl-, halo-C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy-, halo-C ₁ -C ₃ alkoxy-, C ₃ -C ₇ cycloalkyl-, 4- to 7-membered heterocycloalkyl-, -C(=O)-OR ¹⁰ , -C(=O)N(R ^10a )R ^10b , -C(=O)-N(R ^10a )-S( =O) ₂ -R ¹⁰ , -SR ¹⁰ , -S(=O)-R ¹⁰ , -S(=NR ¹¹ )-R ¹⁰ , -S(=O) ₂ -R ¹⁰ , -S(=O) ₂ -N(R ^10a )R ^10b , -S(=O)(=NR ¹¹ )-R ¹⁰ , -N(R ^10a )R ^10b ; R ^4b represents a hydrogen atom or a group selected from the group consisting of C ₁ - C ₃ alkoxy-, C ₁ -C ₃ alkyl-, cyano-; or R ^4a and R ^4b together form a -C ₃ -C ₅ alkyl- group; R ^5a , R ^5b , R ^5c , R ^5d

Independently from each other, a hydrogen atom, a halogen atom or a group selected from the group consisting of cyano-, -NO ₂ , C ₁ -C ₃ alkyl-, halo-C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy-, halo-C ₁ -C ₃ alkoxy-, phenyl-, heteroaryl-, -C(=O)R ¹⁰ , -C(=O)N(H)R ¹⁰ , -C(=O)N(R ^10a )R ^10b , -C(=O)OR ¹⁰ , -N(R ^10a )R ^10b , -N(H)C(=O)R ¹⁰ , -N(R ^10a C(=O)R ^10b , -N(H)C(=O)N(R ^10a )R ^10b , -N(R ^10a )C(=O)N(R ^10b )R ^10c , -N(R ^10a ) C(=O)C(=O)N(R ^10b )R ^10c , -N(H)C(=O)OR ¹⁰ , -N(R ^10a )C(=O)OR ^10b , -N( H)S(=O) ₂ R ¹⁰ , -N(R ^10a )S(=O) ₂ R ^10b , -OR ¹⁰ , -O(C=O)R ¹⁰ , -O(C=O)N(R ^10a ) R ^10b , -O(C=O)OR ¹⁰ , -SR ¹⁰ , -S(=O)R ¹⁰ , -S(=O) ₂ R ¹⁰ , -S(=O) ₂ N(H)R ¹⁰ , -S(=O) ₂ N(R ^10a )R ^10b or -S(=O)(=NR ^10a )R ^10b , the phenyl- or heteroaryl-group is optionally selected from the group consisting of The group is substituted one or more times identically or differently: halo-, cyano-, C ₁ -C ₃ alkyl-, halo-C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy- ; R ⁶ represents a hydrogen atom or a group selected from the group consisting of C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy-(L ² )-, hydroxy-C ₁ -C ₃ alkyl-, aryl-(L ² )-, heteroaryl-(L ² )-; R ⁷ represents a group selected from the group consisting of a pendant oxy group, a C ₁ -C ₆ alkyl group, and a C ₃ - C ₇ cycloalkyl-, 4 to 7 membered heterocycloalkyl-, halo-C ₁ -C ₄ alkyl-, hydroxy-C ₁ -C ₄ alkyl-, cyano-C ₁ -C ₄ alkane Base-, C ₂ -C ₄ alkenyl-, C ₂ -C ₄ alkynyl-, C ₁ -C ₄ alkoxy-, halo-C ₁ -C ₄ alkoxy-, -OH, -CN, Halo-, -C(=O)R ⁸ , -C(=O)-OR ⁸ , -C(=O)N(R ^8a )R ^8b , -N(R ^10a )R ^10b , -S(= O) ₂ R ⁸ , -S(=O)(=NR ¹¹ )-R ¹⁰ , phenyl-, 5- to 6-membered heteroaryl-; R ⁸ represents a hydrogen atom or a C ₁ -C ₆ alkyl-, Halo-C ₁ -C ₃ alkyl-, cyano-C ₁ -C ₄ alkyl-, C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl-, C ₃ -C ₇ cycloalkyl -, phenyl-, 5- to 6-membered heteroaryl- or benzyl-group; R ^8a , R ^8b

Independently from each other, a hydrogen atom or a C ₁ -C ₁₀ alkyl-, C ₃ -C ₇ cycloalkyl-, (C ₃ -C ₇ cycloalkyl)-(L ³ )-, C ₃ -C ₆ alkenyl group -, C ₃ -C ₆ alkynyl-, 4 to 10 membered heterocycloalkyl-, (4 to 10 membered heterocycloalkyl)-(L ³ )-, phenyl-, heteroaryl-, benzene -(L ³ )-, (phenyl)-O-(L ³ )-, heteroaryl-(L ³ )- or (aryl)-(4 to 10 membered heterocycloalkyl)- groups ; C ₁ -C ₁₀ alkyl-, C ₃ -C ₇ cycloalkyl-, (C ₃ -C ₇ cycloalkyl)-(L ³ )-, C ₃ -C ₆ alkenyl-, C ₃ - C ₆ alkynyl-, 4 to 10 membered heterocycloalkyl-, (4 to 10 membered heterocycloalkyl)-(L ³ )-, phenyl-, heteroaryl-, phenyl-(L ³ -, (phenyl)-O-(L ³ )-, heteroaryl-(L ³ )- and (aryl)-(4 to 10 membered heterocycloalkyl)- groups, optionally via R ⁹ Substituting one or more times identically or differently; or R ^8a and R ^8b together with the nitrogen atom to which they are attached represent a 4 to 10 membered heterocycloalkyl- group, the 4 to 10 membered heterocycloalkyl- group R group optionally substituted with identically or differently substituted one or more times ^9; R ⁹ represents a halogen atom or oxo, C ₁ -C ₃ alkyl -, halo -C ₁ -C ₃ alkyl -, hydroxy - C ₁ -C ₃ alkyl-, -CN, -C(=O)R ¹⁰ , -C(=O)N(H)R ^{1 0} , -C(=O)N(R ^10a )R ^10b , -C(=O)OR ¹⁰ , -N(R ^10a )R ^10b , -NO ₂ , -N(H)C(=O)R ¹⁰ , -N(R ^10a )C(=O)R ^10b , -N(H)C(=O)N(R ^10a )R ^10b , -N(R ^10a )C(=O)N(R ^10b )R ^10c , -N(H)C(=O)OR ¹⁰ , -N(R ^10a )C(=O)OR ^10b , -N(H)S(=O) ₂ R ¹⁰ , -N(R ^10a )S (=O) ₂ R ^10b , -OR ¹⁰ , -O(C=O)R ¹⁰ , -O(C=O)N(R ^10a )R ^10b , -O(C=O)OR ¹⁰ , -SR ¹⁰ , -S(=O)R ¹⁰ , -S(=O) ₂ R ¹⁰ , -S(=O) ₂ N(H)R ¹⁰ , -S(=O) ₂ N(R ^10a )R ^10b ,- S(=O)(=NR ^10a )R ^10b or a tetrazolyl- group; or two R ⁹ groups present adjacent to each other on the phenyl- or heteroaryl-ring form a bridge selected from Key: *-C ₃ -C ₅ alkylene-*, *-O(CH ₂ ) ₂ O-*, *-O(CH ₂ )O-*, *-O(CF ₂ )O-*, * -CH ₂ C(R ^10a )(R ^10b )O-*, *-C(=O)N(R ^10a )CH ₂ -*, *-N(R ^10a )C(=O)CH ₂ O-* , *-NHC(=O)NH-*; wherein each * represents a point of attachment to the phenyl- or heteroaryl-ring; R ¹⁰ , R ^10a , R ^10b , R ^10c

Independently from each other, a hydrogen atom or a group selected from the group consisting of C ₁ -C ₃ alkyl-, halo-C ₁ -C ₃ alkyl-, hydroxy-C ₁ -C ₃ alkyl-, C ₁ -C _alkoxy -C ₁ -C ₃ alkyl -, C ₃ -C ₇ cycloalkyl -, the C ₁ -C ₃ alkyl - group optionally substituted by a -N (R ¹²⁾ R ^12a; or R ^10a and R ^10b together with the nitrogen atom to which they are attached represent a 4- to 7-membered heterocycloalkyl- group, which may be substituted identically or differently by R ¹³ as appropriate One or more times; R ¹¹ represents a hydrogen atom or a cyano-, C ₁ -C ₃ alkyl-, -C(=O)R ¹⁰ , -C(=O)N(H)R ¹⁰ , -C(= O) N(R ^10a )R ^10b or -C(=O)OR ¹⁰ group; R ¹² , R ^12a

Representing each other independently of a hydrogen atom or a C ₁ -C ₃ alkyl- group, or R ¹² , R ^12a

The nitrogen atom to which it is attached represents a 4- to 7-membered heterocycloalkyl- group; R ¹³ represents a halogen atom or a cyano group, a hydroxyl group, a pendant oxy group, a C ₁ -C ₃ alkyl group, a trifluoromethyl group- a -C(=O)R ¹⁰ or -C(=O)OR ¹⁰ group; L ¹ represents a group selected from: -C ₁ -C ₄ alkylene-, -CH ₂ -CH=CH- , -C(phenyl)(H)-, -CH ₂ -CH ₂ -O-, -CH ₂ -C(=O)-N(H)-, -CH ₂ -C(=O)-N( R ^10a )-; L ² represents a group selected from: -CH ₂ -, -CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -CH ₂ -; L ³ represents -C ₁ -C ₆ -alkylene a radical - group; p is an integer 0 or 1; or a tautomer, stereoisomer, N-oxide, hydrate, solvate or salt thereof or a mixture thereof.

The invention further relates to a process for the preparation of a compound of the formula (I), to pharmaceutical compositions and combinations comprising the compounds, to the use of such compounds for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of diseases, and to the preparation of such compounds Intermediate compound.

The term as referred to in the text of the present invention preferably has the following meaning: The term "halogen atom" or "halo-" is understood to mean a fluorine, chlorine, bromine or iodine atom.

The term "tertiary oxy" is understood to mean preferably attached to an atom having a suitable bond valence (such as a saturated carbon or sulfur atom) by a double bond to form, for example, a carbonyl-C(=O)- or sulfonate. An oxygen atom of the group -S(=O) ₂ -.

The term "C ₁ -C ₁₀ alkyl-" is understood to preferably mean a straight or branched chain saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. , for example, methyl-, ethyl-, propyl-, butyl-, pentyl-, hexyl-, isopropyl-, isobutyl-, second butyl-, tert-butyl-, isopentyl -, 2-methylbutyl-, 1-methylbutyl-, 1-ethylpropyl-, 1,2-dimethylpropyl-, neopentyl-, 1,1-dimethylpropane Base-, 4-methylpentyl-, 3-methylpentyl-, 2-methylpentyl-, 1-methylpentyl-, 2-ethylbutyl-, 1-ethylbutyl- , 3,3-dimethylbutyl-, 2,2-dimethylbutyl-, 1,1-dimethylbutyl-, 2,3-dimethylbutyl-, 1,3-di Methyl butyl- or 1,2-dimethylbutyl-, heptyl-, octyl-, decyl- or decyl- or an isomer thereof. In particular, the group has 1, 2, 3, 4, 5 or 6 carbon atoms ("C ₁ -C ₆ alkyl-"), more specifically 1, 2, 3 or 4 carbon atoms. ("C ₁ -C ₄ alkyl-"), such as methyl-, ethyl-, propyl-, butyl-, isopropyl-, isobutyl-, second butyl-, tert-butyl a group, even more specifically having 1, 2 or 3 carbon atoms ("C ₁ -C ₃ alkyl-"), such as methyl-, ethyl-, n-propyl- or isopropyl-yl group.

The term "-C ₁ -C ₈ alkylene-" is understood to mean a straight-chain or branched-chain saturated divalent hydrocarbon chain having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms. Or "tether", such as -CH ₂ - ("methylene" or "-C ₁ alkyl"); or for example -CH ₂ -CH ₂ - ("extended ethyl" or "- C ₂ alkylene-"); -CH ₂ -CH ₂ -CH ₂ -, -C(H)(CH ₃ )-CH ₂ - or -C(CH ₃ ) ₂ -) ("Extended propyl" or "-C ₃ alkylene-"); or for example -CH ₂ -C(H)(CH ₃ )-CH ₂ -, -CH ₂ -C(CH ₃ ) ₂ -), -CH ₂ -CH ₂ - CH ₂ -CH ₂ - ("Strengthyl" or "-C ₄ alkyl");"-C ₅ alkyl" - for example -CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH ₂ - ("Extension of pentyl"); or "-C ₆ -alkyl-", for example, -CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH ₂ - ("extension") group. In particular, the alkyl group has 1, 2, 3, 4 or 5 carbon atoms ("-C ₁ -C ₅ alkyl-"); more specifically, 1 or 2 carbon atoms ( "-C ₁ -C ₂ alkylene-"), or 3, 4 or 5 carbon atoms ("-C ₃ -C ₅ alkyl-").

The term "halo-C ₁ -C ₄ alkyl-" is understood to preferably mean a straight-chain or branched-chain saturated monovalent hydrocarbon radical, wherein the term "C ₁ -C ₄ alkyl-" is as defined above, and wherein hydrogen One or more of the atoms are replaced identically or differently by the halogen atom. Preferred is a halo-C ₁ -C ₃ alkyl- group. Specifically, the halogen atom is F, and the resulting group is also referred to as "fluoro-C ₁ -C ₃ alkyl-". The halo-C ₁ -C ₃ alkyl- group or the fluoro-C ₁ -C ₃ alkyl- group is, for example, -CF ₃ , -CHF ₂ , -CH ₂ F, -CF ₂ CF ₃ or -CH ₂ CF ₃ .

The term "cyano-C ₁ -C ₄ alkyl-" is understood to preferably mean a straight-chain or branched-chain saturated monovalent hydrocarbon radical, wherein the term "C ₁ -C ₄ alkyl-" is as defined above, and wherein hydrogen One or more of the atoms are replaced by a cyano group. The cyano-C _l -C ₄ alkyl- group is, for example, -CH ₂ CN, -CH ₂ CH ₂ -CN, -C(CN)H-CH ₃ , -C(CN)H-CH ₂ CN or -CH ₂ CH ₂ CH ₂ CH ₂ -CN.

The term "hydroxy-C ₁ -C ₄ alkyl-" is understood to preferably mean a straight-chain or branched-chain saturated monovalent hydrocarbon radical, wherein the term "C ₁ -C ₄ alkyl-" is as defined above, and wherein the hydrogen atom One or more of them are replaced by a hydroxyl group, with the proviso that no more than one hydrogen atom attached to a single carbon atom is replaced. Preferred is a hydroxy-C ₁ -C ₃ alkyl- group. The hydroxy-C ₁ -C ₄ alkyl-group or preferably a hydroxy-C ₁ -C ₃ alkyl- group is, for example, -CH ₂ OH, -CH ₂ CH ₂ -OH, -C(OH)H -CH ₃ or -C(OH)H-CH ₂ OH.

The term "C ₁ -C ₄ alkoxy-" is understood to mean a straight-chain or branched-chain saturated monovalent group of the formula -O-(C ₁ -C ₄ alkyl-), wherein the term "C ₁ - C ₄ alkyl-" is as defined above, for example methoxy-, ethoxy-, n-propoxy-, isopropoxy-, n-butoxy-, tert-butoxy. Preferred is a C ₁ -C ₃ alkoxy- group.

The term "halo-C ₁ -C ₄ alkoxy-" is understood to preferably mean a straight-chain or branched-chain saturated monovalent C ₁ -C ₄ alkoxy- group as defined above, wherein the hydrogen atom One or more of them are replaced identically or differently by a halogen atom. Preferred is a halo-C ₁ -C ₃ alkoxy- group. Specifically, the halogen atom is F, and the resulting group is also referred to as "fluoro-C ₁ -C ₄ alkoxy-" or preferably "fluoro-C ₁ -C ₃ alkoxy-". The halo-C ₁ -C ₄ alkoxy- group or the fluoro-C ₁ -C ₄ alkoxy- group is, for example, -OCF ₃ , -OCHF ₂ , -OCH ₂ F, -OCF ₂ CF ₃ or -OCH ₂ CF ₃ .

The term "C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl-" is understood to preferably mean a straight-chain or branched-chain saturated monovalent C ₁ -C ₃ alkyl- group as defined above, Wherein one or more of the hydrogen atoms are replaced identically or differently by a C ₁ -C ₃ alkoxy group as defined above, for example methoxyalkyl-, ethoxyalkyl-, propoxyalkyl - or isopropoxyalkyl-.

The term "halo-C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl" is understood to preferably mean a straight-chain or branched-chain saturated monovalent C ₁ -C ₃ alkoxy group as defined above - A C ₁ -C ₃ alkyl group in which one or more of the hydrogen atoms are replaced identically or differently by a halogen atom. Specifically, the halogen atom is F, and the resulting group is also referred to as "fluoro-C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl-". The halo-C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl- group or the fluoro-C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl- group is, for example, -CH ₂ CH ₂ OCF ₃ , -CH ₂ CH ₂ OCHF ₂ , -CH ₂ CH ₂ OCH ₂ F, -CH ₂ CH ₂ OCF ₂ CF ₃ or -CH ₂ CH ₂ OCH ₂ CF ₃ .

The term "C ₂ -C ₆ alkenyl-" is understood to preferably mean one or more double bonds and have 2, 3, 4, 5 or 6 carbon atoms, in particular 3, 4, 5 or 6 One carbon atom ("C ₃ -C ₆ alkenyl-"), more specifically 2 or 4 carbon atoms ("C ₂ -C ₄ alkenyl-") or 3 or 4 carbon atoms ("C ₃ - A linear or branched chain monovalent hydrocarbon group of C ₄ alkenyl-"), it being understood that where the alkenyl- group contains more than one double bond, the double bonds may be separated or conjugated to each other. The alkenyl- group is, for example, vinyl-, allyl-, ( E )-2-methylvinyl-, ( Z )-2-methylvinyl-, homoallyl-, ( E ) -but-2-alkenyl, ( Z )-but-2-enyl-, ( E )-but-1-enyl-, ( Z )-but-1-enyl-, pent-4-ene -( E )-pent-3-enyl-, ( Z )-pent-3-enyl-, ( E )-pent-2-enyl-, ( Z )-pent-2-enyl- , ( E )-pent-1-enyl-, ( Z )-pent-1-enyl-, hex-5-alkenyl-, ( E )-hex-4-enyl-, ( Z )-hexyl 4-alkenyl-, ( E )-hex-3-enyl-, ( Z )-hex-3-enyl-, ( E )-hex-2-enyl-, ( Z )-hex-2 -alkenyl-, ( E )-hex-1-enyl-, ( Z )-hex-1-enyl-, isopropenyl-, 2-methylprop-2-enyl-, 1-methyl Prop-2-enyl-, 2-methylprop-1-enyl-, ( E )-1-methylprop-1-enyl-, ( Z )-1-methylprop-1-enyl -, 3-methylbut-3-enyl-, 2-methylbut-3-enyl-, 1-methylbut-3-enyl-, 3-methylbut-2-enyl-, ( E )-2-methylbut-2-enyl-, ( Z )-2-methylbut-2-enyl-, ( E )-1-methylbut-2-enyl-, ( Z )-1-methylbut-2-enyl-, ( E )-3-methylbut-1-enyl-, ( Z )-3-methylbut-1-enyl-, ( E )- 2-methylbut-1-enyl -, ( Z )-2-methylbut-1-enyl-, ( E )-1-methylbut-1-enyl-, ( Z )-1-methylbut-1-enyl-, 1,1-dimethylprop-2-enyl-, 1-ethylprop-1-enyl-, 1-propylvinyl-, 1-isopropylvinyl-, 4-methylpentane- 4-alkenyl-, 3-methylpent-4-enyl-, 2-methylpent-4-enyl-, 1-methylpent-4-enyl-, 4-methylpent-3- Alkenyl-, ( E )-3-methylpent-3-enyl-, ( Z )-3-methylpent-3-enyl-, ( E )-2-methylpent-3-enyl -, ( Z )-2-methylpent-3-enyl-, ( E )-1-methylpent-3-enyl-, ( Z )-1-methylpent-3-enyl-, ( E )-4-methylpent-2-enyl-, ( Z )-4-methylpent-2-enyl-, ( E )-3-methylpent-2-enyl-, ( Z )-3-methylpent-2-enyl-, ( E )-2-methylpent-2-enyl-, ( Z )-2-methylpent-2-enyl-, ( E )- 1-methylpent-2-enyl-, ( Z )-1-methylpent-2-enyl-, ( E )-4-methylpent-1-enyl-, ( Z )-4- Methylpent-1-enyl-, ( E )-3-methylpent-1-enyl-, ( Z )-3-methylpent-1-enyl-, ( E )-2-methyl Pent-1-enyl-, ( Z )-2-methylpent-1-enyl-, ( E )-1-methylpent-1-enyl-, ( Z )-1-methylpentane- 1-alkenyl-, 3-ethylbut-3-enyl-, 2- Alkenyl-3-yl -, 1-ethyl-3-enyl -, (E) -3- ethyl-2-enyl -, (the Z) -3- ethyl-2-ene -( E )-2-ethylbut-2-enyl-, ( Z )-2-ethylbut-2-enyl-, ( E )-1-ethylbut-2-enyl- , ( Z )-1-ethylbut-2-enyl-, ( E )-3-ethylbut-1-enyl-, ( Z )-3-ethylbut-1-enyl-, 2 -ethylbut-1-enyl-, ( E )-1-ethylbut-1-enyl-, ( Z )-1-ethylbut-1-enyl-, 2-propylpropane-2 -alkenyl-, 1-propylprop-2-enyl-, 2-isopropylpropan-2-enyl-, 1-isopropylpropan-2-enyl-, ( E )-2-propane Propion-1-enyl-, ( Z )-2-propylprop-1-enyl-, ( E )-1-propylprop-1-enyl-, ( Z )-1-propylpropane 1-enyl-, ( E )-2-isopropylpropan-1-enyl-, ( Z )-2-isopropylprop-1-enyl-, ( E )-1-isopropyl Prop-1-henyl-, ( Z )-1-isopropylpropan-1-enyl-, ( E )-3,3-dimethylprop-1-enyl-, ( Z )-3, 3-dimethylprop-1-enyl-, 1-(1,1-dimethylethyl)vinyl-, butane-1,3-dienyl-, pentane-1,4-dienyl - a hex-1,5-dienyl- or methylhexadienyl- group. In particular, the group is a vinyl- or allyl-.

The term "C ₂ -C ₆ alkynyl-" is understood to preferably mean one or more referenced bonds and contain 2, 3, 4, 5 or 6 carbon atoms, in particular 3, 4, 5 or 6 Carbon atoms ("C ₃ -C ₆ alkynyl-", more specifically 2 or 4 carbon atoms ("C ₂ -C ₄ alkynyl-", or 3 or 4 carbon atoms ("C ₃ -C _a linear or branched monovalent hydrocarbon group of ₄ alkynyl-"). The C ₂ -C ₆ alkynyl- group is, for example, ethynyl-, prop-1-ynyl-, prop-2-ynyl-, butyl- 1-alkynyl-, but-2-ynyl-, but-3-ynyl-, pent-1-ynyl-, pent-2-ynyl-, pent-3-ynyl-, pent-4- Alkynyl-, hex-1-ynyl-, hex-2-ynyl-, hex-3-ynyl-, hex-4-ynyl-, hex-5-ynyl-, 1-methylpropane- 2-alkynyl-, 2-methylbut-3-ynyl-, 1-methylbut-3-ynyl-, 1-methylbut-2-ynyl-, 3-methylbut-1- Alkynyl-, 1-ethylprop-2-ynyl-, 3-methylpent-4-ynyl-, 2-methylpent-4-ynyl-, 1-methylpent-4-ynyl -, 2-methylpent-3-ynyl-, 1-methylpent-3-ynyl-, 4-methylpent-2-ynyl-, 1-methylpent-2-ynyl-, 4-methylpent-1-ynyl-, 3-methylpent-1-ynyl-, 2-ethylbut-3-ynyl-, 1-ethylbut-3-ynyl-, 1- Ethyl But-2-ynyl-, 1-propylprop-2-ynyl-, 1-isopropylprop-2-ynyl-, 2,2-dimethylbut-3-ynyl-, 1, 1-dimethylbut-3-ynyl-, 1,1-dimethylbut-2-ynyl- or 3,3-dimethylbut-1-ynyl-group. In particular, the The alkynyl- group is ethynyl-, prop-1-ynyl- or prop-2-ynyl-.

The term "C ₃ -C ₇ cycloalkyl-" is understood to mean a saturated monovalent monocyclic hydrocarbon ring containing 3, 4, 5, 6 or 7 carbon atoms. The C ₃ -C ₇ cycloalkyl- group is, for example, cyclopropyl-, cyclobutyl-, cyclopentyl-, cyclohexyl- or cycloheptyl-cyclo. In particular, the ring contains 3, 4, 5 or 6 carbon atoms ("C ₃ -C ₆ cycloalkyl-"; more specifically, the ring contains 5 or 6 carbon atoms ("C ₅ -C" ₆ cycloalkyl-").

The term "4 to 10 membered heterocycloalkyl-" is understood to mean a group containing 3, 4, 5, 6, 7, 8 or 9 carbon atoms and one or more hetero atom-containing groups selected from -O. ^a saturated monovalent monocyclic or bicyclic hydrocarbon ring of -, -S-, -S(=O)-, -S(=O) ₂ -, -NR ^a - wherein R ^a represents a hydrogen atom or a C ₁ -C ₆ alkane group -, or C ₃ -C ₇ cycloalkyl - group; the heterocyclic group - groups are attached to the remainder may molecule via a carbon atom or (if present) according to any one of the nitrogen atoms. Also included within the scope of this definition are heterospirocyclo-, heterobicycloalkyl-, and bridged heterocycloalkyl as defined below.

The term "heterocycloalkyl-" is understood to mean a saturated monovalent bicyclic hydrocarbon group in which two rings share a common ring carbon atom and wherein the bicyclic hydrocarbon group contains 3, 4, 5, 6, 7, 8 or 9 carbons. An atom and one or more hetero atom-containing groups selected from the group consisting of -O-, -S-, -S(=O)-, -S(=O) ₂ -, -NR ^a -, wherein R ^a represents hydrogen An atom or a C ₁ -C ₆ alkyl- or C ₃ -C ₇ cycloalkyl- group; the heterospirocycloalkyl- group is likely to be via a carbon atom or, if present, a nitrogen atom Connect to the rest of the molecule. The heterospirocycloalkyl- group is, for example, azaspiro[2.3]hexyl-, azaspiro[3.3]heptyl-, oxazaspiro[3.3]heptyl-, thiazaspiro[3.3] Heptyl-, oxaspiro[3.3]heptyl-, oxaza-spiro[5.3]decyl-, oxaza-spiro[4.3]octyl-, oxaza-spiro[5.5]undecyl -, diazaspiro[3.3]heptyl-, thiazaspiro[3.3]heptyl-, thiazepine[4.3]octyl- or azaspiro[5.5]decyl-.

The term "heterobicycloalkyl-" is understood to mean a saturated monovalent bicyclic hydrocarbon group in which two rings share two immediately adjacent ring atoms and wherein the bicyclic hydrocarbon group contains 3, 4, 5, 6, 7, 8 or 9 carbon atoms. And one or more hetero atom-containing groups selected from the group consisting of -O-, -S-, -S(=O)-, -S(=O) ₂ -, -NR ^a -, wherein R ^a represents a hydrogen atom Or a C ₁ -C ₆ alkyl- or C ₃ -C ₇ cycloalkyl- group; the heterobicycloalkyl- group is attached to the molecule via either a carbon atom or, if present, a nitrogen atom The rest. The heterobicycloalkyl- group is, for example, azabicyclo[3.3.0]octyl-, azabicyclo[4.3.0]nonyl-, diazabicyclo[4.3.0]decyl-, oxabicyclo [4.3.0] Mercapto-, thiazabicyclo[4.3.0]nonyl- or azabicyclo[4.4.0]decyl-.

The term "bridged heterocycloalkyl-" is understood to mean a saturated monovalent bicyclic hydrocarbon group in which two rings share two adjacent ring atoms which are not immediately adjacent and wherein the bicyclic hydrocarbon group contains 3, 4, 5, 6, 7, 8 or 9 carbon atoms and one or more hetero atom-containing groups selected from the group consisting of -O-, -S-, -S(=O)-, -S(=O) ₂ -, -NR ^a -, wherein R ^a represents a hydrogen atom or a C ₁ -C ₆ alkyl- or C ₃ -C ₇ cycloalkyl- group; the bridged heterocycloalkyl- group is likely to be via a carbon atom or, if present, a nitrogen atom One is connected to the rest of the molecule. The bridged heterocycloalkyl- group is, for example, azabicyclo[2.2.1]heptyl-, oxazabicyclo[2.2.1]heptyl-,thiazabicyclo[2.2.1]heptyl -, diazabicyclo[2.2.1]heptyl-, azabicyclo[2.2.2]octyl-, diazabicyclo[2.2.2]octyl-, oxazabicyclo[2.2.2] Octyl-, thiazabicyclo[2.2.2]octyl-, azabicyclo[3.2.1]octyl-, diazabicyclo[3.2.1]octyl-, oxazabicyclo[3.2 .1] octyl-, thiazabicyclo[3.2.1]octyl-, azabicyclo[3.3.1]fluorenyl-, diazabicyclo[3.3.1]fluorenyl-, oxazepine Bicyclo[3.3.1]fluorenyl-, thiazepinebicyclo[3.3.1]fluorenyl-, azabicyclo[4.2.1]decyl-, diazabicyclo[4.2.1]fluorenyl-, oxygen Azabicyclo[4.2.1]decyl, thiazabicyclo[4.2.1]decyl-, azabicyclo[3.3.2]nonyl-, diazabicyclo[3.3.2]fluorenyl- , oxazabicyclo[3.3.2]fluorenyl-, thiazabicyclo[3.3.2]nonyl- or azabicyclo[4.2.2]fluorenyl-.

Specifically, the 4 to 10 membered heterocycloalkyl group may contain one, or more, 3, 4, 5 or 6 carbon atoms and the above-mentioned hetero atom-containing groups ("4 to 7" Heterocycloalkyl-"); more specifically, the heterocycloalkyl- may contain one or more of 4 or 5 carbon atoms and the above-mentioned hetero atom-containing groups ("5 members To 6-membered heterocycloalkyl-").

Specifically, but not limited to, the heterocycloalkyl- can be, for example, a 4-membered ring, such as azetidinyl-, oxetanyl-; or a 5-membered ring, such as tetrahydrofuranyl-, pyrrolidine Base-, imidazolidinyl-, pyrazolyl-yl; or 6-membered ring, such as tetrahydropyranyl-, piperidinyl-, morpholinyl-, dithiaalkyl-, thiomorpholinyl-, piperidine Azinyl- or trithiaalkyl-; or a 7-membered ring, such as a diazepanyl-ring.

The term "aryl-" is understood to mean preferably a monovalent aromatic monocyclic or bicyclic or tricyclic hydrocarbon ring system having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms (" a C ₆ -C ₁₄ aryl-" group), specifically a group having 6 carbon atoms ("C ₆ aryl-" group), such as a phenyl- group; or having 9 carbon atoms a group ("C ₉ aryl-" group), such as an indanyl- or fluorenyl- group; or a group having 10 carbon atoms ("C ₁₀ aryl-" group), such as a tetralin a thio-, dihydronaphthyl- or naphthyl- group; or a biphenyl-group ("C ₁₂ aryl-"group); or a group having 13 carbon atoms ("C ₁₃ aryl-" a group), such as a fluorenyl- group; or a group having 14 carbon atoms (" _C14 aryl-" group), such as a fluorenyl- group. The aryl-group is preferably a phenyl-group.

The term "heteroaryl-" is understood to preferably mean an "aryl-" group as defined above wherein at least one of the carbon ring atoms is replaced by a hetero atom selected from the group consisting of oxygen, nitrogen and sulfur. "Heteroaryl-" group contains 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms ("5 to 14 membered heteroaryl-" groups), specifically 5 or 6 or 9 or 10 ring atoms ("5 to 10 membered heteroaryl-" groups), more specifically 5 or 6 ring atoms ("5 to 6 membered heteroaryl-" groups ). In particular, the heteroaryl group is selected from the group consisting of thienyl-, furyl-, pyrrolyl-, oxazolyl-, thiazolyl-, imidazolyl-, pyrazolyl-, isoxazolyl-, isothiazolyl - oxadiazolyl-, triazolyl-, thiadiazolyl-, thia-4H-pyrazolyl-, etc.; and benzo derivatives thereof, such as benzofuranyl-, benzothienyl-, Benzooxazolyl-, benzoisoxazolyl-, benzimidazolyl-, benzotriazolyl-, benzothiadiazolyl-, oxazolyl-, fluorenyl-, isodecyl -etc; or pyridyl-, pyridazinyl-, pyrimidinyl-, pyrazinyl-, triazinyl-, etc.; and benzo derivatives thereof, such as quinolinyl-, quinazolinyl-, isoquinoline Base-etc; or octanoyl-, pyridazinyl-, fluorenyl-, etc.; and benzo derivatives thereof; Lolinyl-, pyridazinyl, quinazolinyl-, quinoxalinyl-, naphthylpyridyl-, acridinyl-, oxazolyl-, acridinyl-, phlezinyl-, phenothiazine -, phenoxazinyl-, a bis- or oxo-yl group; and other bicyclic or tricyclic heteroaryl-groups having a hetero atom in more than one ring, such as pyrrolopyrazolyl-, imidazopyrazolyl-, thienopyrrolyl- , pyrrolooxazolyl-, pyrrolopyridyl-, thienopyrimidinyl, imidazopyrimidinyl, imidazopyridazinyl, imidazopyridyl-, thiazolopyridyl-, pyrazolopyridyl -, pyrrolotriazinyl- and the like.

In general and unless otherwise stated, a heteroaryl or heteroaryl group includes all possible isomeric forms thereof, such as positional isomers thereof. Thus, with respect to some illustrative, non-limiting examples, the term pyridyl-including pyridin-2-yl-, pyridin-3-yl-, and pyridin-4-yl-; or the term thienyl-including thiophen-2-yl- and Thiophen-3-yl-. The heteroaryl-group is preferably a pyridyl-group.

As used throughout this document, for example, in the case of the definition of "C ₁ -C ₆ alkyl-", the term "C ₁ -C ₆ " is understood to mean 1 to 6 (ie 1, 2, 3, 4, 5 or 6 carbon atoms) Alkoxy groups of a limited number of carbon atoms. It should also be understood that the term "C ₁ -C ₆ " should be interpreted as any subrange contained therein, such as C ₁ -C ₆ , C ₂ -C ₅ , C ₃ -C ₄ , C ₁ -C ₂ , C ₁ -C ₃ , C ₁ -C ₄ , C ₁ -C ₅ , C ₁ -C ₆ ; specifically C ₁ -C ₂ , C ₁ -C ₃ , C ₁ -C ₄ , C ₁ -C ₅ , C ₁ -C ₆ ; more specifically C ₁ -C ₄ ; in the case of "C ₁ -C ₃ haloalkyl-" or "halo-C ₁ -C ₃ alkoxy-", even more specific Said C ₁ -C ₂ .

Similarly, as used herein, as used herein, for example, in the context of the definition of "C ₂ -C ₆ alkenyl-" and "C ₂ -C ₆ alkynyl-", the term "C ₂ - C ₆ ′′ is understood to mean an alkenyl- or alkynyl group having a finite number of carbon atoms of 2 to 6 (ie 2, 3, 4, 5 or 6 carbon atoms). It should also be understood that the term "C ₂ -C ₆ " should be interpreted as any subrange contained therein, such as C ₂ -C ₆ , C ₃ -C ₅ , C ₃ -C ₄ , C ₂ -C ₃ , C ₂ - C ₄ , C ₂ - C ₅ ; specifically C ₂ - C ₃ .

Further, as used herein, as used herein, for example, in the context of the definition of "C ₃ -C ₇ cycloalkyl," the term "C ₃ -C ₇ " is understood to mean 3 to 7 (ie, 3, 4, 5, 6 or 7 carbon atoms) a limited number of carbon atom cycloalkyl groups. It should also be understood that the term "C ₃ -C ₇ " should be interpreted as any subrange contained therein, such as C ₃ -C ₆ , C ₄ -C ₅ , C ₃ -C ₅ , C ₃ -C ₄ , C ₄ - C ₆ , C ₅ - C ₇ ; specifically C ₃ - C ₆ .

As used herein, the term "leaving group" refers to an atom or group of atoms that, in a chemical reaction, is replaced with a bonding electron to a stabilizing substance. The leaving group as used herein is suitable for nucleophilic aliphatic and/or aromatic substitutions, such as halogen atoms, in particular chlorine-, bromine- or iodine- or selected from The following groups: methanesulfonyloxy-, p-toluenesulfonyloxy-, trifluoromethanesulfonyloxy-, nonafluorobutanesulfonyloxy-, (4-bromo-benzene) Sulfonyloxy-, (4-nitro-benzene)sulfonyloxy-, (2-nitro-phenyl)-sulfonyloxy-, (4-isopropyl-benzene)sulfonyl Oxy-, (2,4,6-triisopropyl-benzene)-sulfonyloxy-, (2,4,6-trimethyl-benzene)sulfonyloxy-, (4- Tributyl-benzene)sulfonyloxy-, phenylsulfonyloxy- and (4-methoxy-phenyl)sulfonyloxy-.

As used herein, the term "protecting group" is a protecting group attached to the nitrogen in the intermediate used to prepare the compound of formula (I). Such groups are introduced, for example, by chemical modification of the respective amine groups to obtain chemoselectivity in subsequent chemical reactions. Amino protecting groups are described, for example, in TW Greene and PGM Wuts, Protective Groups in Organic Synthesis , 3rd edition, Wiley 1999; more specifically, the groups may be selected from substituted sulfonyl groups such as methylsulfonyl. -, toluenesulfonyl- or phenylsulfonyl-; fluorenyl, such as benzhydryl-, ethionyl- or tetrahydropyranyl-; or a urethane-based group, such as Tributoxycarbonyl-(Boc); or may include hydrazine, as in, for example, 2-(trimethyldecyl)ethoxymethyl- (SEM).

As used herein, the term "one or more" is understood to mean, for example, "one, two, three, four or five times in the definition of a substituent of a compound of the formula of the invention; in particular, once , two, three or four times; more specifically, one, two or three times; or even more specifically, one or two times.

When the plural forms of the word compounds, salts, polymorphs, hydrates, solvates, and the like are used herein, they also mean a single compound, a salt, a polymorph, an isomer, a hydrate, a solvate or an analog thereof.

The compounds of the invention contain one or more asymmetric centers depending on the location and nature of the various substituents desired. Asymmetric carbon atoms can exist in ( R ) or ( S ) configurations. In some cases, asymmetry may also be present by limited rotation about a specified bond (eg, a central bond connecting two substituted aromatic rings of a particular compound).

Substituents on the ring may also exist in cis or trans form. All such configurations are intended to be included within the scope of the invention.

Preferred compounds are those which produce a more desirable biological activity. Isolated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the present compounds are also included within the scope of the invention. Purification and separation of such materials can be accomplished by standard techniques known in the art.

Optical isomers can be obtained according to conventional methods by resolution of the racemic mixture (for example by formation of diastereomeric salts or formation of covalent diastereomers using optically active acids or bases). Examples of suitable acids are tartaric acid, dimercapto tartaric acid, xylylmercapto tartaric acid and camphorsulfonic acid. Mixtures of diastereomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known in the art, such as chromatography or fractional crystallization. The optically active base or acid is then released from the separated diastereomeric salt. Different methods for separating optical isomers involve the use of palm chromatography, which is optimally selected to maximize separation of enantiomers, with or without conventional derivatization (eg, for palm chromatography HPLC columns) ). Suitable palm-shaped HPLC column lines are manufactured by Diacel, especially such as Chiracel OD and Chiracel OJ, all of which can be selected conventionally. Enzymatic separation with or without derivatization is also applicable. The optically active compounds of the present invention can also be obtained by palm-forming synthesis using optically active starting materials.

To limit the different types of isomers to each other, refer to IUPAC Guidelines Part E (Pure Appl Chem 45, 11-30, 1976).

The invention also includes all suitable isotopic variations of the compounds of the invention. An isotopic variation of a compound of the invention is defined as a variant of an atom having at least one atom that has the same atomic number but differs in atomic weight from the atomic mass normally or predominantly found in nature. Examples of isotopes which may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as ² H (氘), ³ H (氚), ¹¹ C, respectively. , ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O, ¹⁸ O, ³² P, ³³ P, ³³ S, ³⁴ S, ³⁵ S, ³⁶ S, ¹⁸ F, ³⁶ Cl, ⁸² Br, ¹²³ I, ¹²⁴ I, ¹²⁹ I and ¹³¹ I. Certain isotopic variations of the compounds of the invention, for example, isotopic variations of one or more radioisotopes (such as ³ H or ¹⁴ C), are useful for drug and/or matrix distribution studies. Deuterated and carbon-14 (i.e., ¹⁴ C) isotopes are particularly preferred due to their ease of preparation and detectability. In addition, isotopic substitutions such as hydrazine may provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and thus may be preferred in some circumstances. Isotopic variations of the compounds of the invention can generally be prepared by conventional procedures known to those skilled in the art, such as by exemplary methods or by the preparation of appropriate isotopic variations using suitable reagents as described in the Examples below. .

The invention includes all possible stereoisomers of the compounds of the invention in the form of a single stereoisomer or in any mixture of any ratio of such stereoisomers. Separation of a single stereoisomer (e.g., a single enantiomer or a single diastereomer) of a compound of the invention may be by any suitable current state of the art method (such as chromatography, especially for example, for palmarity) Chromatography) to achieve.

Additionally, the compounds of the invention may exist in the form of tautomers. For example, any compound of the invention containing a pyrazole moiety as a heteroaryl group can exist, for example, as a 1H tautomer or a 2H tautomer or even a mixture of two tautomers in any amount, or Any of the compounds of the invention wherein the triazole moiety is a heteroaryl group may, for example, be a 1H tautomer, a 2H tautomer or a 4H tautomer or even a mixture of such 1H, 2H and 4H tautomers in any amount. Form of existence, ie

The invention includes all possible tautomers of the compounds of the invention in the form of a single tautomeric form or in any mixture of any of these tautomers.

Additionally, the compounds of the invention may exist in the form of N-oxides which are defined as oxidation of at least one nitrogen of the compounds of the invention. The invention includes all such possible N-oxides.

The invention also relates to suitable forms of the compounds as disclosed herein, such as metabolites, hydrates, solvates, prodrugs, salts (in particular pharmaceutically acceptable salts) and coprecipitates.

The compound of the present invention may exist in the form of a hydrate or a solvate wherein the compound of the present invention contains a polar solvent (especially, for example, water, methanol or ethanol) as a structural element of the crystal lattice of the compound. The amount of polar solvent, especially water, can be present in stoichiometric or non-stoichiometric ratios. In the case of stoichiometric solvates (eg, hydrates), it may be a hemi-/semi-, mono-, sesqui-, di-, tri-, tetra-, penta-, etc. solvate or hydrate, respectively. The invention includes all such hydrates or solvates.

Additionally, the compounds of the invention may exist in free form (for example in the form of the free base, or the free acid or zwitterionic) or may be in the form of a salt. The salt may be any salt, may be an organic or inorganic addition salt, and in particular may be any pharmaceutically acceptable organic or inorganic addition salt conventionally used in pharmacy.

The term "pharmaceutically acceptable salt" refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the invention. See, for example, S. M. Berge et al., "Pharmaceutical Salts", J. Pharm. Sci. 1977, 66, 1-19.

The invention includes all possible salts of the compounds of the invention in the form of a single salt or in any mixture of any of the salts.

Furthermore, the invention includes all possible crystalline forms or polymorphs of the compounds of the invention in the form of a single polymorph or in the form of a mixture of any ratio of more than one polymorph.

According to a first aspect, the invention relates to a compound of formula (I):

Wherein: R ¹ represents C ₁ -C ₃ alkyl-, halo-C ₁ -C ₃ alkyl-, cyano-, -C(=O)OR ¹⁰ or -C(=O)N(R ^10a ) R ^10b group; R ² represents C ₁ -C ₃ alkyl-, halo-C ₁ -C ₃ alkyl-, cyano-, -C(=O)OR ¹⁰ or -C(=O)N( R ^10a ) R ^10b group; R ³ represents a group selected from the group consisting of aryl-, heteroaryl-, C ₅ -C ₆ cycloalkyl- and 5- to 6-membered heterocycloalkyl-; The 5- to 6-membered heterocycloalkyl-group is optionally benzofused; wherein the aryl-, heteroaryl-, C ₅ -C ₆ cycloalkyl- and 5- to 6-membered heterocycloalkyl- The group is optionally substituted one or more times by -(L ² ) _p -R ⁷ ; and wherein two -(L ² ) _p -R ⁷ groups are present in the aryl- or heteroaryl group, if present - If the groups are ortho to each other, a bridge selected from the group consisting of *-C ₃ -C ₈ alkyl-*, *-O(CH ₂ ) ₂ O-*, *-O(CH) ₂ ) O-*, *-O(CF ₂ )O-*, *-CH ₂ C(R ^10a )(R ^10b )O-*, *-C(=O)N(R ^10a )CH ₂ -* , *-N(R ^10a )C(=O)CH ₂ O-*, *-NHC(=O)NH-*; wherein each * represents a point of attachment to the aryl- or heteroaryl- group; R ^4a represents a hydrogen atom or a halogen atom or a group selected from the group consisting of cyano-, hydroxy-, C ₁ -C _Alkyl -, halo -C ₁ -C ₃ alkyl -, C ₁ -C ₃ alkoxy -, halo -C ₁ -C3 alkoxy -, C ₃ -C ₇ cycloalkyl -, 4 To 7 members heterocycloalkyl-, -C(=O)-OR ¹⁰ , - C(=O)N(R ^10a )R ^10b , -C(=O)-N(R ^10a )-S(= O) _{2 -} R ¹⁰ , -SR ¹⁰ , -S(=O)-R ¹⁰ , -S(=NR ¹¹ )-R ¹⁰ , -S(=O) ₂ -R ¹⁰ , -S(=O) ₂ -N(R ^10a )R ^10b , -S(=O)(=NR ¹¹ )-R ¹⁰ , -N(R ^10a )R ^10b ; R ^4b represents a hydrogen atom or a group selected from the group consisting of C ₁ -C ₃ alkoxy-, C ₁ -C ₃ alkyl-, cyano-; or R ^4a and R ^4b together form a -C ₃ -C ₅ alkyl- group; R ^5a , R ^5b , R ^5c , R ^5d

Independently from each other, a hydrogen atom, a halogen atom or a group selected from the group consisting of cyano-, -NO ₂ , C ₁ -C ₃ alkyl-, halo-C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy-, halo-C ₁ -C ₃ alkoxy-, phenyl-, heteroaryl-, -C(=O)R ¹⁰ , -C(=O)N(H)R ¹⁰ , -C(=O)N(R ^10a )R ^10b , -C(=O)OR ¹⁰ , -N(R ^10a )R ^10b , -N(H)C(=O)R ¹⁰ , -N(R ^10a C(=O)R ^10b , -N(H)C(=O)N(R ^10a )R ^10b , -N(R ^10a )C(=O)N(R ^10b )R ^10c , -N(R ^10a ) C(=O)C(=O)N(R ^10b )R ^10c , -N(H)C(=O)OR ¹⁰ , -N(R ^10a )C(=O)OR ^10b , -N( H)S(=O) ₂ R ¹⁰ , -N(R ^10a )S(=O) ₂ R ^10b , -OR ¹⁰ , -O(C=O)R ¹⁰ , -O(C=O)N(R ^10a ) R ^10b , -O(C=O)OR ¹⁰ , -SR ¹⁰ , -S(=O)R ¹⁰ , -S(=O) ₂ R ¹⁰ , -S(=O) ₂ N(H)R ¹⁰ , -S(=O) ₂ N(R ^10a )R ^10b or -S(=O)(=NR ^10a )R ^10b , the phenyl- or heteroaryl-group is optionally selected from the group consisting of The group is substituted one or more times identically or differently: halo-, cyano-, C ₁ -C ₃ alkyl-, halo-C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy- ; R ⁶ represents a hydrogen atom or a group selected from the group consisting of C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy-(L ² )-, hydroxy-C ₁ -C ₃ alkyl-, aryl-(L ² )-, heteroaryl-(L ² )-; R ⁷ represents a group selected from the group consisting of a pendant oxy group, a C ₁ -C ₆ alkyl group, and a C ₃ - C ₇ cycloalkyl-, 4 to 7 membered heterocycloalkyl-, halo-C ₁ -C ₄ alkyl-, hydroxy-C ₁ -C ₄ alkyl-, cyano-C ₁ -C ₄ alkane Base-, C ₂ -C ₄ alkenyl-, C ₂ -C ₄ alkynyl-, C ₁ -C ₄ alkoxy-, halo-C ₁ -C ₄ alkoxy-, -OH, -CN, Halo-, -C(=O)R ⁸ , -C(=O)-OR ⁸ , -C(=O)N(R ^8a )R ^8b , - N(R ^10a )R ^10b , -S(= O) ₂ R ⁸ , -S(=O)(=NR ¹¹ )-R ¹⁰ , phenyl-, 5- to 6-membered heteroaryl-; R ⁸ represents a hydrogen atom or a C ₁ -C ₆ alkyl-, Halo-C ₁ -C ₃ alkyl-, cyano-C ₁ -C ₄ alkyl-, C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl-, C ₃ -C ₇ cycloalkyl -, phenyl-, 5- to 6-membered heteroaryl- or benzyl-group; R ^8a , R ^8b

Independently from each other, a hydrogen atom or a C ₁ -C ₁₀ alkyl-, C ₃ -C ₇ cycloalkyl-, (C ₃ -C ₇ cycloalkyl)-(L ³ )-, C ₃ -C ₆ alkenyl group -, C ₃ -C ₆ alkynyl-, 4 to 10 membered heterocycloalkyl-, (4 to 10 membered heterocycloalkyl)-(L ³ )-, phenyl-, heteroaryl-, benzene -(L ³ )-, (phenyl)-O-(L ³ )-, heteroaryl-(L ³ )- or (aryl)-(4 to 10 membered heterocycloalkyl)- groups ; C ₁ -C ₁₀ alkyl-, C ₃ -C ₇ cycloalkyl-, (C ₃ -C ₇ cycloalkyl)-(L ³ )-, C ₃ -C ₆ alkenyl-, C ₃ - C ₆ alkynyl-, 4 to 10 membered heterocycloalkyl-, (4 to 10 membered heterocycloalkyl)-(L ³ )-, phenyl-, heteroaryl-, phenyl-(L ³ -, (phenyl)-O-(L ³ )-, heteroaryl-(L ³ )- and (aryl)-(4 to 10 membered heterocycloalkyl)- groups, optionally via R ⁹ Substituting one or more times identically or differently; or R ^8a and R ^8b together with the nitrogen atom to which they are attached represent a 4 to 10 membered heterocycloalkyl- group, the 4 to 10 membered heterocycloalkyl- group R group optionally substituted with identically or differently substituted one or more times ^9; R ⁹ represents a halogen atom or oxo, C ₁ -C ₃ alkyl -, halo -C ₁ -C ₃ alkyl -, hydroxy - C ₁ -C ₃ alkyl-, -CN, -C(=O)R ¹⁰ , -C(=O)N(H)R ¹⁰ , -C(=O)N(R ^10a )R ^10b , -C(=O)OR ¹⁰ , -N(R ^10a )R ^10b , -NO ₂ , -N(H)C(=O)R ¹⁰ , -N(R ^10a )C(=O)R ^10b , -N(H)C(=O)N(R ^10a )R ^10b , -N(R ^10a )C(=O)N(R ^10b )R ^10c , -N(H)C(=O)OR ¹⁰ , -N(R ^10a )C(=O)OR ^10b , -N(H)S(=O) ₂ R ¹⁰ , -N(R ^10a )S( =O) ₂ R ^10b , -OR ¹⁰ , -O(C=O)R ¹⁰ , -O(C=O)N(R ^10a )R ^10b , -O(C=O)OR ¹⁰ , -SR ¹⁰ , -S(=O)R ¹⁰ , -S(=O) ₂ R ¹⁰ , -S(=O) ₂ N(H)R ¹⁰ , -S(=O) ₂ N(R ^10a )R ^10b , -S (=O)(=NR ^10a )R ^10b or a tetrazolyl- group; or two R ⁹ groups present adjacent to each other on the phenyl- or heteroaryl-ring form a bridge selected from the group consisting of :*-C ₃ -C ₅ alkylene-*, *-O(CH ₂ ) ₂ O-*, *-O(CH ₂ )O-*, *-O(CF ₂ )O-*, *- CH ₂ C(R ^10a )(R ^10b )O-*, *-C(=O)N(R ^10a )CH ₂ -*, *-N(R ^10a )C(=O)CH ₂ O-*, *-NHC(=O)NH-*; wherein each * represents a point of attachment to the phenyl- or heteroaryl-ring; R ¹⁰ , R ^10a , R ^10b , R ^10c

Independently from each other, a hydrogen atom or a group selected from the group consisting of C ₁ -C ₃ alkyl-, halo-C ₁ -C ₃ alkyl-, hydroxy-C ₁ -C ₃ alkyl-, C ₁ -C _alkoxy -C ₁ -C ₃ alkyl -, C ₃ -C ₇ cycloalkyl -, the C ₁ -C ₃ alkyl - group optionally substituted by a -N (R ¹²⁾ R ^12a; or R ^10a and R ^10b together with the nitrogen atom to which they are attached represent a 4- to 7-membered heterocycloalkyl- group, which may be substituted identically or differently by R ¹³ as appropriate One or more times; R ¹¹ represents a hydrogen atom or a cyano-, C ₁ -C ₃ alkyl-, -C(=O)R ¹⁰ , -C(=O)N(H)R ¹⁰ , -C(= O) N(R ^10a )R ^10b or -C(=O)OR ¹⁰ group; R ¹² , R ^12a

Representing each other independently of a hydrogen atom or a C ₁ -C ₃ alkyl- group, or R ¹² , R ^12a

The nitrogen atom to which it is attached represents a 4- to 7-membered heterocycloalkyl- group; R ¹³ represents a halogen atom or a cyano group, a hydroxyl group, a pendant oxy group, a C ₁ -C ₃ alkyl group, a trifluoromethyl group- a -C(=O)R ¹⁰ or -C(=O)OR ¹⁰ group; L ¹ represents a group selected from: -C ₁ -C ₄ alkylene-, -CH ₂ -CH=CH- , -C(phenyl)(H)-, -CH ₂ -CH ₂ -O-, -CH ₂ -C(=O)-N(H)-, -CH ₂ -C(=O)-N( R ^10a )-; L ² represents a group selected from: -CH ₂ -, -CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -CH ₂ -; L ³ represents -C ₁ -C ₆ -alkylene a radical - group; p is an integer 0 or 1; or a tautomer, stereoisomer, N-oxide, hydrate, solvate or salt thereof or a mixture thereof.

In a preferred embodiment, the invention is directed to a compound of formula (I) above, wherein R ¹ represents C ₁ -C ₃ alkyl-, halo-C ₁ -C ₃ alkyl- or cyano-.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ¹ represents C ₁ -C ₃ alkyl-, halo-C ₁ -C ₃ alkyl- or cyano-, and Wherein at least one of R ¹ and R ² is different from isopropyl-.

In another preferred embodiment, the invention is directed to a compound of formula (I) above, wherein at least one of R ¹ and R ² is different from isopropyl-.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ¹ represents C ₁ -C ₃ alkyl- or halo-C ₁ -C ₃ alkyl-.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ¹ represents a C ₁ -C ₃ alkyl- or halo-C ₁ -C ₃ alkyl- group, and wherein R At least one of ¹ and R ² is different from isopropyl-.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ¹ represents a C ₁ -C ₃ alkyl- or trifluoromethyl- group.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ¹ represents a C ₁ -C ₃ alkyl- or trifluoromethyl- group, and wherein R ¹ and R ² are At least one is different from isopropyl-.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ¹ represents a C ₁ -C ₃ alkyl- group.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ¹ represents a C ₁ -C ₃ alkyl- group, and wherein at least one of R ¹ and R ² is different from Propyl-.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ¹ represents a methyl-, ethyl- or trifluoromethyl- group.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ¹ represents a methyl- or trifluoromethyl- group.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ¹ represents a methyl-group.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ¹ represents a trifluoromethyl- group.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ¹ represents C ₁ -C ₃ alkyl-, fluoro-C ₁ -C ₃ alkyl-, cyano-, -C (=O) OR ¹⁰ or -C(=O)N(R ^10a )R ^10b group.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ¹ represents C ₁ -C ₃ alkyl-, fluoro-C ₁ -C ₃ alkyl-, cyano-, -C (=O) OR ¹⁰ or -C(=O)N(R ^10a )R ^10b group, and wherein at least one of R ¹ and R ² is different from isopropyl-.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ¹ represents C ₁ -C ₃ alkyl-, fluoro-C ₁ -C ₃ alkyl- or cyano- group.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ¹ represents C ₁ -C ₃ alkyl-, fluoro-C ₁ -C ₃ alkyl- or cyano- group, And wherein at least one of R ¹ and R ² is different from isopropyl-.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ¹ represents a -C(=O)N(R ^10a )R ^10b group.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ¹ represents a C ₁ -C ₃ alkyl-, trifluoromethyl- or cyano- group.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ¹ represents a C ₁ -C ₃ alkyl-, trifluoromethyl- or cyano- group, and wherein R ¹ At least one of R ² is different from isopropyl-.

In a preferred embodiment, the invention is directed to a compound of formula (I) above, wherein R ² represents C ₁ -C ₃ alkyl-, halo-C ₁ -C ₃ alkyl- or cyano- group.

In a preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ² represents C ₁ -C ₃ alkyl-, halo-C ₁ -C ₃ alkyl- or cyano- group, And wherein at least one of R ¹ and R ² is different from isopropyl-.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ² represents a C ₁ -C ₃ alkyl- or halo-C ₁ -C ₃ alkyl- group.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ² represents a C ₁ -C ₃ alkyl- or halo-C ₁ -C ₃ alkyl- group, and wherein R At least one of ¹ and R ² is different from isopropyl-.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ² represents a C ₁ -C ₃ alkyl- or fluoro-C ₁ -C ₃ alkyl- group.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ² represents a C ₁ -C ₃ alkyl- or fluoro-C ₁ -C ₃ alkyl- group, and wherein R ¹ And at least one of R ² is different from isopropyl-.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ² represents a C ₁ -C ₃ alkyl- or trifluoromethyl- group.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ² represents a C ₁ -C ₃ alkyl- or trifluoromethyl- group, and wherein R ¹ and R ² are At least one is different from isopropyl-.

In another preferred embodiment, the invention is directed to a compound of formula (I) above, wherein R ² represents a C ₁ -C ₃ alkyl- group.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ² represents a C ₁ -C ₃ alkyl- group, and wherein at least one of R ¹ and R ² is different from Propyl-.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ² represents a methyl-, ethyl- or trifluoromethyl- group.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ² represents a methyl- or trifluoromethyl- group.

In another preferred embodiment, the invention is directed to a compound of formula (I) above, wherein R ² represents a methyl-group.

In another preferred embodiment, the invention relates to compounds of formula (I) above, wherein R ² represents a trifluoromethyl- group.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ² represents C ₁ -C ₃ alkyl-, fluoro-C ₁ -C ₃ alkyl-, -C(=O) OR ¹⁰ or -C(=O)N(R ^10a )R ^10b group.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ² represents C ₁ -C ₃ alkyl-, fluoro-C ₁ -C ₃ alkyl-, -C(=O) OR ¹⁰ or -C(=O)N(R ^10a )R ^10b group, and wherein at least one of R ¹ and R ² is different from isopropyl-.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ² represents C ₁ -C ₃ alkyl-, fluoro-C ₁ -C ₃ alkyl- or -C(=O) N(R ^10a )R ^10b group.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ² represents C ₁ -C ₃ alkyl-, fluoro-C ₁ -C ₃ alkyl- or -C(=O) N(R ^10a )R ^10b group, and wherein at least one of R ¹ and R ² is different from isopropyl-.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ² represents a -C(=O)N(R ^10a )R ^10b group.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ¹ represents a C ₁ -C ₃ alkyl- group, and wherein R ² represents methyl-, ethyl- or trifluoro Methyl-group.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ¹ represents a methyl-, ethyl- or trifluoromethyl- group, and wherein R ² represents C ₁ -C ₃ Alkyl-group.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ¹ represents a C ₁ -C ₃ alkyl- group, and wherein R ² represents methyl- or trifluoromethyl-yl group.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ¹ represents a methyl- or trifluoromethyl- group, and wherein R ² represents C ₁ -C ₃ alkyl-based group.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ¹ represents a methyl- or trifluoromethyl- group, and wherein R ² represents a methyl-group.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ² represents a methyl- or trifluoromethyl- group, and wherein R ¹ represents a methyl-group.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ¹ and R ² each represent a methyl-group.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ¹ represents C ₁ -C ₃ alkyl-, fluoro-C ₁ -C ₃ alkyl-, cyano-, -C (=O)OR ¹⁰ or -C(=O)N(R ^10a )R ^10b group, and wherein R ² represents C ₁ -C ₃ alkyl-, fluoro-C ₁ -C ₃ alkyl- or -C (=O) N(R ^10a )R ^10b group.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ¹ represents C ₁ -C ₃ alkyl-, fluoro-C ₁ -C ₃ alkyl-, cyano-, -C (=O)OR ¹⁰ or -C(=O)N(R ^10a )R ^10b group, and wherein R ² represents C ₁ -C ₃ alkyl-, fluoro-C ₁ -C ₃ alkyl- or -C (=O) N(R ^10a )R ^10b group, and wherein at least one of R ¹ and R ² is different from isopropyl-.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ¹ represents C ₁ -C ₃ alkyl-, fluoro-C ₁ -C ₃ alkyl-, cyano-, -C (=O) OR ¹⁰ or -C(=O)N(R ^10a )R ^10b group, and wherein R ² represents a methyl-, ethyl- or trifluoromethyl- group.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ¹ represents C ₁ -C ₃ alkyl-, fluoro-C ₁ -C ₃ alkyl-, cyano-, -C (=O) OR ¹⁰ or -C(=O)N(R ^10a )R ^10b group, and wherein R ² represents a methyl-group.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ¹ represents C ₁ -C ₃ alkyl-, trifluoromethyl- or cyano- group, and wherein R ² represents Methyl-, ethyl- or trifluoromethyl- group.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ¹ represents C ₁ -C ₃ alkyl-, trifluoromethyl- or cyano- group, and wherein R ² represents Methyl-group.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ³ represents a group selected from aryl- and heteroaryl-; wherein the group is via -(L ² ) _p - R ⁷ is substituted one or more times identically or differently, and wherein two -(L ² ) _p -R ⁷ groups are ortho to each other on the aryl- or heteroaryl-group, The formation is selected from the group consisting of *-C ₃ -C ₅ alkylene-*, *-O(CH ₂ ) ₂ O-*, *-O(CH ₂ )O-*, *-O(CF ₂ )O-* a bridge; wherein each * represents a point of attachment to the aryl- or heteroaryl- group.

In a preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ³ represents a group selected from aryl- and heteroaryl-; wherein the group is via -(L ² ) _p -R ⁷ is replaced one or more times identically or differently.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ³ represents selected from phenyl-, C ₅ -C ₆ cycloalkyl-, 5- to 6-membered heterocycloalkyl- a group of pyridin-3-yl- and pyridin-4-yl-; the 5- to 6-membered heterocycloalkyl-group is optionally benzofused; wherein the phenyl-, C ₅ -C ₆ ring Alkyl-, 5- to 6-membered heterocycloalkyl-, pyridin-3-yl-, and pyridin-4-yl- groups are substituted identically or differently by -(L ² ) _p -R ⁷ one or more times .

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ³ represents selected from phenyl-, C ₅ -C ₆ cycloalkyl-, 5- to 6-membered heterocycloalkyl- a group of pyridin-3-yl- and pyridin-4-yl-; wherein the group is substituted one or more times by -(L ² ) _p -R ⁷ identically or differently.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ³ represents a group selected from C ₅ -C ₆ cycloalkyl-, 5-member to 6-membered heterocycloalkyl-; Wherein the group is substituted one or more times by -(L ² ) _p -R ⁷ identically or differently.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ³ represents a group selected from phenyl-, 5- to 6-membered heteroaryl-; wherein the group is-- L ² ) _p -R ⁷ is substituted one or more times identically or differently.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ³ represents a group selected from the group consisting of phenyl-, pyridin-3-yl-, and pyridin-4-yl-; wherein the group The group - (L ² ) _{p -} R ⁷ is substituted one or more times identically or differently.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ³ represents a phenyl-group; wherein the phenyl-group is identical via -(L ² ) _p -R ⁷ or Replace one or more times differently.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ³ represents a C ₅ -C ₆ cycloalkyl- group; wherein the group is via -(L ² ) _p -R ⁷ Replace one or more times identically or differently.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ³ represents a 5- to 6-membered heterocycloalkyl- group; wherein the group is via -(L ² ) _p -R ⁷ is replaced one or more times identically or differently.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ³ represents an aryl-, heteroaryl-, C ₅ -C ₆ cycloalkyl- and 5 to 6 member heterocycloalkyl - the group; wherein the 5-6 heterocycloalkyl - group via the benzo optionally condensed; wherein the aryl -, heteroaryl -, C ₅ -C ₆ cycloalkyl - And a 5-member to 6-membered heterocycloalkyl- group is optionally substituted one or more times by -(L ² ) _p -R ⁷ ; and wherein two -(L ² ) _p -R ⁷ groups If the group is ortho to each other on the aryl- or heteroaryl-group, it is optionally formed from *-C ₃ -C ₈ alkyl-*, *-O(CH ₂ ) ₂ O-* a bridge of *-O(CH ₂ )O-; wherein each * represents a point of attachment to the aryl- or heteroaryl- group.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ³ represents a group selected from aryl- or 5- to 6-membered heteroaryl- or piperidinyl-; Wherein the aryl- or 5- to 6-membered heteroaryl- or piperidinyl- group is substituted one or more times identically or differently by -(L ² ) _p -R ⁷ .

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ³ represents an aryl-group; wherein the aryl-group is the same as -(L ² ) _p -R ⁷ as appropriate Replace one or more times, either locally or differently.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ³ represents a 5 to 6 membered heteroaryl-group; wherein the 5 to 6 membered heteroaryl-group is considered The case is replaced one or more times by -(L ² ) _p -R ⁷ identically or differently.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ³ represents a piperidinyl- group; wherein the piperidinyl- group is optionally -(L ² ) _p -R ⁷ is replaced one or more times identically or differently.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ³ represents a group selected from the group consisting of phenyl- or 5- to 6-membered heteroaryl-; wherein the phenyl- Or a 5- to 6-membered heteroaryl-group is optionally substituted one or more times by -(L ² ) _p -R ⁷ , or wherein R ³ represents the following group Where * indicates the point of attachment to the rest of the molecule.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ³ represents a phenyl-group; wherein the phenyl-group is optionally the same as -(L ² ) _p -R ⁷ Replace one or more times, either locally or differently.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ³ represents the group below Where * indicates the point of attachment to the rest of the molecule.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ³ represents a phenyl-group substituted one or more times, identically or differently, with a group selected from the group consisting of: C ₁ -C ₃ alkyl-, trifluoromethyl-, cyanomethyl-, methoxymethyl-, C ₁ -C ₃ alkoxy-, trifluoromethoxy-, -CN, fluorine- , chloro-, -C(=O)-C ₁ -C ₃ alkyl, -C(=O)N(R ^8a )R ^8b , -S(=O) ₂ -C ₁ -C ₃ alkyl; Wherein R ³ represents a 5- to 6-membered heteroaryl-group which is optionally substituted one or more times by a group selected from the group consisting of C ₁ -C ₃ alkyl-, cyclopropyl-, C ₁ -C ₃ alkoxy-, -CN, -C(=O)N(R ^8a )R ^8b .

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ³ represents, as appropriate, one or more phenyl-groups substituted one or more times via a group selected from: C _1- C ₃ alkyl-, trifluoromethyl-, cyanomethyl-, methoxymethyl-, C ₁ -C ₃ alkoxy-, trifluoromethoxy-, -CN, fluoro-, Chloro-, -C(=O)-C ₁ -C ₃ alkyl, -C(=O)N(R ^8a )R ^8b , -S(=O) ₂ -C ₁ -C ₃ alkyl.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ³ represents optionally selected from C ₁ -C ₃ alkyl-, cyclopropyl-, C ₁ -C ₃ alkoxy The groups of the radicals -, -CN, -C(=O)N(R ^8a )R ^8b are substituted one or more of the 5 to 6 membered heteroaryl-groups identically or differently.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ³ represents one or more substitutions identically or differently via a group selected from methoxy-, -CN, fluoro- the phenyl - group, or wherein R ³ represents a methoxy group selected by -, - of the CN group of a substituted pyridyl group - or pyrimidinyl group - group, or wherein R ³ represents C ₁ -C selected by A 5-membered heteroaryl-group substituted once with a group of ₃ alkyl-, cyclopropyl-, -CN selected from the group consisting of isoxazolyl-, oxadiazolyl- and thienyl-.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ³ represents phenyl-group substituted one or more times by a group selected from methoxy-, -CN, fluoro- group.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ³ represents pyridyl- or pyrimidinyl-group substituted once with a group selected from methoxy-, -CN.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ³ represents a substitution of _one group selected from the group consisting of C ₁ -C ₃ alkyl-, cyclopropyl-, -CN A heteroaryl-group selected from the group consisting of isoxazolyl-, oxadiazolyl- and thienyl-.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ³ represents phenyl-group substituted one or more times by a group selected from methoxy-, -CN, fluoro- A group, or wherein R ³ represents a pyridyl- or pyrimidinyl- group substituted once by a group selected from methoxy-, -CN.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ³ represents pyridyl- or pyrimidinyl-group substituted once with a group selected from methoxy-, -CN.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ³ represents an isoxazolyl group substituted once with a group selected from C ₁ -C ₃ alkyl-, cyclopropyl- - group.

In a preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ^4a represents a hydrogen atom or a halogen atom or a group selected from the group consisting of cyano-, hydroxy-, methyl-, ethyl- , -Trifluoromethyl-, methoxy-, ethoxy-, C ₃ -C ₇ cycloalkyl-, 4- to 7-membered heterocycloalkyl-, -C(=O)N(R ^10a ) R ^10b , -N(R ^10a )R ^10b .

In another preferred embodiment, the present invention relates to a compound of the above formula (the I), wherein R ^4a represents a hydrogen atom or a halogen atom or a group selected from the group: cyano -, hydroxy -, C ₁ -C ₃ alkoxy a group -, a halo-C ₁ -C ₃ alkyl group, a C ₁ -C ₃ alkoxy group, -C(=O)N(R ^10a )R ^10b , -N(R ^10a )R ^10b .

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ^4a represents a hydrogen atom or a halogen atom or a group selected from the group consisting of cyano-, hydroxy-, methyl-, ethyl. -, -trifluoromethyl-, methoxy-, ethoxy-, -C(=O)N(R ^10a )R ^10b , -N(R ^10a )R ^10b .

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ^4a represents a group selected from the group consisting of C ₃ -C ₇ cycloalkyl-, 4 to 7 membered heterocycloalkyl -.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ^4a represents C ₃ -C ₄ -cycloalkyl-.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ^4a represents a hydrogen atom or a group selected from the group consisting of methyl-, ethyl-, -trifluoromethyl-, A Oxy-, ethoxy-, -C(=O)N(R ^10a )R ^10b , -N(R ^10a )R ^10b .

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ^4a represents a hydrogen atom or a group selected from the group consisting of methyl-, -trifluoromethyl-, methoxy-, -C(=O)NH ₂ .

In another preferred embodiment, the present invention relates to a compound of the above formula (the I), wherein R ^4a represents a hydrogen atom or a halogen atom or a group selected from the group: cyano -, hydroxy -, C ₁ -C ₃ alkoxy -, fluoro-C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy-, fluoro-C ₁ -C ₃ alkoxy-, C ₃ -C ₇ cycloalkyl-, 4 to 7 Heterocycloalkyl-, -C(=O)-OR ¹⁰ , -C(=O)N(R ^10a )R ^10b , -C(=O)-N(R ^10a )-S(=O) ₂ -R ¹⁰ , -SR ¹⁰ , -S(=O)-R ¹⁰ , -S(=NR ¹¹ )-R ¹⁰ , -S(=O) ₂ -R ¹⁰ , -S(=O) ₂ -N( R ^10a ) R ^10b , -S(=O)(=NR ¹¹ )-R ¹⁰ , -N(R ^10a )R ^10b .

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ^4a represents a group selected from the group consisting of C ₁ -C ₃ alkyl-, fluoro-C ₁ -C ₃ alkyl- , C ₁ -C ₃ alkoxy-, C ₃ -C ₅ cycloalkyl, -C(=O)N(R ^10a )R ^10b , -SR ¹⁰ , -S(=O)-R ¹⁰ , -S (=NR ¹¹ )-R ¹⁰ , -S(=O) ₂ -R ¹⁰ , -S(=O) ₂ -N(R ^10a )R ^10b , -N(R ^10a )R ^10b .

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ^4a represents a group selected from the group consisting of C ₁ -C ₃ alkyl-, fluoro-C ₁ -C ₃ alkyl- C ₁ -C ₃ alkoxy-, C ₃ -C ₅ cycloalkyl, -C(=O)N(R ^10a )R ^10b .

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ^4a represents a group selected from the group consisting of isopropyl-, trifluoromethyl-, methoxy-, cyclopropyl. -, -C(=O)-NH ₂ .

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ^4a represents an isopropyl-group.

In another preferred embodiment, the invention is directed to a compound of formula (I) above, wherein R ^4a represents a methoxy- group.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ^4a represents a trifluoromethyl- group.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ^4a represents a -C(=O)-NH ₂ group.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ^4a represents a cyclopropyl- group.

In a preferred embodiment, the invention is directed to a compound of formula (I) above, wherein R ^4b represents a hydrogen atom.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ^4b represents a group selected from the group consisting of C ₁ -C ₃ alkoxy-, C ₁ -C ₃ alkyl-, Cyano-.

In another preferred embodiment, the invention is directed to a compound of formula (I) above, wherein R ^4a and R ^4b together form a -C ₃ -C ₅ alkyl- group.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ^4b represents a group selected from the group consisting of C ₁ -C ₃ alkoxy-, C ₁ -C ₃ alkyl-, cyano- a group, or wherein R ^4a and R ^4b together form a -C ₃ -C ₅ alkyl- group.

In a preferred embodiment, the invention relates to the above compound of formula (I), wherein R ^5a , R ^5b , R ^5c , R ^5d independently of one another represent a hydrogen atom, a halogen atom or a group selected from the group consisting of cyano. -, -NO ₂ , C ₁ -C ₃ alkyl-, halo-C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy-, halo-C ₁ -C ₃ alkoxy-, Phenyl-, heteroaryl-, -C(=O)R ¹⁰ , -C(=O)N(H)R ¹⁰ , -C(=O)N(R ^10a )R ^10b , -C(=O )OR ¹⁰ , -N(R ^10a )R ^10b , -N(H)C(=O)R ¹⁰ , -N(R ^10a )C(=O)R ^10b , -N(R ^10a )C(=O C(=O)N(R ^10b )R ^10c , -N(H)S(=O) ₂ R ¹⁰ ; the phenyl- or heteroaryl-- optionally substituted by C ₁ -C ₃ alkyl- Or multiple times.

In another preferred embodiment, the invention relates to a compound of the above formula (I), wherein R ^5a , R ^5b , R ^5c , R ^5d independently of one another represent a hydrogen atom, a halogen atom or a group selected from the group consisting of cyanide Base-, -NO ₂ , C ₁ -C ₃ alkyl-, fluoro-C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy-, fluoro-C ₁ -C ₃ alkoxy-, benzene Base-, heteroaryl-, -C(=O)R ¹⁰ , -C(=O)N(H)R ¹⁰ , -C(=O)N(R ^10a )R ^10b , -C(=O) OR ¹⁰ , -N(R ^10a )R ^10b , -N(H)C(=O)R ¹⁰ , -N(R ^10a )C(=O)R ^10b , -N(R ^10a )C(=O) C(=O)N(R ^10b )R ^10c , -N(H)S(=O) ₂ R ¹⁰ ; the phenyl- or heteroaryl-- optionally substituted by C ₁ -C ₃ alkyl- or repeatedly.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ^5a , R ^5b , R ^5c , R ^5d independently of one another represent a hydrogen atom, a halogen atom or a group selected from the group consisting of: - NO ₂ , C ₁ -C ₃ alkyl-, fluoro-C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy-, fluoro-C ₁ -C ₃ alkoxy-, -C(=O N(R ^10a )R ^10b , -C(=O)OR ¹⁰ , -N(R ^10a )R ^10b , -N(H)C(=O)R ¹⁰ , -N(R ^10a )C(=O ) R ^10b .

In another preferred embodiment, the invention relates to the above compound of formula (I), wherein R ^5a , R ^5b , R ^5c , R ^5d independently of each other represent a hydrogen atom, a halogen atom or a group selected from the group consisting of: --, trifluoromethyl-, methoxy-, trifluoromethoxy-, -C(=O)OR ¹⁰ , -NH ₂ , -N(H)C(=O)R ¹⁰ , and wherein R ¹⁰ represents methyl-.

In another preferred embodiment, the invention relates to a compound of the above formula (I), wherein R ^5a , R ^5b , R ^5c , R ^5d independently of one another represent a hydrogen atom, a halogen atom or a group selected from the group consisting of cyanide Base-, C ₁ -C ₃ alkyl-, fluoro-C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy-, fluoro-C ₁ -C ₃ alkoxy-, phenyl-, hetero Aryl-, -C(=O)R ¹⁰ , -C(=O)N(H)R ¹⁰ , -C(=O)N(R ^10a )R ^10b , -C(=O)OR ¹⁰ ,- N(R ^10a )R ^10b , -N(H)C(=O)R ¹⁰ , -N(R ^10a )C(=O)R ^10b , -OR ¹⁰ ,

The phenyl- or heteroaryl-group is optionally the same group selected from the group consisting of halo-, cyano-, methyl-, ethyl-, trifluoromethyl-, methoxy, ethoxy- Replace one or more times, either locally or differently.

In another preferred embodiment, the invention relates to a compound of the above formula (I), wherein R ^5a , R ^5b , R ^5c , R ^5d independently of one another represent a hydrogen atom, a halogen atom or a group selected from the group consisting of cyanide Base-, C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy-, -N(R ^10a )R ^10b , -OR ¹⁰ .

In another preferred embodiment, the invention relates to a compound of the above formula (I), wherein R ^5a , R ^5b , R ^5c , R ^5d independently of one another represent a hydrogen atom, a halogen atom or a group selected from the group consisting of cyanide Base-, C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy-, -N(R ^10a )R ^10b , -OH.

In another preferred embodiment, the present invention relates to the above compound of the formula (I), wherein R ^5a , R ^5c , R ^5d independently of each other represent a hydrogen atom, a fluorine atom or a chlorine atom, and wherein R ^5b represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom or a group selected from the group consisting of cyano-, methyl-, methoxy-, -N(H)-CH ₂ -CH ₂ -OCH ₃ and N -piperidinyl- .

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ^5a , R ^5c , R ^5d independently of one another represent a hydrogen atom, a fluorine atom or a chlorine atom.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ^5b represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom or a group selected from the group consisting of cyano-, methyl- , methoxy-, -N(H)-CH ₂ -CH ₂ -OCH ₃ and N -piperidinyl-.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ^5a , R ^5b , R ^5c , R ^5d independently of one another represent a hydrogen atom, a fluorine atom or a chlorine atom.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ⁶ represents a hydrogen atom or a group selected from the group consisting of C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy -(L ² )-, hydroxy-C ₁ -C ₃ alkyl-, aryl-(L ² )-, heteroaryl-(L ² )-, and wherein L ² represents -CH ₂ - or -CH ₂ CH ₂ -.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ⁶ represents a hydrogen atom or a group selected from the group consisting of C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy Base-(L ² )-, hydroxy-C ₁ -C ₃ alkyl.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ⁶ represents a hydrogen atom or a group selected from the group consisting of C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy A group -(L ² )-, hydroxy-C ₁ -C ₃ alkyl, and wherein L ² represents -CH ₂ - or -CH ₂ CH ₂ -.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ⁶ represents a hydrogen atom or a group selected from the group consisting of aryl-(L ² )-, heteroaryl-(L ² )-.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ⁶ represents a hydrogen atom or a group selected from the group consisting of aryl-(L ² )-, heteroaryl-(L ² )-, and wherein L ² represents -CH ₂ - or -CH ₂ CH ₂ -.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ⁶ represents a hydrogen atom.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ⁷ represents a group selected from the group consisting of pendant oxy, C ₁ -C ₃ alkyl-, fluoro-C ₁ -C _3- alkyl-, C ₁ -C ₃ alkoxy-, fluoro-C ₁ -C ₃ alkoxy-, -OH, -CN, halo-, -C(=O)R ⁸ , -C(= O)-OR ⁸ , -C(=O)N(R ^8a )R ^8b , -S(=O) ₂ R ⁸ , phenyl-.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ⁷ represents a group selected from the group consisting of pendant oxy, C ₁ -C ₄ alkyl-, C ₃ -C ₇ ring Alkyl-, 4- to 7-membered heterocycloalkyl-, fluoro-C ₁ -C ₄ alkyl-, hydroxy-C ₁ -C ₄ alkyl-, cyano-C ₁ -C ₄ alkyl-, C _2- C ₄ alkenyl-, C ₁ -C ₄ alkoxy-, fluoro-C ₁ -C ₄ alkoxy-, -OH, -CN, halo-, -C(=O)R ⁸ ,- C(=O)-OR ⁸ , -C(=O)N(R ^8a )R ^8b , -N(R ^10a )R ^10b , -S(=O) ₂ R ⁸ , -S(=O)(= NR ¹¹ )-R ¹⁰ , phenyl-, 5- to 6-membered heteroaryl-.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ⁷ represents a group selected from the group consisting of C ₁ -C ₃ alkyl-, cyclopropyl-, trifluoromethyl- , C ₁ -C ₃ alkoxy-, trifluoromethoxy-, -CN, fluoro-, chloro-, -C(=O)-C ₁ -C ₃ alkyl, -C(=O)N ( R ^8a ) R ^8b , -S(=O) ₂ )-C ₁ -C ₃ alkyl.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ⁷ represents a group selected from the group consisting of C ₁ -C ₃ alkyl-, cyclopropyl-, trifluoromethyl- , C ₁ -C ₃ alkoxy-, trifluoromethoxy-, -CN, fluoro-, chloro-, -C(=O)-C ₁ -C ₃ alkyl, -C(=O)N ( R ^8a ) R ^8b , -S(=O) ₂ -C ₁ -C ₃ alkyl.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ⁷ represents a group selected from the group consisting of C ₁ -C ₃ alkyl-, trifluoromethyl-, C ₁ -C ₃ alkoxy-, trifluoromethoxy-, -CN, fluoro-, chloro-, -C(=O)-C ₁ -C ₃ alkyl, -C(=O)N(R ^8a )R ^8b -S(=O) ₂ -C ₁ -C ₃ alkyl.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ⁷ represents a group selected from the group consisting of C ₁ -C ₃ alkyl-, cyclopropyl-, C ₁ -C ₃ Alkoxy-, -CN, -C(=O)N(R ^8a )R ^8b .

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ⁷ represents a group selected from the group consisting of C ₁ -C ₃ alkyl-, cyclopropyl-, methoxy-, -CN, fluorine -.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ⁷ represents a group selected from the group consisting of methoxy-, -CN, fluoro-.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ⁷ represents a group selected from the group consisting of -CN, fluoro-.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ⁷ represents a group selected from the group consisting of methoxy-, -CN.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ⁷ represents a group selected from the group consisting of methoxy-, fluoro-.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ⁷ represents a group selected from the group consisting of C ₁ -C ₃ alkyl-, cyclopropyl-.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ⁸ represents a hydrogen atom or a C ₁ -C ₆ alkyl- or benzyl-group.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ⁸ represents a hydrogen atom or a C ₁ -C ₆ alkyl- group.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ⁸ represents a hydrogen atom or a C ₁ -C ₆ alkyl-, fluoro-C ₁ -C ₃ alkyl-, cyano- C ₁ -C ₄ alkyl-, C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl-, C ₃ -C ₇ cycloalkyl-, phenyl-, 5- to 6-membered heteroaryl- Or a benzyl-group.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ⁸ represents a hydrogen atom or a C ₁ -C ₆ alkyl-, C ₃ -C ₇ cycloalkyl-, phenyl- or Benzyl-group.

In another preferred embodiment, the invention relates to the above compound of formula (I), wherein R ^8a and R ^8b independently of each other represent a hydrogen atom or a C ₁ -C ₆ alkyl-, C ₃ -C ₇ cycloalkyl group -, (C ₃ -C ₇ cycloalkyl)-(L ³ )-, 4 to 10 membered heterocycloalkyl-, (4 to 10 membered heterocycloalkyl)-(L ³ )-, phenyl -heteroaryl-, phenyl-(L ³ )-, (phenyl)-O-(L ³ )-, heteroaryl-(L ³ )- or (aryl)- (4 to 10 members) Heterocycloalkyl)- group; C ₁ -C ₆ alkyl-, C ₃ -C ₇ cycloalkyl-, (C ₃ -C ₇ cycloalkyl)-(L ³ )-, 4 to 10 Heterocycloalkyl-, (4 to 10 membered heterocycloalkyl)-(L ³ )-, phenyl-, heteroaryl-, phenyl-(L ³ )-, (phenyl)-O- (L ³ )-,heteroaryl-(L ³ )- and (aryl)-(4 to 10 membered heterocycloalkyl)- groups are optionally substituted one or more times by R ⁹ or differently Or wherein R ^8a and R ^8b together with the nitrogen atom to which they are attached represent a 4 to 10 membered heterocycloalkyl- group, the 4 to 10 membered heterocycloalkyl- group optionally being the same as R ⁹ or Replace one or more times differently.

In another preferred embodiment, the invention relates to the above compound of formula (I), wherein R ^8a and R ^8b independently of each other represent a hydrogen atom or a C ₁ -C ₆ alkyl-, C ₃ -C ₇ cycloalkyl group -, (C ₃ -C ₇ cycloalkyl)-(L ³ )-, 4 to 10 membered heterocycloalkyl-, (4 to 10 membered heterocycloalkyl)-(L ³ )-, phenyl -heteroaryl-, phenyl-(L ³ )-, (phenyl)-O-(L ³ )-, heteroaryl-(L ³ )- or (aryl)- (4 to 10 members) Heterocycloalkyl)- group; C ₁ -C ₆ alkyl-, C ₃ -C ₇ cycloalkyl-, (C ₃ -C ₇ cycloalkyl)-(L ³ )-, 4 to 10 Heterocycloalkyl-, (4 to 10 membered heterocycloalkyl)-(L ³ )-, phenyl-, heteroaryl-, phenyl-(L ³ )-, (phenyl)-O- (L ³ )-,heteroaryl-(L ³ )- and (aryl)-(4 to 10 membered heterocycloalkyl)- groups are optionally substituted one or more times by R ⁹ or differently .

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ^8a and R ^8b together with the nitrogen atom to which they are attached represent a 4 to 10 membered heterocycloalkyl- group, said 4 members The 10-membered heterocycloalkyl-group is optionally substituted one or more times with R ⁹ via R ⁹ .

In another preferred embodiment, the invention relates to the above compound of formula (I), wherein R ^8a and R ^8b independently of each other represent a hydrogen atom or a C ₁ -C ₆ alkyl-, C ₃ -C ₇ cycloalkyl group - 4 to 10 membered heterocycloalkyl-, (4 to 10 membered heterocycloalkyl)-(L ³ )-, phenyl-, heteroaryl-, phenyl-(L ³ )- or hetero An aryl-(L ³ )- group; the C ₁ -C ₆ alkyl-, C ₃ -C ₇ cycloalkyl-, 4 to 10 membered heterocycloalkyl-, (4 to 10 membered heterocyclic ring) The alkyl)-(L ³ )-, phenyl-, heteroaryl-, phenyl-(L ³ )- and heteroaryl-(L ³ )- groups are optionally substituted by R ⁹ or differently One or more times; or wherein R ^8a and R ^8b together with the nitrogen atom to which they are attached represent a 4- to 7-membered heterocycloalkyl- group.

In another preferred embodiment, the invention relates to the above compound of formula (I), wherein R ^8a and R ^8b independently of each other represent a hydrogen atom or a C ₁ -C ₆ alkyl-, C ₃ -C ₇ cycloalkyl group - 4 to 10 membered heterocycloalkyl-, (4 to 10 membered heterocycloalkyl)-(L ³ )-, phenyl-, heteroaryl-, phenyl-(L ³ )- or hetero An aryl-(L ³ )- group; the C ₁ -C ₆ alkyl-, C ₃ -C ₇ cycloalkyl-, 4 to 10 membered heterocycloalkyl-, (4 to 10 membered heterocyclic ring) The alkyl)-(L ³ )-, phenyl-, heteroaryl-, phenyl-(L ³ )- and heteroaryl-(L ³ )- groups are optionally substituted by R ⁹ or differently One or more times.

In another preferred embodiment, the invention is directed to a compound of formula (I) above, wherein R ^8a and R ^8b together with the nitrogen atom to which they are attached represent a 4 to 7 membered heterocycloalkyl- group.

In another preferred embodiment, the present invention relates to the above compound of formula (I), wherein R ^8a and R ^8b independently of each other represent a hydrogen atom or a C ₁ -C ₄ alkyl-, C ₃ -C ₅ cycloalkyl group -, 4-7 heterocycloalkyl -, (4-7 heterocycloalkyl) - (L ³⁾ -, phenyl - or heteroaryl group - (L ³⁾ - group; the C ₁ -C ₄ alkyl-, C ₃ -C ₅ cycloalkyl-, 4 to 7 membered heterocycloalkyl-, (4 to 7 membered heterocycloalkyl)-(L ³ )-, phenyl- or The heteroaryl-(L ³ )- group is optionally substituted one or more times by R ⁹ or wherein R ^8a and R ^8b together with the nitrogen atom to which it is attached represent a 4- to 7-membered heterocycloalkane Base-group.

In another preferred embodiment, the present invention relates to the above compound of formula (I), wherein R ^8a and R ^8b independently of each other represent a hydrogen atom or a C ₁ -C ₄ alkyl-, C ₃ -C ₅ cycloalkyl group -, 4-7 heterocycloalkyl -, (4-7 heterocycloalkyl) - (L ³⁾ -, phenyl - or heteroaryl group - (L ³⁾ - group; the C ₁ -C ₄ alkyl-, C ₃ -C ₅ cycloalkyl-, 4 to 7 membered heterocycloalkyl-, (4 to 7 membered heterocycloalkyl)-(L ³ )-, phenyl- or The heteroaryl-(L ³ )- group is optionally substituted one or more times by R ⁹ , or differently.

In another preferred embodiment, the invention relates to the above compound of formula (I), wherein R ⁹ represents a halogen atom or a pendant oxy group, a C ₁ -C ₃ alkyl-, a halo-C ₁ -C ₃ alkyl group -, hydroxy-C ₁ -C ₃ alkyl-, -CN, -C(=O)R ¹⁰ , -C(=O)N(H)R ¹⁰ , -C(=O)N(R ^10a )R ^10b , -C(=O)OR ¹⁰ , -N(R ^10a )R ^10b , -NO ₂ , -N(H)C(=O)R ¹⁰ , -N(R ^10a )C(=O)R ^10b , -N(H)C(=O)N(R ^10a )R ^10b , -N(R ^10a )C(=O)N(R ^10b )R ^10c , -N(H)S(=O) ₂ R ¹⁰ , -N(R ^10a )S(=O) ₂ R ^10b , -OR ¹⁰ , -O(C=O)R ¹⁰ , -O(C=O)OR ¹⁰ or tetrazolyl-group; In a preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ⁹ represents a halogen atom or a pendant oxy group, a C ₁ -C ₃ alkyl-, a halo-C ₁ -C ₃ alkyl-, Hydroxy-C ₁ -C ₃ alkyl-, -CN, -C(=O)R ¹⁰ , -C(=O)N(H)R ¹⁰ , -C(=O)N(R ^10a )R ^10b , -C(=O)OR ¹⁰ , -N(R ^10a )R ^10b , -N(R ^10a )C(=O)R ^10b , -N(R ^10a )C(=O)N(R ^10b )R ^10c , -N(R ^10a )S(=O) ₂ R ^10b , -OR ¹⁰ or tetrazolyl- group; in another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ⁹ Represents a halogen atom or a C ₁ -C ₃ alkane Base-, hydroxy-C ₁ -C ₃ alkyl-, -CN, -C(=O)N(H)R ¹⁰ , -C(=O)N(R ^10a )R ^10b , -C(=O) OR ¹⁰ , -N(R ^10a )R ^10b , -N(R ^10a )C(=O)R ^10b , -N(R ^10a )C(=O)N(R ^10b )R ^10c , -OR ¹⁰ or four An azolyl- group; in another preferred embodiment, the invention relates to a compound of the above formula (I), wherein R ⁹ represents a halogen atom or a pendant oxy group, a C ₁ -C ₃ alkyl group, a fluoro-C ₁ -C ₃ alkyl-, hydroxy-C ₁ -C ₃ alkyl-, -CN, -C(=O)R ¹⁰ , -C(=O)N(H)R ¹⁰ , -C(=O)N (R ^10a )R ^10b , -C(=O)OR ¹⁰ , -N(R ^10a )R ^10b , -NO ₂ , -N(H)C(=O)R ¹⁰ , -N(R ^10a )C( =O)R ^10b , -N(H)S(=O) ₂ R ¹⁰ , -N(R ^10a )S(=O) ₂ R ^10b , -OR ¹⁰ , -S(=O) ₂ R ¹⁰ ,- S(=O) ₂ N(H)R ¹⁰ , -S(=O) ₂ N(R ^10a )R ^10b or a tetrazolyl- group.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ⁹ represents a halogen atom or a C ₁ -C ₃ alkyl-, fluoro-C ₁ -C ₃ alkyl-, hydroxy-C _1- C ₃ alkyl-, -CN, -C(=O)R ¹⁰ , -C(=O)N(H)R ¹⁰ , -C(=O)N(R ^10a )R ^10b , -N( R ^10a ) R ^10b , -N(H)C(=O)R ¹⁰ , -N(R ^10a )C(=O)R ^10b , -OR ¹⁰ groups.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ⁹ represents a halogen atom or a C ₁ -C ₃ alkyl-, -CN, -C(=O)NH ₂ or -OH Group.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ¹⁰ , R ^10a , R ^10b , R ^10c independently of one another represent a hydrogen atom or a group selected from the group consisting of C ₁ -C _3- alkyl-, hydroxy-C ₁ -C ₃ alkyl-.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ¹⁰ , R ^10a , R ^10b , R ^10c independently of one another represent a hydrogen atom or a C ₁ -C ₃ alkyl- group.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ¹⁰ , R ^10a , R ^10b , R ^10c independently of one another represent a hydrogen atom or a group selected from the group consisting of C ₁ -C _3- alkyl-, fluoro-C ₁ -C ₃ alkyl-, hydroxy-C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl-, C ₃ -C ₇ Cycloalkyl-, the C ₁ -C ₃ alkyl- group is optionally substituted once by -N(R ¹² )R ^12a ; or wherein R ^10a and R ^10b together with the nitrogen atom to which it is attached represent 4 to 7 members A heterocycloalkyl- group, the 4 to 7 membered heterocycloalkyl- group, is optionally substituted one or more times by R ¹³ .

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ¹⁰ , R ^10a , R ^10b , R ^10c independently of one another represent a hydrogen atom or a group selected from the group consisting of C ₁ -C _3- alkyl-, fluoro-C ₁ -C ₃ alkyl-, hydroxy-C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl-, C ₃ -C ₇ Cycloalkyl-, the C ₁ -C ₃ alkyl- group is optionally substituted once with -N(R ¹² )R ^12a .

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ^10a and R ^10b together with the nitrogen atom to which they are attached represent a 4 to 7 membered heterocycloalkyl- group, said 4 members The 7-membered heterocycloalkyl-group is optionally substituted one or more times by R ¹³ as the case may be.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ¹⁰ , R ^10a , R ^10b , R ^10c independently of one another represent a hydrogen atom or a group selected from the group consisting of C ₁ -C ₃ alkyl-, hydroxy-C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl-; or wherein R ^10a and R ^10b together with the nitrogen atom to which they are attached represent 4 To 7-membered heterocycloalkyl-group.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ¹⁰ , R ^10a , R ^10b , R ^10c independently of one another represent a hydrogen atom or a group selected from the group consisting of C ₁ -C _3- alkyl-, hydroxy-C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl-.

In another preferred embodiment, the invention is directed to a compound of formula (I) above, wherein R ^10a and R ^10b together with the nitrogen atom to which they are attached represent a 4 to 7 membered heterocycloalkyl- group.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ¹⁰ , R ^10a , R ^10b , R ^10c independently of one another represent a hydrogen atom or a C ₁ -C ₃ alkyl- group.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ¹⁰ , R ^10a , R ^10b , R ^10c independently of one another represent a hydrogen atom or a methyl-group.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ¹¹ represents a hydrogen atom or a cyano-, C ₁ -C ₃ alkyl-, -C(=O)R ¹⁰ or- C(=O)OR ¹⁰ group.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ¹¹ represents a hydrogen atom or a cyano-, -C(=O)R ¹⁰ or -C(=O)OR ¹⁰ group .

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ¹¹ represents a hydrogen atom or a cyano- or -C(=O)OR ¹⁰ group.

In another preferred embodiment, the invention is directed to a compound of formula (I) above, wherein R ¹¹ represents a -C(=O)OR ¹⁰ group.

In another preferred embodiment, the invention relates to compounds of formula (I) above, wherein R ¹¹ represents cyano-.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ¹¹ represents a hydrogen atom.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ¹² and R ^12a independently of one another represent a hydrogen atom or a C ₁ -C ₃ alkyl- group, or wherein R ¹² , R ^12a together with the nitrogen atom to which it is attached represents a 4- to 7-membered heterocycloalkyl- group.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ¹² and R ^12a independently of one another represent a hydrogen atom or a C ₁ -C ₃ alkyl- group.

In another preferred embodiment, the invention is directed to a compound of formula (I) above, wherein R ¹² and R ^12a together with the nitrogen atom to which they are attached represent a 4 to 7 membered heterocycloalkyl- group.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ¹³ represents a halogen atom or a cyano group, a hydroxyl group, a pendant oxy group, a C ₁ -C ₃ alkyl group, a trifluoromethyl group- , -C(=O)R ¹⁰ or -C(=O)OR ¹⁰ groups.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ¹³ represents a fluorine atom or a cyano group, a hydroxyl group, a pendant oxy group, a C ₁ -C ₃ alkyl group, a trifluoromethyl group- , an ethoxymethyl-, methoxycarbonyl- or ethoxycarbonyl- group.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein L ¹ represents a group selected from: -C ₁ -C ₄ alkylene-, -CH ₂ -CH=CH- , -C(phenyl)(H)-, -CH ₂ -CH ₂ -O-, -CH ₂ -C(=O)-N(H)-, -CH ₂ -C(=O)-N( R ^10a )-.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein L ¹ represents a group selected from: -C ₁ -C ₄ alkylene-, -C(phenyl) (H) )-, -CH ₂ -CH ₂ -O-, -CH ₂ -C(=O)-N(H)-, -CH ₂ -C(=O)-N(R ^10a )-.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein L ¹ represents a group selected from: -C ₁ -C ₄ alkylene-, -CH ₂ -CH ₂ -O -.

In another preferred embodiment, the invention is directed to a compound of formula (I) above, wherein L ¹ represents a -C ₁ -C ₄ alkyl- group.

In another preferred embodiment, the invention is directed to a compound of formula (I) above, wherein L ¹ represents a -C ₁ -C ₃ alkyl- group.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein L ¹ represents a group selected from the group consisting of -CH ₂ -, -CH ₂ -CH ₂ -.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein L ¹ represents a group selected from the group consisting of -CH ₂ -, -C(CH ₃ )(H)-, -CH ₂ -CH ₂ -.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein L ¹ represents a -CH ₂ - group.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein L ¹ represents a group selected from the group consisting of -CH ₂ -, -C(CH ₃ )(H)-.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein L ¹ represents a -C(CH ₃ )(H)- group.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein L ² represents a group selected from the group consisting of -CH ₂ -, -CH ₂ -CH ₂ -.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein L ² represents a -CH ₂ - group.

In another preferred embodiment, the invention is directed to a compound of formula (I) above, wherein L ³ represents a -C ₁ -C ₄ alkyl- group.

In another preferred embodiment, the invention is directed to a compound of formula (I) above, wherein L ³ represents a -C ₁ -C ₃ alkylene- group.

In another preferred embodiment, the invention is directed to a compound of formula (I) above, wherein L ³ represents a -C ₁ -C ₂ alkyl- group.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein p represents an integer of 0 or 1.

In another preferred embodiment, the invention is directed to a compound of formula (I) above, wherein p represents an integer of zero.

In another preferred embodiment, the invention is directed to a compound of formula (I) above, wherein p represents an integer of one.

In another preferred embodiment, the invention relates to a compound of formula (I) above, wherein R ¹ represents a C ₁ -C ₃ alkyl-, trifluoromethyl- or cyano- group, wherein R ² represents a a phenyl-, ethyl- or trifluoromethyl- group, wherein R ^4b and R ⁶ represent a hydrogen atom, wherein R ^5a , R ^5c , R ^5d independently of each other represent a hydrogen atom, a fluorine atom or a chlorine atom, and wherein L ¹ represents a group selected from -CH ₂ -, -C(CH ₃ )(H)-.

It will be understood that the invention relates to any subcombination within any of the embodiments of the above formula (I).

Some examples of combinations are given below. However, the invention is not limited to such combinations.

In a preferred embodiment, the invention is directed to a compound of formula (I):

Wherein: R ¹ represents C ₁ -C ₃ alkyl-, halo-C ₁ -C ₃ alkyl-, cyano-, -C(=O)OR ¹⁰ or -C(=O)N(R ^10a ) R ^10b group; R ² represents C ₁ -C ₃ alkyl-, halo-C ₁ -C ₃ alkyl-, cyano-, -C(=O)OR ¹⁰ or -C(=O)N( R ^10a ) R ^10b group; R ³ represents a group selected from the group consisting of aryl-, heteroaryl-, C ₅ -C ₆ cycloalkyl- and 5- to 6-membered heterocycloalkyl-; The 5- to 6-membered heterocycloalkyl-group is optionally benzofused; wherein the aryl-, heteroaryl-, C ₅ -C ₆ cycloalkyl- and 5- to 6-membered heterocycloalkyl- The group is substituted one or more times by -(L ² ) _p -R ⁷ ; and wherein two -(L ² ) _p -R ⁷ groups are present in the aryl- or heteroaryl- group If the group is adjacent to each other, a bridge selected from the group consisting of *-C ₃ -C ₅ alkyl-*, *-O(CH ₂ ) ₂ O-*, *-O(CH ₂ ) O-*, *-O(CF ₂ )O-*, *-CH ₂ C(R ^10a )(R ^10b )O-*, *-C(=O)N(R ^10a )CH ₂ -*,* -N(R ^10a )C(=O)CH ₂ O-*, *-NHC(=O)NH-*; wherein each * represents a point of attachment to the aryl- or heteroaryl- group; R ^4a represents a hydrogen atom or a halogen atom or a group selected from the group: cyano -, hydroxy -, C ₁ -C ₃ alkyl - , halo-C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy-, C ₃ -C ₇ cycloalkyl-, 4 to 7 membered heterocycloalkyl-, -C(=O) N(R ^10a )R ^10b , -N(R ^10a )R ^10b ; R ^4b represents a hydrogen atom or a group selected from the group consisting of C ₁ -C ₃ alkoxy-, C ₁ -C ₃ alkyl-, cyanide Or a combination of R ^4a and R ^4b to form a -C ₃ -C ₅ alkylene group; R ^5a , R ^5b , R ^5c , R ^5d

Independently from each other, a hydrogen atom, a halogen atom or a group selected from the group consisting of cyano-, -NO ₂ , C ₁ -C ₃ alkyl-, halo-C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy-, halo-C ₁ -C ₃ alkoxy-, phenyl-, heteroaryl-, -C(=O)R ¹⁰ , -C(=O)N(H)R ¹⁰ , -C(=O)N(R ^10a )R ^10b , -C(=O)OR ¹⁰ , -N(R ^10a )R ^10b , -N(H)C(=O)R ¹⁰ , -N(R ^10a C(=O)R ^10b , -N(H)C(=O)N(R ^10a )R ^10b , -N(R ^10a )C(=O)N(R ^10b )R ^10c , -N(R ^10a ) C(=O)C(=O)N(R ^10b )R ^10c , -N(H)C(=O)OR ¹⁰ , -N(R ^10a )C(=O)OR ^10b , -N( H)S(=O) ₂ R ¹⁰ , -N(R ^10a )S(=O) ₂ R ^10b , -OR ¹⁰ , -O(C=O)R ¹⁰ , -O(C=O)N(R ^10a ) R ^10b , -O(C=O)OR ¹⁰ , -SR ¹⁰ , -S(=O)R ¹⁰ , -S(=O) ₂ R ¹⁰ , -S(=O) ₂ N(H)R ¹⁰ , -S(=O) ₂ N(R ^10a )R ^10b or -S(=O)(=NR ^10a )R ^10b , the phenyl- or heteroaryl-group is optionally selected from the group consisting of The group is substituted one or more times identically or differently: halo-, cyano-, C ₁ -C ₃ alkyl-, halo-C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy- a group; R ⁶ represents a hydrogen atom or a group selected from the group consisting of C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy-(L ² )-, hydroxy -C ₁ -C ₃ alkyl-, aryl-(L ² )-, heteroaryl-(L ² )-; R ⁷ represents a group selected from the group consisting of a pendant oxy group, a C ₁ -C ₃ alkyl group -, C ₃ -C ₇ cycloalkyl-, 4- to 7-membered heterocycloalkyl-, halo-, C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy-, halo-C _1- C ₃ alkoxy-, -OH, -CN, halo-, -C(=O)R ⁸ , -C(=O)-OR ⁸ , -C(=O)N(R ^8a )R ^8b , -S(=O) ₂ R ⁸ , -S(=O)(=N)R ¹¹ , phenyl-, 5 to 6 membered heteroaryl-; R ⁸ represents a hydrogen atom or C ₁ -C ₆ Alkyl-, halo-C ₁ -C ₃ alkyl-, cyano-C ₁ -C ₄ alkyl-, C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl-, C ₃ -C ₇ cycloalkyl-, phenyl-, 5- to 6-membered heteroaryl- or benzyl-group; R ^8a , R ^8b

Independently from each other, a hydrogen atom or a C ₁ -C ₁₀ alkyl-, C ₃ -C ₇ cycloalkyl-, (C ₃ -C ₇ cycloalkyl)-(L ³ )-, C ₃ -C ₆ alkenyl group -, C ₃ -C ₆ alkynyl-, 4 to 10 membered heterocycloalkyl-, (4 to 10 membered heterocycloalkyl)-(L ³ )-, phenyl-, heteroaryl-, benzene -(L ³ )-, (phenyl)-O-(L ³ )-, heteroaryl-(L ³ )- or (aryl)-(4 to 10 membered heterocycloalkyl)- groups ; C ₁ -C ₁₀ alkyl-, C ₃ -C ₇ cycloalkyl-, (C ₃ -C ₇ cycloalkyl)-(L ³ )-, C ₃ -C ₆ alkenyl-, C ₃ - C ₆ alkynyl-, 4 to 10 membered heterocycloalkyl-, (4 to 10 membered heterocycloalkyl)-(L ³ )-, phenyl-, heteroaryl-, phenyl-(L ³ -, (phenyl)-O-(L ³ )-, heteroaryl-(L ³ )- and (aryl)-(4 to 10 membered heterocycloalkyl)- groups, optionally via R ⁹ Substituting one or more times identically or differently; or R ^8a and R ^8b together with the nitrogen atom to which they are attached represent a 4 to 10 membered heterocycloalkyl- group, the 4 to 10 membered heterocycloalkyl- group R group optionally substituted with identically or differently substituted one or more times ^9; R ⁹ represents a halogen atom or oxo, C ₁ -C ₃ alkyl -, halo -C ₁ -C ₃ alkyl -, hydroxy - C ₁ -C ₃ alkyl-, -CN, -C(=O)R ¹⁰ , -C(=O)N(H)R ¹⁰ , -C(=O)N(R ^10a )R ^10b , -C(=O)OR ¹⁰ , -N(R ^10a )R ^10b , -NO ₂ , -N(H)C(=O)R ¹⁰ , -N(R ^10a )C(=O)R ^10b , -N(H)C(=O)N(R ^10a )R ^10b , -N(R ^10a )C(=O)N(R ^10b )R ^10c , -N(H)C(=O)OR ¹⁰ , -N(R ^10a )C(=O)OR ^10b , -N(H)S(=O) ₂ R ¹⁰ , N(R ^10a )S(= O) ₂ R ^10b , -OR ¹⁰ , -O(C=O)R ¹⁰ , -O(C=O)N(R ^10a )R ^10b , -O(C=O)OR ¹⁰ , -SR ¹⁰ ,- S(=O)R ¹⁰ , -S(=O) ₂ R ¹⁰ , -S(=O) ₂ N(H)R ¹⁰ , -S(=O) ₂ N(R ^10a )R ^10b , -S( =O)(=NR ^10a )R ^10b or a tetrazolyl- group; or two R ⁹ groups present adjacent to each other on the phenyl- or heteroaryl-ring form a bridge selected from the group consisting of: *-C ₃ -C ₅ alkylene-*, *-O(CH ₂ ) ₂ O-*, *-O(CH ₂ )O-*, *-O(CF ₂ )O-*, *-CH ₂ C(R ^10a )(R ^10b )O-*, *-C(=O)N(R ^10a )CH ₂ -*, *-N(R ^10a )C(=O)CH ₂ O-*,* -NHC(=O)NH-*; wherein each * represents a point of attachment to the phenyl- or heteroaryl-ring; R ¹⁰ , R ^10a , R ^10b , R ^10c

Independently from each other, a hydrogen atom or a group selected from the group consisting of C ₁ -C ₃ alkyl-, halo-C ₁ -C ₃ alkyl-, hydroxy-C ₁ -C ₃ alkyl-, C ₃ -C ₇ -cycloalkyl-; R ¹¹ represents a hydrogen atom or a cyano-, C ₁ -C ₃ alkyl-, -C(=O)R ¹⁰ , -C(=O)N(H)R ¹⁰ , -C( =O) N(R ^10a )R ^10b or -C(=O)OR ¹⁰ group; L ¹ represents a group selected from: -C ₁ -C ₄ alkylene-, -CH ₂ -CH=CH -, -C(phenyl)(H)-, -CH ₂ -CH ₂ -O-; L ² represents a group selected from the group consisting of -CH ₂ -, -CH ₂ -CH ₂ -, -CH ₂ - CH ₂ -CH ₂ -; L ³ represents a -C ₁ -C ₆ alkylene group; p is an integer of 0 or 1; or a tautomer, a stereoisomer, an N-oxide, a hydrate thereof, Solvate or salt or a mixture thereof.

In a preferred embodiment, the invention is directed to a compound of formula (I):

Wherein: R ¹ represents C ₁ -C ₃ alkyl-, halo-C ₁ -C ₃ alkyl-, cyano-, -C(=O)OR ¹⁰ or -C(=O)N(R ^10a ) R ^10b group; R ² represents C ₁ -C ₃ alkyl-, halo-C ₁ -C ₃ alkyl-, cyano-, -C(=O)OR ¹⁰ or -C(=O)N( R ^10a ) R ^10b group; R ³ represents a group selected from the group consisting of aryl-, heteroaryl-, C ₅ -C ₆ cycloalkyl- and 5- to 6-membered heterocycloalkyl-; The 5- to 6-membered heterocycloalkyl-group is optionally benzofused; wherein the aryl-, heteroaryl-, C ₅ -C ₆ cycloalkyl- and 5- to 6-membered heterocycloalkyl- The group is substituted one or more times by -(L ² ) _p -R ⁷ ; and wherein two -(L ² ) _p -R ⁷ groups are present in the aryl- or heteroaryl- group If the group is adjacent to each other, a bridge selected from the group consisting of *-C ₃ -C ₅ alkyl-*, *-O(CH ₂ ) ₂ O-*, *-O(CH ₂ ) O-*, *-O(CF ₂ )O-*, wherein each * represents a point of attachment to the aryl- or heteroaryl- group; R ^4a represents a hydrogen atom or a halogen atom or a group selected from the group consisting of : cyano-, hydroxy-, C ₁ -C ₃ alkyl-, halo-C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy-, C ₃ -C ₇ cycloalkyl-, 4 To 7 members heterocycloalkyl-, -C (=O)N(R ^10a )R ^10b , -N(R ^10a )R ^10b ; R ^4b represents a hydrogen atom or a group selected from the group consisting of C ₁ -C ₃ alkoxy-, C ₁ -C ₃ alkane -Cyano- or R ^4a and R ^4b together form a -C ₃ -C ₅ alkyl-group; R ^5a , R ^5b , R ^5c , R ^5d

Independently from each other, a hydrogen atom, a halogen atom or a group selected from the group consisting of cyano-, -NO ₂ , C ₁ -C ₃ alkyl-, halo-C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy-, halo-C ₁ -C ₃ alkoxy-, phenyl-, heteroaryl-, -C(=O)R ¹⁰ , -C(=O)N(H)R ¹⁰ , -C(=O)N(R ^10a )R ^10b , -C(=O)OR ¹⁰ , -N(R ^10a )R ^10b , -N(H)C(=O)R ¹⁰ , -N(R ^10a C(=O)R ^10b , -N(R ^10a )C(=O)C(=O)N(R ^10b )R ^10c , -N(H)S(=O) ₂ R ¹⁰ , the phenyl group Or a heteroaryl-group is optionally substituted one or more times by a C ₁ -C ₃ alkyl-group; R ⁶ represents a hydrogen atom or a group selected from C ₁ -C ₃ Alkyl-, C ₁ -C ₃ alkoxy-(L ² )-, aryl-(L ² )-; R ⁷ represents a group selected from the group consisting of a pendant oxy group, a C ₁ -C ₃ alkyl group- , halo-C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy-, halo-C ₁ -C ₃ alkoxy-, -OH, -CN, halo-, -C(= O) R ⁸ , -C(=O)-OR ⁸ , -C(=O)N(R ^8a )R ^8b , -S(=O) ₂ R ⁸ , phenyl; R ⁸ represents a hydrogen atom or C ₁ -C ₆ alkyl-, C ₃ -C ₇ cycloalkyl-, phenyl- or benzyl-group; R ^8a , R ^8b

Independently from each other, a hydrogen atom or a C ₁ -C ₁₀ alkyl-, C ₃ -C ₇ cycloalkyl-, (C ₃ -C ₇ cycloalkyl)-(L ³ )-, C ₃ -C ₆ alkenyl group -, C ₃ -C ₆ alkynyl-, 4 to 10 membered heterocycloalkyl-, (4 to 10 membered heterocycloalkyl)-(L ³ )-, phenyl-, heteroaryl-, benzene a base-(L ³ )- or (phenyl)-O-(L ³ )-, heteroaryl-(L ³ )- group; the C ₁ -C ₁₀ alkyl-, C ₃ -C ₇ naphthenic -, (C ₃ -C ₇ cycloalkyl)-(L ³ )-, C ₃ -C ₆ alkenyl-, C ₃ -C ₆ alkynyl-, 4 to 10 membered heterocycloalkyl-, ( 4- to 10-membered heterocycloalkyl)-(L ³ )-, phenyl-, heteroaryl-, phenyl-(L ³ )-, (phenyl)-O-(L ³ )- and heteroaryl The benzyl-(L ³ )- group is optionally substituted one or more times by R ⁹ or R ^8a and R ^8b together with the nitrogen atom to which it is attached represents a 4 to 10 membered heterocycloalkyl- group. group, the 4-10 heterocyclyl group - optionally substituted with a group R ⁹ identically or differently substituted one or more times; R ⁹ represents a halogen atom or oxo, C ₁ -C ₃ alkyl -, Halo-C ₁ -C ₃ alkyl-, hydroxy-C ₁ -C ₃ alkyl-, -CN, -C(=O)R ¹⁰ , -C(=O)N(H)R ¹⁰ , -C (=O)N(R ^10a )R ^10b , -C(=O)OR ¹⁰ , -N(R ^10a )R ^10b , -NO ₂ , -N(H)C( =O)R ¹⁰ , -N(R ^10a )C(=O)R ^10b , -N(H)C(=O)N(R ^10a )R ^10b , -N(R ^10a )C(=O)N (R ^10b )R ^10c , -N(H)S(=O) ₂ R ¹⁰ , -N(R ^10a )S(=O) ₂ R ^10b , -OR ¹⁰ , -O(C=O)R ¹⁰ , -O(C=O)OR ¹⁰ or tetrazolyl- group; R ¹⁰ , R ^10a , R ^10b , R ^10c

Independently from each other, a hydrogen atom or a group selected from the group consisting of C ₁ -C ₃ alkyl-, hydroxy-C ₁ -C ₃ alkyl-, C ₃ -C ₇ cycloalkyl-; R ¹¹ represents a hydrogen atom or a cyano-, -C(=O)R ¹⁰ or -C(=O)OR ¹⁰ group; L ¹ represents a group selected from: -C ₁ -C ₄ alkyl-, -CH ₂ -CH =CH-, -C(phenyl)(H)-, -CH ₂ -CH ₂ -O-; L ² represents a group selected from the group consisting of -CH ₂ -, -CH ₂ -CH ₂ -.

L ³ represents a -C ₁ -C ₆ alkylene group; p is an integer of 0 or 1; or a tautomer, stereoisomer, N-oxide, hydrate, solvate or salt thereof or mixture.

In another preferred embodiment, the invention is directed to a compound of formula (I):

Wherein: R ¹ represents C ₁ -C ₃ alkyl-, fluoro-C ₁ -C ₃ alkyl-, cyano-, -C(=O)OR ¹⁰ or -C(=O)N(R ^10a )R ^a group of ^10b ; R ² represents a C ₁ -C ₃ alkyl-, fluoro-C ₁ -C ₃ alkyl-, -C(=O)OR ¹⁰ or -C(=O)N(R ^10a )R ^10b group R ³ represents a group selected from the group consisting of aryl-, heteroaryl-, C ₅ -C ₆ cycloalkyl- and 5- to 6-membered heterocycloalkyl-; wherein the 5 to 6 members are heterozygous cycloalkyl - group via the benzo optionally condensed; wherein the aryl -, heteroaryl -, C ₅ -C ₆ cycloalkyl, - and 5-6 heterocycloalkyl - group by - (L ² ) _p- R ⁷ is substituted one or more times identically or differently; and wherein two -(L ² ) _p -R ⁷ groups are ortho to each other if present in the aryl- or heteroaryl-group And optionally forming a *-C ₃ -C ₅ alkyl-- bridge, wherein each * represents a point of attachment to the aryl- or heteroaryl- group; R ^4a represents a hydrogen atom or a halogen atom or From the following groups: cyano-, hydroxy-, C ₁ -C ₃ alkyl-, fluoro-C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy-, C ₃ -C ₇ naphthenic Base-, 4- to 7-membered heterocycloalkyl-, -C(=O)N(R ^10a )R ^10b , -N(R ^10a )R ^10b ; R ^4b represents a hydrogen atom or a group selected from the group consisting of: C ₁ -C ₃ alkoxy-, C ₁ -C ₃ alkyl-, cyano-; or R ^4a and R ^4b together form a -C ₃ -C ₅ alkyl-group; R ^5a , R ^5b , R ^5c , R ^5d

Independently from each other, a hydrogen atom, a halogen atom or a group selected from the group consisting of cyano-, -NO ₂ , C ₁ -C ₃ alkyl-, fluoro-C ₁ -C ₃ alkyl-, C ₁ -C ₃ Alkoxy-, fluoro-C ₁ -C ₃ alkoxy-, phenyl-, heteroaryl-, -C(=O)N(R ^10a )R ^10b , -C(=O)OR ¹⁰ ,- N(R ^10a )R ^10b , -N(H)C(=O)R ¹⁰ , -N(R ^10a )C(=O)R ^10b , -N(R ^10a )C(=O)C(=O N(R ^10b )R ^10c , -N(H)S(=O) ₂ R ¹⁰ , the phenyl- or heteroaryl-group is optionally the same via a C ₁ -C ₃ alkyl- group or Substituted one or more times differently; R ⁶ represents a hydrogen atom or a group selected from the group consisting of C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy-(L ² )-, aryl-(L ² )-; R ⁷ represents a group selected from the group consisting of a pendant oxy group, a C ₁ -C ₃ alkyl group, a halo-C ₁ -C ₃ alkyl group, a C ₁ -C ₃ alkoxy group, and a halogen. -C ₁ -C ₃ alkoxy-, -OH, -CN, halo-, -C(=O)R ⁸ , -C(=O)-OR ⁸ , -C(=O)N(R ^8a ) R ^8b , -S(=O) ₂ R ⁸ , phenyl; R ⁸ represents a hydrogen atom or a C ₁ -C ₆ alkyl- group; R ^8a , R ^8b

Independently from each other, a hydrogen atom or a C ₁ -C ₁₀ alkyl-, C ₃ -C ₇ cycloalkyl-, (C ₃ -C ₇ cycloalkyl)-(L ³ )-, C ₃ -C ₆ alkenyl group -, C ₃ -C ₆ alkynyl-, 4 to 10 membered heterocycloalkyl-, (4 to 10 membered heterocycloalkyl)-(L ³ )-, phenyl-, heteroaryl-, benzene a base-(L ³ )- or (phenyl)-O-(L ³ )-, heteroaryl-(L ³ )- group; the C ₁ -C ₁₀ alkyl-, C ₃ -C ₇ naphthenic -, (C ₃ -C ₇ cycloalkyl)-(L ³ )-, C ₃ -C ₆ alkenyl-, C ₃ -C ₆ alkynyl-, 4 to 10 membered heterocycloalkyl-, ( 4- to 10-membered heterocycloalkyl)-(L ³ )-, phenyl-, heteroaryl-, phenyl-(L ³ )-, (phenyl)-O-(L ³ )- and heteroaryl The benzyl-(L ³ )- group is optionally substituted one or more times by R ⁹ or R ^8a and R ^8b together with the nitrogen atom to which it is attached represents a 4 to 10 membered heterocycloalkyl- group. group, the 4-10 heterocyclyl group - optionally substituted with a group R ⁹ identically or differently substituted one or more times; R ⁹ represents a halogen atom or oxo, C ₁ -C ₃ alkyl -, Hydroxy-C ₁ -C ₃ alkyl-, -CN, -C(=O)N(H)R ¹⁰ , -C(=O)N(R ^10a )R ^10b , -C(=O)OR ¹⁰ , -N(R ^10a )R ^10b , -N(H)C(=O)R ¹⁰ , -N(R ^10a )C(=O)R ^10b , -N(R ^10a )C(= O) N(R ^10b )R ^10c , -OR ¹⁰ or tetrazolyl- group; R ¹⁰ , R ^10a , R ^10b , R ^10c

Independently from each other, a hydrogen atom or a group selected from the group consisting of C ₁ -C ₃ alkyl-, hydroxy-C ₁ -C ₃ alkyl-, C ₃ -C ₇ cycloalkyl-; R ¹¹ represents a hydrogen atom or a cyano- or -C(=O)OR ¹⁰ group; L ¹ represents a group selected from: -C ₁ -C ₃ alkyl-, -CH ₂ -CH=CH-, -C (phenyl (H)-, -CH ₂ -CH ₂ -O-; L ² represents a group selected from the group consisting of -CH ₂ -, -CH ₂ -CH ₂ -.

L ³ represents a -C ₁ -C ₆ alkylene group; p is an integer of 0 or 1; or a tautomer, stereoisomer, N-oxide, hydrate, solvate or salt thereof or mixture.

In another preferred embodiment, the invention is directed to a compound of formula (I):

Wherein: R ¹ represents a methyl- or trifluoromethyl- group; and R ² represents a methyl-group; or R ¹ represents a methyl-; and R ² represents a methyl- or trifluoromethyl- group ; R ³ represents a group selected from the group consisting of aryl-, heteroaryl-, C ₅ -C ₆ cycloalkyl- and 5- to 6-membered heterocycloalkyl-; wherein the 5- to 6-membered heterocyclic ring alkyl - group is an optionally benzo-condensed; wherein the aryl -, heteroaryl -, C ₅ -C ₆ cycloalkyl, - and 5-6 heterocycloalkyl - group by - (L ² _p- R ⁷ is substituted one or more times identically or differently; and wherein two -(L ² ) _p -R ⁷ groups are ortho to each other on the aryl- or heteroaryl- group, Then, a bridge selected from *-C ₃ -C ₅ alkylene-* is formed as appropriate; wherein each * represents a point of attachment to the aryl- or heteroaryl- group; and R ^4a represents a hydrogen atom or a halogen atom. Or a group selected from the group consisting of cyano-, hydroxy-, C ₁ -C ₃ alkyl-, halo-C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy-, C ₃ -C ₇ cycloalkyl-, 4 to 7 membered heterocycloalkyl-, -C(=O)N(R ^10a )R ^10b , -N(R ^10a )R ^10b ; R ^4b represents a hydrogen atom or is selected from the group consisting of groups: C ₁ -C ₃ alkoxy -, C ₁ -C ₃ alkyl - cyano - Or R ^4a and R ^4b together form a -C ₃ -C ₅ alkylene - ^{group; R 5a, R 5b, R} 5c, R 5d

Independently from each other, a hydrogen atom, a halogen atom or a group selected from the group consisting of cyano-, -NO ₂ , C ₁ -C ₃ alkyl-, halo-C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy-, halo-C ₁ -C ₃ alkoxy-, phenyl-, heteroaryl-, -C(=O)R ¹⁰ , -C(=O)N(H)R ¹⁰ , -C(=O)N(R ^10a )R ^10b , -C(=O)OR ¹⁰ , -N(R ^10a )R ^10b , -N(H)C(=O)R ¹⁰ , -N(R ^10a C(=O)R ^10b , -N(H)C(=O)N(R ^10a )R ^10b , -N(R ^10a )C(=O)N(R ^10b )R ^10c , -N(R ^10a ) C(=O)C(=O)N(R ^10b )R ^10c , -N(H)C(=O)OR ¹⁰ , -N(R ^10a )C(=O)OR ^10b , -N( H)S(=O) ₂ R ¹⁰ , -N(R ^10a )S(=O) ₂ R ^10b , -OR ¹⁰ , -O(C=O)R ¹⁰ , -O(C=O)N(R ^10a ) R ^10b , -O(C=O)OR ¹⁰ , -SR ¹⁰ , -S(=O)R ¹⁰ , -S(=O) ₂ R ¹⁰ , -S(=O) ₂ N(H)R ¹⁰ , -S(=O) ₂ N(R ^10a )R ^10b or -S(=O)(=NR ^10a )R ^10b , the phenyl- or heteroaryl-group is optionally selected from the group consisting of The group is substituted one or more times identically or differently: halo-, cyano-, C ₁ -C ₃ alkyl-, halo-C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy- a group; R ⁶ represents a hydrogen atom or a group selected from the group consisting of C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy-(L ² )-, hydroxy -C ₁ -C ₃ alkyl-, aryl-(L ² )-, heteroaryl-(L ² )-; R ⁷ represents a group selected from the group consisting of a pendant oxy group, a C ₁ -C ₃ alkyl group -, C ₃ -C ₇ cycloalkyl-, 4- to 7-membered heterocycloalkyl-, halo-, C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy-, halo-C _1- C ₃ alkoxy-, -OH, -CN, halo-, -C(=O)R ⁸ , -C(=O)-OR ⁸ , -C(=O)N(R ^8a )R ^8b , -S(=O) ₂ R ⁸ , phenyl-, 5- to 6-membered heteroaryl-; R ⁸ represents a hydrogen atom or a C ₁ -C ₆ alkyl-, halo-C ₁ -C ₃ alkane -, cyano-C ₁ -C ₄ alkyl-, C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl-, C ₃ -C ₇ cycloalkyl-, phenyl-, 5 members to 6-membered heteroaryl- or benzyl-group; R ^8a , R ^8b

Independently from each other, a hydrogen atom or a C ₁ -C ₁₀ alkyl-, C ₃ -C ₇ cycloalkyl-, (C ₃ -C ₇ cycloalkyl)-(L ³ )-, C ₃ -C ₆ alkenyl group -, C ₃ -C ₆ alkynyl-, 4 to 10 membered heterocycloalkyl-, (4 to 10 membered heterocycloalkyl)-(L ³ )-, phenyl-, heteroaryl-, benzene -(L ³ )-, (phenyl)-O-(L ³ )-, heteroaryl-(L ³ )- or (aryl)-(4 to 10 membered heterocycloalkyl)- groups ; C ₁ -C ₁₀ alkyl-, C ₃ -C ₇ cycloalkyl-, (C ₃ -C ₇ cycloalkyl)-(L ³ )-, C ₃ -C ₆ alkenyl-, C ₃ - C ₆ alkynyl-, 4 to 10 membered heterocycloalkyl-, (4 to 10 membered heterocycloalkyl)-(L ³ )-, phenyl-, heteroaryl-, phenyl-(L ³ -, (phenyl)-O-(L ³ )-, heteroaryl-(L ³ )- and (aryl)-(4 to 10 membered heterocycloalkyl)- groups, optionally via R ⁹ Substituting one or more times identically or differently; or R ^8a and R ^8b together with the nitrogen atom to which they are attached represent a 4 to 10 membered heterocycloalkyl- group, the 4 to 10 membered heterocycloalkyl- group R group optionally substituted with identically or differently substituted one or more times ^9; R ⁹ represents a halogen atom or oxo, C ₁ -C ₃ alkyl -, halo -C ₁ -C ₃ alkyl -, hydroxy - C ₁ -C ₃ alkyl-, -CN, -C(=O)R ¹⁰ , -C(=O)N(H)R ^{1 0} , -C(=O)N(R ^10a )R ^10b , -C(=O)OR ¹⁰ , -N(R ^10a )R ^10b , -NO ₂ , -N(H)C(=O)R ¹⁰ , -N(R ^10a )C(=O)R ^10b , -N(H)C(=O)N(R ^10a )R ^10b , -N(R ^10a )C(=O)N(R ^10b )R ^10c , -N(H)C(=O)OR ¹⁰ , -N(R ^10a )C(=O)OR ^10b , -N(H)S(=O) ₂ R ¹⁰ , -N(R ^10a )S (=O) ₂ R ^10b , -OR ¹⁰ , -O(C=O)R ¹⁰ , -O(C=O)N(R ^10a )R ^10b , -O(C=O)OR ¹⁰ , -SR ¹⁰ , -S(=O)R ¹⁰ , -S(=O) ₂ R ¹⁰ , -S(=O) ₂ N(H)R ¹⁰ , -S(=O) ₂ N(R ^10a )R ^10b ,- S(=O)(=NR ^10a )R ^10b or tetrazolyl- group; R ¹⁰ , R ^10a , R ^10b , R ^10c

Independently from each other, a hydrogen atom or a group selected from the group consisting of C ₁ -C ₃ alkyl-, halo-C ₁ -C ₃ alkyl-, hydroxy-C ₁ -C ₃ alkyl-, C ₃ -C ₇ -cycloalkyl-; L ¹ represents a group selected from: -C ₁ -C ₄ alkyl-, -CH ₂ -CH=CH-, -C(phenyl)(H)-, -CH ₂ -CH ₂ -O-; L ² represents a group selected from the group consisting of -CH ₂ -, -CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -CH ₂ -; L ³ represents -C ₁ -C ₆ An alkyl-group; p is an integer 0 or 1; or a tautomer, stereoisomer, N-oxide, hydrate, solvate or salt thereof or a mixture thereof.

In another preferred embodiment, the invention is directed to a compound of formula (I):

Wherein: R ¹ represents C ₁ -C ₃ alkyl-, fluoro-C ₁ -C ₃ alkyl-, cyano-, -C(=O)OR ¹⁰ or -C(=O)N(R ^10a )R ^a group of ^10b ; R ² represents a C ₁ -C ₃ alkyl-, fluoro-C ₁ -C ₃ alkyl-, -C(=O)OR ¹⁰ or -C(=O)N(R ^10a )R ^10b group R ³ represents a group selected from the group consisting of aryl-, heteroaryl-, C ₅ -C ₆ cycloalkyl- and 5- to 6-membered heterocycloalkyl-; wherein the 5 to 6 members are heterozygous cycloalkyl - group via the benzo optionally condensed; wherein the aryl -, heteroaryl -, C ₅ -C ₆ cycloalkyl, - and 5-6 heterocycloalkyl - group optionally substituted with - (L ² ) _p -R ⁷ is substituted one or more times identically or differently; and wherein two -(L ² ) _p -R ⁷ groups are present on the aryl- or heteroaryl-group, In the ortho position, a bridge selected from the group consisting of *-C ₃ -C ₈ alkyl-*, *-O(CH ₂ ) ₂ O-*, *-O(CH ₂ )O-; * represents each of the aryl - aryl or heteroaryl group - the point of attachment of the group; R ^4a represents a hydrogen atom or a halogen atom or a group selected from the group: cyano -, hydroxy -, C ₁ -C ₃ alkyl - , fluorine-C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy-, fluoro-C ₁ -C ₃ alkoxy-, C ₃ -C ₇ cycloalkyl-, 4 to 7 hetero Cycloalkyl-, -C(= O)-OR ¹⁰ , -C(=O)N(R ^10a )R ^10b , -C(=O)-N(R ^10a )-S(=O) ₂ -R ¹⁰ , -SR ¹⁰ , -S( =O)-R ¹⁰ , -S(=NR ¹¹ )-R ¹⁰ , -S(=O) ₂ -R ¹⁰ , -S(=O) ₂ -N(R ^10a )R ^10b , -S(=O (=NR ¹¹ )-R ¹⁰ , -N(R ^10a )R ^10b ; R ^4b represents a hydrogen atom or a group selected from C ₁ -C ₃ alkoxy-, C ₁ -C ₃ alkyl- , cyano-; or R ^4a and R ^4b together form a -C ₃ -C ₅ alkyl-group; R ^5a , R ^5b , R ^5c , R ^5d

Independently from each other, a hydrogen atom, a halogen atom or a group selected from the group consisting of cyano-, -NO ₂ , C ₁ -C ₃ alkyl-, fluoro-C ₁ -C ₃ alkyl-, C ₁ -C ₃ Alkoxy-, fluoro-C ₁ -C ₃ alkoxy-, phenyl-, heteroaryl-, -C(=O)R ¹⁰ , -C(=O)N(H)R ¹⁰ , -C (=O)N(R ^10a )R ^10b , -C(=O)OR ¹⁰ , -N(R ^10a )R ^10b , -N(H)C(=O)R ¹⁰ , -N(R ^10a )C (=O)R ^10b , -N(H)S(=O) ₂ R ¹⁰ , -N(R ^10a )S(=O) ₂ R ^10b , -OR ¹⁰ , -S(=O) ₂ R ¹⁰ , -S(=O) ₂ N(H)R ¹⁰ or -S(=O) ₂ N(R ^10a )R ^10b , the phenyl- or heteroaryl- group optionally being the same group selected from the group below Substituted one or more times: halo-, cyano-, C ₁ -C ₃ alkyl-, fluoro-C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy-; R ⁶ Represents a hydrogen atom or a group selected from the group consisting of C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy-(L ² )-, hydroxy-C ₁ -C ₃ alkyl-, aryl-( L ² )-,heteroaryl-(L ² )-; R ⁷ represents a group selected from the group consisting of a pendant oxy group, a C ₁ -C ₄ alkyl group, a C ₃ -C ₇ cycloalkyl group, and 4 members. To 7-membered heterocycloalkyl-, fluoro-C ₁ -C ₄ alkyl-, hydroxy-C ₁ -C ₄ alkyl-, cyano-C ₁ -C ₄ alkyl-, C ₂ -C ₄ alkenyl -, C ₁ -C ₄ alkoxy-, fluoro-C ₁ -C ₄ alkoxy-, -OH, -CN, halo-, -C(=O)R ⁸ , -C(=O)-OR ⁸ , -C( =O)N(R ^8a )R ^8b , -N(R ^10a )R ^10b , -S(=O) ₂ R ⁸ , -S(=O)(=NR ¹¹ )-R ¹⁰ , phenyl-, 5 To 6 members heteroaryl-; R ⁸ represents a hydrogen atom or a C ₁ -C ₆ alkyl-, fluoro-C ₁ -C ₃ alkyl-, cyano-C ₁ -C ₄ alkyl-, C ₁ - C ₃ alkoxy-C ₁ -C ₃ alkyl-, C ₃ -C ₇ cycloalkyl-, phenyl-, 5- to 6-membered heteroaryl- or benzyl-group; R ^8a , R ^8b

Independently from each other, a hydrogen atom or a C ₁ -C ₆ alkyl-, C ₃ -C ₇ cycloalkyl-, (C ₃ -C ₇ cycloalkyl)-(L ³ )-, 4 to 10 membered heterocyclic ring Alkyl-, (4 to 10 membered heterocycloalkyl)-(L ³ )-, phenyl-, heteroaryl-, phenyl-(L ³ )-, (phenyl)-O-(L ³ a heteroaryl-(L ³ )- or (aryl)-(4 to 10 membered heterocycloalkyl) group; the C ₁ -C ₆ alkyl-, C ₃ -C ₇ naphthenic -, (C ₃ -C ₇ cycloalkyl)-(L ³ )-, 4 to 10 membered heterocycloalkyl-, (4 to 10 membered heterocycloalkyl)-(L ³ )-, benzene Base-, heteroaryl-, phenyl-(L ³ )-, (phenyl)-O-(L ³ )-, heteroaryl-(L ³ )- and (aryl)- (4 to 10) a heterocycloalkyl)- group optionally substituted one or more times by R ⁹ or R ^8a and R ^8b together with the nitrogen atom to which it is attached represents a 4 to 10 membered heterocycloalkyl- group group, the 4-10 heterocyclyl group - optionally substituted with a group R ⁹ identically or differently substituted one or more times; R ⁹ represents a halogen atom or oxo, C ₁ -C ₃ alkyl -, Fluoro-C ₁ -C ₃ alkyl-, hydroxy-C ₁ -C ₃ alkyl-, -CN, -C(=O)R ¹⁰ , -C(=O)N(H)R ¹⁰ , -C( =O)N(R ^10a )R ^10b , -C(=O)OR ¹⁰ , -N(R ^10a )R ^10b , -NO ₂ , -N(H)C (=O)R ¹⁰ , -N(R ^10a )C(=O)R ^10b , -N(H)S(=O) ₂ R ¹⁰ , -N(R ^10a )S(=O) ₂ R ^10b , -OR ¹⁰ , -S(=O) ₂ R ¹⁰ , -S(=O) ₂ N(H)R ¹⁰ , -S(=O) ₂ N(R ^10a )R ^10b or a tetrazolyl- group; R ¹⁰ , R ^10a , R ^10b , R ^10c

Independently from each other, a hydrogen atom or a group selected from the group consisting of C ₁ -C ₃ alkyl-, fluoro-C ₁ -C ₃ alkyl-, hydroxy-C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl-, C ₃ -C ₇ cycloalkyl-, the C ₁ -C ₃ alkyl- group optionally substituted once with -N(R ¹² )R ^12a ; or R ^10a and R ^10b together with the nitrogen atom to which they are attached represent a 4- to 7-membered heterocycloalkyl- group, which may be substituted identically or differently by R ¹³ as appropriate Or multiple times; R ¹¹ represents a hydrogen atom or a cyano-, C ₁ -C ₃ alkyl-, -C(=O)R ¹⁰ or -C(=O)O-R ¹⁰ group; R ¹² , R ^12a

Representing each other independently of a hydrogen atom or a C ₁ -C ₃ alkyl- group, or R ¹² , R ^12a

The nitrogen atom to which it is attached represents a 4- to 7-membered heterocycloalkyl- group; R ¹³ represents a halogen atom or a cyano group, a hydroxyl group, a pendant oxy group, a C ₁ -C ₃ alkyl group, a trifluoromethyl group- a -C(=O)R ¹⁰ or -C(=O)OR ¹⁰ group; L ¹ represents a group selected from the group consisting of -C ₁ -C ₄ alkylene-, -CH ₂ -CH=CH- , -C(phenyl)(H)-, -CH ₂ -CH ₂ -O-, -CH ₂ -C(=O)-N(H)-, -CH ₂ -C(=O)-N( R ^10a )-; L ² represents a group selected from: -CH ₂ -, -CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -CH ₂ -; L ³ represents -C ₁ -C ₄ -alkylene a group-group; p is an integer of 0 or 1; the constraint is that at least one of R ¹ and R ² is different from isopropyl-, or a tautomer, a stereoisomer, an N-oxide, Hydrates, solvates or salts or mixtures thereof.

In another preferred embodiment, the invention is directed to a compound of formula (I):

Wherein: R ¹ represents C ₁ -C ₃ alkyl-, fluoro-C ₁ -C ₃ alkyl-, cyano-, -C(=O)OR ¹⁰ or -C(=O)N(R ^10a )R ^a group of ^10b ; R ² represents a C ₁ -C ₃ alkyl-, fluoro-C ₁ -C ₃ alkyl- or -C(=O)N(R ^10a )R ^10b group; R ³ represents a group selected from the group consisting of Group: aryl- or 5- to 6-membered heteroaryl- or piperidinyl-; wherein the aryl- or 5- to 6-membered heteroaryl- or piperidinyl-group is optionally-- ² ) _p- R ⁷ is substituted one or more times identically or differently; R ^4a represents a hydrogen atom or a halogen atom or a group selected from the group consisting of cyano-, hydroxy-, C ₁ -C ₃ alkyl-, fluorine -C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy-, fluoro-C ₁ -C ₃ alkoxy-, C ₃ -C ₇ cycloalkyl-, 4 to 7-membered heterocycloalkane Base -, -C(=O)-OR ¹⁰ , -C(=O)N(R ^10a )R ^10b , -C(=O)-N(R ^10a )-S(=O) ₂ -R ¹⁰ , -SR ¹⁰ , -S(=O)-R ¹⁰ , -S(=NR ¹¹ )-R ¹⁰ , -S(=O) ₂ -R ¹⁰ , -S(=O) ₂ -N(R ^10a )R ^10b , -S(=O)(=NR ¹¹ )-R ¹⁰ , -N(R ^10a )R ^10b ; R ^4b represents a hydrogen atom or a group selected from the group consisting of C ₁ -C ₃ alkoxy-, C _1- C ₃ alkyl-, cyano-; or R ^4a and R ^4b together form a -C ₃ -C ₅ alkyl-group; R ^5a , R ^5b , R ^5c , R ^5d

Independently from each other, a hydrogen atom, a halogen atom or a group selected from the group consisting of cyano-, -NO ₂ , C ₁ -C ₃ alkyl-, fluoro-C ₁ -C ₃ alkyl-, C ₁ -C ₃ Alkoxy-, fluoro-C ₁ -C ₃ alkoxy-, phenyl-, heteroaryl-, -C(=O)R ¹⁰ , -C(=O)N(H)R ¹⁰ , -C (=O)N(R ^10a )R ^10b , -C(=O)OR ¹⁰ , -N(R ^10a )R ^10b , -N(H)C(=O)R ¹⁰ , -N(R ^10a )C (=O)R ^10b , -N(H)S(=O) ₂ R ¹⁰ , -N(R ^10a )S(=O) ₂ R ^10b , -OR ¹⁰ , -S(=O) ₂ R ¹⁰ , -S(=O) ₂ N(H)R ¹⁰ or -S(=O) ₂ N(R ^10a )R ^10b , the phenyl- or heteroaryl- group optionally being the same group selected from the group below Substituted one or more times: halo-, cyano-, C ₁ -C ₃ alkyl-, fluoro-C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy-; R ⁶ Represents a hydrogen atom; R ⁷ represents a group selected from the group consisting of a pendant oxy group, a C ₁ -C ₄ alkyl group, a C ₃ -C ₇ cycloalkyl group, a 4- to 7-membered heterocycloalkyl group, and a fluorine- C ₁ -C ₄ alkyl-, hydroxy-C ₁ -C ₄ alkyl-, cyano-C ₁ -C ₄ alkyl-, C ₂ -C ₄ alkenyl-, C ₁ -C ₄ alkoxy- , fluoro-C ₁ -C ₄ alkoxy-, -OH, -CN, halo-, -C(=O)R ⁸ , -C(=O)-OR ⁸ , -C(=O)N( R ^8a )R ^8b , -N(R ^10a )R ^10b ,- S(=O) ₂ R ⁸ , -S(=O)(=NR ¹¹ )-R ¹⁰ , phenyl-, 5- to 6-membered heteroaryl-; R ⁸ represents a hydrogen atom or a C ₁ -C ₆ alkane -Fluoro-C ₁ -C ₃ alkyl-, cyano-C ₁ -C ₄ alkyl-, C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl-, C ₃ -C ₇ ring Alkyl-, phenyl-, 5- to 6-membered heteroaryl- or benzyl-group; R ⁸ a, R ^8b

Independently from each other, a hydrogen atom or a C ₁ -C ₆ alkyl-, C ₃ -C ₇ cycloalkyl-, (C ₃ -C ₇ cycloalkyl)-(L ³ )-, 4 to 10 membered heterocyclic ring Alkyl-, (4 to 10 membered heterocycloalkyl)-(L ³ )-, phenyl-, heteroaryl-, phenyl-(L ³ )-, (phenyl)-O-(L ³ a heteroaryl-(L ³ )- or (aryl)-(4 to 10 membered heterocycloalkyl) group; the C ₁ -C ₆ alkyl-, C ₃ -C ₇ naphthenic -, (C ₃ -C ₇ cycloalkyl)-(L ³ )-, 4 to 10 membered heterocycloalkyl-, (4 to 10 membered heterocycloalkyl)-(L ³ )-, benzene Base-, heteroaryl-, phenyl-(L ³ )-, (phenyl)-O-(L ³ )-, heteroaryl-(L ³ )- and (aryl)- (4 to 10) a heterocycloalkyl)- group optionally substituted one or more times by R ⁹ or R ^8a and R ^8b together with the nitrogen atom to which it is attached represents a 4 to 10 membered heterocycloalkyl- group group, the 4-10 heterocyclyl group - optionally substituted with a group R ⁹ identically or differently substituted one or more times; R ⁹ represents a halogen atom or oxo, C ₁ -C ₃ alkyl -, Fluorine-C ₁ -C ₃ alkyl-, hydroxy-C ₁ -C ₃ alkyl-, --CN, -C(=O)R ¹⁰ , -C(=O)N(H)R ¹⁰ , -C (=O)N(R ^10a )R ^10b , -C(=O)OR ¹⁰ , -N(R ^10a )R ^10b , -NO ₂ , -N(H) C(=O)R ¹⁰ , -N(R ^10a )C(=O)R ^10b , -N(H)S(=O) ₂ R ¹⁰ , - N(R ^10a )S(=O) ₂ R ^10b , -OR ¹⁰ , -S(=O) ₂ R ¹⁰ , -S(=O) ₂ N(H)R ¹⁰ , -S(=O) ₂ N(R ^10a )R ^10b or tetrazolyl-group ;R ¹⁰ , R ^10a , R ^10b , R ^10c

Independently from each other, a hydrogen atom or a group selected from the group consisting of C ₁ -C ₃ alkyl-, fluoro-C ₁ -C ₃ alkyl-, hydroxy-C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl-, C ₃ -C ₇ cycloalkyl-, the C ₁ -C ₃ alkyl- group optionally substituted once with -N(R ¹² )R ^12a ; or R ^10a and R ^10b together with the nitrogen atom to which they are attached represent a 4- to 7-membered heterocycloalkyl- group, which may be substituted identically or differently by R ¹³ as appropriate Or multiple times; R ¹¹ represents a hydrogen atom or a cyano- or -C(=O)OR ¹⁰ group; R ¹² , R ^12a

Representing each other independently of a hydrogen atom or a C ₁ -C ₃ alkyl- group, or R ¹² , R ^12a

The nitrogen atom to which it is attached represents a 4- to 7-membered heterocycloalkyl- group; R ¹³ represents a halogen atom or a cyano group, a hydroxyl group, a pendant oxy group, a C ₁ -C ₃ alkyl group, a trifluoromethyl group- a -C(=O)R ¹⁰ or -C(=O)OR ¹⁰ group; L ¹ represents a group selected from: -C ₁ -C ₄ alkylene-, -C(phenyl) (H) )-, -CH ₂ -CH ₂ -O-, -CH ₂ -C(=O)-N(H)-, -CH ₂ -C(=O)-N(R ^10a )-; L ² means From the following groups: -CH ₂ -, -CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -CH ₂ -; L ³ represents a -C ₁ -C ₄ alkyl-group; p is an integer 0 Or 1; the restriction is that at least one of R ¹ and R ² is different from isopropyl-, or a tautomer, stereoisomer, N-oxide, hydrate, solvate or salt thereof or Its mixture.

In a particularly preferred embodiment, the invention is directed to a compound of formula (I):

Wherein: R ¹ represents a C ₁ -C ₃ alkyl-, trifluoromethyl- or cyano- group; R ² represents a methyl-, ethyl- or trifluoromethyl- group; and R ³ represents a selected from a group of the following: phenyl- or 5- to 6-membered heteroaryl-; wherein the phenyl- or 5- to 6-membered heteroaryl-group is likewise the same as -(L ² ) _p -R ⁷ Or differently substituted one or more times; or R ³ represents the following groups Wherein * represents a point of attachment to the rest of the molecule; R ^4a represents a group selected from the group consisting of C ₁ -C ₃ alkyl-, fluoro-C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy -, C ₃ -C ₅ cycloalkyl, -C(=O)N(R ^10a )R ^10b , -SR ¹⁰ , -S(=O)-R ¹⁰ , -S(=NR ¹¹ )-R ¹⁰ , -S(=O) ₂ -R ¹⁰ , -S(=O) ₂ -N(R ^10a )R ^10b , -N(R ^10a )R ^10b ; R ^4b represents a hydrogen atom; R ^5a , R ^5b , R ^5c , R ^5d

Independently from each other, a hydrogen atom, a halogen atom or a group selected from the group consisting of cyano-, C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy-, -N(R ^10a )R ^10b ,- OR ¹⁰ ; R ⁶ represents a hydrogen atom; R ⁷ represents a group selected from C ₁ -C ₃ alkyl-, cyclopropyl-, trifluoromethyl-, C ₁ -C ₃ alkoxy-, three Fluoromethoxy-, -CN, fluoro-, chloro-, -C(=O)-C ₁ -C ₃ alkyl, -C(=O)N(R ^8a )R ^8b , -S(=O) ₂ )-C ₁ -C ₃ alkyl; R ^8a , R ^8b

Independently from each other, represents a hydrogen atom or a C ₁ -C ₆ alkyl-, C ₃ -C ₇ cycloalkyl-, 4 to 10 membered heterocycloalkyl-, (4 to 10 membered heterocycloalkyl)-( L ³ )-, phenyl-, heteroaryl-, phenyl-(L ³ )- or heteroaryl-(L ³ )- group; the C ₁ -C ₆ alkyl-, C ₃ -C ₇ Cycloalkyl-, 4 to 10 membered heterocycloalkyl-, (4 to 10 membered heterocycloalkyl)-(L ³ )-, phenyl-, heteroaryl-, phenyl-(L ³ ) And the heteroaryl-(L ³ )- group is optionally substituted one or more times by R ⁹ or R ^8a and R ^8b together with the nitrogen atom to which it is attached represents a 4 to 7 member heterocyclic ring Alkyl-group; R ⁹ represents a halogen atom or a C ₁ -C ₃ alkyl-, fluoro-C ₁ -C ₃ alkyl-, hydroxy-C ₁ -C ₃ alkyl-, -CN, -C (= O) R ¹⁰ , -C(=O)N(H)R ¹⁰ , -C(=O)N(R ^10a )R ^10b , -N(R ^10a )R ^10b , -N(H)C(=O R ¹⁰ , —N(R ^10a )C(=O)R ^10b , —OR ¹⁰ group; R ¹⁰ , R ^10a , R ^10b , R ^10c

Independently from each other, a hydrogen atom or a group selected from the group consisting of C ₁ -C ₃ alkyl-, hydroxy-C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl -; or R ^10a and R ^10b together with the nitrogen atom to which they are attached represent a 4- to 7-membered heterocycloalkyl- group; L ¹ represents a group selected from: -C ₁ -C ₄ alkyl--, -CH ₂ -CH ₂ -O-; L ² represents a group selected from the group consisting of -CH ₂ -, -CH ₂ -CH ₂ -; L ³ represents a -C ₁ -C ₄ alkyl-group; Is an integer of 0 or 1; or a tautomer, stereoisomer, N-oxide, hydrate, solvate or salt thereof or a mixture thereof.

In another particularly preferred embodiment, the invention is directed to a compound of formula (I):

Wherein: R ¹ represents a C ₁ -C ₃ alkyl-, trifluoromethyl- or cyano- group; R ² represents a methyl-, ethyl- or trifluoromethyl- group; R ³ represents optionally A phenyl-group substituted one or more times by a group selected from the group consisting of C ₁ -C ₃ alkyl-, trifluoromethyl-, cyanomethyl-, methoxymethyl -, C ₁ -C ₃ alkoxy-, trifluoromethoxy-, -CN, fluoro-, chloro-, -C(=O)-C ₁ -C ₃ alkyl, -C(=O)N (R ^8a ) R ^8b , —S(=O) ₂ —C ₁ —C ₃ alkyl; or R ³ represents, as the case may be, one or more substitutions of one or more members selected from the group selected below to 6-membered heteroaryl-group: C ₁ -C ₃ alkyl-, cyclopropyl-, C ₁ -C ₃ alkoxy-, -CN, -C(=O)N(R ^8a )R ^8b ; R ^4a represents a group selected from the group consisting of isopropyl-, trifluoromethyl-, methoxy-, cyclopropyl-, -C(=O)-NH ₂ ; R ^4b represents a hydrogen atom; R ^5a , R ^5c , R ^5d

Each other independently represents a hydrogen atom, a fluorine atom or a chlorine atom; R ^5b represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom or a group selected from the group consisting of cyano-, methyl-, methoxy-, -N (H)-CH ₂ -CH ₂ -OCH ₃ and N -piperidinyl-R ⁶ represent a hydrogen atom; R ^8a , R ^8b

Independently from each other, represents a hydrogen atom or a C ₁ -C ₄ alkyl-, C ₃ -C ₅ cycloalkyl-, 4 to 7 membered heterocycloalkyl-, (4 to 7 membered heterocycloalkyl)-( L ³ )-, phenyl- or heteroaryl-(L ³ )- group; C ₁ -C ₄ alkyl-, C ₃ -C ₅ cycloalkyl-, 4 to 7 membered heterocycloalkyl - (4 to 7 membered heterocycloalkyl)-(L ³ )-, phenyl- or heteroaryl-(L ³ )- group optionally substituted one or more times by R ⁹ or differently Or R ^8a and R ^8b together with the nitrogen atom to which they are attached represent a 4- to 7-membered heterocycloalkyl- group; R ⁹ represents a halogen atom or a C ₁ -C ₃ alkyl-, -CN, -C(= O) NH ₂ or -OH group; L ¹ represents a group selected from: -C ₁ -C ₂ alkyl-, -CH ₂ -CH ₂ -O-; L ³ represents -C ₁ -C ₃ An alkyl-group; or a tautomer, stereoisomer, N-oxide, hydrate, solvate or salt thereof or a mixture thereof.

In another particularly preferred embodiment, the invention is directed to a compound of formula (I):

Wherein: R ¹ represents a methyl- or trifluoromethyl- group; R ² represents a methyl-group; and R ³ represents one or more substitutions by a group selected from methoxy-, -CN, fluoro-; a phenyl-group, or R ³ represents a pyridyl- or pyrimidinyl- group substituted once with a group selected from methoxy-, -CN, or R ³ represents a C ₁ -C ₃ alkane a 5-membered heteroaryl-group substituted once with a group of a base-, cyclopropyl-, or -CN selected from the group consisting of isoxazolyl-, oxadiazolyl- and thienyl-; R ^4a represents -C ( =O)-NH ₂ group; R ^4b represents a hydrogen atom; R ^5a , R ^5b , R ^5c , R ^5d

Independently, each other represents a hydrogen atom, a fluorine atom or a chlorine atom; R ⁶ represents a hydrogen atom; and L ¹ represents a group selected from: -C ₁ -C ₂ alkylene-, -CH ₂ -CH ₂ -O-; Or a tautomer, stereoisomer, N-oxide, hydrate, solvate or salt thereof or a mixture thereof.

In another particularly preferred embodiment, the invention is directed to a compound of formula (I):

Wherein: R ¹ represents a methyl- or trifluoromethyl- group; R ² represents a methyl-group; and R ³ represents one or more substitutions by a group selected from methoxy-, -CN, fluoro-; a phenyl-group, or R ³ represents a pyridyl- or pyrimidinyl- group substituted once with a group selected from methoxy-, -CN; R ^4a represents -C(=O)-NH ₂ group R ^4b represents a hydrogen atom; R ^5a , R ^5b , R ^5c , R ^5d

Independently, each other represents a hydrogen atom, a fluorine atom or a chlorine atom; R ⁶ represents a hydrogen atom; L ¹ represents a -CH ₂ - group; or a tautomer, a stereoisomer, an N-oxide, a hydrate or a solvent thereof; a compound or a salt or a mixture thereof.

In another particularly preferred embodiment, the invention is directed to a compound of formula (I):

Wherein: R ¹ represents a methyl- or trifluoromethyl- group; R ² represents a methyl-group; and R ³ represents a substitution with a group selected from a C ₁ -C ₃ alkyl-, cyclopropyl- group; Isoxazolyl- group; R ^4a represents a -C(=O)-NH ₂ group; R ^4b represents a hydrogen atom; R ^5a , R ^5b , R ^5c , R ^5d

Independently, each other represents a hydrogen atom, a fluorine atom or a chlorine atom; R ⁶ represents a hydrogen atom; L ¹ represents a -CH ₂ - group; or a tautomer, a stereoisomer, an N-oxide, a hydrate or a solvent thereof; a compound or a salt or a mixture thereof.

According to another aspect, the invention encompasses methods of preparing the compounds of the invention, which comprise the steps as described in the experimental section herein.

In a preferred embodiment, the invention relates to a process for the preparation of a compound of the above formula (I), in which an intermediate compound of the formula (II) is obtained:

Wherein R ¹ , R ² , R ³ , R ⁶ and L ¹ are as defined above for the compound of formula (I); react with a compound of formula (III):

Wherein R ^4a , R ^4b , R ^5a , R ^5b , R ^5c and R ^5d are as defined above for the compound of formula (I); thereby obtaining a compound of formula (I):

Wherein R ¹ , R ² , R ³ , R ^4a , R ^4b , R ^5a , R ^5b , R ^5b , R ^5d , R ⁶ and L ¹ are as defined above for the compound of formula (I).

According to another aspect, the invention encompasses intermediate compounds suitable for use in preparing the compounds of formula (I) of the invention, especially in the manner described herein.

In particular, the invention encompasses compounds of the general formula (II):

Wherein R ¹ , R ² , R ³ , R ⁶ and L ¹ are as defined above for the compound of formula (I).

In another preferred embodiment, the invention encompasses intermediate compounds suitable for use in preparing the compounds of formula (I) of the invention, especially in the manner described herein.

In particular, the invention encompasses compounds of the general formula (III):

Wherein R ^4a , R ^4b , R ^5a , R ^5b , R ^5c and R ^5d are as defined above for the compound of formula (I).

According to another aspect, the invention encompasses the use of an intermediate compound of formula (II):

Wherein R ¹ , R ² , R ³ , R ⁶ and L ¹ are as defined above for the compound of formula (I); which is used for the preparation of a compound of formula (I) as defined above.

In another preferred embodiment, the invention encompasses the use of an intermediate compound of formula (III):

Wherein R ^4a , R ^4b , R ^5a , R ^5b , R ^5c and R ^5d are as defined above for the compound of formula (I); which are used for the preparation of a compound of formula (I) as defined above.

As is known to those skilled in the art, the above methods may further comprise, for example, the introduction of a protecting group and the step of cleavage of a protecting group.

The invention also relates to pharmaceutical compositions containing one or more compounds of the invention. Such compositions can be used to achieve the desired pharmacological effects by administering to a patient in need thereof. A patient for the purposes of the present invention is a mammal, including a human, in need of treatment for a particular condition or disease. Accordingly, the invention includes a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of the invention or a salt thereof. The pharmaceutically acceptable carrier is preferably a carrier which is relatively non-toxic and non-toxic to the patient at a concentration consistent with the effective activity of the active ingredient, such that any side effects attributable to the carrier do not impair the beneficial effects of the active ingredient. . The pharmaceutically effective amount of the compound is preferably an amount that produces an effect or exerts an effect on the particular condition being treated. The compounds of the present invention can be administered orally, parenterally, orally, in any effective conventional unit dosage form including immediate release, sustained release and extended release formulations, together with pharmaceutically acceptable carriers well known in the art. Transnasal, ophthalmically, transocular, sublingual, transrectal, transvaginal and the like.

The compounds of the invention may be administered in a single pharmaceutical form or in combination with one or more other pharmaceutical agents, wherein the combination does not cause unacceptable adverse effects. The invention also relates to such combinations. For example, the compounds of the invention may be combined with known anti-hyperproliferative or other indication agents and their analogs, as well as mixtures and combinations thereof. Other indications include, but are not limited to, anti-angiogenic agents, mitotic inhibitors, alkylating agents, antimetabolites, DNA-intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzyme inhibitors , topoisomerase inhibitors, biological response modifiers or anti-hormones.

Preferred additional agents are: 131I-chTNT, abarelix, abiraterone, aclarubicin, aldesleukin, ar Alemtuzumab, alitretinoin, altretamine, aminoglutethimide, amrubicin, amsacrine, anastrozole Anastrozole), arglabin, arsenic trioxide, asparaginase, azacitidine, basiliximab, BAY 80-6946, BAY 1000394, BAY 86- 9766 (RDEA 119), belopotecan, bendamustine, bevacizumab, bexarotene, bicalutamide, biotic group (bisantrene), bleomycin, bortezomib, buserelin, busulfan, cabazitaxel, calcium folinate, left Calcium levofolinate, capecitabine, carboplatin, carmofur, carmustine, catummaxomab, celecoxib , simmexin, cetuximab, chlorambucil, chlormadinone, nitrogen mustard (chlo Rmethine), cisplatin, cladribine, clodronate, clofarabine, crisantaspase, cyclophosphamide, cyproterone, cytarabine, dacarbazine (dacarbazine), dactinomycin, darbepoetin alfa, dasatinib, daunorubicin, decitabine, degarelix (degarelix), denileukin diftitox, denosumab, deslorelin, dibrospidium chloride, paclitaxel, deoxyfluorouridine, small Cockroach (doxorubicin), cranberry + estrone, eculizumab, edrecolomab, elliptinium acetate, eltrombopag, Endostatin, enocitabine, epirubicin, epitiostolol, epoetin alfa, epoetin beta, iriplatin Eptaplatin), eribulin, erlotinib (erlotinib), estradiol, estramustine, etoposide, everolimus, exemestane, fadrozole, filgrastim (filgrastim), fludarabine, fluorouracil, flutamide, formestane, fotemustine, fulvestrant, gallium nitrate Gallium nitrate), ganirelix, gefitinib, gemcitabine, gemtuzumab, glutathione, goserelin ), histamine dihydrochloride, histrine, hydroxyurea, I-125 seed, ibandronic acid, ibritumomab, idarubicin ), ifosfamide, imatinib, imiquimod, improsulfan, interferon alpha, interferon beta, interferon gamma, ipilimumab , irinotecan, ixabepilone, lanreotide, lapatinib, lenalidomide (len Alidomride), lenograstim, lentinan, letrozole, leuprorelin, levamisole, lisuride, lobaplatin ), lomustine, lonidamine, masoprocol, medroxyprogesterone, megestrol, melphalan, mesalamine (mepitiostane), mercaptopurine, methotrexate, methoxsalen, methyl methacrylate, methyltestosterone, mifamurtide, milta Miltefosine, miriplatin, mitobronitol, mitoguazone, mitolacol, mitomycin, mitotan , mitoxantrone, nedaplatin, nelarabine, nilotinib, nilutamide, nimotuzumab, nimo Nistinine, nitracrine, Austria Fauna monoclonal antibody (ofatumumab), omeprazole, oprelvekin, oxaliplatin, p53 gene therapy, paclitaxel, palifermin, palladium 103 seed crystals, pamidronic acid, panitumumab, pazopanib, pegaspargase, PEG-beta epoxide (methoxy PEG- Betacitabine), pegfilgrastim, pegylated interferon alpha-2b, pemetrexed, pentazocine, pentostatin, Peplomycin, perfosfamide, picibanil, pirarubicin, plerixafor, plicamycin, polyamine Poligosam, estradiol polyphosphate, polysaccharide-K, porfimer sodium, pralatrexate, prednimustine, procarbazine, quinine Quinagolide, raloxifene, raltitrexed, ranimustine, razoxane, rui Regorafenib, risedronic acid, rituximab, romidepsin, romiposttim, sargramostim, west Sipuleucel-T, sizofiran, sobuzoxane, sodium glycididazole, sorafenib, streptozocin ), sunitinib, talaporfin, tamibarotene, tamoxifen, tasonermin, teceleukin ), tefflurol (tegafur), fluridine + gimeracil + oteracil, temoporfin, temozolomide, temsirolimus , teniposide, testosterone, tetrofosmin, thalidomide, thiotepa, thymalfasin, tioguanine, tobuzane Anti (tocilizumab), topotecan, toremifene, tositumomab, trobectedin, orcoto Bep monoclonal antibody (trastuzumab), treosulfan, retinoic acid, trilostane, triptorelin, trofosfamide, tryptophan, umbramide (ubenimex), valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, vincristine, vindesine, vinca Vinflunine, vinorelbine, vorinostat, vorozole, 钇-90 glass microspheres, zinostatin, net statin ( Zinostatin stimalamer), zoledronic acid, zorubicin.

An anti-hyper-proliferative agent that may be added to the composition as appropriate includes, but is not limited to, the Cancer Chemotherapy Drug Program in the Merck Index, (1996) 11th Edition, which is incorporated herein by reference. Listed compounds, such as aspartate, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, Dacarbazine, dactinomycin, daunorubicin, cranberry (adriamycine), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, Isocyclophosphamide, irinotecan, formazan tetrahydrofolate, lomustine, dichloromethyldiethylamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine, raloxifene, streptozotocin, tamoxifen, thioguanine, topotecan, vinblastine, Changchun new Alkali and vindesine.

Other anti-hyperproliferative agents suitable for use in the compositions of the present invention include, but are not limited to, Goodman and Gilman's The Pharmacological Basis of Therapeutics (ninth edition), edited by Molinoff et al., published by McGraw-Hill, pp. 1225-1287, ( 1996), which is incorporated herein by reference, for its use in the treatment of the compounds of the genital disease, such as the amine luminide, L-aspartate, azathioprine, 5-aza Clavulabine, busulfan, diethylstilbestrol, 2',2'-difluorodeoxycytidine, taxol, erythrohydroxy adenine, ethinyl estradiol, 5-fluorodeoxyuridine, 5-fluoro Deoxyuridine Monophosphate, fludarabine phosphate, fluoromethylol testosterone, flutamide, hydroxyprogesterone caproate, idamycin, interferon, medroxyprogesterone acetate, acetate A Progesterone, melphalan, mitoxantrone, paclitaxel, pentastatin, N-phosphonium-L-aspartate (PALA), pucamycin, semustine, tilivin Bovine, propionate, thiotepa, trimethyl melamine, uridine and vinorelbine.

Other anti-hyperproliferative agents suitable for use in the compositions of the present invention include, but are not limited to, other anticancer agents such as epothilone and its derivatives, irinotecan, raloxifene, and topotecan.

The compounds of the invention may also be administered in combination with a protein therapeutic. Such protein therapeutics suitable for treating cancer or other angiogenic disorders and suitable for use in the compositions of the invention include, but are not limited to, interferons (e.g., interferon alpha, interferon beta or interferon gamma), super-efficiency single plants Antibody, Tuebingen, TRP-1 protein vaccine, colostatin, anti-FAP antibody, YH-16, gemtuzumab, infliximab, cetuximab, orroche Chemuzumab, dinisin, rituximab, thymosin alpha 1, bevacizumab, mecasermin, mecasermin rinfabate, oprising White pigment, natalizumab, rhMBL, MFE-CP1+ZD-2767-P, ABT-828, ErbB2-specific immunotoxin, SGN-35, MT-103, Lin Feipei, AS-1402, B43-genistein (B43-genistein), L-19-based radioimmunotherapy, AC-9301, NY-ESO-1 vaccine, IMC-1C11, CT-322, rhCC10, r(m)CRP, MORAb-009 , aviscurin (aviscumine), MDX-1307, Her-2 vaccine, APC-8024, NGR-hTNF, rhH1.3, IGN-311, endostatin, volociximab, PRO-1762 , come to sandimumab (lexatu Mumab), SGN-40, pertuzumab, EMD-273063, L19-IL-2 fusion protein, PRX-321, CNTO-328, MDX-214, tigapotide, CAT- 3888, labetuzumab, radioisotope-linked alpha-particles Alpha-particle-emitting radioisotope-linked lintuzumab, EM-1421, HyperAcute vaccine, tucuzuzumab celmoleukin, and glipizumab ( Galiximab), HPV-16-E7, Javelin-prostate cancer, Javelin-melanoma, NY-ESO-1 vaccine, EGF vaccine, CYT-004-MelQbG10, WT1 Peptide, orgoviromab, ovalimumab, zalutumumab, cintredekin besudotox, WX-G250, albumin interferon (Albuferon), Abelibercept, denosumab, vaccine, CTP-37, efungumab or 131I-chTNT-1/B. Monoclonal antibodies suitable for use as protein therapeutics include, but are not limited to, momomona-CD3 (muromonab-CD3), abciximab, edrezumab, daclizumab, true Gentuzumab, alemtuzumab, temimumab, cetuximab, bevivizumab, efalizumab, adalimumab, oma Olimizumab, muramomab-CD3, rituximab, daclizumab, trastuzumab, palivizumab, paclitaxel Resistant to infliximab.

In general, the use of a cytotoxic agent and/or a cytostatic agent in combination with a compound or composition of the invention can be used to: (1) reduce tumor growth or even eliminate tumors as compared to administration of only any one agent Produce better efficacy; (2) provide a smaller dose of administered chemotherapeutic agent; (3) provide chemotherapeutic treatment with complications compared to single-agent chemotherapy and some other combination therapies Less tolerant pharmacological complications that are well tolerated by patients; (4) to provide treatment for a wide range of different cancer types in mammals, especially humans; (5) providing a higher response rate in the patient being treated; (6) providing a longer survival time than the standard chemotherapy treatment in the patient being treated; (7) providing a longer tumor progression time, and/or ( 8) Producing at least as good efficacy and tolerability results as those of the other agents used alone in combination with other cancer agents to produce an antagonistic effect.

Surprisingly, it has been found that a compound of formula (I) above and as defined herein effectively and selectively inhibits GLUT1 and is therefore useful for treating and/or preventing uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses. Or a disease in which the cell is inflammatory, or a disease associated with uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response, or inappropriate cell inflammatory response, such as hematological tumors, solid tumors, and/or metastases thereof, such as leukemia and myeloid development. Adverse syndromes; malignant lymphoma; head and neck tumors, including brain tumors and brain metastases; chest tumors, including non-small cell lung tumors and small cell lung tumors; gastrointestinal tumors; endocrine tumors; breast tumors and other gynecologic tumors; Kidney tumor, bladder tumor and prostate tumor; skin tumor; and sarcoma; and/or its metastasis.

Thus according to another aspect, the invention encompasses a compound of formula (I), or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, as described and defined herein, especially A pharmaceutically acceptable salt thereof, or a mixture of such substances, for use in the treatment or prevention of a disease as mentioned above.

Thus, another particular aspect of the invention is a compound of formula (I) as described above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, especially A pharmaceutically acceptable salt, or a use of a mixture of such substances, for the prevention or treatment of a disease.

Another particular aspect of the invention is the use of a compound of the above formula (I) for the manufacture of a pharmaceutical composition for the treatment or prevention of a disease.

The compounds of the invention are especially useful for the treatment and prevention (ie prevention) of tumor growth and transformation Move, especially with or without any indications and stages of tumor growth pretreatment.

Test methods for specific pharmacological or pharmaceutical properties are well known to those skilled in the art.

The present invention relates to a method of treating a hyperproliferative disorder in a mammal using the compounds of the invention and compositions thereof. The compounds are useful for inhibiting, blocking, reducing, reducing, etc., and/or producing apoptosis of cell proliferation and/or cell division. The method comprises administering to a mammal, including a human, in need thereof, a compound of the invention or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate thereof, in an amount effective to treat the condition , solvates or esters, and the like. Hyperproliferative disorders include, but are not limited to, for example, psoriasis, keloids, and other hyperproliferation affecting the skin; benign prostatic hyperplasia (BPH); solid tumors such as breast cancer, respiratory cancer, brain cancer, genital cancer, digestive tract cancer, Urinary tract cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, thyroid cancer, parathyroid cancer and distant metastatic cancer. These conditions also include lymphoma, sarcoma and leukemia.

Examples of breast cancer include, but are not limited to, invasive breast ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.

Examples of respiratory cancer include, but are not limited to, small cell lung cancer and non-small cell lung cancer, as well as bronchial adenomas and pleural pulmonary blastomas.

Examples of brain cancer include, but are not limited to, brainstem and hypothalamic gliomas, cerebellum and cerebral astrocytoma, chorioblastoma, ependymoma, and neuroectoderm and pineal tumors.

Male reproductive organ tumors include, but are not limited to, prostate cancer and testicular cancer. Tumors of the female reproductive organs include, but are not limited to, endometrial cancer, cervical cancer, ovarian cancer, vaginal cancer and vulvar cancer, and uterine sarcoma.

Gastrointestinal tumors include, but are not limited to, anal cancer, colon cancer, colorectal cancer, esophageal cancer, gallbladder cancer, gastric cancer, pancreatic cancer, rectal cancer, small bowel cancer, and salivary gland cancer.

Urinary tract tumors include, but are not limited to, bladder cancer, penile cancer, kidney cancer, renal pelvic cancer, ureteral cancer, urethral cancer, and human papillary renal cancer.

Eye cancer includes, but is not limited to, intraocular melanoma and retinoblastoma.

Examples of liver cancer include, but are not limited to, hepatocellular carcinoma (hepatocellular carcinoma with or without fibrolamellar variation), cholangiocarcinoma (intrahepatic cholangiocarcinoma), and mixed hepatocyte cholangiocarcinoma.

Skin cancers include, but are not limited to, squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.

Head and neck cancer includes, but is not limited to, laryngeal cancer, hypopharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer, lip and oral cancer, and squamous cell carcinoma. Lymphomas include, but are not limited to, AIDS-associated lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin's disease ( Hodgkin's disease) and lymphoma of the central nervous system.

Sarcomas include, but are not limited to, soft tissue sarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.

Leukemias include, but are not limited to, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.

Such conditions are well characterized in humans and are also present in similar pathogens in other mammals and can be treated by administering the pharmaceutical compositions of the invention.

The term "treating" or "treatment" as used throughout the text is used in a conventional sense, such as managing or caring for an individual to achieve resistance, alleviation, reduction, amelioration, amelioration of a disease or condition (such as cancer). The purpose of the disease, etc.

Based on standard laboratory techniques known for assessing compounds useful in the treatment of hyperproliferative disorders and angiogenic disorders, by standard toxicity testing and by standards for the treatment of conditions identified above for mammals Pharmacological analysis, and by comparison of the results of such results with known agents for treating such conditions, can readily determine the effective dosage of a compound of the invention for treating various contemplated indications. The amount of active ingredient administered to treat any of these conditions can vary greatly depending on, for example, the following considerations: The particular compound and dosage unit, mode of administration, course of treatment, age and sex of the patient being treated, and the nature and extent of the condition being treated.

The total amount of the active ingredient to be administered is generally in the range of from about 0.001 mg to about 200 mg per kg of body weight per day, and preferably from about 0.01 mg to about 20 mg per kg of body weight per day. Clinically useful dosing schedules range from one to three times a day to once every four weeks. In addition, "drug holidays" (wherein not administered to a patient for a certain period of time) may be beneficial to the overall balance between pharmacological effects and tolerance. A unit dose may contain from about 0.5 mg to about 1500 mg of active ingredient and may be administered one or more times a day or less than once a day. The average daily dose administered by injection (including intravenous, intramuscular, subcutaneous and parenteral injection) and by infusion techniques is preferably from 0.01 to 200 mg per kg of total body weight. The average daily rectal dosage regimen is preferably from 0.01 to 200 mg per kg of total body weight. The average daily vaginal dosage regimen is preferably from 0.01 to 200 mg per kg of total body weight. The average daily topical dosage regimen is preferably from 0.1 to 200 mg, and the number of administrations per day is between one and four times. The transdermal concentration is preferably a concentration required to maintain a daily dose of 0.01 to 200 mg/kg. The average daily inhaled dosage regimen is preferably from 0.01 to 100 mg per kg of total weight.

Of course, the specific initial and continuous dosing regimen for each patient will be based on the nature and severity of the condition as determined by the attending physician, the activity of the particular compound employed, the age and general condition of the patient, the time of administration, the route of administration, and the excretion of the drug. The rate, the drug combination, and the like vary. The number of doses of the desired mode of treatment and the compound of the invention or a pharmaceutically acceptable salt or ester or composition thereof can be determined by those skilled in the art using conventional therapeutic tests.

General Synthesis of the Compounds of the General Formula (I) of the Invention

The following paragraphs outline various synthetic methods suitable for the preparation of the compounds of formula (I) and intermediates suitable for their synthesis.

In addition to the routes described below, other routes can be used to synthesize the target compound according to the common knowledge of those skilled in the art of organic synthesis. Thus, the order in which the transformations are illustrated in the following schemes is not intended to be limiting, and suitable synthetic steps from the various schemes can be combined to form additional synthetic sequences. Further, any one of the substituents (in detail, R ¹ , R ² , R ^4a , R ^4b , R ^5a , R ^5b , R ^5c , R ^5d or R ⁶ and via -(L ² ) _p - The interconversion of the R ⁷ group of R ³ can be achieved before and/or after the exemplified conversion. Such modifications may be, for example, introduction of a protecting group, cleavage of a protecting group, reduction or oxidation of a functional group, halogenation, metallation, metal catalyzed coupling reaction (by (but not limited to) Suzuki, Sungogashira And exemplified by Ullmann couplings, ester saponification, guanamine coupling reactions and/or substitution or other reactions known to those skilled in the art. Such conversions include the introduction of a conversion that allows for further interconversion of the substituents. Suitable protecting groups, as well as their introduction and cleavage, are well known to those skilled in the art (see, for example, TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, 3rd edition, Wiley 1999).

Specific examples of such interconversions are described in subsequent paragraphs. Illustratively reference to several specific schemes in the experimental section below, for example for converting R ^5b = bromine to a secondary amine (intermediate 55A); converting R ^5d and R ^5b = bromine to a cyano group - (Examples 102, 103 And converting R ^5b = bromine to phenyl- (Example 166) or by means of a palladium-catalyzed coupling reaction to -C(=O)-OCH ₃ (Example 149); R ⁷ =-C(=O -OCH _{3 is} converted to the corresponding carboxylic acid and converted to a plurality of formamide derivatives by ester hydrolysis followed by methopamide coupling, for example as described in Examples 131 to 143; by means of a Grignard reagent ( Grignard reagent), converting R ^4a = bromine to R ^4a = ethyl (Example 69); and converting R ⁷ = cyano- to a tetrazolyl- group (Example 400). Moreover, as is well known to those skilled in the art, it is possible to perform two or more consecutive steps without performing a process between such steps, such as a "one pot" reaction.

The compound of the formula (I) can be derived from the 4-aminopyrazole derivative of the formula (II) according to Scheme 1, by means of a methotrexate (or peptide) coupling reaction well known to those skilled in the art (wherein R ¹ , R ² , R ³ , R ⁶ and L ^{1 are} as defined for the compound of the formula (I) and a quinoline-4-carboxylic acid derivative of the formula (III) (wherein R ^4a , R ^4b , R ^5a , R ^5b , R ^5c and ^R5d are assembled as defined for the compound of formula (I). The coupling reaction can be carried out by reacting a compound of formula (II) and formula (III) in the presence of a suitable coupling reagent such as HATU (O-(7-azabenzotriazol-1-yl) -N,N, N', N' - four ), TBTU (tetrafluoroboric acid O-(benzotriazol-1-yl) -N,N,N',N' -four ), PyBOP (benzotriazol hexafluoro-1-yl-oxytripyrrolidinyl) or EDC (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride In the case of a salt) and HOBt (1-hydroxy-1H-benzotriazole hydrate)), in the presence of a base such as an aliphatic or aromatic tertiary amine, preferably a formula N (C ₁ -C ₄ -alkane) yl) three of the aliphatic amine ₃₎ of the case, the reaction is performed in a suitable solvent.

Preferably, O-(benzotriazol-1-yl) -N , N , N ', N' -tetramethyltetrafluoroborate is used herein. (TBTU) as a coupling agent, in the presence of N,N -diisopropylethylamine as a base, and in a solvent of tetrahydrofuran, the mesaconamine coupling reaction is carried out at a temperature ranging from 0 ° C to 50 ° C .

It is also preferred herein to use O- (7-azabenzotriazol-1-yl) -N,N,N',N' -tetramethyl hexafluorophosphate. (HATU) as a coupling agent, in the presence of N,N -diisopropylethylamine as a base, and in a dimethyl hydrazine as a solvent, the formamidine is carried out at a temperature ranging from 0 ° C to 50 ° C Amine coupling reaction.

Also preferred herein is benzotriazol-1-yl-oxytripyrrolidinyl ruthenium (PyBOP) as a coupling agent, in the presence of N,N -diisopropylethylamine as a base, Further, the formamide coupling reaction is carried out in a temperature range of 0 ° C to 50 ° C in tetrahydrofuran as a solvent.

Also known to those skilled in the art are 4-aminopyrazole derivatives of formula (II) wherein R ¹ , R ² , R ³ , R ⁶ and L ^{1 are} as defined for the compound of formula (I) And a quinoline-4-carboxylic acid derivative of the formula (III) wherein R ^4a , R ^4b , R ^5a , R ^5b , R ^5c and R ^{5d are} as defined for the compound of the formula (I) Converting a carboxylic acid of formula (III) to the corresponding mercapto halide, for example by reaction with a halogenating agent such as sulfinium chloride, ethylene dichloride or phosphonium chloride, and subsequently using the formula (II) The 4-aminopyrazole derivative is obtained by an amine solution.

Scheme 1: Preparation of a compound of the formula (I) from a 4-aminopyrazole derivative of the formula (II) and a carboxylic acid of the formula (III).

The 4-amino(II)-aminopyrazole intermediate and the quinazoline-4-carboxylic acid derivative of the formula (III) can be used according to the synthesis method described in more detail in the schemes 3, 4 and 5 shown below. preparation. Certain quinazoline-4-carboxylic acids are also commercially available in a number of structural diversity.

If the aminopyrazole derivative of the formula (II) (wherein R ⁶ represents a hydrogen atom) has been used in the meglumine coupling reaction as described above, it is also possible to use the base after the methiamine coupling reaction ( Such as an alkali metal hydride, preferably sodium hydride, the resulting compound of formula (Ia) wherein R ¹ , R ² , R ³ , R ^4a , R ^4b , R ^5a , R ^5b , R ^5c , R ^5d and L ¹ deprotonated as defined for the compound of formula (I), followed by a compound of formula (IV) wherein LG represents a leaving group, preferably chlorine, bromine or iodine, and wherein R ^{6 is} as defined for formula (I) The reaction of a compound, but different from hydrogen, to give a compound of formula (Ib), introducing an R ⁶ group other than hydrogen, as outlined in Scheme 2.

Scheme 2: Preparation of a compound of formula (Ib) from a compound of formula (Ia).

Compounds of formula (IV) are well known to those skilled in the art and are readily commercially available.

The intermediate 4-aminopyrazole derivative of the formula (II) can be obtained, for example, by the 4-nitropyrazole derivative of the formula (V) wherein R ¹ and R ^{2 are} as defined in the formula (I) a compound as defined in the formula (VI) wherein R ³ and L ^{1 are} as defined for the compound of formula (I) and wherein LG represents a leaving group, preferably chlorine, bromine or iodine, in the presence of a suitable base ( The reaction is carried out in the case of, for example, an alkali metal carbonate, preferably cesium carbonate, to give an N- 1-substituted nitropyrazole intermediate of the formula (VII). As another suitable base, 1,8-diazabicyclo (5.4.0) undec-7-ene can be used to carry out the alkylation reaction. Alternatively, the nitro group can be introduced after substituting the above-mentioned -L ¹ -R ³ for the pyrazole N -1; for this reverse synthetic route, see, for example, the scheme for the preparation of the intermediate 30B described in the experimental section below.

In the case where R ¹ and R ² are different from each other, the nitropyrazole intermediate of the formula (VII) is formed as a mixture of the isomers due to the tautomerism peculiar to the pyrazole core. The mixtures can be separated into the pure isomers by a method known to those skilled in the art, such as, for example, by gel column chromatography or by preparative HPLC, immediately after the reaction or at a later or final stage.

The compound of formula (VII) can then be reduced using a reduction method well known to those skilled in the art to provide a monoamine of formula (IIa). Such reduction methods encompass the use of palladium catalyzed hydrogenation; use of elemental hydrogen or an alternative source of hydrogen such as ammonium formate; and the use of zinc powder or powdered iron in the presence of acetic acid; or the use of tin chloride in ethanol as a solvent (II). If the acceptor contains a functional group susceptible to catalytic hydrogenation, such as cyano-, bromo or chloro, in particular if attached to an aromatic ring, the latter reagent is preferred.

Scheme 3: Preparation of the aminopyrazole of formula (IIa) from a compound of formula (V).

4-Nitropyrazoles of formula (V) are well known to those skilled in the art (see, for example, ethyl 3-methyl-4-nitro-1H-pyrazole-5-carboxylate see Journal of Organic Chemistry 1956 , Page 833; 3-methyl-4-nitro-1H-pyrazole-5-carbonitrile See Journal of Heterocyclic Chemistry 1970 , page 863; 3-methyl-4-nitro-1H-pyrazole-5 -carbamamine see Journal of Organic Chemistry 1956 , page 833 or US4282361 (1981); N ,3-dimethyl-4-nitro-1H-pyrazole-5-carboxamide See Chinese Chemical Letters 2012 , 669 pages; N,N ,3-trimethyl-4-nitro-1H-pyrazole-5-carbamamine see DE 1945430 (1968)) and in some cases are also commercially available (eg Fluorochem, Matrix, 3-methyl-4-nitro-1H-pyrazole-5-carboxylic acid ethyl ester of Oakwood; 3,5-dimethyl-4-nitro-1H-pyrazole of ABCR; ABCR, Fluorochem, Matrix 5 -Methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazole). In general, a nitro group can be introduced into a C-4-deficient pyrazole derivative by treatment of a 3,4-disubstituted pyrazole with sulfuric acid and nitric acid (see, for example, Intermediate 1D-5D) to give Formula (V) ) 4-nitropyrazole.

The R ⁶ group other than hydrogen may be introduced later as outlined in Scheme 2, or it may be introduced into the primary amine by means of a reductive amination reaction well known to those skilled in the art, for example by the formula (IIa) The primary amine is reacted with a suitable aldehyde or ketone and then reduced, for example, with sodium cyanoborohydride.

The quinoline-4-carboxylic acid derivative of the formula (III), if not commercially available, can be obtained from the indole-2,3-dione precursor of the formula (VIII) by the following means (see, for example, Monatshefte für Chemie 2013 , 391 pages; Chinese Chemical Letters 2010 , p. 35; The Pfitzinger Reaction. (Review), Chemistry of Heterocyclic Compounds , Vol. 40 ( 2004 ), No. 3, p. 257) (where R ^5a , R ^5b , R ^5c And R ^5d are readily prepared as defined for the compound of formula (I): with a carbonyl compound of formula (IX) wherein R ^4a and R ^{4b are} as defined for the compound of formula (I), for example, comprising sodium hydroxide, In an aqueous buffered solvent of sodium acetate, acetic acid and water, the reaction is carried out at elevated temperature to give the compound of formula (III) directly as outlined in Scheme 4.

Scheme 4: Preparation of quinoline-4-carboxylic acid derivatives of formula (III) from hydrazine-2,3-dione of formula (VIII).

The indole-2,3-dione of formula (VIII) is well known to those skilled in the art and is commercially available or can be obtained, for example, by Chinese Chemical Letters , 2013 , page 929; J. Med. Chem. 2006 . , prepared by the method described on page 4638. The carbonyl compounds of formula (IX) are commercially available in a wide variety of structural diversity.

The chemical reactivity of the group R ^4a present in the compound of formula (III) can be adjusted by the adjacent ring nitrogen atom, allowing chemoselective manipulation of R ^4a . This can be illustrated by, but not limited to, by the synthesis of a small class of such quinoline-4-carboxylic acid derivatives as described in formula (IIId), wherein R ^{4a is} represented as a group -C(=O) N(R ^10a )R ^10b , as outlined in Scheme 5. The diacid of formula (IIIa) can be obtained, for example, by reacting pyruvic acid with the indole-2,3-dione of formula (V) according to Scheme 4, by using methods well known to those skilled in the art. for example, by reaction with thionyl acyl chloride, followed by the formula C ₁ -C ₃ alkyl group -OH aliphatic alcohol, the preferred solvent is methanol decomposition, the carboxyl group into an acyl halide, and readily converted to the formula The respective diesters of (IIIb), wherein R ^4b , R ^5a , R ^5b , R ^5c and R ^{5d are} as defined for the compound of formula (I), and wherein R ^E represents C ₁ -C ₃ alkyl-. The resulting diester of formula (IIIb) is then reacted with an amine of formula (X) wherein R ^10a and R ^{10b are} as defined for the compound of formula (I), thereby obtaining a monodecylamine of formula (IIIc), which is subsequently borrowed those skilled in the art by a known method, the aqueous preferred by the formula C ₁ -C ₃ alkyl group -OH of the aliphatic alcohol in the alkali metal hydroxide is subjected to ester hydrolysis to give formula (IIId) of quinoline 4-carboxylic acid derivative. The sequence in which the scheme for the preparation of Intermediate 2A is described in the following experimental section constitutes an inspiring example of this reaction sequence.

Scheme 5: Chemoselective modification of a R ^4a group in a small class of quinoline-4-carboxylic acid derivatives of formula (III).

The compounds of the general formula (I) are particularly suitable for use in the preparation of alternative synthesis methods by the introduction of such -L ¹ -R ³ moieties in the later stages or for the various derivatives having different -L ¹ -R ³ moieties. 6 in. a 4-aminopyrazole of the formula (X) wherein R ¹ , R ² and R ^{6 are} as defined for the compound of the formula (I) and a quinoline-4-carboxylic acid derivative of the formula (III) (wherein R ^4a , R ^4b , R ^5a , R ^5b , R ^5c and R ^{5d ,} as defined for the compound of formula (I), undergo a methotrexate (or peptide) coupling reaction well known to those skilled in the art, as described above with respect to the scheme 1 is discussed to provide an intermediate compound of formula (XI). The coupling reactions can be carried out by the presence of a suitable coupling reagent (such as HATU (O-(7-azabenzotriazol-1-yl) -N,N ) in the presence of a compound of formula (X) and formula (III) . N', N' - four ), TBTU (tetrafluoroboric acid O- (benzotriazol-1-yl) -N,N,N',N' -four ), PyBOP (benzotriazol hexafluoro-1-yl-oxytripyrrolidinyl) or EDC (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride In the case of a salt) and HOBt (1-hydroxy-1H-benzotriazole hydrate)), in the presence of a base such as an aliphatic or aromatic tertiary amine, preferably a formula N (C ₁ -C ₄ -alkane) yl) three of the aliphatic amine ₃₎ of the case, the reaction is performed in a suitable solvent.

The participation of the pyrazole ring NH in the mesaconamine coupling reaction can result in the formation of an intermediate compound of formula (XI) in the form of a para-isomeric mixture with the corresponding N1 decylamine. This can be learned by this Separation techniques well known to those skilled in the art, such as preparative HPLC, are removed immediately after coupling, or preferably after conversion to the compound of formula (I).

The intermediate compound of the formula (XI) can be obtained by a compound of the formula (VI) wherein R ³ and L ^{1 are} as defined for the compound of the formula (I) and wherein LG represents a leaving group, preferably chlorine, bromine or iodine. In the presence of a suitable inorganic base (such as an alkali metal carbonate, preferably cesium carbonate; or an alkali metal hydride such as sodium hydride) or an organic base (such as potassium third butoxide or 1,8-diazabicyclo[5.4] The reaction in the case of .0]undec-7-ene) is converted to the compound of the formula (I).

The 4-aminopyrazoles of formula (X) are well known to those skilled in the art and in many cases are commercially available.

Scheme 6: Preparation of a compound of the formula (I) from a 4-aminopyrazole derivative of the formula (X) and a carboxylic acid of the formula (III). abbreviation

The characteristic retention time and mass spectrum were determined by analyzing and characterizing the examples by the following analytical methods:

Method 1: UPLC (ACN-HCOOH)

Instrument: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEH C18 1.7 50 x 2.1 mm; Eluent A: Water + 0.1% formic acid, Eluent B: Acetonitrile; Gradient: 0-1.6 min 1-99% B , 1.6-2.0 min 99% B; flow rate 0.8 mL/min; temperature: 60 ° C; injection: 2 μL; DAD scan: 210-400 nm; ELSD

Method 2: UPLC (ACN-NH ₃ )

Instrument: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEH C18 1.7 50 x 2.1 mm; Eluent A: Water + 0.2% ammonia, Eluent B: Acetonitrile; Gradient: 0-1.6 min 1-99% B , 1.6-2.0 min 99% B; flow rate 0.8 mL/min; temperature: 60 ° C; injection: 2 μL; DAD scan: 210-400 nm; ELSD

Method 3: System: Waters automated purification system: pump 2545, sample manager 2767, CFO, DAD 2996, ELSD 2424, SQD; column: XBrigde C18 5 μm 100 x 30 mm; solvent: A = H2O + 0.1 vol% formic acid (99 %), B = acetonitrile; gradient: 0-8 min 10-100% B, 8-10 min 100% B; flow rate: 50 mL/min; temperature: room temperature; solution: up to 250 mg / up to 2.5 mL DMSO or DMF; 1 x 2.5 mL; detection: DAD scan range 210-400 nm; MS ESI+, ESI-, scan range 160-1000 m/z.

Method 4: System: Waters automated purification system: pump 2545, sample manager 2767, CFO, DAD 2996, ELSD 2424, SQD; column: XBrigde C18 5 μm 100 x 30 mm; solvent: A = H2O + 0.1 vol% ammonia (99 %), B = acetonitrile; gradient: 0-8 min 10-100% B, 8-10 min 100% B; flow rate: 50 mL/min; temperature: room temperature; solution: up to 250 mg / up to 2.5 mL DMSO or DMF; 1 x 2.5 mL; detection: DAD scan range 210-400 nm; MS ESI+, ESI-, scan range 160-1000 m/z.

Method 5: (Preparative HPLC) System: Labomatic; Pump: HD-5000; Dissolve Collector: LABOCOL Vario-4000; UV Detector: Knauer UVD 2.1S; Column: Chromatorex C18 10 μm 125 x 30 mm; Solvent: A = water + 0.1 vol% formic acid (99%), B = acetonitrile; flow rate: 150 mL / min; temperature: room temperature; solution: up to 250 mg / 2 mL DMSO; injection: 2 × 2 mL; detection: UV 218 nm; SCPA PrepCon5. Based on the residence time in the analytical UPLC, the following gradient was used for preparative HPLC: Gradient 5a: 0-15 min 1-25% B (Rt(min): 0-0.54)

Gradient 5b: 0-15min 10-50% B(Rt(min): 0.54-0.80)

Gradient 5c: 0-15min 15-55% B(Rt(min): 0.80-1.10)

Gradient 5d: 0-15min 30-70% B (Rt (min): 1.10 - 1.35)

Gradient 5e: 0-15min 40-80% B(Rt(min): 1.35-1.42)

Gradient 5f: 0-15min 65-100% B (Rt (min): 1.42-2.00)

Method 6: Waters automated purification system: pump 2545, sample manager 2767, CFO, DAD 2996, ELSD 2424, SQD; column: XBrigde C18 5 μm 100 x 30 mm; solvent: A = water + 0.1 vol% formic acid (99%) , B = acetonitrile; gradient: 0-8min 50-90% B, 8-10min 100% B; flow rate: 50mL / min; temperature: room temperature; solution: up to 250mg / up to 2.5mL DMSO or DMF; injection: 4 × 0.7 mL; detection: DAD scan range 210-400 nm; MS ESI+, ESI-, scan range 160-1000 m/z.

Method 7: System: Agilent: Prep 1200, 2×Prep pump, DLA, MWD, Prep FC; column: Chiralpak IA 5 μm 250×30 mm; solvent: methanol/ethanol 50:50 (v/v); flow rate: 40 mL/ Min; temperature: room temperature; detection: UV 254nm

Method 8: System: Sepiatec: Prep SFC100; Column: Chiralpak IC 5 μm 250×20 mm; Solvent: CO 2 /ethanol + 0.4% DEA 8/2; Flow rate: 80 mL/min; Temperature: 40 ° C; Detection: UV 254 nm

Method 9: System: Agilent: Prep 1200, 2×Prep pump, DLA, MWD, Prep FC; column: Chiralpak ID 5 μm 250×30 mm; solvent: hexane/2-propanol 70:30 (v/v); Flow rate: 50 mL/min; temperature: room temperature; detection: UV 254 nm

Method 10: System: Agilent: Prep 1200, 2 x Prep pump, DLA, MWD, Gilson: liquid handler 215; column: Chiralpak IC 5 μm 250 x 30 mm; solvent: ACN/ethanol 90: 10 (v/v); Flow rate: 50 mL/min; temperature: room temperature; detection: UV 220 nm

Method 11: System: Waters Acquity UPLC-MS: Binary Solvent Manager, Sample Manager/Processor, Column Manager, PDA, ELSD, SQD 3001; Column: YMC-Triart C18, 50mm x 2.0mm, 1.9 Mm; Solvent: A = H2O + 0.1% by volume of formic acid (99%), B = acetonitrile; Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; Flow rate: 0.8 mL/min; Temperature: 60 ° C; detection: DAD scan range 210-400 nm -> peak table; method: MS ESI +, ESI-conversion -> possible multiple scan ranges

Performing column chromatography on Biotage® Isolera ^TM Spektra four flash purification system.

The NMR peak form of the selected example is stated in terms of its appearance in the spectrum, and possibly higher order effects have not been considered. In the case where the signal is very broadly or partially or completely hidden by the solvent peak, the total number of hydrogen atoms exhibited in the NMR spectrum may differ from the number of hydrogen atoms present in the respective molecule.

The ¹ H-NMR data of the selected examples are listed as a list of ¹ H-NMR peaks. For each signal peak, the delta value in ppm is given, followed by the signal strength reported in parentheses. The delta value-signal strength pairs of the different peaks are separated by a semicolon. Therefore, the peak list is described by the following general formula: δ ₁ (intensity ₁ ); δ ₂ (intensity ₂ ); ...; δ _i (intensity _i ); ...; δ _n (intensity _n ).

The intensity of the sharp signal is related to the height of the signal (in centimeters) in the printed NMR spectrum. This data can be related to the true ratio of signal strength when compared to other signals. In the case of a wide signal, more than one peak or signal center is displayed and its relative intensity compared to the strongest signal exhibited in the spectrum. ^{The 1} H-NMR peak list is similar to the classical ¹ H-NMR readout and therefore typically contains all of the peaks listed in the classical NMR interpretation. In addition, similar to the classical ¹ H-NMR print, the peak list can show the solvent signal, the peak of the signal and/or impurity derived from the stereoisomer of the target compound (which is also the subject of the invention). The peaks of the stereoisomers and/or the peaks of the impurities exhibit a strength which is generally lower than the peak of the target compound (e.g., > 90% purity). Such stereoisomers and/or impurities may be typical for a particular manufacturing process, and thus their peaks may aid in the identification of the reproduction of our manufacturing process based on "by-product fingerprints." An expert who calculates the peak of the target compound by known methods (MestReC, ACD simulation or by using empirically evaluated expected values) can use an additional intensity filter to separate the peaks of the target compound as needed. Such an operation would be similar to the peaking method in the classical ¹ H-NMR interpretation. A detailed description of the NMR data in the form of a peak list can be found in the publication "Reference to the NMR Peak List Data in the Patent Application" (see Research Public Library No. 605005, 2014, August 01, 2014, or http:/ /www.researchdisclosure.com/searching-disclosures ).

If not stated otherwise, the yield expressed in % reflects the purity of the desired product obtained; where appropriate, a purity of significantly less than 90% is clearly specified.

If not stated otherwise, the starting materials mentioned in the scheme are purchased from commercial suppliers.

The IUPAC names for the examples and intermediates were generated using the program ' ACD/Name Lot 12.01 ' from ACD LABS and adapted as needed.

Intermediate Intermediate 1A 6-bromo-2-(trifluoromethyl)quinoline-4-carboxylic acid

300 mg (1.33 mmol) of 5-bromo-1H-indole-2,3-dione was suspended in 3 mL of water in a microwave vial. 82 mg (1.46 mmol) of potassium hydroxide, 152 μL (2.65 mmol) of acetic acid and 152 mg (1.86 mmol) of sodium acetate were added to bring the pH to about 5. The solution was cooled to 10 ° C and 238 μL (2.65 mmol) of 1,1,1-trifluoroacetone was quickly added, and the microwave vial was sealed and heated at 120 ° C for 2 hours in the microwave. The reaction was quenched by the addition of 10% aqueous EtOAc. EtOAc (EtOAc)

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 8.14 (dd, 1 H), 8.21 (d, 1 H), 8.32 (s, 1 H), 9.09 (d, 1 H), 14.50 (br) .s., 1 H).

Intermediate 2A 6-bromo-2-amine-mercaptoquinoline-4-carboxylic acid

Step 1: 6-bromoquinoline-2,4-dicarboxylic acid

Add 1.02 g (11.6 mmol) of pyruvic acid to a mixture of 1.5 g (6.64 mmol) of 5-bromo-1H-indole-2,3-dione in hot 15 mL of 33% aqueous potassium hydroxide solution at 40 ° C This mixture was heated for 16 hours. To the resulting thick paste, 50 mL of a 33% aqueous potassium hydroxide solution was added and stirred. The solid was isolated by filtration and washed with a 33% aqueous potassium hydroxide solution and ethanol. The solid was then diluted in water and a 10% aqueous solution of sulfuric acid (pH less than 7) was added. The solid formed was separated by filtration and dried in vacuo for 8 hours. The solid was the desired 6-bromoquinoline-2,4-dicarboxylic acid which was used without further purification. Yield: 1.5g (74%)

¹ H-NMR (300 MHz, DMSO d ₆ ) δ (ppm) = 8.06 (dd, 1H), 8.18 (d, 1H), 8.52 (s, 1H), 9.08 (d, 1H).

Step 2: Dimethyl 6-bromoquinoline-2,4-dicarboxylate

A mixture of 1.5 g (5.07 mmol) of diacid of Intermediate 2A) and 3.7 mL (50.7 mmol) of sulfinium chloride was heated at 80 ° C for 16 hours. After cooling to 25 ° C, the resulting suspension was evaporated in vacuo to dryness. This crude product was suspended in 10 mL of methanol and refluxed for 3 hours. After cooling to 25 ° C, the solid formed was separated by filtration. Water was added to the filtrate and the solid formed was separated by filtration. The combined crude product was purified via a Biotage chromatography system (25 g EtOAc/EtOAc/EtOAc/EtOAc/EtOAc Using this method, the desired 6-bromoquinoline-2,4-dimethyl is obtained. Dimethyl acrylate. Yield: 180mg (10%)

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 3.98 (s, 3H), 4.02 (s, 3H), 8.10 (dd, 1H), 8.21 (d, 1H), 8.51 (s, 1H) , 8.97 (d, 1H).

Step 3: 6-Bromo-2-amine-methylpyridylquinoline-4-carboxylic acid methyl ester

To a solution of 180 mg (0.56 mmol) of the diester of the intermediate 2A) in 2.0 mL of methanol, 1.19 mL of a solution of 7M ammonia in methanol was added and stirred at 50 ° C for 1 hour. Then 15 equivalents of ammonia were added and stirring was continued at 50 ° C for 2 hours. After cooling to 25 ° C, the solid formed was separated by filtration and dried. Using this method, the desired methyl 6-bromo-2-aminecarboxyquinoline-4-carboxylate was obtained. Yield: 120mg (66%)

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 4.01 (s, 3H), 7.95 (br.s., 1H), 8.04-8.18 (m, 2H), 8.41 (br.s., 1H) ), 8.57 (s, 1H), 8.97 (d, 1H).

Step 4: 6-Bromo-2-amine-methylpyridylquinoline-4-carboxylic acid

To a solution of 120 mg (0.39 mmol) of the compound from step 3) of Intermediate 2A) in 1.79 mL of methanol was added 279 mg of sodium hydroxide in 3.58 mL of water. The mixture was stirred at 25 ° C for 2 hours and then concentrated in vacuo. The residue was diluted with water and a 10% aqueous solution of sulfuric acid was added until pH 2. After stirring for an additional 15 minutes, the solid formed was isolated by filtration and dried in vacuo. Using this method, the desired compound is obtained. Yield: 106 mg (74%)

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 7.89 (br.s., 1H), 8.03 (dt, 1H), 8.07-8.18 (m, 1H), 8.36 (br.s., 1H) ), 8.43 - 8.55 (m, 1H), 9.10 (dd, 1H).

Intermediate 3A 2-Aminomethylmercapto-6,7-difluoroquinoline-4-carboxylic acid

Step 1: 6,7-Difluoroquinoline-2,4-dicarboxylic acid

In a manner similar to step 1) of intermediate 2A), 1.5 g (8.19 mmol) of 5,6-difluoro-1H-indole-2,3-dione were obtained (see for example, Journal of Organic Chemistry, 1958 , 1858). The reaction gave 1.04 g (48%) of 6,7-difluoroquinoline-2,4-dicarboxylic acid.

¹ H-NMR (300 MHz, DMSO d ₆ ) δ (ppm) = 8.30 (dd, 1H), 8.52 (s, 1H), 8.79 (dd, 1H).

Step 2: Dimethyl 6,6-difluoroquinoline-2,4-dicarboxylate

1.04 g (4.11 mmol) of 6,7-difluoroquinoline-2,4-dicarboxylic acid of step 1) of Intermediate 3A) was reacted in a similar manner to Step 2) of Intermediate 2A) to give 640 mg. (52%) dimethyl 6,7-difluoroquinoline-2,4-dicarboxylate.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 3.98 (s, 3H), 4.01 (s, 3H), 8.37 (dd, 1H), 8.50 (s, 1H), 8.69 (dd, 1H) .

Step 3: Methyl 2-aminocarbamido-6,7-difluoroquinoline-4-carboxylate

340 mg (1.21 mmol) of dimethyl 6,7-difluoroquinoline-2,4-dicarboxylate of step 2) of intermediate 3A) are reacted in a manner analogous to step 3) of intermediate 2A) 180 mg (53%) of methyl 2-aminocarbamido-6,7-difluoroquinoline-4-carboxylate were obtained.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 1.16 (t, 1H), 3.99-4.04 (m, 3H), 7.95 (br.s., 1H), 8.16 (dd, 1H), 8.33 (br.s., 1H), 8.56 (s, 1H), 8.70 (dd, 1H).

Step 4: 2-Aminomethylmercapto-6,7-difluoroquinoline-4-carboxylic acid

173 mg (0.65 mmol) of 2-aminoformamido-6,7-difluoroquinoline-4-carboxylic acid methyl ester of step 3) of intermediate 3A) in a procedure analogous to step 4) of intermediate 2A) Reaction 86 mg (52%) of the desired compound are obtained.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 7.95 (br.s., 1H), 8.15 (dd, 1H), 8.34 (br.s., 1H), 8.57 (s, 1H), 8.83 (d, 1H), 14.15 (br.s., 1H).

Intermediate 4A 2-Aminomethylmercaptoquinoline-4-carboxylic acid

Step 1: Dimethyl quinoline-2,4-dicarboxylate

11.4 g (44.9 mmol) of commercially available quinoline-2,4-dicarboxylic acid were reacted in a similar manner to step 2) of Intermediate 2A) to give 6.44 g (59%) of quinoline-2,4-di. Dimethyl formate.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 3.98 (s, 3H), 4.01 (s, 3H), 7.88 (ddd, 1H), 7.96 (ddd, 1H), 8.26 (dd, 1H) , 8.46 (s, 1H), 8.70 (dd, 1H).

Step 2: Methyl 2-aminopyridylquinoline-4-carboxylate

Reaction of 1.0 g (4.08 mmol) of quinolin-2,4-dicarboxylic acid dimethyl ester of step 1) of Intermediate 4A), mp 650 mg (66%) ) 2-Aminoformylquinoline-4-carboxylic acid methyl ester.

¹ H-NMR (400MHz, DMSO d ₆ ) δ (ppm) = 4.01 (s, 3H), 7.85 (ddd, 1H), 7.89 (br.s., 1H), 7.95 (ddd, 1H), 8.22 (d) , 1H), 8.37 (br.s., 1H), 8.53 (s, 1H), 8.71 (d, 1H).

Step 3: 2-Aminomethylmercaptoquinoline-4-carboxylic acid

Step 2) of intermediate 4A) is carried out in a similar manner to step 4) of intermediate 2A) 650 mg (2.82 mmol) of 2-aminopyridylquinoline-4-carboxylic acid methyl ester were reacted to give 540 mg (86%).

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 7.82 (dt, 1H), 7.86 (br.s., 1H), 7.92 (td, 1H), 8.20 (d, 1H), 8.34 (br .s., 1H), 8.50 (s, 1H), 8.78 (d, 1H), 13.98 (br.s., 1H).

Intermediate 5A 2-Aminomethylmercapto-6,8-dichloroquinoline-4-carboxylic acid

Step 1: 6,8-Dichloroquinoline-2,4-dicarboxylic acid

1.5 g (6.94 mmol) of commercially available 5,7-dichloro-1H-indole-2,3-dione was reacted in a similar manner to step 1) of Intermediate 2A) to give 350 mg (17%). 6,8-Dichloroquinoline-2,4-dicarboxylic acid.

1H-NMR (300MHz, DMSO d6) δ (ppm) = 8.29 (d, 1H), 8.58 (s, 1H), 8.88 (d, 1H), 13.99 (br.s., 1H).

Step 2: Dimethyl 6,8-dichloroquinoline-2,4-dicarboxylate

400 mg (1.24 mmol) of 6,8-dichloroquinolin-2,4-dicarboxylic acid of step 1) of Intermediate 5A) was reacted in a similar manner to Step 2) of Intermediate 2A) to give 410 mg (83). %) dimethyl 6,8-dichloroquinoline-2,4-dicarboxylate.

1H-NMR (300MHz, DMSO d6) δ (ppm) = 4.00 (s, 3H), 4.02 (s, 3H), 8.34 (d, 1H), 8.58 (s, 1H), 8.76 (d, 1H).

Step 3: Methyl 2-aminocarbamido-6,8-dichloroquinoline-4-carboxylate

In a similar manner to the step 3) of the intermediate 2A), 310 mg (0.99 mmol) of dimethyl 6,8-dichloroquinoline-2,4-dicarboxylate of the step 2) of the intermediate 5A) is obtained. 140 mg (45%) of 2-aminoformamido-6,8-dichloroquinoline-4-carboxylic acid methyl ester.

1H-NMR (400 MHz, DMSO d6) δ (ppm) = 4.01 (s, 3H), 8.08 (s, 2H), 8.29 (d, 1H), 8.62 (s, 1H), 8.74 (d, 1H).

Step 4: 2-Aminomethylmercapto-6,8-dichloroquinoline-4-carboxylic acid

Reaction of 140 mg (0.47 mmol) of 2-aminoformamyl-6,8-dichloroquinoline-4-carboxylate of step 3) of intermediate 5A) in a similar manner to step 4) of intermediate 2A) Thus, 145 mg (98%) of the desired compound are obtained.

1H-NMR (400MHz, DMSO d6) δ (ppm) = 7.94 (br.s., 1H), 8.00 (br.s., 1H), 8.14 (d, 1H), 8.41 (s, 1H), 8.95 ( d, 1H).

Intermediate 6A 2-(methylamine-mercapto)quinoline-4-carboxylic acid

Step 1: Methyl 2-(methylamine-mercapto)quinoline-4-carboxylate

To a solution of 250 mg (1.02 mmol) of quinolin-2,4-dicarboxylic acid dimethyl ester in step 1) of intermediate 1A) in 2.5 mL of methanol, add 5.1 mL of 2M methylamine in THF and at 50 ° C Stir for 1 hour. After cooling to 25 ° C, Isolute® was added to the reaction mixture and subsequently evaporated to dryness. The absorbed material was then purified using a Biotage chromatography system (25 g snap KP-Sil column, hexane / 0-100% ethyl acetate followed by ethyl acetate / 0-75% methanol). Using this method, the desired methyl 2-(methylamine-mercapto)quinoline-4-carboxylate was obtained. Yield: 156 mg (61%)

1H-NMR (300MHz, DMSO d6) δ (ppm) = 2.90 (d, 3H), 4.01 (s, 3H), 7.80-7.88 (m, 1H), 7.95 (ddd, 1H), 8.21 (d, 1H) , 8.51 (s, 1H), 8.70 (dd, 1H), 9.00 (q, 1H).

Step 2: 2-(Methylamine-mercapto)quinoline-4-carboxylic acid

156 mg (0.64 mmol) of methyl 2-(methylaminecarbamimidino)quinoline-4-carboxylate of step 2) of intermediate 6A) are reacted in a similar manner to step 4) of intermediate 2A) 138 mg (91%) of the desired compound are obtained.

1H-NMR (300MHz, DMSO d6) δ (ppm) = 2.90 (d, 3H), 7.78-7.86 (m, 1H), 7.93 (td, 1H), 8.20 (d, 1H), 8.50 (s, 1H) , 8.78 (d, 1H), 8.98 (q, 1H), 14.03 (br.s., 1H).

Intermediate 7A 2-(dimethylamine-mercapto)quinoline-4-carboxylic acid

Step 1: Methyl 2-(dimethylamine-mercapto)quinoline-4-carboxylate

To a solution of 500 mg (2.04 mmol) of quinoline-2,4-dicarboxylic acid dimethyl ester in step 1) of intermediate 1A) in 5.0 mL of methanol, add 10.2 mL of a solution of 2M dimethylamine in methanol at 50 ° C Stir under 1 hour. A further 15 mL of a 2M solution of dimethylamine in methanol was added and stirring was continued for 16 hours. After cooling to 25 ° C, Isolute® was added to the reaction mixture and subsequently evaporated to dryness. The absorbed material was then purified using a Biotage chromatography system (25 g snap KP-Sil column, hexane / 0-100% ethyl acetate followed by ethyl acetate / 0-75% methanol). Using this method, the desired methyl 2-(dimethylaminecarbamimido)quinoline-4-carboxylate was obtained. Yield: 140mg (25%)

1H-NMR (400MHz, DMSO d6) δ (ppm) = 3.06 (s, 3H), 3.09 (s, 3H), 4.01 (s, 3H), 7.78-7.86 (m, 1H), 7.92 (ddd, 1H) , 8.07 (s, 1H), 8.15 (d, 1H), 8.66 (d, 1H).

Step 2: 2-(Dimethylamine-mercapto)quinoline-4-carboxylic acid

Reaction of 140 mg (0.54 mmol) of methyl 2-(dimethylaminocarbazinyl)quinoline-4-carboxylate of step 2) of intermediate 7A) in a similar manner to step 4) of Intermediate 2A) Thus 68 mg (45%) of the desired title compound are obtained.

1H-NMR (300MHz, DMSO d6) δ (ppm) = 3.03 (s, 3H), 3.07 (s, 3H), 7.74-7.82 (m, 1H), 7.85-7.92 (m, 1H), 8.01 (s, 1H), 8.12 (d, 1H), 8.72 (d, 1H), 14.03 (br.s., 1H).

Intermediate 8A 6-fluoro-2-amine-mercaptoquinoline-4-carboxylic acid

Step 1: 6-fluoroquinoline-2,4-dicarboxylic acid

2.0 g (12.1 mmol) of commercially available 5-fluoro-1H-indole-2,3-dione was reacted in a similar manner to the step 1) of the intermediate 2A) to give 1.86 g (63%) 6- Fluoroquinoline-2,4-dicarboxylic acid.

¹ H-NMR (300 MHz, DMSO d ₆ ) δ (ppm) = 7.83 - 7.92 (m, 1H), 8.33 (dd, 1H), 8.53 - 8.62 (m, 2H), 13.86 (br.s., 1H) .

Step 2: Dimethyl 6-fluoroquinoline-2,4-dicarboxylate

1.86 g (7.91 mmol) of 6-fluoroquinoline-2,4-dicarboxylic acid of Step 1) of Intermediate 8A) was reacted in a similar manner to Step 2) of Intermediate 2A) to give 1.51 g (69). %) dimethyl 6-fluoroquinoline-2,4-dicarboxylate.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 3.98 (s, 3H), 4.01 (s, 3H), 7.91 (ddd, 1H), 8.37 (dd, 1H), 8.48 (dd, 1H) , 8.54 (s, 1H).

Step 3: Methyl 2-aminoformamido-6-fluoroquinoline-4-carboxylate

Step 2) of intermediate 8A) is carried out in a similar manner to step 3) of intermediate 2A) 310 mg (1.18 mmol) of dimethyl 6-fluoroquinoline-2,4-dicarboxylate was reacted to give 210 mg (68%) of ethyl 2-aminocarbazin-6-fluoroquinoline-4-carboxylate.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 4.01 (s, 3H), 7.84-7.95 (m, 2H), 8.28 (dd, 1H), 8.37 (br.s., 1H), 8.48 (dd, 1H), 8.59 (s, 1H).

Step 4: 6-Fluoro-2-amine-methylpyridylquinolin-4-carboxylic acid

210 mg (0.85 mmol) of methyl 2-aminoformamido-6-fluoroquinoline-4-carboxylate of step 3) of intermediate 8A) are reacted in a similar manner to step 4) of intermediate 2A) 156 mg (79%) of the desired compound are obtained.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 7.81 - 7.90 (m, 2H), 8.26 (dd, 1H), 8.32 - 8.37 (m, 1H), 8.55 - 8.62 (m, 2H), 13.75 (br.s., 1H).

Intermediate 9A 6-bromo-7-fluoro-2-(trifluoromethyl)quinoline-4-carboxylic acid

In a manner similar to Intermediate 1A), 1.0 g (4.02 mmol) of commercially available 5-bromo-6-fluoro-1H-indole-2,3-dione was reacted using conventional heating at 105 ° C for 3 hours. Thus, 990 mg (59%) of the desired compound are obtained.

¹ H-NMR (300 MHz, DMSO d ₆ ) δ (ppm) = 8.24 - 8.32 (m, 2H), 9.25 (d, 1H), 14.57 (br.s., 1H).

Intermediate 10A 6-chloro-7-fluoro-2-(trifluoromethyl)quinoline-4-carboxylic acid

In a manner similar to Intermediate 1A), 1.0 g (4.91 mmol) of commercially available 5-chloro-6-fluoro-1H-indole-2,3-dione was reacted by conventional heating at 105 ° C for 3 hours. Thus, 1.02 g (58%) of the desired compound was obtained.

¹ H-NMR (300 MHz, DMSO d ₆ ) δ (ppm) = 8.31 (s, 1H), 8.34 (d, 1H), 9.09 (d, 1H), 11.27 (s, 1H).

Intermediate 11A 6,8-Dichloro-2-(trifluoromethyl)quinoline-4-carboxylic acid

In a manner similar to Intermediate 1A, 1 g (4.63 mmol) of 5,7-dichloro-1H-indole-2,3-dione and 830 μL (9.26 mmol) of 1,1,1-trifluoroacetone, 286 mg (5.10 mmol) of potassium hydroxide, 530 μL (9.26 mmol) of acetic acid and 531 mg (6.48 mmol) of sodium acetate in 10 mL of water were heated in a microwave at 120 ° C for 2 hours to obtain 1.40 g (4.52 mmol, after aqueous treatment). 98%) of the desired compound.

_{1H NMR (300MHz, DMSO d 6} ): δ (ppm) = 8.39 (d, 1 H), 8.42 (s, 1 H), 8.87 (d, 1 H).

Intermediate 12A 6-chloro-2-(trifluoromethyl)quinoline-4-carboxylic acid

In a manner similar to Intermediate 1A, 500 mg (2.75 mmol) of 5-chloro-1H-indole-2,3-dione and 494 μL (9.26 mmol) of 1,1,1-trifluoroacetone, 170 mg (3.03 mmol) ) Potassium hydroxide, 315 μL (5.51 mmol) of acetic acid and 316 mg (3.86 mmol) of sodium acetate in 5 mL of water were heated in a microwave at 120 ° C for 2 hours, thereby obtaining 726 mg (2.63 mmol, 96%) of the desired title after aqueous treatment. Compound.

_{1H NMR (300MHz, DMSO d 6} ): δ (ppm) = 8.03 (dd, 1 H), 8.30 (d, 1 H), 8.33 (s, 1 H), 8.92 (d, 1 H).

Intermediate 13A 8-bromo-2-(trifluoromethyl)quinoline-4-carboxylic acid

In a manner similar to Intermediate 1A, 300 mg (1.33 mmol) of 7-bromo-1H-indole-2,3-dione and 238 μL (2.65 mmol) of 1,1,1-trifluoroacetone, 81 mg (1.46 mmol) Potassium hydroxide, 152 μL (2.65 mmol) of acetic acid and 152 mg (1.86 mmol) of sodium acetate in 3 mL of water were heated in a microwave at 120 ° C for 2 hours to obtain 373 mg (1.17 mmol, 88%) of the desired title after aqueous work. Compound.

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 7.81 (dd, 1 H), 8.35 (s, 1 H), 8.40 (dd, 1 H), 8.78 (dd, 1 H), 14.56 (br) .s., 1 H).

Intermediate 14A 8-bromo-6-methyl-2-(trifluoromethyl)quinoline-4-carboxylic acid

In a manner similar to Intermediate 1A, 300 mg (1.25 mmol) of 7-bromo-5-methyl-1H-indole-2,3-dione and 224 μL (2.50 mmol) of 1,1,1-trifluoroacetone 77 mg (1.37 mmol) of potassium hydroxide, 143 μL (2.50 mmol) of acetic acid and 144 mg (1.75 mmol) of sodium acetate in 3 mL of water were heated in a microwave at 120 ° C for 2 hours, thereby obtaining 352 mg (1.05 mmol, after aqueous treatment). 84%) of the desired compound.

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.58 (s, 3 H), 8.25-8.32 (m, 2 H), 8.53 (s, 1 H), 14.49 (br.s., 1 H) ).

Intermediate 15A 5,6-Dichloro-2-(trifluoromethyl)quinoline-4-carboxylic acid and 6,7-dichloro-2-(trifluoromethyl)quinoline-4-carboxylic acid

In a manner similar to Intermediate 1A, 4,5-dichloro-1H-indole-2,3-dione and 5,6-dichloro-1H-indole-2,3-dione (3:1) 300 mg (1.39 mmol) of a mixture with 249 μL (2.78 mmol) of 1,1,1-trifluoroacetone, 86 mg (1.53 mmol) of potassium hydroxide, 159 μL (2.78 mmol) of acetic acid and 159 mg (1.94 mmol) of sodium acetate 3 mL The water was heated in a microwave at 120 °C for 4 hours to obtain 361 mg (1.16 mmol, 84%) of the desired compound mixture (3:1).

5,6-Dichloro-2-(trifluoromethyl)quinoline-4-carboxylic acid: Method 1: R _t =1.07 min

MS (ESIpos): m/z = 310 (M+H) ⁺

6,7-Dichloro-2-(trifluoromethyl)quinoline-4-carboxylic acid: Method 1: R _t = 1.34 min

MS (ESIpos): m/z = 310 (M+H) ⁺

Intermediate 16A 5-fluoro-2-(trifluoromethyl)quinoline-4-carboxylic acid

In a manner similar to Intermediate 1A, 300 mg (1.81 mmol) of 4-fluoro-1H-indole-2,3-dione and 326 μL (3.63 mmol) of 1,1,1-trifluoroacetone, 112 mg (1.99 mmol) ) Potassium hydroxide, 208 μL (3.63 mmol) of acetic acid and 209 mg (2.54 mmol) of sodium acetate in 3 mL of water were heated in a microwave at 100 ° C for 2 hours, thereby obtaining 315 mg (1.22 mmol, 67%) of the desired title after aqueous treatment. Compound.

1H NMR (400MHz, DMSO d ₆ ): δ (ppm) = 7.83 - 7.92 (m, 1 H), 8.09 (dd, 1 H), 8.25 (s, 1 H), 8.90 (dd, 1 H), 14.50 (br.s., 1 H).

Intermediate 17A 7-fluoro-2-(trifluoromethyl)quinoline-4-carboxylic acid

In a manner similar to the intermediate 1A, 200 mg (1.21 mmol) of 6-fluoro-1H-indole-2,3-dione and 217 μL (2.42 mmol) of 1,1,1-trifluoroacetone, 75 mg (1.33 mmol) Potassium hydroxide, 139 μL (2.42 mmol) of acetic acid and 139 mg (1.70 mmol) of sodium acetate 2 The mL water was heated together in a microwave at 80 ° C for 2 hours. Since the conversion was incomplete, 217 μL (2.42 mmol) of 1,1,1-trifluoroacetone was further added to the reaction mixture and heated at 80 ° C for 1 hour in the microwave. 217 μL (2.42 mmol) of 1,1,1-trifluoroacetone was again added and the reaction mixture was heated for a third time in the microwave at 100 ° C for 1 hour, thereby obtaining 227 mg (0.88 mmol, 72%) of the desired title after aqueous treatment. Compound.

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 7.83 - 7.93 (m, 1 H), 8.10 (dd, 1 H), 8.26 (s, 1 H), 8.90 (dd, 1 H), 14.51 (br.s., 1 H).

Intermediate 18A 6-fluoro-2-(trifluoromethyl)quinoline-4-carboxylic acid

In a manner similar to the intermediate 1A, 200 mg (1.21 mmol) of 6-fluoro-1H-indole-2,3-dione and 217 μL (2.42 mmol) of 1,1,1-trifluoroacetone, 75 mg (1.33 mmol) ) Potassium hydroxide, 139 μL (2.42 mmol) of acetic acid and 139 mg (1.70 mmol) of sodium acetate in 2 mL of water were heated in a microwave at 80 ° C for 2 hours, thereby obtaining 219 mg (0.85 mmol, 70%) of the desired title after aqueous treatment. Compound.

1H NMR (400MHz, DMSO d ₆ ): δ (ppm) = 7.96 (ddd, 1 H), 8.34 (s, 1 H), 8.38. (dd, 1 H), 8.59 (dd, 1 H), 14.47 ( Br.s., 1 H).

Intermediate 19A 6,7-difluoro-2-(trifluoromethyl)quinoline-4-carboxylic acid

In a manner similar to Intermediate 1A, 265 mg (1.45 mmol) of 5,6-difluoro-1H-indole-2,3-dione and 259 μL (2.89 mmol) of 1,1,1-trifluoroacetone, 89 mg (1.59 mmol) potassium hydroxide, 166 μL (2.89 mmol) of acetic acid and 166 mg (2.03 mmol) of sodium acetate in 2.7 mL of water were heated in a microwave at 120 ° C for 1 hour. Since the conversion was incomplete, 259 μL (2.89 mmol) of 1,1,1-trifluoroacetone was further added to the reaction mixture and heated at 120 ° C for 1 hour in the microwave to obtain 312 mg (1.13 mmol, after aqueous treatment). 78%) of the desired compound.

_{1H NMR (300MHz, DMSO d 6} ): δ (ppm) = 8.33 (s, 1 H), 8.41 (dd, 1 H), 8.81 (dd, 1 H), 14.62 (br.s., 1 H).

Intermediate 20A 2-(trifluoromethyl)quinoline-4-carboxylic acid

3.0 g (20.4 mmol) of commercially available 1H-indole-2,3-dione was reacted in a similar manner to the intermediate 1A) to give 4.68 g (92%) of the desired compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 7.88 - 7.93 (m, 1H), 8.00 (ddd, 1H), 8.24 (s, 1H), 8.26 (d, 1H), 8.78 (dd, 1H), 14.39 (br.s., 1H).

Intermediate 21A 6-(Trifluoromethoxy)-2-(trifluoromethyl)quinoline-4-carboxylic acid

In a manner similar to Intermediate 1A, 200 mg (0.87 mmol) of 5-(trifluoromethoxy)- 1H-indole-2,3-dione with 388 μL (4.33 mmol) of 1,1,1-trifluoroacetone, 53 mg (0.95 mmol) of potassium hydroxide, 99 μL (1.73 mmol) of acetic acid and 99 mg (1.21 mmol) of acetic acid 2 mL of sodium was heated in a microwave at 120 ° C for 1 hour to obtain 269 mg (0.83 mmol, 96%) of the desired compound.

1H NMR (400MHz, DMSO d ₆ ): δ (ppm) = 8.01 (dd, 1 H), 8.38 (s, 1 H), 8.44 (d, 1 H), 8.85-8.89 (m, 1 H), 14.57 (br.s., 1 H).

Intermediate 22A 7-bromo-2-(trifluoromethyl)quinoline-4-carboxylic acid

In a manner similar to Intermediate 1A, 300 mg (1.33 mmol) of 6-bromo-1H-indole-2,3-dione and 238 μL (2.65 mmol) of 1,1,1-trifluoroacetone, 82 mg (1.46 mmol) ) Potassium hydroxide, 152 μL (2.65 mmol) of acetic acid and 152 mg (1.86 mmol) of sodium acetate in 3 mL of water were heated in a microwave at 120 ° C for 2 hours, thereby obtaining 361 mg (1.13 mmol, 85%) of the desired title after aqueous treatment. Compound.

1H NMR (400MHz, DMSO d ₆ ): δ (ppm) = 8.07 (dd, 1 H), 8.30 (s, 1 H), 8.54 (d, 1 H), 8.76 (d, 1 H), 14.49 (br) .s., 1 H).

Intermediate 23A 2,6-bis(trifluoromethyl)quinoline-4-carboxylic acid

In a manner similar to Intermediate 1A, 300 mg (1.39 mmol) of 5-(trifluoromethyl)- 1H-indole-2,3-dione with 250 μL (2.79 mmol) of 1,1,1-trifluoroacetone, 86 mg (1.53 mmol) of potassium hydroxide, 160 μL (2.79 mmol) of acetic acid and 160 mg (1.95 mmol) of acetic acid 3 mL of sodium was heated together in a microwave at 120 ° C for 1 hour. Since the conversion was incomplete, 250 μL (2.79 mmol) of 1,1,1-trifluoroacetone was further added to the reaction mixture and further heated in the microwave at 120 ° C for 1 hour, thereby obtaining 302 mg (0.78 mmol, after aqueous treatment). 56%) of the desired compound.

_{1H NMR (300MHz, DMSO d 6} ): δ (ppm) = 8.27 (dd, 1 H), 8.43 (s, 1 H), 8.50 (d, 1 H), 9.31 (s, 1 H).

Intermediate 24A 6-chloro-2-cyclopropylquinoline-4-carboxylic acid

In a manner similar to Intermediate 1A), from 5.0 g (27.5 mmol) of commercially available 5-chloro-1H-indole-2,3-dione and 4.63 g (55.1 mmol) of 1-cyclopropylethanone instead of 1,1,1-Trifluoroacetone and heating was carried out at 105 ° C for 5 hours to give a solid comprising the desired compound and a filtrate. The two fractions were combined and 2N aqueous sodium hydroxide solution was added until pH 10, and then extracted three times with 30 mL of ethyl acetate. The aqueous phase was then acidified with a 10% aqueous solution of sulfuric acid until pH 3. The solid formed was separated by filtration and dried. Using this method, the desired compound is obtained. Yield: 150mg (2.1%)

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 1.06-1.12 (m, 4H), 2.40 (t, 1H), 7.74 (dd, 1H), 7.87-7.96 (m, 2H), 8.71 ( d, 1H), 13.83 (s, 1H).

Intermediate 25A 2-cyclopropyl-5-fluoroquinoline-4-carboxylic acid

In a manner similar to Intermediate 1A, 300 mg (1.82 mmol) of 4-fluoro-1H-indole-2,3-dione and 900 μL (9.08 mmol) of 1-cyclopropylethanone, 112 mg (2.00 mmol) of hydrogen Potassium oxide, 208 μL (3.63 mmol) of acetic acid and 209 mg (2.54 mmol) of sodium acetate in 3 mL of water were heated in a microwave at 150 ° C for 6 hours. The reaction mixture was quenched with 10% aqueous hydrochloric acid and filtered. The filtrate was extracted with EtOAc. EtOAc (EtOAc)EtOAc.

1H NMR (400MHz, DMSO d ₆ ): δ (ppm) = 1.10-1.17 (m, 4 H), 2.40-2.47 (m, 1 H), 7.52-7.60 (m, 2 H), 7.93 (s, 1) H), 8.35-8.41 (m, 1 H,) 13.98 (br.s, 1 H).

Intermediate 26A 2-cyclopropyl-6-fluoroquinoline-4-carboxylic acid

In a manner similar to the intermediate 25A, 300 mg (1.82 mmol) of 5-fluoro-1H-indole-2,3-dione and 900 μL (9.08 mmol) of 1-cyclopropyl ethyl ketone, 112 mg (2.00 mmol) of hydrogen Potassium oxide, 208 μL (3.63 mmol) of acetic acid and 209 mg (2.54 mmol) of sodium acetate in 3 mL of water were heated together for 24 hours to reflux. The reaction mixture was filtered, EtOAc EtOAcjjjjjjjjj

1H NMR (400MHz, DMSO d ₆ ): δ (ppm) = 0.54-0.64 (m, 1 H), 0.66-0.83 (m, 3 H), 1.92-2.04 (m, 1 H), 6.09 (br.s) , 1 H), 6.74 (dd, 1 H), 6.98 (ddd, 1 H), 7.16 (dd, 1 H), 10.19 (s, 1 H).

Intermediate 27A 8-bromo-2-cyclopropylquinoline-4-carboxylic acid

In a similar manner to the intermediate 25A, 300 mg (1.33 mmol) of 7-bromo-1H-indole-2,3-dione and 658 μL (6.64 mmol) of 1-cyclopropylethanone, 81 mg (1.46 mmol) of hydrogen Potassium oxide, 152 μL (2.65 mmol) of acetic acid and 152 mg (1.86 mmol) of sodium acetate in 3 mL of water were heated under reflux for 24 hours. The reaction mixture was further heated in a microwave at 150 ° C for 6 hours due to low conversion. The reaction mixture was quenched with 10% aqueous hydrochloric acid and filtered. The filtrate was extracted with EtOAc (EtOAc)EtOAc. The crude reaction mixture was purified via preparative HPLC EtOAc (EtOAc):

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 1.10 - 1.22 (m, 4 H), 2.40-2.47 (m, 1 H), 7.49 (dd, 1 H), 7.94 (s, 1 H) , 8.13 (dd, 1 H), 8.57 (dd, 1 H), 14.02 (br.s, 1 H).

Intermediate 28A 2-cyclopropyl-8-fluoroquinoline-4-carboxylic acid

In a similar manner to the intermediate 25A, 300 mg (1.82 mmol) of 7-fluoro-1H-indole-2,3-dione and 900 μL (9.08 mmol) of 1-cyclopropylethanone, 112 mg (2.00 mmol) of hydrogen Potassium oxide, 208 μL (3.63 mmol) of acetic acid and 209 mg (2.54 mmol) of sodium acetate in 3 mL of water were heated under reflux for 24 hours. The reaction mixture was further heated in a microwave at 150 ° C for 6 hours due to low conversion. The reaction mixture was quenched with 10% aqueous hydrochloric acid and filtered. The filtrate was extracted with EtOAc (EtOAc)EtOAc. The crude reaction mixture was purified via mp EtOAc (m.)

1H NMR (400MHz, DMSO d ₆ ): δ (ppm) = 1.10-1.15 (m, 4 H), 2.40-2.48 (m, 1 H), 7.51-7.62 (m, 2 H), 7.92 (s, 1 H), 8.34 - 8.42 (m, 1 H), 13.96 (br.s., 1 H).

Intermediate 29A 7-bromo-2-cyclopropylquinoline-4-carboxylic acid

In a similar manner to the intermediate 25A, 300 mg (1.33 mmol) of 6-bromo-1H-indole-2,3-dione and 658 μL (6.64 mmol) of 1-cyclopropylethanone, 81 mg (1.50 mmol) of hydrogen Potassium oxide, 152 μL (2.65 mmol) of acetic acid and 152 mg (1.86 mmol) of sodium acetate in 3 mL of water were heated in a microwave at 160 ° C for 4 hours. After the aqueous workup, the crude reaction mixture was purified mpqqqqqqqq

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 1.02-1.17 (m, 4 H) 2.41 (quin, 1 H) 7.73 (dd, 1 H) 7.90 (s, 1 H) 8.11 (d, 1 H) 8.55 (d, 1 H) 13.99 (br.s., 1 H).

Intermediate 30A 6-bromo-2-cyclobutylquinoline-4-carboxylic acid

In a manner similar to Intermediate 1A), from 3.0 g (13.3 mmol) of commercially available 5-bromo-1H-indole-2,3-dione and 2.61 g (26.5 mmol) of 1-cyclobutyl ethyl ketone instead of 1,1,1-Trifluoroacetone and the reaction mixture was obtained by conventional heating at 100 ° C for 16 hours, which was filtered after cooling. The filtrate was extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and evaporated to dryness after Isolute®. The absorbed material was then purified using a Biotage chromatography system (50 g snap KP-Sil column, hexane / 0-100% ethyl acetate followed by ethyl acetate / 0-100% methanol) to afford the crude material. This was dissolved in 100 mL of a saturated aqueous solution of sodium hydrogencarbonate and stirred at 25 ° C for 30 minutes. This aqueous mixture was then extracted twice with 50 mL of ethyl acetate. The aqueous phase was then acidified using 10% sulfuric acid until pH 3. The solid formed was separated by filtration and dried. Using this method, the desired compound is obtained. Yield: 90mg (2.0%)

¹ H-NMR (400MHz, DMSO d ₆ ) δ (ppm) = 1.83-1.93 (m, 1H), 1.99-2.13 (m, 1H), 2.30-2.43 (m, 4H), 3.84-3.96 (m, 1H) ), 7.84 (s, 1H), 7.89 (dd, 1H), 7.98 (d, 1H), 8.91 (d, 1H), 13.42 (br.s., 1H).

Intermediate 31A 8-bromo-2-methylquinoline-4-carboxylic acid

In a similar manner to the intermediate 25A, 2 g (8.85 mmol) of 7-bromo-1H-indole-2,3-dione and 3.25 mL (44.24 mmol) of acetone, 546 mg (9.73 mmol) of potassium hydroxide, 1.01 mL (17.70 mmol) acetic acid and 1.02 g (12.39 mmol) of sodium acetate in 20 mL of water were heated at 130 ° C for 2 hours in the microwave. Since the conversion was incomplete, 3.25 mL (44.24 mmol) of acetone was further added to the reaction mixture and heated at 130 ° C for 2 hours in the microwave to obtain 2.00 g (7.51 mmol, 85%) of the desired title compound after aqueous work. .

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.76 (s, 3 H), 7.46-7.60 (m, 1 H), 7.91 (s, 1 H), 8.13 - 8.24 (m, 1 H) , 8.57-8.68 (m, 1 H), 14.02 (br.s., 1 H).

Intermediate 32A 2-Aminoformamido-6-chloro-7-fluoroquinoline-4-carboxylic acid

Step 1: 6-Chloro-7-fluoroquinoline-2,4-dicarboxylic acid

10.0 g (50.1 mmol) of commercially available 5-chloro-6-fluoro-1H-indole-2,3-dione was reacted in a similar manner to Step 1) of Intermediate 2A) to give 3.63 g (25). %) 6-chloro-7-fluoroquinoline-2,4-dicarboxylic acid.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 8.14 (d, 1H), 8.38 (s, 1H), 9.19 (d, 1H).

Step 2: Dimethyl 6-chloro-7-fluoroquinoline-2,4-dicarboxylate

3.36 g (13.5 mmol) of 6-chloro-7-fluoroquinoline-2,4-dicarboxylic acid of step 1) of intermediate 32A) is reacted in a similar manner to step 2) of intermediate 2A). 3.12 g (74%) of dimethyl 6-chloro-7-fluoroquinoline-2,4-dicarboxylate.

¹ H-NMR (500MHz, DMSO d ₆ ) δ (ppm) = 3.98 (s, 3H), 4.01 (s, 3H), 8.29 (d, 1H), 8.46 (s, 1H), 8.94 (d, 1H) .

Step 3: 2-Aminoformamido-6-chloro-7-fluoroquinoline-4-carboxylic acid methyl ester

Reaction of 3.12 g (10.5 mmol) of dimethyl 6-chloro-7-fluoroquinoline-2,4-dicarboxylate of step 2) of intermediate 32A) in a similar manner to step 3) of intermediate 2A) Thus, 2.52 g (77%) of 2-aminocarbamido-6-chloro-7-fluoroquinoline-4-carboxylic acid methyl ester was obtained.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 4.01 (s, 3H), 7.98 (br.s., 1H), 8.11 (d, 1H), 8.36 (br.s., 1H), 8.54 (s, 1H), 8.96 (d, 1H).

Step 4: 2-Aminoformamido-6-chloro-7-fluoroquinoline-4-carboxylic acid

520 mg (1.84 mmol) of 2-aminoformamido-6-chloro-7-fluoroquinoline-4-carboxylic acid A of step 3) of intermediate 32A) in a similar manner to step 4) of intermediate 2A) The ester was reacted to give 390 mg (63%) of desired compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 7.92 (br.s., 1H), 8.06 (d, 1H), 8.31 (br.s., 1H), 8.51 (s, 1H), 9.10 (d, 1H).

Intermediate 33A 5-bromo-2-(trifluoromethyl)quinoline-4-carboxylic acid

In a manner similar to the intermediate 25A), 300 mg (1.33 mmol) of 4-bromo-1H-indole-2,3-dione and 238 μL (2.65 mmol) of 1,1,1-trifluoroacetone, 82 mg (1.46) Methyl hydroxide, 152 μL (2.65 mmol) of acetic acid and 152 mg (1.86 mmol) of sodium acetate in 5 mL of water were heated at 120 ° C for 2 hours in the microwave. The reaction mixture was quenched with EtOAc EtOAc (EtOAc)

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 7.90 (dd, 1 H), 8.15 (s, 1 H), 8.24 (dd, 1 H), 8.30 (dd, 1 H), 14.33 (br) .s., 1 H).

Intermediate 34A 2-cyclopropyl-6-(trifluoromethyl)quinoline-4-carboxylic acid

In a manner similar to the intermediate 2A, 200 mg (0.93 mmol) of 5-(trifluoromethyl)-1H-indole-2,3-dione and 230 μL (2.32 mmol) of 1-cyclopropyl ethyl ketone, 156 mg (2.79 mmol) 3 mL of potassium hydroxide and 500 μL of water were heated in a microwave at 130 ° C for 6 hours. The reaction mixture was quenched with EtOAc (EtOAc)EtOAc. The crude reaction mixture was purified via preparative HPLC EtOAc (EtOAc):

Method 1: R _t = 1.15 min

MS (ESIpos): m/z = 282 (M+H) ⁺

Intermediate 35A 8-fluoro-2-(trifluoromethyl)quinoline-4-carboxylic acid

In a manner similar to the intermediate 25A, 100 mg (0.61 mmol) of 7-fluoro-1H-indole-2,3-dione and 543 μL (6.06 mmol) of 1,1,1-trifluoroacetone, 37 mg (0.66 mmol) ) Potassium hydroxide, 69 μL (1.21 mmol) of acetic acid and 70 mg (0.85 mmol) of sodium acetate 2.5 The mL water was heated together at 70 ° C for 15 hours. The reaction mixture was quenched with 1M aqueous HCI and filtered. This crude product was purified by preparative HPLC EtOAc (EtOAc)

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 7.82 - 7.95 (m, 2 H), 8.35 (s, 1 H), 8.60 (d, 1 H), 14.52 (br.s., 1 H) ).

Intermediate 36A 2-cyclopropyl-8-(trifluoromethyl)quinoline-4-carboxylic acid

In a manner similar to the intermediate 25A, 300 mg (1.39 mmol) of 7-(trifluoromethyl)-1H-indole-2,3-dione and 238 μL (2.65 mmol) of 1-cyclopropylethanone, 86 mg (1.53 mmol) potassium hydroxide, 160 μL (2.79 mmol) of acetic acid and 160 mg (1.96 mmol) of sodium acetate in 5 mL of water were heated in a microwave at 160 ° C for 4 hours. The reaction mixture was quenched with 1M aqueous HCI and filtered. This crude product was purified by preparative HPLC EtOAc (EtOAc)

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 1.07-1.20 (m, 4 H), 2.41-2.48 (m, 1 H), 7.71 (t, 1 H), 8.04 (s, 1 H) , 8.16 (d, 1 H), 8.86 (d, 1 H), 14.08 (br.s., 1 H).

Intermediate 37A 2-Aminomethylmercapto-7-fluoroquinoline-4-carboxylic acid

step 1:

6.02 g (84%) of 7-fluoroquinoline were obtained from 5.0 g (30.3 mmol) of commercially available 6-fluoro-1H-indole-2,3-dione in a similar manner to step 1) of Intermediate 2A). -2,4-dicarboxylic acid.

¹ H-NMR (300 MHz, DMSO d ₆ ) δ (ppm) = 7.78 (ddd, 1H), 7.99 (dd, 1H), 8.42 (s, 1H), 8.89 (dd, 1H).

Step 2:

In a manner analogous to the step 2) of the intermediate 2A), 3.06 g (44%) of 7 g (25.5 mmol) of 7-fluoroquinolin-2,4-dicarboxylic acid from step 1) of Intermediate 37A). - fluoroquinoline-2,4-dicarboxylic acid dimethyl ester.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 3.98 (s, 3H), 4.01 (s, 3H), 7.85 (ddd, 1H), 8.07 (dd, 1H), 8.45 (s, 1H) , 8.80 (dd, 1H).

Step 3:

In a manner analogous to step 3) of intermediate 2A), 3.03 g (11.6 mmol) of dimethyl 7-fluoroquinoline-2,4-dicarboxylate from step 2) of intermediate 37A) gave 2.33 g (81). %) Methyl 2-aminoformamido-7-fluoroquinoline-4-carboxylate.

¹ H-NMR (400MHz, DMSO d ₆ ) δ (ppm) = 4.03 (s, 3H), 7.83 (ddd, 1H), 7.94 (dd, 1H), 7.97 (s, 1H), 8.39 (s, 1H) , 8.52 (s, 1H), 8.83 (dd, 1H).

Step 4:

In a similar manner to the step 4) of the intermediate 2A), 3.0 g (12.1 mmol) of 2-aminopyridinyl-7-fluoroquinoline-4-carboxylic acid methyl ester of Step 3) of Intermediate 37A) gave 2.38. g (80%) of the desired compound.

¹ H-NMR (300 MHz, DMSO d ₆ ) δ (ppm) = 7.76 (ddd, 1H), 7.84-7.96 (m, 2H), 8.35 (br.s., 1H), 8.46 (s, 1H), 8.89 (dd, 1H), 14.02 (br.s., 1H).

Intermediate 38A 2-Aminomethylmercapto-6-chloroquinoline-4-carboxylic acid

step 1:

2.71 g (49%) of 6-chloroquinoline were obtained from 3.9 g (21.5 mmol) of commercially available 5-chloro-1H-indole-2,3-dione in a similar manner to step 1) of Intermediate 2A). 2,4-dicarboxylic acid.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 7.96 (dd, 1H), 8.26 (d, 1H), 8.53 (s, 1H), 8.92 (d, 1H), 13.94 (br.s. , 1H).

Step 2:

2.7 g (10.7 mmol) of 6-chloroquinoline-2,4-dicarboxylic acid of step 1) of intermediate 38A) was obtained in a similar manner to step 2) of Intermediate 2A). Chloroquinoline-2,4-dicarboxylic acid dimethyl ester.

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 3.98 (s, 3H), 4.01 (s, 3H), 7.99 (dd, 1H), 8.29 (d, 1H), 8.51 (s, 1H) , 8.79 (d, 1H).

Step 3:

1.54 g (87%) of 1.74 g (6.21 mmol) of 6-chloroquinoline-2,4-dicarboxylic acid dimethyl ester from step 2) of Intermediate 38A). ) 2-Aminomethylmercapto-6-chloroquinoline-4-carboxylic acid methyl ester.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 4.02 (s, 3H), 7.96 (br.s., 1H), 8.00 (dd, 1H), 8.24 (d, 1H), 8.42 (br) .s., 1H), 8.60 (s, 1H), 8.82 (d, 1H).

Step 4:

In a similar manner to step 4) of intermediate 2A), from the first experiment 0.5 g (1.9 mmol) and the second experiment 1.0 g (3.78 mmol) of intermediate 38A), step 2) of 2-aminocarbenyl- Methyl 6-chloroquinoline-4-carboxylate gave the title compound as a y.

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 7.90 (br.s., 1H), 7.95 (dd, 1H), 8.21 (d, 1H), 8.37 (br.s., 1H), 8.57 (s, 1H), 8.91 (d, 1H), 14.20 (br.s., 1H).

Intermediate 39A 2-aminoformamido-5-fluoroquinoline-4-carboxylic acid

step 1:

4.62 g (64%) of 5-fluoroquinoline were obtained from 5.07 g (30.7 mmol) of commercially available 4-fluoro-1H-indole-2,3-dione in a similar manner to step 1) of Intermediate 2A). -2,4-dicarboxylic acid.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 7.76 (ddd, 1H), 7.97 (dd, 1H), 8.38 (s, 1H), 8.90 (dd, 1H).

Step 2:

4.62 g (80%) of 5.62 g (19.6 mmol) of 5-fluoroquinoline-2,4-dicarboxylic acid from step 1) of Intermediate 39A). - fluoroquinoline-2,4-dicarboxylic acid dimethyl ester.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 3.98 (s, 3H), 4.01 (s, 3H), 7.84 (ddd, 1H), 8.06 (dd, 1H), 8.44 (s, 1H) , 8.80 (dd, 1H).

Step 3:

4.79 g (72 g) of step 7. %) Methyl 2-aminoformamido-5-fluoroquinoline-4-carboxylate.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 4.01 (s, 3H), 7.80 (ddd, 1H), 7.89-7.96 (m, 2H), 8.36 (br.s., 1H), 8.50 (s, 1H), 8.80 (dd, 1H).

Step 4:

1.02 (6.04 mmol) of 2-aminomethylindolyl-5-fluoroquinoline-4-carboxylic acid methyl ester of step 3) of Intermediate 39A) was obtained in the form of step 4) of Intermediate 2A). g (72%) of the desired compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 7.73-7.82 (m, 1H), 7.86-7.94 (m, 2H), 8.35 (s, 1H), 8.47 (s, 1H), 8.90 ( Dd, 1H), 13.97 (br.s., 1H).

Intermediate 40A 2-aminoformamido-5-methylquinoline-4-carboxylic acid

step 1:

1.64 g (49%) of 5-methyl was obtained from 2.0 g (12.4 mmol) of commercially available 4-methyl-1H-indole-2,3-dione in a similar manner to step 1) of Intermediate 2A). Quinoline-2,4-dicarboxylic acid.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.67-2.75 (m, 3H), 7.62-7.70 (m, 1H), 7.82 (dd, 1H), 8.00-8.05 (m, 1H), 8.09 (d, 1H).

Step 2:

Step 1) from intermediate 40A) in a similar manner to step 2) of intermediate 2A) 1.64 g (7.09 mmol) of 5-methylquinoline-2,4-dicarboxylic acid gave 2.1 g (110% of starting material) of dimethyl 5-methylquinoline-2,4-dicarboxylate.

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 2.57 (s, 3H), 4.01 (s, 3H), 3.98 (s, 3H), 7.70 (d, 1H), 7.82-7.89 (m, 1H), 8.12 (d, 1H), 8.16 (s, 1H).

Step 3:

In a similar manner to the step 3) of the intermediate 2A), from the step 2) of the intermediate 2A), 2.1 g (8.1 mmol) of dimethyl 5-methylquinoline-2,4-dicarboxylate gave 1.90 g ( 91%) methyl 2-aminoformamido-5-methylquinoline-4-carboxylate.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.55 (s, 3H), 3.99 (s, 3H), 7.64 (dt, 1H), 7.82 (dd, 1H), 7.86 (br.s. , 1H), 8.06 (d, 1H), 8.12 (s, 1H), 8.33 (br.s., 1H).

Step 4:

1.9 g (12.1 mmol) of 2-aminoformamido-5-methylquinoline-4-carboxylic acid methyl ester from step 3) of intermediate 40A) in a similar manner to step 4) of intermediate 2A) A solid was obtained, so the aqueous solution was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and then filtered and evaporated in vacuo. The solid was stirred in a mixture of ethyl acetate and methanol to give crystals, crystals,

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 2.67 (s, 3H), 7.58 (d, 1H), 7.78 (dd, 1H), 7.82 (br.s., 1H), 7.98 (s , 1H), 8.03 (d, 1H), 8.30 (br.s., 1H).

Intermediate 41A 2-Aminomethylmercapto-6-methylquinoline-4-carboxylic acid

step 1:

4.22 g (56%) of 6-methyl was obtained from 5.13 g (31.8 mmol) of commercially available 5-methyl-1H-indole-2,3-dione in a similar manner to step 1) of Intermediate 2A). Quinoline-2,4-dicarboxylic acid.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.59 (s, 3H), 2.63 - 2.75 (m, 1H), 7.79 (dd, 1H), 8.14 (d, 1H), 8.44 (s, 1H), 8.57 (s, 1H).

Step 2:

In a manner analogous to the step 2) of the intermediate 2A), 4.17 g (54%) was obtained from 4.2 g (18.2 mmol) of 6-methylquinoline-2,4-dicarboxylic acid from step 1) of Intermediate 41A). Dimethyl 6-methylquinoline-2,4-dicarboxylate.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.58 (s, 3H), 4.00 (s, 3H), 3.96 (s, 3H), 7.80 (dd, 1H), 8.15 (d, 1H) , 8.41 - 8.51 (m, 2H).

Step 3:

3.72 g (12.2 mmol) of dimethyl 6-methylquinoline-2,4-dicarboxylate of step 2) of intermediate 41A) was obtained in a procedure analogous to step 3) of Intermediate 2A). 88%) methyl 2-aminocarbamido-6-methylquinoline-4-carboxylate.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.57 (s, 3H), 4.00 (s, 3H), 7.78 (dd, 1H), 7.86 (br.s., 1H), 8.10 (d) , 1H), 8.34 (br.s., 1H), 8.40-8.53 (m, 2H).

Step 4:

In a manner similar to the step 4) of the intermediate 2A), from the step 3) of the intermediate 3A), 500 mg (2.05 mmol) of 2-aminocarbazin-6-methylquinoline-4-carboxylic acid methyl ester gave 480 mg. (102%, including some moisture) of the desired compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.56 (s, 3H), 7.76 (dd, 1H), 7.84 (br.s., 1H), 8.09 (d, 1H), 8.32 (br) .s., 1H), 8.46 (s, 1H), 8.55 (s, 1H), 13.95 (br.s., 1H).

Intermediate 42A 2-Aminomercapto-7-methoxyquinoline-4-carboxylic acid

step 1:

2.71 g (38%) 7-A was obtained from 5.0 g (28.2 mmol) of commercially available 6-methoxy-1H-indole-2,3-dione in a manner similar to step 1) of Intermediate 2A). Oxyquinoline-2,4-dicarboxylic acid.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 3.96 (s, 3H), 7.49 (dd, 1H), 7.60 (d, 1H), 8.31 (s, 1H), 8.69 (d, 1H) .

Step 2:

</ RTI> </ RTI> </ RTI> </RTI> </RTI> </RTI> </RTI> </RTI> </RTI> </RTI> </RTI> </RTI> </RTI> </RTI> Dimethyl 7-methoxyquinoline-2,4-dicarboxylate.

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 3.98 (s, 3H), 3.99 (s, 3H), 4.01 (s, 3H), 7.54 (dd, 1H), 7.67 (d, 1H) , 8.34 (s, 1H), 8.63 (d, 1H).

Step 3:

545 mg (1.98 mmol) of dimethyl 7-methoxyquinoline-2,4-dicarboxylate from step 2) of Intermediate 42A) gave 408 mg (79). %) Methyl 2-aminoformamido-7-methoxyquinoline-4-carboxylate.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 3.98 (s, 3H), 4.01 (s, 3H), 7.51 (dd, 1H), 7.58 (d, 1H), 7.88 (br.s. , 1H), 8.34 (br.s., 1H), 8.39 (s, 1H), 8.63 (d, 1H).

Step 4:

In a similar manner to the step 4) of the intermediate 2A), 400 mg (1.54 mmol) of 2-aminopyridinyl-7-methoxyquinoline-4-carboxylic acid methyl ester of Step 3) of Intermediate 42A) was obtained. 349 mg (44%) of the desired compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 3.95 (s, 3H), 7.38-7.46 (m, 1H), 7.53 (dd, 1H), 7.79 (br.s., 1H), 8.18 -8.30 (m, 2H), 8.67 (dd, 1H).

Intermediate 43A 2-Aminomethylmercapto-8-chloroquinoline-4-carboxylic acid

step 1:

3.34 g (48%) of 8-chloroquinoline were obtained from 5.0 g (27.5 mmol) of commercially available 7-chloro-1H-indole-2,3-dione in a similar manner to step 1) of Intermediate 2A). 2,4-dicarboxylic acid.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 6.57 (t, 1H), 7.15 (br.s., 2H), 7.47 (ddd, 2H), 7.69-7.79 (m, 1H), 8.05 -8.13 (m, 1H), 8.41 (s, 1H), 8.72 (d, 1H).

Step 2:

In a manner analogous to the step 2) of the intermediate 2A), 2.32 g (yield: 58%) of the 3.34 g (13.3 mmol) of 8-chloroquinolin-2,4-dicarboxylic acid from the step 1) of Intermediate 43A). Chloroquinoline-2,4-dicarboxylic acid dimethyl ester.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 3.99 (s, 3H), 4.01 (s, 3H), 7.84 (dd, 1H), 8.16 (dd, 1H), 8.53 (s, 1H) , 8.66 (dd, 1H).

Step 3:

In a similar manner to Step 3) of Intermediate 2A), 2.24 g (8.01 mmol) of dimethyl 8-chloroquinoline-2,4-dicarboxylate of Step 2) of Intermediate 43A) gave 1.69 g (76%) ) 2-Aminomethylmercapto-8-chloroquinoline-4-carboxylic acid methyl ester.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 4.02 (s, 3H), 7.81 (dd, 1H), 8.04-8.10 (m, 2H), 8.14 (dd, 1H), 8.58 (s, 1H), 8.66 (dd, 1H).

Step 4:

1.60 g of 1.68 g (6.35 mmol) of 2-aminoformamido-8-chloroquinoline-4-carboxylic acid methyl ester of step 3) of Intermediate 43A). (100%) of the desired compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 7.81 (ddd, 1H), 8.04-8.10 (m, 1H), 8.14 (d, 1H), 8.51 (s, 1H), 8.57 (s, 1H), 8.76 (d, 1H), 14.16 (s, 1H).

Intermediate 44A 2-Aminomethylmercapto-5,7-difluoroquinoline-4-carboxylic acid

step 1:

850 mg (32%) of 5,7 were obtained from 1.85 g (10.1 mmol) of commercially available 4,6-difluoro-1H-indole-2,3-dione in a similar manner to step 1) of Intermediate 2A). -difluoroquinoline-2,4-dicarboxylic acid.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 7.74 (ddd, 1H), 7.78 - 7.87 (m, 1H), 7.91 (s, 1H).

Step 2:

910 mg (92%) of 850 mg (3.36 mmol) of 5,7-difluoroquinolin-2,4-dicarboxylic acid from step 1) of Intermediate 44A). Dimethyl 5,7-difluoroquinoline-2,4-dicarboxylate.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 3.96 (s, 3H), 3.97 (s, 3H), 7.91 (ddd, 1H), 8.00 (ddd, 1H), 8.24 (s, 1H) .

Step 3:

950 mg (3.24 mmol) of dimethyl 5,7-difluoroquinoline-2,4-dicarboxylate of step 2) of Intermediate 44A) gave 850 mg (m. 92%) methyl 2-aminocarbamido-5,7-difluoroquinoline-4-carboxylate.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 3.96 (s, 3H), 7.79-7.94 (m, 2H), 8.00 (br.s., 1H), 8.21 (s, 1H), 8.38 (br.s., 1H).

Step 4:

230 mg (0.86 mmol) of 2-aminoformamido-5,7-difluoroquinoline-4-carboxylic acid methyl ester from step 3) of intermediate 44A) in a procedure analogous to step 4) of intermediate 2A) 150 mg (65%) of the desired title compound are obtained.

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 7.77-7.85 (m, 2H), 7.96 (br.s., 1H), 8.07 (s, 1H), 8.34 (br.s., 1H ), 14.02 (br.s., 1H).

Intermediate 45A 2-Aminomercapto-7-fluoro-6-methoxyquinoline-4-carboxylic acid

step 1:

1.3 g (30%) from 3.11 g (15.9 mmol) of commercially available 6-fluoro-5-methoxy-1H-indole-2,3-dione in a similar manner to step 1) of Intermediate 2A) 7-Fluoro-6-methoxyquinoline-2,4-dicarboxylic acid.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 4.02 (s, 3H), 8.02 (d, 1H), 8.43 (d, 1H), 8.48 (s, 1H), 13.72 (br.s. , 1H).

Step 2:

In a manner similar to the step 2) of the intermediate 2A), from the step 1) of the intermediate 1A), 1.3 g (4.9 mmol) of 7-fluoro-6-methoxyquinolin-2,4-dicarboxylic acid gave 960 mg. (57%) dimethyl 7-fluoro-6-methoxyquinoline-2,4-dicarboxylate.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 3.97 (s, 3H), 4.03 (s, 3H), 4.05 (s, 3H), 8.10 (d, 1H), 8.33 (d, 1H) , 8.48 (s, 1H).

Step 3:

960 mg (3.27 mmol) of dimethyl 7-fluoro-6-methoxyquinoline-2,4-dicarboxylate from step 2) of intermediate 45A) in a procedure analogous to step 3) of Intermediate 2A) 520 mg (57%) of crude 2-aminocarbazin-7-fluoro-6-methoxyquinoline-4-carboxylate were obtained which was used without further purification.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 4.03 (s, 3H), 4.05 (s, 3H), 7.88 (br.s., 1H), 7.95 (d, 1H), 8.29 (br) .s., 1H), 8.35 (d, 1H), 8.54 (s, 1H).

Step 4:

520 mg (1.87 mmol) of 2-aminoformamido-7-fluoro-6-methoxyquinolin-4- from step 3) of Intermediate 45A) in a procedure analogous to Step 4) of Intermediate 2A) Methyl formate gave 440 mg (61%) of the desired compound, which included about 31% corresponding diacid.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 4.01 (s, 3H), 7.78 (br.s., 1H), 7.78 (d, 1H), 8.21. (br.s., 1H), 8.44-8.49 (m, 2H).

Intermediate 46A 2-Aminomethylmercapto-6-methoxyquinoline-4-carboxylic acid

step 1:

3.01 (42%) 6-A was obtained from 5.0 g (38.2 mmol) of commercially available 5-methoxy-1H-indole-2,3-dione in a similar manner to Step 1) of Intermediate 2A). Oxyquinoline-2,4-dicarboxylic acid.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 3.94 (s, 3H), 7.57 (dd, 1H), 8.14 (d, 1H), 8.25 (d, 1H), 8.48 (s, 1H) , 13.66 (br.s., 1H).

Step 2:

In a similar manner to the step 2) of the intermediate 2A), from the step 1) of the intermediate 1A), 3.0 g (12.1 mmol) of 6-methoxyquinoline-2,4-dicarboxylic acid gave 2.65 g (77%). Dimethyl 6-methoxyquinoline-2,4-dicarboxylate.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 3.95 (s, 6H), 4.00 (s, 3H), 7.60 (dd, 1H), 8.13-8.20 (m, 2H), 8.48 (s, 1H).

Step 3:

2.65 g (9.63 mmol) of dimethyl 6-methoxyquinoline-2,4-dicarboxylate from step 2) of Intermediate 46A), 1.45 g, m. (55%) methyl 2-aminoformamido-6-methoxyquinoline-4-carboxylate.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 3.97 (s, 3H), 4.03 (s, 3H), 7.62 (dd, 1H), 7.82 (br.s., 1H), 8.14 (d) , 1H), 8.18 (d, 1H), 8.30 (br.s., 1H), 8.56 (s, 1H).

Step 4:

Step 3) from intermediate 46A) in a similar manner to step 4) of intermediate 2A) 1.45 g (5.57 mmol) of 2-aminoformamido-6-methoxyquinoline-4-carboxylic acid methyl ester gave 1.33 g (92%)

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 3.93 (s, 3H), 7.57 (dd, 1H), 7.79 (s, 1H), 8.09 (d, 1H), 8.25 (d, 1H) , 8.27 (br.s., 1H), 8.51 (s, 1H), 13.72 (br.s., 1H), 13.79-13.79 (m, 1H).

Intermediate 47A 2-Aminomethylmercapto-8-fluoroquinoline-4-carboxylic acid

step 1:

4.75 g (60%) of 8-fluoroquinoline was obtained from 5.36 g (32.5 mmol) of commercially available 7-fluoro-1H-indole-2,3-dione in a manner similar to step 1) of Intermediate 2A). -2,4-dicarboxylic acid.

¹ H-NMR (300 MHz, DMSO d ₆ ) δ (ppm) = 7.72 - 7.87 (m, 2H), 8.51 (s, 1H), 8.59 (d, 1H).

Step 2:

4.70 g (72%) of 8.70 g (20.0 mmol) of 8-fluoroquinoline-2,4-dicarboxylic acid from step 1) of Intermediate 47A). - fluoroquinoline-2,4-dicarboxylic acid dimethyl ester.

¹ H-NMR (300 MHz, DMSO d ₆ ) δ (ppm) = 3.99 (s, 3H), 4.02 (s, 3H), 7.77-7.92 (m, 2H), 8.48 - 8.57 (m, 2H).

Step 3:

4.90 g (16.7 mmol) of dimethyl 8-fluoroquinoline-2,4-dicarboxylate from step 2) of Intermediate 47A) gave 3.90 g (85). %) Methyl 2-aminoformamido-8-fluoroquinoline-4-carboxylate.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 4.03 (s, 3H), 7.74 - 7.92 (m, 2H), 8.00 (br.s., 1H), 8.24 (s, 1H), 8. (d, 1H), 8.61 (s, 1H).

Step 4:

190 mg (500 mg (2.01 mmol) of 2-aminopyridyl-8-fluoroquinoline-4-carboxylic acid methyl ester of step 3) of Intermediate 47A) 40%) of the desired compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 7.71-7.85 (m, 2H), 7.96 (br.s., 1H), 8.20 (s, 1H), 8.53-8.62 (m, 2H) .

Intermediate 48A 2-Aminomethylmercapto-7-chloroquinoline-4-carboxylic acid

step 1:

6.61 g (119%) of crude 7-chloroquinoline were obtained from 4.0 g (22.0 mmol) of commercially available 6-chloro-1H-indole-2,3-dione in a similar manner to step 1) of Intermediate 2A). -2,4-Dicarboxylic acid, which was used without further purification.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 7.78 (dd, 1H), 8.29 (d, 1H), 8.47 (s, 1H), 8.84 (d, 1H).

Step 2:

7.5 g (29.8 mmol) of 7-chloroquinoline-2,4-dicarboxylic acid from step 1) of Intermediate 48A) gave 4.60 g (55%) of 7- Chloroquinoline-2,4-dicarboxylic acid dimethyl ester.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 3.98 (s, 3H), 4.01 (s, 3H), 7.92 (dd, 1H), 8.35 (d, 1H), 8.47 (s, 1H) , 8.75 (d, 1H).

Step 3:

In a similar manner to the step 3) of the intermediate 2A), 4.50 g (16.1 mmol) of dimethyl 7-fluoroquinoline-2,4-dicarboxylate of Step 2) of Intermediate 48A) gave 3.72 g (83). %) Methyl 2-aminocarbamido-7-chloroquinoline-4-carboxylate.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 4.00 (s, 3H), 7.89 (dd, 1H), 7.97 (br.s., 1H), 8.23 (d, 1H), 8.38 (br) .s., 1H), 8.53 (s, 1H), 8.75 (d, 1H).

Step 4:

In a similar manner to the step 4) of the intermediate 2A), from EtOAc (400 mg (1.51 mmol) of ethyl 2-aminocarbazin-7-chloroquinoline-4-carboxylate of %) The desired compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 7.65 (dd, 1H), 7.75 (br.s., 1H), 8.06 (d, 1H), 8.18 (s, 1H), 8.22 (br) .s., 1H), 8.86 (d, 1H).

Intermediate 49A 2-Aminomethylmercapto-6-chloro-8-fluoroquinoline-4-carboxylic acid

step 1:

590 mg (17%) 6- obtained from 2.5 g (12.5 mmol) of commercially available 5-chloro-7-fluoro-1H-indole-2,3-dione in a similar manner to step 1) of Intermediate 2A). Chloro-8-fluoroquinoline-2,4-dicarboxylic acid.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 7.99 (dd, 1H), 8.56 (s, 1H), 8.74 - 8.77 (m, 1H).

Step 2:

550 mg (2.19%) of 590 mg (2.19 mmol) of 6-chloro-8-fluoroquinoline-2,4-dicarboxylic acid from step 1) of Intermediate 49A) Dimethyl 6-chloro-8-fluoroquinoline-2,4-dicarboxylate.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 3.99 (s, 3H), 4.02 (s, 3H), 8.06 (dd, 1H), 8.57-8.62 (m, 2H).

Step 3:

550 mg (1.85 mmol) of dimethyl 6-chloro-8-fluoroquinoline-2,4-dicarboxylate of step 2) of Intermediate 49A) gave 480 mg. (83%) methyl 2-aminocarbamido-6-chloro-8-fluoroquinoline-4-carboxylate.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 4.01 (s, 3H), 7.98-8.07 (m, 2H), 8.23 (br.s., 1H), 8.60-8.62 (m, 1H) , 8.63 (s, 1H).

Step 4:

480 mg (1.70 mmol) of 2-aminoformamido-6-chloro-8-fluoroquinoline-4-carboxylic acid A from step 3) of Intermediate 49A) in a procedure analogous to Step 4) of Intermediate 2A) The ester gave 430 mg (85%) of the desired compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 7.93 - 8.01 (m, 2H), 8.19 (br.s., 1H), 8.60 (s, 1H), 8.73 - 8.76 (m, 1H) .

Intermediate 50A 2-Aminomercapto-7-fluoro-6-methylquinoline-4-carboxylic acid

step 1:

In a manner similar to step 1) of intermediate 2A), from 18.0 g (100 mmol) of commercially available 6-fluoro-5-methyl-1H-indole-2,3-dione ([CAS number 749240-55- 9], for example Fluorochem) gave 8.55 g (33%) of 7-fluoro-6-methylquinolin-2,4-dicarboxylic acid.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.51 (s, 3H), 7.95 (d, 1H), 8.41 (s, 1H), 8.72 (d, 1H).

Step 2:

8.5 g of 8.55 g (34.3 mmol) of 7-fluoro-6-methylquinoline-2,4-dicarboxylic acid from step 1) of Intermediate 50A), mp. (69%) dimethyl 7-fluoro-6-methylquinoline-2,4-dicarboxylate.

¹ H-NMR (400MHz, DMSO d ₆ ) δ (ppm) = 2.51 (s, 3H), 3.98 (s, 3H), 4.02 (s, 3H), 7.99 (d, 1H), 8.40 (s, 1H) , 8.61 (d, 1H).

Step 3:

6.93 g (25.0 mmol) of dimethyl 7-fluoro-6-methylquinoline-2,4-dicarboxylate from step 2) of intermediate 50A) in a procedure analogous to step 3) of intermediate 2A) 4.86 g (72%) of methyl 2-aminocarbamido-7-fluoro-6-methylquinoline-4-carboxylate are obtained.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.50 (s, 3H), 4.00 (s, 3H), 7.85 (d, 1H), 7.89 (br.s., 1H), 8.31 (br) .s., 1H), 8.45 (s, 1H), 8.60 (d, 1H).

Step 4:

1.50 g (5.72 mmol) of 2-aminoformamido-7-fluoro-6-methylquinoline-4- from step 3) of intermediate 50A) in a procedure analogous to step 4) of Intermediate 2A) Methyl formate gave 1.34 g (90%) of the desired compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.51 (s, 3H), 7.85 (d, 1H), 7.89 (br.s., 1H), 8.32 (br.s., 1H), 8.45 (s, 1H), 8.71 (d, 1H), 13.94 (br.s., 1H).

Intermediate 51A 6-fluoro-2-methoxyquinoline-4-carboxylic acid

The title compound was prepared according to the procedure described in US 6,699,879, 2004, starting from commercially available 6-fluoro-2-hydroxyquinoline-4-carboxylic acid ([607-40-9], for example, ABCR).

¹ H-NMR (400MHz, DMSO d ₆ ) δ (ppm) = 4.01 (s, 3H), 7.49 (s, 1H), 7.64 (td, 1H), 7.91 (dd, 1H), 8.34 (dd, 1H) , 14.00 (br.s., 1H).

Intermediate 52A 2-(azetidin-1-ylcarbonyl)-7-fluoroquinoline-4-carboxylic acid

step 1:

To a solution of 500 mg (1.90 mmol) of 7-fluoroquinoline-2,4-dicarboxylic acid dimethyl ester of the intermediate 2A) in EtOAc (EtOAc m. The reaction mixture was stirred at 24 ° C for 14 hours. The solid formed was separated by filtration and dried. Using this method, 390 mg (69%) of the desired methyl 2-(azetidin-1-ylcarbonyl)-7-fluoroquinoline-4-carboxylate was obtained.

¹ H-NMR (400MHz, DMSO d ₆ ) δ (ppm) = 2.30-2.40 (m, 2H), 4.02 (s, 3H), 4.16 (dd, 2H), 4.77 (t, 2H), 7.81 (ddd, 1H), 7.97 (dd, 1H), 8.40 (s, 1H), 8.79 (dd, 1H).

Step 2:

390 mg (1.35 mmol) of 2-(azetidin-1-ylcarbonyl)-7-fluoroquinoline-4 from step 1) of intermediate 52A) in a procedure analogous to step 4) of Intermediate 2A) Methyl formate afforded 210 mg (42%) of the desired compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.34 (quin, 2H), 4.16 (t, 2H), 4.76 (t, 2H), 7.76 (ddd, 1H), 7.93 (dd, 1H) , 8.35 (s, 1H), 8.87 (dd, 1H), 14.07 (br.s., 1H).

Intermediate 53A 7-fluoro-2-[(3-hydroxypropyl)aminemethanyl]quinoline-4-carboxylic acid

step 1:

To a solution of step 2) 500 mg (1.90 mmol) of dimethyl 7-fluoroquinoline-2,4-dicarboxylate in 10 mL of MeOH (m.) -alcohol. The reaction mixture was stirred at 24 ° C for 14 hours and then evaporated to dryness. The desired mixture of the desired material (yield: 7-fluoro-2-[(3-hydroxypropyl)amine-carbamoyl]quinoline-4-carboxylic acid methyl ester and the corresponding bis-amine (850 mg) was used in the next step.

Step 2:

7-Fluoro-2-[(3-hydroxypropyl)aminemethanyl]quinoline-4-carboxylic acid A from Step 1) of Intermediate 53A) in a similar manner to Step 4) of Intermediate 2A) The 850 mg mixture of the ester and the corresponding bis-indoleamine gave 190 mg of the crude material.

Intermediate 54A 7-fluoro-2-{[2-(morpholin-4-yl)ethyl]aminemethanyl}quinoline-4-carboxylic acid

step 1:

To a solution of 500 mg (1.90 mmol) of 7-fluoroquinoline-2,4-dicarboxylic acid dimethyl ester of the intermediate 2A) in 10 mL of methanol, 0.50 mL (3.80 mmol) of 2-(morpholine-4) -yl)ethylamine. The reaction mixture was stirred at 24 ° C for 3 days and then evaporated to dryness. The desired mixture of the desired substance 7-fluoro-2-{[2-(morpholin-4-yl)ethyl]amine-carbamoyl}quinoline-4-carboxylic acid methyl ester and the corresponding bis-indoleamine (800 mg) Any further purification was used in the next step.

Step 2:

7-Fluoro-2-{[2-(morpholin-4-yl)ethyl]aminecarbenyl} from step 1) of intermediate 54A) in a similar manner to step 4) of intermediate 2A) A mixture of 800 mg of the quinoline-4-carboxylic acid methyl ester and the corresponding bis-indoleamine afforded 250 mg of the starting material.

Intermediate 55A 2-Aminomercapto-6-[(2-methoxyethyl)amino]quinoline-4-carboxylic acid

step 1:

To a solution of 3.30 g (9.71 mmol) of 6-bromo-2-amine-methylpyridylquinoline-4-carboxylic acid methyl ester of the intermediate 3A) in 60 mL of toluene, 2.49 g (10.2 mmol) of bis (4) -Methoxyphenyl)methanol and 185 mg (0.97 mmol) of p-toluenesulfonic acid and using a water separator, the mixture was heated to reflux for 5 hours. After cooling, the reaction mixture was diluted with EtOAc EtOAc. The crude product was purified via a Biotage chromatography system (50 g cartridge KP-Sil column, hexane / 0-100% ethyl acetate) to afford 2.47 g (41%) 2-{[double (4) Methyl-methoxyphenyl)methyl]amine-carbamoyl}-6-bromoquinoline-4-carboxylate.

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 3.72 (s, 6H), 4.00 (s, 3H), 6.31-6.35 (m, 1H), 6.88-6.93 (m, 4H), 7.28- 7.34 (m, 4H), 8.08 (dd, 1H), 8.21 (d, 1H), 8.54 (s, 1H), 8.95 (d, 1H), 9.38-9.43 (m, 1H).

Step 2:

17.2 g (90.0 mmol) of methyl 2-{[bis(4-methoxyphenyl)methyl]aminocarbazino}-6-bromoquinoline-4-carboxylate of Step 1) of Intermediate 55A) 84.2 mg (1.12 mmol) of 2-methoxyethylamine, 85.5 mg (0.093 mmol) of bis(diphenylmethyleneacetone) dipalladium (0), 108 mg (0.187 mmol) of Xantphos and 669 mg (2.06 mmol) of cesium carbonate A 500 mg (0.93 mmol) suspension in 5.4 mL of dioxane was heated to 80 °C for 3 hours. After cooling to room temperature, the mixture was diluted with EtOAc and EtOAc (EtOAc)EtOAc. The residue was purified via a Biotage chromatography system (25 g K K K K K K K K K K (69%) methyl 2-{[bis(4-methoxyphenyl)methyl]amine-methylmethyl}-6-[(2-methoxyethyl)amino]quinoline-4-carboxylate .

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 3.31 (s, 3H), 3.34 (q, 2H), 3.58 (t, 2H), 3.72 (s, 6H), 3.95 (s, 3H) , 6.28 (d, 1H), 6.88-6.93 (m, 4H), 6.95 (t, 1H), 7.25-7.31 (m, 4H), 7.40 (dd, 1H), 7.60 (d, 1H), 7.91 (d , 1H), 8.38 (s, 1H), 9.01 (d, 1H).

Step 3:

425 mg (0.80 mmol) of 2-{[bis(4-methoxyphenyl)methyl]aminemethanyl}-6-[(2-methoxyethyl) to step 2) of Intermediate 55A) 0.33 mL (4.32 mmol) of trifluoro-acetic acid and 0.64 mL (4.01 mmol) of triethyl decane were added to a solution of methylamino]quinoline-4-carboxylate in 10 mL of dichloromethane, and then the mixture was heated to 40 ° C for 14 hours. An additional 0.64 mL (4.01 mmol) of triethyldecane and 0.5 mL of trifluoro-acetic acid were added and heated to 40 ° C for 14 hours. And add another 0.38mL (2.41mmol) triethyl decane and 0.2 mL trifluoro-acetic acid and heated to 45 ° C for 14 hours. After cooling to room temperature, the mixture was evaporated to dryness and passed through a Biotage chromatography system (10 g snap KP-Sil column, hexane / 0-100% ethyl acetate followed by ethyl acetate / 0-80% The residue was purified to give 196 mg (81%) ofyield of 2-aminocarbazin-6-[(2-methoxyethyl)amino]quinoline-4-carboxylate as the desired compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 3.31 (s, 3H), 3.34 (q, 4H), 3.59 (t, 2H), 3.95 (s, 3H), 6.88-6.95 (m, 1H), 7.41 (dd, 1H), 7.59-7.63 (m, 2H), 7.86 (d, 1H), 8.08 (br.s., 1H), 8.40 (s, 1H).

Step 4:

196 mg (0.65 mmol) of 2-aminomethylmercapto-6-[(2-methoxyethyl)amino group from step 3) of intermediate 55A) in a procedure analogous to step 4) of Intermediate 2A) Methyl quinoline-4-carboxylate gave 71 mg (36%) of desired compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 3.31 (s, 3H), 3.33 (t, 2H), 3.58 (t, 2H), 7.39 (dd, 1H), 7.58 (br.s. , 1H), 7.67 (d, 1H), 7.85 (d, 1H), 8.06 (br.s., 1H), 8.38 (s, 1H).

Intermediate 56A 2-Aminomercapto-6-(piperidin-1-yl)quinoline-4-carboxylic acid

step 1:

196 mg (0.65 mmol) of 2-{[bis(4-methoxyphenyl)methyl]aminecarbenamide from step 1) of Intermediate 55A) in a procedure analogous to Step 2) of Intermediate 55A) Methyl-6-bromoquinoline-4-carboxylate and 70.5 mg (0.83 mmol) of piperidine gave 260 mg (70%) of 2-{[bis(4-methoxyphenyl)methyl] as the desired compound. Aminomethylamino}-6-(piperidin-1-yl)quinoline-4- Methyl formate.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 1.59-1.72 (m, 6H), 3.42-3.48 (m, 4H), 3.74 (s, 6H), 3.98 (s, 3H), 6.31 ( d,1H), 6.89-6.96 (m, 4H), 7.31 (d, 4H), 7.77-7.82 (m, 1H), 7.99 (d, 1H), 8.04 (d, 1H), 8.44 (s, 1H) , 9.14 (d, 1H).

Step 2:

260 mg (0.48 mmol) of 2-{[bis(4-methoxyphenyl)methyl]aminecarbenamide from step 1) of intermediate 56A) in a procedure analogous to step 3) of Intermediate 55A) Methyl-6-(piperidin-1-yl)quinoline-4-carboxylate gave 72 mg (34%) of 2-amine-carbazin-6-(piperidin-1-yl)quinoline as the desired compound. -4-methyl formate.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 1.58-1.72 (m, 6H), 3.39-3.47 (m, 4H), 3.97 (s, 3H), 7.68 (br.s., 1H) , 7.78 (dd, 1H), 7.94-8.00 (m, 2H), 8.15 (br.s., 1H), 8.44 (s, 1H).

Step 3:

72 mg (0.23 mmol) of 2-aminoformamido-6-(piperidin-1-yl)quinoline-4 from step 3) of intermediate 56A) in a procedure analogous to step 4) of Intermediate 2A) Methyl formate afforded 24 mg (35%) of the desired compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 1.55-1.74 (m, 6H), 3.34 - 3.46 (m, 4H), 7.68 (br.s., 1H), 7.77 (d, 1H) , 7.96 (d, 1H), 8.06 (br.s., 1H), 8.15 (br.s., 1H), 8.43 (s, 1H), 13.65 (br.s., 1H).

Intermediate 57A 2-amine sulfonylquinoline-4-carboxylic acid

This compound can be prepared by reacting commercially available 2,4-dibromoquinoline as a starting material with sodium sulfite to give 4-bromoquinolin-2-sulfonic acid (similar to US 2008/45568, Chemische Berichte 1920, Volume 53, page 1021). Subsequently, 4-bromoquinolin-2-sulfonamide can be obtained by successively reacting with sulfinium chloride and ammonia. Finally, a carbonylation reaction using methanol containing hexacarbonyl molybdenum in the presence of palladium(II) acetate/1,3-bis(diphenylphosphino)-propane/triethylamine as a catalyst system is followed by Saponification of the introduced methyl ester with sodium hydroxide provides the title compound.

Intermediate 58A 2-(methylaminesulfonyl)quinoline-4-carboxylic acid

The title compound is obtained in the same manner as described for 2-amine sulfonylquinoline-4-carboxylic acid (Intermediate 57A) using methylamine instead of ammonia.

Intermediate 59A 2-(dimethylaminesulfonyl)quinoline-4-carboxylic acid

The title compound can be obtained in a manner analogous to that described for 2-aminosulfonylquinoline-4-carboxylic acid (Intermediate 57A) using dimethylamine instead of ammonia.

Intermediate 60A 2-[(methylsulfonyl)amine-carbamoyl]quinoline-4-carboxylic acid

step 1:

Between 750 ° C and -30 ° C, a solution of 500 mg (2.17 mmol) of 2-aminopyridylquinoline-4-carboxylic acid methyl ester (Step 2 of Intermediate 4A) in 8.1 mL of THF was given 8.7 mL. 1 M bis(trimethyldecyl decylamine) lithium solution (similar to WO 2012/7877). After stirring for 30 minutes, 0.67 mL (8.69 mmol) of methanesulfonic acid chloride was added at -60 ° C and stirred at -60 ° C for 2 hours. The reaction mixture was poured into water. This aqueous phase was extracted three times with ethyl acetate. The aqueous phase was then evaporated to dryness in vacuo and then stirred in a mixture of methanol and dichloromethane (ratio 1:1). This organic phase was then adsorbed onto Isolute® HM-N (Biotage) under evaporation and passed through a Biotage chromatography system (25 g snap KP-Sil column, hexane/80-100% ethyl acetate followed by acetic acid) Ethyl ester / 0-100% methanol) was purified to give 320 mg (41%) of 2-[(methylsulfonyl)aminecarbazinyl]quinoline-4-carboxylic acid methyl ester.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 3.15 (s, 3H), 4.03 (s, 3H), 7.83 (ddd, 1H), 7.90-7.96 (m, 1H), 8.27 (d, 1H), 8.53 (s, 1H), 8.70 (d, 1H), 12.14 (br.s., 1H).

Step 2:

320 mg (1.04 mmol) of 2-[(methylsulfonyl)amine-carbamoyl]quinoline-4-carboxylic acid A from Step 1) of Intermediate 60A) in a procedure analogous to Step 4) of Intermediate 2A) The ester gave 120 mg (35%) of the desired compound.

¹ H-NMR (400MHz, DMSO d ₆ ) δ (ppm) = 3.43 (s, 3H), 7.89 (ddd, 1H), 7.98 (ddd, 1H), 8.31 (dd, 1H), 8.45 (s, 1H) , 8.80 (dd, 1H).

Intermediate 1B 1-(4-fluorobenzyl)-3,5-dimethyl-4-nitro-1H-pyrazole

150 mg (1.06 mmol) of 3,5-dimethyl-4-nitro-1H-pyrazole (CAS No. 14531-55-6) was dissolved in 5 mL of acetonitrile and 158 μL (1.28 mmol) of 1-(bromomethyl) was added. -4-fluorobenzene and 416 mg (1.28 mmol) of cesium carbonate. The suspension was stirred at 60 ° C for 2 hours. The reaction mixture was then filtered, the filtrate was evaporated and the residue was partitioned between ethyl acetate and water. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with EtOAc EtOAc m.

1H NMR (400MHz, CDCl ₃ ): δ (ppm) = 2.55 (s, 3 H), 2.58 (s, 3 H), 5.23 (s, 2 H), 7.05 (m, 2 H), 7.13-7.19 ( m, 2 H).

Intermediate 2B 1-(3-fluorobenzyl)-3,5-dimethyl-4-nitro-1H-pyrazole

In a manner similar to Intermediate 1B, 400 mg (2.83 mmol) of 3,5-dimethyl-4-nitro-1H-pyrazole and 417 μL (3.40 mmol) of 1-(bromomethyl)-3-fluorobenzene. It was heated at 60 ° C for 2 hours together with 1.11 g (3.40 mmol) of cesium carbonate in 10 mL of acetonitrile. The reaction mixture was then filtered, the filtrate was evaporated and the residue was crystallisjjjjjjjjjjjj The isolute was applied to a Biotage snap-on cartridge (25 g; KP-Sil) pre-equilibrated with hexane and purified by silica gel column chromatography (solvent: hexane / 0-40% ethyl acetate) to give 682 mg. (2.74mmol, 97%) Things.

Method 1: R _t =1.21 min

MS (ESIpos): m/z = 250 (M+H) ⁺

Intermediate 3B 1-(2-fluorobenzyl)-3,5-dimethyl-4-nitro-1H-pyrazole

In a manner similar to the intermediate 1B, 200 mg (1.42 mmol) of 3,5-dimethyl-4-nitro-1H-pyrazole and 205 μL (1.70 mmol) of 1-(bromomethyl)-2-fluorobenzene And 554 mg (1.70 mmol) of cesium carbonate in 5 mL of acetonitrile were heated at 60 ° C for 2 hours. The reaction mixture was then filtered, the filtrate was evaporated and the residue was crystallisjjjjjjjjjjjj The isolute was applied to a Biotage snap-on cartridge (25 g; KP-Sil) pre-equilibrated with hexane and purified by silica gel column chromatography (solvent: hexane / 0-40% ethyl acetate) to yield 336 mg. (1.35 mmol, 95%) of the desired compound.

1H NMR (300MHz, CDCl ₃ ): δ (ppm) = 2.54 (s, 3 H) 2.62 (s, 3 H) 5.31 (s, 2 H) 7.01-7.20 (m, 3 H) 7.28-7.41 (m, 1 H).

Intermediate 4B 1-(3,4-difluorobenzyl)-3,5-dimethyl-4-nitro-1H-pyrazole

In a manner similar to Intermediate 1B, 400 mg (2.83 mmol) of 3,5-dimethyl-4-nitro-1H-pyrazole and 435 μL (3.40 mmol) of 4-(bromomethyl)-1,2- Difluorobenzene and 1.11 g (3.40 mmol) of cesium carbonate in 10 mL of acetonitrile were heated at 60 ° C for 2 hours. The reaction mixture was then filtered, and the filtrate was evaporated.

Method 1: R _t = 1.23 min

MS (ESIpos): m/z = 266 (M+H) ⁺ .

Intermediate 5B 1-(2,4-difluorobenzyl)-3,5-dimethyl-4-nitro-1H-pyrazole

In a similar manner to the intermediate 1B, 400 mg (2.83 mmol) of 3,5-dimethyl-4-nitro-1H-pyrazole and 436 μL (3.40 mmol) of 1-(bromomethyl)-2,4- Difluorobenzene and 1.11 g (3.40 mmol) of cesium carbonate in 10 mL of acetonitrile were heated at 60 ° C for 2 hours. The reaction mixture was then filtered, and the filtrate was evaporated.

Method 1: R _t = 1.23 min

MS (ESIpos): m/z = 266 (M+H) ⁺ .

Intermediate 6B 1-(2,6-difluorobenzyl)-3,5-dimethyl-4-nitro-1H-pyrazole

In a manner similar to Intermediate 1B, 400 mg (2.83 mmol) of 3,5-dimethyl-4-nitro-1H-pyrazole and 436 μL (3.40 mmol) of 2-(bromomethyl)-1,3- Difluorobenzene and 1.11 g (3.40 mmol) of cesium carbonate in 10 mL of acetonitrile were heated at 60 ° C for 2 hours. The reaction mixture was then filtered, and the filtrate was evaporated.

Method 1: R _t = 1.19 min

MS (ESIpos): m/z = 266 (M+H) ⁺ .

Intermediate 7B 3,5-Dimethyl-4-nitro-1-(2,4,6-trifluorobenzyl)-1H-pyrazole

In a similar manner to the intermediate 1B, 400 mg (2.83 mmol) of 3,5-dimethyl-4-nitro-1H-pyrazole and 446 μL (3.40 mmol) of 2-(bromomethyl)-1,3, 5-Trifluorobenzene and 1.11 g (3.40 mmol) of cesium carbonate were added together with 10 mL of acetonitrile at 60 ° C for 2 hours. The reaction mixture was then filtered, and the filtrate was evaporated.

Method 1: R _t = 1.18 min

MS (ESIpos): m/z = 286 (M+H) ⁺ .

Intermediate 8B 4-[(3,5-Dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]benzonitrile

In a manner similar to Intermediate 1B, 6.0 g (42.5 mmol) of 3,5-dimethyl-4-nitro-1H-pyrazole and 10.0 g (51.0 mmol) of 4-(bromomethyl)-benzene were obtained. The nitrile was reacted to give 9.56 g (yield: 88%) of the desired compound after the crude product was purified from EtOAc EtOAc EtOAc EtOAc

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 2.40 (s, 3H), 2.56 (s, 3H), 5.48 (s, 2H), 7.35 (d, 2H), 7.82 (d, 2H) .

Intermediate 9B 3-[(3,5-Dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]benzonitrile

In a manner similar to Intermediate 1B, 400 mg (2.83 mmol) of 3,5-dimethyl-4-nitro-1H-pyrazole and 666 mg (3.40 mmol) of 3-(bromomethyl)benzonitrile and 1.11 g (3.40 mmol) of cesium carbonate 10 mL of acetonitrile was heated together at 60 ° C for 2 hours. The reaction mixture was then filtered, the filtrate was evaporated and the residue was crystallisjjjjjjjjjjjj Isolute was applied to a Biotage snap cartridge (25 g; KP-Sil) pre-equilibrated with hexane and purified by cartridge chromatography (solvent: hexane / 0-50% ethyl acetate) to dry After that 705 mg (2.75 mmol, 97%) of the desired compound was obtained.

1H NMR (400MHz, CDCl ₃ ): δ (ppm) = 2.56 (s, 3 H), 2.59 (s, 3 H), 5.29 (s, 2 H), 7.40 (d, 1 H), 7.44 - 7.53 ( m, 2 H), 7.64 (d, 1 H).

Intermediate 10B 2-[(3,5-Dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]benzonitrile

In a manner similar to the intermediate 1B), 1.5 g (10.6 mmol) of 3,5-dimethyl-4-nitro-1H-pyrazole and 2.5 g (12.8 mmol) of 2-(bromomethyl)-benzene were obtained. The acetonitrile was reacted to give 2.48 g (yield: 89%) of the desired title compound after the crude product was purified from EtOAc (EtOAc).

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 2.37 (s, 3H), 2.64 (s, 3H), 5.53 (s, 2H), 7.22 (d, 1H), 7.49-7.57 (m, 1H), 7.69 (td, 1H), 7.89 (dd, 1H).

Intermediate 11B 1-(4-methoxybenzyl)-3,5-dimethyl-4-nitro-1H-pyrazole

In a manner similar to the intermediate 1B), 1.5 g (10.6 mmol) of 3,5-dimethyl-4-nitro-1H-pyrazole and 2.56 g (12.8 mmol) of 1-(bromomethyl)-4 were obtained. -Methoxybenzene reaction, resulting in 2.41 g (85%) of the desired title after purification of the crude product via a Biotage chromatography system (50 g cartridge KP-Sil column, hexane / 30-100% ethyl acetate) Compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.39 (s, 3H), 2.57 (s, 3H), 3.72 (s, 3H), 5.26 (s, 2H), 6.87-6.93 (m, 2H), 7.14-7.20 (m, 2H).

Intermediate 12B 1-(3-methoxybenzyl)-3,5-dimethyl-4-nitro-1H-pyrazole

In a manner similar to the intermediate 1B, 200 mg (1.42 mmol) of 3,5-dimethyl-4-nitro-1H-pyrazole and 341 mg (1.70 mmol) of 1-(bromomethyl)-3-methoxy The benzene was heated at 60 ° C for 2 hours with 554 mg (1.70 mmol) of cesium carbonate in 10 mL of acetonitrile. The reaction mixture was then filtered, the filtrate was evaporated and the residue was crystallisjjjjjjjjjjjj Isolute was applied to a Biotage snap cartridge (25 g; KP-Sil) pre-equilibrated with hexane and purified by cartridge chromatography (solvent: hexane / 0-50% ethyl acetate) to dry Afterwards 368 mg (1.41 mmol, 99%) of the desired title compound.

Method 1: R _t = 1.19 min

MS (ESIpos): m/z = 262 (M+H) ⁺ .

Intermediate 13B 3,5-Dimethyl-1-(4-methylbenzyl)-4-nitro-1H-pyrazole

In a manner similar to Intermediate 1B, 400 mg (2.83 mmol) of 3,5-dimethyl-4-nitrate The benzyl-1H-pyrazole was heated at 60 ° C for 2 hours with 10 mL of acetonitrile containing 629 mg (3.40 mmol) of 1-(bromomethyl)-4-toluene and 1.11 g (3.40 mmol) of cesium carbonate. The reaction mixture was then filtered, and the filtrate was evaporated to give 686 mg (····

Method 1: R _t = 1.28 min

MS (ESIpos): m/z = 246 (M+H) ⁺ .

Intermediate 14B 3,5-Dimethyl-1-(3-methylbenzyl)-4-nitro-1H-pyrazole

In a manner similar to the intermediate 1B, 400 mg (2.83 mmol) of 3,5-dimethyl-4-nitro-1H-pyrazole and 629 mg (3.40 mmol) of 1-(bromomethyl)-3-toluene and 1.11 g (3.40 mmol) of cesium carbonate in 10 mL of acetonitrile was heated at 60 ° C for 2 hours. After the reaction mixture was filtered, the filtrate was evaporated to give 681 mg (yel.

Method 1: R _t = 1.27 min

MS (ESIpos): m/z = 246 (M+H) ⁺ .

Intermediate 15B 3,5-Dimethyl-1-(2-methylbenzyl)-4-nitro-1H-pyrazole

In a similar manner to the intermediate 1B, 400 mg (2.83 mmol) of 3,5-dimethyl-4-nitro-1H-pyrazole and 629 mg (3.40 mmol) of 1-(bromomethyl)-2-toluene and 1.11 g (3.40 mmol) of cesium carbonate in 10 mL of acetonitrile was heated at 60 ° C for 2 hours. The reaction mixture was then filtered, and the filtrate was evaporated.

Method 1: R _t = 1.26 min

MS (ESIpos): m/z = 246 (M+H) ⁺ .

Intermediate 16B 4-[(3,5-Dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]pyridine

In a manner similar to the intermediate 1B), 1.5 g (10.6 mmol) of 3,5-dimethyl-4-nitro-1H-pyrazole and 3.23 g (12.8 mmol) of 4-(bromomethyl)pyridine hydrogen were obtained. The bromate reaction was carried out after purification of the crude product via a Biotage chromatography system (25 g snap KP-Sil column, hexane / 0-100% ethyl acetate followed by ethyl acetate / 0 - 45% methanol) , 1.576 g (62%) of the desired title compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.41 (s, 3H), 2.56 (s, 3H), 5.44 (s, 2H), 7.08-7.15 (m, 2H), 8.49-8.56 ( m, 2H).

Intermediate 17B 3-[(3,5-Dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]pyridine

In a manner similar to the intermediate 1B), 1.8 g (12.8 mmol) of 3,5-dimethyl-4-nitro-1H-pyrazole and 3.87 g (15.3 mmol) of 3-(bromomethyl)pyridine hydrogen were obtained. Bromate reaction, after purification of the crude product via a Biotage chromatography system (50 g cartridge KP-Sil cartridge, hexane / 0-100% ethyl acetate followed by ethyl acetate / 0-45% methanol) , 2.24 g (68%) of the desired title compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.38 (s, 3H), 2.62 (s, 3H), 5.41 (s, 2H), 7.38 (dd, 1H), 7.61 (dt, 1H) , 8.48-8.53 (m, 2H).

Intermediate 18B 2-[(3,5-Dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]pyridine

In a manner similar to Intermediate 1B, 300 mg (2.13 mmol) of 3,5-dimethyl-4-nitro-1H-pyrazole and 645 mg (2.55 mmol) of 2-(bromomethyl)pyridine hydrobromide salt It was heated at 60 ° C for 2 hours with 1.52 g (4.68 mmol) of cesium carbonate in 10 mL of acetonitrile. The reaction mixture was then filtered, the filtrate was evaporated and the residue was crystallisjjjjjjjjjjjj Isolute was applied to a Biotage snap cartridge (25 g; KP-Sil) pre-equilibrated with hexane and purified by cartridge chromatography (solvent: hexane / 0-75% ethyl acetate) to dry Afterwards 467 mg (2.01 mmol, 95%) of the desired title compound.

1H NMR (300MHz, CDCl ₃ ): δ (ppm) = 2.55 (s, 3 H), 2.64 (s, 3 H), 5.38 (s, 2 H), 7.08 (d, 1 H), 7.21 - 7.26 ( m, 1 H), 7.69 (td, 1 H), 8.58 (d, 1 H).

Intermediate 19B 3,5-Dimethyl-4-nitro-1-[4-(trifluoromethoxy)benzyl]-1H-pyrazole

In a manner similar to Intermediate 1B, 400 mg (2.83 mmol) of 3,5-dimethyl-4-nitro-1H-pyrazole and 544 μL (3.40 mmol) of 1-(bromomethyl)-4-(III) Fluoromethoxy)benzene and 1.11 g (3.40 mmol) of cesium carbonate in 10 mL of acetonitrile were heated at 60 ° C for 2 hours. The reaction mixture was then filtered, and the filtrate was evaporated.

Method 1: R _t = 1.35 min

MS (ESIpos): m/z = 316 (M+H) ⁺ .

Intermediate 20B 3,5-Dimethyl-4-nitro-1-[3-(trifluoromethoxy)benzyl]-1H-pyrazole

In a manner similar to Intermediate 1B, 400 mg (2.83 mmol) of 3,5-dimethyl-4-nitro-1H-pyrazole and 551 μL (3.40 mmol) of 1-(bromomethyl)-3-(three Fluoromethoxy)benzene and 1.11 g (3.40 mmol) of cesium carbonate in 10 mL of acetonitrile were heated at 60 ° C for 2 hours. After the reaction mixture was filtered, the filtrate was evaporated, mjjjjjjjj

Method 1: R _t = 1.35 min

MS (ESIpos): m/z = 316 (M+H) ⁺ .

Intermediate 21B 3,5-Dimethyl-4-nitro-1-[2-(trifluoromethoxy)benzyl]-1H-pyrazole

In a manner similar to the intermediate 1B, 400 mg (2.83 mmol) of 3,5-dimethyl-4-nitro-1H-pyrazole and 548 μL (3.40 mmol) of 1-(bromomethyl)-2-(III) Fluoromethoxy)benzene and 1.11 g (3.40 mmol) of cesium carbonate in 10 mL of acetonitrile were heated at 60 ° C for 2 hours. The reaction mixture was then filtered, and the filtrate was evaporated to give 893 mg (2.

Method 1: R _t = 1.35 min

MS (ESIpos): m/z = 316 (M+H) ⁺ .

Intermediate 22B 3,5-Dimethyl-4-nitro-1-[4-(trifluoromethyl)benzyl]-1H-pyrazole

In a similar manner to the intermediate 1B, 400 mg (2.83 mmol) of 3,5-dimethyl-4-nitro-1H-pyrazole and 813 mg (3.40 mmol) of 1-(bromomethyl)-4-(3) The fluoromethyl)benzene was heated together with 10.10 g (3.40 mmol) of cesium carbonate in 10 mL of acetonitrile at 60 ° C for 2 hours. The reaction mixture was then filtered, the filtrate was evaporated and the residue was crystallisjjjjjjjjjjjj Isolute was applied to a Biotage snap-on cartridge (25 g; KP-Sil) pre-equilibrated with hexane and purified via a silica gel column chromatography (solvent: hexane-ethyl acetate) to afford 790 mg after drying ( 2.64 mmol, 93%) of the desired compound.

1H NMR (300MHz, CDCl ₃ ): δ (ppm) = 2.53-2.57 (m, 3 H), 2.58 (s, 3 H), 5.33 (s, 2 H), 7.27 (d, 2 H), 7.63 ( d, 2 H).

Intermediate 23B 1-(3,4-difluorobenzyl)-5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazole

In a similar manner to the intermediate 1B), 1.2 g (6.15 mmol) of 5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazole and 1.53 g (7.38 mmol) of 4-( Reaction of bromomethyl)-1,2-difluorobenzene to give 1.76 after purification of the crude product via a Biotage chromatography system (25 g K K-Sil column, hexane / 0-70% ethyl acetate) g (85%) of the desired compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.65 (s, 3H), 5.53 (s, 2H), 7.12 (ddd, 1H), 7.38 (ddd, 1H), 7.45 (dt, 1H) .

Intermediate 24B 1-(2,4-difluorobenzyl)-5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazole

In a manner similar to the intermediate 1B), 1.2 g (6.15 mmol) of 5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazole and 1.53 g (7.38 mmol) 1-( Bromomethyl)-2,4-difluorobenzene was reacted to obtain 1.73 after purification of the crude product via a Biotage chromatography system (25 g K K-Sil column, hexane / 0-70% ethyl acetate). g (83%) of the desired compound.

¹ H-NMR (300 MHz, DMSO d ₆ ) δ (ppm) = 2.68 (s, 3H), 5.54 (s, 2H), 7.12 (tdd, 1H), 7.27-7.44 (m, 2H).

Intermediate 25B 1-(4-fluorobenzyl)-5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazole

In a manner similar to the intermediate 1B), 3.51 g (18.0 mmol) of 5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazole and 4.08 g (21.6 mmol) of 1-( Bromomethyl)-4-fluorobenzene was reacted to obtain 4.21 g (73) after purification of the crude product via a Biotage chromatography system (25 g K K-Sil column, hexane / 0-70% ethyl acetate). %) The desired compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.66 (s, 3H), 5.53 (s, 2H), 7.17-7.24 (m, 2H), 7.30-7.37 (m, 2H).

Intermediate 26B 4-{[5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}benzonitrile

In a manner similar to the intermediate 1B), 4.30 g (22.0 mmol) of 5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazole and 5.19 g (26.5 mmol) of 4-( Reaction of bromomethyl)benzonitrile to give 6.30 g (88%) after purification of the crude product via a Biotage chromatography system (100 g cartridge KP-Sil column, hexane / 0-70% ethyl acetate) The title compound is desired.

¹ H-NMR (300 MHz, DMSO d ₆ ) δ (ppm) = 2.63 (s, 3H), 5.67 (s, 2H), 7.38-7.44 (m, 2H), 7.83-7.88 (m, 2H).

Intermediate 27B 1-(4-chlorobenzyl)-3,5-dimethyl-4-nitro-1H-pyrazole

1.72 g (12.2 mmol) of 3,5-dimethyl-4-nitro-1H-pyrazole and 3.00 g (14.6 mmol) of 1-(bromomethyl)-4 were obtained in a similar manner to the intermediate 1B). -Chlorobenzene reaction, after purification of the crude product via Biotage chromatography system (50 g snap KP-Sil column, hexane / 0-100% ethyl acetate followed by ethyl acetate / 0-45% methanol) , 3.5 g (101%, purity: 94%) of the desired title compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.39 (s, 3H), 2.57 (s, 3H), 5.36 (s, 2H), 7.18-7.25 (m, 2H), 7.38-7.44 ( m, 2H).

Intermediate 28B 1-(3-chloro-4-fluorobenzyl)-3,5-dimethyl-4-nitro-1H-pyrazole

In a manner similar to the intermediate 1B), 1.58 g (11.2 mmol) of 3,5-dimethyl-4-nitro-1H-pyrazole and 3.00 g (13.4 mmol) of 4-(bromomethyl)-2 were obtained. -Chloro-1-fluorobenzene reaction, thus passing through Biotage chromatography system (50g snap KP-Sil column, hexane / 0-100% ethyl acetate, followed by ethyl acetate / 0-45% methanol) After purification of the crude product, 3.16 g (85%)

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.39 (s, 3H), 2.59 (s, 3H), 5.35 (s, 2H), 7.21 (ddd, 1H), 7.39 (t, 1H) , 7.49 (dd, 1H).

Intermediate 29B 5-[(3,5-Dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]pyridine-2-carbonitrile

In a similar manner to the intermediate 1B), 2.98 g (21.1 mmol) of 3,5-dimethyl-4-nitro-1H-pyrazole and 5.00 g (25.4 mmol) of 5-(bromomethyl)pyridine- 2-carbonitrile reaction, after purifying the crude product via a Biotage chromatography system (100 g cartridge KP-Sil column, hexane / 20-100% ethyl acetate), 3.69 g (64%) .

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.39 (s, 3H), 2.61 (s, 3H), 5.53 (s, 2H), 7.81 (dd, 1H), 8.02 (dd, 1H) , 8.66 (d, 1H).

Intermediate 30B 1-benzyl-3,5-dimethyl-4-nitro-1H-pyrazole

Step 1:1 - Benzyl-3,5-dimethyl-1H-pyrazole:

In a manner similar to Intermediate 1B, 500 mg (5.20 mmol) of 3,5-dimethyl-1H-pyrazole was combined with 10 mL of acetonitrile containing 741 μL (6.24 mmol) of benzyl bromide and 2.03 g (6.24 mmol) of cesium carbonate. Heat at 60 ° C for 2 hours. The reaction mixture was then filtered, the filtrate was evaporated and the residue was crystallisjjjjjjjjjjjj The isolute was applied to a Biotage snap-on cartridge (25 g; KP-Sil) pre-equilibrated with hexane and purified by cartridge chromatography (solvent: hexane-ethyl acetate) to obtain 508 mg after drying ( 2.73 mmol, 52%) 1-benzyl-3,5-dimethyl-1H- Pyrazole.

_{1H NMR (400MHz, CDCl 3)} : δ (ppm) = 2.15 (s, 3 H), 2.26 (s, 3 H), 5.23 (s, 2 H), 5.86 (s, 1 H), 7.08 (d, 2 H), 7.22 - 7.26 (m, 1 H), 7.28-7.35 (m, 2 H).

Step 2: 1-Benzyl-3,5-dimethyl-4-nitro-1H-pyrazole:

500 mg (2.68 mmol) of 1-benzyl-3,5-dimethyl-1H-pyrazole was dissolved in 4 mL of acetic anhydride and 200 μL (3.14 mmol) of concentrated nitric acid was slowly added to 1 mL of acetic anhydride at 0 °C. Solution. Stirring was continued for 24 hours at 25 °C. The reaction mixture was then carefully poured into a saturated aqueous solution of sodium bicarbonate and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate The residue was dissolved in dichloromethane and adsorbed on Isolute® HM-N (Biotage) under evaporation. The isolute was applied to a Biotage snap-on cartridge (25 g; KP-Sil) pre-equilibrated with hexane and purified by silica gel column chromatography (solvent: hexane-ethyl acetate) to obtain 610 mg after drying ( 2.64 mmol, 98%) of the desired compound.

Method 1: R _t = 1.18 min

MS (ESIpos): m/z = 232 (M+H) ⁺ .

Intermediate 31B Methyl 4-[(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]benzoate

In a manner similar to Intermediate 1B), 10.3 g (72.8 mmol) of 3,5-dimethyl-4-nitro-1H-pyrazole and 20.0 g (87.3 mmol) of 4-(bromomethyl)benzoic acid were obtained. The methyl ester was reacted to give 18.3 g (82 g) after two subsequent purifications of the crude product via a Biotage chromatography system (100 and 50 g snap KP-Sil column, hexane / 0-100% ethyl acetate). %) Compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.40 (s, 3H), 2.56 (s, 3H), 3.83 (s, 3H), 5.47 (s, 2H), 7.25-7.34 (m, 2H), 7.89-7.96 (m, 2H).

Intermediate 32B Methyl {4-[(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]phenyl}acetate

In a manner similar to Intermediate 1B), 2.42 g (17.1 mmol) of 3,5-dimethyl-4-nitro-1H-pyrazole and 5.00 g (20.6 mmol) of [4-(bromomethyl)benzene were obtained. Reaction of methyl acetate to give 3.81 g (55%) of the desired title after purification of the crude product via a Biotage chromatography system (50 g cartridge KP-Sil column, hexane / 0-100% ethyl acetate) Compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.39 (s, 3H), 2.58 (s, 3H), 3.59 (s, 3H), 3.65 (s, 2H), 5.33 (s, 2H) , 7.13-7.17 (m, 2H), 7.22-7.26 (m, 2H).

Intermediate 33B 1-(cyclohexylmethyl)-3,5-dimethyl-4-nitro-1H-pyrazole

In a manner similar to the intermediate 1B), 3.32 g (23.5 mmol) of 3,5-dimethyl-4-nitro-1H-pyrazole and 5.00 g (28.2 mmol) of (bromomethyl)cyclohexane were reacted. Thus pure in the Biotage chromatography system (100g snap KP-Sil column, hexane / 0-100% ethyl acetate) After the crude product was obtained, 4.76 g (yiel.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 0.89 - 1.04 (m, 2H), 1.06-1.22 (m, 3H), 1.50 (d, 2H), 1.55-1.69 (m, 3H), 1.72-1.85 (m, 1H), 2.38 (s, 3H), 2.55 (s, 3H), 3.90 (d, 2H).

Intermediate 34B 1-[(5-chloro-2-thienyl)methyl]-3,5-dimethyl-4-nitro-1H-pyrazole

In a manner similar to the intermediate 1B), 1.41 g (9.98 mmol) of 3,5-dimethyl-4-nitro-1H-pyrazole and 2.00 g (12.0 mmol) of 2-chloro-5-(chloroform) were obtained. Thiophene reaction, after purification of the crude product via a Biotage chromatography system (25 g snap KP-Sil column, hexane / 0-100% ethyl acetate followed by ethyl acetate / 0-50% methanol) , 2.51 g (88%) of the desired title compound.

¹ H-NMR (400MHz, DMSO d ₆ ) δ (ppm) = 2.39 (s, 3H), 2.62 (s, 3H), 5.49 (s, 2H), 6.98-7.01 (m, 1H), 7.01-7.04 ( m, 1H).

Intermediate 35B 3,5-Dimethyl-1-[(1-methyl-1H-pyrazol-3-yl)methyl]-4-nitro-1H-pyrazole

0.90 g (6.38 mmol) of 3,5-dimethyl-4-nitro-1H-pyrazole and 1.00 g (7.66 mmol) of 3-(chloromethyl)-1 were obtained in a similar manner to the intermediate 1B). -methyl-1H-pyrazole reaction, Thus, after purification of the crude product via a Biotage chromatography system (25 g K K-Sil column, hexane / 0-100% ethyl acetate followed by ethyl acetate / 0-50% methanol), 1.28 g ( 83%) of the desired compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.37 (s, 3H), 2.62 (s, 3H), 3.77 (s, 3H), 5.24 (s, 2H), 6.13 (d, 1H) , 7.61 (d, 1H).

Intermediate 36B 2-[(3,5-Dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]-3-methylpyridine

In a similar manner to the intermediate 1B, 200 mg (1.41 mmol) of 3,5-dimethyl-4-nitro-1H-pyrazole and 316 mg (1.70 mmol) of 2-(bromomethyl)-6-methyl Pyridine hydrobromide salt and 554 mg (1.70 mmol) of cesium carbonate in 10 mL of acetonitrile were heated at 60 ° C for 2 hours. The reaction mixture was then filtered, the filtrate was evaporated and the residue was crystallisjjjjjjjjjjjj Isolute was applied to a Biotage snap cartridge (25 g; KP-Sil) pre-equilibrated with hexane and purified by cartridge chromatography (solvent: hexane / 0-75% ethyl acetate) to dry After that 339 mg (1.38 mmol, 97%) of the desired compound was obtained.

1H NMR (300MHz, CDCl ₃ ): δ (ppm) = 2.47-2.60 (m, 6 H), 2.64 (s, 3 H), 5.34 (s, 2 H), 6.78 (d, 1 H), 7.09 ( d, 1 H), 7.55 (t, 1 H).

Intermediate 37B 3,5-Dimethyl-1-[4-(methylsulfonyl)benzyl]-4-nitro-1H-pyrazole

0.66 g (4.67 mmol) of 3,5-dimethyl-4-nitro-1H-pyrazole and 1.40 g (5.62 mmol) of 4-(bromomethyl)phenyl group were obtained in a similar manner to the intermediate 1B). Methyl hydrazine reaction, after purification of the crude product via Biotage chromatography system (25 g snap KP-Sil column, hexane / 0-100% ethyl acetate followed by ethyl acetate / 0-15% methanol) , 0.71 g (48%) of the desired title compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.40 (s, 3H), 2.59 (s, 3H), 3.19 (s, 3H), 5.50 (s, 2H), 7.40-7.46 (m, 2H), 7.87-7.93 (m, 2H).

Intermediate 38B 4-[(3,5-Dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]-2-fluorobenzonitrile

0.66 g (4.67 mmol) of 3,5-dimethyl-4-nitro-1H-pyrazole and 1.00 g (5.62 mmol) of 4-(bromomethyl)-2 were obtained in a similar manner to the intermediate 1B). -Fluorobenzonitrile reaction, resulting in 1.14 g (86%) of the desired title after purification of the crude product via a Biotage chromatography system (25 g K K-Sil column, hexane / 30-100% ethyl acetate) Compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.37 (s, 3H), 2.61 (s, 3H), 5.49 (s, 2H), 7.30 (t, 1H), 7.68 (dd, 1H) , 7.91 (dd, 1H).

Intermediate 39B 3-[(3,5-Dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]pyridine-2-carbonitrile

In a manner similar to Intermediate 1B), 1.49 g (10.6 mmol) of 3,5-dimethyl-4-nitro-1H-pyrazole and 2.50 g (12.7 mmol) of 3-(bromomethyl)pyridine- 2-carbonitrile reaction to purify the crude product via a Biotage chromatography system (50 g snap KP-Sil column, hexane / 0-100% ethyl acetate followed by ethyl acetate / 0-15% methanol) Thereafter, 2.36 g (82%) of the desired title compound was obtained.

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 2.37 (s, 3H), 2.67 (s, 3H), 5.58 (s, 2H), 7.71-7.74 (m, 2H), 8.71 (t, 1H).

Intermediate 40B 2-[(3,5-Dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]nicotinonitrile

In a manner similar to Intermediate 1B), 1.49 g (10.6 mmol) of 3,5-dimethyl-4-nitro-1H-pyrazole and 2.50 g (12.7 mmol) of 2-(bromomethyl)nicotine were obtained. The nitrile was reacted to obtain a crude product after purification of the crude product via a Biotage chromatography system (50 g K K-Sil column, hexane / 0-100% ethyl acetate followed by ethyl acetate / 0-15% methanol) 2.16 g (75%) of the desired compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.36 (s, 3H), 2.63 (s, 3H), 5.69 (s, 2H), 7.57 (dd, 1H), 8.38 (dd, 1H) , 8.75 (dd, 1H).

Intermediate 41B 4-[(3,5-Dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]-N-(2-hydroxyethyl)benzamide

Step 1: 4-[(3,5-Dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]benzoic acid

To 1.0 g (3.468 mmol) of methyl 4-[(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]benzoate (Intermediate 31B) in 10 mL of methanol and 1 mL An aqueous solution of 2.56 g (63.9 mmol) of sodium hydroxide in 20 mL of water was added to the solution in THF. This mixture was heated at 40 ° C for 3 hours and evaporated after cooling to 25 ° C. 10 mL of water was added to the residue and then a 10% aqueous solution of sulfuric acid was added until pH 3. The obtained solid was separated by filtration and dried to give 890 mg (91%) of 4-[(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]benzoic acid.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.40 (s, 3H), 2.56 (s, 3H), 5.45 (s, 2H), 7.28 (d, 2H), 7.91 (d, 2H) , 12.83 (br.s., 1H).

Step 2: 4-[(3,5-Dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]-N-(2-hydroxyethyl)benzamide

To a solution of 890 mg (3.23 mmol) of the acid prepared in step 1) of Intermediate 41B) in 10 mL of DMSO, 1.84 g (4.85 mmol) of HATU, 0.85 mL of N , N -diisopropylethylamine and 0.23 mL were added. (3.88 mmol) 2-aminoethanol. The reaction mixture was stirred at 25 ° C for 2 hours. Water was added to this mixture and it was then extracted twice with 30 mL of ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate The crude product was purified via a Biotage chromatography system (25 g K K K K K K K K K K The desired non-completely pure compound.

¹ H-NMR (400MHz, DMSO d ₆ ) δ (ppm) = 2.40 (s, 3H), 2.57 (s, 3H), 3.30 (q, 2H), 3.48 (q, 2H), 4.68 (t, 1H) , 5.41 (s, 2H), 7.25 (d, 2H), 7.81 (d, 2H), 8.39 (t, 1H).

Intermediate 42B 1-(3-Fluoro-4-methoxybenzyl)-3,5-dimethyl-4-nitro-1H-pyrazole

In a manner similar to the intermediate 1B), 1.07 g (7.61 mmol) of 3,5-dimethyl-4-nitro-1H-pyrazole and 2.00 g (9.13 mmol) of 3-fluoro-4-methoxy Benzyl bromide reaction to purify the crude product via a Biotage chromatography system (25 g snap KP-Sil column, hexane/10-100% ethyl acetate followed by ethyl acetate / 0-25% methanol) Thereafter, 2.09 g (93%) of the desired title compound was obtained.

¹ H-NMR (500MHz, DMSO d ₆ ) δ (ppm) = 2.39 (s, 3H), 2.58 (s, 3H), 3.80 (s, 3H), 5.27 (s, 2H), 6.98-7.02 (m, 1H), 7.07-7.15 (m, 2H).

Intermediate 43B 2-methoxy-5-{[5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}pyridine

547 mg (2.80 mmol) of 5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazole and 530 mg (3.36 mmol) of 5-(chloroform) in a similar manner to the intermediate 1B) (meth)-2-methoxypyridine (Journal of Organic Chemistry, 2011 , 8336), thus passing through a Biotage chromatography system (25g snap KP-Sil column, hexane/10-100% ethyl acetate, After purification of the crude product, EtOAc /EtOAc (EtOAc)

¹ H-NMR (400MHz, DMSO d ₆ ) δ (ppm) = 2.69 (s, 3H), 3.83 (s, 3H), 5.48 (s, 2H), 6.82 (d, 1H), 7.63 (dd, 1H) , 8.18 (d, 1H).

Intermediate 44B 1-[3-(4-methoxyphenyl)propyl]-3,5-dimethyl-4-nitro-1H-pyrazole

In a manner similar to the intermediate 1B), 2.00 g (14.2 mmol) of 3,5-dimethyl-4-nitro-1H-pyrazole and 3.14 g (17.0 mmol) of 1-(3-chloropropyl) were obtained. 4-methoxybenzene (available from Ablock Pharmatech Inc. or Matrix Scientific) for reaction via Biotage chromatography system (50g snap KP-Sil column, hexane / 0-70% ethyl acetate) After purifying the crude product, 2.91 g (67%) of desired compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 1.94-2.04 (m, 2H), 2.38 (s, 3H), 2.50-2.55 (m, 5H), 3.70 (s, 3H), 4.04 ( t, 2H), 6.81-6.85 (m, 2H), 7.08-7.13 (m, 2H).

Intermediate 45B 4-[(3,5-Dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]nicotinonitrile

In a manner similar to the intermediate 1B), 1.06 g (7.50 mmol) of 3,5-dimethyl-4-nitro-1H-pyrazole and 2.50 g (8.99 mmol) of 4-(bromomethyl)nicotine were obtained. Nitrile hydrobromide (commercially available from Santai Labs; the parent compound is commercially available, for example, from Aquila Pharmatech or Ellanova Laboratories) for reaction via a Biotage chromatography system (25g and a second 50g snap-on KP-Sil column), After two subsequent purifications of the crude product from hexane / 0-100%EtOAcEtOAcEtOAcEtOAcEtOAc

¹ H-NMR (400MHz, DMSO d ₆ ) δ (ppm) = 2.39 (s, 3H), 2.62 (s, 3H), 5.62 (s, 2H), 7.15 (d, 1H), 8.78 (d, 1H) , 9.04 (s, 1H).

Intermediate 46B 3,5-Dimethyl-4-nitro-1-(2-phenoxyethyl)-1H-pyrazole

780 mg (5.53 mmol) of 3,5-dimethyl-4-nitro-1H-pyrazole and 1.50 g (6.64 mmol) of 4-(2-bromoethoxy) in a similar manner to the intermediate 1B) Benzoonitrile ([CAS No. 37142-39-5], available from, for example, Combi-Blocks Inc. or ACC Corporation) is reacted via a Biotage chromatography system (50g snap-on KP-Sil column, hexane) After purification of the crude product / EtOAc (EtOAc):

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.39 (s, 3H), 2.64 (s, 3H), 4.43 (t, 2H), 4.52 (t, 2H), 7.07-7.14 (m, 2H), 7.73-7.80 (m, 2H).

Intermediate 47B 4-[(3,5-Dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]-3-fluorobenzonitrile

934 mg (6.62 mmol) of 3,5-dimethyl-4-nitro-1H-pyrazole and 1.70 g (7.94 mmol) of 4-(bromomethyl)-3-, in a similar manner to the intermediate 1B) Fluorobenzonitrile ([CAS No. 105942-09-4], available from, for example, ABCR) for reaction via Biotage chromatography system (50g snap KP-Sil column, hexane / 0-100% acetic acid) Ethyl ester) After purification of the crude product, 1.84 g (yield:

¹ H-NMR (400MHz, DMSO d ₆ ) δ (ppm) = 2.38 (s, 3H), 2.63 (s, 3H), 5.50 (s, 2H), 7.31 (t, 1H), 7.70 (dd, 1H) , 7.92 (dd, 1H).

Intermediate 48B 2-{[5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}benzonitrile

2.07 g (10.6 mmol) of 5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazole was dissolved in 37 mL together with 2.50 (12.8 mmol) of 2-(bromomethyl)benzonitrile. In DMSO. In Tim After adding 2.4 ml (15.9 mmol) of DBU, the reaction mixture was stirred at room temperature for 18 hours. The mixture was then diluted with EtOAc (EtOAc)EtOAc. This material was purified via a EtOAc EtOAc EtOAc (EtOAc)

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 2.72 (s, 3H), 5.75 (s, 2H), 7.32 (d, 1H), 7.55-7.61 (m, 1H), 7.73 (td, 1H), 7.94 (dd, 1H).

Intermediate 49B 1-(4-methoxybenzyl)-5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazole

In a manner similar to the intermediate 1B), 5.0 g (25.6 mmol) of 5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazole and 4.82 g (30.8 mmol) of 1-( Chloromethyl)-4-methoxybenzene was reacted to obtain 6.7 g after purification of the crude product via a Biotage chromatography system (50 g K K-Sil column, hexane / 0-100% ethyl acetate) (79%) of the desired compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.65 (s, 3H), 3.73 (s, 3H), 5.45 (s, 2H), 6.93 (d, 2H), 7.22 (d, 2H) .

Intermediate 50B 5-[(3,5-Dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]-2-methoxypyridine

In a similar manner to the intermediate 1B), in two experiments, 187 mg (1.32 mmol) / 2.31 g (16.4 mmol) of 3,5-dimethyl-4-nitro-1H-pyrazole and 250 mg (1.59). Ment) / 3.10 g (19.7 mmol) of 5-(chloromethyl)-2-methoxypyridine (Journal of Organic Chemistry, 2011 , 8336), thus passing through a Biotage chromatography system (50 g snap-on KP-Sil) Column, hexane/10-100% ethyl acetate, followed by ethyl acetate / 0-25% and a second 50 g snap KP-Sil column, hexane/10-100% ethyl acetate) After two subsequent purifications of the combined crude product, 3.23 g (70%) of the desired compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.38 (s, 3H), 2.62 (s, 3H), 3.82 (s, 3H), 5.29 (s, 2H), 6.79 (d, 1H) , 7.58 (dd, 1H), 8.13 (d, 1H).

Intermediate 51B 4-{[5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}nicotinonitrile

In a similar manner to the intermediate 1B), in two experiments, 250 mg (1.28 mmol) / 1.17 g (6.0 mmol) of 5-methyl-4-nitro-3-(trifluoromethyl)-1H- Pyrazole and 427 mg (1.54 mmol) / 2.0 g (7.20 mmol) of 4-(bromomethyl)nicotinonitrile hydrobromide (available from Santai Labs; the parent compound is commercially available, for example, from Aquila Pharmatech or Ellanova Laboratories) Reaction, thus passing through Biotage chromatography system (50g snap KP-Sil column, hexane/10-100% ethyl acetate, followed by ethyl acetate / 0-45% methanol and second 25g snap KP After two subsequent purifications of the combined crude product of -Sil column, hexanes/10-100% ethyl acetate, then ethyl acetate / 0-5% methanol, g (50%) of the desired compound.

¹ H-NMR (400MHz, DMSO d ₆ ) δ (ppm) = 2.67 (s, 3H), 5.83 (s, 2H), 7.24 (dd, 1H), 8.81 (d, 1H), 9.07 (s, 1H) .

Intermediate 52B 5-{[5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}pyridine-2-carbonitrile

In a manner similar to the intermediate 1B), 2.48 g (12.7 mmol) of 5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazole and 3.00 g (15.2 mmol) 5- ( Bromomethyl)pyridine-2-carbonitrile ([308846-06-2], available, for example, from Fluorochem, Apollo Scientific) for reaction via a Biotage chromatography system (50g snap-on KP-Sil column) After two subsequent purifications of the crude product from EtOAc/EtOAc (EtOAc:EtOAc)

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 2.68 (s, 3H), 5.73 (s, 2H), 7.90 (dd, 1H), 8.07 (d, 1H), 8.73 (d, 1H) .

Intermediate 53B 3-fluoro-4-{[5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}benzonitrile

1.29 g (6.62 mmol) of 5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazole and 1.70 g (7.94 mmol) of 4-(in a similar manner to Intermediate 1B). Bromomethyl)-3-fluorobenzonitrile ([CAS No. 105942-09-4], available from, for example, ABCR) for purification in crude material via Biotage chromatography system (50g snap KP-Sil column, hexane / 0-100% ethyl) After the product, 1.89 g (78%).

¹ H-NMR (400MHz, DMSO d ₆ ) δ (ppm) = 2.68 (s, 3H), 5.70 (s, 2H), 7.43 (t, 1H), 7.73 (dd, 1H), 7.95 (dd, 1H) .

Intermediate 54B 1-(4-fluorobenzyl)-5-methyl-4-nitro-1H-pyrazole-3-carbonitrile

In a manner similar to the intermediate 1B), 2.008 g (13.1 mmol) of 5-methyl-4-nitro-1H-pyrazole-3-carbonitrile (prepared according to Journal of Heterocyclic Chemistry, 1970 , page 863; Or a tautomer thereof and 2.98 g (15.8 mmol) of 1-(bromomethyl)-4-fluorobenzene, thereby passing through a Biotage chromatography system (twice for a 50 g snap-on KP-Sil column, Crude product of alkane / 0-100% ethyl acetate followed by ethyl acetate / 0-10% methanol and finally 50 g snap KP-Sil column, hexane / 0-100% ethyl acetate After three subsequent purifications, 2.66 g (78%, purity about 90%) of the desired compound was obtained.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.64 (s, 3H), 5.54 (s, 2H), 7.16-7.24 (m, 4H).

Intermediate 55B 4-[(3,5-Diethyl-4-nitro-1H-pyrazol-1-yl)methyl]benzonitrile

In a similar manner to the intermediate 48B), 800 mg (4.73 mmol) of 3,5-diethyl-4-nitro-1H-pyrazole (intermediate 1D) and 1.11 g (5.67 mmol) of 4-(bromomethyl) Reaction of the benzonitrile to obtain 1.30 g (94%) of the desired title after purification of the crude product via a Biotage chromatography system (25 g K K-Sil column, hexane / 0-99% ethyl acetate) Compound.

¹ H-NMR (400MHz, DMSO d ₆ ) δ (ppm) = 1.00 (t, 3H), 1.18 (t, 3H), 2.86 (q, 2H), 2.98 (d, 2H), 5.52 (s, 2H) , 7.35 (d, 2H), 7.83 (d, 2H).

Intermediate 56B 4-{[5-ethyl-4-nitro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}benzonitrile

In a manner similar to the intermediate 48B), 1.00 g (4.78 mmol) of 5-ethyl-4-nitro-3-(trifluoromethyl)-1H-pyrazole (intermediate 2D) and 1.13 g (5.74). Ment) 4-(bromomethyl)benzonitrile was reacted to give 1.21 after purification of the crude product via a Biotage chromatography system (25 g s. KP-Sil column, hexanes/10-90% ethyl acetate). g (72%) of the desired compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 1.06 (t, 3H), 3.07 (q, 2H), 5.71 (s, 2H), 7.43 (d, 2H), 7.78 (d, 2H) .

Intermediates 57B and 58B 4-{[5-isopropyl-4-nitro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}benzonitrile and 4-{[3-isopropyl- 4-nitro-5-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}benzonitrile

1.50 g (6.72 mmol) of 5-isopropyl-4-nitro-3-(trifluoromethyl)-1H-pyrazole (Intermediate 3D) and 1.58 g (in a similar manner to Intermediate 48B) 8.07 mmol) 4-(bromomethyl)benzonitrile was reacted via two subsequent Biotage chromatography systems (25 g snap KP-Sil column, hexane/10-90% ethyl acetate and finally 25 g) After purifying the crude product mixture by snap-on KP-Sil column, hexanes/10-60% ethyl acetate), 1.26 g (50%) of 4-{[5-isopropyl-4-nitrate as the desired compound. 3-(3-trifluoromethyl)-1H-pyrazol-1-yl]methyl}benzonitrile and 400 mg (17%) of the isomer 4-{[3-isopropyl-4-nitrate 5--5-(Trifluoromethyl)-1H-pyrazol-1-yl]methyl}benzonitrile.

4-{[5-Isopropyl-4-nitro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}benzonitrile (Intermediate 57B): ¹ H-NMR ( 400 MHz, DMSO d ₆ ) δ (ppm) = 1.23 (d, 5H), 3.58 (spt, 1H), 5.77 (s, 2H), 7.38 (d, 2H), 7.86 (d, 2H).

4-{[3-Isopropyl-4-nitro-5-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}benzonitrile (Intermediate 58B): ¹ H-NMR ( 400 MHz, DMSO d ₆ ) δ (ppm) = 1.29 (d, 6H), 3.47 (spt, 1H), 5.77 (s, 2H), 7.32 (d, 2H), 7.87 (d, 2H).

Intermediates 59B and 60B 4-[(3-isopropyl-5-methyl-4-nitro-1H-pyrazol-1-yl)methyl]benzonitrile and 4-[(5-isopropyl-3-methyl) -4-nitro-1H-pyrazol-1-yl)methyl]benzonitrile

2.00 g (11.8 mmol) of 3-isopropyl-5-methyl-4-nitro-1H-pyrazole (Intermediate 4D) and 2.78 g (14.2 mmol) 4 were obtained in a similar manner to Intermediate 48B) -(bromomethyl)benzene The nitrile was reacted to obtain 3.22 g (96%) as a mixture of the desired compound after purification of the crude product mixture via a Biotage chromatography system (100 g cartridge KP-Sil column, hexane / 0-100% ethyl acetate). 4-[(3-isopropyl-5-methyl-4-nitro-1H-pyrazol-1-yl)methyl]benzonitrile and its isomer 4-[(5-iso) Propyl-3-methyl-4-nitro-1H-pyrazol-1-yl)methyl]benzonitrile.

NMR as a major product of 4-[(3-isopropyl-5-methyl-4-nitro-1H-pyrazol-1-yl)methyl]benzonitrile: ¹ H-NMR (300 MHz, DMSO d ₆ ) δ (ppm) = 1.21 (d, 6H), 2.53 (s, 3H), 3.47 (spt, 1H), 5.52 (s, 2H), 7.30 (d, 2H), 7.83 (d, 2H).

Intermediates 61B and 62B 4-[(3-ethyl-5-methyl-4-nitro-1H-pyrazol-1-yl)methyl]benzonitrile and 4-[(5-ethyl-3-methyl-4) -nitro-1H-pyrazol-1-yl)methyl]benzonitrile

490 mg (3.16 mmol) of 3-ethyl-5-methyl-4-nitro-1H-pyrazole (Intermediate 5D) and 743 mg (3.79 mmol) of 4-(bromo) in a manner analogous to Intermediate 48B) Methyl)benzonitrile is reacted to obtain a mixture of the desired compounds after purification of the crude product mixture via a Biotage chromatography system (25 g snap KP-Sil column, hexanes/10-90% ethyl acetate) 656 mg (77%) 4-[(3-ethyl-5-methyl-4-nitro-1H-pyrazol-1-yl)methyl]benzonitrile and its isomer 4-[( 5-ethyl-3-methyl-4-nitro-1H-pyrazol-1-yl)methyl]benzonitrile.

NMR of the mixture: ¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 1.00/1.17 (t, 3H), 2.41/2.55 (s, 3H), 2.84/2.99 (q, 2H), 5.50 (s , 2H), 7.31-7.38 (m, 2H), 7.81-7.86 (m, 2H).

Intermediate 63B (±)-4-[1-(3,5-Dimethyl-4-nitro-1H-pyrazol-1-yl)ethyl]benzonitrile

In a manner similar to the intermediate 48B), 823 mg (5.83 mmol) of 3,5-dimethyl-4-nitro-1H-pyrazole and 1.47 g (7.00 mmol) of 4-(1-bromoethyl)benzene. The carbonitrile (available, for example, from Bio Farma Ltd. or Enamine or prepared according to WO 2012/11707 A2, page/page column 29-30), is thus passed through a Biotage chromatography system (25g snap-on KP-Sil column, After purifying the crude product mixture with hexanes / 10-90% ethyl acetate, 449 mg (27%) of desired compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 1.78 (d, 3H), 2.42 (s, 3H), 2.55 (s, 3H), 5.88 (q, 1H), 7.43 (d, 2H) , 7.79-7.86 (m, 2H).

Intermediate 64B (±)-4-{1-[5-Methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethyl}benzonitrile

In a similar manner to the intermediate 48B), 1.54 g (7.89 mmol) of 5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazole and 1.99 g (9.47 mmol) of 4-( 1-Bromoethyl)benzonitrile (available, for example, from Bio Farma Ltd. or Enamine or prepared according to WO2012/11707 A2, page/page 29-30), thereby passing through a Biotage chromatography system (25g snap) KP-Sil tube After purification of the crude product mixture by column, hexanes EtOAc (EtOAc)

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 1.81 (d, 3H), 2.61 (s, 3H), 6.07 (q, 1H), 7.43-7.49 (m, 2H), 7.82-7.89 ( m, 2H).

Intermediate 65B (±)-5-Methyl-4-nitro-1-(1-phenylethyl)-3-(trifluoromethyl)-1H-pyrazole

In a manner similar to the intermediate 48B), 1.00 g (5.13 mmol) of 5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazole and 1.04 g (5.64 mmol). Bromoethyl)benzene was reacted to obtain 1.03 g (64%) after purification of the crude product mixture via a Biotage chromatography system (50 g cartridge KP-Sil column, hexane / 0-100% ethyl acetate) Compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 1.81 (d, 3H), 2.61 (s, 3H), 5.94 (q, 1H), 7.24 - 7.41 (m, 5H).

Intermediate 66B 4-[3-(3,5-Dimethyl-4-nitro-1H-pyrazol-1-yl)propyl]benzonitrile

750 mg (5.31 mmol) of 3,5-dimethyl-4-nitro-1H-pyrazole and 1.43 g (6.38 mmol) of 4-(3-bromopropyl)benzene were obtained in a similar manner to the intermediate 48B). Formonitrile (according to Pharmazie, 1982, p. 178 or WO2005/123747, 2005; page/page bar 53-54) The reaction was carried out to give 1.06 g (yield: 68%) of the desired compound after purification of the crude product mixture from Biotage chromatography system (25 g, KP-Sil column, hexane/30-100% ethyl acetate).

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.05 (quin, 2H), 2.37 (s, 3H), 2.53 (s, 3H), 2.68 (t, 2H), 4.08 (t, 2H) , 7.42 (d, 2H), 7.73 (d, 2H).

Intermediate 67B 6-[(3,5-Dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]nicotinonitrile

In a manner similar to the intermediate 1B), 1.19 g (8.46 mmol) of 3,5-dimethyl-4-nitro-1H-pyrazole and 2.00 g (10.2 mmol) of 6-(bromomethyl)nicotine were obtained. Nitrile ([CAS No. 158626-15-4], available, for example, from Fluorchem, BePharm, FCH Group Company) for reaction via Biotage chromatography system (25g snap KP-Sil column, hexane / 0-) After purifying the crude product with 100% ethyl acetate then ethyl acetate / EtOAc EtOAc (EtOAc)

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.37 (s, 3H), 2.58 (s, 3H), 5.59 (s, 2H), 7.48 (d, 1H), 8.32 (dd, 1H) , 8.95 (dd, 1H).

Intermediate 68B 6-{[5-Methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}nicotinonitrile

In a manner similar to Intermediate 1B), 1.65 g (8.46 mmol) of 5-methyl-4-nitro -3-(Trifluoromethyl)-1H-pyrazole and 2.00 g (10.2 mmol) of 6-(bromomethyl)nicotinonitrile ([CAS No. 158626-15-4], available, for example, in Fluorchem, BePharm, FCH The reaction was purchased by Group Company to purify crude via Biotage chromatography system (25g snap KP-Sil column, hexane / 0-100% ethyl acetate followed by ethyl acetate / 0-15% methanol) After the product, 2.51 g (86%) of desired compound was obtained.

¹ H-NMR (400MHz, DMSO d ₆ ) δ (ppm) = 2.63 (s, 3H), 5.82 (s, 2H), 7.62 (dd, 1H), 8.36 (dd, 1H), 8.96 (dd, 1H) .

Intermediate 69B Methyl 4-{[5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}benzoate

In a manner similar to the intermediate 1B), 2.50 g (12.8 mmol) of 5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazole and 3.52 g (15.4 mmol) of 4-( Reaction of methyl bromomethyl)benzoate to obtain 3.86 g (85%) after purification of the crude product via a Biotage chromatography system (50 g K K-Sil column, hexane / 20-80% ethyl acetate) ) the desired compound.

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 2.63 (s, 3H), 3.84 (s, 3H), 5.65 (s, 2H), 7.36 (d, 2H), 7.92-7.98 (m, 2H).

Intermediate 70B (±)-[{4-[(3,5-Dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]phenyl}(methyl)oxyl-yl-λ ⁶ - sulfiliylalkyl 1 urethane

step 1:

In a manner similar to the intermediate 1B), 3.30 g (23.4 mmol) of 3,5-dimethyl-4-nitro-1H-pyrazole and 4.85 g (28.1 mmol) of 1-(chloromethyl)-4 were obtained. -(Methylthio)benzene reaction, thus passing through Biotage chromatography system (100g snap KP-Sil column, hexane / 0-100% ethyl acetate, followed by ethyl acetate / 0-10% methanol After purifying the crude product, 5.47 g (76%) of 3,5-dimethyl-1-[4-(methylthio)benzyl]-4-nitro-1H-pyrazole was obtained.

^{1 H-NMR (300MHz, DMSO} d 6) δ (ppm) = 2.39 (s, 3H), 2.44 (s, 3H), 2.57 (s, 3H), 5.30 (s, 2H), 7.10-7.18 (m, 2H), 7.20-7.26 (m, 2H).

Step 2

550 mg (1.98 mmol) of 3,5-dimethyl-1-[4-(methylthio)benzyl]-4-nitrate from the intermediate 70B of Step 1 at a temperature between 10 ° C and 20 ° C 133 mg (1.87 mmol) of m-chloroperoxybenzoic acid (MCPBA) was administered portionwise in a stirred solution of pyridine-1H-pyrazole in 6.38 mL of dichloromethane. The mixture was then stirred at room temperature for a further 30 minutes. After diluting the mixture with 50 mL of dichloromethane, EtOAc (EtOAc)EtOAc. This material was used in conjunction with 4.95 g (17.8 mmol) of 3,5-dimethyl-1-[4-(methylthio)benzyl]-4-nitro-1H-pyrene from the product of Step 1 Intermediate 70B. The azole-like starting material from the second experiment was purified via Biotage chromatography system (100 g snap KP-Sil column, hexane / 0-100% ethyl acetate followed by ethyl acetate / 0-80% methanol). Thus, 3.47 g (60%) of (±)-3,5-dimethyl-1-[4-(methylsulfinyl)benzyl]-4-nitro-1H-pyrazole was obtained.

¹ H-NMR (400MHz, DMSO d ₆ ) δ (ppm) = 2.42 (s, 3H), 2.61 (s, 3H), 2.74 (s, 3H), 5.46 (s, 2H), 7.41 (d, 2H) , 7.66-7.70 (m, 2H).

Step 3

To 3.48 g (11.9 mmol) of (±)-3,5-dimethyl-1-[4-(methylsulfinyl)benzyl]-4-nitro-1H- from intermediate 2B of step 2 Pyrazole dissolved in 5.00mL of dichloromethane 1.54 g (23.7 mmol) of sodium azide was administered to the solution and then 3.16 mL of concentrated sulfuric acid (gas evolution) was carefully administered at 0 °C. After stirring at 25 ° C for 1 hour, the mixture was heated to 40 ° C and stirred at this temperature for about 1 day. After cooling to 0 ° C, 0.75 g (11.8 mmol) of sodium azide was further added and stirring was continued at 40 ° C for 3 days. While cooling at 0 ° C, 60 mL of ice water was carefully added to the reaction mixture. The reaction mixture was extracted three times with dichloromethane. The first combined organic phase was washed with a 25% aqueous sodium hydroxide solution, dried over sodium sulfate, filtered and evaporated to dry.

While cooling at 0 ° C, the pH of the aqueous phase from the first extraction was adjusted to 9 with a 25% aqueous sodium hydroxide solution. This aqueous phase was then extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and evaporated to dry.

The combined crude product was purified via a Biotage chromatography system (50 g cartridge KP-Sil column, hexane / 0-100% ethyl acetate followed by ethyl acetate / 0-20% methanol). The ratio of 2 gives the starting material (±)-3,5-dimethyl-1-[4-(methylsulfinyl)benzyl]-4-nitro-1H-pyrazole and the product (±) A 2.44 g mixture of -3,5-dimethyl-1-[4-(methylsulfonimidomethyl)benzyl]-4-nitro-1H-pyrazole.

To a solution of 2.44 g of this mixture in 64.0 mL of pyridine was added 3.78 mL (39.6 mmol) of ethyl chloroformate and stirred at this temperature for 16 hr. The reaction mixture was poured into brine and then extracted three times with ethyl acetate. The combined organic phases were evaporated to dryness then toluene was added and the mixture was evaporated to dry. The toluene addition and evaporation process was repeated twice more and then via a Biotage chromatography system (50 g snap KP-Sil column, hexane / 0-100% ethyl acetate followed by ethyl acetate / 0-75% methanol) The crude product was purified to give 2.15 g (69%) of desired compound.

¹ H-NMR (300 MHz, DMSO d ₆ ) δ (ppm) = 1.06 (t, 3H), 2.40 (s, 3H), 2.60 (s, 3H), 3.43 (s, 3H), 3.79 - 3.97 (m, 2H), 5.51 (s, 2H), 7.46 (d, 2H), 7.91 (d, 2H).

Intermediate 71B 1-{4-[(3,5-Dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]phenyl}-N,N-dimethylmethylamine

step 1:

In a manner similar to Intermediate 1B), 2.67 g (18.9 mmol) of 3,5-dimethyl-4-nitro-1H-pyrazole and 15.0 g (56.8 mmol) of 1,4-bis(bromomethyl) Benzene reaction, thus four subsequent runs of crude product via Biotage chromatography system (first 100g, all other 50g snap KP-Sil column, hexane/10-90% ethyl acetate) After purification, 3.02 g (45%) of 1-[4-(bromomethyl)benzyl]-3,5-dimethyl-4-nitro-1H-pyrazole was obtained.

¹ H-NMR (400MHz, DMSO d ₆ ) δ (ppm) = 2.39 (s, 3H), 2.57 (s, 3H), 4.67 (s, 2H), 5.35 (s, 2H), 7.18 (d, 2H) , 7.42 (d, 2H).

Step 2

100 mg (0.31 mmol) of 1-[4-(bromomethyl)benzyl]-3,5-dimethyl-4-nitro-1H-pyrazole from Step 1 Intermediate 71B in 2.0 mL DMSO A solution of 0.19 mL (0.37 mmol) of 2M dimethylamine in THF and 70.4 mg (0.46 mmol) of DBU were successively added to the stirred solution. The mixture was stirred at room temperature for 20 hours. Similarly, 400 mg (1.23 mmol) of 1-[4-(bromomethyl)benzyl]-3,5-dimethyl-4-nitro-1H-pyrazole and 0.74 from the intermediate 71B of Step 1. A second experiment was carried out as a starting material in a solution of mL (1.48 mmol) of 2M dimethylamine in THF. The combined reaction mixture was diluted with EtOAc (EtOAc)EtOAc. The material was purified via a Biotage chromatography system (25 g EtOAc EtOAc EtOAc EtOAc

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.10 (s, 6H), 2.39 (s, 3H), 2.57 (s, 3H), 3.33 (s, 2H), 5.33 (s, 2H) , 7.14 (d, 2H), 7.25 (d, 2H).

Intermediate 72B 4-{[3-Methyl-4-nitro-5-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}benzonitrile

In a manner similar to the intermediate 1B), 10.0 g (51.3 mmol) of 5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazole and 12.1 g (61.5 mmol) of 4-( Bromomethyl)benzonitrile was reacted to obtain 4-{[5- after purification of the crude product via a Biotage chromatography system (100 g cartridge KP-Sil column, hexane / 0-70% ethyl acetate). Methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}benzonitrile (Intermediate 26B) as the main component and 690 mg (4.3%) of the title compound .

¹ H-NMR (500 MHz, DMSO d ₆ ) δ (ppm) = 2.49 (s, 3H), 5.74 (s, 2H), 7.34 (d, 2H), 7.83-7.87 (m, 2H).

Intermediate 73B 4-[(3,5-Dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]-3,5-difluorobenzonitrile

step 1:

To a solution of 1.00 g (6.53 mmol) of 3,5-difluoro-4-methylbenzonitrile in 8.0 mL of tetrachloromethane was added 1.28 g (7.18 mmol) of N-bromobutaneimine and 54 mg ( 0.33 mmol) azobisisobutyronitrile. The mixture was heated to reflux for 16 hours. After cooling to room temperature, diluted with ethyl acetate and the resulting mixture was washed organic phase with 1M NaS ₂ O ₃ solution, dried over sodium sulfate, filtered and evaporated to dryness. The resulting material was purified via a Biotage chromatography system (25 g K K-Sil column, hexane / 0-100% ethyl acetate followed by ethyl acetate / 0-90% methanol) to yield 1.6 g (95%) 4-(Bromomethyl)-3,5-difluorobenzonitrile as the desired compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 4.68 (s, 2H), 7.86 - 7.93 (m, 2H).

Step 2:

558 mg (3.95 mmol) of 3,5-dimethyl-4-nitro-1H-pyrazole and 1.10 g (4.74 mmol) of 4-(Steps from Intermediate 1B) of Step 1 were obtained in a similar manner to Intermediate 1B). Reaction with bromomethyl)-3,5-difluorobenzonitrile, thus passing through a Biotage chromatography system (25g snap KP-Sil column, hexane / 0-100% ethyl acetate, followed by ethyl acetate After purification of the crude product / EtOAc (EtOAc)

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.31 (s, 3H), 2.68 (s, 3H), 5.42 (s, 2H), 7.83-7.89 (m, 2H).

Intermediate 74B 3,5-Difluoro-4-{[5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}benzonitrile

1.04 g (5.35 mmol) of 5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazole and 1.49 g from Intermediate 1B of Step 1 were obtained in a similar manner to Intermediate 1B). (6.42 mmol) 4-(bromomethyl)-3,5-difluorobenzonitrile was reacted via a Biotage chromatography system (25 g snap KP-Sil column, hexane / 0-100% acetic acid Ester, followed by ethyl acetate / 0- After purification of the crude product by EtOAc (EtOAc):

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.74 (s, 3H), 5.64 (s, 2H), 7.78-7.97 (m, 2H).

Intermediate 75B 1-[4-(Methoxymethyl)benzyl]-5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazole

179 mg (3.31) was administered to 500 mg (1.32 mmol) of 1-[4-(bromomethyl)benzyl]-3,5-dimethyl-4-nitro-1H-pyrazole from Step 1 Intermediate 71B. Methyl) a solution of sodium methoxide in 17 mL of methanol. The mixture was stirred at room temperature for 15 hours. The reaction mixture was diluted with 50 mL of ethyl acetate and the obtained organic phase was washed with water. After separation of the phases, the aqueous phase was extracted with EtOAc (EtOAc)EtOAc. The material was purified via a Biotage chromatography system (25 g snap KP-Sil column, hexane / 0-100% ethyl acetate followed by ethyl acetate / 0-100% methanol) to give 380 mg (85%) Title compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.65 (s, 3H), 3.28 (s, 3H), 4.40 (s, 2H), 5.55 (s, 2H), 7.24 (d, 2H) , 7.33 (d, 2H).

Intermediate 76B (4-{[5-Methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}phenyl)acetonitrile

To 1.00 g (2.64 mmol) of 1-[4-(bromomethyl)benzene from Intermediate 71B of Step 1. 156 mg (3.17 mmol) of sodium cyanide was administered to a solution of 3-,5-dimethyl-4-nitro-1H-pyrazole in 15 mL of DMSO. The mixture was stirred at 40 ° C for 2 hours. After cooling to room temperature, the reaction mixture was diluted with 150 mL of ethyl acetate and this organic layer was washed with water. After separation of the phases, the aqueous phase was extracted with EtOAc (EtOAc)EtOAc. The material was purified via a Biotage chromatography system (25 g snap KP-Sil column, hexane / 0-100% ethyl acetate followed by ethyl acetate / 0-100% methanol) to afford 780 mg (86%) Title compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.66 (s, 3H), 4.04 (s, 2H), 5.56 (s, 2H), 7.29 (d, 2H), 7.37 (d, 2H) .

Intermediate 77B 3-[(3,5-Dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]-N-methyl-1,2,4-oxadiazol-5-carboxamide

In a manner similar to Intermediate 1B, 549 mg (3.89 mmol) of 3,5-dimethyl-4-nitro-1H-pyrazole and 820 mg (4.67 mmol) of 3-(chloromethyl)-N-methyl -1,2,4-oxadiazol-5-carboxamide (CAS No. 1123169-42-5) and 1.90 g (5.84 mmol) of cesium carbonate in 20 mL of acetonitrile were heated at 60 ° C for 2 hours. The reaction mixture was then filtered, the filtrate evaporated, mjjjjjjj The residue was purified by flash chromatography eluting elut elut elut elut elut elut

^{1 H NMR (300MHz, DMSO- d} 6): δ (ppm) = 2.39 (s, 3H), 2.67 (s, 3H), 2.77 (s, 3H), 5.69 (s, 2H), 9.27 (br.s ., 1H).

Intermediate 78B 4-[(3,5-Dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]piperidine-1-carboxylic acid tert-butyl ester

2.11 g (14.98 mmol) of 3,5-dimethyl-4-nitro-1H-pyrazole with 5 g (17.97 mmol) of 3-(bromomethyl)piperidine-1-carboxylic acid tert-butyl ester (CAS) No. 158407-04-6) and 3.35 mL (22.47 mmol) of 1,8-diazabicyclo (5.4.0) eleven-7-ene 50 mL DMSO were heated to 60 ° C overnight. Water was added to the reaction mixture, and extracted with ethyl acetate. The combined organic phases were washed with water and brine, dried, filtered and evaporated. The crude title compound (5.07 g, 94%) was used without further purification.

^{1 H NMR (400MHz, DMSO- d} 6): δ (ppm) = 1.11 (dddd, 2H), 1.38 (s, 9H), 1.46 (br.d., 2H), 1.99 (m, 1H), 2.39 ( s, 3H), 2.57 (s, 3H), 2.65 (m, 2H), 3.92 (br.d., 2H), 3.98 (d, 2H).

Intermediate 79B 5-methyl-3-{[5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}-1,2-oxazole

6.15 g (31.5 mmol) of 5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazole and 4.98 g (37.9 mmol) of 3-(chloro) were obtained in a similar manner to the intermediate 78B. Methyl)-5-methyl-1,2-oxazole (CAS No. 35166-37-1) was reacted to give 8.55 g (26.5 mmol, 84%) of desired title after purification of the crude product by flash chromatography. Compound.

¹ H NMR (400 MHz, DMSO- d ₆ ): δ (ppm) = 2.39 (s, 3H), 2.67 (s, 3H), 5.64 (s, 2H), 6.25 (s, 1H).

Intermediate 80B 5-ethyl-3-{[5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}-1,2,4-oxadiazole

2.22 g (11.4 mmol) of 5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazole and 2.00 g (13.6 mmol) of 3-(chloro) were obtained in a similar manner to the intermediate 78B. Methyl)-5-ethyl-1,2,4-oxadiazole (CAS No. 83227-01-4) was reacted to obtain 2.35 g (7.30 mmol, 64%) after purification of the crude product by flash chromatography. The title compound is required.

¹ H NMR (400 MHz, DMSO- d ₆ ): δ (ppm) = 1.25 (t, 3H), 2.71 (s, 3H), 2.95 (q, 2H), 5.80 (s, 2H).

Intermediate 81B 3-ethyl-5-{[5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}-1,2-oxazole

In a similar manner to the intermediate 78B, 1.12 g (5.72 mmol) of 5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazole and 1.00 g (6.87 mmol) of 5- (chloro) Methyl)-3-ethyl-1,2-oxazole (CAS No. 64988-69-8) was reacted to give 690 mg (2.15 mmol, 38%) of the title compound after purification of the crude product by flash chromatography. .

^{1 H NMR (300MHz, DMSO- d} 6): δ (ppm) = 1.16 (t, 3H), 2.61 (q, 2H), 2.70 (s, 3H), 5.78 (s, 2H), 6.52 (s, 1H ).

Intermediate 82B 5-[(3,5-Dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]-3-methyl-1,2-oxazole

393 mg (2.79 mmol) of 3,5-dimethyl-4-nitro-1H-pyrazole and 440 mg (3.34 mmol) of 5-(chloromethyl)-3-methyl were used in a similar manner to the intermediate 78B. -1,2-oxazole (CAS No. 40340-41-8) was reacted to give 525 mg (2.11 mmol, 76%) of the desired compound.

^{1 H NMR (300MHz, DMSO- d} 6): δ (ppm) = 2.20 (s, 3H), 2.39 (s, 3H), 2.64 (s, 3H), 5.56 (s, 2H), 6.36 (s, 1H ).

Intermediate 83B 3-[(3,5-Dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]-5-methyl-1,2-oxazole

In a manner similar to the intermediate 78B, 8.94 g (63.3 mmol) of 3,5-dimethyl-4-nitro-1H-pyrazole and 10 g (76.0 mmol) of 3-(chloromethyl)-5- The benzyl-1,2-oxazole (CAS number 35166-37-1) was reacted to give 9.38 g (37.7 mmol, 60%) of the desired compound.

^{1 H NMR (400MHz, DMSO- d} 6): δ (ppm) = 2.37 (s, 3H), 2.39 (s, 3H), 2.61 (s, 3H), 5.42 (s, 2H), 6.16 (s, 1H ).

Intermediate 84B 4-{[5-Methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}piperidine-1-carboxylic acid tert-butyl ester

In a manner similar to the intermediate 78B, 2.38 g (11.98 mmol) of 5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazole and 4 g (14.38 mmol) of 4-(bromo) The reaction was carried out to give the title compound (3.

_{^{1 H NMR (300MHz, CDCl 3}} ): δ (ppm) = 1.24 (dddd, 2H), 1.46 (s, 9H), 1.57 (br.d., 2H), 2.13 (m, 1H), 2.68 (s, 3H), 2.69 (m, 2H), 4.03 (d, 2H), 4.16 (m, 2H).

Intermediate 85B 5-[(3,5-Dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]-3-ethyl-1,2-oxazole

808 mg (5.72 mmol) of 3,5-dimethyl-4-nitro-1H-pyrazole and 1.00 g (6.87 mmol) of 5-(chloromethyl)-3-B were obtained in a similar manner to the intermediate 78B. The benzyl-1,2-oxazole (CAS No. 64988-69-8) was reacted to give 1.34 g (4.82 mmol, 84%) of the desired compound.

^{1 H NMR (300MHz, DMSO- d} 6): δ (ppm) = 1.16 (t, 3H), 2.39 (s, 3H), 2.60 (q, 2H), 2.64 (s, 3H), 5.56 (s, 2H ), 6.41 (s, 1H).

Intermediate 86B 4-[(3,5-Dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]piperidine

5.28 g (14.0 mmol) of 3-[(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]piperidine-1-carboxylic acid tert-butyl ester (Intermediate 78B) The solution in 125 mL of dichloromethane was stirred with 10.8 mL (140.4 mmol) of trifluoroacetic acid for 4.5 hours. NH ₂ The reaction was derivatized silica gel mixture was filtered, and the filtrate was evaporated to give 3.36g of the title compound in the form of a crude product, which was used without further purification.

^{1 H NMR (400MHz, DMSO- d} 6): δ (ppm) = 1.11 (dddd, 2H), 1.42 (d, 2H), 1.88 (m, 1H), 2.39 (s, 3H), 2.57 (s, 3H ), 2.40 (m, 2H), 2.92 (m, 2H), 3.94 (d, 2H).

Intermediate 87B 4-[(3,5-Dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]-1-(ethylsulfonyl)piperidine

3.36 g (crude, about 12.7 mmol) of 4-[(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]piperidine (Intermediate 86B) in 30 mL of DMF The solution was stirred overnight with 1.68 mL (17.8 mmol) of ethanesulfonium chloride and 10.6 mL (76.1 mmol) of triethylamine. A saturated aqueous solution of sodium hydrogencarbonate and ethyl acetate were added to the reaction. The mixture was extracted with butanol and the combined organic phases were washed with brine, dried, filtered and evaporated. Purification by flash chromatography gave 2.53 g (yiel.

^{1 H NMR (400MHz, DMSO- d} 6): δ (ppm) = 1.19 (t, 3H), 1.26 (dddd, 2H), 1.57 (m, 2H), 1.97 (m, 1H), 2.40 (s, 3H ), 2.58 (s, 3H), 2.75 (m, 2H), 3.00 (q, 2H), 3.58 (m, 2H), 3.90 (d, 2H), 4.02 (s, 2H).

Intermediate 88B 5-[(3,5-Dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]-3-(propan-2-yl)-1,2-oxazole

737 mg (5.22 mmol) of 3,5-dimethyl-4-nitro-1H-pyrazole and 1.00 g (6.27 mmol) of 5-(chloromethyl)-3- (in a similar manner to Intermediate 78B) Reaction of the propan-2-yl)-1,2-oxazole (CAS No. 64988-71-2) gave 1.07 g (3.64 mmol, 70%) of the desired compound.

^{1 H NMR (300MHz, DMSO- d} 6): δ (ppm) = 1.19 (d, 6H), 2.39 (s, 3H), 2.65 (s, 3H), 2.96 ( septet, 1H), 5.56 (s, 2H), 6.47 (s, 1H).

Intermediate 89B 5-cyclopropyl-3-[(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]-1,2-oxazole

746 mg (5.29 mmol) of 3,5-dimethyl-4-nitro-1H-pyrazole and 1 g (6.35 mmol) of 3-(chloromethyl)-5-cyclopropane in a similar manner to Intermediate 78B The benzyl-1,2-oxazole (CAS No. 1060817-59-5) was reacted to give 1.31 g (4.81 mmol, 91%) of the desired compound.

^{1 H NMR (400MHz, DMSO- d} 6): δ (ppm) = 0.86 (m, 2H), 1.04 (m, 2H), 2.11 (m, 1H), 2.39 (s, 3H), 2.60 (s, 3H ), 5.39 (s, 2H), 6.12 (s, 1H).

Intermediate 90B 3-methyl-5-{[5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}-1,2-oxazole

1.17 mg (6.02 mmol) of 5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazole and 1 g (7.22 mmol) of 5-(chloroform) were obtained in a similar manner to the intermediate 78B. Reaction of 3-methyl-1,2-oxazole (CAS No. 40340-41-8) to give 1.40 g (4.58 mmol, 76%) of the title compound after purification of the crude product by flash chromatography. .

^{1 H NMR (300MHz, DMSO- d} 6): δ (ppm) = 2.21 (s, 3H), 2.70 (s, 3H), 5.77 (s, 2H), 6.45 (s, 1H).

Intermediate 91B 5-[(3,5-Dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]thiophene-2-carbonitrile

291 mg (2.06 mmol) of 3,5-dimethyl-4-nitro-1H-pyrazole and 500 mg (2.47 mmol) of 5-(bromomethyl)thiophene-2-yl were obtained in a similar manner to the intermediate 78B. The nitrile (CAS No. 134135-41-4) was reacted to give 472 mg (1.44 mmol, 58%) of the desired compound.

^{1 H NMR (400MHz, DMSO- d} 6): δ (ppm) = 2.41 (s, 3H), 2.63 (s, 3H), 5.67 (s, 2H), 7.26 (d, 1H), 7.86 (d, 1H ).

Intermediate 92B 5-{[5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}thiophene-2-carbonitrile

In a similar manner to the intermediate 78B, 402 mg (2.06 mmol) of 5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazole and 500 mg (2.47 mmol) of 5-(bromomethyl) The reaction of the thiophene-2-carbonitrile (CAS No. 134135-41-4) gave 630 mg (1.79 mmol, 72%) of the desired compound.

¹ H NMR (400 MHz, DMSO- d ₆ ): δ (ppm) = 2.70 (s, 3H), 5.78 (s, 2H), 7.31 (d, 1H), 7.90 (d, 1H).

Intermediate 93B 2-{[5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}pyrimidine-5-carbonitrile

In a manner similar to the intermediate 1B), 2.05 g (10.5 mmol) of 5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazole and 2.50 g (12.6 mmol) 2-( Bromomethyl)pyrimidine-5-carbonitrile (available, for example, in ABCR) is reacted via a Biotage chromatography system (25g snap KP-Sil column, hexane / 0-100% ethyl acetate, followed by After purifying the crude product mixture as ethyl acetate / 0-25% methanol, 2.9 g (86%) of desired compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.61 (s, 3H), 5.97 (s, 2H), 9.30 (s, 2H).

Intermediate 94B 6-{[5-Methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}pyridazine-3-carbonitrile

Step 1: 6-(Chloromethyl)pyridazine-3-carbonitrile

To a solution of 250 mg (2.10 mmol) of 6-methylpyridazine-3-carbonitrile in 20 mL of dichloromethane was added 161 mg (0.69 mmol) of trichloroisocyanuric acid and the reaction mixture was heated to 90 ° C. 5 hours. After cooling to 25 &lt;0&gt;C, the mixture was evaporated to dryness to give crude 6-(chloromethyl)pyridazin-3-carbonitrile which was used in the next step without any further purification. In a second experiment, the reaction was repeated using 1.75 g (14.7 mmol) of 6-methylpyridazine-3-carbonitrile to give 2.5 g of crude 6-(chloromethyl)pyridazin-3-carbonitrile.

Step 2:

In a similar manner to the intermediate 1B), 322 mg in the first experiment and 2.5 g in the second experiment were combined with 341 mg (1.78 mmol) and in the second experiment with 1.68 (8.58 mmol) 5- Methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazole reaction, thus passing through a Biotage chromatography system (1.50 g snap KP-Sil column, hexane / 0-100% acetic acid Ethyl ester, followed by ethyl acetate / 0-100% methanol / 2.25 g snap KP-Sil column, hexane / 0-100% ethyl acetate, followed by ethyl acetate / 0-25% methanol / 3.25 After three subsequent purifications of the combined crude product by g-kapped KP-Sil column, hexane / 0-100% ethyl acetate, 0.63 g (9.6%, purity about 40%) of the title compound .

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) = 6.06 (s, 2H), 8.00 (d, 1H), 8.42 (d, 1H).

Intermediate 1C 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazole-4-amine

9.33 g (37.43 mmol) of 1-(4-fluorobenzyl)-3,5-dimethyl-4-nitro-1H-pyrazole (intermediate 1B) was dissolved in 250 mL of methanol and added 1.99 g ( 1.87 mmol) palladium on carbon (10% by weight) and 23.6 g (374.3 mmol) in ammonium formate. The reaction mixture was heated at 80 ° C for 1 hour. The suspension was then filtered through celite and the filtrate was evaporated. The residue was partitioned between water and ethyl acetate. The layers were separated and EtOAc (EtOAc m.

1H NMR (300MHz, CDCl ₃ ): δ (ppm) = 2.05 (s, 3 H), 2.20 (s, 3 H), 2.56 (br.s., 2 H), 5.13 (s, 2 H), 6.86 -7.12 (m, 4 H).

Intermediate 2C 1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazole-4-amine

In a manner similar to the intermediate 1C), 682 mg (2.74 mmol) of 1-(3-fluorobenzyl)-3,5-dimethyl-4-nitro-1H-pyrazole (intermediate 2B) 145 mg (0.14 mmol) of palladium/carbon (10% by weight) and 1.38 g (21.90 mmol) of ammonium formate 5 mL of methanol were heated at 80 ° C for 1 hour, whereby after filtration and aqueous treatment, 454 mg (2.07 mmol, 76%) was obtained. The title compound is required.

1H NMR (400MHz, CDCl ₃ ): δ (ppm) = 2.06 (s, 3 H), 2.21 (s, 3 H), 2.54 (br.s., 2 H), 5.16 (s, 2 H), 6.72 (d, 1 H), 6.84 (d, 1 H), 6.93 (td, 1 H), 7.22 - 7.26 (m, 1 H).

Intermediate 3C 1-(2-fluorobenzyl)-3,5-dimethyl-1H-pyrazole-4-amine

In a manner similar to Intermediate 1C), 336 mg (1.35 mmol) of 1-(2-fluorobenzyl)-3,5-dimethyl-4-nitro-1H-pyrazole (Intermediate 3B) 71 mg (0.07 mmol) of palladium/carbon (10% by weight) and 680 mg (10.78 mmol) of ammonium formate in 25 mL of methanol were heated at 80 ° C for 1 hour, whereby after filtration and aqueous treatment, 275 mg (1.25 mmol, 93%) was obtained. The title compound is desired.

1H NMR (400MHz, CDCl ₃ ): δ (ppm) = 2.09 (s, 3 H), 2.20 (s, 3 H), 5.22 (s, 2 H), 6.79-6.86 (m, 1 H), 7.03- 7.09 (m, 2 H), 7.19-7.26 (m, 1 H).

Intermediate 4C 1-(3,4-difluorobenzyl)-3,5-dimethyl-1H-pyrazole-4-amine

726 mg (2.72 mmol) of 1-(3,4-difluorobenzyl)-3,5-dimethyl-4-nitro-1H-pyrazole (Intermediate 4B) in a similar manner to Intermediate 1C) It was heated at 80 ° C for 1 hour with 25 mL of methanol containing 144 mg (0.14 mmol) of palladium/carbon (10% by weight) and 1.37 g (21.73 mmol) of ammonium formate, so that after filtration and aqueous treatment, 644 mg (2.20 mmol) was obtained. , 81%) of the desired compound.

Method 1: R _t = 0.65 min

MS (ESIpos): m/z = 238 (M+H) ⁺ .

Intermediate 5C 1-(2,4-difluorobenzyl)-3,5-dimethyl-1H-pyrazole-4-amine

716 mg (2.68 mmol) of 1-(2,4-difluorobenzyl)-3,5-dimethyl-4-nitro-1H-pyrazole (Intermediate 5B) in a similar manner to Intermediate 1C) It was heated at 80 ° C for 1 hour with 25 mL of methanol containing 142 mg (0.13 mmol) of palladium/carbon (10% by weight) and 1.35 g (21.43 mmol) of ammonium formate, so that after filtration and aqueous treatment, 635 mg (2.67 mmol) was obtained. , 99%) of the desired compound.

Method 1: R _t = 0.64 min

MS (ESIpos): m/z = 238 (M+H) ⁺ .

Intermediate 6C 1-(2,6-difluorobenzyl)-3,5-dimethyl-1H-pyrazole-4-amine

719 mg (2.69 mmol) of 1-(2,6-difluorobenzyl)-3,5-dimethyl-4-nitro-1H-pyrazole (Intermediate 6B) in a similar manner to Intermediate 1C) ) together with 20 mL of methanol containing 143 mg (0.13 mmol) of palladium/carbon (10% by weight) and 1.36 g (21.52 mmol) of ammonium formate at 80 ° C After heating for 1 hour, after filtration and aqueous workup, 644 mg (2.20 mmol, 81%)

Method 1: R _t = 0.63 min

MS (ES1pos): m/z = 238 (M + H) ⁺ .

Intermediate 7C 3,5-Dimethyl-1-(2,4,6-trifluorobenzyl)-1H-pyrazole-4-amine

708 mg (2.48 mmol) of 3,5-dimethyl-4-nitro-1-(2,4,6-trifluorobenzyl)-1H-pyrazole in the same manner as Intermediate 1C) The compound 7B) was heated at 80 ° C for 1 hour together with 25 mL of methanol containing 132 mg (0.12 mmol) of palladium/carbon (10% by weight) and 1.25 g (19.86 mmol) of ammonium formate, so that after filtration and aqueous treatment, 602 mg ( 2.33 mmol, 94%) of the desired compound.

Method 1: R _t = 0.64 min

MS (ESIpos): m/z = 256 (M+H) ⁺ .

Intermediate 8C 4-[(4-Amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]benzonitrile

a solution of 2.25 g (8.78 mmol) of 4-[(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]benzonitrile (Intermediate 8B) in 100 mL of ethanol Add 50mL of water, 10mL of B Acid and 2.01 g (30.7 mmol) of zinc powder. The reaction mixture was stirred at 60 ° C for 2 hours. After cooling to 25 ° C, the suspension was filtered over Celite, washed with ethyl acetate and evaporated. 100 mL of water and 30 mL of a concentrated aqueous solution of sodium carbonate were added to the residue. The aqueous phase was extracted three times with 100 mL of ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfatesssssssssssssssssssssssssssssssssssssss Thus, 1.77 g (89%) of the desired compound was obtained.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 1.97 (s, 3H), 1.99 (s, 3H), 3.43 (br.s., 2H), 5.17 (s, 2H), 7.10-7.21 (m, 2H), 7.77 (d, 2H).

Intermediate 9C 3-[(4-Amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]benzonitrile

To a solution of 500 mg (1.95 mmol) of 3-[(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]benzonitrile (Intermediate 9B) in 10 mL of ethanol 1.85 g (9.76 mmol) of tin (II) chloride was added. The reaction mixture was stirred at 78 ° C for 8 hours. After cooling to room temperature, the reaction mixture was brought to pH 8 via the addition of 2M sodium hydroxide solution. The resulting precipitate was separated by filtration and the filtrate was extracted with dichloromethane. The combined organic layers were washed with EtOAc EtOAc m.

Intermediate 10C 2-[(4-Amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]benzonitrile

a solution of 2.48 g (9.68 mmol) of 2-[(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]benzonitrile (Intermediate 10B) in 51 mL of ethanol 10.9 g (48.4 mmol) of stannous chloride dihydrate was added thereto. The reaction mixture was stirred under reflux for 5 hours and then at 70 ° C for 20 hours. After cooling to 25 ° C, the mixture was evaporated. A 5 M aqueous sodium hydroxide solution was added to the residue to give a basic pH. The aqueous phase was extracted three times with 80 mL of ethyl acetate. The combined organic layers were washed with EtOAcq EtOAc (EtOAc) Purification gave 1.91 g (83%) of desired compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 1.98 (s, 3H), 2.04 (s, 3H), 3.42 (br.s., 2H), 5.24 (s, 2H), 6.86 (d) , 1H), 7.42-7.50 (m, 1H), 7.62 (td, 1H), 7.83 (dd, 1H).

Intermediate 11C 1-(4-methoxybenzyl)-3,5-dimethyl-1H-pyrazole-4-amine

In a manner similar to Intermediate 1C), 2.41 g (9.22 mmol) of 1-(4-methoxybenzyl)-3,5-dimethyl-4-nitro-1H-pyrazole (intermediate) 11B) reaction, after purifying the crude product via Biotage chromatography system (50 g snap KP-Sil column, hexane / 20-70% ethyl acetate), 2.35 g (105%) of the desired non-completely pure Compound without Use any further purification.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 1.98 (s, 6H), 3.65 (br.s., 2H), 3.70 (s, 3H), 4.97 (s, 2H), 6.84 (d) , 2H), 6.99 (d, 2H).

Intermediate 12C 1-(3-methoxybenzyl)-3,5-dimethyl-1H-pyrazole-4-amine

In a similar manner to the intermediate 1C), 339 mg (1.30 mmol) of 1-(3-methoxybenzyl)-3,5-dimethyl-4-nitro-1H-pyrazole (intermediate 12B) It was heated at 80 ° C for 1 hour with 5 mg of methanol containing 69 mg (0.07 mmol) of palladium/carbon (10% by weight) and 654 mg (10.38 mmol) of ammonium formate, thereby obtaining 294 mg (1.27 mmol, 98 after filtration and aqueous treatment). %) The desired compound.

1H NMR (300MHz, CDCl ₃ ): δ (ppm) = 2.06 (s, 3 H), 2.20 (s, 3 H), 2.51 (br.s., 2 H), 3.76 (s, 3 H), 5.15 (s, 2 H), 6.55-6.71 (m, 2 H), 6.73-6.84 (m, 1 H), 7.21. (t, 1 H).

Intermediate 13C 3,5-Dimethyl-1-(4-methylbenzyl)-1H-pyrazole-4-amine

In a manner similar to the intermediate 1C), 686 mg (2.80 mmol) of 3,5-dimethyl-1-(4-methylbenzyl)-4-nitro-1H-pyrazole (intermediate 13B) 149 mg (0.14 mmol) of palladium on carbon (10% by weight) and 1.41 g (22.37 mmol) of ammonium formate in 25 mL of methanol at 80 ° C After heating for 1 hour, 550 mg (2.53 mmol, 90%) of the desired compound was obtained after filtration and water.

Method 1: R _t = 0.69 min

MS (ESIpos): m/z = 216 (M+H) ⁺ .

Intermediate 14C 3,5-Dimethyl-1-(3-methylbenzyl)-1H-pyrazole-4-amine

In a similar manner to the intermediate 1C), 681 mg (2.78 mmol) of 3,5-dimethyl-1-(3-methylbenzyl)-4-nitro-1H-pyrazole (intermediate 14B) The mixture of 147 mg (0.14 mmol) of palladium/carbon (10% by weight) and 1.40 g (22.21 mmol) of ammonium formate was heated at 80 ° C for 1 hour, thereby obtaining 541 mg (2.49 mmol, 90 after filtration and aqueous treatment). %) The desired compound.

Method 1: R _t = 0.69 min

MS (ESIpos): m/z = 216 (M+H) ⁺ .

Intermediate 15C 3,5-Dimethyl-1-(2-methylbenzyl)-1H-pyrazole-4-amine

In a similar manner to the intermediate 1C), 695 mg (2.83 mmol) of 3,5-dimethyl-1-(2-methylbenzyl)-4-nitro-1H-pyrazole (intermediate 15B) 155 mg (0.14 mmol) of palladium on carbon (10 wt%) and 1.43 g (22.67 mmol) of ammonium formate in 25 mL of methanol at 80 ° C After heating for 1 hour, after filtration and aqueous workup, 600 mg (2.60 mmol, 91%) of the desired compound was obtained.

Method 1: R _t = 0.69 min

MS (ESIpos): m/z = 216 (M+H) ⁺ .

Intermediate 16C 3,5-Dimethyl-1-(pyridin-4-ylmethyl)-1H-pyrazole-4-amine

1.57 g (6.76 mmol) of 4-[(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]pyridine (intermediate) in a similar manner to Intermediate 1C) 16B) The reaction gave 0.38 g (22%) of desired compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 1.97 (s, 3H), 1.99 (s, 3H), 5.12 (s, 2H), 6.94 (d, 2H), 8.44 - 8.49 (m, 2H).

Intermediate 17C 3,5-Dimethyl-1-(pyridin-3-ylmethyl)-1H-pyrazole-4-amine

In a manner similar to the intermediate 10C), 1.00 g (4.31 mmol) of 3-[(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]pyridine (intermediate) 17B) The reaction afforded 0.27 g (28%) of desired compound.

¹ H-NMR (300 MHz, DMSO d ₆ ) δ (ppm) = 1.97-1.99 (m, 3H), 2.02 (s, 3H), 3.40 (br.s., 2H), 5.10 (s, 2H), 7.29 -7.34 (m, 1H), 7.40 (dt, 1H), 8.31 (d, 1H), 8.44 (dd, 1H).

Intermediate 18C 3,5-Dimethyl-1-(pyridin-2-ylmethyl)-1H-pyrazole-4-amine

467 mg (2.01 mmol) of 2-[(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]pyridine (Intermediate 18B) in a similar manner to Intermediate 1C) It was heated at 80 ° C for 1 hour with 5 mg of methanol containing 107 mg (0.10 mmol) of palladium/carbon (10% by weight) and 1.01 g (16.09 mmol) of ammonium formate, so that after filtration and aqueous treatment, 327 mg (1.62 mmol, 80%) of the desired compound.

1H NMR (300MHz, CDCl ₃ ): δ (ppm) = 2.08 (s, 3 H), 2.22 (s, 3 H), 2.46 (br.s., 2 H), 5.30 (s, 2 H), 6.77 (d, 1 H), 7.10-7.22 (m, 1 H), 7.59 (td, 1 H), 8.48-8.60 (m, 1 H).

Intermediate 19C 3,5-Dimethyl-1-[4-(trifluoromethoxy)benzyl]-1H-pyrazole-4-amine

In a manner similar to the intermediate 1C), 837 mg (2.66 mmol) of 3,5-dimethyl-4-nitro-1-[4-(trifluoromethoxy)benzyl]-1H-pyrazole ( Intermediate 19B) was heated with 80 ml of methanol containing 141 mg (0.13 mmol) of palladium/carbon (10% by weight) and 1.34 g (21.24 mmol) of ammonium formate at 80 ° C for 1 hour, so that after filtration and aqueous treatment, 750 mg was obtained. (2.10 mmol, 79%) of the desired compound.

Method 1: R _t = 0.79 min

MS (ESIpos): m/z = 286 (M+H) ⁺ .

Intermediate 20C 3,5-Dimethyl-1-[3-(trifluoromethoxy)benzyl]-1H-pyrazole-4-amine

In a similar manner to the intermediate 1C), 707 mg (2.24 mmol) of 3,5-dimethyl-4-nitro-1-[3-(trifluoromethoxy)benzyl]-1H-pyrazole ( Intermediate 20B) was heated at 80 ° C for 1 hour with 20 mL of methanol containing 119 mg (0.11 mmol) of palladium/carbon (10% by weight) and 1.13 g (17.94 mmol) of ammonium formate, so that after filtration and aqueous treatment, 639 mg was obtained. (1.43 mmol, 64%) of the desired compound.

Method 1: R _t = 0.79 min

MS (ESIpos): m/z = 286 (M+H) ⁺ .

Intermediate 21C 3,5-Dimethyl-1-[2-(trifluoromethoxy)benzyl]-1H-pyrazole-4-amine

In a similar manner to the intermediate 1C), 893 mg (2.83 mmol) of 3,5-dimethyl-4-nitro-1-[2-(trifluoromethoxy)benzyl]-1H-pyrazole ( Intermediate 21B) was heated at 80 ° C for 1 hour with 20 mg of methanol containing 150 mg (0.14 mmol) of palladium on carbon (10% by weight) and 1.43 g (22.66 mmol) of ammonium formate, so that after filtration and aqueous treatment, 688 mg was obtained. (1.33 M, 47%) of the desired compound.

Method 1: R _t = 0.78 min

MS (ESIpos): m/z = 286 (M+H) ⁺ .

Intermediate 22C 3,5-Dimethyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrazole-4-amine

790 mg (2.64 mmol) of 3,5-dimethyl-4-nitro-1-[4-(trifluoromethyl)benzyl]-1H-pyrazole in the same manner as Intermediate 1C) The compound 22B) was heated at 80 ° C for 1 hour with 5 mg of methanol containing 140 mg (0.13 mmol) of palladium/carbon (10% by weight) and 1.33 g (21.12 mmol) of ammonium formate, thereby obtaining 653 mg after filtration and aqueous treatment. 2.42 mmol, 92%) of the desired compound.

1H NMR (300MHz, CDCl ₃ ): δ (ppm) = 2.07 (s, 3 H), 2.17-2.26 (m, 3 H), 2.76 (br.s., 2 H), 5.22 (s, 2 H) , 7.15 (m, 2 H), 7.56 (m, 2 H).

Intermediate 23C 1-(3,4-difluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole-4-amine

In a manner similar to Intermediate 1C), 0.20 g (0.623 mmol) in the first experiment and 1.56 g (4.86 mmol) 1-(3,4-difluorobenzyl)-5- in the second experiment. Methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazole (Intermediate 23B) was reacted via a Biotage chromatography system (50 g snap KP-Sil column, hexane/40) -100% ethyl acetate) combined purification of two coarse After the product, 0.90 g (yiel.

¹ H-NMR (400MHz, DMSO d ₆ ) δ (ppm) = 2.07 (s, 3H), 4.02 (s, 2H), 5.25 (s, 2H), 6.91 (ddd, 1H), 7.17 (ddd, 1H) , 7.40 (dt, 1H).

Intermediate 24C 1-(2,4-difluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole-4-amine

In a manner analogous to Intermediate 1C), 1.73 g (5.39 mmol) of 1-(2,4-difluorobenzyl)-5-methyl-4-nitro-3-(trifluoromethyl)- 1H-pyrazole (Intermediate 24B) was reacted to give 1.91 g (113) after purification of the crude product via a Biotage chromatography system (50 g cartridge KP-Sil column, hexane/40-100% ethyl acetate). %) a non-completely pure compound which was used without any further purification.

^{1 H-NMR (300MHz, DMSO} d 6) δ (ppm) = 2.11 (s, 3H), 4.02 (s, 2H), 5.26 (s, 2H), 6.99-7.12 (m, 2H), 7.28 (td, 1H).

Intermediate 25C 1-(4-fluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole-4-amine

In a manner similar to Intermediate 1C), 4.21 g (13.9 mmol) of 1-(4-fluorobenzyl)-5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrene The azole (intermediate 25B) was reacted to obtain 3.37 g (76%) of the crude product after purification of the crude product via a Biotage chromatography system (100 g cartridge KP-Sil column, hexane/10-70% ethyl acetate). Title compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.06 (s, 3H), 3.99 (s, 2H), 5.24 (s, 2H), 7.13 - 7.21 (m, 4H).

Intermediate 26C 4-{[4-Amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}benzonitrile

In a manner analogous to Intermediate 8C), 3.20 g (10.3 mmol) of 4-{[5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazol-1-yl] Reaction of the benzyl carbonitrile (intermediate 26B) to give 2.66 g after purification of the crude product via a Biotage chromatography system (50 g cartridge KP-Sil column, hexane / 30-80% ethyl acetate) 87%) of the desired compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.05 (s, 3H), 4.06 (s, 2H), 5.38 (s, 2H), 7.19-7.26 (m, 2H), 7.79-7.85 ( m, 2H).

Intermediate 27C 1-(4-chlorobenzyl)-3,5-dimethyl-1H-pyrazole-4-amine

3.50 g (13.2 mmol) of 1-(4-chlorobenzyl)-3,5-dimethyl-4-nitro-1H-pyrazole (Intermediate 27B) in a similar manner to Intermediate 10C) The reaction gave 2.85 g (83%) of desired compound which was not completely purified.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 1.97 (s, 3H), 1.98 (s, 3H), 3.38 (s, 2H), 5.06 (s, 2H), 7.03 (d, 2H) , 7.33 - 7.38 (m, 2H).

Intermediate 28C 1-(3-chloro-4-fluorobenzyl)-3,5-dimethyl-1H-pyrazole-4-amine

1.50 g (5.29 mmol) of 1-(3-chloro-4-fluorobenzyl)-3,5-dimethyl-4-nitro-1H-pyrazole (in a similar manner to Intermediate 10C) Intermediate 28B) was reacted to give 1.24 g (yield: 74%) of desired compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 1.99 (s, 6H), 3.40 (s, 2H), 5.06 (s, 2H), 7.01 (ddd, 1H), 7.20 (dd, 1H) , 7.30-7.39 (m, 1H).

Intermediate 29C 5-[(4-Amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]pyridine-2-carbonitrile

In a manner analogous to Intermediate 8C), 3.69 g (14.3 mmol) of 5-[(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]pyridine-2- The carbonitrile (intermediate 29B) was reacted to obtain 1.00 g (28%) of the crude product after purification of the crude product via a Biotage chromatography system (50 g cartridge KP-Sil column, ethyl acetate / 0-50% methanol). Title compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 1.98 (s, 3H), 2.02 (s, 3H), 3.71 (br.s., 2H), 5.23 (s, 2H), 7.55 (dd , 1H), 7.97 (d, 1H), 8.45 (d, 1H).

Intermediate 30C 1-Benzyl-3,5-dimethyl-1H-pyrazole-4-amine

610 mg (2.64 mmol) of 1-benzylmethyl-3,5-dimethyl-4-nitro-1H-pyrazole (Intermediate 30B) and 140 mg (0.13 mmol) in a similar manner to Intermediate 1C) Palladium/carbon (10% by weight) and 1.33 g (21.12 mmol) of ammonium formate 5 mL of methanol were heated at 80 ° C for 1 hour to give 525 mg (2.61 mmol, 98%) of the desired compound.

_{1H NMR (300MHz, CDCl 3)} : δ (ppm) = 2.06 (s, 3 H), 2.21 (s, 3 H), 2.43 (br.s., 2 H), 5.18 (s, 2 H), 7.06 (d, 2 H), 7.20-7.26 (m, 1 H), 7.28-7.40 (m, 2 H).

Intermediate 31C Methyl 4-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]benzoate

7.00 g (24.2 mmol) of methyl 4-[(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]benzoate was obtained in a similar manner to Intermediate 10C) (Intermediate 31B) was reacted to give 5.02 g (72%) of desired title compound after purification of the crude product from Biotage chromatography system (50 g K K-Sil column, ethyl acetate / 0-40% methanol). It contains a small amount of the corresponding ethyl ester.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 1.97 (s, 3H), 1.99 (s, 3H), 3.40 (s, 2H), 3.82 (s, 3H), 5.16 (s, 2H) , 7.10-7.16 (m, 2H), 7.86-7.92 (m, 2H).

Intermediate 32C Methyl {4-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]phenyl}acetate

In a manner similar to Intermediate 1C), 3.81 g (12.7 mmol) of {4-[(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]phenyl} Methyl acetate (Intermediate 32B) was reacted via a Biotage chromatography system (50 g snap KP-Sil column, hexanes / 80-100% ethyl acetate followed by ethyl acetate / 0-75% methanol After purifying the crude product, 1.91 g (yield: 73%) of

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 1.98 (s, 3H), 1.99 (s, 3H), 3.33 (br.s., 2H), 3.58 (s, 3H), 3.62 (s) , 2H), 5.03 (s, 2H), 6.95-7.01 (m, 2H), 7.15-7.19 (m, 2H).

Intermediate 33C 1-(cyclohexylmethyl)-3,5-dimethyl-1H-pyrazole-4-amine

1.00 g (4.21 mmol) of 1-(cyclohexylmethyl)-3,5-dimethyl-4-nitro-1H-pyrazole (Intermediate 33B) was reacted in a similar manner to Intermediate 1C). Thus, after purifying the crude product via a Biotage chromatography system (25 g, K K-Sil column, ethyl acetate / 0-40% methanol), 0.68 g (78%)

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 0.80-0.98 (m, 2H), 1.06-1.20 (m, 3H), 1.47 (d, 2H), 1.54-1.71 (m, 4H), 1.95 (s, 3H), 2.02 (s, 3H), 3.24 (s, 2H), 3.61 (d, 2H).

Intermediate 34C 1-[(5-chloro-2-thienyl)methyl]-3,5-dimethyl-1H-pyrazole-4-amine

In a manner similar to Intermediate 8C), 100 mg (0.37 mmol) of 1-[(5-chloro-2-thienyl)methyl]-3,5-dimethyl-4-nitro-1H-pyrazole (Intermediate 34B) was reacted to give 150 mg (167%) of crude material.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 1.97 (s, 3H), 2.05 (s, 3H), 5.15 (s, 2H), 6.83 (d, 1H), 6.93 (d, 1H) .

Intermediate 35C 3,5-Dimethyl-1-[(1-methyl-1H-pyrazol-3-yl)methyl]-1H-pyrazole-4-amine

In a manner similar to the intermediate 8C), 100 mg (0.43 mmol) of 3,5-dimethyl-1-[(1-methyl-1H-pyrazol-3-yl)methyl]-4-nitro -1H-pyrazole (Intermediate 35B) was reacted to give 210 mg (241%) after purification of the crude product via a Biotage chromatography system (10 g cartridge KP-Sil column, ethyl acetate / 0-100% methanol). The crude product, which contains the desired title compound, was used in the next step.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 1.94 (s, 3H), 2.05 (s, 3H), 3.74 (s, 3H), 4.92 (s, 2H), 5.88 (d, 1H) , 7.53 (d, 2H).

Intermediate 36C 3,5-Dimethyl-1-[(3-methylpyridin-2-yl)methyl]-1H-pyrazole-4-amine

In a similar manner to the intermediate 1C), 339 mg (1.38 mmol) of 2-[(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]-3-methylpyridine (Intermediate 36B) was heated at 80 ° C for 1 hour with 5 mL of methanol containing 73 mg (0.07 mmol) of palladium/carbon (10% by weight) and 694 mg (11.01 mmol) of ammonium formate, so that after filtration and aqueous treatment, 212 mg was obtained. (0.98 mmol, 71%) of the desired compound.

1H NMR (400MHz, CDCl ₃ ): δ (ppm) = 2.07 (s, 3 H), 2.22 (s, 3 H), 2.42 - 2.67 (m, 5 H), 5.27 (s, 2 H), 6.46 ( d, 1 H), 7.01 (d, 1 H), 7.46 (t, 1 H).

Intermediate 37C 3,5-Dimethyl-1-[4-(methylsulfonyl)benzyl]-1H-pyrazole-4-amine

In a similar manner to the intermediate 8C), 0.10 g (0.323 mmol) in the first experiment and 0.61 g (1.97 mmol) in the second experiment, 3,5-dimethyl-1-[4-(methylsulfonate) Benzyl)benzylidene-4-nitro-1H-pyrazole (Intermediate 37B) was reacted via Biotage chromatography system (25g snap KP-Sil column, hexane / 0-100% acetic acid) After purification of the two crude products in ethyl acetate, followed by ethyl acetate / 0-25% methanol, 0.45 g (yield: 70%) of

¹ H-NMR (500MHz, DMSO d ₆ ) δ (ppm) = 1.99 (s, 3H), 2.00 (s, 3H), 3.16 (s, 3H), 3.49 (s, 2H), 5.19 (s, 2H) , 7.23 - 7.27 (m, 2H), 7.83 - 7.87 (m, 2H).

Intermediate 38C 4-[(4-Amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]-2-fluorobenzonitrile

1.14 g (4.16 mmol) of 4-[(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]-2-fluoro in a similar manner to Intermediate 8C) The benzonitrile (Intermediate 38B) was reacted to give 1.02 g (95%) after purification of the crude product via a Biotage chromatography system (25 g, KP-Sil column, ethyl acetate / 0-40% methanol). The title compound is desired.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 1.98 (s, 3H), 2.02 (s, 3H), 3.62 (br.s., 2H), 5.19 (s, 2H), 6.85 (t , 1H), 7.63 (dd, 1H), 7.85 (dd, 1H).

Intermediate 39C 3-[(4-Amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]pyridine-2-carbonitrile

In a manner similar to Intermediate 8C), 0.50 g (1.94 mmol) in the first experiment and 1.86 g (7.23 mmol) 3-[(3,5-dimethyl-4-nitro) in the second experiment. -1H-pyrazole-1- Methyl]pyridine-2-carbonitrile (Intermediate 39B) is reacted via a Biotage chromatography system (50 g snap KP-Sil column, hexane/60-100% ethyl acetate followed by acetic acid) Ethyl acetate / 0-90% methanol) After purification of the two crude products, 0.61 g (29%) of the desired compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 1.97 (s, 3H), 2.08 (s, 3H), 3.94 (br.s., 2H), 5.28 (s, 2H), 7. , 1H), 7.67 (dd, 1H), 8.64 (dd, 1H).

Intermediate 40C 2-[(4-Amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]nicotinonitrile

In a manner analogous to Intermediate 8C), 2.16 g (8.40 mmol) of 2-[(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]nicotinonitrile ( Intermediate 40B) was reacted to purify the crude product via a Biotage chromatography system (50 g cartridge KP-Sil column, hexane/60-100% ethyl acetate followed by ethyl acetate/0-90% methanol) Thereafter, 1.11 g (52%) of the desired title compound was obtained.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 1.91 (s, 3H), 2.13 (s, 3H), 3.61 (br.s., 2H), 5.31 (s, 2H), 7.51 (dd , 1H), 8.30 (dd, 1H), 8.74 (dd, 1H).

Intermediate 41C 4-[(4-Amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]-N-(2-hydroxyethyl)benzamide

In a manner similar to Intermediate 1C), 100 mg (0.31 mmol) in the first experiment and 1.0 g (3.14 mmol) in the second experiment 4-[(3,5-dimethyl-4-nitro-) 1H-pyrazol-1-yl)methyl]-N-(2-hydroxyethyl)benzamide (Intermediate 41B) is reacted via a Biotage chromatography system (25g snap-on KP-Sil column) After purifying the combined crude product, ethyl acetate (10-100% methanol) afforded 1.04 g (104%) of desired compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 1.99 (s, 3H), 3.16 (s, 3H), 3.24 - 3.34 (m, 2H), 3.44 - 3.52 (m, 2H), 5.11 5.23 (s, 2H), 7.07/7.16 (d, 2H), 7.71-7.82 (m, 2H), 8.34-8.47 (m, 3H).

Intermediate 42C 1-(3-Fluoro-4-methoxybenzyl)-3,5-dimethyl-1H-pyrazole-4-amine

In a manner similar to Intermediate 8C), 100 mg (0.36 mmol) in the first experiment and 1.80 g (6.45 mmol) 1-(3-fluoro-4-methoxybenzyl) in the second experiment. 3,5-Dimethyl-4-nitro-1H-pyrazole (Intermediate 42B) was reacted via a Biotage chromatography system (100 g snap-on KP-Sil column, hexane/80-100% acetic acid) After purification of the combined crude product, EtOAc (EtOAc)

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 1.98 (s, 3H), 1.99 (s, 3H), 3.60 (br.s., 2H), 3.78 (s, 3H), 4.99 (s) , 2H), 6.79-6.89 (m, 2H), 7.07 (t, 1H).

Intermediate 43C 1-[(6-Methoxypyridin-3-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazole-4-amine

In a manner similar to the intermediate 8C), 800 mg (2.53 mmol) of 2-methoxy-5-{[5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazole- 1-yl]methyl}pyridine (Intermediate 43B) was reacted via a Biotage chromatography system (25 g snap KP-Sil column, hexanes / 50-100% ethyl acetate, then ethyl acetate / After purification of the crude product from 0-50% EtOAc, EtOAc (EtOAc)

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 2.11 (s, 3H), 3.81 (s, 3H), 3.98 (s, 2H), 5.19 (s, 2H), 6.79 (d, 1H) , 7.46 (dd, 1H), 8.03 (d, 1H).

Intermediate 44C 1-[3-(4-methoxyphenyl)propyl]-3,5-dimethyl-1H-pyrazole-4-amine

In a manner similar to the intermediate 9C), 500 mg (1.73 mmol) of 1-[3-(4-methoxyphenyl)propyl]-3,5-dimethyl-4-nitro-1H-pyridin The azole (Intermediate 44B) was taken to give 430 mg (93%)

¹ H-NMR (300 MHz, DMSO d ₆ ) δ (ppm) = 1.86 (tt, 2H), 1.96 (s, 3H), 2.00 (s, 3H), 2.45 (t, 2H), 3.29 (br.s. , 2H), 3.70 (s, 3H), 3.77 (t, 2H), 6.83 (d, 2H), 7.10 (d, 2H).

Intermediate 45C 4-[(4-Amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]nicotinonitrile

In a manner similar to Intermediate 9C), 500 mg (1.94 mmol) in the first experiment and 960 mg (3.73 mmol) in the second experiment 4-[(3,5-dimethyl-4-nitro-1H) -pyrazol-1-yl)methyl]nicotinonitrile (Intermediate 45B) was reacted and purified via a Biotage chromatography system (50 g snap KP-Sil column, ethyl acetate / 0-35% methanol) After the combined crude product, 630 mg (49%)

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 1.99 (s, 3H), 2.04 (s, 3H), 3.82 (br.s., 2H), 5.30 (s, 2H), 6.75 (d) , 1H), 8.73 (d, 1H), 8.99 (s, 1H).

Intermediate 46C 3,5-Dimethyl-1-(2-phenoxyethyl)-1H-pyrazole-4-amine

1.39 g (4.86 mmol) of 3,5-dimethyl-4-nitro-1-(2-phenoxyethyl)-1H-pyrazole (Intermediate 46B) in a similar manner to Intermediate 9C) ) reaction, resulting in 938mg (73%) of the title compound, m.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 1.95 (s, 3H), 2.08 (s, 3H), 3.30 (s, 2H), 4.16 - 4.34 (m, 4H), 7.05 (d, 2H), 7.73 (d, 2H).

Intermediate 47C 4-[(4-Amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]-3-fluorobenzonitrile

1.84 g (6.71 mmol) of 4-[(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]-3-fluoro in a similar manner to the intermediate 8C) Benzoonitrile (Intermediate 47B) is reacted via a Biotage chromatography system (50g snap KP-Sil column, hexane/25-100% ethyl acetate, followed by ethyl acetate/0-100% methanol) After purification of the crude product, 1.24 g (72%)

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 1.98 (s, 3H), 2.02 (s, 3H), 3.47 (br.s., 2H), 5.19 (s, 2H), 6.86 (t , 1H), 7.62 (dd, 1H), 7.84 (dd, 1H).

Intermediate 48C 2-{[4-Amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}benzonitrile

In a manner similar to Intermediate 8C), 2.50 g (8.06 mmol) of 2-{[5-methyl-4- Nitro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}benzonitrile (Intermediate 48B) was reacted via a Biotage chromatography system (50 g snap-on KP-Sil tube) After the crude product was purified by EtOAc EtOAcjjjjjjj

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 2.14 (s, 3H), 4.09 (s, 2H), 5.45 (s, 2H), 6.99 (d, 1H), 7.48-7.59 (m, 1H), 7.70 (td, 1H), 7.90 (dd, 1H).

Intermediate 49C 1-(4-Methoxybenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole-4-amine

In a manner similar to Intermediate 8C), 500 mg (1.59 mmol) in the first experiment and 6.20 g (19.7 mmol) of 1-(4-methoxybenzyl)-5-methyl in the second experiment. 4-Nitro-3-(trifluoromethyl)-1H-pyrazole (Intermediate 49B) was reacted via a Biotage chromatography system (100 g snap-on KP-Sil column, hexane/80-100) After purifying the combined crude product, EtOAc (EtOAc:EtOAc)

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 2.06 (s, 3H), 3.71 (s, 3H), 3.96 (br.s., 2H), 5.16 (s, 2H), 6.83-6.93 (m, 2H), 7.04-7.10 (m, 2H).

Intermediate 50C 1-[(6-methoxypyridin-3-yl)methyl]-3,5-dimethyl-1H-pyrazole-4-amine

In a manner similar to the intermediate 1C), 500 mg (1.91 mmol) of 5-[(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]-2-methoxy Pyridine (Intermediate 50B) is reacted via a Biotage chromatography system (10 g snap KP-Sil column, hexanes / 80-100% ethyl acetate followed by ethyl acetate / 0-75% methanol) After purification of the crude product, 214 mg (46%)

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 1.97 (s, 3H), 2.02 (s, 3H), 3.35 (s, 2H), 3.80 (s, 3H), 5.00 (s, 2H) , 6.74 (d, 1H), 7.38 (dd, 1H), 7.94 (d, 1H).

Intermediate 51C 4-{[4-Amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl-1methyl}nicotinonitrile

1.20 g (3.86 mmol) of 4-{[5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazol-1-yl]-A was obtained in a similar manner to Intermediate 10C) The nicotinic nitrile (intermediate 51B) was reacted to give 690 mg (62%) after purification of the crude product via a Biotage chromatography system (50 g cartridge KP-Sil column, ethyl acetate / 0-35% methanol). The title compound is required.

¹ H-NMR (400MHz, DMSO d ₆ ) δ (ppm) = 2.12 (s, 3H), 4.13 (s, 2H), 5.52 (s, 2H), 6.86 (d, 1H), 8.78 (d, 1H) , 9.03 (s, 1H).

Intermediate 52C 5-{[4-Amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}pyridine-2-carbonitrile

In a manner similar to the intermediate 8C), 2.60 g (8.25 mmol) of 5-{[5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazol-1-yl]- Reaction of pyridine-2-carbonitrile (Intermediate 52B) via a Biotage chromatography system (50 g snap KP-Sil column, hexanes / 20-100% ethyl acetate, then ethyl acetate / After purification of the crude product from 0-40%MeOH, 670 mg (26%)

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.12 (s, 3H), 4.09 (s, 2H), 5.45 (s, 2H), 7.66 (dd, 1H), 8.03 (d, 1H) , 8.57 (d, 1H).

Intermediate 53C 4-{[4-Amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}-3-fluorobenzonitrile

In a manner similar to Intermediate 8C), 250 mg (0.76 mmol) in the first experiment and 1.64 g (5.00 mmol) 3-fluoro-4-{[5-methyl-4-nitro in the second experiment. -3-(Trifluoromethyl)-1H-pyrazol-1-yl]methyl}benzonitrile (Intermediate 53B reaction, thus via a Biotage chromatography system (50g snap-on KP-Sil column, After purification of the combined crude product from EtOAc/EtOAc (EtOAc:EtOAc)

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.10 (s, 3H), 4.06 (s, 2H), 5.39 (s, 2H), 7.03 (t, 1H), 7.68 (dd, 1H) , 7.89 (dd, 1H).

Intermediate 54C 4-amino-1-(4-fluorobenzyl)-5-methyl-1H-pyrazole-3-carbonitrile

To a mixture of 40 ml of ethanol, 20 mL of water and 0.25 mL of acetic acid, 2.0 g (36 mmol) of iron filings were added. The mixture was heated to 75 ° C and then 1.00 g (3.84 mmol) of 1-(4-fluorobenzyl)-5-methyl-4-nitro-1H-pyrazole-3-carbonitrile (Intermediate 54B) ) and stirred for one hour. After cooling to 25 ° C, the suspension was filtered over Celite, washed with ethyl acetate and evaporated. 50 mL of water and 40 mL of a concentrated aqueous solution of sodium carbonate were added to the residue. The aqueous phase was extracted three times with 100 mL of ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfatessssssssssssssssssssssssssssssssssssssss Purification followed by ethyl acetate / 0-100% MeOH afforded 320 mg (34%) of desired compound.

¹ H-NMR (300 MHz, DMSO d ₆ ) δ (ppm) = 2.06 (s, 3H), 4.54 (s, 2H), 5.25 (s, 2H), 7.09 - 7.26 (m, 4H).

Intermediate 55C 4-[(4-Amino-3,5-diethyl-1H-pyrazol-1-yl)methyl]benzonitrile

1.29 g (4.54 mmol) of 4-[(3,5-diethyl-4-nitro-1H-pyrazol-1-yl)methyl]benzonitrile (in a similar manner to Intermediate 8C) Intermediate 55B) was reacted to give 1.16 g (91%) of the desired compound, which was used without any further purification.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 0.87 (t, 3H), 1.10 (t, 3H), 2.40-2.47 (m, 4H), 3.42 (s, 2H), 5.21. 2H), 7.14 (d, 2H), 7.76 (d, 2H).

Intermediate 56C 4-{[4-Amino-5-ethyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}benzonitrile

In a similar manner to the intermediate 8C), 200 mg (0.62 mmol) in the first experiment and 1.00 g (3.08 mmol) in the second experiment 4-{[5-ethyl-4-nitro-3-( Trifluoromethyl)-1H-pyrazol-1-yl]methyl}benzonitrile (Intermediate 56B) was reacted via a Biotage chromatography system (25g snap KP-Sil column, hexane/50) After purifying the combined crude product - 100% ethyl acetate (EtOAc:EtOAc)

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 0.87 (t, 3H), 2.55 (q, 2H), 4.05 (s, 2H), 5.39 (s, 2H), 7.23 (d, 2H) , 7.82 (d, 2H).

Intermediate 57C 4-{[4-Amino-5-isopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}benzonitrile

In a manner similar to the intermediate 8C), 400 mg (1.18 mmol) of 4-{[5-isopropyl-4-nitro-3-(trifluoromethyl)-1H-pyrazol-1-yl]- Reaction of benzonitrile (intermediate 57B), Thus, 380 mg (103%, purity: about 80%) of the desired compound was obtained, which was used without any further purification.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 1.11 (d, 6H), 3.04 (spt, 1H), 3.90 (s, 2H), 5.45 (s, 2H), 7.20 (d, 2H) , 7.84 (d, 2H).

Intermediate 58C 4-{[4-Amino-3-isopropyl-5-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}benzonitrile

In a manner similar to the intermediate 8C), 440 mg (1.30 mmol) of 4-{[3-isopropyl-4-nitro-5-(trifluoromethyl)-1H-pyrazol-1-yl] Benzene carbonitrile (intermediate 58B) is reacted via a Biotage chromatography system (25g snap KP-Sil column, hexane / 0-100% ethyl acetate, followed by ethyl acetate / 0-50 After purifying the crude product, EtOAc (MeOH)

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 1.17 (d, 6H), 3.00 (spt, 1H), 4.44 (s, 2H), 5.33 (s, 2H), 7.13 (d, 2H) , 7.78 (d, 2H).

Intermediates 59C and 60C 4-[(4-Amino-3-isopropyl-5-methyl-1H-pyrazol-1-yl)methyl]benzonitrile and 4-[(4-amino-5-isopropyl) -3-methyl-1H-pyrazol-1-yl)methyl]benzonitrile

In a similar manner to the intermediate 8C), 1.00 (3.52 mmol) in the first experiment and 2.22 g (7.81 mmol) in the second experiment 4-[(3-isopropyl-5-methyl-4-) nitro-1H-pyrazole -1-yl)methyl]benzonitrile (Intermediate 59B) was reacted via a Biotage chromatography system (50 g snap KP-Sil column, hexane / 0-100% ethyl acetate followed by acetic acid) Ethyl ester / 0-80% methanol) After purification of the combined crude product, 2.32 g (48%) of 4-[(4-amino-3-isopropyl-5-methyl-1H-pyrazole-1) -yl)methyl]benzonitrile as the main product and a small amount of its isomer 4-[(4-amino-5-isopropyl-3-methyl-1H-pyrazol-1-yl) A Benzobenzonitrile is the desired compound.

NMR as a major product of 4-[(4-amino-3-isopropyl-5-methyl-1H-pyrazol-1-yl)methyl]benzonitrile: ¹ H-NMR (300 MHz, DMSO d ₆ ) δ (ppm) = 1.15 (d, 6H), 1.95 (s, 3H), 2.89 (spt, 1H), 3.76 (s, 2H), 5.20 (s, 2H), 7.12 (d, 2H), 7.76 (d, 2H).

Intermediates 61C and 62C 4-[(4-Amino-3-ethyl-5-methyl-1H-pyrazol-1-yl)methyl]benzonitrile and 4-[(4-amino-5-ethyl-3) -methyl-1H-pyrazol-1-yl)methyl]benzonitrile

4-[(3-ethyl-5-methyl-4-nitro-1H-pyrazol-1-yl)methyl]benzonitrile and 4-[(in a similar manner to Intermediate 8C) 650 mg (2.41 mmol) of a mixture of 5-ethyl-3-methyl-4-nitro-1H-pyrazol-1-yl)methyl]benzonitrile (intermediate 61 and 62B) was reacted to give 4- [(4-Amino-3-ethyl-5-methyl-1H-pyrazol-1-yl)methyl]benzonitrile and 4-[(4-Amino-5-ethyl-3-methyl) A mixture of 571 mg (96%) of </RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt;

NMR of the mixture: ¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 0.89/1.11 (t, 3H), 1.98 / 2.01 (s, 3H), 2.40-2.49 (m, 2H), 5.21. , 2H), 7.12-7.20 (m, 2H), 7.76-7.82 (m, 2H).

Intermediate 63C (±)-4-[1-(4-Amino-3,5-dimethyl-1H-pyrazol-1-yl)ethyl]benzonitrile

440 mg (1.63 mmol) of (±)-4-[1-(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)ethyl ester in a similar manner to Intermediate 8C) The benzonitrile (Intermediate 63B) was reacted to give 410 mg (91%) of the desired compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 1.69 (d, 3H), 1.93 (s, 3H), 2.02 (s, 3H), 3.41 (br.s., 2H), 5.44 (q) , 1H), 7.21 (d, 2H), 7.71-7.77 (m, 2H).

Intermediate 64C (±)-4-{1-[4-Amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethyl}benzonitrile

1.54 g (4.75 mmol) of (±)-4-{1-[5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazole was obtained in a similar manner to Intermediate 8C) -1 -yl}ethyl}benzonitrile (Intermediate 64B) was reacted to purify the crude product via a Biotage chromatography system (25 g snap KP-Sil column, hexane / 30-100% ethyl acetate) Thereafter, 1.03 g (66%) of the desired compound was obtained.

¹ H-NMR (400MHz, DMSO d ₆ ) δ (ppm) = 1.74 (d, 3H), 2.02 (s, 3H), 4.03 (s, 2H), 5.70 (q, 1H), 7.28 (d, 2H) , 7.80-7.84 (m, 2H).

Intermediate 65C (±)-5-Methyl-1-(1-phenylethyl)-3-(trifluoromethyl)-1H-pyrazole-4-amine

In a manner similar to Intermediate 8C), 200 mg (0.67 mmol) in the first experiment and 800 mg (2.67 mmol) (±)-5-methyl-4-nitro-1-(1) in the second experiment. -Phenylethyl)-3-(trifluoromethyl)-1H-pyrazole (Intermediate 65B) was reacted via a Biotage chromatography system (both 50g snap-on KP-Sil column, hexane/ After two subsequent purifications of the combined crude product, EtOAc (EtOAc:EtOAc)

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 1.72 (d, 3H), 2.01 (s, 3H), 3.94 (s, 2H), 5.55 (q, 1H), 7.07-7.12 (m, 2H), 7.19-7.38 (m, 3H).

Intermediate 66C 4-[3-(4-Amino-3,5-dimethyl-1H-pyrazol-1-yl)propyl]benzonitrile

In a manner similar to the intermediate 10C), 1.05 g (3.67 mmol) of 34-[3-(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)propyl]benzene The nitrile (Intermediate 66B) was taken to give 931 mg (EtOAc).

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 1.86-1.97 (m, 5H), 2.01 (s, 3H), 2.61 (t, 2H), 3.36 (br.s., 2H), 3.80 (t, 2H), 7.41 (d, 2H), 7.73 (d, 2H).

Intermediate 67C 6-[(4-Amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]nicotinonitrile

In a manner analogous to Intermediate 8C), 2.11 g (8.20 mmol) of 6-[(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]nicotinonitrile ( Intermediate 67B) was reacted to purify the crude product via a Biotage chromatography system (25 g cartridge KP-Sil column, hexane / 25-100% ethyl acetate followed by ethyl acetate / 0-100% methanol) After that, 760 mg (44%) of the desired compound was obtained.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.00 (s, 3H), 2.03 (s, 3H), 3.65 (br.s., 2H), 5.26 (s, 2H), 6.89 (d) , 1H), 8.24 (dd, 1H), 8.97 (d, 1H).

Intermediate 68C 6-{[4-Amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}nicotinonitrile

In a manner similar to the intermediate 8C), 2.15 g (8.07 mmol) of 6-{[5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazol-1-yl]- Base nicotinic nitrile (intermediate 68B) was reacted via a Biotage chromatography system (25g snap KP-Sil column, hexanes / 25-100% ethyl acetate, followed by ethyl acetate / 0-100) After purifying the crude product, EtOAc (m.)

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 2.11 (s, 3H), 4.07 (s, 2H), 5.48 (s, 2H), 7.20 (d, 1H), 8.31 (dd, 1H) , 8.99 (d, 1H).

Intermediate 69C Methyl 4-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}benzoate

In a manner similar to Intermediate 10C), 3.00 g (8.74 mmol) of 4-{[5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazol-1-yl] Methyl benzoate (Intermediate 69B) was reacted to give 2.62 g after purification of the crude product via a Biotage chromatography system (100 g K K-Sil column, hexane / 0-100% ethyl acetate) (86%) of the desired compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.05 (s, 3H), 3.83 (s, 3H), 4.05 (s, 2H), 5.36 (s, 2H), 7.20 (d, 2H) , 7.93 (d, 2H).

Intermediate 70C (±)-[{4-[(4-Amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]phenyl}(methyl)oxyl-yl-λ ⁶ -sulfinyl]ethyl carbamate

In a manner similar to Intermediate 8C), 500 mg (1.31 mmol) in the first experiment and 1.60 g (4.21 mmol) (±)-[{4-[(3,5-dimethyl) in the second experiment. 4-Nitro-1H-pyrazol-1-yl)methyl]phenyl}(methyl)oxylyl-λ ⁶ -sulfinyl]ethyl carbamate (Intermediate 70B), thereby After purifying the combined crude product via Biotage chromatography system (100 g snap KP-Sil column, hexane / 0-100% ethyl acetate followed by ethyl acetate / 0-25% methanol), 650 mg (34%) of the desired compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 1.09 (t, 3H), 2.02 (s, 3H), 2.03 (s, 3H), 3.18 (s, 2H), 3.43 (s, 3H) , 3.86-3.96 (m, 2H), 5.22 (s, 2H), 7.30 (d, 2H), 7.87-7.91 (m, 2H).

Intermediate 71C 1-{4-[(dimethylamino)methyl]benzyl}-3,5-dimethyl-1H-pyrazole-4-amine

In a manner similar to the intermediate 10C), 100 mg (0.35 mmol) of 1-{4-[(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]phenyl The reaction was carried out with the title compound, mp.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 1.98 (s, 6H), 2.09 (s, 6H), 3.42 (br.s., 2H), 5.04 (s, 2H), 6.98 (d) , 2H), 7.19 (d, 2H).

Intermediate 72C 4-{[4-Amino-3-methyl-5-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}benzonitrile

In a similar manner to the intermediate 8C), 150 mg (0.48 mmol) in the first experiment and 540 mg (8.26 mmol) in the second experiment 4-{[3-methyl-4-nitro-5-(three Fluoromethyl)-1H-pyrazol-1-yl]methyl}benzonitrile (Intermediate 72B) was reacted via a Biotage chromatography system (25g snap KP-Sil column, hexane/20- 70% ethyl acetate) purified combined crude After the product, 536 mg (86%).

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.09 (s, 3H), 4.49 (s, 2H), 5.32 (s, 2H), 7.19 (d, 2H), 7.77-7.84 (m, 2H).

Intermediate 73C 4-[(4-Amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]-3,5-difluorobenzonitrile

In a manner analogous to Intermediate 8C), 1.03 g (3.52 mmol) of 4-[(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]-3,5 -Difluorobenzonitrile (Intermediate 73B) is reacted via a Biotage chromatography system (25g snap KP-Sil column, hexane / 50-100% ethyl acetate, followed by ethyl acetate / 0- After purifying the crude product with 100% MeOH, EtOAc (EtOAc)

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 1.90 (s, 3H), 2.15 (s, 3H), 3.75 (s, 2H), 5.11 (s, 2H), 7.76-7.86 (m, 2H).

Intermediate 74C 4-{[4-Amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}-3,5-difluorobenzonitrile

In a manner similar to Intermediate 8C), 1.90 g (4.67 mmol) of 3,5-difluoro-4-{[5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyridin Zyridin-1-yl]methyl}benzonitrile (Intermediate 74B) is reacted via a Biotage chromatography system (25g snap KP-Sil column, hexane/50- After purifying the crude product with EtOAc (EtOAc)EtOAc (EtOAc)

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.20 (s, 3H), 3.99 (s, 2H), 5.31 (s, 2H), 7.80-7.87 (m, 2H).

Intermediate 75C 1-[4-(methoxymethyl)benzyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazole-4-amine

380 mg (1.15 mmol) of 1-[4-(methoxymethyl)benzyl]-5-methyl-4-nitro-3-(trifluoromethyl) in a similar manner to Intermediate 1C) -1H-pyrazole (intermediate 75B) is reacted via a Biotage chromatography system (10 g snap KP-Sil column, hexane / 0-100% ethyl acetate, followed by ethyl acetate / 0-) After purifying the crude product with 100% MeOH, 280 mg (77%)

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.07 (s, 3H), 3.27 (s, 3H), 4.01 (s, 2H), 4.38 (s, 2H), 5.26 (s, 2H) , 7.09 (d, 2H), 7.29 (d, 2H).

Intermediate 76C (4-{[4-Amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}phenyl)acetonitrile

780 mg (2.41 mmol) in a manner similar to the intermediate 8C) (4-{[5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazol-1-yl]- }}phenyl)acetonitrile (intermediate 76B) Thus, after purification of the crude product via a Biotage chromatography system (25 g snap KP-Sil column, hexane / 0-100% ethyl acetate followed by ethyl acetate / 0-100% methanol), 580 mg (78%) of the desired compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.08 (s, 3H), 3.99-4.03 (m, 4H), 5.26 (s, 2H), 7.13 (d, 2H), 7.33 (d, 2H).

Intermediate 77C 3-[(4-Amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]-N-methyl-1,2,4-oxadiazol-5-carboxamide

621 mg (2.11 mmol) of 3-[(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]-N-methyl was obtained in a similar manner to Intermediate 10C) -1,2,4-oxadiazol-5-carboxamide (Intermediate 77B) was reacted to give 380 mg (yiel.

^{1 H-NMR (400MHz, CDCl} 3) δ (ppm) = 2.17 (s, 3H), 2.20 (s, 3H), 2.55 (br.s., 2H), 3.01 (d, 3H), 5.30 (s, 2H), 7.09 (br.s., 1H).

Intermediate 78C 4-[(4-Amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]piperidine-1-carboxylic acid tert-butyl ester

3.54 g (8.37 mmol) of 4-[(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]piperidine-1 was obtained in a similar manner to Intermediate 1C) - tert-butyl formate (intermediate 78B), Thus 1.68 g (62%) of the desired compound are obtained after flash chromatography.

_{^{1 H NMR (300MHz, CDCl 3}} ): δ (ppm) = 1.14 (dddd, 2H), 1.44 (s, 9H), 1.54 (br.d., 2H), 2.01 (m, 1H), 2.16 (s, 3H), 2.18 (s, 3H), 2.64 (dd, 2H), 3.77 (d, 2H), 4.09 (m, 2H).

Intermediate 79C 5-methyl-1-[(5-methyl-1,2-oxazol-3-yl)methyl]-3-(trifluoromethyl)-1H-pyrazole-4-amine

In a manner similar to the intermediate 10C), 4.55 g (15.7 mmol) of 5-methyl-3-{[5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazole- Reaction of 1-yl]methyl}-1,2-oxazole (Intermediate 79B) gave 3.08 g (68%) of the desired compound.

^{1 H NMR (400MHz, DMSO- d} 6): δ (ppm) = 2.14 (s, 3H), 2.36 (s, 3H), 4.02 (br.s., 2H), 5.29 (s, 2H), 6.03 ( s, 1H).

Intermediate 80C 1-[(5-ethyl-1,2,4-oxadiazol-3-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazole-4-amine

1.94 g (6.04 mmol) of 5-methyl-3-{[5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazole-in a similar manner to Intermediate 10C) Reaction of 1-yl]methyl}-1,2-oxazole (Intermediate 80B) gave 1.49 g (81%) of desired compound.

^{1 H NMR (400MHz, DMSO- d} 6): δ (ppm) = 1.25 (t, 3H), 2.18 (s, 3H), 2.93 (q, 2H), 4.04 (br.s., 2H), 5.42 ( s, 2H).

Intermediate 81C 1-[(3-ethyl-1,2-oxazol-5-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazole-4-amine

690 mg (2.29 mmol) of 3-ethyl-5-{[5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazole-1 was obtained in a similar manner to Intermediate 10C) -Methyl}-1,2-oxazole (Intermediate 81B) was reacted to give 269 mg (41%) of the desired compound.

^{1 H NMR (400MHz, DMSO- d} 6): δ (ppm) = 1.16 (t, 3H), 2.18 (s, 3H), 2.59 (q, 2H), 4.06 (br.s., 2H), 5.43 ( s, 2H), 6.32 (s, 1H).

Intermediate 82C 3,5-Dimethyl-1-[(3-methyl-1,2-oxazol-5-yl)methyl]-1H-pyrazole-4-amine

630 mg (2.67 mmol) of 5-[(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]-3-methyl was obtained in a similar manner to Intermediate 10C) -1,2-oxazole (Intermediate 82B) was reacted to give 442 mg (76%) of the desired compound.

^{1 H NMR (400MHz, DMSO- d} 6): δ (ppm) = 1.97 (s, 3H), 2.09 (s, 3H), 2.17 (s, 3H), 3.62 (br.s., 2H), 5.19 ( s, 2H), 6.09 (s, 1H).

Intermediate 83C 3,5-Dimethyl-1-[(5-methyl-1,2-oxazol-3-yl)methyl]-1H-pyrazole-4-amine

In a manner similar to Intermediate 8C), 200 mg (847 μmol) of 3-[(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]-5-methyl- 1,2-oxazole (Intermediate 83B) was reacted to give 67 mg (31%) of the desired compound.

^{1 H NMR (400MHz, DMSO- d} 6): δ (ppm) = 1.98 (s, 3H), 2.06 (s, 3H), 2.33 (s, 3H), 3.97 (br.s., 2H), 5.07 ( s, 2H), 5.90 (s, 1H).

Intermediate 84C 4-{[4-Amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}piperidine-1-carboxylic acid tert-butyl ester

In a manner similar to Intermediate 1C), 1.89 g (4.58 mmol) of 4-{[5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazol-1-yl]- The reaction was carried out without further purification. The title compound was obtained from the title compound.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ (ppm) = 1.17 (dddd, 2H), 1.46 (s, 9H), 1.54 (m, 2H), 2.07 (m, 1H), 2.17 (s, 3H), 2.66 (m, 2H), 3.87 (d, 2H), 4.12 (m, 2H).

Intermediate 85C 5-methyl-1-(piperidin-4-ylmethyl)-3-(trifluoromethyl)-1H-pyrazole-4-amine

800 mg (1.88 mmol) of 4-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}piperidine-1-carboxylic acid tert-butyl A solution of the ester (Intermediate 84C) in 11 mL dichloromethane was stirred with 1.45 mL (18.8 mmol) trifluoroacetic acid for 4 hr. NH ₂ The reaction was derivatized silica gel mixture was filtered, and the filtrate was evaporated to give 1.0g of the title compound in the form of a crude product, which was used without further purification.

^{1 H NMR (300MHz, DMSO- d} 6): δ (ppm) = 1.33 (dddd, 2H), 1.62 (m, 2H), 2.08 (m, 1H), 2.18 (s, 3H), 2.83 (m, 2H ), 3.25 (m, 2H), 3.94 (d, 2H).

Intermediate 86C 1-{[1-(ethylsulfonyl)piperidin-4-yl]methyl}-5-methyl-3-(trifluoromethyl)-1H-pyrazole-4-amine

500 mg (crude, about 800 μmol) of 5-methyl-1-(piperidin-4-ylmethyl)-3-(trifluoromethyl)-1H-pyrazol-4-amine (intermediate 85C) in 3 mL The solution in DMF was stirred with 106 μL (1.12 mmol) of ethanesulfonium chloride and 670 μL (4.80 mmol) of triethylamine for 30 minutes. A saturated aqueous solution of sodium hydrogencarbonate and ethyl acetate were added to the reaction. The mixture was extracted with butanol and the combined organic phases were washed with brine, dried, filtered and evaporated. Purification by flash chromatography gave 144 mg (48%).

^{1 H NMR (400MHz, DMSO- d} 6): δ (ppm) = 1.19 (t, 3H), 1.21 (dddd, 2H), 1.53 (m, 2H), 1.91 (m, 1H), 2.14 (s, 3H ), 2.75 (m, 2H), 3.00 (q, 2H), 3.58 (m, 2H), 3.90 (d, 2H), 3.94 (s, 2H).

Intermediate 87C 1-[(3-ethyl-1,2-oxazol-5-yl)methyl]-3,5-dimethyl-1H-pyrazole-4-amine

In a manner similar to Intermediate 10C), 1.34 g (4.82 mmol) of 5-[(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]-3-ethyl The benzyl-1,2-oxazole (Intermediate 85B) was reacted to give 1.09 g (95%) of the desired compound.

^{1 H NMR (400MHz, DMSO- d} 6): 6 (ppm) = 1.14 (t, 3H), 1.96 (s, 3H), 2.09 (s, 3H), 2.57 (q, 2H), 3.41 (br.s .2H), 5.19 (s, 2H), 6.15 (s, 1H).

Intermediate 88C 1-{[1-(ethylsulfonyl)piperidin-4-yl]methyl}-3,5-dimethyl-1H-pyrazole-4-amine

In a similar manner to the intermediate 10C), 2.53 g (7.27 mmol) of 4-[(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]-1-( Ethylsulfonyl)piperidine (Intermediate 87B) was reacted to give 2.20 g (96%) of desired compound.

^{1 H NMR (400MHz, DMSO- d} 6): δ (ppm) = 1.17 (m, 2H), 1.19 (t, 3H), 1.52 (m, 2H), 1.84 (m, 1H), 1.96 (s, 3H ), 2.05 (s, 3H), 2.72 (m, 2H), 2.99 (q, 2H), 3.27 (s, 2H), 3.56 (m, 2H), 3.71 (d, 2H).

Intermediate 89C 3,5-Dimethyl-1-{[3-(propan-2-yl)-1,2-oxazol-5-yl]methyl}-1H-pyrazole-4-amine

In a manner analogous to Intermediate 10C), 1.06 g (3.61 mmol) of 5-[(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]-3-( The reaction of propan-2-yl)-1,2-oxazole (Intermediate 88B) gave 877 mg (99%) of desired compound.

^{1 H NMR (400MHz, DMSO- d} 6): δ (ppm) = 1.17 (d, 6H), 1.97 (s, 3H), 2.10 (s, 3H), 2.94 ( septet, 1H), 3.41 (br. s., 2H), 5.19 (s, 2H), 6.21 (s, 1H).

Intermediate 90C 1-[(5-cyclopropyl-1,2-oxazol-3-yl)methyl]-3,5-dimethyl-1H-pyrazole-4-amine

1.30 g (3.77 mol) of 5-cyclopropyl-3-[(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl) A was obtained in a similar manner to Intermediate 10C) The reaction of 1,1,2-oxazole (Intermediate 89B) gave 1.07 g (98%) of the desired compound.

^{1 H NMR (300MHz, DMSO- d} 6): δ (ppm) = 0.84 (m, 2H), 1.01 (m, 2H), 1.97 (s, 3H), 2.05 (s, 3H), 2.08 (m, 1H ), 3.39 (br.s., 2H), 5.03 (s, 2H), 5.88 (s, 1H).

Intermediate 91C 5-methyl-1-[(3-methyl-1,2-oxazol-5-yl)methyl]-3-(trifluoromethyl)-1H-pyrazole-4-amine

In a manner similar to the intermediate 10C), 1.40 g (4.58 mmol) of 3-methyl-5-{[5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazole- 1-Methyl]methyl}-1,2-oxazole (Intermediate 90B) was reacted to give 1.00 g (75%) of desired compound.

^{1 H NMR (400MHz, DMSO- d} 6): δ (ppm) = 2.17 (s, 3H), 2.20 (s, 3H), 4.04 (br.s., 2H), 5.43 (s, 2H), 6.25 ( s, 1H).

Intermediate 92C 5-[(4-Amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]thiophene-2-carbonitrile

468 mg (1.43 mmol) of 5-[(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)methyl]thiophene-2-yl was obtained in a similar manner to Intermediate 8C) The nitrile (Intermediate 91B) was reacted to give 188 mg (37%) of the desired compound.

^{1 H NMR (400MHz, DMSO- d} 6): δ (ppm) = 1.99 (s, 3H), 2.06 (s, 3H), 3.43 (br.s., 2H), 5.33 (s, 2H), 7.10 ( d, 1H), 7.80 (d, 1H).

Intermediate 93C 5-{[4-Amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl 1 methyl}thiophene-2-carbonitrile

In a manner similar to Intermediate 8C), 630 mg (1.79 mmol) of 5-{[5-methyl-4- Reaction of nitro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}thiophene-2-carbonitrile (Intermediate 92B) to give 514 mg (65%) without purification. The title compound is desired.

^{1 H NMR (400MHz, DMSO- d} 6): δ (ppm) = 2.15 (s, 3H), 4.06 (br.s., 2H), 5.56 (s, 2H), 7.19 (d, 1H), 7.85 ( d, 1H).

Intermediate 94C 2-{[4-Amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}pyrimidine-5-carbonitrile

2.40 g (7.69 mmol) of 2-{[5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazol-1-yl]-A was obtained in a similar manner to Intermediate 10C) Reaction of pyrimidine-5-carbonitrile (Intermediate 93B), thus passing through a Biotage chromatography system (25 g snap KP-Sil column, hexane / 0-100% ethyl acetate, then ethyl acetate / After purification of the crude product from 0-100% methanol, 490 mg (11%, purity 50%)

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.09 (s, 3H), 4.03 (s, 2H), 5.62 (s, 2H), 9.28 (s, 2H).

Intermediate 95C 6-{[4-Amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}pyridazine-3-carbonitrile

In a manner similar to the intermediate 10C), 400 mg (1.28 mmol) of 6-{[5-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl The reaction of pyridazine-3-carbonitrile (Intermediate 94B) afforded 400 mg (110%) of crude material use.

¹ H-NMR (400MHz, DMSO d ₆ ) δ (ppm) = 2.15 (s, 3H), 4.12 (s, 2H), 5.73 (s, 2H), 7.63 (d, 1H), 8.34 (d, 1H) .

Intermediate 1D 3,5-diethyl-4-nitro-1H-pyrazole

0.26 mL of 65% nitric acid was carefully added dropwise to a solution of 200 mg (1.61 mmol) of commercially available 3,5-diethyl-1H-pyrazole in 0.71 mL of concentrated sulfuric acid at 0 °C. After stirring for 10 minutes, the reaction mixture was heated to 115 ° C and stirring was continued at this temperature for 4 hours. After cooling to 25 ° C, the mixture was poured into 20 ml of ice water and extracted three times with ethyl acetate. The combined organic layers were washed with EtOAc EtOAc EtOAc. The second experiment was carried out in the same manner with 1.23 g (9.90 mmol) of 3,5-diethyl-1H-pyrazole. The combined crude product was purified via EtOAc EtOAc EtOAc (EtOAc)

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 1.20 (t, 6H), 2.89 (q, 4H), 13.37 (br.s., 1H).

Intermediate 2D 5-ethyl-4-nitro-3-(trifluoromethyl)-1H-pyrazole

In a manner similar to Intermediate 1D), 3.50 g (21.3 mmol) of 5-ethyl-3-(trifluoromethyl)-1H-pyrazole (available, for example, from Aldrich, Princeton BioMolecular Research). The reaction was carried out to give 4.27 g (yield: 96%) of the desired title compound after the crude product was purified from EtOAc EtOAc EtOAc

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 1.25 (t, 3H), 3.00 (q, 2H).

Intermediate 3D 5-isopropyl-4-nitro-3-(trifluoromethyl)-1H-pyrazole

In a similar manner to the intermediate 1D), 3.50 g (19.6 mmol) of 5-isopropyl-3-(trifluoromethyl)-1H-pyrazole (available, for example, from Bellen Chemistry Co. or according to US2011/) 105429, column 27 prepared) reaction whereby 3.77 g (82%) was obtained after purification of the crude product via a Biotage chromatography system (50 g cartridge KP-Sil column, hexane/10-100% ethyl acetate). The title compound is desired.

¹ H-NMR (300 MHz, DMSO d ₆ ) δ (ppm) = 1.31 (d, 6H), 3.65 (spt, 1H), 14.43 (br.s., 1H).

Intermediate 4D 3-isopropyl-5-methyl-4-nitro-1H-pyrazole

In a manner similar to Intermediate 1D), 520 mg (4.19 mmol) in the first experiment and 1.62 g (13.0 mmol) of 3-isopropyl-5-methyl-1H-pyrazole in each of the other two experiments. Or a tautomer thereof (commercially available, for example, from Fluorochem) to purify the crude product via a Biotage chromatography system (50 g snap KP-Sil column, hexane / 20-70% ethyl acetate) Thereafter, 4.48 g (88%) of the desired title compound was obtained.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 1.23 (d, 6H), 2.45 (br.s., 3H), 3.50 (br.s., 1H), 13.31 (br.s., 1H).

Intermediate 5D 3-ethyl-5-methyl-4-nitro-1H-pyrazole

In a manner analogous to intermediate 1D), 2.20 g (20.0 mmol) of 3-ethyl-5-methyl-1H-pyrazole or its tautomers (eg Chemische Berichte, 1928, 2406, page 2410 or The reaction was prepared as described in Journal fuer Praktische Chemie (Leipzig), 1930, page 150, and thus purified via Biotage chromatography system (25g snap KP-Sil column, hexane/10-70% ethyl acetate) After the crude product, 495 mg (15%)

¹ H-NMR (300 MHz, DMSO d ₆ ) δ (ppm) = 1.18 (t, 3H), 2.44 (s, 3H), 2.86 (q, 2H), 13.34 (br.s., 1H).

Instance Example 1 2-methoxy-N-[1-(4-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-4-carboxamide

50 mg (0.22 mmol) of 1-(4-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 11C) was dissolved in 5 mL of tetrahydrofuran and added 52 mg (0.26) Methyl) 2-methoxyquinoline-4-carboxylic acid, 56 μL (0.32 mmol) N,N -diisopropylethylamine and 104 mg (0.32 mmol) TBTU. The reaction mixture was stirred at 25 ° C for 24 hours. After evaporation, the residue was taken up in EtOAc (EtOAc m.

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.12 (s, 3 H), 2.16 (s, 3 H), 3.73 (s, 3 H), 4.04 (s, 3 H), 5.16 (s) , 2 H), 6.91 (d, 2 H), 7.14 (d, 2 H), 7.21 (s, 1 H), 7.47-7.55 (m, 1 H), 7.69-7.77 (m, 1 H), 7.83 -7.89 (m, 1 H), 8.01 - 8.08 (m, 1 H), 9.88 (s, 1 H).

Example 2 6-Bromo-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(propan-2-yl)quinoline-4- Formamide

In a manner similar to Example 1), 75 mg (0.34 mmol) of 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 1C) with 120 mg (0.41 mmol) 6-bromo-2-isopropylquinoline-4-carboxylic acid, 89 μL (0.51 mmol) of N , N -diisopropylethylamine and 164 mg (0.51 mmol) of TBTU in 5 mL of tetrahydrofuran at 25 ° C Stir for 24 hours. The reaction mixture was evaporated and the residue was partitioned betweenEtOAc and water. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate The residue was dissolved in dichloromethane and adsorbed on Isolute® HM-N (Biotage) under evaporation. Isolute was applied to a Biotage snap-on cartridge (25 g; KP-Sil) pre-equilibrated with hexane and purified by cartridge chromatography (solvent: hexane / 0-100% ethyl acetate) to yield 152 mg. (0.31 mmol, 90%) of the desired compound.

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 1.35 (s, 3 H), 1.38 (s, 3 H), 2.14 (s, 3 H), 2.18 (s, 3 H), 3.23-3.32 (m, 1 H), 5.25 (s, 2 H), 7.15-7.27 (m, 4 H), 7.75 (s, 1 H), 7.88-7.94 (m, 1 H), 7.98 (d, 1 H) , 8.33 (d, 1 H), 9.97 (s, 1 H).

Example 3 6-Bromo-N-[1-(4-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4 -Procarbamide

In a manner similar to Example 1), 50 mg (0.22 mmol) of 1-(4-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 11C) Containing 83 mg (0.26 mmol) of 6-bromo-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 1A), 56 μL (0.32 mmol) of N , N -diisopropylethylamine and 104 mg (0.32 mmol) The TBTU of 5 mL of tetrahydrofuran was stirred at 25 ° C for 24 hours to give 78 mg (0.14 mmol, 67%) of desired title compound after preparative HPLC (Method 3).

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.14 (s, 3 H), 2.19 (s, 3 H), 3.71-3.77 (m, 3 H), 5.18 (s, 2 H), 6.92 (d, 2 H), 7.15 (d, 2 H), 8.11-8.19 (m, 1 H), 8.23 (d, 1 H), 8.28 (s, 1 H), 8.50 (d, 1 H), 10.13 (s, 1 H).

Example 4 N-[1-(4-Methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2,6-dimethylquinoline-4-carboxamide

In a manner similar to Example 1), 50 mg (0.22 mmol) of 1-(4-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 11C) Containing 52 mg (0.26 mmol) of 2,6-dimethylquinoline-4-carboxylic acid, 56 μL (0.32 mmol) of N , N -diisopropylethylamine and 104 mg (0.32 mmol) of TBTU in 5 mL of tetrahydrofuran at 25 ° C After stirring for 24 hours, 47 mg (0.11 mmol, 52%) of desired title compound was obtained after preparative HPLC (Method 3).

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.13 (s, 3 H), 2.17 (s, 3 H), 2.69 (s, 3 H), 3.73 (s, 3 H), 5.16 (s) , 2 H), 6.91 (d, 2 H), 7.16 (d, 2 H), 7.56 (s, 1 H), 7.61 (dd, 1 H), 7.85-7.92 (m, 2 H), 9.84 (s , 1 H).

Example 5 6-Bromo-N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4- Formamide

In a manner similar to Example 1), 50 mg (0.22 mmol) of 4-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]benzonitrile (intermediate) 8C) with 84 mg (0.27 mmol) of 6-bromo-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 1A), 58 μL (0.33 mmol) N,N -diisopropylethylamine and 106 mg (0.33 mmol) TBTU of 5 mL of tetrahydrofuran was stirred at 25 ° C for 24 hours to afford 26 mg (0.04 mmol, 21%) of the desired compound.

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.16 (s, 3 H), 2.19 (s, 3 H), 5.39 (s, 2 H), 7.32 (d, 2 H), 7.85 (d) , 2 H), 8.11-8.19 (m, 1 H), 8.23 (d, 1 H), 8.30 (s, 1 H), 8.51 (d, 1 H), 10.19 (s, 1 H).

Example 6 6-Bromo-N-[1-(2-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4- Formamide

In a manner similar to Example 1), 50 mg (0.22 mmol) of 2-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]benzonitrile (intermediate) 10C) with 84 mg (0.27 mmol) of 6-bromo-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 1A), 58 μL (0.33 mmol) of N , N -diisopropylethylamine and 106 mg (0.33 mmol) TBTU of 5 mL of tetrahydrofuran was stirred at 25 ° C for 24 hours to afford 67 mg (0.13 mmol, 57%) of the desired compound.

1H NMR (400MHz, DMSO d ₆ ): δ (ppm) = 2.14 (s, 3 H), 2.27 (s, 3 H), 5.45 (s, 2 H), 7.11 (d, 1 H), 7.50-7.56 (m, 1 H), 7.72 (td, 1 H), 7.90 (dd, 1 H), 8.15 (dd, 1 H), 8.23 (d, 1 H), 8.31 (s, 1 H), 8.52 (d) , 1 H), 10.22 (s, 1 H).

Example 7 2-cyclopropyl-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-6-methylquinoline-4-carboxamide

In a manner similar to Example 1), 100 mg (0.45 mmol) of 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 1C) with 124 mg (0.54 mmol) 2-cyclopropyl-6-methylquinoline-4-carboxylic acid, 119 μL (0.68 mmol) of N , N -diisopropylethylamine and 220 mg (0.68 mmol) of TBTU in 5 mL of tetrahydrofuran at 25 ° C Stir under 24 hours. The reaction mixture was evaporated and the residue was partitioned betweenEtOAc and water. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate The residue was dissolved in dichloromethane and adsorbed on Isolute® HM-N (Biotage) under evaporation. The isolute was applied to a Biotage snap cartridge (25 g; KP-Sil) pre-equilibrated with hexanes and purified by silica gel column chromatography (solvent: hexane / 0-100% ethyl acetate). The obtained crude product was purified again by preparative HPLC (Method 3) to yield 100 mg (0.43 mmol, 51%

1H NMR (400MHz, DMSO d ₆ ): δ (ppm) = 1.04-1.10 (m, 2 H), 1.12 (dt, 2 H), 2.14 (s, 3 H), 2.18 (s, 3 H), 2.31 -2.39 (m, 1 H), 2.47 (s, 3 H), 5.24 (s, 2 H), 7.16-7.28 (m, 4 H), 7.54 - 7.59 (m, 2 H), 7.81 (d, 1) H), 7.85 (s, 1 H), 9.83 (s, 1 H).

Example 8 6,8-Dichloro-N-[1-(4-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quina Porphyrin-4-carboxamide

In a manner similar to Example 1), 50 mg (0.22 mmol) of 1-(4-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 11C) Containing 80 mg (0.26 mmol) of 6,8-dichloro-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 11A), 56 μL (0.33 mmol) of N , N -diisopropylethylamine and 104 mg (0.32 mmol) TBTU of 5 mL of THF was stirred at 25 ° C for 24 hours to give 59 mg (0.11 mmol, 52%)

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.14 (s, 3 H), 2.18 (s, 3 H), 3.73 (s, 3 H), 5.17 (s, 2 H), 6.91 (m) , 2 H), 7.15 (m, 2 H), 8.29 (d, 1 H), 8.39-8.43 (m, 2 H), 10.19 (s, 1 H).

Example 9 6-Bromo-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-methyl Guanamine

In a manner similar to Example 1), 150 mg (0.68 mmol) of 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 1C) with 262 mg (0.82 mmol) 6-bromo-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 1A), 179 μL (1.03 mmol) N , N -diisopropylethylamine and 329 mg (1.03 mmol) TBTU 15 mL of tetrahydrofuran was stirred together at 25 ° C for 24 hours. The reaction mixture was evaporated and the residue was taken crystalljjjjjjjjjjjjj The isolute was applied to a Biotage snap-on cartridge (25 g; KP-Sil) pre-equilibrated with hexane and purified by silica gel column chromatography (solvent: hexane / 0-80% ethyl acetate) to obtain 286 mg. (0.55 mmol, 80%) of the desired compound.

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.15 (s, 3 H), 2.19 (s, 3 H), 5.25 (s, 2 H), 7.13 - 7.29 (m, 4 H), 8.15 (dd, 1 H), 8.23 (d, 1 H), 8.29 (s, 1 H), 8.50 (d, 1 H), 10.17 (s, 1 H).

Example 10 2-cyclopropyl-6-fluoro-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-4-carboxamide

In a manner similar to Example 1), 75 mg (0.34 mmol) of 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 1C) with 94 mg (0.41 mmol) 2-cyclopropyl-6-fluoroquinoline-4-carboxylic acid (Intermediate 26A), 89 μL (0.51 mmol) N , N -diisopropylethylamine and 164 mg (0.51 mmol) of TBTU in 5 mL of tetrahydrofuran The mixture was stirred for 24 hours at 25 ° C to give 72 mg (0.16 mmol, 48%) of desired title compound.

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 1.07-1.19 (m, 4 H), 2.13 (s, 3 H), 2.17 (s, 3 H), 2.33 - 2.44 (m, 1 H) , 5.24 (s, 2 H), 7.10-7.32 (m, 4 H), 7.61-7.70 (m, 1 H), 7.72 (s, 1 H), 7.81 (dd, 1 H), 7.99 (dd, 1 H), 9.92 (s, 1 H).

Example 11 6,8-Dichloro-N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline -4-carboxamide

In a manner similar to Example 1), 50 mg (0.22 mmol) of 4-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]benzonitrile (intermediate) 8C) with 82 mg (0.27 mmol) of 6,8-dichloro-2-(trifluoromethyl)quinoline-4-carboxylic acid (intermediate 11A), 58 μL (0.33 mmol) of N , N -diisopropyl The amine and 106 mg (0.33 mmol) of TBTU in 5 mL of THF were stirred at <RTI ID=0.0></RTI></RTI><RTIgt;

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.16 (s, 3 H), 2.18 (s, 3 H), 5.38 (s, 2 H), 7.32 (d, 2 H), 7.85 (d) , 2 H), 8.30 (d, 1 H), 8.40 (d, 1 H), 8.42 (s, 1 H), 10.23 (s, 1 H).

Example 12 6-bromo-2-cyclopropyl-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-4-carboxamide

In a manner similar to Example 1), 100 mg (0.45 mmol) of 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 1C) with 159 mg (0.54 mmol) 6-bromo-2-cyclopropylquinoline-4-carboxylic acid, 119 μL (0.68 mmol) of N , N -diisopropylethylamine and 220 mg (0.68 mmol) of TBTU in 5 mL of tetrahydrofuran at 25 ° C Stir for 24 hours. The reaction mixture was evaporated and the residue was partitioned betweenEtOAc and water. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate The obtained crude product was purified by EtOAc (EtOAc)

1H NMR (400MHz, DMSO d ₆ ): δ (ppm) = 1.09-1.19 (m, 4 H), 2.13 (s, 3 H), 2.17 (s, 3 H), 2.35-2.44 (m, 1 H) , 5.24 (s, 2 H), 7.15-7.28 (m, 4 H), 7.72 (s, 1 H), 7.87 (d, 2 H), 8.29 (t, 1 H), 9.95 (s, 1 H) .

Example 13 6-Bromo-N-[1-(2,6-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline- 4-carboxamide

In a manner similar to Example 1), 50 mg (0.21 mmol) of 1-(2,6-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 6C) With 80 mg (0.25 mmol) of 6-bromo-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 1A), 55 μL (0.32 mmol) of N , N -diisopropylethylamine and 102 mg (0.32) Methyl) TBTU of 3 mL of tetrahydrofuran was stirred at 25 ° C for 24 hours. The reaction mixture was diluted with EtOAc (EtOAc m.)

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.07 (s, 3 H), 2.32 (s, 3 H), 5.25 (s, 2 H), 7.15 (t, 2 H), 7.41 - 7.54 (m, 1 H), 8.15 (dd, 1 H), 8.23 (d, 1 H), 8.30 (s, 1 H), 8.49 (d, 1 H), 10.15 (s, 1 H).

Example 14 6-Chloro-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-methyl Guanamine

In a manner similar to Example 1), 60 mg (0.27 mmol) of 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 1C) with 91 mg (0.33 mmol) 6-chloro-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 12A), 71 μL (0.41 mmol) N , N -diisopropylethylamine and 132 mg (0.41 mmol) TBTU 5 mL of tetrahydrofuran were stirred at 25 ° C for 24 hours to give 112 mg (0.23 mmol, 86%) of the desired compound.

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.15 (s, 3 H), 2.19 (s, 3 H), 5.25 (s, 2 H), 7.14 - 7.29 (m, 4 H), 8.04 (dd, 1 H) 8.27-8.37 (m, 3 H), 10.16 (s, 1 H).

Example 15 N-[1-(4-Cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-methoxyquinoline-4-carboxamide

In a manner similar to Example 1), 50 mg (0.22 mmol) of 4-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]benzonitrile (intermediate) 8C) together with 54 mg (0.27 mmol) of 2-methoxyquinoline-4-carboxylic acid, 58 μL (0.33 mmol) of N , N -diisopropylethylamine and 106 mg (0.33 mmol) of TBTU in 5 mL of tetrahydrofuran at 25 ° C After stirring for 24 hours, 29 mg (0.07 mmol, 31%) of desired title compound was obtained after preparative HPLC (Method 3).

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.14 (s, 3 H), 2.16 (s, 3 H), 4.04 (s, 3 H), 5.37 (s, 2 H), 7.23 (s) , 1 H), 7.31 (d, 2 H), 7.51 (td, 1 H), 7.73 (td, 1 H), 7.80-7.90 (m, 3 H), 8.06 (d, 1 H), 9.91 (s , 1 H).

Example 16 8-bromo-2-cyclopropyl-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-4-carboxamide

In a manner similar to Example 1), 60 mg (0.27 mmol) of 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 1C) with 96 mg (0.33 mmol) 8-bromo-2-cyclopropylquinoline-4-carboxylic acid (Intermediate 27A), 71 μL (0.41 mmol) N , N -diisopropylethylamine and 132 mg (0.41 mmol) of TBTU in 5 mL of tetrahydrofuran The mixture was stirred at 25 ° C for 24 hours to give 75 mg (0.15 mmol, 56%) of desired title compound after preparative HPLC (Method 3).

1H NMR (400MHz, DMSO d ₆ ): δ (ppm) = 1.13-1.23 (m, 4 H), 2.14 (s, 3 H), 2.18 (s, 3 H), 2.41-2.47 (m, 1 H) , 5.24 (s, 2 H), 7.15-7.26 (m, 4 H), 7.47 (dd, 1 H), 7.74 (s, 1 H), 8.08 (dd, 1 H), 8.13 (dd, 1 H) , 9.92 (s, 1 H).

Example 17 N-[1-(2,4-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-methoxyquinoline-4-carboxamide

In a manner similar to Example 1), 50 mg (0.21 mmol) of 1-(2,4-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 5C) Stir at 25 ° C with 5 mg of tetrahydrofuran containing 51 mg (0.25 mmol) of 2-methoxyquinoline-4-carboxylic acid, 55 μL (0.31 mmol) of N , N -diisopropylethylamine and 101 mg (0.32 mmol) of TBTU. After 24 hours, 10 mg (0.02 mmol, 11%) of desired title compound was obtained after preparative HPLC (Method 3).

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.11 (s, 3 H), 2.21 (s, 3 H), 4.04 (s, 3 H), 5.25 (s, 2 H), 7.05-7.18 (m, 2 H), 7.22 (s, 1 H), 7.23-7.33 (m, 1 H), 7.47-7.55 (m, 1 H), 7.73 (td, 1 H), 7.83-7.89 (m, 1 H), 8.05 (d, 1 H), 9.89 (s, 1 H).

Example 18 8-bromo-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline- 4-carboxamide

In a manner similar to Example 1), 150 mg (0.68 mmol) of 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 1C) with 263 mg (0.82 mmol) 8-bromo-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 13A), 179 μL (1.03 mmol) N , N -diisopropylethylamine and 329 mg (1.03 mmol) TBTU 5 mL of tetrahydrofuran was stirred together at 25 ° C for 24 hours. The reaction mixture was evaporated, dissolved in dichloromethane and taken on EtOAc EtOAc (EtOAc). The isolute was applied to a Biotage snap cartridge (25 g; KP-Sil) pre-equilibrated with hexanes and purified by silica gel column chromatography (solvent: hexane / 0-80% ethyl acetate). The obtained crude product was purified again by preparative HPLC (Method 3) to yield 280 mg (0.54 mmol, 79%

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.16 (s, 3 H), 2.20 (s, 3 H), 5.25 (s, 2 H), 7.15-7.27 (m, 4 H), 7.76 -7.84 (m, 1 H), 8.27 (dd, 1 H), 8.32 (s, 1 H), 8.41 (dd, 1 H), 10.14 (s, 1 H).

Example 19 2-cyclopropyl-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-4-carboxamide

In a manner similar to Example 1), 100 mg (0.46 mmol) of 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 1C) with 117 mg (0.55 mmol) 2-cyclopropylquinoline-4-carboxylic acid, 119 μL (0.68 mmol) of N , N -diisopropylethylamine and 220 mg (0.68 mmol) of TBTU in 5 mL of tetrahydrofuran were stirred at 25 ° C for 3 hours. The reaction mixture was evaporated and the residue was partitioned betweenEtOAc and water. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate The residue was dissolved in dichloromethane and adsorbed on Isolute® HM-N (Biotage) under evaporation. The isolute was applied to a Biotage snap cartridge (25 g; KP-Sil) pre-equilibrated with hexanes and purified by silica gel column chromatography (solvent: hexane / 0-100% ethyl acetate). The obtained crude product was purified again by preparative HPLC (Method 3) to yield 100 mg (0.43 mmol, 51%

1H NMR (400MHz, DMSO d ₆ ): δ (ppm) = 1.07-1.13 (m, 2 H), 1.13-1.18 (m, 2 H), 2.14 (s, 3 H), 2.18 (s, 3 H) , 2.34 - 2.43 (m, 1 H), 5.24 (s, 2 H), 7.15-7.27 (m, 4 H), 7.56 (ddd, 1 H), 7.62 (s, 1 H), 7.73 (ddd, 1 H), 7.91 (d, 1 H), 8.06-8.11 (m, 1 H), 9.86 (s, 1 H).

Example 20 6,8-Dichloro-N-[1-(2,6-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl) Quinoline-4-carboxamide

In a manner similar to Example 1), 50 mg (0.21 mmol) of 1-(2,6-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 6C) And containing 78 mg (0.25 mmol) of 6,8-dichloro-2-(trifluoromethyl)quinoline-4-carboxylic acid (intermediate 11A), 55 μL (0.31 mmol) of N , N -diisopropylethylamine and 101 mg (0.31 mmol) of TBTU in 5 mL of tetrahydrofuran were stirred at 25 ° C for 24 hours to afford 75 mg (0.13 mmol, 64%) of the desired compound.

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.06 (s, 3 H), 2.32 (s, 3 H), 5.24 (s, 2 H), 7.15 (t, 2 H), 7.41 - 7.54 (m, 1 H), 8.28 (d, 1 H), 8.38-8.45 (m, 2 H), 10.20 (s, 1 H).

Example 21 8-bromo-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-6-methyl-2-(trifluoromethyl)quina Porphyrin-4-carboxamide

In a manner similar to Example 1), 150 mg (0.68 mmol) of 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 1C) with 274 mg (0.82 mmol) 8-bromo-6-methyl-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 14A), 179 μL (1.03 mmol) N , N -diisopropylethylamine and 329 mg (1.03 mmol) TBTU of 5 mL of tetrahydrofuran was stirred at 25 ° C for 24 hours. The reaction mixture was evaporated, dissolved in dichloromethane and taken on EtOAc EtOAc (EtOAc). The isolute was applied to a Biotage snap cartridge (25 g; KP-Sil) pre-equilibrated with hexane and purified by column chromatography (solvent: hexane / 0-80% ethyl acetate) to yield 289 mg. (0.54 mmol, 79%) of the desired compound.

1H NMR (400MHz, DMSO d ₆ ): δ (ppm) = 1.35 (s, 3 H), 1.39 (s, 3 H), 1.75 (s, 3 H), 4.44 (s, 2 H), 6.31-6.50 (m, 4 H), 7.17-7.26 (m, 1 H), 7.44 (s, 1 H), 7.48 (d, 1 H), 9.28 (s, 1 H).

Example 22 5,6-Dichloro-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline- 4-carboxamide

In a manner similar to Example 1), 50 mg (0.23 mmol) of 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 1C) and 5 , 84 mg (0.27 mmol) of 6-dichloro-2-(trifluoromethyl)quinoline-4-carboxylic acid and 6,7-dichloro-2-(trifluoromethyl)quinoline-4-carboxylic acid ( 3:1) (Intermediate 15A), 60 μL (0.34 mmol) of N , N -diisopropylethylamine and 109 mg (0.34 mmol) of TBTU in 5 mL of tetrahydrofuran were stirred at 25 ° C for 24 hours to prepare HPLC. After the method 6), 32 mg (0.06 mmol, 27%) of desired title compound. Further, after preparative HPLC, 23 mg (0.04 mmol, 20%) of 6,7-dichloro-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyridyl was isolated. Zol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide (Example 106).

1H NMR (400MHz, DMSO d ₆ ): δ (ppm) = 2.17 (s, 3 H), 2.22 (s, 3 H), 5.23 (s, 2 H), 7.14 - 7.27 (m, 4 H), 8.20 (s, 1 H), 8.24 (d, 1 H), 8.31 (d, 1 H), 10.01 (s, 1 H).

Example 23 N-{3,5-Dimethyl-1-[4-(trifluoromethoxy)benzyl]-1H-pyrazol-4-yl}-2-methoxyquinoline-4-carboxamidine amine

In a manner similar to Example 1), 100 mg (0.18 mmol, 50%) of 3,5-dimethyl-1-[4-(trifluoromethoxy)benzyl]-1H-pyrazole-4- Amine (Intermediate 19C) with 3 mL of tetrahydrofuran containing 43 mg (0.21 mmol) of 2-methoxyquinoline-4-carboxylic acid, 46 μL (0.26 mmol) of N , N -diisopropylethylamine and 84 mg (0.26 mmol) of TBTU The mixture was stirred at 25 ° C for 24 hours to give 68 mg (0.14 mmol, 81%) of the desired compound.

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.13 (s, 3 H), 2.18 (s, 3 H), 4.04 (s, 3 H), 5.29 (s, 2 H), 7.22 (s) , 1 H), 7.30 (d, 2 H), 7.37 (d, 2 H), 7.48-7.55 (m, 1 H), 7.70-7.77 (m, 1 H), 7.86 (d, 1 H), 8.05 (d, 1 H), 9.91 (s, 1 H).

Example 24 6-Bromo-N-[3,5-dimethyl-1-(2-methylbenzyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4- Formamide

In a manner similar to Example 1), 50 mg (0.23 mmol, 50%) of 3,5-dimethyl-1-(2-methylbenzyl)-1H-pyrazol-4-amine (Intermediate 15C) And 89 mg (0.28 mmol) of 6-bromo-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 1A), 49 μL (0.35 mmol) of N , N -diisopropylethylamine and 112 mg ( 0.35 mmol) TBTU of 3 mL of tetrahydrofuran was stirred at 25 ° C for 24 hours to give 48 mg (0.09 mmol, 38%) of desired title compound after preparative HPLC (Method 3).

1H NMR (300MHz, DMF): δ (ppm) = 2.27 (d, 6 H), 2.42 (s, 3 H), 5.36 (s, 2 H), 6.74 (d, 1 H), 7.13 - 7.28 (m) , 3 H), 8.20 (dd, 1 H), 8.27 (d, 1 H), 8.43 (s, 1 H), 8.71 (d, 1 H), 10.29 (s, 1 H).

Example 25 6,8-Dichloro-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline- 4-carboxamide

In a manner similar to Example 1), 50 mg (0.23 mmol) of 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 1C) and 85 mg (0.27 mmol) 6,8-Dichloro-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 11A), 60 μL (0.34 mmol) N , N -diisopropylethylamine and 110 mg (0.34) The TBTU of 3 mL of tetrahydrofuran was stirred at 25 ° C for 24 hours to give 75 mg (0.15 mmol, 64%) of desired title compound after preparative HPLC (Method 3).

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.15 (s, 3 H), 2.19 (s, 3 H), 5.25 (s, 2 H), 7.14 - 7.29 (m, 4 H), 8.29 (d, 1 H), 8.41 (d, 1 H), 8.42 (s, 1 H), 10.21 (s, 1 H).

Example 26 5-fluoro-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-methyl Guanamine

In a manner similar to Example 1), 50 mg (0.23 mmol) of 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 1C) and 71 mg (0.27 mmol) 5-fluoro-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 16A), 60 μL (0.34 mmol) N , N -diisopropylethylamine and 110 mg (0.34 mmol) TBTU 3 mL of tetrahydrofuran were stirred at 25 ° C for 24 hours to give 98 mg (0.21 mmol, 92%) of the desired compound.

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.15 (s, 3 H), 2.19 (s, 3 H), 5.25 (s, 2 H), 7.13 - 7.27 (m, 4 H), 7.87 (td, 1 H), 8.09 (dd, 1 H), 8.20 (s, 1 H), 8.38 (dd, 1 H), 10.12 (s, 1 H).

Example 27 N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-methoxyquinoline-4-carboxamide

In a manner similar to Example 1), 150 mg (0.68 mmol) of 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 1C) with 167 mg (0.82 mmol) 2-methoxyquinoline-4-carboxylic acid, 179 μL (1.03 mmol) of N , N -diisopropylethylamine and 329 mg (1.03 mmol) of TBTU in 5 mL of tetrahydrofuran were stirred at 25 ° C for 2 hours. The reaction mixture was evaporated and the residue was partitioned betweenEtOAc and water. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate The residue was dissolved in dichloromethane and adsorbed on Isolute® HM-N (Biotage) under evaporation. The isolute was applied to a Biotage snap cartridge (25 g; KP-Sil) pre-equilibrated with hexanes and purified by silica gel column chromatography (solvent: hexane / 0-100% ethyl acetate). The obtained crude product was purified again by preparative HPLC (Method 3) to yield 228 mg (0.56 mmol, 82%

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.13 (s, 3 H), 2.17 (s, 3 H), 4.04 (s, 3 H), 5.24 (s, 2 H), 7.11-7.30 (m, 5 H), 7.44 - 7.56 (m, 1 H), 7.66-7.78 (m, 1 H), 7.82-7.91 (m, 1 H), 8.00-8.10 (m, 1 H), 9.91 (s , 1 H).

Example 28 6,8-Dichloro-N-[3,5-dimethyl-1-(3-methylbenzyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline -4-carboxamide

In a manner similar to Example 1), 50 mg (0.23 mmol) of 3,5-dimethyl-1-(3-methylbenzyl)-1H-pyrazol-4-amine (Intermediate 14C) 86 mg (0.28 mmol) of 6,8-dichloro-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 11A), 61 μL (0.35 mmol) of N , N -diisopropylethylamine and 112 mg ( 0.35 mmol) TBTU of 5 mL of tetrahydrofuran was stirred at 25 ° C for 24 hours to afford 95 mg (0.19 mmol, 81%) of the desired compound.

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.15 (s, 3 H), 2.19 (s, 3 H), 2.29 (s, 3 H), 5.21. (s, 2 H), 6.95 (d) , 1 H), 7.03 (s, 1 H), 7.10 (d, 1 H), 7.24 (t, 1 H), 8.30 (d, 1 H), 8.37-8.43 (m, 2 H), 10.19 (s , 1 H).

Example 29 7-Fluoro-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-methyl Guanamine

In a manner similar to Example 1), 50 mg (0.23 mmol) of 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 1C) and 71 mg (0.27 mmol) 7-fluoro-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 17A), 60 μL (0.34 mmol) N , N -diisopropylethylamine and 109 mg (0.34 mmol) TBTU The 3 mL of tetrahydrofuran was stirred at 25 ° C for 24 hours to afford 93 mg (0.20 mmol, 89%) of the desired compound.

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.15 (s, 3 H), 2.19 (s, 3 H), 5.25 (s, 2 H), 7.10-7.29 (m, 4 H), 7.87 (td, 1 H), 8.09 (dd, 1 H), 8.20 (s, 1 H), 8.38 (dd, 1 H), 10.12 (s, 1 H).

Example 30 6-Fluoro-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-methyl Guanamine

In a manner similar to Example 1), 50 mg (0.23 mmol) of 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 1C) and 71 mg (0.27 mmol) 6-fluoro-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 18A), 60 μL (0.34 mmol) N , N -diisopropylethylamine and 110 mg (0.34 mmol) TBTU 3 mL of tetrahydrofuran were stirred at 25 ° C for 3 hours to obtain 95 mg (0.19 mmol, 81%) of desired title compound after preparative HPLC (Method 3).

1H NMR (300MHz, CDCl ₃ ): δ (ppm) = 2.23 (s, 3 H), 2.31 (s, 3 H), 5.25 (s, 2 H), 6.99-7.10 (m, 2 H), 7.15 ( Dd, 3 H), 7.62 - 7.74 (m, 1 H), 7.93 (s, 1 H), 8.09 (dd, 1 H), 8.33 (dd, 1 H).

Example 31 6,8-Dichloro-N-[3,5-dimethyl-1-(4-methylbenzyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline -4-carboxamide

In a manner similar to Example 1), 50 mg (0.23 mmol) of 3,5-dimethyl-1-(4-methylbenzyl)-1H-pyrazol-4-amine (Intermediate 13C) 86 mg (0.29 mmol) of 6,8-dichloro-2-(trifluoromethyl)quinoline-4-carboxylic acid (intermediate 11A), 61 μL (0.35 mmol) of N , N -diisopropylethylamine and 112 mg ( 0.35 mmol) TBTU of 5 mL of tetrahydrofuran was stirred at 25 ° C for 24 hours. The reaction mixture was evaporated, dissolved in dichloromethane and taken on EtOAc EtOAc (EtOAc). Isolute was applied to a Biotage snap cartridge (25 g; KP-Sil) pre-equilibrated with hexane and purified by cartridge chromatography (solvent: hexane / 0-40% ethyl acetate) to give 50 mg. (0.09 mmol, 42%) of the desired compound.

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.14 (s, 3 H), 2.17 (s, 3 H), 2.28 (s, 3 H), 5.20 (s, 2 H), 7.07 (m) , 2 H), 7.16 (m, 2 H), 8.29 (d, 1 H), 8.37-8.45 (m, 2 H), 10.20 (s, 1 H).

Example 32 6-Bromo-N-[1-(4-fluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl) Quinoline-4-carboxamide

In a manner similar to Example 1), 75 mg (0.20 mmol, 74%) of 1-(4-fluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole-4- Amine (Intermediate 25C) with 78 mg (0.24 mmol) of 6-bromo-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 1A), 53 μL (0.30 mmol) N , N -diisopropyl Ethylamine and 98 mg (0.30 mmol) of TBTU in 3 mL of tetrahydrofuran were stirred at 25 ° C for 24 hours to afford 62 mg (0.10 mmol, 49%).

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.31 (s, 3 H), 5.47 (s, 2 H), 7.19-7.36 (m, 4 H), 8.11-8.20 (m, 1 H) , 8.20-8.30 (m, 2 H), 8.42 (d, 1 H), 10.52 (s, 1 H).

Example 33 N-(1-Benzyl-3,5-dimethyl-1H-pyrazol-4-yl)-6-bromo-2-(trifluoromethyl)quinoline-4-carboxamidine amine

In a manner similar to Example 1), 50 mg (0.25 mmol) of 1-benzyl-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 30C) and 95 mg (0.30 mmol) -Bromo-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 1A), 65 μL (0.37 mmol) of N , N -diisopropylethylamine and 120 mg (0.37 mmol) of TBTU in 5 mL of tetrahydrofuran After stirring for 24 hours at 25 ° C, 72 mg (0.14 mmol, 57%) of desired title compound was obtained after preparative HPLC (Method 3).

1H NMR (400MHz, DMSO d ₆ ): δ (ppm) = 2.15 (s, 3 H), 2.19 (s, 3 H), 5.26 (s, 2 H), 7.16-7.21 (m, 2 H), 7.26 -7.32 (m, 1 H), 7.33 - 7.39 (m, 2 H), 8.12-8.17 (m, 1 H), 8.23 (d, 1 H), 8.29 (s, 1 H), 8.51 (d, 1) H), 10.16 (s, 1 H).

Example 34 5-bromo-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-methyl Guanamine

In a manner similar to Example 1), 50 mg (0.23 mmol) of 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 1C) and 88 mg (0.27 mmol) 5-bromo-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 33A), 60 μL (0.34 mmol) N , N -diisopropylethylamine and 109 mg (0.34 mmol) TBTU 5 mL of tetrahydrofuran were stirred at 25 ° C for 24 hours to obtain 48 mg (0.09 mmol, 40%) of desired title compound after preparative HPLC (Method 3).

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.18 (s, 3 H), 2.23 (s, 3 H), 5.22 (s, 2 H), 7.13 - 7.29 (m, 4 H), 7.86 -7.94 (m, 1 H), 8.12 (s, 1 H), 8.25 (dd, 1 H), 8.33 (dd, 1 H), 10.07 (s, 1 H).

Example 35 6,8-Dichloro-N-[1-(3,4-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl) Quinoline-4-carboxamide

In a manner similar to Example 1), 50 mg (0.21 mmol) of 1-(3,4-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 4C) And containing 78 mg (0.25 mmol) of 6,8-dichloro-2-(trifluoromethyl)quinoline-4-carboxylic acid (intermediate 11A), 55 μL (0.32 mmol) of N , N -diisopropylethylamine and 102 mg (0.32 mmol) of TBTU in 5 mL of tetrahydrofuran were stirred at 25 ° C for 24 hours to afford 35 mg (0.05 mmol, 28%) of the desired compound.

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.15 (s, 3 H), 2.20 (s, 3 H), 5.26 (s, 2 H), 7.02 (br.s., 1 H), 7.20 (d, 1 H), 7.37-7.51 (m, 1 H), 8.30 (d, 1 H), 8.37-8.44 (m, 2 H), 10.21 (s, 1 H).

Example 36 2-bromo-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-4-carboxamide

In a manner similar to Example 1), 750 mg (3.42 mmol) of 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 1C) with 1.03 g (4.10 mmol) of 2-bromoquinoline-4-carboxylic acid, 894 μL (5.13 mmol) of N , N -diisopropylethylamine and 1.65 g (5.13 mmol) of TBTU in 5 mL of tetrahydrofuran were stirred at 25 ° C for 2 hours. The reaction mixture was evaporated and the residue was partitioned betweenEtOAc and water. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate The residue was dissolved in dichloromethane and adsorbed on Isolute® HM-N (Biotage) under evaporation. The isolute was applied to a Biotage snap-on cartridge (100 g; KP-Sil) pre-equilibrated with hexane and purified by cartridge chromatography (solvent: hexane / 0-100% ethyl acetate) to give 1.47. g (3.24 mmol, 95%) of the desired compound.

1H NMR (400MHz, DMSO d ₆ ): δ (ppm) = 2.14 (s, 3 H), 2.18 (s, 3 H), 5.24 (s, 2 H), 7.15-7.27 (m, 4 H), 7.77 (ddd, 1 H), 7.90 (ddd, 1 H), 7.94 (s, 1 H), 8.06 (d, 1 H), 8.16 (dd, 1 H), 10.02 (s, 1 H).

Example 37 7-Bromo-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroacridine-9 -Procarbamide

50 mg (0.23 mmol) of 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 1C) with 105 mg (0.34 mmol) of 7-bromo-1 , 2,3,4-tetrahydroacridine-9-carboxylic acid, 60 μL (0.34 mmol) of N , N -diisopropylethylamine, 52 mg (0.34 mmol) of HOBt and 219 mg (1.14 mmol) of EDC 5 mL N,N -Methylformamide was stirred together at 25 ° C for 24 hours. The reaction mixture was partitioned between dichloromethane and water. The organic layer was washed with brine, dried over sodium sulfate The residue was purified by EtOAc EtOAcqqqqq

1H NMR (300MHz, CDCl ₃ ): δ (ppm) = 1.90-2.04 (m, 4 H), 2.27 (s, 3 H), 2.35 (s, 3 H), 3.02-3.17 (m, 4 H), 5.23(s, 2 H), 6.97-7.10 (m, 3 H), 7.10-7.21 (m, 2 H), 7.73 (dd, 1 H), 7.87 (d, 1 H), 8.05 (d, 1 H) ).

Example 38 6,8-Dichloro-N-[1-(4-fluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(three Fluoromethyl)quinoline-4-carboxamide

In a manner similar to Example 1), 75 mg (0.20 mmol, 74%) of 1-(4-fluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole-4- Amine (Intermediate 25C) with 76 mg (0.24 mmol) of 6,8-dichloro-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 11A), 53 μL (0.30 mmol) N , N - Isopropylethylamine and 98 mg (0.30 mmol) of TBTU in 5 mL of tetrahydrofuran were stirred at 25 ° C for 24 hours to afford 71 mg (0.12 mmol, 61%) of the desired compound.

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.31 (s, 3 H), 5.47 (s, 2 H), 7.18-7.37 (m, 4 H), 8.20 (d, 1 H), 8.36 -8.45 (m, 2 H), 10.56 (s, 1 H).

Example 39 6,7-Difluoro-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline- 4-carboxamide

In a manner similar to Example 1), 50 mg (0.23 mmol) of 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 1C) with 76 mg (0.27 mmol) 6,7-difluoro-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 19A), 60 μL (0.34 mmol) N , N -diisopropylethylamine and 110 mg (0.34) The TBTU of 5 mL of tetrahydrofuran was stirred at 25 ° C for 24 hours to give 50 mg (0.11 mmol, 46%) of the desired compound.

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.14 (s, 3 H), 2.18 (s, 3 H), 5.25 (s, 2 H), 7.14-7.28 (m, 4 H), 8.26 (dd, 1 H), 8.31 (s, 1 H), 8.42 (dd, 1 H), 10.19 (s, 1 H).

Example 40 2-cyclopropyl-8-fluoro-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-4-carboxamide

In a manner similar to Example 1), 75 mg (0.34 mmol) of 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 1C) with 95 mg (0.41 mmol) 2-cyclopropyl-8-fluoroquinoline-4-carboxylic acid (Intermediate 28A), 89 μL (0.51 mmol) N , N -diisopropylethylamine and 165 mg (0.51 mmol) of TBTU in 5 mL of tetrahydrofuran The mixture was stirred for 24 hours at 25 ° C to give 103 mg (0.23 mmol, 68%) of desired title compound.

1H NMR (400MHz, DMSO d ₆ ): δ (ppm) = 1.10-1.20 (m, 4 H), 2.14 (s, 3 H), 2.18 (s, 3 H), 2.39-2.48 (m, 1 H) , 5.24 (s, 2 H), 7.10-7.30 (m, 4 H), 7.48-7.64 (m, 2 H), 7.72 (s, 1 H), 7.84-7.94 (m, 1 H), 9.91 (s , 1 H).

Example 41 6-Bromo-N-[1-(2,4-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline- 4-carboxamide

50 mg (0.21 mmol) of 1-(2,4-difluorobenzyl)-3,5-dimethyl-1H-pyrazole-4-amine (Intermediate 5C) was dissolved in 5 mL of tetrahydrofuran and added 81 mg (0.25 mmol) 2 6-bromo-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 1A), 55 μL (0.32 mmol) N , N -diisopropylethylamine and 164 mg (0.32 mmol) 5 mL of tetrahydrofuran of PyBOP. The reaction mixture was stirred at 25 ° C for 24 hours. After evaporation, the residue was taken up in EtOAc (EtOAc) (m.) Compound.

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.13 (s, 3 H), 2.24 (s, 3 H), 5.27 (s, 2 H), 7.05-7.23 (m, 2 H), 7.24 -7.35 (m, 1 H), 8.15 (dd, 1 H), 8.23 (d, 1 H), 8.30 (s, 1 H), 8.50 (d, 1 H), 10.19 (s, 1 H).

Example 42 N-[1-(2,6-Difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-methoxyquinoline-4-carboxamide

In a manner similar to Example 1), 50 mg (0.21 mmol) of 1-(2,6-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 6C) Stir at 25 ° C with 5 mg of tetrahydrofuran containing 51 mg (0.25 mmol) of 2-methoxyquinoline-4-carboxylic acid, 55 μL (0.32 mmol) of N , N -diisopropylethylamine and 102 mg (0.32 mmol) of TBTU. After 24 hours, 59 mg (0.13 mmol, 62%) of desired title compound was obtained after preparative HPLC (Method 3).

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.04 (s, 3 H), 2.30 (s, 3 H), 4.04 (s, 3 H), 5.23 (s, 2 H), 7.15 (t , 2 H), 7.22 (s, 1 H), 7.40-7.56 (m, 2 H), 7.69-7.77 (m, 1 H), 7.86 (d, 1 H), 8.05 (d, 1 H), 9.88 (s, 1 H).

Example 43 6-Bromo-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-methylquinoline-4-carboxamide

In a manner similar to Example 1), 750 mg (3.42 mmol) of 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 1C) with 1.09 g (4.10 mmol) 6-bromo-2-methylquinoline-4-carboxylic acid, 894 μL (5.13 mmol) N , N -diisopropylethylamine and 1.65 g (5.13 mmol) TBTU in 20 mL of tetrahydrofuran at 25 ° C Stir under 2 hours. The reaction mixture was evaporated and the residue was partitioned betweenEtOAc and water. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate The residue was dissolved in dichloromethane and adsorbed on Isolute® HM-N (Biotage) under evaporation. The isolute was applied to a Biotage snap-on cartridge (100 g; KP-Sil) pre-equilibrated with hexane and purified by silica gel column chromatography (solvent: hexane / 0-100% ethyl acetate) to give 847 mg. (1.81 mmol, 53%) of the desired compound.

1H NMR (400MHz, DMSO d ₆ ): δ (ppm) = 2.13 (s, 3 H), 2.17 (s, 3 H), 2.72 (s, 3 H), 5.24 (s, 2 H), 7.16-7.27 (m, 4 H), 7.72 (s, 1 H), 7.89-7.93 (m, 1 H), 7.94-7.98 (m, 1 H), 8.32 (d, 1 H), 9.96 (s, 1 H) .

Example 44 N-[1-(4-Cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2,6-dimethylquinoline-4-carboxamide

In a manner similar to Example 1), 50 mg (0.22 mmol) of 4-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]benzonitrile (intermediate) 8C) together with 5 mL of tetrahydrofuran containing 53 mg (0.27 mmol) of 2,6-dimethylquinoline-4-carboxylic acid, 58 μL (0.33 mmol) of N , N -diisopropylethylamine and 106 mg (0.33 mmol) of TBTU After stirring for 24 hours at 25 ° C, 32 mg (0.08 mmol, 35%) of the desired compound was obtained after preparative HPLC (Method 3).

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.15 (s, 3 H), 2.17 (s, 3 H), 2.69 (s, 3 H), 5.37 (s, 2 H), 7.33 (d) , 2 H), 7.57 (s, 1 H), 7.61 (dd, 1 H), 7.82-7.92 (m, 4 H), 9.87 (s, 1 H).

Example 45 N-[3,5-Dimethyl-1-(4-methylbenzyl)-1H-pyrazol-4-yl]-2,6-dimethylquinoline-4-carboxamide

In a manner similar to Example 1), 50 mg (0.23 mmol) of 3,5-dimethyl-1-(4-methylbenzyl)-1H-pyrazol-4-amine (Intermediate 13C) 56 mg (0.28 mmol) of 2,6-dimethylquinoline-4-carboxylic acid, 60 μL (0.35 mmol) of N , N -diisopropylethylamine and 112 mg (0.35 mmol) of TBTU in 5 mL of tetrahydrofuran were stirred at 25 ° C. After 24 hours, 48 mg (0.12 mmol, 51%) of desired title compound was obtained after preparative HPLC (Method 3).

1H NMR (400MHz, DMSO d ₆ ): δ (ppm) = 2.14 (s, 3 H), 2.16 (s, 3 H), 2.28 (s, 3 H), 2.48 (s, 3 H), 2.69 (s) , 3 H), 5.19 (s, 2 H), 7.08 (d, 2 H), 7.16 (d, 2 H), 7.56 (s, 1 H), 7.61 (dd, 1 H), 7.85-7.91 (m , 2 H), 9.83 (s, 1 H).

Example 46 2-cyclopropyl-5-fluoro-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-4-methyl Guanamine

In a manner similar to Example 1), 75 mg (0.34 mmol) of 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 1C) with 95 mg (0.41 mmol) 2-cyclopropyl-5-fluoroquinoline-4-carboxylic acid (Intermediate 25A), 89 μL (0.51 mmol) N , N -diisopropylethylamine and 165 mg (0.51 mmol) of TBTU in 5 mL of tetrahydrofuran The mixture was stirred at 25 ° C for 24 hours to give 75 mg (0.17 mmol, 51%) of desired title compound.

1H NMR (400MHz, DMSO d ₆ ): δ (ppm) = 1.10 - 1.21. (m, 4 H), 2.14 (s, 3 H), 2.18 (s, 3 H), 2.40-2.48 (m, 1 H) , 5.24 (s, 2 H), 7.13 - 7.27 (m, 4 H), 7.49 - 7.62 (m, 2 H), 7.72 (s, 1 H), 7.84 - 7.93 (m, 1 H), 9.91 (s , 1 H).

Example 47 6-Bromo-N-[1-(3,4-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl) Quinoline-4-carboxamide

50 mg (0.22 mmol) of 1-(3,4-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 4C) in a similar manner to Example 41) And 81 mg (0.25 mmol) of 6-bromo-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 1A), 55 μL (0.32 mmol) of N , N -diisopropylethylamine and 165 mg (0.32) 5 ml of tetrahydrofuran of PyBOP was stirred at 25 ° C for 24 hours to obtain 25 mg (0.04 mmol, 21%) of the desired title compound after preparative HPLC (Method 3).

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.16 (s, 3 H), 2.20 (s, 3 H), 5.26 (s, 2 H), 7.03 (dd, 1 H), 7.17-7.29 (m, 1 H), 7.44 (dt, 1 H), 8.15 (dd, 1 H), 8.23 (d, 1 H), 8.30 (s, 1 H), 8.50 (d, 1 H), 10.19 (s) , 1 H).

Example 48 6,8-Dichloro-N-[1-(2,4-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl) Quinoline-4-carboxamide

In a manner similar to Example 1), 50 mg (0.22 mmol) of 1-(2,4-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 5C) And containing 78 mg (0.25 mmol) of 6,8-dichloro-2-(trifluoromethyl)quinoline-4-carboxylic acid (intermediate 11A), 53 μL (0.32 mmol) of N , N -diisopropylethylamine and 102 mg (0.32 mmol) of TBTU in 5 mL of tetrahydrofuran were stirred at 25 ° C for 24 hours to afford 48 mg (0.09 mmol, 41%) of the desired compound.

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.11 (d, 3 H), 2.23 (d, 3 H), 5.25 (d, 2 H), 7.11 (br.s., 2 H), 7.28 (d, 1 H), 8.28 (d, 1 H), 8.42 (d, 2 H), 10.22 (d, 1 H).

Example 49 6-Bromo-N-[3,5-dimethyl-1-(2,4,6-trifluorobenzyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl) Quinoline-4-carboxamide

50 mg (0.20 mmol) of 3,5-dimethyl-1-(2,4,6-trifluorobenzyl)-1H-pyrazol-4-amine (intermediate) in a similar manner to Example 41) 7C) with 75 mg (0.24 mmol) of 6-bromo-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 1A), 51 μL (0.29 mmol) of N , N -diisopropylethylamine and 153 mg (0.29 mmol) of PyBOP in 5 mL of tetrahydrofuran was stirred at 25 °C for 24 hours to afford 71 mg (0.11 mmol, 59%) of the desired compound.

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.07 (s, 3 H), 2.31 (s, 3 H), 5.16-5.32 (m, 2 H), 7.26 (t, 2 H), 8.15 (dd, 1 H), 8.23 (d, 1 H), 8.30 (s, 1 H), 8.46-8.54 (m, 1 H), 10.16 (s, 1 H).

Example 50 N-[3,5-Dimethyl-1-(2,4,6-trifluorobenzyl)-1H-pyrazol-4-yl]-2-methoxyquinolin-4- Formamide

In a manner similar to Example 1), 50 mg (0.20 mmol) of 3,5-dimethyl-1-(2,4,6-trifluorobenzyl)-1H-pyrazol-4-amine (intermediate) 7C) together with 5 mg of tetrahydrofuran containing 48 mg (0.24 mmol) of 2-methoxyquinoline-4-carboxylic acid, 51 μL (0.29 mmol) of N , N -diisopropylethylamine and 165 mg (0.51 mmol) of TBTU at 25 ° C After stirring for 24 hours, 6 mg (0.01 mmol, 7%) of the desired compound was obtained after preparative HPLC (Method 5d).

1H NMR (400MHz, DMSO d ₆ ): δ (ppm) = 2.05 (s, 2 H), 2.11 (s, 1 H), 2.21 (s, 1 H), 2.30 (s, 2 H), 4.04 (s) , 3 H), 5.19 (s, 2 H), 7.19-7.31 (m, 3 H), 7.51 (td, 1 H), 7.73 (td, 1 H), 7.86 (d, 1 H), 8.05 (d) , 1 H), 9.77-9.93 (m, 1 H).

Example 51 N-[3,5-Dimethyl-1-(2-methylbenzyl)-1H-pyrazol-4-yl]-2-methoxyquinoline-4-carboxamidine amine

In a manner similar to Example 1), 50 mg (0.23 mmol) of 3,5-dimethyl-1-(2-methylbenzyl)-1H-pyrazol-4-amine (Intermediate 15C) 56 mg (0.28 mmol) of 2-methoxyquinoline-4-carboxylic acid, 61 μL (0.35 mmol) of N , N -diisopropylethylamine and 112 mg (0.35 mmol) of TBTU in 5 mL of tetrahydrofuran were stirred at 25 ° C for 24 hours. Thus, after preparative HPLC (Method 3), 43 mg (0.10 mmol, 44%)

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.14 (s, 6 H), 2.35 (s, 3 H), 4.05 (s, 3 H), 5.25 (s, 2 H), 6.60 (d) , 1 H), 7.09-7.26 (m, 4 H), 7.52 (td, 1 H), 7.74 (td, 1 H), 7.83-7.90 (m, 1 H), 8.07 (d, 1 H), 9.91 (s, 1 H).

Example 52 6-Bromo-N-[3,5-dimethyl-1-(3-methylbenzyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)quina Porphyrin-4-carboxamide

In a manner similar to Example 1), 50 mg (0.23 mmol) of 3,5-dimethyl-1-(3-methylbenzyl)-1H-pyrazol-4-amine (Intermediate 14C) 89 mg (0.28 mmol) of 6-bromo-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 1A), 61 μL (0.35 mmol) of N , N -diisopropylethylamine and 112 mg (0.35 mmol) The TBTU of 5 mL of tetrahydrofuran was stirred at 25 ° C for 24 hours to give 84 mg (0.16 mmol, 69%) of desired title compound.

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.15 (s, 3 H), 2.19 (s, 3 H), 2.28 (s, 3 H), 5.21. (s, 2 H), 6.95 (d) , 1 H), 7.03 (s, 1 H), 7.10 (d, 1 H), 7.24 (t, 1 H), 8.11-8.18 (m, 1 H), 8.23 (d, 1 H), 8.30 (s) , 1 H), 8.50 (d, 1 H), 10.18 (s, 1 H).

Example 53 8-bromo-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-methylquinoline-4-carboxamidine amine

In a manner similar to Example 1), 750 mg (3.42 mmol) of 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 1C) with 1.09 g (4.10 mmol) 8-bromo-2-methylquinoline-4-carboxylic acid (intermediate 13A), 894 μL (5.13 mmol) N , N -diisopropylethylamine and 1.65 g (5.13 mmol) of TBTU 5 mL The tetrahydrofuran was stirred together at 25 ° C for 2 hours. The reaction mixture was evaporated and the residue was taken crystalljjjjjjjjjjj The isolute was applied to a Biotage snap cartridge (100 g; KP-Sil) pre-equilibrated with hexane and purified by cartridge chromatography (solvent: hexane / 0-100% ethyl acetate) to yield 1.38. g (2.95 mmol, 86%) of the desired compound.

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.14 (s, 3 H), 2.18 (s, 3 H), 2.78 (s, 3 H), 5.24 (s, 2 H), 7.10-7.29 (m, 4 H), 7.53 (t, 1 H), 7.73 (s, 1 H), 8.05-8.23 (m, 2 H), 9.93 (s, 1 H).

Example 54 6-Bromo-N-[3,5-dimethyl-1-(4-methylbenzyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)quina Porphyrin-4-carboxamide

In a manner similar to Example 1), 50 mg (0.23 mmol) of 3,5-dimethyl-1-(4-methylbenzyl)-1H-pyrazol-4-amine (Intermediate 13C) 89 mg (0.28 mmol) of 6-bromo-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 1A), 61 μL (0.35 mmol) of N , N -diisopropylethylamine and 112 mg (0.35 mmol) 5 mL of tetrahydrofuran of TBTU was stirred at 25 ° C for 24 hours. The reaction mixture was evaporated and dissolved in acetonitrile. The precipitated product was isolated by EtOAc (EtOAc) elute

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.15 (s, 3 H), 2.17 (s, 3 H), 2.28 (s, 3 H), 5.21. (s, 2 H), 7.08 (m) , 2 H), 7.16 (m, 2 H), 8.15 (dd, 1 H), 8.23 (d, 1 H), 8.29 (s, 1 H), 8.50 (d, 1 H), 10.16 (s, 1) H).

Example 55 N-[1-(3,4-Difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-methoxyquinoline-4-methyl Guanamine

In a manner similar to Example 1), 50 mg (0.21 mmol) of 1-(3,4-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 4C) Stir at 25 ° C with 5 mg of tetrahydrofuran containing 51 mg (0.25 mmol) of 2-methoxyquinoline-4-carboxylic acid, 55 μL (0.32 mmol) of N , N -diisopropylethylamine and 102 mg (0.32 mmol) of TBTU. After 24 hours, 19 mg (0.04 mmol, 20%) of desired title compound was obtained after preparative HPLC (Method 3).

1H NMR (400MHz, DMSO d ₆ ): δ (ppm) = 2.14 (s, 3 H), 2.16-2.20 (m, 3 H), 4.04 (s, 3 H), 5.25 (s, 2 H), 7.02 (ddd, 1 H), 7.18-7.27 (m, 2 H), 7.43 (dt, 1 H), 7.51 (ddd, 1 H), 7.73 (ddd, 1 H), 7.84-7.89 (m, 1 H) , 8.05 (dd, 1 H), 9.90 (s, 1 H).

Example 56 6-bromo-N-{3,5-dimethyl-1-[4-(trifluoromethoxy)benzyl]-1H-pyrazol-4-yl}-2-(trifluoro Methyl)quinoline-4-carboxamide

In a manner similar to Example 1), 100 mg (0.18 mmol, 50%) of 3,5-dimethyl-1-[4-(trifluoromethoxy)benzyl]-1H-pyrazole-4- Amine (Intermediate 19c) with 67 mg (0.21 mmol) of 6-bromo-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 1A), 46 μL (0.26 mmol) N , N -diisopropyl Ethylamine and 84 mg (0.26 mmol) of TBTU in 3 mL of tetrahydrofuran were stirred at 25 ° C for 24 hours to afford 84 mg (0.14 mmol, 82%) of the desired compound.

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.15 (s, 3 H), 2.20 (s, 3 H), 5.31 (s, 2 H), 7.30 (d, 2 H), 7.38 (d) , 2 H), 8.15 (dd, 1 H), 8.23 (d, 1 H), 8.30 (s, 1 H), 8.50 (d, 1 H), 10.19 (s, 1 H).

Example 57 6,8-Dichloro-N-[3,5-dimethyl-1-(2,4,6-trifluorobenzyl)-1H-pyrazol-4-yl]-2-(trifluoro Methyl)quinoline-4-carboxamide

In a manner similar to Example 1), 50 mg (0.20 mmol) of 3,5-dimethyl-1-(2,4,6-trifluorobenzyl)-1H-pyrazol-4-amine (intermediate) 7C) with 73 mg (0.24 mmol) of 6,8-dichloro-2-(trifluoromethyl)quinoline-4-carboxylic acid (intermediate 11A), 51 μL (0.29 mmol) of N , N -diisopropyl The amine and 94 mg (0.29 mmol) of TBTU in 5 mL of tetrahydrofuran were stirred at 25 ° C for 24 hours. The reaction mixture was evaporated and dissolved in acetonitrile. The precipitated product was isolated by EtOAc (EtOAc) elute

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.06 (s, 3 H), 2.31 (s, 3 H), 5.21. (s, 2 H), 7.26 (t, 2 H), 8.26-8.33 (m, 1 H), 8.37-8.45 (m, 2 H), 10.20 (s, 1 H).

Example 58 N-{3,5-Dimethyl-1-[4-(trifluoromethoxy)benzyl]-1H-pyrazol-4-yl}-2,6-dimethyl Quinoline-4-carboxamide

In a manner similar to Example 1), 100 mg (0.18 mmol, 50%) of 3,5-dimethyl-1-[4-(trifluoromethoxy)benzyl]-1H-pyrazole-4- Amine (Intermediate 19C) with 42 mg (0.21 mmol) of 2,6-dimethylquinoline-4-carboxylic acid, 46 μL (0.26 mmol) of N , N -diisopropylethylamine and 84 mg (0.26 mmol) of TBTU 3 mL of tetrahydrofuran were stirred at 25 ° C for 24 hours to obtain 77 mg (0.16 mmol, 94%) of desired title compound after preparative HPLC (Method 3).

1H NMR (400MHz, DMSO d ₆ ): δ (ppm) = 2.14 (s, 3 H), 2.19 (s, 3 H), 2.69 (s, 3 H), 5.29 (s, 2 H), 7.31 (d) , 2 H), 7.37 (d, 2 H), 7.55-7.64 (m, 2 H), 7.85-7.92 (m, 2 H), 9.85 (s, 1 H).

Example 59 N-(1-Benzyl-3,5-dimethyl-1H-pyrazol-4-yl)-6,8-dichloro-2-(trifluoromethyl)quinoline-4- Formamide

In a manner similar to Example 1), 50 mg (0.25 mmol) of 1-benzyl-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 30C) and containing 92 mg (0.30 mmol) , 8-dichloro-2-(trifluoromethyl)quinoline-4-carboxylic acid (intermediate 11A), 65 μL (0.37 mmol) of N , N -diisopropylethylamine and 10 mg of TBTU of 120 mg (0.37 mmol) Tetrahydrofuran was stirred at 25 ° C for 24 hours to give 79 mg (0.16 mmol, 63%) of desired title compound after preparative HPLC (Method 3).

1H NMR (400MHz, DMSO d ₆ ): δ (ppm) = 2.14 (s, 3 H), 2.18 (s, 3 H), 5.25 (s, 2 H), 7.14-7.20 (m, 2 H), 7.24 -7.31 (m, 1 H), 7.32-7.38 (m, 2 H), 8.29 (d, 1 H), 8.38 (d, 1 H), 8.40 (s, 1 H), 10.19 (s, 1 H) .

Example 60 6,8-Dichloro-N-{3,5-dimethyl-1-[4-(trifluoromethoxy)benzyl]-1H-pyrazol-4-yl}-2- (trifluoromethyl)quinoline-4-carboxamide

In a manner similar to Example 1), 100 mg (0.18 mmol, 50%) of 3,5-dimethyl-1-[4-(trifluoromethoxy)benzyl]-1H-pyrazole-4- Amine (Intermediate 19C) with 65 mg (0.21 mmol) of 6,8-dichloro-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 11A), 46 μL (0.26 mmol) N , N - Isopropylethylamine and 84 mg (0.26 mmol) of TBTU in 3 mL of tetrahydrofuran were stirred at 25 ° C for 24 hours to afford 69 mg (0.12 mmol, 68%) of the desired compound.

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.15 (s, 3 H), 2.20 (s, 3 H), 5.31 (s, 2 H), 7.30 (d, 2 H), 7.38 (d) , 2 H), 8.30 (d, 1 H), 8.38-8.45 (m, 2 H), 10.23 (s, 1 H).

Example 61 N-[3,5-Dimethyl-1-(4-methylbenzyl)-1H-pyrazol-4-yl]-2-methoxyquinoline-4-carboxamidine amine

In a manner similar to Example 1), 50 mg (0.23 mmol) of 3,5-dimethyl-1-(4-methylbenzyl)-1H-pyrazol-4-amine (Intermediate 13C) 56 mg (0.28 mmol) of 2-methoxyquinoline-4-carboxylic acid, 61 μL (0.35 mmol) of N , N -diisopropylethylamine and 112 mg (0.35 mmol) of TBTU in 5 mL of tetrahydrofuran were stirred at 25 ° C for 24 hours. Thus, 79 mg (0.16 mmol, 63%) of the desired title compound was obtained after preparative HPLC (Method 3).

1H NMR (400MHz, DMSO d ₆ ): δ (ppm) = 2.13 (s, 3 H), 2.15 (s, 3 H), 2.28 (s, 3 H), 4.04 (s, 3 H), 5.19 (s) , 2 H), 7.07 (d, 2 H), 7.16 (d, 2 H), 7.21 (s, 1 H), 7.51 (ddd, 1 H), 7.73 (ddd, 1 H), 7.86 (d, 1) H), 8.02-8.08 (m, 1 H), 9.87 (s, 1 H).

Example 62 N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2,6-dimethylquinoline-4-carboxamidine amine

In a manner similar to Example 1), 80 mg (0.36 mmol) of 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 1C) was combined with 88 mg (0.44 mmol) 2,6-dimethylquinoline-4-carboxylic acid, 95 μL (0.55 mmol) of N , N -diisopropylethylamine and 176 mg (0.55 mmol) of TBTU in 5 mL of tetrahydrofuran were stirred at 25 ° C. hour. The reaction mixture was evaporated and the residue was partitioned betweenEtOAc and water. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate The residue was dissolved in dichloromethane and adsorbed on Isolute® HM-N (Biotage) under evaporation. The isolute was applied to a Biotage snap cartridge (25 g; KP-Sil) pre-equilibrated with hexane and purified by cartridge chromatography (solvent: hexane / 0-100% ethyl acetate) to give 119 mg. (0.30 mmol, 81%) of the desired compound.

1H NMR (400MHz, CDCl ₃ ): δ (ppm) = 2.21 (s, 3 H), 2.29 (s, 3 H), 2.51 (s, 3 H), 2.71 (s, 3 H), 5.21. 2 H), 7.02 (t, 2 H), 7.14 (dd, 2 H), 7.36 (s, 1 H), 7.43 (s, 1 H), 7.55 (dd, 1 H), 7.92 (d, 1 H) ), 7.98 (s, 1 H).

Example 63 N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-6-(trifluoromethoxy)-2-(trifluoro) Methyl)quinoline-4-carboxamide

In a manner similar to Example 1), 50 mg (0.23 mmol) of 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 1C) with 89 mg (0.27 mmol) 6-(trifluoromethoxy)-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 21A), 60 μL (0.34 mmol) N , N -diisopropylethylamine and 110 mg (0.34 mmol) of TBTU in 3 mL of tetrahydrofuran were stirred at 25 ° C for 3 hours to give 108 mg (0.21 mmol, 90%) of the desired compound.

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.14 (s, 3 H), 2.19 (s, 3 H), 5.25 (s, 2 H), 7.14 - 7.29 (m, 4 H), 8.02 (dd, 1 H), 8.22 (s, 1 H), 8.36 (s, 1 H), 8.45 (d, 1 H), 10.19 (s, 1 H).

Example 64 N-[1-(3,4-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2,6-dimethylquinolin-4- Formamide

50 mg (0.21 mmol) of 1-(3,4-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 4C) in a similar manner to Example 41) With 5 mg of tetrahydrofuran containing 51 mg (0.25 mmol) of 2,6-dimethylquinoline-4-carboxylic acid, 55 μL (0.32 mmol) of N , N -diisopropylethylamine and 165 mg (0.32 mmol) of PyBOP at 25 ° C After stirring for 24 hours, 35 mg (0.08 mmol, 39%) of desired title compound was obtained after preparative HPLC (Method 3).

1H NMR (400MHz, DMSO d ₆ ): δ (ppm) = 2.15 (s, 3 H), 2.19 (s, 3 H), 2.70 (s, 3 H), 5.25 (s, 2 H), 7.03 (ddd , 1 H), 7.23 (ddd, 1 H), 7.44 (dt, 1 H), 7.57-7.66 (m, 2 H), 7.86-7.94 (m, 2 H), 9.87 (s, 1 H).

Example 65 N-(1-Benzyl-3,5-dimethyl-1H-pyrazol-4-yl)-2-methoxyquinoline-4-carboxamide

In a manner similar to Example 1), 50 mg (0.25 mmol) of 1-benzyl-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 30C) and 61 mg (0.30 mmol) -Methoxyquinoline-4-carboxylic acid, 65 μL (0.37 mmol) of N , N -diisopropylethylamine and 120 mg (0.37 mmol) of TBTU in 5 mL of tetrahydrofuran were stirred at 25 ° C for 24 hours for preparative HPLC (Method 3) 45 mg (0.12 mmol, 46%)

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.13 (s, 3 H), 2.16 (s, 3 H), 4.04 (s, 3 H), 5.25 (s, 2 H), 7.14-7.20 (m, 2 H), 7.22 (s, 1 H), 7.25-7.32 (m, 1 H), 7.32-7.40 (m, 2 H), 7.47-7.55 (m, 1 H), 7.69-7.77 (m , 1 H), 7.86 (d, 1 H), 8.05 (d, 1 H), 9.90 (s, 1 H).

Example 66 6,8-Dichloro-N-[3,5-dimethyl-1-(pyridin-2-ylmethyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline -4-carboxamide

In a manner similar to Example 1), 50 mg (0.25 mmol) of 3,5-dimethyl-1-(pyridin-2-ylmethyl)-1H-pyrazol-4-amine (Intermediate 18C) 92 mg (0.30 mmol) of 6,8-dichloro-2-(trifluoromethyl)quinoline-4-carboxylic acid (intermediate 11A), 65 μL (0.37 mmol) of N , N -diisopropylethylamine and 120 mg ( 0.37 mmol) TBTU of 5 mL of tetrahydrofuran was stirred at 25 ° C for 24 hours to give 35 mg (0.07 mmol, 28%) of desired title compound after preparative HPLC (Method 3).

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.14 (s, 3 H), 2.24 (s, 3 H), 5.34 (s, 2 H), 7.04 (d, 1 H), 7.28-7.35 (m, 1 H), 7.80 (td, 1 H), 8.31 (d, 1 H), 8.40 (d, 1 H), 8.42 (s, 1 H), 8.51 - 8.57 (m, 1 H), 10.22 (s, 1 H).

Example 67 6,8-Dichloro-N-[1-(3-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl) Quinoline-4-carboxamide

In a manner similar to Example 1), 50 mg (0.22 mmol) of 1-(3-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 12C) Containing 80 mg (0.26 mmol) of 6,8-dichloro-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 11A), 56 μL (0.32 mmol) of N , N -diisopropylethylamine and 104 mg (0.32 mmol) TBTU of 5 mL of tetrahydrofuran was stirred at 25 °C for 24 hours to afford 71 mg (0.13 mmol, 62%) of the desired compound.

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.15 (s, 3 H), 2.18 (s, 3 H), 3.73 (s, 3 H), 5.23 (s, 2 H), 6.68-6.74 (m, 2 H), 6.82-6.89 (m, 1 H), 7.27 (t, 1 H), 8.30 (d, 1 H), 8.41 (d, 1 H), 8.43 (s, 1 H), 10.22 (s, 1 H).

Example 68 6,8-Dichloro-N-[1-(2-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl) Quinoline-4-carboxamide

In a manner similar to Example 1), 50 mg (0.22 mmol) of 2-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]benzonitrile (intermediate) 10C) with 82 mg (0.27 mmol) of 6,8-dichloro-2-(trifluoromethyl)quinoline-4-carboxylic acid (intermediate 11A), 58 μL (0.33 mmol) of N , N -diisopropyl The amine and 106 mg (0.33 mmol) of TBTU in 5 mL of THF were stirred at <RTI ID=0.0></RTI></RTI><RTIgt;

1H NMR (400MHz, DMSO d ₆ ): δ (ppm) = 2.14 (s, 3 H), 2.27 (s, 3 H), 5.44 (s, 2 H), 7.11 (d, 1 H), 7.50-7.56 (m, 1 H), 7.71 (td, 1 H), 7.90 (dd, 1 H), 8.31 (d, 1 H), 8.40 (d, 1 H), 8.43 (s, 1 H), 10.25 (s) , 1 H).

Example 69 2-ethyl-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-4-carboxamide

100 mg (0.22 mmol) of 2-bromo-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyridyl Zin-4-yl]quinoline-4-carboxamide (Example 36) was dissolved in 5 mL of dry tetrahydrofuran and cooled to 0 °C. To this solution was added 110 μL (0.33 mmol, 3M in tetrahydrofuran) ethylmagnesium bromide solution and the reaction mixture was stirred at 25 ° C for 4 hours. The reaction mixture was evaporated and the residue was partitioned between water andEtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated. The crude mixture was pre-purified by preparative HPLC (Method 3) and was subjected to another preparative HPLC (Method 5c) to afford 68 mg (0.13 mmol, 58%)

1H NMR (300MHz, CDCl ₃ ): δ (ppm) = 1.41 (t, 3 H), 2.27 (s, 3 H), 2.34 (s, 3 H), 3.18 (q, 2 H), 5.36 (s, 2 H), 7.00-7.11 (m, 2 H), 7.11-7.21 (m, 2 H), 7.82-7.92 (m, 2 H), 7.98 (t, 1 H), 8.26 (d, 1 H), 8.41 (d, 1 H), 9.39 (s, 1 H).

Example 70 6-bromo-N-[3,5-dimethyl-1-(pyridin-2-ylmethyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)quina Porphyrin-4-carboxamide

In a manner similar to Example 1), 50 mg (0.25 mmol) of 3,5-dimethyl-1-(pyridin-2-ylmethyl)-1H-pyrazol-4-amine (Intermediate 18C) 95 mg (0.30 mmol) of 6-bromo-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 1A), 65 μL (0.37 mmol) N , N -diisopropylethylamine and 119 mg (0.37 mmol) The TBTU of 5 mL of tetrahydrofuran was stirred at 25 °C for 24 hours to give 52 mg (0.10 mmol, 41%) of the desired compound.

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.14 (s, 3 H), 2.24 (s, 3 H), 5.34 (s, 2 H), 7.05 (d, 1 H), 7.28-7.36 (m, 1 H), 7.80 (td, 1 H), 8.15 (dd, 1 H), 8.24 (d, 1 H), 8.30 (s, 1 H), 8.51 (d, 1 H), 8.53 - 8.57 (m, 1 H), 10.18 (s, 1 H).

Example 71 6-Bromo-N-[1-(3-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quina Porphyrin-4-carboxamide

50 mg (0.22 mmol) of 3-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]benzonitrile (intermediate) in a similar manner to Example 1) 9C) with 85 mg (0.27 mmol) of 6-bromo-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 1A), 58 μL (0.33 mmol) of N , N -diisopropylethylamine and 106 mg (0.33 mmol) TBTU of 5 mL of tetrahydrofuran was stirred at 25 ° C for 24 hours to give 86 mg (0.16 mmol, 73%) of desired title compound.

1H NMR (400MHz, DMSO d ₆ ): δ (ppm) = 2.16 (s, 3 H), 2.21 (s, 3 H), 5.34 (s, 2 H), 7.50 (d, 1 H), 7.57-7.64 (m, 2 H), 7.79 (d, 1 H), 8.15 (dd, 1 H), 8.23 (d, 1 H), 8.30 (s, 1 H), 8.51 (d, 1 H), 10.19 (s) , 1 H).

Example 72 6-Bromo-N-[1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline- 4-carboxamide

In a manner similar to Example 1), 50 mg (0.23 mmol) of 1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 2C) with 88 mg (0.27mmol) 6- bromo-2- (trifluoromethyl) quinolin-4-carboxylic acid (intermediate 1A), 60μL (0.34mmol) N , N - diisopropylethylamine and 110mg (0.34mmol) TBTU 5 mL of tetrahydrofuran were stirred at 25 ° C for 24 hours to give 72 mg (0.13 mmol, 59%) of the desired compound.

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.17 (s, 3 H), 2.20 (s, 3 H), 5.30 (s, 2 H), 6.89-7.07 (m, 2 H), 7.07 -7.22 (m, 1 H), 7.34-7.49 (m, 1 H), 8.15 (dd, 1 H), 8.24 (d, 1 H), 8.30 (s, 1 H), 8.52 (d, 1 H) , 10.18 (s, 1 H).

Example 73 N-[1-(4-fluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2,6-dimethylquina Porphyrin-4-carboxamide

In a manner similar to Example 1), 75 mg (0.20 mmol, 75%) of 1-(4-fluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole-4- Amine (Intermediate 25C) with 49 mg (0.24 mmol) of 2,6-dimethylquinoline-4-carboxylic acid, 53 [mu]L (0.30 mmol) of N , N -diisopropylethylamine and 98 mg (0.30 mmol) of TBTU 3 mL of tetrahydrofuran were stirred at 25 ° C for 24 hours to obtain 55 mg (0.12 mmol, 58%) of desired title compound after preparative HPLC (Method 3).

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.27 (s, 3 H), 2.70 (s, 3 H), 5.46 (s, 2 H), 7.20-7.36 (m, 4 H), 7.52 (s, 1 H), 7.62 (dd, 1 H), 7.82 (s, 1 H), 7.90 (d, 1 H), 10.20 (s, 1 H).

Example 74 6-Bromo-N-[1-(2-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline- 4-carboxamide

In a manner similar to Example 1), 50 mg (0.23 mmol) of 1-(2-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 3C) and 88 mg (0.27 mmol) 6-bromo-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 1A), 60 μL (0.34 mmol) N , N -diisopropylethylamine and 110 mg (0.34 mmol) TBTU 5 mL of tetrahydrofuran were stirred at 25 ° C for 24 hours to obtain 77 mg (0.14 mmol, 60%) of desired title compound after preparative HPLC (Method 3).

1H NMR (400MHz, DMSO d ₆ ): δ (ppm) = 2.14 (s, 3 H), 2.23 (s, 3 H), 5.30 (s, 2 H), 7.03-7.10 (m, 1 H), 7.16 -7.28 (m, 2 H), 7.34-7.41 (m, 1 H), 8.15 (dd, 1 H), 8.23 (d, 1 H), 8.30 (s, 1 H), 8.51 (d, 1 H) , 10.17 (s, 1 H).

Example 75 N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-hydroxy-6-methoxyquinolin-4- Formamide

In a manner similar to Example 1), 100 mg (0.46 mmol) of 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 1C) with 120 mg (0.55 mmol) 2-hydroxy-6-methoxyquinoline-4-carboxylic acid, 119 μL (0.68 mmol) of N , N -diisopropylethylamine and 220 mg (0.68 mmol) of TBTU in 5 mL of tetrahydrofuran at 25 ° C Stir for 3 hours. The reaction mixture was evaporated and the residue was partitioned betweenEtOAc and water. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate The residue was dissolved in dichloromethane and adsorbed on Isolute® HM-N (Biotage) under evaporation. Isolute was applied to a Biotage snap cartridge (25 g; KP-Sil) pre-equilibrated with hexanes and purified via a silica gel column chromatography (solvent: dichloromethane / 0-10% methanol). The obtained crude product was dissolved in N,N -dimethylformamide and the obtained precipitate was separated by filtration, washed with tri-butyl methyl ether and dried under high vacuum to obtain 119 mg (0.28 mmol, 62%). Title compound.

1H NMR (400MHz, DMSO d ₆ ): δ (ppm) = 2.12 (s, 3 H), 2.16 (s, 3 H), 3.75 (s, 3 H), 5.23 (s, 2 H), 6.71 (s) , 1 H), 7.15-7.28 (m, 6 H), 7.34 (d, 1 H), 9.88 (s, 1 H), 11.89 (s, 1 H).

Example 76 N-[3,5-Dimethyl-1-(3-methylbenzyl)-1H-pyrazol-4-yl]-2-methoxyquinoline-4-carboxamidine amine

In a manner similar to Example 1), 50 mg (0.23 mmol) of 3,5-dimethyl-1-(3-methylbenzyl)-1H-pyrazol-4-amine (Intermediate 14C) 57 mg (0.28 mmol) of 2-methoxyquinoline-4-carboxylic acid, 61 μL (0.35 mmol) of N , N -diisopropylethylamine and 112 mg (0.35 mmol) of TBTU in 5 mL of tetrahydrofuran were stirred at 25 ° C for 24 hours. Thus, 68 mg (0.17 mmol, 72%) of the desired compound was obtained after preparative HPLC (Method 3).

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.12 (s, 3 H), 2.15 (s, 3 H), 2.28 (s, 3 H), 4.03 (s, 3 H), 5.19 (s) , 2 H), 6.94 (d, 1 H), 7.02 (s, 1 H), 7.09 (d, 1 H), 7.19-7.27 (m, 2 H), 7.50 (td, 1 H), 7.72 (td) , 1 H), 7.85 (d, 1 H), 8.04 (d, 1 H), 9.89 (s, 1 H).

Example 77 N-[1-(2-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-methoxyquinoline-4-carboxamide

In a manner similar to Example 41), 100 mg (0.46 mmol) of 1-(2-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 3C) with 111 mg (0.55 mmol) 2-methoxyquinoline-4-carboxylic acid, 119 μL (0.68 mmol) of N , N -diisopropylethylamine and 356 mg (0.68 mmol) of PyBOP in 5 mL of tetrahydrofuran were stirred at 25 ° C for 24 hours. Thus 115 mg (0.28 mmol, 62%) of the desired title compound was obtained after preparative HPLC (Method 3).

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.11 (s, 3 H), 2.21 (s, 3 H), 4.04 (s, 3 H), 5.29 (s, 2 H), 6.99-7.10 (m, 1 H), 7.15-7.29 (m, 3 H), 7.32-7.42 (m, 1 H), 7.47-7.57 (m, 1 H), 7.69-7.79 (m, 1 H), 7.86 (d) , 1 H), 8.05 (d, 1 H), 9.92 (s, 1 H).

Example 78 2-cyano-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-4-carboxamide

To 100 mg (0.17 mmol) of 2-bromo-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-4-carboxamide ( Example 36) 28 mg (0.24 mmol) of zinc cyanide and 25 mg (0.02 mmol) of ruthenium (triphenylphosphine) palladium (0) were added to a solution of degassed 2.0 mL of N , N -dimethylformamide. The reaction mixture was heated in a microwave at 150 ° C for 10 minutes. The reaction suspension was poured onto a two-phase mixture of water and ethyl acetate and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate The residue was dissolved in 2.5mL N, N - and purified (Method 3) via preparative HPLC in dimethylformamide to obtain 54mg (0.14mmol, 61%) the desired title compound after drying.

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.15 (s, 3 H), 2.19 (s, 3 H), 5.24 (s, 2 H), 7.15-7.27 (m, 4 H), 7.88 - 7.95 (m, 1 H), 7.97-8.05 (m, 1 H), 8.20-8.29 (m, 2 H), 8.36 (s, 1 H), 10.07 (s, 1 H).

Example 79 2-cyclopropyl-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-6-(trifluoromethyl)quinoline-4 -Procarbamide

In a manner similar to Example 1), 13 mg (0.06 mmol) of 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 1C) and 20 mg (0.07 mmol) 2-cyclopropyl-6-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 34A), 15 μL (0.09 mmol) N , N -diisopropylethylamine and 29 mg (0.09 mmol) The TBTU of 5 mL of tetrahydrofuran was stirred at 25 ° C for 24 hours to obtain 25 mg (0.05 mmol, 85%) of the desired title compound after preparative HPLC (Method 3).

1H NMR (400MHz, DMSO d ₆ ): δ (ppm) = 1.14-1.24 (m, 4 H), 2.14 (s, 3 H), 2.18 (s, 3 H), 2.42-2.48 (m, 1 H) , 5.25 (s, 2 H), 7.14 - 7.31 (m, 4 H), 7.84 (s, 1 H), 8.00 (dd, 1 H), 8.12 (d, 1 H), 8.50 (s, 1 H) , 10.02 (s, 1 H).

Example 80 N-[1-(2-Cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-methoxyquinoline-4-carboxamidine amine

In a manner similar to Example 1), 50 mg (0.22 mmol) of 2-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]benzonitrile (intermediate) 10C) together with 54 mg (0.27 mmol) of 2-methoxyquinoline-4-carboxylic acid, 58 μL (0.33 mmol) of N , N -diisopropylethylamine and 106 mg (0.33 mmol) of TBTU in 5 mL of tetrahydrofuran at 25 ° C This was stirred for 24 hours to give 15 mg (0.03 mmol, 16%) of desired title compound after preparative HPLC (Method 3).

1H NMR (400MHz, DMSO d ₆ ): δ (ppm) = 2.12 (s, 3 H), 2.24 (s, 3 H), 4.05 (s, 3 H), 5.43 (s, 2 H), 7.09 (d) , 1 H), 7.24 (s, 1 H), 7.49-7.56 (m, 2 H), 7.68-7.77 (m, 2 H), 7.84-7.93 (m, 2 H), 8.06 (d, 1 H) , 9.94 (s, 1 H).

Example 81 2-methoxy-N-[1-(3-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-4-methyl Guanamine

In a manner similar to Example 1), 50 mg (0.22 mmol) of 1-(3-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 12C) 53 mg (0.26 mmol) of 2-methoxyquinoline-4-carboxylic acid, 60 μL (0.35 mmol) of N , N -diisopropylethylamine and 111 mg (0.35 mmol) of TBTU in 5 mL of tetrahydrofuran were stirred at 25 ° C. An hour, whereby 35 mg (0.07 mmol, 29%) of the desired compound was obtained after preparative HPLC (Method 3).

1H NMR (400MHz, DMSO d ₆ ): δ (ppm) = 2.14 (s, 3 H), 2.16 (s, 3 H), 3.73 (s, 3 H), 4.04 (s, 3 H), 5.22 (s) , 2 H), 6.69-6.74 (m, 2 H), 6.83-6.88 (m, 1 H), 7.22 (s, 1 H), 7.27 (t, 1 H), 7.51 (ddd, 1 H), 7.73 (ddd, 1 H), 7.83-7.89 (m, 1 H), 8.06 (dd, 1 H), 9.88 (s, 1 H).

Example 82 6,8-Dichloro-N-{3,5-dimethyl-1-[(3-methylpyridin-2-yl)methyl]-1H-pyrazol-4-yl}-2- (trifluoromethyl)quinoline-4-carboxamide

In a manner similar to Example 1), 50 mg (0.23 mmol) of 3,5-dimethyl-1-[(3-methylpyridin-2-yl)methyl]-1H-pyrazol-4-amine ( Intermediate 36C) with 86 mg (0.28 mmol) of 6,8-dichloro-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 11A), 60 μL (0.35 mmol) N , N -diisopropyl The ethylamine and 111 mg (0.35 mmol) of TBTU in 5 mL of tetrahydrofuran were stirred at 25 ° C for 24 hours to afford 35 mg (0.07 mmol, 29%) of the desired compound.

1H NMR (400MHz, DMSO d ₆ ): δ (ppm) = 2.14 (s, 3 H), 2.24 (s, 3 H), 2.47 (s, 3 H), 5.28 (s, 2 H), 6.72 (d) , 1 H), 7.17 (d, 1 H), 7.66 (t, 1 H), 8.31 (d, 1 H), 8.40 (d, 1 H), 8.43 (s, 1 H), 10.23 (s, 1) H).

Example 83 6-bromo-N-{3,5-dimethyl-1-[2-(trifluoromethoxy)benzyl]-1H-pyrazol-4-yl}-2-(trifluoro Methyl)quinoline-4-carboxamide

In a manner similar to Example 1), 100 mg (0.18 mmol, 50%) of 3,5-dimethyl-1-[2-(trifluoromethoxy)benzyl]-1H-pyrazole-4- Amine (Intermediate 21C) with 67 mg (0.21 mmol) of 6-bromo-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 1A), 45 μL (0.26 mmol) N , N -diisopropyl Ethylamine and 84 mg (0.26 mmol) of TBTU in 3 mL of THF were stirred at 25 ° C for 24 hours to afford 68 mg (0.11 mmol, 60%) of the desired compound.

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.15 (s, 3 H), 2.18-2.22 (m, 3 H), 5.32 (s, 2 H), 6.96 (d, 1 H), 7.33 - 7.50 (m, 3 H), 8.15 (dd, 1 H), 8.23 (d, 1 H), 8.32 (s, 1 H), 8.51 (d, 1 H), 10.22 (s, 1 H).

Example 84 N-[1-(2,6-Difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2,6-dimethylquinolin-4- Formamide

In a manner similar to Example 1), 50 mg (0.21 mmol) of 1-(2,6-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 6C) With 25 mg (0.25 mmol) of 2,6-dimethylquinoline-4-carboxylic acid, 55 μL (0.32 mmol) of N , N -diisopropylethylamine and 101 mg (0.32 mmol) of TBTU in 3 mL of tetrahydrofuran at 25 ° C After stirring for 24 hours, 59 mg (0.14 mmol, 66%) of desired title compound was obtained after preparative HPLC (Method 3).

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.06 (s, 3 H), 2.30 (s, 3 H), 2.70 (s, 3 H), 5.24 (s, 2 H), 7.15 (t) , 2 H), 7.41 - 7.54 (m, 1 H), 7.55-7.65 (m, 2 H), 7.84 - 7.93 (m, 2 H), 9.84 (s, 1 H).

Example 85 8-Fluoro-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline- 4-carboxamide

In a manner similar to Example 1), 43 mg (0.20 mmol) of 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 1C) and 61 mg (0.24 mmol) 8-fluoro-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 35A), 51 μL (0.29 mmol) N , N -diisopropylethylamine and 94 mg (0.29 mmol) TBTU 3 mL of tetrahydrofuran were stirred at 25 ° C for 2 hours to obtain 65 mg (0.14 mmol, 66%) of desired title compound after preparative HPLC (Method 3).

1H NMR (400MHz, DMSO d ₆ ): δ (ppm) = 2.15 (s, 3 H), 2.19 (s, 3 H), 5.25 (s, 2 H), 7.15-7.26 (m, 4 H), 7.83 -7.94 (m, 2 H), 8.07-8.12 (m, 1 H), 8.30 (s, 1 H), 10.12 (s, 1 H).

Example 86 N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2,8-dimethylquinoline-4-carboxamidine amine

In a manner similar to Example 1), 100 mg (0.46 mmol) of 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 1C) with 110 mg (0.55 mmol) 2,8-dimethylquinoline-4-carboxylic acid, 119 μL (0.68 mmol) of N , N -diisopropylethylamine and 219 mg (0.68 mmol) of TBTU in 5 mL of tetrahydrofuran were stirred at 25 ° C. hour. The reaction mixture was evaporated and the residue was partitioned betweenEtOAc and water. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate The residue was dissolved in dichloromethane and adsorbed on Isolute® HM-N (Biotage) under evaporation. The isolute was applied to a Biotage snap cartridge (25 g; KP-Sil) pre-equilibrated with hexanes and purified by silica gel column chromatography (solvent: hexane / 0-100% ethyl acetate). The obtained crude product was purified again by preparative HPLC (Method 3) to yield 136 mg (0.33 mmol, 73%

1H NMR (400MHz, CDCl ₃ ): δ (ppm) = 2.22 (s, 3 H), 2.30 (s, 3 H), 2.80 (s, 3 H), 2.82 (s, 3 H), 5.23 (s, 2 H), 6.98-7.08 (m, 3 H), 7.11-7.18 (m, 2 H), 7.42 - 7.51 (m, 2 H), 7.60 (d, 1 H), 8.07 (d, 1 H).

Example 87 N-[1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-methoxyquinoline-4-carboxamide

In a manner similar to Example 1), 50 mg (0.23 mmol) of 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 2C) with 56 mg (0.27 mmol) 2-methoxyquinoline-4-carboxylic acid, 60 μL (0.34 mmol) of N , N -diisopropylethylamine and 110 mg (0.34 mmol) of TBTU in 5 mL of tetrahydrofuran were stirred at 25 ° C for 24 hours. Thus, 56 mg (0.13 mmol, 59%) of the desired compound was obtained after preparative HPLC (Method 3).

1H NMR (400MHz, DMSO d ₆ ): δ (ppm) = 2.14 (s, 3 H), 2.17 (s, 3 H), 4.04 (s, 3 H), 5.28 (s, 2 H), 6.91-6.98 (m, 1 H), 7.00 (d, 1 H), 7.08-7.16 (m, 1 H), 7.22 (s, 1 H), 7.37-7.45 (m, 1 H), 7.48-7.55 (m, 1 H), 7.70-7.77 (m, 1 H), 7.86 (d, 1 H), 8.03 - 8.08 (m, 1 H), 9.90 (s, 1 H).

Example 88 7-Bromo-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline- 4-carboxamide

In a manner similar to Example 1), 50 mg (0.23 mmol) of 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 1C) and 88 mg (0.27 mmol) 7-Bromo-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 22A), 60 μL (0.34 mmol) N , N -diisopropylethylamine and 110 mg (0.34 mmol) TBTU 3 mL of tetrahydrofuran were stirred at 25 ° C for 24 hours to obtain 83 mg (0.16 mmol, 70%) of desired title compound after preparative HPLC (Method 3).

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.14 (s, 3 H), 2.19 (s, 3 H), 5.25 (s, 2 H), 7.13 - 7.28 (m, 4 H), 8.06 (dd, 1 H), 8.24 (d, 1 H), 8.27 (s, 1 H), 8.55 (d, 1 H), 10.14 (s, 1 H).

Example 89 6,8-Dichloro-N-[3,5-dimethyl-1-(2-methylbenzyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl) Quinoline-4-carboxamide

In a manner similar to Example 1), 50 mg (0.23 mmol) of 3,5-dimethyl-1-(2-methylbenzyl)-1H-pyrazol-4-amine (Intermediate 15C) 86 mg (0.28 mmol) of 6,8-dichloro-2-(trifluoromethyl)quinoline-4-carboxylic acid (intermediate 11A), 61 μL (0.35 mmol) of N , N -diisopropylethylamine and 111 mg ( 0.35 mmol) TBTU of 5 mL of tetrahydrofuran was stirred at 25 ° C for 24 hours. The reaction mixture was evaporated and dissolved in water. The precipitate was isolated by filtration, washed with EtOAc EtOAc (EtOAc)

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.16 (s, 6 H), 2.35 (s, 3 H), 5.26 (s, 2 H), 6.59 (d, 1 H), 7.09-7.25 (m, 3 H), 8.32 (d, 1 H), 8.38-8.50 (m, 2 H), 10.25 (s, 1 H).

Example 90 6-Fluoro-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-methylquinoline-4-carboxamidine amine

In a manner similar to Example 1), 100 mg (0.46 mmol) of 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 1C) with 113 mg (0.55 mmol) 6-fluoro-2-methylquinoline-4-carboxylic acid, 119 μL (0.68 mmol) of N , N -diisopropylethylamine and 220 mg (0.68 mmol) of TBTU in 5 mL of tetrahydrofuran were stirred at 25 ° C 3 hours. The reaction mixture was evaporated and the residue was partitioned betweenEtOAc and water. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate The residue was dissolved in dichloromethane and adsorbed on Isolute® HM-N (Biotage) under evaporation. The isolute was applied to a Biotage snap cartridge (25 g; KP-Sil) pre-equilibrated with hexanes and purified by silica gel column chromatography (solvent: hexane / 0-100% ethyl acetate). The obtained crude product was purified again by preparative HPLC (Method 3) to yield 75 mg (0.18 mmol, 40%)

1H NMR (400MHz, DMSO d ₆ ): δ (ppm) = 2.13 (s, 3 H), 2.17 (s, 3 H), 2.72 (s, 3 H), 5.24 (s, 2 H), 7.15-7.28 (m, 4 H), 7.67-7.74 (m, 2 H), 7.83 (dd, 1 H), 8.08 (dd, 1 H), 9.92 (s, 1 H).

Example 91 6,8-Dichloro-N-[1-(3-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl) Quinoline-4-carboxamide

50 mg (0.22 mmol) of 3-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]benzonitrile (intermediate) in a similar manner to Example 1) 9C) with 82 mg (0.27 mmol) of 6,8-dichloro-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 11A), 58 μL (0.33 mmol) of N , N -diisopropyl The amine and 106 mg (0.33 mmol) of TBTU in 5 mL of THF were stirred at <RTI ID=0.0></RTI></RTI><RTIgt;

1H NMR (400MHz, DMSO d ₆ ): δ (ppm) = 2.16 (s, 3 H), 2.21 (s, 3 H), 5.34 (s, 2 H), 7.47-7.52 (m, 1 H), 7.57 -7.63 (m, 2 H), 7.76-7.81 (m, 1 H), 8.31 (d, 1 H), 8.40 (d, 1 H), 8.42 (s, 1 H), 10.22 (s, 1 H) .

Example 92 N-(1-Benzyl-3,5-dimethyl-1H-pyrazol-4-yl)-2,6-dimethylquinoline-4-carboxamide

In a manner similar to Example 1), 50 mg (0.25 mmol) of 1-benzyl-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 30C) and 60 mg (0.30 mmol) , 6-dimethylquinoline 4-carboxylic acid, 65 μL (0.37 mmol) of N , N -diisopropylethylamine and 120 mg (0.37 mmol) of TBTU in 5 mL of tetrahydrofuran were stirred at 25 ° C for 3 hours to prepare After HPLC (Method 3), 56 mg (0.15 mmol, 59%)

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.14 (s, 3 H), 2.16 (s, 3 H), 2.68 (s, 3 H), 5.24 (s, 2 H), 7.11-7.22 (m, 2 H), 7.24-7.40 (m, 3 H), 7.55 (s, 1 H), 7.60 (dd, 1 H), 7.85-7.92 (m, 2 H), 9.83 (s, 1 H) .

Example 93 6,8-Dichloro-N-{3,5-dimethyl-1-[3-(trifluoromethoxy)benzyl]-1H-pyrazol-4-yl}-2- (trifluoromethyl)quinoline-4-carboxamide

In a manner similar to Example 1), 50 mg (0.18 mmol) of 3,5-dimethyl-1-[3-(trifluoromethoxy)benzyl]-1H-pyrazol-4-amine (middle) 20C) with 65 mg (0.21 mmol) of 6,8-dichloro-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 11A), 46 μL (0.26 mmol) of N , N -diisopropyl Ethylamine and 84 mg (0.26 mmol) of TBTU in 3 mL of tetrahydrofuran were stirred at 25 ° C for 24 hours to afford 59 mg (0.10 mmol, 58%) of the desired compound.

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.15 (s, 3 H), 2.19 (s, 3 H), 5.34 (s, 2 H), 7.14-7.21 (m, 2 H), 7.30 (d, 1 H), 7.51 (t, 1 H), 8.30 (d, 1 H), 8.38-8.45 (m, 2 H), 10.24 (s, 1 H).

Example 94 6,8-Dichloro-N-[1-(2-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline- 4-carboxamide

In a manner similar to Example 1), 50 mg (0.23 mmol) of 1-(2-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 3C) with 85 mg (0.27 mmol) 6,8-Dichloro-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 11A), 60 μL (0.34 mmol) N , N -diisopropylethylamine and 110 mg (0.34) The TBTU of 5 mL of tetrahydrofuran was stirred at 25 ° C for 24 hours to give 74 mg (0.14 mmol, 63%) of the desired compound.

1H NMR (400MHz, DMSO d ₆ ): δ (ppm) = 2.13 (s, 3 H), 2.23 (s, 3 H), 5.30 (s, 2 H), 7.06 (td, 1 H), 7.16-7.25 (m, 2 H), 7.33 - 7.41 (m, 1 H), 8.30 (d, 1 H), 8.40 (d, 1 H), 8.42 (s, 1 H), 10.21 (s, 1 H).

Example 95 N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-3-methoxy-2-methylquinoline-4- Formamide

Dissolve 50 mg (0.23 mmol) of 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazole-4-amine (Intermediate 1C) in 2 mL of N,N -dimethylformamidine In the amine. 64 mg (0.29 mmol) of 3-methoxy-2-methylquinoline-4-carboxylic acid ( J. Chem. Soc. 1963 , pp. 491-497), 60 μL (0.34 mmol) of N , N -diisopropyl Ethylethylamine, 218 mg (1.14 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 52 mg (0.34 mmol) of 1-hydroxy-1H-benzotriazole (Single) hydrate and the reaction mixture was stirred at 25 ° C for 24 hours. The reaction mixture was partitioned between dichloromethane and water. The layers were separated and the organic layer was washed w... The residue was purified by EtOAc EtOAc (EtOAc)

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.17 (s, 3 H), 2.21 (s, 3 H), 2.67 (s, 3 H), 3.93 (s, 3 H), 5.24 (s) , 2 H), 7.14-7.30 (m, 4 H), 7.57-7.66 (m, 1 H), 7.66-7.74 (m, 1 H), 7.76-7.82 (m, 1 H), 7.98 (d, 1) H), 9.92 (s, 1 H).

Example 96 N-[1-(2,4-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2,6-dimethylquinolin-4- Formamide

50 mg (0.21 mmol) of 1-(2,4-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 5C) in a similar manner to Example 41) With 5 mg of tetrahydrofuran containing 51 mg (0.25 mmol) of 2,6-dimethylquinoline-4-carboxylic acid, 55 μL (0.32 mmol) of N , N -diisopropylethylamine and 165 mg (0.32 mmol) of PyBOP at 25 ° C After stirring for 24 hours, 34 mg (0.08 mmol, 38%) of desired title compound was obtained after preparative HPLC (Method 3).

1H NMR (400MHz, DMSO d ₆ ): δ (ppm) = 2.12 (s, 3 H), 2.22 (s, 3 H), 2.71 (s, 3 H), 5.25 (s, 2 H), 7.05-7.22 (m, 2 H), 7.25-7.33 (m, 1 H), 7.58-7.66 (m, 2 H), 7.85-7.94 (m, 2 H), 9.87 (s, 1 H).

Example 97 6-bromo-N-[1-(3-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl) Quinoline-4-carboxamide

In a manner similar to Example 1), 50 mg (0.21 mmol) of 1-(3-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 12C) Containing 83 mg (0.26 mmol) of 6-bromo-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 1A), 56 μL (0.32 mmol) of N , N -diisopropylethylamine and 104 mg (0.32 mmol) The TBTU of 5 mL of tetrahydrofuran was stirred at 25 ° C for 24 hours to obtain 77 mg (0.14 mmol, 65%) of desired title compound after preparative HPLC (Method 3).

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.16 (s, 3 H), 2.18 (s, 3 H), 3.73 (s, 3 H), 5.23 (s, 2 H), 6.68-6. (m, 2 H), 6.82-6.89 (m, 1 H), 7.27 (t, 1 H), 8.12-8.19 (m, 1 H), 8.23 (d, 1 H), 8.30 (s, 1 H) , 8.50 (d, 1 H), 10.18 (s, 1 H).

Example 98 N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2,6-bis(trifluoromethyl)quinoline- 4-carboxamide

In a manner similar to Example 1), 50 mg (0.23 mmol of 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 1C) and 106 mg ( 0.27 mmol, 80%) 2,6-bis(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 23A), 60 μL (0.34 mmol) N , N -diisopropylethylamine and 110 mg (0.34 mmol) The TBTU of 3 mL of tetrahydrofuran was stirred at 25 °C for 24 hours to give 59 mg (0.11 mmol, 49%) of the desired compound.

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.15 (s, 3 H), 2.20 (s, 3 H), 5.25 (s, 2 H), 7.10-7.30 (m, 4 H), 8.28 (dd, 1 H), 8.42 (s, 1 H), 8.51 (d, 1 H), 8.70 (s, 1 H), 10.22 (s, 1 H).

Example 99 2-Chloro-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-4-carboxamide

In a manner similar to Example 1), 100 mg (0.45 mmol) of 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 1C) with 114 mg (0.55 mmol) 2-chloroquinoline-4-carboxylic acid, 119 μL (0.68 mmol) of N , N -diisopropylethylamine and 220 mg (0.68 mmol) of TBTU in 5 mL of tetrahydrofuran were stirred at 25 ° C for 3 hours. The reaction mixture was evaporated and the residue was partitioned betweenEtOAc and water. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate The residue was dissolved in dichloromethane and adsorbed on Isolute® HM-N (Biotage) under evaporation. The isolute was applied to a Biotage snap cartridge (25 g; KP-Sil) pre-equilibrated with hexane and purified by cartridge chromatography (solvent: hexane / 0-100% ethyl acetate) to give 65 mg. (0.15 mmol, 33%) of the desired compound.

1H NMR (400MHz, DMSO d ₆ ): δ (ppm) = 2.14 (s, 3 H), 2.19 (s, 3 H), 5.24 (s, 2 H), 7.15-7.27 (m, 4 H), 7.76 (ddd, 1 H), 7.84 (s, 1 H), 7.90 (ddd, 1 H), 8.05 (d, 1 H), 8.14 - 8.19 (m, 1 H), 10.02 (s, 1 H).

Example 100 7-Bromo-2-cyclopropyl-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-4-methyl Guanamine

In a manner similar to Example 1), 50 mg (0.23 mmol of 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 1C) and 80 mg ( 0.27 mmol) 7-bromo-2-cyclopropylquinoline-4-carboxylic acid (intermediate 29A), 60 μL (0.34 mmol) of N , N -diisopropylethylamine and 110 mg (0.34 mmol) of TBTU in 3 mL of tetrahydrofuran After stirring for 24 hours at 25 ° C, 75 mg (0.11 mmol, 66%) of desired title compound was obtained after preparative HPLC (Method 3).

1H NMR (400MHz, DMSO d ₆ ): δ (ppm) = 1.08-1.19 (m, 4 H), 2.12 (s, 3 H), 2.16 (s, 3 H), 2.36-2.44 (m, 1 H) , 5.24 (s, 2 H), 7.08-7.30 (m, 4 H), 7.63-7.77 (m, 2 H), 8.04 (d, 1 H), 8.11 (d, 1 H), 9.91 (s, 1) H).

Example 101 N-[3,5-Dimethyl-1-(3-methylbenzyl)-1H-pyrazol-4-yl]-2,6-dimethylquinoline-4-methyl Guanamine

In a manner similar to Example 1), 50 mg (0.23 mmol of 3,5-dimethyl-1-(3-methylbenzyl)-1H-pyrazol-4-amine (Intermediate 14C) with 56 mg (0.28 mmol) 2,6-dimethylquinoline-4-carboxylic acid, 61 μL (0.35 mmol) of N , N -diisopropylethylamine and 112 mg (0.35 mmol) of TBTU in 5 mL of tetrahydrofuran were stirred at 25 ° C. An hour was obtained to give 43 mg (0.11 mmol, 46%)

1H NMR (400MHz, DMSO d ₆ ): δ (ppm) = 2.14 (s, 3 H), 2.17 (s, 3 H), 2.29 (s, 3 H), 2.69 (s, 3 H), 5.20 (s) , 2 H), 6.96 (d, 1 H), 7.04 (s, 1 H), 7.10 (d, 1 H), 7.24 (t, 1 H), 7.56 (s, 1 H), 7.61 (dd, 1 H), 7.86-7.91 (m, 2 H), 9.83 (s, 1 H).

Example 102 8-cyano-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-6-methyl-2-(trifluoro Methyl)quinoline-4-carboxamide

In a manner similar to Example 80, containing 100 mg (0.19 mmol) of 8-bromo-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl] Add 24 mg (0.21 mmol) of degassed 2.3 mL of N , N -dimethylformamide to -6-methyl-2-(trifluoromethyl)quinoline-4-carboxamide (Example 21) Zinc cyanide and 22 mg (0.02 mmol) of ruthenium (triphenylphosphine)palladium(0) were heated in a microwave at 150 °C for 10 minutes. The reaction suspension was poured onto a two-phase mixture of water and ethyl acetate and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate The residue was dissolved in 2.5mL N, N - and purified (Method 3) via preparative HPLC in dimethylformamide to obtain 20mg (0.04mmol, 22%) the desired title compound after drying.

1H NMR (400MHz, DMSO d ₆ ): δ (ppm) = 2.15 (s, 3 H), 2.20 (s, 3 H), 2.60 (s, 3 H), 5.25 (s, 2 H), 7.16-7.28 (m, 4 H), 8.35 (s, 1 H), 8.37 (s, 1 H), 8.53 (d, 1 H), 10.16 (s, 1 H).

Example 103 6-Cyano-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quina Porphyrin-4-carboxamide

In a manner similar to Example 80, containing 100 mg (0.19 mmol) of 6-bromo-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl] 2- (trifluoromethyl) quinoline-4-acyl-amine (example 9) was degassed of 2.4mL N, N - dimethylformamide was added in 25mg (0.21mmol) and 22mg zinc cyanide (0.02 mmol) hydrazine (triphenylphosphine) palladium (0) and the reaction mixture was heated in a microwave at 150 ° C for 10 min. The reaction suspension was poured onto a two-phase mixture of water and ethyl acetate and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate The residue was dissolved in 2.5mL N, N - and purified (Method 3) via preparative HPLC in dimethylformamide to obtain 45mg (0.10mmol, 50%) the desired title compound after drying.

1H NMR (400MHz, DMSO d ₆ ): δ (ppm) = 2.16 (s, 3 H), 2.20 (s, 3 H), 5.26 (s, 2 H), 7.15-7.28 (m, 4 H), 8.31 (dd, 1 H), 8.40 (s, 1 H), 8.45 (d, 1 H), 8.83 (d, 1 H), 10.22 (s, 1 H).

Example 104 6,8-Dichloro-N-[1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl) Quinoline-4-carboxamide

In a manner similar to Example 1), 50 mg (0.23 mmol of 1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 2C) with 85 mg ( 0.27 mmol) 6,8-dichloro-2-(trifluoromethyl)quinoline-4-carboxylic acid (intermediate 11A), 60 μL (0.34 mmol) N , N -diisopropylethylamine and 110 mg (0.34 mmol) The TBTU of 5 mL of tetrahydrofuran was stirred at 25 ° C for 24 hours to obtain 77 mg (0.15 mmol, 65%) of the desired title compound after preparative HPLC (Method 3).

1H NMR (400MHz, DMSO d ₆ ): δ (ppm) = 2.16 (s, 3 H), 2.19 (s, 3 H), 5.29 (s, 2 H), 6.90-6.98 (m, 1 H), 7.01 (d, 1 H), 7.13 (td, 1 H), 7.41 (td, 1 H), 8.31 (d, 1 H), 8.40 (d, 1 H), 8.42 (s, 1 H), 10.22 (s) , 1 H).

Example 105 N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-methylquinoline-4-carboxamide

In a manner similar to Example 1), 150 mg (0.68 mmol) of 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 1C) with 154 mg (0.82 mmol) 2-methylquinoline-4-carboxylic acid, 179 μL (1.03 mmol) of N , N -diisopropylethylamine and 329 mg (1.03 mmol) of TBTU in 5 mL of tetrahydrofuran were stirred at 25 ° C for 2 hours. The reaction mixture was evaporated and the residue was partitioned betweenEtOAc and water. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate The residue was dissolved in dichloromethane and adsorbed on Isolute® HM-N (Biotage) under evaporation. Isolute was applied to a Biotage snap-on cartridge (25 g; KP-Sil) pre-equilibrated with hexane and purified by silica gel column chromatography (solvent: ethyl acetate / 0-20% methanol) to yield 237 mg ( 0.61 mmol, 89%) of the desired compound.

1H NMR (300MHz, CDCl ₃ ): δ (ppm) = 2.23 (s, 3 H), 2.31 (s, 3 H), 2.81 (s, 3 H), 5.24 (s, 2 H), 6.98-7.08 ( m, 2 H), 7.11-7.23 (m, 3 H), 7.48 (s, 1 H), 7.55-7.64 (m, 1 H), 7.72-7.81 (m, 1 H), 8.07-8.15 (m, 1 H), 8.25 (d, 1 H).

Example 106 6,7-Dichloro-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl) Quinoline-4-carboxamide

In a manner similar to Example 1), 50 mg (0.23 mmol) of 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 1C) and 5 , 84 mg (0.27 mmol) of 6-dichloro-2-(trifluoromethyl)quinoline-4-carboxylic acid and 6,7-dichloro-2-(trifluoromethyl)quinoline-4-carboxylic acid ( 3:1) (Intermediate 15A), 60 μL (0.34 mmol) of N , N -diisopropylethylamine and 109 mg (0.34 mmol) of TBTU in 5 mL of tetrahydrofuran were stirred at 25 ° C for 24 hours to prepare HPLC. After the method 6), 23 mg (0.04 mmol, 20%) Further, after preparative HPLC, 32 mg (0.06 mmol, 27%) of 5,6-dichloro-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyridyl was isolated. Zol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide (Example 22).

1H NMR (400MHz, DMSO d ₆ ): δ (ppm) = 2.14 (s, 3 H), 2.19 (s, 3 H), 5.25 (s, 2 H), 7.13 - 7.28 (m, 4 H), 8.33 (s, 1 H), 8.57 (s, 1 H), 8.65 (s, 1 H), 10.19 (s, 1 H).

Example 107 N-{3,5-Dimethyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrazol-4-yl}-2,6-dimethylquina Porphyrin-4-carboxamide

50 mg (0.19 mmol) of 3,5-dimethyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrazole-4-amine (intermediate) in a similar manner to Example 1) 22C) together with 5 mL of tetrahydrofuran containing 44 mg (0.22 mmol) of 2,6-dimethylquinoline-4-carboxylic acid, 49 μL (0.28 mmol) of N , N -diisopropylethylamine and 89 mg (0.28 mmol) of TBTU After stirring for 3 hours at 25 ° C, 58 mg (0.12 mmol, 67%) of desired title compound was obtained after preparative HPLC (Method 3).

1H NMR (400MHz, DMSO d ₆ ): δ (ppm) = 2.14 (s, 3 H), 2.17 (s, 3 H), 2.68 (s, 3 H), 5.36 (s, 2 H), 7.37 (d) , 2 H), 7.56 (s, 1 H), 7.60 (dd, 1 H), 7.74 (d, 2 H), 7.85-7.91 (m, 2 H), 9.86 (s, 1 H).

Example 108 2-cyclopropyl-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-8-(trifluoromethyl) Quinoline-4-carboxamide

In a manner similar to Example 1), 50 mg (0.23 mmol) of 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 1C) with 77 mg (0.27 mmol) 2-cyclopropyl-8-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 36A), 60 μL (0.34 mmol) N , N -diisopropylethylamine and 110 mg (0.34 mmol) The TBTU of 5 mL of tetrahydrofuran was stirred at 25 ° C for 24 hours to obtain 92 mg (0.18 mmol, 80%) of the desired title compound after preparative HPLC (Method 3).

1H NMR (400MHz, DMSO d ₆ ): δ (ppm) = 1.11-1.22 (m, 4 H), 2.15 (s, 3 H), 2.19 (s, 3 H), 2.40-2.47 (m, 1 H) , 5.25 (s, 2 H), 7.13 - 7.29 (m, 4 H), 7.69 (t, 1 H), 7.84 (s, 1 H), 8.16 (d, 1 H), 8.35 (d, 1 H) , 9.94 (s, 1 H).

Example 109 N-[1-(3-Methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2,6-dimethylquinolin-4- Formamide

In a manner similar to Example 1), 50 mg (0.22 mmol) of 1-(3-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 12C) Containing 52 mg (0.26 mmol) of 2,6-dimethylquinoline-4-carboxylic acid, 56 μL (0.32 mmol) of N , N -diisopropylethylamine and 104 mg (0.32 mmol) of TBTU in 5 mL of tetrahydrofuran at 25 ° C After stirring for 24 hours, 52 mg (0.12 mmol, 57%) of desired title compound was obtained after preparative HPLC (Method 3).

1H NMR (400MHz, DMSO d ₆ ): δ (ppm) = 2.15 (s, 3 H), 2.17 (s, 3 H), 2.69 (s, 3 H), 3.73 (s, 3 H), 5.22 (s) , 2 H), 6.70-6.76 (m, 2 H), 6.83-6.89 (m, 1 H), 7.27 (t, 1 H), 7.57 (s, 1 H), 7.61 (dd, 1 H), 7.86 -7.92 (m, 2 H), 9.84 (s, 1 H).

Example 110 N-[3,5-Dimethyl-1-(pyridin-2-ylmethyl)-1H-pyrazol-4-yl]-2-methoxyquinoline-4-carboxamidine amine

In a manner similar to Example 1), 50 mg (0.25 mmol) of 3,5-dimethyl-1-(pyridin-2-ylmethyl)-1H-pyrazol-4-amine (Intermediate 18C) 60 mg (0.30 mmol) of 2-methoxyquinoline-4-carboxylic acid, 65 μL (0.37 mmol) of N , N -diisopropylethylamine and 119 mg (0.37 mmol) of TBTU in 5 mL of tetrahydrofuran were stirred at 25 ° C for 24 hours. Thus, after preparative HPLC (Method 3), 64 mg (0.16 mmol, 66%)

1H NMR (400MHz, DMSO d ₆ ): δ (ppm) = 2.12 (s, 3 H), 2.21 (s, 3 H), 4.05 (s, 3 H), 5.33 (s, 2 H), 7.03 (d) , 1 H), 7.23 (s, 1 H), 7.29-7.34 (m, 1 H), 7.52 (td, 1 H), 7.74 (td, 1 H), 7.79 (td, 1 H), 7.86 (d) , 1 H) 8.06 (d, 1 H), 8.52 - 8.56 (m, 1 H), 9.91 (s, 1 H).

Example 111 N-[3,5-Dimethyl-1-(2-methylbenzyl)-1H-pyrazol-4-yl]-2,6-dimethylquinoline-4-methyl Guanamine

In a manner similar to Example 1), 50 mg (0.23 mmol) of 3,5-dimethyl-1-(2-methylbenzyl)-1H-pyrazol-4-amine (Intermediate 15C) 56 mg (0.28 mmol) of 2,6-dimethylquinoline-4-carboxylic acid, 61 μL (0.35 mmol) of N , N -diisopropylethylamine and 112 mg (0.35 mmol) of TBTU in 5 mL of tetrahydrofuran were stirred at 25 ° C 24 hours. The reaction mixture was evaporated and acetonitrile was added. The precipitated product was isolated by EtOAc (EtOAc) elute

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.15 (s, 6 H), 2.35 (s, 3 H), 2.70 (s, 3 H), 5.25 (s, 2 H), 6.61 (d) , 1 H), 7.09-7.24 (m, 3 H), 7.57-7.66 (m, 2 H), 7.85-7.94 (m, 2 H), 9.89 (s, 1 H).

Example 112 N-[1-(2-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2,6-dimethylquinoline-4-carboxamidine amine

In a manner similar to Example 1), 50 mg (0.23 mmol) of 1-(2-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 3C) with 55 mg (0.27 mmol) 2,6-dimethylquinoline-4-carboxylic acid, 60 μL (0.34 mmol) of N , N -diisopropylethylamine and 110 mg (0.34 mmol) of TBTU in 5 mL of tetrahydrofuran were stirred at 25 ° C. An hour, whereby 28 mg (0.06 mmol, 30%) of the desired compound was obtained after preparative HPLC (Method 3).

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.13 (s, 3 H), 2.22 (s, 3 H), 2.70 (s, 3 H), 5.29 (s, 2 H), 7.03-7.11 (m, 1 H), 7.14-7.30 (m, 2 H), 7.33-7.43 (m, 1 H), 7.57 (s, 1 H), 7.61 (dd, 1 H), 7.85-7.93 (m, 2) H), 9.85 (s, 1 H).

Example 113 6-Bromo-N-{3,5-dimethyl-1-[3-(trifluoromethoxy)benzyl]-1H-pyrazol-4-yl}-2-(trifluoro Methyl)quinoline-4-carboxamide

In a manner similar to Example 1), 100 mg (0.18 mmol, 50%) of 3,5-dimethyl-1-[3-(trifluoromethoxy)benzyl]-1H-pyrazole-4- Amine (Intermediate 20C) with 67 mg (0.21 mmol) of 6-bromo-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 1A), 46 μL (0.26 mmol) N , N -diisopropyl Ethylamine and 84 mg (0.26 mmol) of TBTU in 3 mL of THF were stirred at 25 ° C for 24 hours to afford 76 mg (0.13 mmol

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.16 (s, 3 H), 2.20 (s, 3 H), 5.34 (s, 2 H), 7.13 - 7.22 (m, 2 H), 7.32 (s, 1 H), 7.47-7.56 (m, 1 H), 8.11-8.19 (m, 1 H), 8.23 (d, 1 H), 8.31 (s, 1 H), 8.50 (d, 1 H) , 10.20 (s, 1 H).

Example 114 N-[1-(2-Cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2,6-dimethylquinoline-4-methyl Guanamine

In a manner similar to Example 1), 50 mg (0.22 mmol) of 2-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]benzonitrile (intermediate) 10C) together with 5 mL of tetrahydrofuran containing 53 mg (0.27 mmol) of 2,6-dimethylquinoline-4-carboxylic acid, 58 μL (0.33 mmol) of N , N -diisopropylethylamine and 106 mg (0.33 mmol) of TBTU After stirring for 24 hours at 25 ° C, 54 mg (0.13 mmol, 59%) of desired title compound was obtained after preparative HPLC (Method 3).

1H NMR (400MHz, DMSO d ₆ ): δ (ppm) = 2.13 (s, 3 H), 2.25 (s, 3 H), 2.70 (s, 3 H), 5.44 (s, 2 H), 7.11 (d) , 1 H), 7.50-7.56 (m, 1 H), 7.58 (s, 1 H), 7.61 (dd, 1 H), 7.72 (td, 1 H), 7.87-7.93 (m, 3 H), 9.90 (s, 1 H).

Example 115 N-{3,5-Dimethyl-1-[3-(trifluoromethoxy)benzyl]-1H-pyrazol-4-yl}-2-methoxyquin Porphyrin-4-carboxamide

In a manner similar to Example 1), 100 mg (0.18 mmol, 50%) of 3,5-dimethyl-1-[3-(trifluoromethoxy)benzyl]-1H-pyrazole-4- Amine (Intermediate 20C) with 3 mg of tetrahydrofuran containing 43 mg (0.21 mmol) of 2-methoxyquinoline-4-carboxylic acid, 46 μL (0.26 mmol) of N , N -diisopropylethylamine and 84 mg (0.26 mmol) of TBTU The mixture was stirred at 25 ° C for 24 hours to give 68 mg (0.14 mmol, 81%) of the desired compound.

1H NMR (300MHz, DMSO d ₆ ): δ (ppm) = 2.14 (s, 3 H), 2.17 (s, 3 H), 4.04 (s, 3 H), 5.33 (s, 2 H), 7.13-7.20 (m, 2 H), 7.23 (s, 1 H), 7.30 (d, 1 H), 7.46-7.55 (m, 2 H), 7.69-7.77 (m, 1 H), 7.86 (d, 1 H) , 8.05 (d, 1 H), 9.92 (s, 1 H).

Example 116 6-bromo-N-{3,5-dimethyl-1-[(3-methylpyridin-2-yl)methyl]-1H-pyrazol-4-yl}-2-(three Fluoromethyl)quinoline-4-carboxamide

In a manner similar to Example 1), 50 mg (0.23 mmol) of 3,5-dimethyl-1-[(3-methylpyridin-2-yl)methyl]-1H-pyrazol-4-amine ( Intermediate 36C) with 89 mg (0.28 mmol) of 6-bromo-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 1A), 60 μL (0.35 mmol) of N , N -diisopropylethylamine The mixture was stirred at 25 ° C for 24 hours with 111 mg (0.35 mmol) of TBTU in 5 mL of tetrahydrofuran. The reaction mixture was evaporated and dissolved in 2.5 mL of N,N -dimethylformamide to precipitate the desired product. The suspension was filtered and the precipitate was washed with EtOAc (EtOAc) elute

1H NMR (400MHz, DMSO d ₆ ): δ (ppm) = 2.15 (s, 3 H), 2.24 (s, 3 H), 2.47 (s, 3 H), 5.29 (s, 2 H), 6.73 (d) , 1 H), 7.17 (d, 1 H), 7.67 (t, 1 H), 8.15 (dd, 1 H), 8.23 (d, 1 H), 8.30 (s, 1 H), 8.52 (d, 1) H), 10.19 (s, 1 H).

Example 117 N-{3,5-Dimethyl-1-[3-(trifluoromethoxy)benzyl]-1H-pyrazol-4-yl}-2,6-dimethyl Quinoline-4-carboxamide

In a manner similar to Example 1), 100 mg (0.18 mmol, 50%) of 3,5-dimethyl-1-[3-(trifluoromethoxy)benzyl]-1H-pyrazole-4- Amine (Intermediate 20C) with 42 mg (0.21 mmol) of 2,6-dimethylquinoline-4-carboxylic acid, 46 μL (0.26 mmol) of N , N -diisopropylethylamine and 84 mg (0.26 mmol) of TBTU 3 mL of tetrahydrofuran were stirred at 25 ° C for 24 hours to give 65 mg (0.14 mmol, 79%) of the desired title compound after preparative HPLC (Method 3).

1H NMR (400MHz, DMSO d ₆ ): δ (ppm) = 2.15 (s, 3 H), 2.18 (s, 3 H), 2.69 (s, 3 H), 5.33 (s, 2 H), 7.15-7.21 (m, 2 H), 7.30 (d, 1 H), 7.51 (t, 1 H), 7.55-7.63 (m, 2 H), 7.86-7.92 (m, 2 H), 9.86 (s, 1 H) .

Example 118 6-Bromo-N-[1-(2-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(propan-2-yl)quinoline- 4-carboxamide

a solution of 75 mg (0.26 mmol) of 2-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]benzonitrile (Intermediate 10C) in 2.1 mL DMSO 145 mg (0.31 mmol) of HATU, 67 μL of N , N -diisopropylethylamine and 69 mg (0.31 mmol) of 6-bromo-2-isopropylquinoline-4-carboxylic acid were added thereto. The reaction mixture was stirred at 25 ° C for 20 hours. This mixture was directly purified by preparative HPLC (Method 4) to give 115 mg (85%) of

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 1.36 (d, 6H), 2.12 (s, 3H), 2.24 (s, 3H), 3.28 (q, 1H), 5.43 (s, 2H) , 7.09 (d, 1H), 7.49-7.55 (m, 1H), 7.71 (td, 1H), 7.76 (s, 1H), 7.87-7.93 (m, 2H), 7.95-8.00 (m, 1H), 8.33 (d, 1H), 10.00 (s, 1H).

Example 119 6-bromo-N ⁴ -[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine

85.4 mg (0.39 mmol) of 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 1C) and 106 mg were obtained in a manner similar to Example 118) (0.36 mmol) 6-Bromo-2-amine-methylpyridylquinoline-4-carboxylic acid (Intermediate 2A) was obtained to give 26 mg (15%) of desired compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.13 (s, 3H), 2.17 (s, 3H), 5.24 (s, 2H), 7.14-7.30 (m, 4H), 7.94 (s, 1H), 8.04-8.11 (m, 1H), 8.14 (d, 1H), 8.35 (s, 1H), 8.42 (s, 1H), 8.47 (d, 1H), 10.16 (s, 1H).

Example 120 6,7-difluoro-N ⁴ -[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-2,4-dimethyl Guanamine

49.6 mg (0.23 mmol) of 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 1C) and 190 mg were obtained in a similar manner to Example 118) (0.19mmol, purity 25%) 2-Aminoformamido-6,7-difluoroquinoline-4-carboxylic acid (Intermediate 3A) is reacted to give 6.4 mg (7%) after purification via preparative HPLC (Method 4) Title compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.12 (s, 3H), 2.16 (s, 3H), 5.24 (s, 2H), 7.12-7.30 (m, 4H), 7.96 (br. s., 1H), 8.11-8.29 (m, 2H), 8.32-8.42 (m, 2H), 10.17 (s, 1H).

Example 121 6-Chloro-7-fluoro-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl) Quinoline-4-carboxamide

In a similar manner to Example 118), 110 mg (0.50 mmol) of 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 1C) and 150 mg ( 0.42 mmol, purity 825%) 6-chloro-7-fluoro-2-(trifluoromethyl)oxazoline-4-carboxylic acid (Intermediate 10A) was reacted, after purification via preparative HPLC (Method 3) 87 mg (40%) of the desired compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.13 (s, 3H), 2.18 (s, 3H), 5.24 (s, 2H), 7.13 - 7.28 (m, 4H), 8.30 (s, 1H), 8.36 (d, 1H), 8.52 (d, 1H), 10.20 (s, 1H).

Example 122 N ⁴ -[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine

In a similar manner to Example 118), 121 mg (0.56 mmol) of 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 1C) and 100 mg ( 0.42 mmol, purity 82%) 2-Aminoformylquinoline-4-carboxylic acid (Intermediate 4A) was reacted to give 64 mg (30%) of desired title compound after purified by preparative HPLC (Method 3).

¹ H-NMR (300 MHz, DMSO d ₆ ) δ (ppm) = 2.14 (s, 3H), 2.18 (s, 3H), 5.24 (s, 2H), 7.13 - 7.29 (m, 4H), 7.76 - 7.85 ( m, 1H), 7.88-7.97 (m, 2H), 8.16-8.29 (m, 3H), 8.39 (br.s., 1H), 10.06 (s, 1H).

Example 123 6-bromo-2-cyclopropyl-N-[1-(3,4-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline- 4-carboxamide

97 mg (0.41 mmol) of 1-(3,4-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 4C) was obtained in a procedure analogous to Example 118) And 100 mg (0.34 mmol) of 6-bromo-2- Cyclopropylquinoline-4-carboxylic acid was reacted to give 103 mg (56%) of desired compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 1.07-1.20 (m, 4H), 2.13 (s, 3H), 2.17 (s, 3H), 2.34 - 2.45 (m, 1H), 5.25 ( s, 2H), 7.01 (dd, 1H), 7.17-7.28 (m, 1H), 7.43 (dt, 1H), 7.72 (s, 1H), 7.86 (d, 2H), 8.28 (s, 1H), 9.98 (s, 1H).

Example 124 6-bromo-7-fluoro-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl) Quinoline-4-carboxamide

93.4 mg (0.43 mmol) of 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 1C) and 150 mg were obtained in a similar manner to Example 118) (0.36 mmol, purity 80%) of 6-bromo-7-fluoro-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 9A), after purification via preparative HPLC (Method 4) 89.8 mg (45%) of the desired compound are obtained.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.14 (s, 3H), 2.18 (s, 3H), 5.24 (s, 2H), 7.12-7.28 (m, 4H), 8.25-8.34 ( m, 2H), 8.67 (d, 1H), 10.20 (s, 1H).

Example 125 6-Chloro-2-cyclopropyl-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-4-methyl Guanamine

In a similar manner to Example 118), 73 mg (0.33 mmol) of 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 1C) and 75 mg ( 0.30 mmol, purity 80%) 6-chloro-2-cyclopropylquinoline-4-carboxylic acid (Intermediate 24A) was reacted to give 71 mg (48%) of desired title after purification by preparative HPLC (Method 3) Compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 1.08-1.18 (m, 4H), 2.12 (s, 3H), 2.16 (s, 3H), 2.35-2.43 (m, 1H), 5.23 ( s, 2H), 7.15-7.26 (m, 4H), 7.72 (s, 1H), 7.75 (dd, 1H), 7.93 (d, 1H), 8.12 (d, 1H), 9.94 (s, 1H).

Example 126 N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-di Formamide

109 mg (0.39 mmol) of 4-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl} was obtained in a manner analogous to Example 118) Benzoonitrile (Intermediate 26C) and 70 mg (0.32 mmol) of 2-aminopyridylquinoline-4-carboxylic acid (Intermediate 4A) were reacted to give 42 mg (26) after purification by preparative HPLC (Method 4). %) The desired compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.27 (s, 3H), 5.61 (s, 2H), 7.38 (d, 2H), 7.77-7.86 (m, 1H), 7.86-7.99 ( m, 4H), 8.20 (dd, 2H), 8.26 (s, 1H), 8.40 (s, 1H), 10.43 (s, 1H).

Example 127 6,8-dichloro-N ⁴ -[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-2,4-dimethyl Guanamine

In a similar manner to Example 118), 120 mg (0.55 mmol) of 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 1C) and 145 mg ( 0.46 mmol, purity 90%) 2-aminoformamido-6,8-dichlorozoline-4-carboxylic acid (Intermediate 5A) was reacted to give 7.6 mg after purification by preparative HPLC (Method 3). 3%) of the desired compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.12 (s, 3H), 2.17 (s, 3H), 5.24 (s, 2H), 7.13 - 7.29 (m, 4H), 8.13 (d, 2H), 8.24-8.28 (m, 1H), 8.28-8.32 (m, 1H), 8.44 (s, 1H), 10.23 (s, 1H).

Example 128 N ⁴ -[1-(3,4-difluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4- Dimethylamine

In a similar manner to Example 118), 113 mg (0.39 mmol) of 1-(3,4-difluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole-4- The amine (intermediate 23C) and 70 mg (0.32 mmol) of 2-aminopyridinium quinoline-4-carboxylic acid (Intermediate 4A) were reacted to give 50 mg (29%) after purification by preparative HPLC (Method 4) The title compound is desired.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.32 (s, 3H), 5.48 (s, 2H), 7.15 (tt, 1H), 7.27-7.37 (m, 2H), 7.77-7.86 ( m, 1H), 7.90 (s, 1H), 7.91-7.97 (m, 1H), 8.20 (t, 2H), 8.26 (s, 1H), 8.38 (s, 1H), 10.38 (s, 1H).

Example 129 6-Bromo-N-[1-(3,4-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(propan-2-yl)quina Porphyrin-4-carboxamide

96.8 mg (0.41 mmol) of 1-(3,4-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 4C) was obtained in a similar manner to Example 118) Reaction with 100 mg (0.34 mmol) of 6-bromo-2-isopropylquinoline-4-carboxylic acid afforded 124 mg (64%) of desired compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 1.36 (d, 6H), 2.14 (s, 3H), 2.17 (s, 3H), 3.28 (q, 1H), 5.25 (s, 2H) , 7.01 (ddd, 1H), 7.17-7.25 (m, 1H), 7.43 (dt, 1H), 7.74 (s, 1H), 7.90 (dd, 1H), 7.97 (d, 1H), 8.32 (d, 1H) ), 9.96 (s, 1H).

Example 130 N ⁴ -[1-(4-fluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethyl Guanamine

In a manner similar to Example 118), 114 mg (0.42 mmol) of 1-(4-fluorophenyl) 5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-amine (Intermediate 25C) and 75 mg (0.35 mmol) 2-aminopyridylquinoline-4-carboxylic acid (middle The reaction of the compound 4A) gave 50 mg (27%) of the desired compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.28 (s, 3H), 5.46 (s, 2H), 7.19-7.37 (m, 4H), 7.77-7.86 (m, 1H), 7.88- 7.99 (m, 2H), 8.15-8.24 (m, 2H), 8.25 (s, 1H), 8.40 (s, 1H), 10.39 (s, 1H).

Example 131 4-{[4-({[6-bromo-2-(trifluoromethyl)quinolin-4-yl]carbonyl}amino)-3,5-dimethyl-1H-pyrazole- Methyl 1-methyl]methyl}benzoate

In a manner similar to Example 118), 1.00 g (3.86 mmol) of 4-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]benzoic acid methyl ester ( Intermediate 31C) is reacted with 1.03 g (3.21 mmol) of 6-bromo-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 1A) to give the reaction mixture after stirring, with water and ethyl acetate It is diluted. The resulting solid was isolated by filtration and purified to give 870 mg (45%) of desired compound. The filtrate was evaporated and purified via a Biotage chromatography system (25 g cartridge KP-Sil column, hexane / 0-100% ethyl acetate followed by ethyl acetate / 0-60% methanol) and reacted. 660 mg (33%) of the desired compound are obtained.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.15 (s, 3H), 2.17 (s, 3H), 3.84 (s, 3H), 5.36 (s, 2H), 7.29 (d, 2H) , 7.95 (d, 2H), 8.14 (dd, 1H), 8.22 (d, 1H), 8.29 (s, 1H), 8.50 (d, 1H), 10.19 (s, 1H).

Example 132 4-{[4-({[6-bromo-2-(trifluoromethyl)quinolin-4-yl]carbonyl}amino)-3,5-dimethyl-1H-pyrazole- 1-yl]methyl}benzoic acid

To 720 mg (1.28 mmol) of 4-{[4-({[6-bromo-2-(trifluoromethyl)quinolin-4-yl]carbonyl}amino)-3,5-dimethyl-1H- A solution of 950 mg (23.7 mmol) sodium hydroxide in 21.8 mL of water was added to a solution of pyrazol-1-yl]methyl}benzoic acid methyl ester (Example 131) in 11 mL of methanol and 1 mL THF. This mixture was heated at 40 ° C for 3 hours and evaporated after cooling to 25 ° C. 10 mL of water was added to the residue and then a 10% aqueous solution of sulfuric acid was added until pH 3. The resulting solid was isolated by filtration and dried to give EtOAcjjjjj

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.15 (s, 3H), 2.17 (s, 3H), 5.35 (s, 2H), 7.22-7.32 (m, 2H), 7.89-7.97 ( m, 2H), 8.14 (dd, 1H), 8.22 (d, 1H), 8.29 (s, 1H), 8.50 (d, 1H), 10.19 (s, 1H), 11.28 (s, 1H).

Example 133 6-bromo-N-[1-(4-aminoformamidobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl) Quinoline-4-carboxamide

To a solution of 200 mg (0.36 mmol) of the acid from Example 132) in 1.32 mL of DMSO was added 146 mg (0.38 mmol) of HATU, 74 [mu]L of N , N -diisopropylethylamine and 0.61 mL of 0.5 M ammonia in dioxane. Solution. The reaction mixture was stirred at 25 ° C for 1 hour. This mixture was directly purified via preparative HPLC (Method 3) to afford 43 mg (29%)

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.15 (s, 3H), 2.18 (s, 3H), 5.31 (s, 2H), 7.21. (d, 2H), 7.33 (br.s. , 1H), 7.84 (d, 2H), 7.91 (br.s., 1H), 8.14 (dd, 1H), 8.22 (d, 1H), 8.28 (s, 1H), 8.50 (d, 1H), 10.17 (s, 1H).

Example 134 6-bromo-N-{3,5-dimethyl-1-[4-(phenylamine-mercapto)benzyl]-1H-pyrazol-4-yl}-2-(three Fluoromethyl)quinoline-4-carboxamide

88 mg (0.16 mmol) of the acid from Example 132) and 18 mg (0.19 mmol) of aniline were reacted in a similar manner to Example 133) to afford 59 mg (56%) after purification by preparative HPLC (Method 3) Title compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.16 (s, 3H), 2.20 (s, 3H), 5.36 (s, 2H), 7.04-7.13 (m, 1H), 7.27-7.39 ( m, 4H), 7.75 (d, 2H), 7.92 (d, 2H), 8.14 (dd, 1H), 8.23 (d, 1H), 8.30 (s, 1H), 8.50 (d, 1H), 10.19 (s , 1H), 10.21 (s, 1H).

Example 135 6-bromo-N-{3,5-dimethyl-1-[4-(methylamine-mercapto)benzyl]-1H-pyrazol-4-yl}-2-(three Fluoromethyl)quinoline-4-carboxamide

A solution of 88 mg (0.16 mmol) of the acid from Example 132) and 96 μL (0.19 mmol) of 2M methylamine in THF was reacted in a similar manner to Example 133), after purification by preparative HPLC (Method 3) 60 mg (63%) of the desired title compound are obtained.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.15 (s, 3H), 2.18 (s, 3H), 2.76 (d, 3H), 5.31 (s, 2H), 7.22 (d, 2H) , 7.79 (d, 2H), 8.14 (dd, 1H), 8.22 (d, 1H), 8.29 (s, 1H), 8.39 (q, 1H), 8.50 (d, 1H), 10.18 (s, 1H).

Example 136 6-Bromo-N-[3,5-dimethyl-1-(4-{[2-(morpholin-4-yl)ethyl]aminemethanyl}benzyl)-1H- Pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide

150 mg (0.27 mmol) of the acid from Example 132) and 30 mg (0.23 mmol) of 2-(morpholin-4-yl)ethylamine were reacted in a similar manner to Example 133), thus, via preparative HPLC (Method 3 After purification, 49 mg (63%) of the desired compound was obtained.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.15 (s, 3H), 2.18 (s, 3H), 3.03 - 3.24 (m, 2H), 3.46-3.72 (m, 6H), 4.00 ( d, 2H), 5.33 (s, 2H), 7.29 (d, 2H), 7.84 (d, 2H), 8.15 (dd, 1H), 8.23 (d, 1H), 8.28 (s, 1H), 8.48 (d) , 1H), 10.19 (s, 1H).

Example 137 6-bromo-N-(1-{4-[(2-methoxyethyl)aminemethanyl]benzyl}-3,5-dimethyl-1H-pyrazole- 4-yl)-2-(trifluoromethyl)quinoline-4-carboxamide

88 mg (0.16 mmol) from Example 132) was obtained in a similar manner to Example 133) The acid was reacted with 15 mg (0.19 mmol) of 2-methoxyethylamine to afford 63 mg (yield: 61%).

^{1 H-NMR (300MHz, DMSO} d 6) δ (ppm) = 2.15 (s, 3H), 2.18 (s, 3H), 3.25 (s, 3H), 3.37-3.48 (m, 4H), 5.31 (s, 2H), 7.19-7.27 (m, 2H), 7.77-7.85 (m, 2H), 8.14 (dd, 1H), 8.22 (d, 1H), 8.29 (s, 1H), 8.44 - 8.52 (m, 1H) , 10.18 (s, 1H).

Example 138 6-bromo-N-(3,5-dimethyl-1-{4-[(pyridin-3-ylmethyl)aminemethanyl]benzyl}-1H-pyrazole- 4-yl)-2-(trifluoromethyl)quinoline-4-carboxamide

150 mg (0.27 mmol) of the acid from Example 132) and 25 mg (0.23 mmol) of 1-(pyridin-3-yl)methylamine were reacted in a similar manner to Example 133), thus, via preparative HPLC (Method 3) After purification, 47 mg (36%) of desired title compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.15 (s, 3H), 2.18 (s, 3H), 4.51 (d, 2H), 5.32 (s, 2H), 7.25 (d, 2H) , 7.44 (dd, 1H), 7.77-7.89 (m, 3H), 8.14 (dd, 1H), 8.22 (d, 1H), 8.29 (s, 1H), 8.49 (d, 2H), 8.58 (s, 1H) ), 9.08 (t, 1H), 10.18 (s, 1H).

Example 139 6-bromo-N-(1-{4-[(2-hydroxyethyl)aminemethanyl]benzyl}-3,5-dimethyl-1H-pyrazole-4- 2-(trifluoromethyl)quinoline-4-carboxamide

88 mg (0.16 mmol) of the acid from Example 132) and 12 mg (0.19 mmol) of 2-amino-ethanol were reacted in a similar manner to Example 133) to give 61 mg after purification by preparative HPLC (Method 3) (61%) of the desired compound.

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 2.15 (s, 3H), 2.17 (s, 3H), 3.45-3.53 (m, 2H), 4.72 (br.s., 1H), 5.31 (s, 2H), 7.20-7.25 (m, 2H), 7.79-7.85 (m, 2H), 8.11-8.16 (m, 1H), 8.22 (d, 1H), 8.28 (s, 1H), 8.40 (t , 1H), 8.47-8.51 (m, 1H), 10.20 (s, 1H).

Example 140 N-{1-[4-(benzylaminocarbamoyl)benzyl]-3,5-dimethyl-1H-pyrazol-4-yl}-6-bromo-2- (trifluoromethyl)quinoline-4-carboxamide

88 mg (0.16 mmol) of the acid from Example 132) and 21 mg (0.19 mmol) of benzylamine were reacted in a similar manner to Example 133), thus, via preparative HPLC (Method 3) After purification, 58 mg (54%) of desired title compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.15 (s, 3H), 2.18 (s, 3H), 4.47 (d, 2H), 5.32 (s, 2H), 7.19-7.36 (m, 7H), 7.87 (d, 2H), 8.14 (dd, 1H), 8.22 (d, 1H), 8.29 (s, 1H), 8.50 (d, 1H), 9.01 (t, 1H), 10.18 (s, 1H) ).

Example 141 6-bromo-N-{3,5-dimethyl-1-[4-(morpholin-4-ylcarbonyl)benzyl]-1H-pyrazol-4-yl}-2- (trifluoromethyl)quinoline-4-carboxamide

150 mg (0.27 mmol) of the acid from Example 132) and 20 mg (0.23 mmol) of morpholine were reacted in a manner similar to Example 133) to give 54 mg (44%) after purification by preparative HPLC (Method 3). The title compound is desired.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.15 (s, 3H), 2.19 (s, 3H), 3.36-3.69 (m, 8H), 5.30 (s, 2H), 7.19-7.25 ( m, 2H), 7.37-7.44 (m, 2H), 8.14 (dd, 1H), 8.23 (d, 1H), 8.29 (s, 1H), 8.50 (d, 1H), 10.18 (s, 1H).

Example 142 6-bromo-N-[1-(4-{[2-(dimethylamino)ethyl]aminemethanyl}benzyl)-3,5-dimethyl-1H-pyridyl Zin-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide

88 mg (0.16 mmol) of the acid from Example 132) and 17 mg (0.19 mmol) of N,N-dimethylethane-1,2-diamine were reacted in a similar manner to Example 133). After purification by HPLC (Method 3), 58 mg (56%)

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.15 (s, 3H), 2.18 (s, 3H), 2.82 (s, 6H), 3.22 (t, 2H), 3.58 (q, 2H) , 5.33 (s, 2H), 7.24-7.32 (m, 2H), 7.79-7.86 (m, 2H), 8.14 (dd, 1H), 8.23 (d, 1H), 8.28 (s, 1H), 8.48 (d) , 1H), 8.63 (t, 1H), 10.18 (s, 1H).

Example 143 6-bromo-N-{1-[4-(dimethylaminocarbamimidyl)benzyl]-3,5-dimethyl-1H-pyrazol-4-yl}-2- (trifluoromethyl)quinoline-4-carboxamide

In a similar manner to Example 133), 88 mg (0.16 mmol) of the acid from Example 132) and a solution of 96 μL (0.19 mmol) of 2M dimethylamine in tetrahydrofuran were reacted so that After purification by preparative HPLC (Method 3), 64 mg (65%)

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.15 (s, 3H), 2.19 (s, 3H), 2.89 (s, 3H), 2.96 (s, 3H), 5.30 (s, 2H) , 7.17-7.23 (m, 2H), 7.35-7.42 (m, 2H), 8.14 (dd, 1H), 8.22 (d, 1H), 8.29 (s, 1H), 8.50 (d, 1H), 10.18 (s , 1H).

Example 144 6-bromo-2-cyclobutyl-N-[1-(3,4-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline- 4-carboxamide

93 mg (0.39 mmol) of 1-(3,4-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 4C) was obtained in a manner analogous to Example 118) Reaction with 100 mg (0.33 mmol) of 6-bromo-2-cyclobutylquinoline-4-carboxylic acid (Intermediate 30A), after purification by preparative HPLC (Method 3) to give 53 mg (28%) .

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 1.87-1.97 (m, 1H), 2.03-2.12 (m, 1H), 2.13 (s, 3H), 2.17 (s, 3H), 2.29- 2.47 (m, 4H), 3.90 (q, 1H), 5.25 (s, 2H), 7.01 (ddd, 1H), 7.21 (ddd, 1H), 7.43 (dt, 1H), 7.69 (s, 1H), 7.91 (dd, 1H), 7.99 (d, 1H), 8.32 (d, 1H), 9.96 (s, 1H).

Example 145 6-Chloro-2-cyclopropyl-N-[1-(3,4-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline- 4-carboxamide

86 mg (0.36 mmol) of 1-(3,4-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 4C) was obtained in a procedure similar to Example 118) Reaction with 75 mg (0.30 mmol) of 6-chloro-2-cyclopropylquinoline-4-carboxylic acid (Intermediate 24A) afforded 66 mg (42%) of the desired title compound after purification by preparative HPLC (Method 3) .

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 1.06-1.20 (m, 4H), 2.13 (s, 3H), 2.17 (s, 3H), 2.36-2.43 (m, 1H), 5.25 ( s, 2H), 6.97-7.05 (m, 1H), 7.22 (ddd, 1H), 7.43 (dt, 1H), 7.71-7.78 (m, 2H), 7.93 (d, 1H), 8.12 (d, 1H) , 9.98 (s, 1H).

Example 146 6-bromo-2-cyclobutyl-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-4-methyl Guanamine

67 mg (0.31 mmol) of 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 1C) and 85 mg (85 mg) Reaction of 0.28 mmol) of 6-bromo-2-cyclobutylquinoline-4-carboxylic acid (Intermediate 30A) afforded 82 mg (53%) of desired compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 1.84-1.95 (m, 1H), 2.03-2.11 (m, 1H), 2.11-2.14 (m, 3H), 2.16 (s, 3H), 2.30-2.47 (m, 4H), 3.90 (q, 1H), 5.24 (s, 2H), 7.14-7.27 (m, 4H), 7.68 (s, 1H), 7.90 (dd, 1H), 7.99 (d, 1H), 8.32 (d, 1H), 9.95 (s, 1H).

Example 147 6-bromo-N-{1-[(6-cyanopyridin-3-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-2-(three Fluoromethyl)quinoline-4-carboxamide

In a manner similar to Example 118), 100 mg (0.38 mmol) of 5-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]pyridine-2-carbonitrile (Intermediate 29C) and 100 mg (0.31 mmol) of 6-bromo-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 1A) are reacted, after purification by preparative HPLC (Method 4) 8 mg (4.6%) of the desired compound.

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 2.14 (s, 3H), 2.23 (s, 3H), 5.43 (s, 2H), 7.75 (dd, 1H), 8.05 (d, 1H) , 8.14 (dd, 1H), 8.22 (d, 1H), 8.29 (s, 1H), 8.50 (d, 1H), 8.60 (d, 1H), 10.19 (s, 1H).

Example 148 6-Bromo-N-[1-(4-chlorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-methyl Guanamine

In a similar manner to Example 118), 111 mg (0.47 mmol) of 1-(4-chlorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine ( Intermediate 27C) and 100 mg ( 0.31 mmol) of 6-bromo-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 1A), whereby after purification by preparative HPLC (Method 3), 121 mg (68%) .

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 2.14 (s, 3H), 2.18 (s, 3H), 5.26 (s, 2H), 7.17-7.22 (m, 2H), 7.39-7.45 ( m, 2H), 8.14 (dd, 1H), 8.22 (d, 1H), 8.28 (s, 1H), 8.49 (d, 1H), 10.16 (s, 1H).

Example 149 4-{[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]aminemethanyl}-2-(trifluoromethyl) Methyl quinoline-6-carboxylate

150 mg (0.29 mmol) of 6-bromo-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl) Quinoline-4-carboxamide (Example 9), 35 μL (0.86 mmol) methanol, 114 mg (0.43 mmol) Mo(CO) ₆ (molybdenum hexacarbonyl), 8.35 (0.029 mmol) tri-tert-butylphosphonium tetrafluoroborate 27.0 mg (0.029 mmol) of trans-bis(μ-acetate) bis(di-o-tolylphosphino)benzyl dipalladium(II) and 131 mg (0.86 mmol) of 1,8-diazabicyclo[ 5.4.0] A solution of 11-7-ene in 2.0 mL of THF was heated in a microwave reactor at 125 °C for 20 minutes. This mixture was combined with 500 mg (0.96 mmol) of 6-bromo-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]- from the second experiment. 2-(Trifluoromethyl)quinoline-4-carboxamide (Example 9) was taken up as a second mixture of starting materials on Isolute and passed through a Biotage chromatography system (10 g snap-on KP-Sil column) Purified by hexane/10-70% ethyl acetate. This crude product was purified via EtOAc (EtOAc):

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.17 (s, 3H), 2.21 (s, 3H), 3.94 (s, 3H), 5.25 (s, 2H), 7.13 - 7.29 (m, 4H), 8.34 (s, 1H), 8.35-8.44 (m, 2H), 8.97 (s, 1H), 10.19 (s, 1H).

Example 150 (4-{[4-({[6-Bromo-2-(trifluoromethyl)quinolin-4-yl]carbonyl}amino)-3,5-dimethyl-1H-pyrazole Methyl-1-methyl]methyl}phenyl)acetate

In a manner similar to Example 118), 1.00 g (3.66 mmol) of {4-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]phenyl}acetic acid The methyl ester (intermediate 32C) and 0.98 g (3.05 mmol) of 6-bromo-2-(trifluoromethyl)quinoline-4-carboxylic acid (intermediate 1A) are reacted to give the reaction mixture after stirring, water and acetic acid The ethyl ester was diluted. After phase separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were then washed with brine, dried over sodium sulfate, filtered and evaporated. The crude product was purified via a Biotage chromatography system (25 g, K K-Sil column, hexane / 50-100% ethyl acetate followed by ethyl acetate / 0-90% methanol) to yield 960 mg (50%) The title compound is desired.

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 2.14 (s, 3H), 2.18 (s, 3H), 3.59 (s, 3H), 3.65 (s, 2H), 5.23 (s, 2H) , 7.13 (d, 2H), 7.24 (d, 2H), 8.14 (dd, 1H), 8.22 (d, 1H), 8.27 (s, 1H), 8.50 (d, 1H), 10.14 (s, 1H).

Example 151 (4-{[4-({[6-Bromo-2-(trifluoromethyl)quinolin-4-yl]carbonyl}amino)-3,5-dimethyl-1H-pyrazole-1- Methyl}phenyl)acetic acid

960 mg (1.67 mmol) of 4-{[4-({[6-bromo-2-(trifluoromethyl)quinolin-4-yl]carbonyl}amino)- Reaction of methyl 3,5-dimethyl-1H-pyrazol-1-yl]methyl}phenyl)acetate (Example 150) gave 1.02 g (yield: 95%, purity 95%) of the desired compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.14 (s, 3H), 2.18 (s, 3H), 3.54 (s, 2H), 5.23 (s, 2H), 7.08-7.15 (m, 2H), 7.20-7.27 (m, 2H), 8.14 (dd, 1H), 8.22 (d, 1H), 8.28 (s, 1H), 8.50 (d, 1H), 10.16 (s, 1H), 11.83 (br .s., 1H).

Example 152 N-{1-[4-(2-Amino-2-oxoethyl)benzyl]-3,5-dimethyl-1H-pyrazol-4-yl}-6-bromo-2 -(trifluoromethyl)quinoline-4-carboxamide

100 mg (0.18 mmol) of 4-{[4-({[6-bromo-2-(trifluoromethyl)quinolin-4-yl]carbonyl}amino)- 3,5-Dimethyl-1H-pyrazol-1-yl]methyl}phenyl)acetic acid (Example 151) was reacted to give 44 mg (43%) after purification by preparative HPLC (Method 3) Title compound.

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 2.14 (s, 3H), 2.18 (s, 3H), 3.34 (s, 2H), 5.21 (s, 2H), 6.83 (br.s. , 1H), 7.10 (d, 2H), 7.22 (d, 2H), 7.41 (br.s., 1H), 8.14 (dd, 1H), 8.22 (d, 1H), 8.27 (s, 1H), 8.50 (d, 1H), 10.13 (s, 1H).

Example 153 6-Bromo-N-(3,5-dimethyl-1-{4-[2-(methylamino)-2-yloxyethyl]benzyl}-1H-pyrazole-4- 2-(trifluoromethyl)quinoline-4-carboxamide

100 mg (0.18 mmol) of 4-{[4-({[6-bromo-2-(trifluoromethyl)quinolin-4-yl]carbonyl}amino)- 3,5-Dimethyl-1H-pyrazol-1-yl]methyl}phenyl)acetic acid (Example 151) was reacted to afford 42 mg (40%) after purification by preparative HPLC (Method 3) Title compound.

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 2.14 (s, 3H), 2.18 (s, 3H), 2.55 (d, 3H), 3.35 (s, 2H), 5.21 (s, 2H) , 7.07-7.13 (m, 2H), 7.18-7.25 (m, 2H), 7.90 (q, 1H), 8.14 (dd, 1H), 8.22 (d, 1H), 8.27 (s, 1H), 8.49 (d) , 1H), 10.13 (s, 1H).

Example 154 N-(1-{4-[2-(benzylamino)-2-oxoethyl]benzyl}-3,5-dimethyl-1H-pyrazole- 4-yl)-6-bromo-2-(trifluoromethyl)quinoline-4-carboxamide

In a similar manner to Example 140), 100 mg (0.18 mmol) of (4-{[4-({[6-bromo-2-(trifluoromethyl)quinolin-4-yl)carbonyl}amino)- 3,5-Dimethyl-1H-pyrazol-1-yl]methyl}phenyl)acetic acid (Example 151) was reacted to give 15 mg (12%) after purification by preparative HPLC (Method 3) Title compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.14 (s, 3H), 2.18 (s, 3H), 3.45 (s, 2H), 4.24 (d, 2H), 5.22 (s, 2H) , 7.11 (d, 2H), 7.17-7.33 (m, 7H), 8.14 (dd, 1H), 8.22 (d, 1H), 8.28 (s, 1H), 8.48-8.56 (m, 2H), 10.15 (s , 1H).

Example 155 6-bromo-N-(3,5-dimethyl-1-{4-[2-o-oxy-2-(phenylamino)ethyl]benzyl}-1H-pyridyl Zin-4-yl)-2-(trifluoromethyl)quinoline-4-carboxamide

100 mg (0.18 mmol) of 4-{[4-({[6-bromo-2-(trifluoromethyl)quinolin-4-yl]carbonyl}amino)- 3,5-Dimethyl-1H-pyrazol-1-yl]methyl}phenyl)acetic acid (Example 151) was reacted to afford 51 mg (44%) after purification by preparative HPLC (Method 3) Title compound.

^{1 H-NMR (300MHz, DMSO} d 6) δ (ppm) = 2.14 (s, 3H), 2.18 (s, 3H), 3.61 (s, 2H), 5.22 (s, 2H), 6.97-7.06 (m, 1H), 7.14 (d, 2H), 7.22-7.33 (m, 4H), 7.57 (d, 2H), 8.14 (dd, 1H), 8.22 (d, 1H), 8.28 (s, 1H), 8.49 (d) , 1H), 10.10-10.18 (m, 2H).

Example 156 6-bromo-N-(1-{4-[2-(dimethylamino)-2-oxoethyl]benzyl}-3,5-dimethyl-1H-pyridyl Zin-4-yl)-2-(trifluoromethyl)quinoline-4-carboxamide

100 mg (0.18 mmol) of 4-{[4-({[6-bromo-2-(trifluoromethyl)quinolin-4-yl]carbonyl}amino)- 3,5-Dimethyl-1H-pyrazol-1-yl]methyl}phenyl)acetic acid (Example 151) was reacted to give 57 mg (53%) after purification by preparative HPLC (Method 3) Title compound.

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 2.14 (s, 3H), 2.19 (s, 3H), 2.81 (s, 3H), 2.98 (s, 3H), 3.65 (s, 2H) , 5.22 (s, 2H), 7.11 (d, 2H), 7.19 (d, 2H), 8.14 (dd, 1H), 8.22 (d, 1H), 8.28 (s, 1H), 8.50 (d, 1H), 10.14 (s, 1H).

Example 157 6-bromo-N-[3,5-dimethyl-1-(4-{2-o-oxy-2-[(pyridin-3-ylmethyl)amino]ethyl}benzene Methyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide

100 mg (0.18 mmol) of 4-{[4-({[6-bromo-2-(trifluoromethyl)quinolin-4-yl]carbonyl}amino)- 3,5-Dimethyl-1H-pyrazol-1-yl]methyl}phenyl)acetic acid (Example 151) was reacted to give 44 mg (37%) after purification by preparative HPLC (Method 3) Title compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.14 (s, 3H), 2.18 (s, 3H), 3.48 (s, 2H), 4.35 (d, 2H), 5.22 (s, 2H) , 7.09-7.16 (m, 2H), 7.20-7.27 (m, 2H), 7.64 (dd, 1H), 7.97 (d, 1H), 8.14 (dd, 1H), 8.22 (d, 1H), 8.27 (s) , 1H), 8.49 (d, 1H), 8.57-8.67 (m, 3H), 10.14 (s, 1H).

Example 158 6-bromo-N-(3,5-dimethyl-1-{4-[2-(morpholin-4-yl)-2-yloxyethyl]benzyl}-1H-pyridyl Zin-4-yl)-2-(trifluoromethyl)quinoline-4-carboxamide

100 mg (0.18 mmol) of 4-{[4-({[6-bromo-2-(trifluoromethyl)quinolin-4-yl]carbonyl}amino)- 3,5-Dimethyl-1H-pyrazol-1-yl]methyl}phenyl)acetic acid (Example 151) was reacted to give 57 mg (49%) after purification by preparative HPLC (Method 3) Title compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.14 (s, 3H), 2.18 (s, 3H), 3.38-3.57 (m, 8H), 3.68 (s, 2H), 5.22 (s, 2H), 7.07-7.15 (m, 2H), 7.16-7.23 (m, 2H), 8.14 (dd, 1H), 8.22 (d, 1H), 8.27 (s, 1H), 8.50 (d, 1H), 10.14 (s, 1H).

Example 159 6-Bromo-N-[1-(4-{2-[(2-hydroxyethyl)amino]-2-oxoethyl}benzyl)-3,5-dimethyl -1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide

In a similar manner to Example 139, 100 mg (0.18 mmol) of (4-{[4-({[6-bromo-2-(trifluoromethyl)quinolin-4-yl)carbonyl}amino)-3) ,5-Dimethyl-1H-pyrazol-1-yl]methyl}phenyl)acetic acid (Example 151) was reacted to give 48 mg (44%) of desired title after purification by preparative HPLC (Method 3). Compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.14 (s, 3H), 2.18 (s, 3H), 3.09 (q, 2H), 3.33 - 3.43 (m, 4H), 4.66 (t, 1H), 5.21 (s, 2H), 7.06-7.13 (m, 2H), 7.19-7.26 (m, 2H), 8.03 (t, 1H), 8.14 (dd, 1H), 8.22 (d, 1H), 8.28 (s, 1H), 8.49 (d, 1H), 10.15 (s, 1H).

Example 160 6-Bromo-N-[3,5-dimethyl-1-(pyridin-4-ylmethyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)quina Porphyrin-4-carboxamide

94.8 mg (0.47 mmol) of 3,5-dimethyl-1-(pyridin-4-ylmethyl)-1H-pyrazol-4-amine (Intermediate 16C) and in a similar manner to Example 118) 100 mg (0.31 mmol) of 6-bromo-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 1A) was reacted to give 80 mg (47%) after purification by preparative HPLC (Method 3) Title compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.16 (s, 3H), 2.19 (s, 3H), 5.46 (s, 2H), 7.32 (d, 2H), 8.15 (dd, 1H) , 8.23 (d, 1H), 8.30 (s, 1H), 8.50 (d, 1H), 8.69 (d, 2H), 10.22 (s, 1H).

Example 161 6-bromo-N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(three Fluoromethyl)quinoline-4-carboxamide

In a manner analogous to Example 118), 84.1 mg (0.30 mmol) of 4-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl }benzonitrile (Intermediate 26C) and 90 mg (0.25 mmol) of 6-bromo-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 1A) are reacted via preparative HPLC (Method 4) After purification, 38 mg (25%) of the desired compound was obtained.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.29 (s, 3H), 5.60 (s, 2H), 7.35-7.40 (m, 2H), 7.86-7.92 (m, 2H), 8.15 ( Dd, 1H), 8.20-8.27 (m, 2H), 8.42 (d, 1H), 10.52 (s, 1H).

Example 162 2-cyclopropyl-N-[1-(3,4-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-6-fluoroquinoline-4-methyl Guanamine

84.1 mg (0.30 mmol) of 1-(3,4-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 4C) was obtained in a similar manner to Example 118) And 90 mg (0.25 mmol) of 2-cyclopropyl-6-fluoroquinoline-4-carboxylic acid (Intermediate 26A) were reacted to give 142 mg (66%) of desired title after purification by preparative HPLC (Method 3) Compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 1.05-1.19 (m, 4H), 2.13 (s, 3H), 2.17 (s, 3H), 2.35-2.42 (m, 1H), 5.25 ( s, 2H), 6.96-7.05 (m, 1H), 7.17-7.27 (m, 1H), 7.43 (dt, 1H), 7.66 (td, 1H), 7.72 (s, 1H), 7.80 (dd, 1H) , 7.98 (dd, 1H), 9.95 (s, 1H).

Example 163 2-(Dimethylamino)-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-4-methyl Guanamine

84.1 mg (0.30 mmol) of 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 1C) and 90 mg were obtained in a similar manner to Example 118) (0.25 mmol) 2-(dimethylamino)quinoline-4-carboxylic acid was reacted to give 90 mg (44%) of desired compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.12 (s, 3H), 2.16 (s, 3H), 3.20 (s, 6H), 5.23 (s, 2H), 7.13 - 7.27 (m, 6H), 7.48-7.64 (m, 2H), 7.87 (d, 1H), 9.78 (s, 1H).

Example 164 6-Bromo-N-[1-(4-hydroxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quina Porphyrin-4-carboxamide

To 100 mg (0.19 mmol) of 6-bromo-N-[1-(4-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2 at 25 °C - (trifluoromethyl) quinoline-4-acyl-amine (example 3) by the solution of 6.8mL 1M BBr ₃ solution was added dropwise the dichloromethane. After stirring for 20 hours, the mixture was cooled with ice and 1 mL methanol was carefully added to the mixture. Subsequently, 8.2 mL of concentrated sodium bicarbonate solution was added and stirring was continued for 30 minutes. After adding 50 mL of water, the mixture was extracted three times with 80 mL of ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate The crude product was purified via EtOAc (EtOAc)

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 2.13 (s, 3H), 2.17 (s, 3H), 5.10 (s, 2H), 6.68-6.75 (m, 2H), 7.00-7.06 ( m, 2H), 8.14 (dd, 1H), 8.22 (d, 1H), 8.26 (s, 1H), 8.49 (d, 1H), 9.37 (s, 1H), 10.12 (s, 1H).

Example 165 6-Chloro-N-[1-(3,4-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl) Quinoline-4-carboxamide

103 mg (0.44 mmol) of 1-(3,4-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 4C) in a manner analogous to Example 118) And 100 mg (0.36 mmol) of 6-chloro-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 12A) were reacted to give 89 mg (47%) after purification by preparative HPLC (Method 4) The title compound is desired.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.14 (s, 3H), 2.19 (s, 3H), 5.25 (s, 2H), 7.01 (ddd, 1H), 7.22 (ddd, 1H) , 7.43 (dt, 1H), 8.04 (dd, 1H), 8.28-8.35 (m, 3H), 10.18 (s, 1H).

Example 166 N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-6-phenyl-2-(trifluoromethyl)quina Porphyrin-4-carboxamide

150 mg (0.29 mmol) of 6-bromo-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl) Quinoline-4-carboxamide (Example 9), 70 mg (0.58 mmol) phenyl Acid, 210 mg (0.29 mmol) [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride, 91.5 mg (0.86 mmol) sodium carbonate in 0.38 mL water and 2.95 mL dioxins The mixture in the alkane was heated in a microwave reactor at 105 °C for 90 minutes. After cooling, the mixture was purified with EtOAc EtOAcqqqqqq

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.15 (s, 3H), 2.19 (s, 3H), 5.24 (s, 2H), 7.14 - 7.27 (m, 4H), 7.44 - 7.51 ( m,1H), 7.52-7.59 (m, 2H), 7.77-7.82 (m, 2H), 8.22 (s, 1H), 8.31-8.38 (m, 2H), 8.50 (s, 1H), 10.14 (s, 1H).

Example 167 6,8-Dichloro-N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2- (trifluoromethyl)quinoline-4-carboxamide

In a similar manner to Example 118), 87 mg (0.31 mmol) of 4-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl} Benzoonitrile (Intermediate 26C) and 80 mg (0.26 mmol) of 6,8-dichloro-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 11A) are reacted via preparative HPLC (method 4) After purification, 68 mg (44%) of desired compound.

^{1 H-NMR (300MHz, DMSO} d 6) δ (ppm) = 2.29 (s, 3H), 5.60 (s, 2H), 7.33-7.40 (m, 2H), 7.85-7.92 (m, 2H), 8.19 ( d, 1H), 8.38 (s, 1H), 8.42 (d, 1H), 10.58 (s, 1H).

Example 168 N-[1-(3,4-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-7-fluoro-2-(trifluoromethyl) Quinoline-4-carboxamide

In a manner similar to Example 118), 82 mg (0.35 mmol) of 1-(3,4-difluorobenzoate) -3,5-Dimethyl-1H-pyrazole-4-amine (Intermediate 4C) and 75 mg (0.29 mmol) of 7-fluoro-2-(trifluoromethyl)quinoline-4-carboxylic acid (middle The reaction of the product 17A) gave 88 mg (yield: 57%) of the desired title compound after purification by preparative HPLC (Method 3).

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.15 (s, 3H), 2.19 (s, 3H), 5.25 (s, 2H), 6.97-7.04 (m, 1H), 7.16-7. m, 1H), 7.43 (dt, 1H), 7.86 (td, 1H), 8.08 (dd, 1H), 8.20 (s, 1H), 8.37 (dd, 1H), 10.13 (s, 1H).

Example 169 N-[1-(4-Cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-6,7-difluoro-2-(trifluoromethyl) Quinoline-4-carboxamide

98 mg (0.43 mmol) of 4-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]benzonitrile (intermediate) in a similar manner to Example 118) 8C) and 100 mg (0.36 mmol) of 6,7-difluoro-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 19A) are reacted after purification via preparative HPLC (Method 3) 121 mg (66%) of the desired compound.

¹ H-NMR (300 MHz, DMSO d ₆ ) δ (ppm) = 2.14 (s, 3H), 2.17 (s, 3H), 5.38 (s, 2H), 7.23 - 7.33 (m, 2H), 7.80 - 7.88 ( m, 2H), 8.26 (dd, 1H), 8.31 (s, 1H), 8.41 (dd, 1H), 10.21 (s, 1H).

Example 170 6-Bromo-N-[1-(cyclohexylmethyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline- 4-carboxamide

77 mg (0.31 mmol) of 1-(cyclohexylmethyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 33C) and 100 mg (0.31 mmol). 6-Bromo-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 1A) was reacted to give 87 mg (52%) of desired compound.

1H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 0.97 (q, 2H), 1.06-1.28 (m, 3H), 1.49-1.87 (m, 6H), 2.11 (s, 3H), 2.19 (s) , 3H), 3.80 (d, 2H), 8.14 (dd, 1H), 8.22 (d, 1H), 8.28 (s, 1H), 8.49 (d, 1H), 10.12 (s, 1H).

Example 171 6-Bromo-N-[3,5-dimethyl-1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)quina Porphyrin-4-carboxamide

In a manner similar to Example 118), 90 mg (0.45 mmol) of 3,5-dimethyl-1- (pyridin-2-ylmethyl)-1H-pyrazol-4-amine (Intermediate 18C) and 119 mg (0.37 mmol) of 6-bromo-2-(trifluoromethyl)quinoline-4-carboxylic acid (intermediate) 1A) Reaction, whereby after purification via preparative HPLC (Method 3), 74 mg (38%).

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.14 (s, 3H), 2.23 (s, 3H), 5.32 (s, 2H), 7.43 (dd, 1H), 7.62 (d, 1H) , 8.14 (dd, 1H), 8.22 (d, 1H), 8.29 (s, 1H), 8.45-8.56 (m, 3H), 10.18 (s, 1H).

Example 172 N ⁴ -[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-N ² -methylquinoline-2,4-dimethyl Guanamine

In a similar manner to Example 118), 79 mg (0.36 mmol) of 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 1C) and 69 mg ( 0.30 mmol) 2-(Methylamine-mercapto)quinoline-4-carboxylic acid (Intermediate 6A) was obtained to give 98 mg (yield: 70%).

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.14 (s, 3H), 2.18 (s, 3H), 2.91 (d, 3H), 5.24 (s, 2H), 7.13 - 7.29 (m, 4H), 7.76-7.85 (m, 1H), 7.94 (td, 1H), 8.16-8.28 (m, 3H), 9.00 (q, 1H), 10.06 (s, 1H).

Example 173 N-[1-(3,4-Difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-5-fluoro-2-(trifluoromethyl) Quinoline-4-carboxamide

110 mg (0.46 mmol) of 1-(3,4-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 4C) was obtained in a procedure similar to Example 118) And 100 mg (0.39 mmol) of 5-fluoro-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 16A), whereby after purification by preparative HPLC, the material was obtained and dissolved in 30 mL of ethyl acetate In the ester. The organic phase was washed with EtOAc EtOAc m.

¹ H-NMR (300 MHz, DMSO d ₆ ) δ (ppm) = 2.15 (s, 3H), 2.19 (s, 3H), 5.25 (s, 2H), 6.96-7.05 (m, 1H), 7.21. 1H), 7.43 (dt, 1H), 7.86 (td, 1H), 8.09 (dd, 1H), 8.20 (s, 1H), 8.37 (dd, 1H), 10.14 (s, 1H).

Example 174 N-[1-(3,4-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-6-fluoro-2-(trifluoromethyl) Quinoline-4-carboxamide

In a similar manner to Example 118), 79 mg (0.36 mmol) of 1-(3,4-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 4C) Reaction with 69 mg (0.30 mmol) of 6-fluoro-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 18A) afforded 118 mg (57%) after purification by preparative HPLC (Method 3) The title compound is desired.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.14 (s, 3H), 2.19 (s, 3H), 5.25 (s, 2H), 6.97-7.05 (m, 1H), 7.17-7.26 ( m, 1H), 7.43 (dt, 1H), 7.91-8.03 (m, 2H), 8.28 (s, 1H), 8.37 (dd, 1H), 10.14 (s, 1H).

Example 175 N-[1-(2-Cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-6,7-difluoro-2-(trifluoromethyl) Quinoline-4-carboxamide

In a similar manner to Example 118), 74 mg (0.33 mmol) of 2-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]benzonitrile ( intermediate) 10C) and 75 mg (0.27 mmol) of 6,7-difluoro-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 19A) are reacted, after purification by preparative HPLC (Method 4) 96 mg (70%) of the desired compound.

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 2.12 (s, 3H), 2.25 (s, 3H), 5.43 (s, 2H), 7.09 (d, 1H), 7.52 (td, 1H) , 7.67-7.73 (m, 1H), 7.89 (dd, 1H), 8.26 (dd, 1H), 8.31 (s, 1H), 8.40 (dd, 1H), 10.22 (s, 1H).

Example 176 6-Bromo-N-ethyl-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl) Quinoline-4-carboxamide

To 0 mg (0.38 mmol) of 6-bromo-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2- ( at 0 ° C) Trifluoromethyl)quinoline-4-carboxamide (Example 9) was added 16 mg (0.40, 60% in mineral oil) to a solution of 2.0 mL of N,N -dimethylformamide. After stirring at 0 ° C for 1 hour, 37 μL of ethyl iodide was added and stirring was continued at 25 ° C for 3 hours. This mixture was purified by HPLC (Method 4) to give 126 mg (56%)

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 1.16 (t, 3H), 1.84 (s, 3H), 2.03 (s, 3H), 3.66 (dq, 1H), 4.04 (dq, 1H) , 4.85-5.05 (m, 2H), 6.19 (dd, 2H), 6.86 (t, 2H), 7.95 (s, 1H), 8.04 (dd, 1H), 8.13 (d, 1H), 8.21 (d, 1H) ).

Example 177 N-[1-(3,4-Difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-6,7-difluoro-2-(trifluoromethyl) Quinoline-4-carboxamide

103 mg (0.36 mmol) of 1-(3,4-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 4C) in a manner analogous to Example 118) And 100 mg (0.43 mmol) of 6,7-difluoro-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 19A) to give 85 mg after purification by preparative HPLC (Method 3) 43%) of the desired compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.14 (s, 3H), 2.18-2.19 (m, 3H), 5.25 (s, 2H), 7.01 (ddd, 1H), 7.20 (ddd, 1H), 7.43 (dt, 1H), 8.25 (dd, 1H), 8.29 (s, 1H), 8.39 (dd, 1H), 10.18 (s, 1H).

Example 178 N ⁴ -[1-(4-fluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-N2-methylquinoline- 2,4-dimethylamine

98 mg (0.36 mmol) of 1-(4-fluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole-4-amine (in the middle) 25C) and 69 mg (0.30 mmol) of 2-(methylamine-mercapto)quinoline-4-carboxylic acid (Intermediate 6A) were reacted to give 75 mg (48%) after purification by preparative HPLC (Method 3) The title compound is required.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.28 (s, 3H), 2.91 (d, 3H), 5.46 (s, 2H), 7.20-7.35 (m, 4H), 7.78-7.85 ( m, 1H), 7.94 (ddd, 1H), 8.20 (dd, 2H), 8.24 (s, 1H), 9.01 (q, 1H), 10.40 (s, 1H).

Example 179 6-bromo-N-[1-(2,4-difluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(three Fluoromethyl)quinoline-4-carboxamide

In a manner similar to Example 118), 87 mg (0.30 mmol) of 1-(2,4-difluorobenzene) 5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-amine (Intermediate 24C) and 80 mg (0.25 mmol) of 6-bromo-2-(trifluoromethyl)quinoline 4-carboxylic acid (Intermediate 1A) was reacted to give 112 mg (yield: 74%) of the desired compound.

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 2.34 (s, 3H), 5.48 (s, 2H), 7.15 (td, 1H), 7.27-7.37 (m, 2H), 8.15 (dd, 1H), 8.21-8.27 (m, 2H), 8.41 (d, 1H), 10.49 (s, 1H).

Example 180 6-bromo-N-{1-[(5-chlorothien-2-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-2-(trifluoro Methyl)quinoline-4-carboxamide

In a manner similar to Example 118), 90 mg (0.37 mmol) of 1-[(5-chloro-2-thienyl)methyl]-3,5-dimethyl-1H-pyrazol-4-amine (middle) The compound 34C) and 99 mg (0.31 mmol) of 6-bromo-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 1A) were reacted to give 19 mg after purification by preparative HPLC (Method 3). 11%) of the desired compound.

^{1 H-NMR (300MHz, DMSO} d 6) δ (ppm) = 2.14 (s, 3H), 2.24 (s, 3H), 5.37 (s, 2H), 6.95-7.02 (m, 2H), 8.14 (dd, 1H), 8.22 (d, 1H), 8.28 (s, 1H), 8.48 (d, 1H), 10.16 (s, 1H).

Example 181 N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-methyl Guanamine

In a similar manner to Example 118), 81 mg (0.37 mmol) of 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 1C) and 75 mg ( Reaction of 0.31 mmol) of 2-(trifluoromethyl)quinoline-4-carboxylic acid afforded 84 mg (56%) of desired compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.15 (s, 3H), 2.19 (s, 3H), 5.24 (s, 2H), 7.13 - 7.28 (m, 4H), 7.86-7.94 ( m, 1H), 7.96-8.05 (m, 1H), 8.18 (s, 1H), 8.27 (d, 2H), 10.09 (s, 1H).

Example 182 N-[1-(4-Cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-6,7-difluoro-2- (trifluoromethyl)quinoline-4-carboxamide

In a similar manner to Example 118), 97 mg (0.35 mmol) of 4-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl} Benzoonitrile (Intermediate 26C) and 80mg (0.29 mmol) 6,7-difluoro-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 19A) was reacted to give 102 mg (63%) after purification by preparative HPLC (Method 4) The title compound is required.

¹ H-NMR (400MHz, DMSO d ₆ ) δ (ppm) = 2.28 (s, 3H), 5.60 (s, 2H), 7.34-7.40 (m, 2H), 7.85-7.92 (m, 2H), 8.15 ( Dd, 1H), 8.25 (s, 1H), 8.42 (dd, 1H), 10.54 (s, 1H).

Example 183 N-{1-[(6-Cyanopyridin-3-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-6,7-difluoro-2- (trifluoromethyl)quinoline-4-carboxamide

In a similar manner to Example 118), 115 mg (0.43 mmol) of 5-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]pyridine-2-carbonitrile (Intermediate 29C) and 100 mg (0.36 mmol) of 6,7-difluoro-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 19A) for purification via preparative HPLC (Method 4) Thereafter, 10 mg (5.1%) of the desired title compound was obtained.

¹ H-NMR (600MHz, DMSO d ₆ ) δ (ppm) = 2.13 (s, 3H), 2.22 (s, 3H), 5.43 (s, 2H), 7.75 (dd, 1H), 8.05 (d, 1H) , 8.25 (dd, 1H), 8.30 (s, 1H), 8.40 (dd, 1H), 8.59 (d, 1H), 10.21 (s, 1H).

Example 184 6-bromo-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-4-carboxamide

In a similar manner to Example 118), 72 mg (0.33 mmol) of 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 1C) and 75 mg ( Reaction of 6-bromoquinoline-4-carboxylic acid afforded 73 mg (50%) of the desired title compound after purified by preparative HPLC (Method 3).

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.13 (s, 3H), 2.17 (s, 3H), 5.24 (s, 2H), 7.14-7.28 (m, 4H), 7.81 (d, 1H), 7.97 (dd, 1H), 8.07 (d, 1H), 8.39 (d, 1H), 9.07 (d, 1H), 10.00 (s, 1H).

Example 185 6-bromo-N-[1-(3,4-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-methylquinolin-4- Formamide

107 mg (0.45 mmol) of 1-(3,4-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 4C) was obtained in a manner analogous to Example 118) And 100 mg (0.38 mmol) of 6-bromo-2-methylquinoline-4-carboxylic acid, after purification via preparative HPLC (method 3) 107 mg (53%) of the desired compound are obtained.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.13 (s, 3H), 2.17 (s, 3H), 2.71 (s, 3H), 5.25 (s, 2H), 7.01 (ddd, 1H) , 7.23 (ddd, 1H), 7.43 (dt, 1H), 7.73 (s, 1H), 7.87-7.93 (m, 1H), 7.93-7.98 (m, 1H), 8.31 (d, 1H), 9.98 (s , 1H).

Example 186 N-[1-(3-chloro-4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2,6-dimethylquinolin-4- Formamide

151 mg (0.60 mmol) of 1-(3-chloro-4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 28C) The reaction with 100 mg (0.50 mmol) of 2,6-dimethylquinoline-4-carboxylic acid afforded 168 mg (74%) of the desired compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.14 (s, 3H), 2.18 (s, 3H), 2.48 (s, 3H), 2.70 (s, 3H), 5.25 (s, 2H) , 7.19 (ddd, 1H), 7.38-7.45 (m, 2H), 7.59-7.65 (m, 2H), 7.86-7.92 (m, 2H), 9.87 (s, 1H).

Example 187 6-bromo-N-{3,5-dimethyl-1-[(1-methyl-1H-pyrazol-3-yl)methyl]-1H-pyrazol-4-yl}-2- (trifluoromethyl)quinoline-4-carboxamide

In a similar manner to Example 118), 210 mg (1.02 mmol) of 3,5-dimethyl-1-[(1-methyl-1H-pyrazol-3-yl)methyl]-1H-pyrazole- 4-amine (Intermediate 35C) and 273 mg (0.85 mmol) of 6-bromo-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 1A) were reacted to afford purified by preparative HPLC (Method 3) After that, 36 mg (8.1%) of the desired compound was obtained.

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 2.11 (s, 3H), 2.24 (s, 3H), 3.79 (s, 3H), 5.12 (s, 2H), 6.07 (d, 1H) , 7.60 (d, 1H), 8.14 (dd, 1H), 8.22 (d, 1H), 8.27 (s, 1H), 8.48 (d, 1H), 10.11 (s, 1H).

Example 188 N-[1-(4-Cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2,6-dimethyl Quinoline-4-carboxamide

In a manner analogous to Example 118), 134 mg (0.48 mmol) of 4-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl} Benzoonitrile (Intermediate 26C) and 80mg (0.40 mmol) 2,6-dimethylquinoline-4-carboxylic acid was reacted to give 132 mg (yield: 70%) of the desired compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.25 (s, 3H), 2.47 (s, 3H), 2.69 (s, 3H), 5.59 (s, 2H), 7.38 (d, 2H) , 7.52 (s, 1H), 7.62 (dd, 1H), 7.81 (s, 1H), 7.86-7.93 (m, 3H), 10.22 (s, 1H).

Example 189 7-Bromo-N-[1-(3,4-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl) Quinoline-4-carboxamide

89 mg (0.36 mmol) of 1-(3,4-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 4C) was obtained in a procedure similar to Example 118) Reaction with 100 mg (0.31 mmol) of 7-bromo-2-methylquinoline-4-carboxylic acid (Intermediate 22A) afforded 78 mg (42%).

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.14 (s, 3H), 2.19 (s, 3H), 5.25 (s, 2H), 7.00 (ddd, 1H), 7.20 (ddd, 1H) , 7.43 (dt, 1H), 8.05 (dd, 1H), 8.20-8.27 (m, 2H), 8.53 (d, 1H), 10.13 (s, 1H).

Example 190 6-Bromo-N-[1-(3-chloro-4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl) Quinoline-4-carboxamide

In a similar manner to Example 118), 95 mg (0.38 mmol) of 1-(3-chloro-4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine ( Intermediate 28C) And 100 mg (0.31 mmol) of 6-bromo-2-methylquinoline-4-carboxylic acid (Intermediate 1A), whereby after purification by preparative HPLC (Method 3), 106 mg (58%) .

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.15 (s, 3H), 2.20 (s, 3H), 5.26 (s, 2H), 7.14-7.21 (m, 1H), 7.36-7.45 ( m, 2H), 8.11-8.16 (m, 1H), 8.22 (d, 1H), 8.28 (s, 1H), 8.50 (d, 1H), 10.17 (s, 1H).

Example 191 N-[1-(3-chloro-4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-6,7-difluoro-2-(trifluoromethyl) Quinoline-4-carboxamide

110 mg (0.43 mmol) of 1-(3-chloro-4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 28C) And 100mg (0.36mmol) 6,7- Reaction of difluoro-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 19A) afforded 119 mg (60%)

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 2.14 (s, 3H), 2.19 (s, 3H), 5.26 (s, 2H), 7.18 (ddd, 1H), 7.35-7.45 (m, 2H), 8.26 (dd, 1H), 8.30 (s, 1H), 8.40 (dd, 1H), 10.18 (s, 1H).

Example 192 N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-6-methoxyquinoline-4-carboxamide

In a manner similar to Example 118), 130 mg (0.59 mmol) of 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 1C) and 100 mg ( Reaction of 6-methoxyquinoline-4-carboxylic acid afforded 106 mg (52%) of desired compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.14 (s, 3H), 2.17 (s, 3H), 3.86 (s, 3H), 5.23 (s, 2H), 7.13 - 7.29 (m, 4H), 7.46-7.53 (m, 2H), 7.67 (d, 1H), 8.02 (d, 1H), 8.85 (d, 1H), 9.89 (s, 1H).

Example 193 6,7-Difluoro-N-[1-(4-fluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(three Fluoromethyl)quinoline-4-carboxamide

95 mg (0.35 mmol) of 1-(4-fluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole-4-amine (in the middle) 25C) and 80 mg (0.29 mmol) of 6,7-difluoro-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 19A), after purification via preparative HPLC (Method 4) 110 mg (66%) of the desired compound are obtained.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.29 (s, 3H), 5.46 (s, 2H), 7.17-7.35 (m, 4H), 8.14 (dd, 1H), 8.25 (s, 1H), 8.43 (dd, 1H), 10.52 (s, 1H).

Example 194 6-Bromo-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-N-(2-methoxyethyl)- 2-(trifluoromethyl)quinoline-4-carboxamide

In a manner similar to Example 176), 200 mg (0.38 mmol) of 6-bromo-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl] -2-(trifluoromethyl)quinoline-4-carboxamide Example 9) was reacted with 1.50 mL (0.46 mmol) of 1-bromo-2-methoxyethane to afford 56 mg (23%) of desired compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 1.77 (s, 3H), 2.03 (s, 3H), 3.31 (s, 3H), 3.44 - 3.58 (m, 2H), 3.68 - 3.77 ( m,1H),4.23-4.32(m,1H),4.86-5.01(m,2H),6.22(dd,2H),6.83-6.91(m,2H),7.82(s,1H),8.04(dd, 1H), 8.12 (d, 1H), 8.22 (d, 1H).

Example 195 N-[1-(cyclohexylmethyl)-3,5-dimethyl-1H-pyrazol-4-yl]-6,7-difluoro-2-(trifluoromethyl) Quinoline-4-carboxamide

In a similar manner to Example 118), 90 mg (0.43 mmol) of 1-(cyclohexylmethyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 33C) and 100 mg (0.36 mmol) Reaction of 6,7-difluoro-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 19A) to give 53 mg (30%) of desired title after purification by preparative HPLC (Method 4) Compound.

¹ H-NMR (300 MHz, DMSO d ₆ ) δ (ppm) = 0.88-1.27 (m, 5H), 1.47-1.85 (m, 6H), 2.10 (s, 3H), 2.19 (s, 3H), 3.80 ( d, 2H), 8.20-8.30 (m, 2H), 8.41 (dd, 1H), 10.12 (s, 1H).

Example 196 N-[3,5-Dimethyl-1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl]-6,7-difluoro-2-(trifluoromethyl) Quinoline-4-carboxamide

In a similar manner to Example 118), 90 mg (0.45 mmol) of 3,5-dimethyl-1-(pyridin-3-ylmethyl)-1H-pyrazol-4-amine (Intermediate 17C) and 103 mg (0.37 mmol) 6,7-difluoro-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 19A) was reacted to give 25 mg (14%) after purification via preparative HPLC (Method 3) The title compound is required.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.13 (s, 3H), 2.22 (s, 3H), 5.32 (s, 2H), 7.45 (dd, 1H), 7.64 (d, 1H) , 8.20-8.32 (m, 2H), 8.41 (dd, 1H), 8.45-8.49 (m, 1H), 8.51 - 8.57 (m, 1H), 10.19 (s, 1H).

Example 197 6-bromo-N-[1-(3,4-difluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(three Fluoromethyl)quinoline-4-carboxamide

In a similar manner to Example 118), 87 mg (0.30 mmol) of 1-(3,4-difluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole-4- Amine (Intermediate 23C) and 80 mg (0.25 Ethyl 6-bromo-2-methylquinoline-4-carboxylic acid (Intermediate 1A) was reacted to give 80 mg (52%) of desired compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.31 (s, 3H), 5.47 (s, 2H), 7.08 (ddd, 1H), 7.34 (ddd, 1H), 7.48 (dt, 1H) , 8.12-8.18 (m, 1H), 8.21-8.27 (m, 2H), 8.41 (d, 1H), 10.50 (s, 1H).

Example 198 N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(morpholin-4-yl)quinoline-4-methyl Guanamine

In a similar manner to Example 118), 93 mg (0.43 mmol) of 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 1C) and 100 mg ( 0.39 mmol) 2-(morpholin-4-yl)quinoline-4-carboxylic acid was reacted to give 63 mg (33%) of desired compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.12 (s, 3H), 2.16 (s, 3H), 3.72 (d, 8H), 5.23 (s, 2H), 7.14-7.26 (m, 4H), 7.30 (t, 1H), 7.39 (s, 1H), 7.54-7.67 (m, 2H), 7.89 (d, 1H), 9.80 (s, 1H).

Example 199 6,8-Dichloro-N-[1-(3,4-difluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]- 2-(trifluoromethyl)quinoline-4-carboxamide

In a similar manner to Example 118), 90 mg (0.31 mmol) of 1-(3,4-difluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole-4- Reaction of the amine (Intermediate 23C) with 80 mg (0.26 mmol) of 6,8-dichloro-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 11A), whereby preparative HPLC (Method 4) After purification, 68 mg (44%) of desired title compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.31 (s, 3H), 5.47 (s, 2H), 7.08 (ddd, 1H), 7.33 (ddd, 1H), 7.48 (dt, 1H) , 8.19 (d, 1H), 8.37 (s, 1H), 8.40 (d, 1H), 10.54 (s, 1H).

Example 200 N-Benzyl-6-bromo-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoro Methyl)quinoline-4-carboxamide

In a manner similar to Example 176), 200 mg (0.38 mmol) of 6-bromo-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl] -2-(trifluoromethyl)quinoline-4-carboxamide Example 9) was reacted with 55 μL (0.46 mmol) of benzyl bromide to afford 152 mg (61%) of the desired compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 1.42 (s, 3H), 1.81 (s, 3H), 4.77 (d, 1H), 4.85 (d, 2H), 5.21. (d, 1H) , 6.15 (dd, 2H), 6.87 (t, 2H), 7.29-7.40 (m, 5H), 7.95 (s, 1H), 8.04 (dd, 1H), 8.12 (d, 1H), 8.22 (d, 1H) ).

Example 201 N-{1-[(6-Cyanopyridin-3-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-2,6-dimethyl Quinoline-4-carboxamide

In a manner similar to Example 118), 159 mg (0.60 mmol) of 5-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]pyridine-2-carbonitrile (Intermediate 29C) and 100 mg (0.506 mmol) of 2,6-dimethylquinoline-4-carboxylic acid to give 13 mg (5.7%) of the desired title compound after purification by preparative HPLC (Method 3).

¹ H-NMR (600MHz, DMSO d ₆ ) δ (ppm) = 2.14 (s, 3H), 2.21 (s, 3H), 2.50 (s, 3H), 2.75 (s, 3H), 5.43 (s, 2H) , 7.66-7.73 (m, 2H), 7.76 (dd, 1H), 7.91 (s, 1H), 7.95 (d, 1H), 8.05 (d, 1H), 8.59 (d, 1H), 9.97 (s, 1H) ).

Example 202 N-(1-{4-[(2-hydroxyethyl)aminemethanyl]benzyl}-3,5-dimethyl-1H-pyrazol-4-yl)- 2,6-dimethylquinoline-4-carboxamide

In a manner similar to Example 118), 100 mg (0.35 mmol) of 4-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]-N-(2- Hydroxyethyl)benzamide (Intermediate 41C) and 58 mg (0.29 mmol) of 2,6-dimethylquinoline-4-carboxylic acid were reacted to give 3.9 mg after purification by preparative HPLC (Method 3) (2.7%) of the desired compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.14 (s, 3H), 2.16 (s, 3H), 2.48 (s, 3H), 2.69 (s, 3H), 3.49 (t, 3H) , 5.30 (s, 2H), 7.19-7.27 (m, 2H), 7.52-7.64 (m, 2H), 7.77-7.84 (m, 2H), 7.85-7.93 (m, 2H), 8.37 (t, 1H) , 9.85 (s, 1H).

Example 203 N-[1-(3,4-difluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2,6-dimethyl Quinolinol-4-carboxamide

139 mg (0.48 mmol) of 1-(3,4-difluorobenzene in a similar manner to Example 118) Methyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-amine (Intermediate 23C) and 80 mg (0.40 mmol) of 2,6-dimethylquinoline-4-carboxylic acid Reaction, whereby after purification via preparative HPLC (Method 4), 135 mg (68%)

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.27 (s, 3H), 2.47 (s, 3H), 2.69 (s, 3H), 5.46 (s, 2H), 7.08 (ddd, 1H) , 7.34 (ddd, 1H), 7.44 - 7.52 (m, 2H), 7.61 (dd, 1H), 7.82 (s, 1H), 7.89 (d, 1H), 10.18 (s, 1H).

Example 204 N-[1-(2,4-difluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2,6-dimethyl Quinolinol-4-carboxamide

In a similar manner to Example 118), 139 mg (0.48 mmol) of 1-(2,4-difluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole-4- Reaction of the amine (Intermediate 24C) and 80 mg (0.40 mmol) of 2,6-dimethylquinoline-4-carboxylic acid afforded 133 mg (68%)

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.31 (s, 3H), 2.47 (s, 3H), 2.69 (s, 3H), 5.47 (s, 2H), 7.10-7.20 (m, 1H), 7.26-7.38 (m, 2H), 7.52 (s, 1H), 7.61 (dd, 1H), 7.81 (s, 1H), 7.90 (d, 1H), 10.19 (s, 1H).

Example 205 6,8-Dichloro-N-[1-(2,4-difluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]- 2-(trifluoromethyl)quinoline-4-carboxamide

In a similar manner to Example 118), 90 mg (0.31 mmol) of 1-(2,4-difluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole-4- Amine (Intermediate 24C) and 80 mg (0.26 mmol) of 6,8-dichloro-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 11A) are reacted via preparative HPLC (Method 4) After purification, 76 mg (49%) of desired title compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.35 (s, 3H), 5.48 (s, 2H), 7.08-7.20 (m, 1H), 7.25-7.41 (m, 2H), 8.19 ( d, 1H), 8.36-8.44 (m, 2H), 10.55 (s, 1H).

Example 206 N-[1-(cyclohexylmethyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2,6-dimethylquinoline-4-carboxamidine amine

In a similar manner to Example 118), 124 mg (0.60 mmol) of 1-(cyclohexylmethyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 33C) and 100 mg (0.50) Mm) 2,6-two Methylquinoline-4-carboxylic acid was reacted to give 123 mg (60%) of desired title compound after purification by preparative HPLC (Method 3).

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 0.88-1.29 (m, 5H), 1.48-1.84 (m, 6H), 2.10 (s, 3H), 2.17 (s, 3H), 2.48 ( s, 3H), 2.70 (s, 3H), 3.79 (d, 2H), 7.57-7.67 (m, 2H), 7.85-7.94 (m, 2H), 9.82 (s, 1H).

Example 207 N-[1-(3,4-difluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-6,7-difluoro- 2-(trifluoromethyl)quinoline-4-carboxamide

109 mg (0.35 mmol) of 1-(3,4-difluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole-4-, as in Example 118) Reaction of the amine (Intermediate 23C) with 80 mg (0.29 mmol) of 6,7-difluoro-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 19A), whereby preparative HPLC (Method 4) After purification, 117 mg (70%) of desired title compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.30 (s, 3H), 5.47 (s, 2H), 7.07 (ddd, 1H), 7.33 (ddd, 1H), 7.48 (dt, 1H) , 8.14 (dd, 1H), 8.25 (s, 1H), 8.42 (dd, 1H), 10.52 (s, 1H).

Example 208 N-[3,5-Dimethyl-1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl]-2,6-dimethylquinoline-4-methyl Guanamine

In a similar manner to Example 118), 90 mg (0.45 mmol) of 3,5-dimethyl-1-(pyridin-3-ylmethyl)-1H-pyrazol-4-amine (Intermediate 17C) and 75 mg (0.37 mmol) 2,6-dimethylquinoline-4-carboxylic acid was reacted to give 68 mg (45%) of desired compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.14 (s, 3H), 2.24 (s, 3H), 2.51 (s, 3H), 2.77 (s, 3H), 5.38 (s, 2H) , 7.68 (dd, 1H), 7.71-7.77 (m, 2H), 7.88-7.93 (m, 2H), 7.97 (d, 1H), 8.60 (d, 1H), 8.66 (dd, 1H), 10.00 (s , 1H).

Example 209 N ⁴ -[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-N ² ,N ² - dimethylquinoline-2,4- Dimethylamine

In a similar manner to Example 118), 59 mg (0.27 mmol) of 1-(4-fluorobenzyl)- 3,5-Dimethyl-1H-pyrazole-4-amine (Intermediate 1C) and 68 mg (0.22 mmol, purity 80%) of 2-(dimethylaminocarbamimidino)quinoline-4-carboxylic acid (middle The reaction of the compound 7A) gave 67 mg (yield: 62%)

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.13 (s, 3H), 2.17 (s, 3H), 3.04 (s, 3H), 3.09 (s, 3H), 5.23 (s, 2H) , 7.14-7.27 (m, 4H), 7.76 (ddd, 1H), 7.81 (s, 1H), 7.89 (ddd, 1H), 8.12 (d, 1H), 8.19 (d, 1H), 10.00 (s, 1H) ).

Example 210 N-[1-(2,4-difluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-6,7-difluoro- 2-(trifluoromethyl)quinoline-4-carboxamide

In a manner similar to Example 118), 101 mg (0.35 mmol) of 1-(2,4-difluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole-4- Amine (Intermediate 24C) and 80 mg (0.29 mmol, purity 80%) of 6,7-difluoro-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 19A) were reacted via preparative HPLC (Method 4) After purification, 111 mg (68%) of Compound

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.34 (s, 3H), 5.48 (s, 2H), 7.11-7.20 (m, 1H), 7.26-7.39 (m, 2H), 8.14 ( Dd, 1H), 8.26 (s, 1H), 8.43 (dd, 1H), 10.53 (s, 1H).

Example 211 N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-4-carboxamide

152 mg (0.69 mmol) of 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 1C) and 100 mg (100 mg) Reaction of 0.58 mmol) of quinoline-4-carboxylic acid afforded 162 mg (68%) of the desired compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.13 (s, 3H), 2.17 (s, 3H), 5.24 (s, 2H), 7.13 - 7.28 (m, 4H), 7.66-7.74 ( m, 2H), 7.83 (td, 1H), 8.11 (d, 1H), 8.17 (d, 1H), 9.02 (d, 1H), 9.92 (s, 1H).

Example 212 6-chloro-N ⁴ -[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-di Formamide

In a manner similar to Example 118), 96 mg (0.42 mmol) of 4-[(4-amino-3,5-) Dimethyl-1H-pyrazol-1-yl)methyl]benzonitrile (Intermediate 8C) and 95 mg (0.35 mmol) 2-Aminomethylmercapto-6-chloro-7-fluoroquinoline-4-carboxylic acid (Intermediate 32A) was reacted to give 8.7 mg (4.6%) of desired compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.13 (s, 3H), 2.16 (s, 3H), 5.37 (s, 2H), 7.28-7.36 (m, 2H), 7.79-7.87 ( m, 2H), 7.98 (br.s., 1H), 8.12 (d, 1H), 8.33 - 8.42 (m, 2H), 8.51 (d, 1H), 10.22 (s, 1H).

Example 213 6-chloro-N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoro Quinoline-2,4-dimethylamine

In a similar manner to Example 118), 119 mg (0.42 mmol) of 4-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl} Benzoonitrile (Intermediate 26C) and 95 mg (0.35 mmol) of 2-aminoformamido-6-chloro-7-fluoroquinoline-4-carboxylic acid (Intermediate 32A) are reacted via preparative HPLC (Method 3 After purification, 72 mg (37%) of desired title compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.26 (s, 3H), 5.60 (s, 2H), 7.35-7.43 (m, 2H), 7.85-7.92 (m, 2H), 7.99 ( Br.s., 1H), 8.14 (d, 1H), 8.36 (s, 1H), 8.38 (br.s., 1H), 8.43 (d, 1H), 10.54 (s, 1H).

Example 214 6-chloro-7-fluoro-N ⁴ -[1-(4-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-2,4- Dimethylamine

98 mg (0.42 mmol) of 1-(4-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 11C) and in a similar manner to Example 118) 95 mg (0.35 mmol) of 2-aminoformamido-6-chloro-7-fluoroquinoline-4-carboxylic acid (Intermediate 32A) was reacted to give 9.1 mg (4.8) after purification by preparative HPLC (Method 3). %) The desired compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.12 (s, 3H), 2.16 (s, 3H), 3.73 (s, 3H), 5.16 (s, 2H), 6.87-6.94 (m, 2H), 7.12-7.19 (m, 2H), 7.97 (br.s., 1H), 8.12 (d, 1H), 8.34-8.40 (m, 2H), 8.50 (d, 1H), 10.16 (s, 1H) ).

Example 215 6-chloro-N ⁴ -[1-(2-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-di Formamide

96 mg (0.42 mmol) of 2-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]benzonitrile (intermediate) in a similar manner to Example 118) 10C) and 95 mg (0.35 mmol) of 2-aminoformamido-6-chloro-7-fluoroquinoline-4-carboxylic acid (Intermediate 32A) are reacted to give 14 mg after purification by preparative HPLC (Method 3) (6.8%) of the desired compound.

^{1 H-NMR (300MHz, DMSO} d 6) δ (ppm) = 2.12 (s, 3H), 2.24 (s, 3H), 5.43 (s, 2H), 7.11 (d, 1H), 7.47-7.56 (m, 1H), 7.71 (td, 1H), 7.89 (dd, 1H), 7.98 (br.s., 1H), 8.13 (d, 1H), 8.34-8.42 (m, 2H), 8.52 (d, 1H), 10.25 (s, 1H).

Example 216 N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-6,7-difluoroquine Porphyrin-2,4-dimethylamine

In a manner similar to Example 118), 133 mg (0.48 mmol) of 4-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl} Benzoonitrile (Intermediate 26C) and 100 mg (0.40 mmol) of 2-aminocarbamimidyl-6,7-difluoroquinoline-4-carboxylic acid (Intermediate 3A) are reacted via preparative HPLC (Method 3) After purification, 20 mg (9.4%) of the desired compound was obtained.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.26 (s, 3H), 5.60 (s, 2H), 7.34-7.42 (m, 2H), 7.85-7.92 (m, 2H), 7.99 ( s, 1H), 8.09-8.22 (m, 1H), 8.34-8.41 (m, 2H), 10.54 (s, 1H).

Example 217 6-bromo-N-{3,5-dimethyl-1-[4-(methylsulfonyl)benzyl]-1H-pyrazol-4-yl}-2-(trifluoromethyl) Quinoline-4-carboxamide

In a manner similar to Example 118), 112 mg (0.40 mmol) of 3,5-dimethyl-1-[4-(methylsulfonyl)benzyl]-1H-pyrazol-4-amine (intermediate) 37C) and 107 mg (0.33 mmol) of 6-bromo-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 1A) were reacted to give 105 mg (52) after purification by preparative HPLC (Method 3). %) The desired compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.15 (s, 3H), 2.20 (s, 3H), 3.19 (s, 3H), 5.39 (s, 2H), 7.42 (d, 2H) , 7.92 (d, 2H), 8.14 (dd, 1H), 8.22 (d, 1H), 8.29 (s, 1H), 8.50 (d, 1H), 10.18 (s, 1H).

Example 218 6-Bromo-N-[1-(4-cyano-3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quina Porphyrin-4-carboxamide

In a manner similar to Example 118), 92 mg (0.38 mmol) of 4-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]-2-fluorobenzoic acid Reaction of the nitrile (intermediate 38C) with 100 mg (0.31 mmol) of 6-bromo-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 1A), after purification via preparative HPLC (Method 3) This gave 74 mg (42%) of desired compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.13 (s, 3H), 2.23 (s, 3H), 5.39 (s, 2H), 7.15 (t, 1H), 7.71 (dd, 1H) , 7.90 (dd, 1H), 8.14 (dd, 1H), 8.22 (d, 1H), 8.29 (s, 1H), 8.50 (d, 1H), 10.19 (s, 1H).

Example 219 N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-6-fluoroquinoline- 2,4-dimethylamine

In a similar manner to Example 118), 145 mg (0.52 mmol) of 4-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl} Benzoonitrile (Intermediate 26C) and 125 mg (0.43 mmol, purity 81%) of 6-fluoro-2-amine-methylpyridyl quinoline-4-carboxylic acid (Intermediate 8A) were reacted via preparative HPLC (Method 3 After purification, 97 mg (44%) of the desired compound was obtained.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.26 (s, 3H), 5.60 (s, 2H), 7.39 (d, 2H), 7.84-7.95 (m, 5H), 8.25-8.33 ( m, 1H), 8.36 (s, 1H), 8.39 (br.s., 1H), 10.47 (s, 1H).

Example 220 N ⁴ -{1-[(2-Cyanopyridin-3-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-6,7-difluoroquine Porphyrin-2,4-dimethylamine

In a similar manner to Example 118), 100 mg (0.44 mmol) of 3-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]pyridine-2-carbonitrile (Intermediate 39C) and 92 mg (0.37 mmol) of 2-aminoformamido-6,7-difluoroquinoline-4-carboxylic acid (Intermediate 3A), after purification via preparative HPLC (Method 3) 48 mg (27%) of the desired title compound are obtained.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.10 (s, 3H), 2.27 (s, 3H), 5.47 (s, 2H), 7.61 (dd, 1H), 7.76 (dd, 1H) , 7.97 (s, 1H), 8.11-8.29 (m, 2H), 8.37 (s, 1H), 8.40 (s, 1H), 8.71 (dd, 1H), 10.25 (s, 1H).

Example 221 N ⁴ -[1-(2-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-6-fluoroquinoline-2,4-dimethylhydrazine amine

117 mg (0.52 mmol) of 2-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]benzonitrile (intermediate) in a similar manner to Example 118) 10C) and 125 mg (0.43 mmol, purity 81%) of 6-fluoro-2-amine-methylpyridyl quinoline-4-carboxylic acid (Intermediate 8A) are reacted to give 96 mg after purification by preparative HPLC (Method 3) (48%) of the desired compound.

^{1 H-NMR (300MHz, DMSO} d 6) δ (ppm) = 2.12 (s, 3H), 2.24 (s, 3H), 5.43 (s, 2H), 7.11 (d, 1H), 7.47-7.57 (m, 1H), 7.66-7.75 (m, 1H), 7.83-7.94 (m, 3H), 7.99 (dd, 1H), 8.28 (dd, 1H), 8.35-8.43 (m, 2H), 10.18 (s, 1H) .

Example 222 N ⁴ -{1-[(3-Cyanopyridin-2-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-6,7-difluoroquine Porphyrin-2,4-dimethylamine

100 mg (0.44 mmol) of 2-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]nicotinonitrile (intermediate) in a similar manner to Example 118) 40C) and 92 mg (0.37 mmol) of 2-aminoformamido-6,7-difluoroquinoline-4-carboxylic acid (Intermediate 3A) are reacted to give 40 mg after purification by preparative HPLC (Method 3) 22%) of the desired compound.

¹ H-NMR (400MHz, DMSO d ₆ ) δ (ppm) = 2.06 (s, 3H), 2.30 (s, 3H), 5.52 (s, 2H), 7.57 (dd, 1H), 7.95 (s, 1H) , 8.13 - 8.26 (m, 2H), 8.34 - 8.41 (m, 3H), 8.79 (dd, 1H), 10.20 (s, 1H).

Example 223 N ⁴ -{1-[(2-Cyanopyridin-3-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}quinoline-2,4-di Formamide

In a similar manner to Example 118), 100 mg (0.44 mmol) of 3-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]pyridine-2-carbonitrile (Intermediate 39C) and 79 mg (0.37 mmol) of 2-aminopyridylquinoline-4-carboxylic acid (Intermediate 4A) were reacted to afford 46 mg (28%) after purification by preparative HPLC (Method 3) Title compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.12 (s, 3H), 2.29 (s, 3H), 5.48 (s, 2H), 7.61 (dd, 1H), 7.73-7.86 (m, 2H), 7.88-7.99 (m, 2H), 8.21 (d, 1H), 8.26 (d, 1H), 8.29 (s, 1H), 8.39 (br.s., 1H), 8.71 (dd, 1H), 10.13(s, 1H).

Example 224 N ⁴ -{3,5-Dimethyl-1-[4-(methylsulfonyl)benzyl]-1H-pyrazol-4-yl}quinoline-2,4-dimethyl Guanamine

In a manner similar to Example 118), 112 mg (0.40 mmol) of 3,5-dimethyl-1-[4-(methylsulfonyl)benzyl]-1H-pyrazol-4-amine (intermediate) 37C) and 72 mg (0.33 mmol) of 2-aminopyridylquinoline-4-carboxylic acid (Intermediate 4A) were taken to give 70 mg (42%) of desired compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.15 (s, 3H), 2.20 (s, 3H), 3.19 (s, 3H), 5.39 (s, 2H), 7.43 (d, 2H) , 7.77-7.84 (m, 1H), 7.86-7.96 (m, 4H), 8.20 (d, 1H), 8.25 (d, 1H), 8.27 (s, 1H), 8.35-8.40 (m, 1H), 10.08 (s, 1H).

Example 225 N ⁴ -{1-[(6-Cyanopyridin-3-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}quinoline-2,4-di Formamide

105 mg (0.46 mmol) of 5-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]pyridine-2-carbonitrile were obtained in a similar manner to Example 118) (Intermediate 29C) and 91 mg (0.42 mmol) of 2-aminopyridylquinoline-4-carboxylic acid (Intermediate 4A) were reacted to afford 28 mg (15%) after purification by preparative HPLC (Method 3) Title compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.14 (s, 3H), 2.22 (s, 3H), 5.43 (s, 2H), 7.72-7.85 (m, 2H), 7.86-7.97 ( m, 2H), 8.04 (d, 1H), 8.17-8.29 (m, 3H), 8.37 (br.s., 1H), 8.60 (d, 1H), 10.09 (s, 1H).

Example 226 6,7-difluoro-N ⁴ -[1-(4-Methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine

105 mg (0.46 mmol) of 1-(4-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 11C) in a similar manner to Example 118) 91 mg (0.42 mmol) of 2-aminoformamido-6,7-difluoroquinoline-4-carboxylic acid (Intermediate 3A) was taken to give a solid which was obtained after filtration of the reaction mixture, which was used without further purification. 128 mg (62%) of the desired compound.

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 2.11 (s, 3H), 2.16 (s, 3H), 3.72 (s, 3H), 5.16 (s, 2H), 6.87-6.94 (m, 2H), 7.12-7.18 (m, 2H), 7.95 (s, 1H), 8.15 (dd, 1H), 8.22 (dd, 1H), 8.35 (s, 1H), 8.37 (s, 1H), 10.14 (s , 1H).

Example 227 6-fluoro-N ⁴ -[1-(4-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-2,4-dimethyl Guanamine

120 mg (0.52 mmol) of 1-(4-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 11C) and in a similar manner to Example 118) 125 mg (0.43 mmol, purity 81%) of 6-fluoro-2-aminepyridylquinoline-4-carboxylic acid (Intermediate 8A) was reacted to give 95 mg (47%) after purification by preparative HPLC (Method 3). The title compound is required.

^{1 H-NMR (300MHz, DMSO} d 6) δ (ppm) = 2.12 (s, 3H), 2.16 (s, 3H), 3.73 (s, 3H), 5.16 (s, 2H), 6.86-6.95 (m, 2H), 7.11-7.19 (m, 2H), 7.81-7.92 (m, 2H), 7.97 (dd, 1H), 8.27 (dd, 1H), 8.35-8.41 (m, 2H), 10.09 (s, 1H) .

Example 228 N ⁴ -[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-6-fluoroquinoline-2,4-dimethylhydrazine amine

In a manner similar to Example 118), 117 mg (0.52 mmol) of 4-[(4-amino-3,5- Dimethyl-1H-pyrazol-1-yl)methyl]benzonitrile (Intermediate 8C) and 125 mg (0.43 mmol, purity 81%) 6-fluoro-2-amine-methylpyridylquinolin-4-carboxylic acid (Intermediate 8A) was reacted to give 115 mg (57%) of desired compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.14 (s, 3H), 2.16 (s, 3H), 5.37 (s, 2H), 7.32 (d, 2H), 7.80-7.94 (m, 4H), 7.98 (dd, 1H), 8.28 (dd, 1H), 8.34-8.42 (m, 2H), 10.15 (s, 1H).

Example 229 6-fluoro-N ⁴ -[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine

105 mg (0.48 mmol) of 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 1C) and 156 mg (105 mg) 0.40 mmol, purity 60%) 6-fluoro-2-amine-methylpyridylquinoline-4-carboxylic acid (Intermediate 8A) was reacted to give 57 mg (31%) after purification by preparative HPLC (Method 3) Title compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.12 (s, 3H), 2.17 (s, 3H), 5.24 (s, 2H), 7.14 - 7.29 (m, 4H), 7.83 - 8.01 ( m, 3H), 8.27 (dd, 1H), 8.35-8.43 (m, 2H), 10.13 (s, 1H).

Example 230 N ⁴ -[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-6,7-difluoroquinoline-2,4-di Formamide

105 mg (0.46 mmol) of 4-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]benzonitrile (intermediate) in a manner analogous to Example 118) 8C) and 91 mg (0.42 mmol) of 2-aminoformamido-6,7-difluoroquinoline-4-carboxylic acid (Intermediate 3A) were reacted using a Biotage chromatography system (10 g snap-on KP-Sil tube) Column, hexane/90-100% ethyl acetate, then ethyl acetate /EtOAc (EtOAc:EtOAc:EtOAc) Title compound.

¹ H-NMR (400MHz, DMSO d ₆ ) δ (ppm) = 2.13 (s, 3H), 2.16 (s, 3H), 5.37 (s, 2H), 7.29-7.35 (m, 2H), 7.81-7.87 ( m, 2H), 7.95 (s, 1H), 8.16 (dd, 1H), 8.24 (dd, 1H), 8.35 (s, 1H), 8.39 (s, 1H), 10.20 (s, 1H).

Example 231 N ⁴ -{3,5-Dimethyl-1-[4-(methylsulfonyl)benzyl]-1H-pyrazol-4-yl}-6,7-difluoroquinoline- 2.4-dimethylamine

In a manner similar to Example 118), 112 mg (0.40 mmol) of 3,5-dimethyl-1-[4-(methylsulfonyl)benzyl]-1H-pyrazol-4-amine (intermediate) 37C) and 84 mg (0.33 mmol) of 2-aminoformamido-6,7-difluoroquinoline-4-carboxylic acid (Intermediate 3A) are reacted to give 45 mg after purification by preparative HPLC (Method 3). 25%) of the desired compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.13 (s, 3H), 2.18 (s, 3H), 3.20 (s, 3H), 5.39 (s, 2H), 7.38-7.46 (m, 2H), 7.88-7.95 (m, 2H), 7.97 (br.s., 1H), 8.10-8.28 (m, 2H), 8.34-8.41 (m, 2H), 10.21 (s, 1H).

Example 232 N ⁴ -[1-(2-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine

126 mg (0.56 mmol) of 2-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]benzonitrile (intermediate) in a similar manner to Example 118) 10C) and 100 mg (0.46 mmol) of 2-aminopyridylquinoline-4-carboxylic acid (Intermediate 4A) were obtained to give 118 mg (55%) of desired compound.

^{1 H-NMR (300MHz, DMSO} d 6) δ (ppm) = 2.13 (s, 3H), 2.26 (s, 3H), 5.44 (s, 2H), 7.10 (d, 1H), 7.47-7.56 (m, 1H), 7.71 (td, 1H), 7.77-7.86 (m, 1H), 7.86-7.97 (m, 3H), 8.17-8.30 (m, 3H), 8.37 (br.s., 1H), 10.10 (s , 1H).

Example 233 2-cyclopropyl-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-6-methoxyquinoline- 4-carboxamide

108 mg (0.49 mmol) of 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 1C) and 100 mg (10 mg) Reaction of 0.41 mmol) of 2-cyclopropyl-6-methoxyquinoline-4-carboxylic acid afforded 127 mg (64%).

¹ H-NMR (300 MHz, DMSO d ₆ ) δ (ppm) = 1.00 - 1.13 (m, 4H), 2.13 (s, 3H), 2.17 (s, 3H), 2.27-2.38 (m, 1H), 3.80- 3.83 (m, 3H), 5.23 (s, 2H), 7.14-7.28 (m, 4H), 7.35-7.46 (m, 2H), 7.57 (s, 1H), 7.82 (d, 1H), 9.85 (s, 1H).

Example 234 6-bromo-N-{1-[(3-cyanopyridin-2-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-2-(three Fluoromethyl)quinoline-4-carboxamide

100 mg (0.44 mmol) of 2-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]nicotinonitrile (intermediate) in a similar manner to Example 118) 40C) and 117 mg (0.37 mmol) of 6-bromo-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 1A) were reacted to give 7.7 mg after purification by preparative HPLC (Method 3). 3.8%) of the desired compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.08 (s, 3H), 2.32 (s, 3H), 5.53 (s, 2H), 7.57 (dd, 1H), 8.12-8.17 (m, 1H), 8.23 (d, 1H), 8.29 (s, 1H), 8.37 (dd, 1H), 8.50 (d, 1H), 8.79 (dd, 1H), 10.18 (s, 1H).

Example 235 N ⁴ -[1-(2-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-6,7-difluoroquinoline-2,4-di Formamide

108 mg (0.48 mmol) of 2-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]benzonitrile (intermediate) in a similar manner to Example 118) 10C) and 100 mg (0.40 mmol) of 2-aminoformamido-6,7-difluoroquinoline-4-carboxylic acid (Intermediate 3A) are reacted to give 35 mg after purification by preparative HPLC (Method 3) 18%) of the desired compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.11 (s, 3H), 2.24 (s, 3H), 5.43 (s, 2H), 7.10 (d, 1H), 7.48-7.56 (m, 1H), 7.67-7.75 (m, 1H), 7.90 (dd, 1H), 7.97 (s, 1H), 8.11-8.30 (m, 2H), 8.36-8.43 (m, 2H), 10.24 (s, 1H) .

Example 236 6,7-difluoro-N ⁴ -[1-(3-Fluoro-4-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline -2,4-dimethylamine

118 mg (0.48 mmol) of 1-(3-fluoro-4-methoxybenzyl)-3,5-dimethyl-1H-pyrazole-4-amine (in the middle) The compound 42C) is reacted with 100 mg (0.40 mmol) of 2-aminoformamido-6,7-difluoroquinoline-4-carboxylic acid (Intermediate 3A) to give 80 mg after purification by preparative HPLC (Method 3) (38%) of the desired compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.12 (s, 3H), 2.16 (s, 3H), 3.81 (s, 3H), 5.18 (s, 2H), 6.94-7.07 (m, 2H), 7.14 (t, 1H), 7.97 (br.s., 1H), 8.11-8.30 (m, 2H), 8.32-8.42 (m, 2H), 10.17 (s, 1H).

Example 237 6-chloro-7-fluoro-N ⁴ -[1-(3-Fluoro-4-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quin Porphyrin-2,4-dimethylamine

In a similar manner to Example 118), 111 mg (0.45 mmol) of 1-(3-fluoro-4-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (middle) The compound 42C) was reacted with 100 mg (0.37 mmol) of 2-aminoformamido-6-chloro-7-fluoroquinoline-4-carboxylic acid (Intermediate 32A) to afford after purification by preparative HPLC (Method 3) 24 mg (12%) of the desired compound.

^{1 H-NMR (300MHz, DMSO} d 6) δ (ppm) = 2.16 (s, 3H), 2.12 (s, 3H), 3.81 (s, 3H), 5.18 (s, 2H), 6.95-7.07 (m, 2H), 7.15 (t, 1H), 7.99 (br.s., 1H), 8.12 (d, 1H), 8.34-8.42 (m, 2H), 8.51 (d, 1H), 10.20 (s, 1H).

Example 238 N ⁴ -[1-(3-Fluoro-4-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-2,4-dimethyl Guanamine

In a manner similar to Example 118), 138 mg (0.45 mmol) of 1-(3-fluoro-4-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (middle 42C) and 100 mg (0.46 mmol) of 2-aminopyridylquinoline-4-carboxylic acid (Intermediate 4A) were reacted to give 91 mg (43%) of the desired compound after purification by preparative HPLC (Method 3) .

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.14 (s, 3H), 2.18 (s, 3H), 3.81 (s, 3H), 5.18 (s, 2H), 6.95-7.07 (m, 2H), 7.15 (t, 1H), 7.77-7.85 (m, 1H), 7.87-7.97 (m, 2H), 8.18-8.30 (m, 3H), 8.39 (br.s., 1H), 10.05 (s) , 1H).

Example 239 N-[1-(3-Fluoro-4-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-methoxyquinoline- 4-carboxamide

In a manner similar to Example 118), 147 mg (0.59 mmol) of 1-(3-fluoro-4-methoxy Benzylmethyl)-3,5-dimethyl-1H-pyrazole-4-amine (Intermediate 42C) and 100 mg (0.49 mmol) of 2-methoxyquinoline-4-carboxylic acid are reacted After purification by HPLC (Method 3), 142 mg (yiel.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.12 (s, 3H), 2.16 (s, 3H), 3.80 (s, 3H), 4.03 (s, 3H), 5.17 (s, 2H) , 6.94-7.05(m,2H), 7.14(t,1H), 7.21(s,1H),7.44-7.55(m,1H),7.72(td,1H),7.82-7.89(m,1H),8.04 (d, 1H), 9.88 (s, 1H).

Example 240 N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoroquinoline- 2,4-dimethylamine

In a manner analogous to Example 118), 144 mg (0.51 mmol) of 4-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl} Benzoonitrile (Intermediate 26C) and 100 mg (0.43 mmol) of 2-aminoformamido-7-fluoroquinoline-4-carboxylic acid (Intermediate 37A) are reacted, after purification via preparative HPLC (Method 3) 98 mg (44%) of the desired compound are obtained.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.27 (s, 3H), 5.61 (s, 2H), 7.38 (d, 2H), 7.73-7.84 (m, 1H), 7.86-7.95 ( m, 3H), 7.97 (br.s., 1H), 8.23-8.33 (m, 2H), 8.40 (br.s., 1H), 10.48 (s, 1H).

Example 241 6-chloro-N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-8-fluoro Quinoline-2,4-dimethylamine

In a similar manner to Example 118), 125 mg (0.45 mmol) of 4-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl} Benzoonitrile (Intermediate 26C) and 100 mg (0.37 mmol) of 2-aminoformamido-6-chloro-8-fluoroquinoline-4-carboxylic acid (Intermediate 49A) were reacted via preparative HPLC (Method 3 After purification, 35 mg (16%) of the desired compound was obtained.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.26 (s, 3H), 5.60 (s, 2H), 7.38 (d, 2H), 7.89 (d, 2H), 8.00-8.10 (m, 3H), 8.29 (br.s., 1H), 8.42 (s, 1H), 10.56 (s, 1H).

Example 242 N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoro-6- Oxyquinoline-2,4-dimethylamine

In a manner analogous to Example 118), 76 mg (0.27 mmol) of 4-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl} Benzoonitrile (Intermediate 26C) and 100 mg (0.23 mmol, about 60% purity) of 2-aminocarbamido-7-fluoro-6-methoxyquinoline-4-carboxylic acid (Intermediate 45A) are reacted After purification by preparative HPLC (Method 3), 19 mg (15%)

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.27 (s, 3H), 3.96 (s, 3H), 5.59 (s, 2H), 7.40 (d, 2H), 7.69 (d, 1H) , 7.84-7.97 (m, 4H), 8.24 (s, 1H), 8.27-8.30 (m, 1H), 10.43 (s, 1H).

Example 243 N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-5,7-difluoroquine Porphyrin-2,4-dimethylamine

In a similar manner to Example 118), 106 mg (0.38 mmol) of 4-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl} Benzoonitrile (Intermediate 26C) and 130 mg (0.31 mmol, about 60% purity) of 2-aminoformamido-5,7-difluoroquinoline-4-carboxylic acid (Intermediate 44A) are reacted via preparative After purification by HPLC (Method 5d), 18 mg (11%)

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 2.26 (s, 3H), 5.59 (s, 2H), 7.37 (d, 2H), 7.80-7.91 (m, 4H), 8.01 (s, 1H), 8.04 (s, 1H), 8.40 (s, 1H), 10.29 (s, 1H).

Example 244 N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-5-methylquinoline -2,4-dimethylamine

In a similar manner to Example 118), 58 mg (0.21 mmol) of 4-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl} Benzoonitrile (Intermediate 26C) and 60 mg (0.26 mmol) of 2-aminoformamido-5-methylquinoline-4-carboxylic acid (Intermediate 40A) are reacted after purification via preparative HPLC (Method 4) Yield 16 mg (11%) of the desired compound.

¹ H-NMR (400MHz, DMSO d ₆ ) δ (ppm) = 2.30 (s, 3H), 3.33 (s, 3H), 5.62 (s, 2H), 7.41 (d, 2H), 7.64 (d, 1H) , 7.83 (dd, 1H), 7.88-7.93 (m, 3H), 8.06-8.11 (m, 2H), 8.36-8.42 (m, 1H), 10.47 (s, 1H).

Example 245 N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-6-methoxyquin Porphyrin-2,4-dimethylamine

In a similar manner to Example 118), 130 mg (0.46 mmol) of 4-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl} Benzoonitrile (Intermediate 26C) and 100 mg (0.26 mmol) of 2-aminoformamido-6-methoxyquinoline-4-carboxylic acid (Intermediate 46A) were reacted to give purified via preparative HPLC (Method 3) After that, 95 mg (47%) of the desired compound was obtained.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.27 (s, 3H), 3.88 (s, 3H), 5.60 (s, 2H), 7.39 (d, 2H), 7.51 (d, 1H) , 7.60 (dd, 1H), 7.83 (br.s., 1H), 7.89 (d, 2H), 8.11 (d, 1H), 8.22 (s, 1H), 8.32 (br.s., 1H), 10.40 (s, 1H).

Example 246 7-chloro-N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline- 2,4-dimethylamine

In a similar manner to Example 118), 112 mg (0.40 mmol) of 4-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl} Benzoonitrile (Intermediate 26C) and 100 mg (0.40 mmol) of 2-aminoformamido-7-chloroquinoline-4-carboxylic acid (Intermediate 48A) were reacted via a Biotage chromatography system (10 g snap-on KP- After purification by EtOAc / EtOAc / EtOAc (EtOAc)

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.26 (s, 3H), 5.60 (s, 2H), 7.38 (d, 2H), 7.80-7.93 (m, 3H), 7.98 (s, 1H), 8.16-8.26 (m, 2H), 8.30 (s, 1H), 8.40 (s, 1H), 10.49 (s, 1H).

Example 247 N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-8-fluoroquinoline- 2,4-dimethylamine

In a similar manner to Example 118), 108 mg (0.38 mmol) of 4-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl} Benzoonitrile (Intermediate 26C) and 90 mg (0.38 mmol) of 2-aminomethylmethyl-8-fluoroquinoline-4-carboxylic acid (Intermediate 47A) are reacted, after purification via preparative HPLC (Method 3) Yield 64 mg (31%) of the desired compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.27 (s, 3H), 5.60 (s, 2H), 7.38 (d, 2H), 7.76-7.85 (m, 2H), 7.86-7.92 ( m, 2H), 7.97-8.04 (m, 2H), 8.26 (s, 1H), 8.33 (s, 1H), 10.49 (s, 1H).

Example 248 6-chloro-N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline- 2,4-dimethylamine

In a similar manner to Example 118), 268 mg (0.96 mmol) of 4-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl} Benzoonitrile (Intermediate 26C) and 200 mg (0.80 mmol) of 2-aminoformamido-6-chloroquinoline-4-carboxylic acid (Intermediate 38A) are reacted to afford after purification by preparative HPLC (Method 4) 91 mg (22%) of the desired compound.

¹ H-NMR (400MHz, DMSO d ₆ ) δ (ppm) = 2.26 (s, 3H), 5.60 (s, 2H), 7.39 (d, 2H), 7.89 (d, 2H), 7.94 (s, 1H) , 7.98 (dd, 1H), 8.20-8.25 (m, 2H), 8.35 (s, 1H), 8.41 (s, 1H), 10.49 (s, 1H).

Example 249 N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-5-fluoroquinoline- 2,4-dimethylamine

In a similar manner to Example 118), 120 mg (0.43 mmol) of 4-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl} Benzoonitrile (Intermediate 26C) and 100 mg (0.43 mmol) of 2-aminoformamido-5-fluoroquinoline-4-carboxylic acid (Intermediate 39A) were reacted via a Biotage chromatography system (10 g snap KP) -Sil column, hexane / 80-100% EtOAc (EtOAc)

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.26 (s, 3H), 5.60 (s, 2H), 7.38 (d, 2H), 7.74-7.84 (m, 1H), 7.84-7.92 ( m, 3H), 7.97 (br.s., 1H), 8.24-8.32 (m, 2H), 8.39 (s, 1H), 10.48 (s, 1H).

Example 250 N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-5-fluoroquinoline- 2,4-dimethylamine

In a manner analogous to Example 118), 617 mg (2.20 mmol) of 4-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl} Benzoonitrile (Intermediate 26C) and 570 mg (1.84 mmol) of 6-bromo-2-amine-methylpyridylquinoline-4-carboxylic acid (Intermediate 2A) were reacted via a Biotage chromatography system (two 25g snaps) After two subsequent purifications of the KP-Sil column, hexane / 0-100% ethyl acetate, then ethyl acetate / 0-60% methanol, 480 mg (45%)

¹ H-NMR (400MHz, DMSO d ₆ ) δ (ppm) = 2.26 (s, 3H), 5.60 (s, 2H), 7.39 (d, 2H), 7.89 (d, 2H), 7.94 (s, 1H) , 8.08 (dd, 1H), 8.14 (d, 1H), 8.34 (s, 1H), 8.38-8.44 (m, 2H), 10.49 (s, 1H).

Example 251 N ⁴ -[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-dimethylhydrazine amine

116 mg (0.51 mmol) of 4-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]benzonitrile (intermediate) in a similar manner to Example 118) 8C) and 100 mg (0.40 mmol) of 2-aminoformamido-7-fluoroquinoline-4-carboxylic acid (Intermediate 37A) were reacted to give 103 mg (53%) after purification by preparative HPLC (Method 3) The title compound is desired.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.14 (s, 3H), 2.17 (s, 3H), 5.37 (s, 2H), 7.31 (d, 2H), 7.77 (ddd, 1H) , 7.84 (d, 2H), 7.91 (dd, 1H), 7.95 (br.s., 1H), 8.28 (s, 1H), 8.31 - 8.42 (m, 2H), 10.14 (s, 1H).

Example 252 6-chloro-N ⁴ -[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-8-fluoroquinoline-2,4-di Formamide

In a manner analogous to Example 118), 101 mg (0.45 mmol) of 4-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]benzonitrile (intermediate) 8C) and 100 mg (0.37 mmol) of 2-aminoformamido-6-chloro-8-fluoroquinoline-4-carboxylic acid (Intermediate 49A) are reacted to give 85 mg after purification by preparative HPLC (Method 3) (44%) of the desired compound.

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 2.16 (s, 3H), 2.13 (s, 3H), 5.37 (s, 2H), 7.32 (d, 2H), 7.82-7.87 (m, 2H), 7.96-8.05 (m, 2H), 8.14 (d, 1H), 8.25 (s, 1H), 8.45 (s, 1H), 10.22 (s, 1H).

Example 253 N ⁴ -[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-5,7-difluoroquinoline-2,4-di Formamide

In a manner analogous to Example 118), 162 mg (0.71 mmol) of 4-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]benzonitrile ( intermediate) 8C) and 150 mg (0.37 mmol) of 2-aminoformamido-5,7-difluoroquinoline-4-carboxylic acid (Intermediate 44A) are reacted to give 165 mg (yield after purification by preparative HPLC (Method 5c). 57%) of the desired compound.

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 2.17 (s, 3H), 2.13 (s, 3H), 5.36 (s, 2H), 7.31 (d, 2H), 7.75-7.90 (m, 4H), 8.00 (s, 1H), 8.10 (s, 1H), 8.39 (s, 1H), 9.90 (s, 1H).

Example 254 N ⁴ -[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-7-fluoro-6-methoxyquinoline- 2,4-dimethylamine

62 mg (0.27 mmol) of 4-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]benzonitrile (intermediate) in a similar manner to Example 118) 8C) and 100mg (0.23mmol, Approximately 60% pure) 2-aminoformamido-7-fluoro-6-methoxyquinoline-4-carboxylic acid (Intermediate 45A) was reacted to give 26 mg after purification via preparative HPLC (Method 3). 24%) of the desired compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.15 (s, 3H), 2.17 (s, 3H), 3.97 (s, 3H), 5.37 (s, 2H), 7.33 (d, 2H) , 7.78 (d, 1H), 7.82-7.86 (m, 3H), 7.93 (d, 1H), 8.25-8.29 (m, 2H), 10.11 (s, 1H).

Example 255 8-chloro-N ⁴ -[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylhydrazine amine

In a manner analogous to Example 118), 108 mg (0.48 mmol) of 4-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]benzonitrile ( intermediate) 8C) and 100 mg (0.40 mmol) of 2-aminoformamido-8-chloroquinoline-4-carboxylic acid (Intermediate 43A) were reacted to give 6.7 mg (3.3%) after purification by preparative HPLC (Method 4) The title compound is desired.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.16 (s, 3H), 2.19 (s, 3H), 5.39 (s, 2H), 7.33 (d, 2H), 7.80 (dd, 1H) , 7.86 (d, 2H), 8.08 (d, 1H), 8.12-8.17 (m, 2H), 8.23 (dd, 1H), 8.37 (s, 1H), 10.17 (s, 1H).

Example 256 N ⁴ -[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-7-fluoro-6-methylquinoline-2,4- Dimethylamine

In a manner analogous to Example 118), 104 mg (0.48 mmol) of 4-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]benzonitrile ( intermediate) 8C) and 100 mg (0.40 mmol) of 2-aminoformamido-7-fluoro-6-methylquinoline-4-carboxylic acid (Intermediate 50A) are reacted, after purification by preparative HPLC (Method 4) 93 mg (49%) of the desired compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.16 (s, 3H), 2.18 (s, 3H), 2.50 (s, 3H), 5.39 (s, 2H), 7.34 (d, 2H) , 7.80-7.90 (m, 3H), 7.92 (s, 1H), 8.18 (d, 1H), 8.26 (s, 1H), 8.35 (s, 1H), 10.13 (s, 1H).

Example 257 N ⁴ -[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-5-methylquinoline-2,4-dimethyl Guanamine

In a similar manner to Example 118), 47 mg (0.21 mmol) of 4-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]benzonitrile (intermediate) 8C) and 60mg (0.40mmol) 2- The reaction was carried out by the reaction of preparative HPLC (method 4) to afford 44 mg (37%) of the desired compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.17 (s, 3H), 2.20 (s, 3H), 2.51 (s, 3H), 5.38 (s, 2H), 7.34 (d, 2H) , 7.63 (d, 1H), 7.79-7.87 (m, 3H), 7.90 (d, 1H), 8.07-8.11 (m, 2H), 8.34 - 8.43 (m, 1H), 10.10 (s, 1H).

Example 258 N ⁴ -[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-6-methoxyquinoline-2,4-di Formamide

105 mg (0.46 mmol) of 4-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]benzonitrile (intermediate) in a manner analogous to Example 118) 8C) and 100 mg (0.39 mmol) of 2-aminoformamido-6-methoxyquinoline-4-carboxylic acid (Intermediate 46A) are reacted to give 120 mg (66) after purification by preparative HPLC (Method 3). %) The desired compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.15 (s, 3H), 2.17 (s, 3H), 3.89 (s, 3H), 5.37 (s, 2H), 7.33 (d, 2H) , 7.55-7.63 (m, 2H), 7.84 (d, 3H), 8.10 (d, 1H), 8.25 (s, 1H), 8.30 (d, 1H), 10.07 (s, 1H).

Example 259 N ⁴ -[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine

105 mg (0.46 mmol) of 4-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]benzonitrile (intermediate) in a manner analogous to Example 118) 8C) and 100 mg (0.46 mmol) of 2-aminopyridylquinoline-4-carboxylic acid (Intermediate 4A) were reacted to afford 51 mg (24%) of the desired compound.

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 2.15 (s, 3H), 2.17 (s, 3H), 5.37 (s, 2H), 7.32 (d, 2H), 7.78-7.96 (m, 5H), 8.20 (d, 1H), 8.25 (d, 1H), 8.27 (s, 1H), 8.38 (s, 1H), 10.08 (s, 1H).

Example 260 7-chloro-N ⁴ -[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylhydrazine amine

In a similar manner to Example 118), 90 mg (0.40 mmol) of 4-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]benzonitrile (intermediate) 8C) and 100mg (0.40mmol) 2-Aminoformamido-7-chloroquinoline-4-carboxylic acid (Intermediate 48A) was reacted to afford 41 mg (24%) of the desired compound.

^{1 H-NMR (300MHz, DMSO} d 6) δ (ppm) = 2.14 (s, 3H), 2.16 (s, 3H), 5.37 (s, 2H), 7.31 (d, 2H), 7.81-7.88 (m, 3H), 7.97 (s, 1H), 8.23 (d, 1H), 8.27-8.33 (m, 2H), 8.40 (s, 1H), 10.15 (s, 1H).

Example 261 6-chloro-N ⁴ -[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylhydrazine amine

In a manner analogous to Example 118), 217 mg (0.96 mmol) of 4-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]benzonitrile ( intermediate) 8C) and 200 mg (0.80 mmol) of 2-aminoformamido-6-chloroquinoline-4-carboxylic acid (Intermediate 38A) are reacted to give 33 mg (8.6%) after purification by preparative HPLC (Method 4) Title compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.14 (s, 3H), 2.16 (s, 3H), 5.37 (s, 2H), 7.32 (d, 2H), 7.84 (d, 2H) , 7.93 (s, 1H), 7.97 (dd, 1H), 8.22 (d, 1H), 8.31 (d, 1H), 8.38 (s, 1H), 8.40 (br.s., 1H), 10.17 (s, 1H).

Example 262 N ⁴ -[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-5-fluoroquinoline-2,4-dimethylhydrazine amine

97 mg (0.43 mmol) of 4-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]benzonitrile (intermediate) in a similar manner to Example 118) 8C) and 100 mg (0.43 mmol) of 2-aminoformamido-5-fluoroquinoline-4-carboxylic acid (Intermediate 39A) were reacted to give 97 mg (47%) after purification by preparative HPLC (Method 3) The title compound is desired.

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 2.14 (s, 3H), 2.16 (s, 3H), 5.37 (s, 2H), 7.31 (d, 2H), 7.73-7.80 (m, 1H), 7.82-7.87 (m, 2H), 7.91 (dd, 1H), 7.96 (d, 1H), 8.27 (s, 1H), 8.34 (dd, 1H), 8.39 (d, 1H), 10.15 (s , 1H).

Example 263 N ⁴ -[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-8-fluoroquinoline-2,4-dimethylhydrazine amine

In a manner similar to Example 118), 87 mg (0.38 mmol) of 4-[(4-amino-3,5-) Dimethyl-1H-pyrazol-1-yl)methyl]benzonitrile (Intermediate 8C) and 90 mg (0.38 mmol) 2-Aminomethylmercapto-8-fluoroquinoline-4-carboxylic acid (Intermediate 47A) The reaction, whereby after purification via preparative HPLC (Method 3), afforded 77 mg (41%)

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.14 (s, 3H), 2.17 (s, 3H), 5.37 (s, 2H), 7.31 (d, 2H), 7.74-7.88 (m, 4H), 7.99 (s, 1H), 8.04-8.08 (m, 1H), 8.25 (s, 1H), 8.35 (s, 1H), 10.15 (s, 1H).

Example 264 N ⁴ -[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-6-methylquinoline-2,4-dimethyl Guanamine

98 mg (0.43 mmol) of 4-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]benzonitrile (intermediate) in a similar manner to Example 118) 8C) and 100 mg (0.43 mmol) of 2-aminoformamido-6-methylquinoline-4-carboxylic acid (Intermediate 41A) were reacted to give 17 mg (8.5%) after purification by preparative HPLC (Method 3) The title compound is required.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.15 (s, 3H), 2.17 (s, 3H), 2.54 (s, 3H), 5.37 (s, 2H), 7.33 (d, 2H) , 7.77 (dd, 1H), 7.81-7.88 (m, 3H), 8.01 (s, 1H), 8.09 (d, 1H), 8.23 (s, 1H), 8.35 (s, 1H), 10.07 (s, 1H) ).

Example 265 N-[1-(4-Cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-6-fluoro-2-methoxyquinolin-4- Formamide

86 mg (0.38 mmol) of 4-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]benzonitrile (intermediate) in a similar manner to Example 118) 8C) and 70 mg (0.32 mmol) of 6-fluoro-2-methoxyquinoline-4-carboxylic acid (Intermediate 51A) were reacted to give 112 mg (78%) after purification by preparative HPLC (Method 4) Title compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.12 (s, 3H), 2.14 (s, 3H), 4.03 (s, 3H), 5.36 (s, 2H), 7.30 (d, 2H) , 7.34 (s, 1H), 7.61-7.69 (m, 1H), 7.78 (dd, 1H), 7.84 (d, 2H), 7.92 (dd, 1H), 9.98 (s, 1H).

Example 266 N ⁴ -[1-(2-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-dimethylhydrazine amine

In a manner similar to Example 118), 116 mg (0.51 mmol) of 2-[(4-amino-3,5- Dimethyl-1H-pyrazol-1-yl)methyl]benzonitrile (Intermediate 10C) and 100 mg (0.43 mmol) 2-Aminomethylmercapto-7-fluoroquinoline-4-carboxylic acid (Intermediate 37A) The reaction, whereby after purification via preparative HPLC (Method 3), 86 mg (43%)

^{1 H-NMR (300MHz, DMSO} d 6) δ (ppm) = 2.12 (s, 3H), 2.25 (s, 3H), 5.44 (s, 2H), 7.09 (d, 1H), 7.48-7.56 (m, 1H), 7.67-7.83 (m, 2H), 7.87-8.00 (m, 3H), 8.29 (s, 1H), 8.32-8.42 (m, 2H), 10.17 (s, 1H).

Example 267 N ⁴ -[1-(2-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-5-fluoroquinoline-2,4-dimethylhydrazine amine

In a similar manner to Example 118), 87 mg (0.38 mmol) of 2-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]benzonitrile (intermediate) 10C) and 75 mg (0.32 mmol) of 2-aminoformamido-5-fluoroquinoline-4-carboxylic acid (Intermediate 39A) are reacted to give 35 mg (23%) after purification by preparative HPLC (Method 3) The title compound is desired.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.14 (s, 3H), 2.26 (s, 3H), 5.45 (s, 2H), 7.11 (d, 1H), 7.50-7.58 (m, 1H), 7.69-7.75 (m, 1H), 7.75-7.82 (m, 1H), 7.86-8.01 (m, 3H), 8.30 (s, 1H), 8.33-8.44 (m, 2H), 10.19 (s, 1H).

Example 268 6-bromo-N ⁴ -[1-(2-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine

In a manner similar to Example 118), 92 mg (0.41 mmol) of 2-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]benzonitrile (intermediate) 10C) and 100 mg (0.34 mmol) of 6-bromo-2-amine-methylpyridyl quinoline-4-carboxylic acid (Intermediate 2A) were reacted via preparative HPLC (Method 3) and via Biotage chromatography system (10 g) After a subsequent additional purification of a snap-on KP-Sil column, hexanes / 50-100% ethyl acetate, then ethyl acetate / 0-100% methanol, afforded 26 mg (14%) of the desired compound.

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 2.14 (s, 3H), 2.26 (s, 3H), 5.45 (s, 2H), 7.12 (d, 1H), 7.49-7.58 (m, 1H), 7.73 (td, 1H), 7.91 (dd, 1H), 7.96 (br.s., 1H), 8.07-8.13 (m, 1H), 8.13-8.19 (m, 1H), 8.39 (s, 1H) ), 8.43 (br.s., 1H), 8.50 (d, 1H), 10.23 (s, 1H).

Example 269 6-chloro-N ⁴ -[1-(2-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-8-fluoroquinoline-2,4-di Formamide

In a manner analogous to Example 118), 101 mg (0.45 mmol) of 2-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]benzonitrile ( intermediate) 10C) and 100 mg (0.37 mmol) of 2-aminoformamido-6-chloro-8-fluoroquinoline-4-carboxylic acid (Intermediate 49A) are reacted to give 33 mg after purification by preparative HPLC (Method 3) (17%) of the desired compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.11 (s, 3H), 2.24 (s, 3H), 5.43 (s, 2H), 7.10 (d, 1H), 7.52 (t, 1H) , 7.71 (t, 1H), 7.90 (d, 1H), 7.99-8.07 (m, 2H), 8.15 (s, 1H), 8.28 (s, 1H), 8.46 (s, 1H), 10.27 (s, 1H) ).

Example 270 6-chloro-N ⁴ -[1-(2-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoro Quinoline-2,4-dimethylamine

In a similar manner to Example 118), 94 mg (0.34 mmol) of 2-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl} Benzoonitrile (intermediate 48C) and 75 mg (0.28 mmol) of 2-aminoformamido-6-chloro-7-fluoroquinoline-4-carboxylic acid (Intermediate 32A) are reacted via preparative HPLC (Method 3 After purification, 45 mg (29%) of the desired compound was obtained.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.36 (s, 3H), 5.67 (s, 2H), 7.24 (d, 1H), 7.59 (td, 1H), 7.78 (td, 1H) , 7.95 (dd, 1H), 8.00-8.06 (m, 1H), 8.15 (d, 1H), 8.39 (s, 1H), 8.42 (d, 1H), 8.45 (d, 1H), 10.60 (s, 1H) ).

Example 271 N ⁴ -[1-(2-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-di Formamide

In a similar manner to Example 118), 117 mg (0.42 mmol) of 2-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl} Benzoonitrile (intermediate 48C) and 75 mg (0.28 mmol) of 2-aminopyridylquinoline-4-carboxylic acid (Intermediate 4A) were reacted to give 53 mg (31) after purification by preparative HPLC (Method 3). %) The desired compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.37 (s, 3H), 5.68 (s, 2H), 7.23 (d, 1H), 7.59 (td, 1H), 7.78 (td, 1H) , 7.84 (ddd, 1H), 7.91-7.99 (m, 3H), 8.20-8.25 (m, 2H), 8.29 (s, 1H), 8.42 (d, 1H), 10.47 (s, 1H).

Example 272 N ⁴ -[1-(2-Cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoroquinoline- 2,4-dimethylamine

In a similar manner to Example 118), 108 mg (0.38 mmol) of 2-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl} Benzoonitrile (intermediate 48C) and 75 mg (0.32 mmol) of 2-aminoformamido-7-fluoroquinoline-4-carboxylic acid (Intermediate 37A) are reacted, after purification via preparative HPLC (Method 3) 65 mg (39%) of the desired title compound are obtained.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.36 (s, 3H), 5.68 (s, 2H), 7.22 (d, 1H), 7.59 (td, 1H), 7.73-7.86 (m, 2H), 7.91-8.01 (m, 3H), 8.27-8.34 (m, 2H), 8.41 (d, 1H), 10.52 (s, 1H).

Example 273 N ⁴ -[1-(2-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-5-fluoroquinoline- 2,4-dimethylamine

In a similar manner to Example 118), 108 mg (0.38 mmol) of 2-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl} Benzoonitrile (intermediate 48C) and 75 mg (0.32 mmol) of 2-aminoformamido-5-fluoroquinoline-4-carboxylic acid (Intermediate 39A) are reacted, after purification via preparative HPLC (Method 3) Yield 64 mg (39%) of the desired compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.36 (s, 3H), 5, 68 (s, 2H), 7.22 (d, 1H), 7.59 (td, 1H), 7.73-7.85 ( m, 2H), 7.90-8.02 (m, 3H), 8.27-8.34 (m, 2H), 8.41 (d, 1H), 10.52 (s, 1H).

Example 274 6-bromo-N ⁴ -[1-(2-Cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline- 2,4-dimethylamine

In a similar manner to Example 118), 85 mg (0.31 mmol) of 2-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl} Benzoonitrile (intermediate 48C) and 75 mg (0.25 mmol) of 6-bromo-2-amine-methylpyridylquinoline-4-carboxylic acid (Intermediate 2A) are reacted, after purification via preparative HPLC (Method 3) 39 mg (26%) of the desired compound are obtained.

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 2.36 (s, 3H), 5.67 (s, 2H), 7.24 (d, 1H), 7.56-7.61 (m, 1H), 7.75-7.81 ( m,1H), 7.93-8.00 (m, 2H), 8.10 (dd, 1H), 8.16 (d, 1H), 8.37 (s, 1H), 8.41-8.48 (m, 2H), 10.55 (s, 1H) .

Example 275 7-fluoro-N ⁴ -[1-(4-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-2,4-dimethyl Guanamine

119 mg (0.51 mmol) of 1-(4-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 11C) and 100 mg (0.43 mmol) of 2-aminoformamido-7-fluoroquinoline-4-carboxylic acid (Intermediate 37A), whereby after purification by preparative HPLC (Method 3), 100 mg (48%) .

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.12 (s, 3H), 2.16 (s, 3H), 3.72 (s, 3H), 5.16 (s, 2H), 6.90 (d, 2H) , 7.15 (d, 2H), 7.76 (td, 1H), 7.90 (dd, 1H), 7.95 (br.s., 1H), 8.26 (s, 1H), 8.33 (dd, 1H), 8.38 (br. s., 1H), 10.09 (s, 1H).

Example 276 6-chloro-8-fluoro-N ⁴ -[1-(4-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-2,4- Dimethylamine

103 mg (0.48 mmol) of 1-(4-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 11C) in a similar manner to Example 118) 100 mg (0.37 mmol) of 2-aminoformamido-6-chloro-8-fluoroquinoline-4-carboxylic acid (Intermediate 49A) was reacted to give 28 mg (15%) after purification by preparative HPLC (Method 3) The title compound is required.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.11 (s, 3H), 2.16 (s, 3H), 3.72 (s, 3H), 5.16 (s, 2H), 6.91 (d, 2H) , 7.15 (d, 2H), 7.97-8.07 (m, 2H), 8.13 (s, 1H), 8.27 (br.s., 1H), 8.43 (s, 1H), 10.19 (s, 1H).

Example 277 N ⁴ -[1-(4-Methoxybenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4- Dimethylamine

In a manner similar to Example 118), 198 mg (0.69 mmol) of 1-(4-methoxybenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-amine (Intermediate 49C) and 125 mg (0.58 Methyl) 2-Aminoformylquinoline-4-carboxylic acid (Intermediate 4A) was obtained to give 126 mg (44%) of the desired compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.27 (s, 3H), 3.74 (s, 3H), 5.38 (s, 2H), 6.95 (d, 2H), 7.22 (d, 2H) , 7.77-7.86 (m, 1H), 7.88-7.98 (m, 2H), 8.16-8.29 (m, 3H), 8.40 (br.s., 1H), 10.37 (s, 1H).

Example 278 6-chloro-7-fluoro-N ⁴ -[1-(4-methoxybenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole-4- Quinoline-2,4-dimethylamine

159 mg (0.56 mmol) of 1-(4-methoxybenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-amine were obtained in a manner analogous to Example 118) (Intermediate 49C) and 125 mg (0.47 mmol) of 2-aminoformamido-6-chloro-7-fluoroquinoline-4-carboxylic acid (Intermediate 32A) were reacted after purification via preparative HPLC (Method 3) Yield 93 mg (35%) of the desired compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.26 (s, 3H), 3.74 (s, 3H), 5.38 (s, 2H), 6.95 (d, 2H), 7.22 (d, 2H) , 8.01 (s, 1H), 8.13 (d, 1H), 8.34 (s, 1H), 8.38-8.45 (m, 2H), 10.50 (s, 1H).

Example 279 6,7-difluoro-N ⁴ -[1-(4-Methoxybenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl] Quinoline-2,4-dimethylamine

170 mg (0.60 mmol) of 1-(4-methoxybenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-amine were obtained in a manner analogous to Example 118) (Intermediate 49C) and 125 mg (0.50 mmol) of 2-aminoformamido-6,7-difluoroquinoline-4-carboxylic acid (Intermediate 3A), after purification via preparative HPLC (Method 3) 29 mg (11%) of the desired compound are obtained.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.26 (s, 3H), 3.74 (s, 3H), 5.38 (s, 2H), 6.95 (d, 2H), 7.22 (d, 2H) , 7.98 (s, 1H), 8.09-8.21 (m, 2H), 8.35 (s, 1H), 8.38 (br.s., 1H), 10.48 (s, 1H).

Example 280 N ⁴ -{1-[(6-Methoxypyridin-3-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl} Quinoline-2,4-dimethylamine

In a similar manner to Example 118), 156 mg (0.56 mmol) of 1-[(6-methoxypyridin-3-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H- Pyrazole-4-amine (Intermediate 43C) and 100 The reaction was carried out by the preparative HPLC (method 3) to give 96 mg (42%) of the desired compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.32 (s, 3H), 3.84 (s, 3H), 5.42 (s, 2H), 6.86 (d, 1H), 7.63 (dd, 1H) , 7.78-7.85 (m, 1H), 7.90 (d, 1H), 7.94 (ddd, 1H), 8.15-8.23 (m, 3H), 8.25 (s, 1H), 8.35-8.42 (m, 1H), 10.37 (s, 1H).

Example 281 6-chloro-7-fluoro-N ⁴ -{1-[(6-Methoxypyridin-3-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H- Pyrazol-4-yl}quinoline-2,4-dimethylamine

In a similar manner to Example 118), 128 mg (0.45 mmol) of 1-[(6-methoxypyridin-3-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H- Pyrazole-4-amine (Intermediate 43C) and 100 mg (0.37 mmol) of 2-aminocarbamido-6-chloro-7-fluoroquinoline-4-carboxylic acid (Intermediate 32A) were reacted via preparative HPLC (Method 3) After purification, 72 mg (35%).

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.31 (s, 3H), 3.84 (s, 3H), 5.42 (s, 2H), 6.86 (d, 1H), 7.64 (dd, 1H) , 8.01 (br.s., 1H), 8.07-8.21 (m, 2H), 8.32-8.46 (m, 3H), 10.52 (s, 1H).

Example 282 N ⁴ -{1-[(6-Methoxypyridin-3-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}quinoline-2,4- Dimethylamine

In a manner similar to Example 118), 129 mg (0.56 mmol) of 1-[(6-methoxypyridin-3-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 50C) and 100 mg (0.46 mmol) of 2-aminopyridylquinoline-4-carboxylic acid (Intermediate 4A) were reacted to afford 92 mg (44%) after purification by preparative HPLC (Method 3) Title compound.

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 2.15 (s, 3H), 2.24 (s, 3H), 3.85 (s, 3H), 5.22 (s, 2H), 6.83 (d, 1H) , 7.59 (dd, 1H), 7.83 (ddd, 1H), 7.88-7.98 (m, 2H), 8.10 (d, 1H), 8.22 (d, 1H), 8.25-8.28 (m, 1H), 8.29 (s) , 1H), 8.37-8.43 (m, 1H), 10.06 (s, 1H).

Example 283 6-chloro-7-fluoro-N ⁴ -{1-[(6-Methoxypyridin-3-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl} Quinoline-2,4-dimethylamine

In a similar manner to Example 118), 104 mg (0.45 mmol) of 1-[(6-methoxypyridin-3-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-amine (Intermediate 50C) and 100 mg (0.37 mmol) of 2-aminoformamido-6-chloro-7-fluoroquinoline-4-carboxylic acid (Intermediate 32A) were reacted after purification via preparative HPLC (Method 3) This gave 32 mg (17%) of the desired compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.11 (s, 3H), 2.20 (s, 3H), 3.83 (s, 3H), 5.19 (s, 2H), 6.81 (d, 1H) , 7.57 (dd, 1H), 7.99 (br.s., 1H), 8.05-8.18 (m, 2H), 8.35-8.43 (m, 2H), 8.50 (d, 1H), 10.19 (s, 1H).

Example 284 N ⁴ -{1-[3-(4-Methoxyphenyl)propyl]-3,5-dimethyl-1H-pyrazol-4-yl}quinoline-2,4-di Formamide

In a manner similar to Example 118), 144 mg (0.56 mmol) of 1-[3-(4-methoxyphenyl)propyl]-3,5-dimethyl-1H-pyrazol-4-amine ( Intermediate 44C) was reacted with 100 mg (0.46 mmol) of 2-aminopyridylquinoline-4-carboxylic acid (Intermediate 4A) to give 114 mg (48%) of desired title after purification by preparative HPLC (Method 4) Compound.

¹ H-NMR (400MHz, DMSO d ₆ ) δ (ppm) = 2.01 (tt, 2H), 2.14 (s, 3H), 2.19 (s, 3H), 2.56 (t, 2H), 3.73 (s, 3H) , 3.97 (t, 2H), 6.84-6.90 (m, 2H), 7.16 (dd, 2H), 7.83 (ddd, 1H), 7.89-7.98 (m, 2H), 8.20-8.30 (m, 3H), 8.38 -8.44 (m, 1H), 10.03 (s, 1H).

Example 285 6-chloro-N ⁴ -{1-[(3-Cyanopyridin-4-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-7-fluoroquin Porphyrin-2,4-dimethylamine

In a manner similar to Example 118), 102 mg (0.45 mmol) of 4-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]nicotinonitrile (intermediate) 45C) and 100 mg (0.40 mmol) of 2-aminoformamido-6-chloro-7-fluoroquinoline-4-carboxylic acid (Intermediate 32A) are reacted to give 31 mg after purification by preparative HPLC (Method 3) (18%) of the desired compound.

¹ H-NMR (400MHz, DMSO d ₆ ) δ (ppm) = 2.14 (s, 3H), 2.25 (s, 3H), 5.52 (s, 2H), 6.98 (d, 1H), 8.01 (d, 1H) , 8.15 (d, 1H), 8.39-8.43 (m, 2H), 8.54 (d, 1H), 8.83 (d, 1H), 9.07 (d, 1H), 10.32 (s, 1H).

Example 286 N ⁴ -{1-[(3-Cyanopyridin-4-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}quinoline-2,4-di Formamide

126 mg (0.56 mmol) of 4-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]nicotinonitrile (intermediate) in a similar manner to Example 118) 45C) and 100 mg (0.46 mmol) of 2-aminopyridylquinoline-4-carboxylic acid (Intermediate 4A) were taken to give 94 mg (44%).

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 2.16 (s, 3H), 2.26 (s, 3H), 5.52 (s, 2H), 6.98 (d, 1H), 7.83 (ddd, 1H) , 7.88-7.99 (m, 2H), 8.23 (d, 1H), 8.26-8.30 (m, 1H), 8.31 (s, 1H), 8.41 (d, 1H), 8.83 (d, 1H), 9.07 (s , 1H), 10.17 (s, 1H).

Example 287 6-chloro-N ⁴ -{1-[(3-Cyanopyridin-4-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazole-4- -7-fluoroquinoline-2,4-dimethylamine

In a similar manner to Example 118), 126 mg (0.45 mmol) of 4-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl} Nicotinonitrile (Intermediate 51C) and 100 mg (0.37 mmol) of 2-aminoformamido-6-chloro-7-fluoroquinoline-4-carboxylic acid (Intermediate 32A) are reacted via preparative HPLC (Method 3 After purification, 23 mg (11%) of the desired compound was obtained.

¹ H-NMR (400MHz, DMSO d ₆ ) δ (ppm) = 2.34 (s, 3H), 5.76 (s, 2H), 7.08 (d, 1H), 8.03 (s, 1H), 8.16 (d, 1H) , 8.40 (s, 1H), 8.42 (d, 1H), 8.45 (d, 1H), 8.89 (d, 1H), 9.11 (s, 1H), 10.64 (s, 1H).

Example 288 N ⁴ -{1-[(3-Cyanopyridin-4-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}quin Porphyrin-2,4-dimethylamine

In a similar manner to Example 118), 156 mg (0.56 mmol) of 4-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl} Nicotinonitrile (Intermediate 51C) and 100 mg (0.46 mmol) of 2-aminopyridylquinoline-4-carboxylic acid (Intermediate 4A) are reacted to give 75 mg (33) after purification via preparative HPLC (Method 3). %) The desired compound.

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 2.35 (s, 3H), 5.77 (s, 2H), 7.07 (d, 1H), 7.80-7.88 (m, 1H), 7.90-8.01 ( m, 2H), 8.23 (dd, 2H), 8.30 (s, 1H), 8.42 (s, 1H), 8.88 (d, 1H), 9.11 (s, 1H), 10.51 (s, 1H).

Example 289 N ⁴ -{1-[(6-Cyanopyridin-3-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}quin Porphyrin-2,4-dimethylamine

In a similar manner to Example 118), 115 mg (0.41 mmol) of 5-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl} Pyridine-2-carbonitrile (Intermediate 52C) and 74 mg (0.34 mmol) of 2-aminopyridinium quinoline-4-carboxylic acid (Intermediate 4A) were reacted, after purification by preparative HPLC (Method 3) 38 mg (23%) of the desired compound.

¹ H-NMR (400MHz, DMSO d ₆ ) δ (ppm) = 2.33 (s, 3H), 5.66 (s, 2H), 7.79-7.86 (m, 2H), 7.90 (d, 1H), 7.94 (ddd, 1H), 8.09 (dd, 1H), 8.18-8.23 (m, 2H), 8.26 (s, 1H), 8.39 (d, 1H), 8.69 (d, 1H), 10.42 (s, 1H).

Example 290 N ⁴ -{1-[(6-Cyanopyridin-3-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}-7- Fluoroquinoline-2,4-dimethylamine

In a similar manner to Example 118), 108 mg (0.38 mmol) of 5-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl} Pyridine-2-carbonitrile (Intermediate 52C) and 75 mg (0.32 mmol) of 2-aminoformamido-7-fluoroquinoline-4-carboxylic acid (Intermediate 37A) were reacted via preparative HPLC (Method 4) After purification, 55 mg (23%) of desired title compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.34 (s, 3H), 5.68 (s, 2H), 7.78-7.88 (m, 2H), 7.94 (dd, 1H), 7.98 (d, 1H), 8.11 (dd, 1H), 8.27-8.33 (m, 2H), 8.41 (d, 1H), 8.70 (d, 1H), 10.50 (s, 1H).

Example 291 N ⁴ -{1-[(6-Cyanopyridin-3-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}-5- Fluoroquinoline-2,4-dimethylamine

In a similar manner to Example 118), 108 mg (0.38 mmol) of 5-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl} Pyridine-2-carbonitrile (Intermediate 52C) and 75 mg (0.32 mmol) of 2-aminocarbazin-5-fluoroquinoline-4-carboxylic acid (Intermediate 39A) were reacted via preparative HPLC (Method 4) After purification, 67 mg (23%) of desired compound.

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 2.34 (s, 3H), 5.68 (s, 2H), 7.78-7.87 (m, 2H), 7.94 (dd, 1H), 7.98 (d, 1H), 8.05-8.17 (m, 1H), 8.26-8.33 (m, 2H), 8.41 (d, 1H), 8.70 (d, 1H), 10.50 (s, 1H).

Example 292 N ⁴ -{1-[(6-Cyanopyridin-3-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-7-fluoroquinoline- 2,4-dimethylamine

116 mg (0.51 mmol) of 5-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]pyridine-2-carbonitrile were obtained in a manner analogous to Example 118) (Intermediate 29C) and 100 mg (0.43 mmol) of 2-aminopyridinyl-7-fluoroquinoline-4-carboxylic acid (Intermediate 37A) were reacted to afford 37 mg after purification by preparative HPLC (Method 3) 17%) of the desired compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.15 (s, 3H), 2.23 (s, 3H), 5.45 (s, 2H), 7.74-7.84 (m, 2H), 7.87-7.95 ( m, 1H), 7.97 (s, 1H), 8.06 (d, 1H), 8.29 (s, 1H), 8.34 - 8.42 (m, 2H), 8.62 (d, 1H), 10.17 (s, 1H).

Example 293 6-bromo-N ⁴ -{1-[(6-Cyanopyridin-3-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}quinoline- 2,4-dimethylamine

In a manner similar to Example 118), 92 mg (0.41 mmol) of 5-[(4-amino-3,5- Dimethyl-1H-pyrazol-1-yl)methyl]pyridine-2-carbonitrile (Intermediate 29C) and 100 mg (0.34 mmol) of 6-bromo-2-aminemethylmercaptoquinoline-4-carboxylic acid ( Intermediate 2A) was reacted to give 27 mg (14%) of the desired compound after purified by preparative HPLC (Method 3).

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.15 (s, 3H), 2.23 (s, 3H), 5.45 (s, 2H), 7.78 (dd, 1H), 7.96 (br.s. , 1H), 8.01-8.19 (m, 3H), 8.38 (s, 1H), 8.43 (s, 1H), 8.49 (d, 1H), 8.63 (d, 1H), 10.22 (s, 1H).

Example 294 6-chloro-N ⁴ -{1-[2-(4-Cyanophenoxy)ethyl]-3,5-dimethyl-1H-pyrazol-4-yl}-7-fluoroquin Porphyrin-2,4-dimethylamine

In a similar manner to Example 118), 114 mg (0.45 mmol) of 3,5-dimethyl-1-(2-phenoxyethyl)-1H-pyrazol-4-amine (Intermediate 46C) and 100 mg (0.37 mmol) 2-Aminoformamido-6-chloro-7-fluoroquinoline-4-carboxylic acid (Intermediate 32A) was reacted to give a solid material which was further purified by washing with ethyl acetate. Thus 107 mg (51%) of the desired compound are obtained.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.10 (s, 3H), 2.25 (s, 3H), 4.36-4.46 (m, 4H), 7.07-7.13 (m, 2H), 7.72 7.77 (m, 2H), 7.98 (s, 1H), 8.12 (d, 1H), 8.35-8.40 (m, 2H), 8.49 (d, 1H), 10.17 (s, 1H).

Example 295 N ⁴ -{1-[2-(4-Cyanophenoxy)ethyl]-3,5-dimethyl-1H-pyrazol-4-yl}quinoline-2,4-dimethylamine

142 mg (0.56 mmol) of 3,5-dimethyl-1-(2-phenoxyethyl)-1H-pyrazol-4-amine (Intermediate 46C) and 100 mg were obtained in a similar manner to Example 118) (0.46 mmol) 2-Aminoformylquinoline-4-carboxylic acid (Intermediate 4A) was taken to give 47 mg (21%) of desired compound.

¹ H-NMR (400MHz, DMSO d ₆ ) δ (ppm) = 2.12 (s, 3H), 2.26 (s, 3H), 4.36-4.46 (m, 4H), 7.08-7.13 (m, 2H), 7.72 7.77 (m, 2H), 7.78-7.84 (m, 1H), 7.88 (s, 1H), 7.93 (ddd, 1H), 8.20 (d, 1H), 8.24 (d, 1H), 8.27 (s, 1H) , 8.37 (d, 1H), 10.02 (s, 1H).

Example 296 6-chloro-N ⁴ -[1-(4-Cyano-2-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-7-fluoroquinoline- 2,4-dimethylamine

In a manner similar to Example 118), 142 mg (0.55 mmol) of 4-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]-3-fluorobenzoic acid The nitrile (intermediate 47C) and 124 mg (0.46 mmol) of 2-aminocarbazin-6-chloro-7-fluoroquinoline-4-carboxylic acid (intermediate 32A) were reacted to give 105 mg (44%) after filtration. Title compound.

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 2.12 (s, 3H), 2.22 (s, 3H), 5.40 (s, 2H), 7.17 (t, 1H), 7.73 (dd, 1H) , 7.92 (dd, 1H), 8.01 (br.s., 1H), 8.14 (d, 1H), 8.38-8.45 (m, 2H), 8.53 (d, 1H), 10.26 (s, 1H).

Example 297 N ⁴ -[1-(4-Cyano-2-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylhydrazine amine

In a manner similar to Example 118), 166 mg (0.65 mmol) of 4-[(4-amino-3,5-) Dimethyl-1H-pyrazol-1-yl)methyl]-3-fluorobenzonitrile (Intermediate 47C) and 116 mg (0.54 mmol) of 2-aminopyridylquinoline-4-carboxylic acid (Intermediate 4A) The reaction, after purification via preparative HPLC (Method 3), afforded 113 mg (45%)

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.14 (s, 3H), 2.24 (s, 3H), 5.40 (s, 2H), 7.16 (t, 1H), 7.73 (dd, 1H) , 7.80-7.86 (m, 1H), 7.88-7.98 (m, 3H), 8.22 (d, 1H), 8.27 (d, 1H), 8.30 (s, 1H), 8.39-8.43 (m, 1H), 10.12 (s, 1H).

Example 298 N ⁴ -[1-(4-Cyano-2-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-6,7-difluoroquinoline- 2,4-dimethylamine

In a similar manner to Example 118), 152 mg (0.59 mmol) of 4-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]-3-fluorobenzoic acid Reaction of the nitrile (intermediate 47C) with 124 mg (0.49 mmol) of 2-aminocarbamido-6,7-difluoroquinoline-4-carboxylic acid (Intermediate 3A) after purification via preparative HPLC (Method 3) , 35 mg (14%) of the desired title compound.

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 2.12 (s, 3H), 2.22 (s, 3H), 5.40 (s, 2H), 7.16 (t, 1H), 7.73 (dd, 1H) , 7.92 (dd, 1H), 7.99 (s, 1H), 8.18 (dd, 1H), 8.26 (dd, 1H), 8.39 (s, 1H), 8.41 (s, 1H), 10.24 (s, 1H).

Example 299 6-bromo-N ⁴ -[1-(4-Cyano-2-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-2,4-di Formamide

In a manner similar to Example 118), 99 mg (0.41 mmol) of 4-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]-3-fluorobenzoic acid The nitrile (intermediate 47C) and 100 mg (0.34 mmol) of 6-bromo-2-amine-methylpyridylquinoline-4-carboxylic acid (intermediate 2A) are reacted to give 47 mg after purification by preparative HPLC (method 3) (25%) of the desired compound.

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 2.12 (s, 3H), 2.21 (s, 3H), 5.38 (s, 2H), 7.16 (t, 1H), 7.71 (dd, 1H) , 7.90 (dd, 1H), 7.93 (d, 1H), 8.07 (dd, 1H), 8.14 (d, 1H), 8.37 (s, 1H), 8.40 (d, 1H), 8.48 (d, 1H), 10.19 (s, 1H).

Example 300 N ⁴ -[1-(4-cyano-2-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-di Formamide

In a manner similar to Example 118), 94 mg (0.38 mmol) of 4-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]-3-fluorobenzate Reaction of the nitrile (intermediate 47C) with 75 mg (0.32 mmol) of 2-aminoformamido-7-fluoroquinoline-4-carboxylic acid (Intermediate 37A) to give 40 mg after purification via preparative HPLC (Method 3) (40%) of the desired compound.

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 2.12 (s, 3H), 2.22 (s, 3H), 5.38 (s, 2H), 7.15 (t, 1H), 7.71 (dd, 1H) , 7.77 (ddd, 1H), 7.88-7.95 (m, 3H), 8.28 (s, 1H), 8.32-8.39 (m, 2H), 10.14 (s, 1H).

Example 301 N ⁴ -[1-(4-cyano-2-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-5-fluoroquinoline-2,4-di Formamide

In a manner similar to Example 118), 94 mg (0.38 mmol) of 4-[(4-amino-3,5- Dimethyl-1H-pyrazol-1-yl)methyl]-3-fluorobenzonitrile (Intermediate 47C) and 75 mg (0.32 mmol) 2-Aminomethylindol-5-fluoroquinoline-4-carboxylic acid (Intermediate 39A) was reacted to give 63 mg (39%) of the desired compound.

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 2.12 (s, 3H), 2.22 (s, 3H), 5.38 (s, 2H), 7.15 (t, 1H), 7.71 (dd, 1H) , 7.77 (ddd, 1H), 7.88-7.95 (m, 3H), 8.28 (s, 1H), 8.33-8.39 (m, 2H), 10.14 (s, 1H).

Example 302 N ⁴ -[1-(4-Cyano-2-fluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline- 2,4-dimethylamine

In a manner analogous to Example 118), 178 mg (0.57 mmol) of 4-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl} 3-Fluorobenzonitrile (Intermediate 53C) and 102 mg (0.47 mmol) of 2-aminopyridylquinoline-4-carboxylic acid (Intermediate 4A) are reacted, after purification via preparative HPLC (Method 3) 75 mg (31%) of the desired compound are obtained.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.33 (s, 3H), 5.63 (s, 2H), 7.33 (t, 1H), 7.78 (dd, 1H), 7.84 (ddd, 1H) , 7.91 - 8.01 (m, 3H), 8.22 (ddd, 2H), 8.28 (s, 1H), 8.42 (d, 1H), 10.44 (s, 1H).

Example 303 6-chloro-N ⁴ -[1-(4-Cyano-2-fluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]- 7-fluoroquinoline-2,4-dimethylguanamine

In a manner analogous to Example 118), 166 mg (0.53 mmol) of 4-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl} 3-Fluorobenzonitrile (Intermediate 53C) and 118 mg (0.44 mmol) of 2-aminocarbamido-6-chloro-7-fluoroquinoline-4-carboxylic acid (Intermediate 32A) are reacted After purification by HPLC (Method 4), 52 mg (21.

¹ H-NMR (400MHz, DMSO d ₆ ) δ (ppm) = 2.32 (s, 3H), 5.63 (s, 2H), 7.33 (t, 1H), 7.78 (dd, 1H), 7.97 (dd, 1H) , 8.02 (d, 1H), 8.15 (d, 1H), 8.38 (s, 1H), 8.42 (br.s., 1H), 8.44 (d, 1H), 10.57 (s, 1H).

Example 304 N ⁴ -[1-(4-Cyano-2-fluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-6,7-di Fluoroquinoline-2,4-dimethylamine

In a manner analogous to Example 118), 166 mg (0.53 mmol) of 4-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl} 3-Fluorobenzonitrile (Intermediate 53C) and 111 mg (0.44 mmol) of 2-aminocarbamido-6,7-difluoroquinoline-4-carboxylic acid (Intermediate 3A) were reacted via preparative HPLC (Method 3) After purification, 107 mg (43%) of Compound

¹ H-NMR (400MHz, DMSO d ₆ ) δ (ppm) = 2.32 (s, 3H), 5.63 (s, 2H), 7.33 (t, 1H), 7.78 (dd, 1H), 7.97 (dd, 1H) , 8.00 (s, 1H), 8.12 - 8.23 (m, 2H), 8.37 - 8.42 (m, 2H), 10.56 (s, 1H).

Example 305 6-bromo-N ⁴ -[1-(4-Cyano-2-fluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl] Quinoline-2,4-dimethylamine

In a similar manner to Example 118), 121 mg (0.41 mmol) of 4-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl} 3-Fluorobenzonitrile (Intermediate 53C) and 100 mg (0.34 mmol) of 6-bromo-2-amine-methylpyridylquinoline-4-carboxylic acid (Intermediate 2A) were reacted via preparative HPLC (Method 3 After purification, 71 mg (35%) of the desired compound was obtained.

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 2.31 (s, 3H), 5.61 (s, 2H), 7.32 (t, 1H), 7.77 (dd, 1H), 7.91-7.98 (m, 2H), 8.08 (dd, 1H), 8.15 (d, 1H), 8.35 (s, 1H), 8.38-8.44 (m, 2H), 10.50 (s, 1H).

Example 306 N ⁴ -[1-(4-Cyano-2-fluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-5-fluoro Quinoline-2,4-dimethylamine

In a similar manner to Example 118), 115 mg (0.38 mmol) of 4-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl} 3-Fluorobenzonitrile (Intermediate 53C) and 75 mg (0.32 mmol) of 2-Aminomethylindol-5-fluoroquinoline-4-carboxylic acid (Intermediate 39A) were reacted via preparative HPLC (Method 3 After purification, 65 mg (38%) of the desired compound was obtained.

¹ H-NMR (400MHz, DMSO d ₆ ) δ (ppm) = 2.33 (s, 3H), 5.63 (s, 2H), 7.32 (t, 1H), 7.72-7.88 (m, 2H), 7.88-8.04 ( m, 3H), 8.22-8.37 (m, 2H), 8.41 (br.s., 1H), 10.50 (s, 1H).

Example 307 6-chloro-N ⁴ -[3-cyano-1-(4-fluorobenzyl)-5-methyl-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4- Dimethylamine

In a similar manner to Example 118), 100 mg (0.41 mmol) of 4-amino-1-(4-fluorobenzyl)-5-methyl-1H-pyrazole-3-carbonitrile (Intermediate 54C) And 92 mg (0.34 mmol) of 2-aminoformamido-6-chloro-7-fluoroquinoline-4-carboxylic acid (Intermediate 32A) were reacted to give 71 mg (38) after purification by preparative HPLC (Method 3). %) The desired compound.

¹ H-NMR (400MHz, DMSO d ₆ ) δ (ppm) = 2.31 (s, 3H), 5.48 (s, 2H), 7.18-7.29 (m, 2H), 7.30-7.40 (m, 2H), 8.02 ( s, 1H), 8.15 (d, 1H), 8.35-8.49 (m, 2H), 8.57 (d, 1H), 10.86 (s, 1H).

Example 308 N ⁴ -[3-cyano-1-(4-fluorobenzyl)-5-methyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine

In a similar manner to Example 118), 100 mg (0.41 mmol) of 4-amino-1-(4-fluorobenzyl)-5-methyl-1H-pyrazole-3-carbonitrile (Intermediate 54C) Reaction with 74 mg (0.34 mmol) of 2-aminopyridylquinoline-4-carboxylic acid (Intermediate 4A) afforded 23 mg (15%) of the desired compound.

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 2.31 (s, 3H), 5.49 (s, 2H), 7.25 (t, 2H), 7.35 (dd, 2H), 7.84 (d, 1H) , 7.89-8.03 (m, 2H), 8.23 (d, 1H), 8.30 (d, 1H), 8.34 (s, 1H), 8.42 (br.s., 1H), 10.73 (s, 1H).

Example 309 6-Bromo-N-[1-(4-cyanobenzyl)-3,5-diethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quina Porphyrin-4-carboxamide

95 mg (0.36 mmol) of 4-[(4-amino-3,5-diethyl-1H-pyrazol-1-yl)methyl]benzonitrile (intermediate) in a manner analogous to Example 118) 55C) and 100mg (0.31mmol) Reaction of 6-bromo-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 1A) afforded 129 mg (71%)

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 1.02 (t, 3H), 1.19 (t, 3H), 2.52-2.66 (m, 4H), 5.42 (s, 2H), 7.30 (d, 2H), 7.85 (d, 2H), 8.15 (dd, 1H), 8.21-8.27 (m, 2H), 8.45 (d, 1H), 10.14 (s, 1H).

Example 310 N ⁴ -[1-(4-cyanobenzyl)-3,5-diethyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine

141 mg (0.56 mmol) of 4-[(4-amino-3,5-diethyl-1H-pyrazol-1-yl)methyl]benzonitrile (intermediate) in a similar manner to Example 118) 55C) and 100 mg (0.46 mmol) of 2-aminopyridinylquinoline-4-carboxylic acid (Intermediate 4A) were obtained to afford 112 mg (51%) of desired compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 1.03 (t, 3H), 1.19 (t, 3H), 2.51-2.66 (m, 4H), 5.41 (s, 2H), 7.31 (d, 2H), 7.78-7.98 (m, 5H), 8.17-8.28 (m, 2H), 8.40 (s, 1H), 10.05 (s, 1H).

Example 311 6-chloro-N ⁴ -[1-(4-cyanobenzyl)-3,5-diethyl-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-di Formamide

In a manner analogous to Example 118), 113 mg (0.45 mmol) of 4-[(4-amino-3,5-diethyl-1H-pyrazol-1-yl)methyl]benzonitrile ( intermediate) 55C) and 100 mg (0.37 mmol) of 2-aminoformamido-6-chloro-7-fluoroquinoline-4-carboxylic acid (Intermediate 32A) are reacted to give 78 mg after purification by preparative HPLC (Method 4) (39%) of the desired compound.

¹ H-NMR (300 MHz, DMSO d ₆ ) δ (ppm) = 1.01 (t, 3H), 1.18 (t, 3H), 2.52-2.66 (m, 4H), 5.41 (s, 2H), 7.31 (d, 2H), 7.85 (d, 2H), 8.01 (s, 1H), 8.13 (d, 1H), 8.33 (s, 1H), 8.37-8.47 (m, 2H), 10.18 (s, 1H).

Example 312 N ⁴ -[1-(4-cyanobenzyl)-3,5-diethyl-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-dimethylhydrazine amine

98 mg (0.38 mmol) of 4-[(4-amino-3,5-diethyl-1H-pyrazol-1-yl)methyl]benzonitrile (intermediate) in a similar manner to Example 118) 55C) and 75mg (0.32mmol) 2-Aminoformamido-7-fluoroquinoline-4-carboxylic acid (Intermediate 37A) was reacted to give 109 mg (yield: 69%) of the desired compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 1.02 (t, 3H), 1.18 (t, 3H), 2.50-2.66 (m, 4H), 5.41 (s, 2H), 7.31 (d, 2H), 7.75-7.87 (m, 3H), 7.91 (dd, 1H), 7.97 (s, 1H), 8.24 (s, 1H), 8.30 (dd, 1H), 8.40 (s, 1H), 10.10 (s) , 1H).

Example 313 7-chloro-N ⁴ -[1-(4-cyanobenzyl)-3,5-diethyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylhydrazine amine

In a similar manner to Example 118), 122 mg (0.48 mmol) of 4-[(4-amino-3,5-diethyl-1H-pyrazol-1-yl)methyl]benzonitrile ( intermediate) 55C) and 100 mg (0.40 mmol) of 2-aminoformamido-7-chloroquinoline-4-carboxylic acid (Intermediate 48A) were reacted to give 96 mg (49%) after purification by preparative HPLC (Method 4) Title compound.

¹ H-NMR (300 MHz, DMSO d ₆ ) δ (ppm) = 1.01 (t, 3H), 1.18 (t, 3H), 2.51-2.67 (m, 4H), 5.41 (s, 2H), 7.31 (d, 2H), 7.81-7.93 (m, 3H), 7.99 (br.s., 1H), 8.21-8.29 (m, 2H), 8.41 (s, 1H), 10.10 (s, 1H).

Example 314 6-chloro-N ⁴ -[1-(4-cyanobenzyl)-5-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoro Quinoline-2,4-dimethylamine

105 mg (0.36 mmol) of 4-{[4-amino-5-ethyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl} was obtained in a manner analogous to Example 118) Benzoonitrile (Intermediate 56C) and 80 mg (0.30 mmol) of 2-aminoformamido-6-chloro-7-fluoroquinoline-4-carboxylic acid (Intermediate 32A) were reacted via preparative HPLC (Method 3 After purification, 61 mg (35%) of the desired compound was obtained.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 1.05 (t, 3H), 2.73 (q, 2H), 5.62 (s, 2H), 7.38 (d, 2H), 7.89 (d, 2H) , 8.00 (s, 1H), 8.14 (d, 1H), 8.32 (s, 1H), 8.35-8.44 (m, 2H), 10.52 (s, 1H).

Example 315 N ⁴ -[1-(4-cyanobenzyl)-5-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoroquinoline- 2,4-dimethylamine

In a manner similar to Example 118), 121 mg (0.41 mmol) of 4-{[4-amino-5- Ethyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}benzonitrile (Intermediate 56C) and 80 mg (0.34 mmol) of 2-amine-mercapto-7-fluoroquinoline 4-carboxylic acid (Intermediate 37A) was reacted to give 66 mg (yield: 36%) of the desired compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 1.05 (t, 3H), 2.72 (q, 2H), 5.62 (s, 2H), 7.38 (d, 2H), 7.74-7.85 (m, 1H), 7.86-7.99 (m, 4H), 8.22-8.30 (m, 2H), 8.38 (br.s., 1H), 10.44 (s, 1H).

Example 316 N ⁴ -[1-(4-cyanobenzyl)-5-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-5-fluoroquinoline- 2,4-dimethylamine

In a similar manner to Example 118), 121 mg (0.41 mmol) of 4-{[4-amino-5-ethyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl} Benzoonitrile (Intermediate 56C) and 80 mg (0.34 mmol) of 2-aminoformamido-5-fluoroquinoline-4-carboxylic acid (Intermediate 39A) are reacted, after purification via preparative HPLC (Method 3) 78 mg (36%) of the desired compound are obtained.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 1.05 (t, 3H), 2.72 (q, 2H), 5.62 (s, 2H), 7.38 (d, 2H), 7.75-7.85 (m, 1H), 7.87-7.98 (m, 4H), 8.22-8.29 (m, 2H), 8.38 (s, 1H), 10.44 (s, 1H).

Example 317 N ⁴ -[1-(4-cyanobenzyl)-5-isopropyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4- Dimethylamine

In a manner similar to Example 118), 232 mg (0.41 mmol, about 80% purity) of 4-{[4-amino-5-isopropyl-3-(trifluoromethyl)-1H-pyrazole-1 -Methyl}benzonitrile (Intermediate 57C) and 203 mg (0.75 mmol) of 2-aminopyridylquinoline-4-carboxylic acid (Intermediate 4A) were reacted via two subsequent preparative HPLCs (methods) 4) After purification, 27 mg (6.7%) of desired title compound.

¹ H-NMR (500MHz, DMSO d ₆ ) δ (ppm) = 1.22 (d, 6H), 3.24 (spt, 1H), 5.64 (s, 2H), 7.36 (d, 2H), 7.82 (ddd, 1H) , 7.87-7.97 (m, 4H), 8.18-8.24 (m, 3H), 8.38-8.42 (m, 1H), 10.36 (s, 1H).

Example 318 N ⁴ -[1-(4-cyanobenzyl)-5-isopropyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoroquinoline -2,4-dimethylamine

In a manner similar to Example 118), 148 mg (0.38 mmol, purity about 80%) 4-{[4-Amino-5-isopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}benzonitrile (Intermediate 57C) and 75 mg (0.332 mmol) 2-Aminoformamido-7-fluoroquinoline-4-carboxylic acid (Intermediate 37A) was reacted to give 12 mg (6.7%) of the desired compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 1.20 (d, 6H), 3.24 (spt, 1H), 5.64 (s, 2H), 7.36 (d, 2H), 7.78-7.85 (m, 1H), 7.89 (d, 3H), 7.96 (d, 1H), 8.22 (s, 1H), 8.27 (dd, 1H), 8.39 (d, 1H), 10.41 (s, 1H).

Example 319 N ⁴ -[1-(4-cyanobenzyl)-3-isopropyl-5-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4- Dimethylamine

In a manner analogous to Example 118), 175 mg (0.57 mmol) of 4-{[4-amino-3-isopropyl-5-(trifluoromethyl)-1H-pyrazol-1-yl]methyl }benzonitrile (Intermediate 58C) and 102 mg (0.47 mmol) of 2-aminopyridylquinoline-4-carboxylic acid (Intermediate 4A) were reacted via preparative HPLC (Method 3) and finally via Biotage chromatography. After purification of the system (10 g EtOAc EtOAc EtOAc (EtOAc)

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 1.30 (d, 6H), 3.09 (spt, 1H), 5.63 (s, 2H), 7.34 (d, 2H), 7.79-8.00 (m, 5H), 8.17-8.29 (m, 3H), 8.40-8.47 (m, 1H), 10.53 (s, 1H).

Example 320 N ⁴ -[1-(4-cyanobenzyl)-3-isopropyl-5-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoroquinoline -2,4-dimethylamine

In a manner analogous to Example 118), 175 mg (0.57 mmol) of 4-{[4-amino-3-isopropyl-5-(trifluoromethyl)-1H-pyrazol-1-yl]methyl The reaction of benzonitrile (intermediate 58C) and 111 mg (0.47 mmol) of 2-aminoformamido-7-fluoroquinoline-4-carboxylic acid (Intermediate 37A) after purification via preparative HPLC (Method 5d) , 27 mg (9.9%) of the desired title compound are obtained.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 1.29 (d, 6H), 3.08 (spt, 1H), 5.63 (s, 2H), 7.34 (d, 2H), 7.83 (ddd, 1H) , 7.89 (d, 2H), 7.94 (dd, 1H), 8.00 (d, 1H), 8.24 (s, 1H), 8.28 (dd, 1H), 8.42 (s, 1H), 10.58 (s, 1H).

Example 321 N ⁴ -[1-(4-cyanobenzyl)-3-isopropyl-5-methyl-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4- Dimethylamine

In a manner similar to Example 118), 163 mg (0.64 mmol) of 4-[(4-amino-3-isopropyl-5-methyl-1H-pyrazol-1-yl)methyl]benzonitrile (Intermediate 59C) with a small amount of 4-[(4-amino-5-isopropyl-3-methyl-1H-pyrazol-1-yl)methyl]benzonitrile (Intermediate 60C) and 125 mg ( 0.53 mmol) 2-Aminoformamido-7-fluoroquinoline-4-carboxylic acid (Intermediate 37A) was reacted together to give 80 mg (30%) of the desired compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 1.23 (d, 6H), 2.13 (s, 3H), 2.98 (spt, 1H), 5.41 (s, 2H), 7.29 (d, 2H) , 7.77 (ddd, 1H), 7.84 (d, 2H), 7.91 (dd, 1H), 7.94 (d, 1H), 8.25 (s, 1H), 8.31 (dd, 1H), 8.37 (d, 1H), 10.07 (s, 1H).

Example 322 and instance 323 N ⁴ -[1-(4-cyanobenzyl)-3-isopropyl-5-methyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine and N ⁴ -[1-(4-cyanobenzyl)-5-isopropyl-3-methyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine

In a manner similar to Example 118), 176 mg (0.69 mmol) of 4-[(4-amino-3-isopropyl-5-methyl-1H-pyrazol-1-yl)methyl]benzonitrile (Intermediate 59C) with a small amount of 4-[(4-amino-5-isopropyl-3-methyl-1H-pyrazol-1-yl)methyl]benzonitrile (Intermediate 60C) and 125 mg ( 0.58 mmol) the reaction with acyl 2- carbamoyl-4-carboxylic acid (intermediate 4A), so that after purification by preparative HPLC (method 5d), to give ^{99mg (36%) N 4 -} [1- (4 -Cyanobenzyl)-3-isopropyl-5-methyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine and 3.4 mg (1.2%) The structure N ⁴ -[1-(4-cyanobenzyl)-5-isopropyl-3-methyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine as The title compound is desired.

N ⁴ -[1-(4-Cyanobenzyl)-3-isopropyl-5-methyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylhydrazine as an example 322 NMR of the amine: ¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 1.25 (d, 6H), 2.16 (s, 3H), 3.01 (spt, 1H), 5.43 (s, 2H), 7.31 ( d, 2H), 7.80-7.88 (m, 3H), 7.90-7.97 (m, 2H), 8.23 (t, 2H), 8.27 (s, 1H), 8.41 (s, 1H), 10.05 (s, 1H) .

N ⁴ -[1-(4-cyanobenzyl)-5-isopropyl-3-methyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylhydrazine as an example 323 NMR of the amine: ¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm) = 1.29 (d, 6H), 2.31 (s, 3H), 3.02 (spt, 1H), 5.38 (s, 2H), 5.74 (d) , 1H), 7.22 (d, 2H), 7.32 (s, 1H), 7.66 (d, 2H), 7.78 (ddd, 1H), 7.89 (ddd, 1H), 8.09 (d, 1H), 8.23 (d, 1H), 8.46-8.53 (m, 2H).

Example 324 6-chloro-N ⁴ -[1-(4-cyanobenzyl)-3-isopropyl-5-methyl-1H-pyrazol-4-yl]-7-fluoroquinoline- 2,4-dimethylamine

In a manner similar to Example 118), 142 mg (0.56 mmol) of 4-[(4-amino-3-isopropyl-5-methyl-1H-pyrazol-1-yl)methyl]benzonitrile (Intermediate 59C) and 125 mg (0.47 mmol) of 2-aminopyridinyl-6-chloro-7-fluoroquinoline-4-carboxylic acid (Intermediate 32A) were reacted to give a solid. 18%) of the desired compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 1.24 (d, 6H), 2.14 (s, 3H), 2.99 (spt, 1H), 5.42 (s, 2H), 7.31 (d, 2H) , 7.86 (d, 2H), 8.01 (br.s., 1H), 8.14 (d, 1H), 8.37 (s, 1H), 8.41 (s, 1H), 8.48 (d, 1H), 10.18 (br. s., 1H).

Example 325 and instance 326 N ⁴ -[1-(4-cyanobenzyl)-3-ethyl-5-methyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine and N ⁴ -[1-(4-cyanobenzyl)-5-ethyl-3-methyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine

4-[(4-Amino-3-ethyl-5-methyl-1H-pyrazol-1-yl)methyl]benzonitrile and 4-[(4) in a similar manner to Example 118) 267 mg (1.10 mmol) of a mixture of -amino-5-ethyl-3-methyl-1H-pyrazol-1-yl)methyl]benzonitrile (Intermediate 61C and 62C) and 200 mg (0.93 mmol) 2 -Aminoformylquinoline-4-carboxylic acid (Intermediate 4A) is reacted and purified first by Biotage chromatography system (25g snap KP-Sil column, ethyl acetate / 0-30% methanol) and finally via preparative HPLC (method 7) purification / isolation after, to give ^{72mg (16%) N 4 -} [1- (4- cyanophenyl) -3-ethyl-5-methyl -1H- pyrazol - 4-yl]quinoline-2,4-dimethylamine and 65 mg (14%) of its isomer N ⁴ -[1-(4-cyanobenzyl)-5-ethyl-3- Methyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine as the desired compound.

N ⁴ -[1-(4-Cyanobenzyl)-3-ethyl-5-methyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylguanamine as an example 325 NMR: ¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 1.18 (t, 3H), 2.16 (s, 3H), 2.56 (q, 2H), 5.40 (s, 2H), 7.31 (d) , 2H), 7.78-7.86 (m, 3H), 7.87-7.90 (m, 1H), 7.91-7.96 (m, 1H), 8.20 (d, 1H), 8.23 (d, 1H), 8.26 (s, 1H) ), 8.37 (s, 1H), 10.06 (s, 1H).

N ⁴ -[1-(4-Cyanobenzyl)-5-ethyl-3-methyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylguanamine as an example 326 NMR: ¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 1.04 (t, 3H), 2.16 (s, 3H), 2.64 (q, 2H), 5.40 (s, 2H), 7.33 (d) , 2H), 7.75-7.87 (m, 3H), 7.90 (br.s., 1H), 7.92-7.97 (m, 1H), 8.20-8.26 (m, 2H), 8.26 (s, 1H), 8.39 ( s, 1H), 10.06 (s, 1H).

Example 327 and Example 328 N ⁴ -[1-(4-cyanobenzyl)-3-ethyl-5-methyl-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-dimethylamine and N ⁴ -[1-(4-cyanobenzyl)-5-ethyl-3-methyl-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-dimethylamine

In a manner similar to Example 118), 4-[(4-amino-3-ethyl-5-methyl-1H-pyrazol-1-yl)methyl]benzonitrile and 4-[(4) 247 mg (1.03 mmol) of a mixture of -amino-5-ethyl-3-methyl-1H-pyrazol-1-yl)methyl]benzonitrile (Intermediate 61C and 62C) and 200 mg (0.85 mmol) 2 -Aminoformamido-7-fluoroquinoline-4-carboxylic acid (Intermediate 37A) is reacted first via Biotage chromatography system (25g snap KP-Sil column, ethyl acetate / 0-30% methanol) ) and finally purified by preparative HPLC (method 8) purification / isolation after, to give ^{39mg (9.0%) N 4 -} [1- (4- cyanophenyl) -3-ethyl-5-methyl -1H -pyrazol-4-yl]-7-fluoroquinoline-2,4-dimethylamine and 11 mg (2.9%) of its isomer N ⁴ -[1-(4-cyanobenzyl) 5-5-Ethyl-3-methyl-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-dimethylamine as the title compound.

As an example 327, N ⁴ -[1-(4-cyanobenzyl)-3-ethyl-5-methyl-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4- NMR of dimethyl hydrazine: ¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 1.19 (t, 3H), 2.17 (s, 3H), 2.57 (q, 2H), 5.41 (s, 2H) , 7.30-7.35 (m, 2H), 7.76-7.82 (m, 1H), 7.86 (d, 2H), 7.93 (dd, 1H), 7.97 (br.s., 1H), 8.28 (s, 1H), 8.31-8.37 (m, 1H), 8.40 (br.s., 1H), 10.13 (s, 1H).

N ⁴ -[1-(4-Cyanobenzyl)-5-ethyl-3-methyl-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4- NMR of dimethylhydrazine: ¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 1.04 (t, 3H), 2.16 (s, 3H), 2.64 (q, 2H), 5.41 (s, 2H) , 7.31-7.36(m,2H), 7.77-7.83(m,1H),7.86(d,2H),7.91-7.95(m,1H),7.96-7.98(m,1H),8.27(s,1H) , 8.31-8.37 (m, 1H), 8.39-8.42 (m, 1H), 10.13 (s, 1H).

Example 329 (±)-N ⁴ -{1-[1-(4-Cyanophenyl)ethyl]-3,5-dimethyl-1H-pyrazol-4-yl}quinoline-2,4-di Formamide

In a manner similar to Example 118), 133 mg (0.56 mmol) of (±)-4-[1-(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)ethyl] Benzoonitrile (Intermediate 63C) and 100 mg (0.46 mmol) of 2-aminopyridylquinoline-4-carboxylic acid (Intermediate 4A) were reacted to give 81 mg (40) after purification by preparative HPLC (Method 4) %) The desired compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 1.79 (d, 3H), 2.13 (s, 3H), 2.18 (s, 3H), 5.70 (q, 1H), 7.40 (d, 2H) , 7.77-7.84 (m, 3H), 7.88 (d, 1H), 7.90-7.95 (m, 1H), 8.20 (d, 1H), 8.24 (dd, 1H), 8.26 (s, 1H), 8.37 (d) , 1H), 10.04 (s, 1H).

Example 330 (±)-6-chloro-N ⁴ -{1-[1-(4-cyanophenyl)ethyl]-3,5-dimethyl-1H-pyrazol-4-yl}-7-fluoro Quinoline-2,4-dimethylamine

107 mg (0.45 mmol) of (±)-4-[1-(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)ethyl] in a manner analogous to Example 118) Benzoonitrile (Intermediate 63C) and 100 mg (0.37 mmol) of 2-aminoformamido-6-chloro-7-fluoroquinoline-4-carboxylic acid (Intermediate 32A) were reacted via preparative HPLC (Method 4 After purification, 66 mg (35%) of the desired compound was obtained.

¹ H-NMR (400MHz, DMSO d ₆ ) δ (ppm) = 1.79 (d, 3H), 2.16 (s, 3H), 2.12 (s, 3H), 5.69 (q, 1H), 7.40 (d, 2H) , 7.80-7.88 (m, 2H), 7.92-8.01 (m, 1H), 8.10 (d, 1H), 8.34-8.40 (m, 2H), 8.50 (d, 1H), 10.18 (s, 1H).

Example 331 (±)-N ⁴ -{1-[1-(4-Cyanophenyl)ethyl]-3,5-dimethyl-1H-pyrazol-4-yl}-8-fluoroquinoline- 2,4-dimethylamine

In a manner similar to Example 118), 123 mg (0.51 mmol) of (±)-4-[1-(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)ethyl] Benzoonitrile (Intermediate 63C) and 100 mg (0.43 mmol) of 2-aminomethylmethyl-8-fluoroquinoline-4-carboxylic acid (Intermediate 47A) are reacted, after purification via preparative HPLC (Method 4) 80 mg (38%) of the desired compound are obtained.

¹ H-NMR (400MHz, DMSO d ₆ ) δ (ppm) = 1.79 (d, 3H), 2.13 (s, 3H), 2.17 (s, 3H), 5.70 (q, 1H), 7.40 (d, 2H) , 7.74-7.86 (m, 4H), 7.96 (s, 1H), 8.02-8.07 (m, 1H), 8.22 (s, 1H), 8.33 (s, 1H), 10.09 (s, 1H).

Example 332 (±)-N ⁴ -{1-[1-(4-Cyanophenyl)ethyl]-3,5-dimethyl-1H-pyrazol-4-yl}-8-fluoroquinoline- 2,4-dimethylamine

In a similar manner to Example 118), 90 mg (0.36 mmol) of (±)-4-[1-(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)ethyl] Benzoonitrile (Intermediate 63C) and 100 mg (0.31 Ethyl 6-bromo-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 1A) was obtained to give 119 mg (yield: 68%).

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 1.79 (d, 3H), 2.13 (s, 3H), 2.18 (s, 3H), 5.70 (q, 1H), 7.39 (d, 2H) , 7.80-7.85 (m, 2H), 8.11-8.16 (m, 1H), 8.20-8.24 (m, 1H), 8.27 (s, 1H), 8.49 (d, 1H), 10.14 (s, 1H).

Example 333 (±)-N ⁴ -{1-[1-(4-Cyanophenyl)ethyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}quin Porphyrin-2,4-dimethylamine

In a manner similar to Example 118), 163 mg (0.56 mmol) of (±)-4-{1-[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazole-1 -yl]ethyl}benzonitrile (Intermediate 64C) and 100 mg (0.46 mmol) of 2-aminopyridylquinoline-4-carboxylic acid (Intermediate 4A) were reacted via a Biotage chromatography system (10 g snap) After purification of the mp.

¹ H-NMR (400MHz, DMSO d ₆ ) δ (ppm) = 1.85 (d, 3H), 2.22 (s, 3H), 5.96 (q, 1H), 7.43 (d, 2H), 7.81 (ddd, 1H) , 7.85-7.91 (m, 3H), 7.91-7.96 (m, 1H), 8.16-8.22 (m, 2H), 8.25 (s, 1H), 8.36-8.40 (m, 1H), 10.37 (s, 1H) .

Example 334 (±)-7-fluoro-N ⁴ -[5-Methyl-1-(1-phenylethyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine

560 mg (2.08 mmol) of (±)-5-methyl-1-(1-phenylethyl)-3-(trifluoromethyl)-1H-pyrazole-4-, in a similar manner to Example 118) The amine (intermediate 65C) and 406 mg (1.73 mmol) of 2-aminoformamido-7-fluoroquinoline-4-carboxylic acid (intermediate 37A) were reacted via a Biotage chromatography system (25 g snap-on KP-Sil) Column, hexane / 0-100% ethyl acetate, followed by ethyl acetate / 0-100% methanol) afforded 816 mg (97%) of EtOAc EtOAc This gave 86 mg (9.9%) of the desired compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 1.85 (d, 3H), 2.22 (s, 3H), 5.84 (q, 1H), 7.24 - 7.43 (m, 5H), 7.76 - 7.85 ( m, 1H), 7.93 (dd, 1H), 7.97 (br.s., 1H), 8.24-8.33 (m, 2H), 8.40 (br.s., 1H), 10.42 (s, 1H).

Example 335 and Example 336 ( R or S )-7-fluoro-N ⁴ -[5-Methyl-1-(1-phenylethyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine and ( S or R )-7-fluoro-N ⁴ -[5-Methyl-1-(1-phenylethyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine

A 816 mg racemic mixture of the title compound from Example 334 was isolated via mp EtOAc (EtOAc) to afford 129 </RTI> </RTI> <RTIgt; </RTI> </RTI> <RTIgt; a mixture of enantiomers.

Example 337 6-cyano-N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline -2,4-dimethylamine

150 mg (0.27 mmol) of N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-5-fluoroquin A solution of porphyrin-2,4-dimethylguanamine (Example 250), 34.8 mg (0.30 mmol) of zinc cyanide and 31.1 mg (0.027 mmol) of Pd(PPh ₃ ) ₄ in 6.1 mL of DMF was heated to 150 ° C. 2 hours. The same amount of zinc cyanide and Pd(PPh ₃ ) _{4 were} subsequently added and the mixture was heated at 150 ° C for 2 hours, at 60 ° C for 14 hours and at 150 ° C for 7 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate. The organic phase was washed with sodium bicarbonate and brine, dried over sodium sulfate, filtered and evaporated. The crude product was purified via preparative EtOAc (EtOAc)

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 2.28 (s, 3H), 5.60 (s, 2H), 7.39 (d, 2H), 7.89 (d, 2H), 8.04 (br.s. , 1H), 8.24 (dd, 1H), 8.35 (d, 1H), 8.44 (s, 1H), 8.49 (s, 1H), 8.69-8.72 (m, 1H), 10.57 (br.s., 1H) .

Example 338 8-chloro-N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline- 2,4-dimethylamine

In a manner analogous to Example 118), 134 mg (0.48 mmol) of 4-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl} Benzoonitrile (Intermediate 26C) and 100 mg (0.40 mmol) of 2-aminoformamido-8-chloroquinoline-4-carboxylic acid (Intermediate 43A) are reacted, after purification by preparative HPLC (Method 4) 29 mg (14%) of the desired compound.

¹ H-NMR (400MHz, DMSO d ₆ ) δ (ppm) = 2.27 (s, 3H), 5.60 (s, 2H), 7.38 (d, 2H), 7.77-7.82 (m, 1H), 7.87-7.91 ( m, 2H), 8.05-8.18 (m, 4H), 8.34 (s, 1H), 10.48 (s, 1H).

Example 339 N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-methoxyquin Porphyrin-2,4-dimethylamine

In a manner similar to Example 118), 205 mg (0.73 mmol) of 4-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl} Benzoonitrile (Intermediate 26C) and 150mg (0.61 mmol) 2-Aminoformamido-7-methoxyquinoline-4-carboxylic acid (Intermediate 42A) was reacted via a Biotage chromatography system (10 g snap KP-Sil column, hexanes/ After 40-100% ethyl acetate), which was purified by two subsequent preparative HPLC (Methods 5d), 36 mg (10%)

¹ H-NMR (400MHz, DMSO d ₆ ) δ (ppm) = 2.25 (s, 3H), 3.97 (s, 3H), 5.60 (s, 2H), 7.38 (d, 2H), 7.47 (dd, 1H) , 7.55 (d, 1H), 7.84-7.91 (m, 3H), 8.08-8.12 (m, 2H), 8.30-8.34 (m, 1H), 10.37 (s, 1H).

Example 340 2-(azetidin-1-ylcarbonyl)-N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H- Pyrazol-4-yl]-7-fluoroquinoline-4-carboxamide

In a similar manner to Example 118), 97 mg (0.35 mmol) of 4-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl} Benzoonitrile (Intermediate 26C) and 105 mg (0.29 mmol) of 2-(azetidin-1-ylcarbonyl)-7-fluoroquinoline-4-carboxylic acid (Intermediate 52A) are reacted to give a solid. It was filtered and washed with THF. After drying of the solid, 38 mg (24%) of desired title compound.

¹ H-NMR (400MHz, DMSO d ₆ ) δ (ppm) = 2.25 (s, 3H), 2.34 (quin, 2H), 4.16 (t, 2H), 4.74 (t, 2H), 5.60 (s, 2H) , 7.38 (d, 2H), 7.77 (td, 1H), 7.89 (d, 2H), 7.95 (dd, 1H), 8.12 (s, 1H), 8.25 (dd, 1H), 10.44 (s, 1H).

Example 341 N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoro-N ² -(3-hydroxypropyl)quinoline-2,4-dimethylamine

In a manner similar to Example 118), 139 mg (0.50 mmol) of 4-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl} The reaction of benzonitrile (intermediate 26C) and 192 mg (0.50 mmol) including 7-fluoro-2-[(3-hydroxypropyl)aminomethane]quinoline-4-carboxylic acid (intermediate 53A), thereby After two subsequent purifications via preparative HPLC (Method 4), 10 mg (4.2%) of desired title compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 1.76 (quin, 2H), 2.28 (s, 3H), 3.42-3.56 (m, 4H), 4.57 (t, 1H), 5.62 (s, 2H), 7.40 (d, 2H), 7.80 (td, 1H), 7.86-7.96 (m, 3H), 8.26-8.36 (m, 2H), 9.08 (t, 1H), 10.49 (s, 1H).

Example 342 N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoro-N ² -[2- (morpholin-4-yl)ethyl]quinoline-2,4-dimethylamine

In a similar manner to Example 118), 121 mg (0.43 mmol) of 4-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl} Benzoonitrile (Intermediate 26C) and 121 mg (0.43 mmol) including 7-fluoro-2-{[2-(morpholin-4-yl)ethyl]amine-carbenyl}quinoline-4-carboxylic acid (intermediate) The starting material of 54A) was reacted to give 43 mg (18%) of the desired title compound after purification by preparative HPLC (Method 4).

¹ H-NMR (400MHz, DMSO d ₆ ) δ (ppm) = 2.28 (s, 3H), 2.42-2.48 (m, 4H), 2.55 (t, 2H), 3.52 (q, 2H), 3.58-3.63 ( m, 4H), 5.62 (s, 2H), 7.40 (d, 2H), 7.78-7.86 (m, 1H), 7.87-7.99 (m, 3H), 8.26-8.34 (m, 2H), 9.00 (t, 1H), 10.50 (s, 1H).

Example 343 N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoro-6- Quinolinol-2,4-dimethylamine

In a similar manner to Example 118), 135 mg (0.48 mmol) of 4-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl} Benzoonitrile (Intermediate 26C) and 100 mg (0.40 mmol) of 2-aminoformamido-7-fluoro-6-methylquinoline-4-carboxylic acid (Intermediate 50A) are reacted via preparative HPLC (method 4) After purification, 83 mg (39%) of desired compound.

¹ H-NMR (500MHz, DMSO d ₆ ) δ (ppm) = 2.26 (s, 3H), 2.47 (s, 3H), 5.60 (s, 2H), 7.39 (d, 2H), 7.86-7.93 (m, 4H), 8.10 (d, 1H), 8.23 (s, 1H), 8.34 (d, 1H), 10.44 (s, 1H).

Example 344 N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-6-[(2-methoxy Ethylethyl)amino]quinoline-2,4-dimethylamine

In a similar manner to Example 118), 82 mg (0.29 mmol) of 4-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl} Benzoonitrile (Intermediate 26C) and 71 mg (0.24 mmol) of 2-aminoformamido-6-[(2-methoxyethyl)amino]quinoline-4-carboxylic acid (Intermediate 55A) are reacted After purification via preparative HPLC (Method 4), 33 mg (23%)

¹ H-NMR (500MHz, DMSO d ₆ ) δ (ppm) = 2.25 (s, 3H), 3.23 - 3.28 (m, 5H), 3.53 (t, 2H), 5.59 (s, 2H), 6.76 (t, 1H), 6.92 (d, 1H), 7.37-7.41 (m, 3H), 7.61 (d, 1H), 7.85 (d, 1H), 7.88 (d, 2H), 8.03 (s, 1H), 8.09 (d) , 1H), 10.19 (s, 1H).

Example 345 N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-6-(piperidin-1- Quinoline-2,4-dimethylamine

In a similar manner to Example 118), 27 mg (0.096 mmol) of 4-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl} Benzoonitrile (Intermediate 26C) and 24 mg (0.080 mmol) of 2-aminoformamido-6-(piperidin-1-yl)quinoline-4-carboxylic acid (Intermediate 56A) were reacted via preparative HPLC (Method 5d) After purification, 11 mg (23%)

¹ H-NMR (500 MHz, DMSO d ₆ ) δ (ppm) = 1.59-1.69 (m, 6H), 2.27 (s, 3H), 3.35-3.43 (m, 4H), 5.61 (s, 2H), 7.32 ( d,1H), 7.41 (d, 2H), 7.72 (d, 1H), 7.79 (dd, 1H), 7.90 (d, 2H), 7.98 (d, 1H), 8.10 (s, 1H), 8.16-8.24 (m, 1H), 10.29 (s, 1H).

Example 346 6-chloro-N ⁴ -{1-[3-(4-Cyanophenyl)propyl]-3,5-dimethyl-1H-pyrazol-4-yl}-7-fluoroquinoline- 2,4-dimethylamine

In a similar manner to Example 118), 114 mg (0.45 mmol) of 4-[3-(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)propyl]benzonitrile ( Intermediate 66C) is reacted with 100 mg (0.37 mmol) of 2-aminoformamido-6-chloro-7-fluoroquinoline-4-carboxylic acid (Intermediate 32A), after purification via preparative HPLC (Method 4) This gave 26 mg (13%) of the desired compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.07 (quin, 2H), 2.12 (s, 3H), 2.18 (s, 3H), 2.72 (t, 2H), 4.00 (t, 2H) , 7.47 (d, 2H), 7.75-7.80 (m, 2H), 8.01 (s, 1H), 8.14 (d, 1H), 8.38 (s, 1H), 8.41 (d, 1H), 8.51 (d, 1H) ), 10.18 (s, 1H).

Example 347 N ⁴ -{1-[3-(4-Cyanophenyl)propyl]-3,5-dimethyl-1H-pyrazol-4-yl}quinoline-2,4-dimethyl Guanamine

In a manner similar to Example 118), 141 mg (0.56 mmol) of 4-[3-(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)propyl]benzonitrile ( Intermediate 66C) is reacted with 100 mg (0.46 mmol) of 2-aminopyridylquinoline-4-carboxylic acid (Intermediate 4A) to give 74 mg (34%) of desired title after purification by preparative HPLC (Method 4) Compound.

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 2.07 (quin, 2H), 2.13 (s, 3H), 2.20 (s, 3H), 2.73 (t, 2H), 4.00 (t, 2H) , 7.47 (d, 2H), 7.75-7.80 (m, 2H), 7.80-7.85 (m, 1H), 7.91 (d, 1H), 7.93-7.98 (m, 1H), 8.22 (d, 1H), 8.26 (dd, 1H), 8.28 (s, 1H), 8.41 (d, 1H), 10.04 (s, 1H).

Example 348 6-bromo-N-{1-[3-(4-cyanophenyl)propyl]-3,5-dimethyl-1H-pyrazol-4-yl}-2-(trifluoromethyl) Quinoline-4-carboxamide

In a similar manner to Example 118), 95 mg (0.38 mmol) of 4-[3-(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)propyl]benzonitrile ( Intermediate 66C) is reacted with 100 mg (0.31 mmol) of 6-bromo-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 1A) to give 66 mg after purification via preparative HPLC (Method 4) (37%) of the desired compound.

¹ H-NMR (400MHz, DMSO d ₆ ) δ (ppm) = 2.07 (quin, 2H), 2.14 (s, 3H), 2.20 (s, 3H), 2.72 (t, 2H), 4.00 (t, 2H) , 7.47 (d, 2H), 7.75-7.81 (m, 2H), 8.16 (dd, 1H), 8.24 (d, 1H), 8.29 (s, 1H), 8.50 (d, 1H), 10.14 (s, 1H) ).

Example 349 N-{1-[3-(4-Cyanophenyl)propyl]-3,5-dimethyl-1H-pyrazol-4-yl}-2-methoxyquinoline- 4-carboxamide

150 mg (0.59 mmol) of 4-[3-(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)propyl]benzonitrile (in a similar manner to Example 118) Intermediate 66C) was reacted with 100 mg (0.49 mmol) of 2-methoxyquinoline-4-carboxylic acid to afford 43 mg (19%) of the desired compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.06 (quin, 2H), 2.11 (s, 3H), 2.18 (s, 3H), 2.72 (t, 2H), 3.98 (t, 2H) , 4.05(s,3H), 7.22(s,1H), 7.47(d,2H), 7.50-7.56(m,1H), 7.68-7.81(m,3H),7.87(d,1H),8.06(d , 1H), 9.86 (s, 1H).

Example 350 6-bromo-N ⁴ -{1-[(5-Cyanopyridin-2-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}quinoline- 2,4-dimethylamine

In a similar manner to Example 118), 69 mg (0.31 mmol) of 6-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]nicotinonitrile (intermediate) 67C) and 75 mg (0.25 mmol) of 6-bromo-2-amine-methylpyridyl quinoline-4-carboxylic acid (Intermediate 2A) are reacted to give 18 mg (13%) after purification by preparative HPLC (Method 4) The title compound is desired.

¹ H-NMR (500MHz, DMSO d ₆ ) δ (ppm) = 2.12 (s, 3H), 2.21 (s, 3H), 5.46 (s, 2H), 7.23 (d, 1H), 7.94 (s, 1H) , 8.08 (dd, 1H), 8.14 (d, 1H), 8.32 (dd, 1H), 8.37 (s, 1H), 8.41 (d, 1H), 8.48 (d, 1H), 9.00 (dd, 1H), 10.20(s, 1H).

Example 351 6-chloro-N ⁴ -{1-[(5-Cyanopyridin-2-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-7-fluoroquin Porphyrin-2,4-dimethylamine

In a manner similar to Example 118), 108 mg (0.48 mmol) of 6-[(4-amino-3,5- Dimethyl-1H-pyrazol-1-yl)methyl]nicotinic nitrile (Intermediate 67C) and 106 mg (0.40 mmol) of 2-aminomethylmethyl-6-chloro-7-fluoroquinoline-4-carboxylic acid (Intermediate 32A) was reacted to give 15 mg (yield: 7.7%) of the desired title compound after purification by preparative HPLC (Method 3).

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 2.13 (s, 3H), 2.22 (s, 3H), 5.47 (s, 2H), 7.24 (d, 1H), 8.01 (s, 1H) , 8.14 (d, 1H), 8.34 (dd, 1H), 8.38-8.46 (m, 2H), 8.53 (d, 1H), 9.01 (dd, 1H), 10.26 (s, 1H).

Example 352 N ⁴ -{1-[(5-Cyanopyridin-2-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-5-fluoroquinoline- 2,4-dimethylamine

In a similar manner to Example 118), 87 mg (0.38 mmol) of 6-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]nicotinonitrile (intermediate) 67C) and 75 mg (0.32 mmol) of 2-aminoformamido-5-fluoroquinoline-4-carboxylic acid (Intermediate 39A) were reacted to give 58 mg (36%) after purification by preparative HPLC (Method 4) The title compound is desired.

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 2.12 (s, 3H), 2.21 (s, 3H), 5.45 (s, 2H), 7.22 (d, 1H), 7.73-7.81 (m, 1H), 7.89-7.97 (m, 2H), 8.28 (s, 1H), 8.30-8.39 (m, 3H), 8.99 (dd, 1H), 10.14 (s, 1H).

Example 353 6-bromo-N-{1-[(5-cyanopyridin-2-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-2-(three Fluoromethyl)quinoline-4-carboxamide

108 mg (0.48 mmol) of 6-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]nicotinonitrile (intermediate) in a similar manner to Example 118) 67C) and 127 mg (0.40 mmol) of 6-bromo-2-(trifluoromethyl)quinoline-4-carboxylic acid (Intermediate 1A) are reacted to give 76 mg (34) after purification by preparative HPLC (Method 3) %) The desired compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.15 (s, 3H), 2.24 (s, 3H), 5.48 (s, 2H), 7.24 (d, 1H), 8.16 (dd, 1H) , 8.24 (d, 1H), 8.30-8.39 (m, 2H), 8.52 (d, 1H), 9.01 (d, 1H), 10.23 (s, 1H).

Example 354 N ⁴ -{1-[(5-Cyanopyridin-2-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-6,7-difluoroquine Porphyrin-2,4-dimethylamine

108 mg (0.48 mmol) of 6-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]nicotinonitrile (intermediate) in a similar manner to Example 118) 67C) and 100mg (0.40mmol) 2-Aminoformamidin-6,7-difluoroquinoline-4-carboxylic acid (Intermediate 3A) was reacted to afford 58 mg (30%) of desired compound.

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 2.13 (s, 3H), 2.22 (s, 3H), 5.47 (s, 2H), 7.24 (d, 1H), 7.99 (s, 1H) , 8.18 (dd, 1H), 8.26 (dd, 1H), 8.34 (dd, 1H), 8.39 (br.d, 1H), 8.41 (s, 1H), 9.01 (dd, 1H), 10.24 (s, 1H) ).

Example 355 N ⁴ -{1-[(5-Cyanopyridin-2-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}quinoline-2,4-di Formamide

108 mg (0.48 mmol) of 6-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]nicotinonitrile (intermediate) in a similar manner to Example 118) 67C) and 86 mg (0.40 mmol) of 2-aminopyridinylquinoline-4-carboxylic acid (Intermediate 4A) were taken to give 46 mg (26%) of the desired compound.

¹ H-NMR (400MHz, DMSO d ₆ ) δ (ppm) = 2.15 (s, 3H), 2.24 (s, 3H), 5.47 (s, 2H), 7.24 (d, 1H), 7.83 (ddd, 1H) , 7.88-8.01 (m, 2H), 8.22 (d, 1H), 8.27 (d, 1H), 8.30 (s, 1H), 8.34 (dd, 1H), 8.41 (br.d, 1H), 9.02 (dd , 1H), 10.12 (s, 1H).

Example 356 N ⁴ -{1-[(5-Cyanopyridin-2-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-7-fluoroquinoline- 2,4-dimethylamine

In a similar manner to Example 118), 87 mg (0.38 mmol) of 6-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]nicotinonitrile (intermediate) 67C) and 75 mg (0.32 mmol) of 2-aminoformamido-7-fluoroquinoline-4-carboxylic acid (Intermediate 37A) were reacted to give 51 mg (33%) after purification by preparative HPLC (Method 4) The title compound is desired.

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 2.12 (s, 3H), 2.21 (s, 3H), 5.45 (s, 2H), 7.22 (d, 1H), 7.77 (ddd, 1H) , 7.88-7.97 (m, 2H), 8.28 (s, 1H), 8.30-8.39 (m, 3H), 8.99 (dd, 1H), 10.14 (s, 1H).

Example 357 N-{1-[(5-Cyanopyridin-2-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-2-methoxyquin Porphyrin-4-carboxamide

108 mg (0.48 mmol) of 6-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]nicotinonitrile (intermediate) in a similar manner to Example 118) 67C) and 80mg (0.40mmol) 2-Methoxyquinoline-4-carboxylic acid was reacted to give 98 mg (54%) of desired compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.13 (s, 3H), 2.22 (s, 3H), 4.05 (s, 3H), 5.46 (s, 2H), 7.22 (d, 1H) , 7.24 (s, 1H), 7.53 (ddd, 1H), 7.74 (ddd, 1H), 7.87 (d, 1H), 8.07 (dd, 1H), 8.33 (dd, 1H), 9.01 (dd, 1H), 9.95 (s, 1H).

Example 358 6-bromo-N ⁴ -{1-[(5-Cyanopyridin-2-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazole-4- Quinoline-2,4-dimethylamine

86 mg (0.31 mmol) of 6-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl} was obtained in a similar manner to Example 118). Nicotinonitrile (Intermediate 68C) and 75 mg (0.25 mmol) of 6-bromo-2-amine-methylpyridylquinoline-4-carboxylic acid (Intermediate 2A) are reacted, after purification via preparative HPLC (Method 4) 37 mg (33%) of the desired compound are obtained.

^{1 H-NMR (500MHz, DMSO} d 6) δ (ppm) = 2.30 (s, 3H), 5.71 (s, 2H), 7.48 (d, 1H), 7.95 (d, 1H), 8.07-8.11 (m, 1H), 8.15 (d, 1H), 8.35 (s, 1H), 8.38 (dd, 1H), 8.40-8.43 (m, 2H), 9.00-9.02 (m, 1H), 10.50 (s, 1H).

Example 359 6-chloro-N ⁴ -{1-[(5-Cyanopyridin-2-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazole-4- -7-fluoroquinoline-2,4-dimethylamine

In a manner analogous to Example 118), 175 mg (0.56 mmol) of 6-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl} Nicotinonitrile (Intermediate 68C) and 125 mg (0.47 mmol) of 2-aminoformamido-6-chloro-7-fluoroquinoline-4-carboxylic acid (Intermediate 32A) were reacted via preparative HPLC (Method 3 After purification, 53 mg (20%) of the desired compound was obtained.

¹ H-NMR (400MHz, DMSO d ₆ ) δ (ppm) = 2.31 (s, 3H), 5.73 (s, 2H), 7.50 (d, 1H), 8.03 (s, 1H), 8.16 (d, 1H) , 8.35-8.51 (m, 5H), 9.01-9.07 (m, 1H), 10.57 (s, 1H).

Example 360 N ⁴ -{1-[(5-Cyanopyridin-2-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}-7-fluoroquinoline- 2,4-dimethylamine

In a similar manner to Example 118), 108 mg (0.38 mmol) of 6-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl} Nicotinonitrile (Intermediate 68C) and 75 mg (0.32 mmol) of 2-aminoformamido-7-fluoroquinoline-4-carboxylic acid (Intermediate 37A) are reacted, after purification via preparative HPLC (Method 4) 52 mg (32%) of the desired compound are obtained.

¹ H-NMR (400MHz, DMSO d ₆ ) δ (ppm) = 2.32 (s, 3H), 5.73 (s, 2H), 7.50 (d, 1H), 7.79-7.85 (m, 1H), 7.94 (dd, 1H), 7.98 (d, 1H), 8.27-8.34 (m, 2H), 8.37-8.45 (m, 2H), 9.02 (dd, 1H), 10.49 (s, 1H).

Example 361 N ⁴ -{1-[(5-Cyanopyridin-2-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}quin Porphyrin-2,4-dimethylamine

195 mg (0.62 mmol, purity about 90%) of 6-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-, in a similar manner to Example 118) Reaction of benzylidene nitrile (Intermediate 68C) and 112 mg (0.52 mmol) of 2-aminopyridylquinoline-4-carboxylic acid (Intermediate 4A) for purification via preparative HPLC (Method 3) Yield 61 mg (24%) of the desired compound.

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 2.31 (s, 3H), 5.71 (s, 2H), 7.48 (d, 1H), 7.82 (ddd, 1H), 7.90 (d, 1H) , 7.94 (ddd, 1H), 8.19-8.23 (m, 2H), 8.27 (s, 1H), 8.34-8.41 (m, 2H), 9.01 (dd, 1H), 10.41 (s, 1H).

Example 362 6-bromo-N-{1-[(5-cyanopyridin-2-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazole-4- }--2-(trifluoromethyl)quinoline-4-carboxamide

In a similar manner to Example 118), 150 mg (0.62 mmol, purity about 90%) of 6-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazole-1- Reaction of benzylidene nicotinonitrile (intermediate 68C) and 128 mg (0.40 mmol) of 6-bromo-2-(trifluoromethyl)quinoline-4-carboxylic acid (intermediate 1A), whereby preparative HPLC (Method 3) After purification, 120 mg (50%).

¹ H-NMR (400MHz, DMSO d ₆ ) δ (ppm) = 2.34 (s, 3H), 5.73 (s, 2H), 7.50 (d, 1H), 8.17 (dd, 1H), 8.25 (d, 1H) , 8.28 (s, 1H), 8.40 (dd, 1H), 8.44 (d, 1H), 9.02 (dd, 1H), 10.55 (s, 1H).

Example 363 N ⁴ -{1-[(5-Cyanopyridin-2-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}-5- Fluoroquinoline-2,4-dimethylamine

In a similar manner to Example 118), 108 mg (0.38 mmol) of 6-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl} Nicotinonitrile (Intermediate 68C) and 75 mg (0.32 mmol) of 2-aminoformamido-5-fluoroquinoline-4-carboxylic acid (Intermediate 39A) are reacted, after purification via preparative HPLC (Method 4) Yield 63 mg (38%) of the desired compound.

¹ H-NMR (400MHz, DMSO d ₆ ) δ (ppm) = 2.30 (s, 3H), 5.71 (s, 2H), 7.48 (d, 1H), 7.80 (ddd, 1H), 7.92 (dd, 1H) , 7.95 (br.s., 1H), 8.25-8.32 (m, 2H), 8.35-8.41 (m, 3H), 9.00 (dd, 1H), 10.46 (s, 1H).

Example 364 N ⁴ -{1-[(5-Cyanopyridin-2-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}- 6,7-difluoroquinoline-2,4-dimethylamine

In a manner similar to Example 118), 188 mg (0.58 mmol, about 90% purity) of 6-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazole-1- Methyl nicotinic nitrile 68C) and 121 mg (0.48 mmol) of 2-aminoformamido-6,7-difluoroquinoline-4-carboxylic acid (Intermediate 3A) are reacted to give 65 mg after purification by preparative HPLC (Method 3). 22%) of the desired compound.

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 2.31 (s, 3H), 5.73 (s, 2H), 7.50 (d, 1H), 8.01 (br.s., 1H), 8.13-8.23 (m, 2H), 8.37-8.42 (m, 3H), 9.01-9.04 (m, 1H), 10.55 (s, 1H).

Example 365 N-{1-[(5-Cyanopyridin-2-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}-2- Methoxyquinoline-4-carboxamide

In a manner similar to Example 118), 200 mg (0.64 mmol, purity about 90%) of 6-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazole-1- Reaction of benzylidene nitrile (intermediate 68C) and 108 mg (0.53 mmol) of 2-methoxyquinoline-4-carboxylic acid to give 118 mg (46%) after purification by preparative HPLC (Method 3) The title compound is required.

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 2.30 (s, 3H), 4.05 (s, 3H), 5.72 (s, 2H), 7.19 (s, 1H), 7.49 (dd, 1H) , 7.53 (ddd, 1H), 7.75 (ddd, 1H), 7.88 (d, 1H), 8.02 (dd, 1H), 8.39 (dd, 1H), 9.02 (dd, 1H), 10.28 (s, 1H).

Example 366 N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-6-methylquinoline -2,4-dimethylamine

In a similar manner to Example 118), 121 mg (0.43 mmol) of 4-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl} Benzoonitrile (Intermediate 26C) and 100 mg (0.43 mmol) of 2-aminoformamido-6-methylquinoline-4-carboxylic acid (Intermediate 41A) are reacted after purification via preparative HPLC (Method 3) , 18 mg (8.3%) of the desired title compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.26 (s, 3H), 2.54 (s, 3H), 5.60 (s, 2H), 7.39 (d, 2H), 7.78 (dd, 1H) , 7.85-7.92 (m, 3H), 7.95 (s, 1H), 8.10 (d, 1H), 8.22 (s, 1H), 8.35 (d, 1H), 10.39 (s, 1H).

Example 367 4-{[4-{[(2-Aminomethyl-7-fluoroquinolin-4-yl)carbonyl]amino}-5-methyl-3-(trifluoromethyl)- Methyl 1H-pyrazol-1-yl]methyl}benzoate

In a manner similar to Example 118), 2.62 g (8.36 mmol) of 4-{[4-amino-5-- Methyl 3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}benzoate (Intermediate 69C) and 1.63 g (6.97 mmol) of 2-amine-carbazino-7-fluoroquine The oxo-4-carboxylic acid (Intermediate 37A) was reacted to give a crude product which was stirred at room temperature in a mixture of ethyl acetate and methanol (9 > A solid was obtained after filtration, which was dried to give the title compound.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.26 (s, 3H), 3.84 (s, 3H), 5.58 (s, 2H), 7.36 (d, 2H), 7.79 (ddd, 1H) , 7.92 (dd, 1H), 7.96-8.03 (m, 3H), 8.23-8.34 (m, 2H), 8.40 (br.s., 1H), 10.47 (s, 1H).

Example 368 4-{[4-{[(2-Aminomethyl-7-fluoroquinolin-4-yl)carbonyl]amino}-5-methyl-3-(trifluoromethyl)- 1H-pyrazol-1-yl]methyl}benzoic acid

To 1.00 g (1.89 mmol) of 4-{[4-{[(2-aminocarbazinyl-7-fluoroquinolin-4-yl)carbonyl]amino}-5-methyl-3-(trifluoromethyl) Methyl-1H-pyrazol-1-yl]methyl}benzoate (Example 367) A solution of 680 mg of sodium hydroxide in 26.1 mL of water was added to a solution of 13.1 mL of methanol and 10 mL of THF. The mixture was stirred at 25 ° C for 2 hours and then concentrated in vacuo. The residue was diluted with water and a 10% aqueous solution of sulfuric acid was added until pH 5. The solid formed was isolated by filtration and dried in vacuo to give 1.10 g (107% of EtOAc).

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.26 (s, 3H), 5.57 (s, 2H), 7.33 (d, 2H), 7.78 (ddd, 1H), 7.89-7.99 (m, 4H), 8.24-8.31 (m, 2H), 8.37 (d, 1H), 10.45 (s, 1H), 12.53 (br.s., 1H).

Example 369 N ⁴ -[1-(4-Aminomethylbenzyl)methyl-(3-trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoroquin Porphyrin-2,4-dimethylamine

A solution of 0.51 mL (0.25 mmol) of 0.5 M ammonia in dioxane and 90 mg (0.17 mmol) of 4-{[4-{[(2-aminocarbazin-7-) Fluoroquinolin-4-yl)carbonyl]amino}-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}benzoic acid (Example 368), thus After purification by preparative HPLC (Method 5c), 33 mg (35%)

¹ H-NMR (400MHz, DMSO d ₆ ) δ (ppm) = 2.28 (s, 3H), 5.55 (s, 2H), 7.29 (d, 2H), 7.39 (br.s., 1H), 7.80 (ddd , 1H), 7.89 (d, 2H), 7.93 (dd, 1H), 7.98 (br.s., 2H), 8.27 (s, 1H), 8.30 (dd, 1H), 8.41 (s, 1H), 10.47 (s, 1H).

Example 370 7-fluoro-N ⁴ -{5-Methyl-1-[4-(methylamine-mercapto)benzyl]-3-(trifluoromethyl)-1H-pyrazole- 4-yl}quinoline-2,4-dimethylamine

A solution of 0.21 mL (0.42 mmol) of 2M methylamine in THF and 180 mg (0.35 mmol) of 4-{[4-{[(2-aminocarbazin-7-fluoroquine) in a manner analogous to Example 118) Phenyl-4-yl)carbonyl]amino}-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}benzoic acid (Example 368) was reacted, thus After purification by HPLC (Method 3), 14 mg (7.4%)

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.28 (s, 3H), 2.78 (d, 3H), 5.55 (s, 2H), 7.31 (d, 2H), 7.77-7.86 (m, 3H), 7.93 (dd, 1H), 7.98 (d, 1H), 8.27 (s, 1H), 8.30 (dd, 1H), 8.39-8.46 (m, 2H), 10.47 (s, 1H).

Example 371 N ⁴ -{1-[4-(Dimethylaminomethane)benzyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazole-4- -7-fluoroquinoline-2,4-dimethylamine

A solution of 0.21 mL (0.42 mmol) of 2M dimethylamine in THF and 180 mg (0.35 mmol) of 4-{[4-{[(2-aminocarbazin-7-fluoro) in a similar manner to Example 118) Quinoline-4-yl)carbonyl]amino}-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}benzoic acid (Example 368) is reacted After preparative HPLC (Method 3) purification, 115 mg (7.4%)

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 2.29 (s, 3H), 2.94 (d, 6H), 5.54 (s, 2H), 7.28 (d, 2H), 7.43-7.47 (m, 2H), 7.80 (ddd, 1H), 7.94 (dd, 1H), 7.98 (d, 1H), 8.27 (s, 1H), 8.30 (dd, 1H), 8.41 (d, 1H), 10.47 (s, 1H) ).

Example 372 N ⁴ -{1-[4-(azetidin-1-ylcarbonyl)benzyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazole- 4-yl}-7-fluoroquinoline-2,4-dimethylamine

In a manner similar to Example 118), 0.028 mL (0.42 mmol) of azetidine and 180 mg (0.35 mmol) of 4-{[4-{[(2-aminocarbazin-7-fluoroquinolin-4). -yl)carbonyl]amino}-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}benzoic acid (Example 368) was reacted via preparative HPLC ( Method 4) After purification, 53 mg (26%) of desired compound.

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 0.95 (d, 2H), 2.21-2.31 (m, 5H), 4.04 (t, 2H), 4.30 (t, 2H), 5.55 (s, 2H), 7.30 (d, 2H), 7.64-7.68 (m, 2H), 7.81 (ddd, 1H), 7.94 (dd, 1H), 7.98 (d, 1H), 8.27 (s, 1H), 8.30 (dd , 1H), 8.41 (d, 1H), 10.48 (s, 1H).

Example 373 7-fluoro-N ⁴ -[1-{4-[(2-methoxyethyl)aminemethanyl]benzyl}-5-methyl-3-(trifluoromethyl) -1H-pyrazol-4-yl]quinoline-2,4-dimethylamine

31.5 mg (0.35 mmol) of 2-methoxyethylamine and 180 mg (0.35 mmol) of 4-{[4-{[(2-aminoformamido-7-fluoroquinoline) were obtained in a manner similar to Example 118) 4-yl)carbonyl]amino}-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}benzoic acid (Example 368) reaction, thus After purification by HPLC (Method 3), 105 mg (51%)

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.28 (s, 3H), 3.26 (s, 3H), 3.39 - 3.49 (m, 4H), 5.55 (s, 2H), 7.31 (d, 2H), 7.80 (ddd, 1H), 7.87 (d, 2H), 7.93 (dd, 1H), 7.98 (d, 1H), 8.27 (s, 1H), 8.30 (dd, 1H), 8.41 (d, 1H) ), 8.52 (t, 1H), 10.47 (s, 1H).

Example 374 N ⁴ -[1-(4-{[2-(Dimethylamino)ethyl]aminemethanyl}benzyl)-5-methyl-3-(trifluoromethyl)- 1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-dimethylamine

36.9 mg (0.42 mmol) of N,N-dimethylethane-1,2-diamine and 180 mg (0.35 mmol) of 4-{[4-{[(2-amine). Mercapto-7-fluoroquinolin-4-yl)carbonyl]amino}-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}benzoic acid (example) 368) Reaction, whereby after purification via preparative HPLC (Method 4), 67 mg (32%)

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 2.17 (s, 6H), 2.28 (s, 3H), 2.39 (t, 2H), 3.35 (q, 2H), 5.55 (s, 2H) , 7.31 (d, 2H), 7.77-7.87 (m, 1H), 7.93 (dd, 1H), 7.98 (d, 1H), 8.26-8.32 (m, 2H), 8.35-8.43 (m, 2H), 10.47 (s, 1H).

Example 375 7-fluoro-N ⁴ -[1-{4-[(2-hydroxyethyl)aminemethanyl]benzyl}-5-methyl-3-(trifluoromethyl)- 1H-pyrazol-4-yl]quinoline-2,4-dimethylamine

In a manner similar to Example 118), 25.6 mg (0.42 mmol) of 2-aminoethanol and 180 mg (0.35 mmol) of 4-{[4-{[(2-aminocarbazin-7-fluoroquinolin-4). -yl)carbonyl]amino}-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}benzoic acid (Example 368) was reacted via preparative HPLC ( After two subsequent purifications of methods 3 and 5c), 22 mg (11%) of the desired compound was obtained.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.26 (s, 3H), 3.30 (q, 2H), 3.48 (t, 3H), 4.70 (br.s., 1H), 5.53 (s) , 2H), 7.29 (d, 2H), 7.75-7.99 (m, 5H), 8.23-8.32 (m, 2H), 8.37-8.47 (m, 2H), 10.46 (s, 1H).

Example 376 (±)-[{4-[(4-{[(2-Aminomethylsulfonyl-4-yl)carbonyl]amino}-3,5-dimethyl-1H-pyrazole- 1-yl)methyl]phenyl}(methyl)oxy ion-λ ⁶ -sulfinyl]ethyl carbamate

In a manner similar to Example 118), 500 mg (1.43 mmol) of (±)-[{4-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl] Phenyl}(methyl)oxylyl-λ ⁶ -sulfinyl]urethane (intermediate 70C) and 257 mg (1.19 mmol) of 2-aminopyridylquinoline-4-carboxylic acid (intermediate) 4A) Reaction, thus obtaining 390 mg after purification via a Biotage chromatography system (25 g snap KP-Sil column, hexane / 0-100% ethyl acetate followed by ethyl acetate / 0-10% methanol) (60%) of the desired compound. 40 mg of the title compound was purified by preparative HPLC (Method 5c).

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 1.09 (t, 3H), 2.16 (s, 3H), 2.23 (s, 3H), 3.45 (s, 3H), 3.85-3.98 (m, 2H), 5.41 (s, 2H), 7.46 (d, 2H), 7.80-7.85 (m, 1H), 7.89-7.99 (m, 4H), 8.22 (d, 1H), 8.27 (d, 1H), 8.29 (s, 1H), 8.40 (d, 1H), 10.11 (s, 1H).

Example 377 (±)-N ⁴ -{3,5-Dimethyl-1-[4-(S-methylsulfonimidomethyl)benzyl]-1H-pyrazol-4-yl}quin Porphyrin-2,4-dimethylamine

To 225 mg (0.41 mmol) of (±)-[{4-[(4-{[(2-aminocarbazinoquinolin-4-yl)carbonyl]amino}-3,5-dimethyl-1H- Pyrazol-1-yl)methyl]phenyl}(methyl)oxylyl-λ ⁶ -sulfinyl]urethane (Example 376) 551 μL 21% in a solution of 4.2 mL of ethanol A solution of sodium ethoxide in ethanol. The reaction mixture was stirred at 60 ° C for one hour and 50 ml of water was added after cooling to room temperature. The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with aq. EtOAc EtOAc. The crude product was purified via a Biotage chromatography system (25 g K K K K K K K K K K K K The title compound is desired.

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 2.15 (s, 3H), 2.20 (s, 3H), 3.04 (d, 3H), 4.17 (s, 1H), 5.36 (s, 2H) , 7.38 (d, 2H), 7.77-7.83 (m, 1H), 7.87-7.96 (m, 4H), 8.20 (d, 1H), 8.24 (d, 1H), 8.27 (s, 1H), 8.37 (d , 1H), 10.09 (s, 1H).

Example 378 and example 379 ( S or R )-7-fluoro-N ⁴ -[5-Methyl-1-(1-phenylethyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine and ( R or S )-7-fluoro-N ⁴ -[5-Methyl-1-(1-phenylethyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine

A 110 mg racemic mixture of the title compound from Example 377 was isolated via EtOAc (EtOAc).

Example 380 2-bromo-N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-4-carboxamide

898 mg (3.97 mmol) of 4-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]benzonitrile (intermediate) in a manner analogous to Example 118) 8C) and 1.00g (3.97mmol) of 2-bromoquinoline-4-carboxylic acid were reacted via a Biotage chromatography system (25g snap KP-Sil column, hexane / 0-100% ethyl acetate, followed by After three subsequent purifications of ethyl acetate / 0-100% methanol, 1.69 g (93%)

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 2.14 (s, 3H), 2.16 (s, 3H), 5.37 (s, 2H), 7.30 (d, 2H), 7.76 (ddd, 1H) , 7.81 - 7.93 (m, 3H), 7.95 (s, 1H), 8.06 (d, 1H), 8.15 (d, 1H), 10.06 (s, 1H).

Example 381 N-[1-(4-Cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(methylthio)quinoline-4- Formamide

In a similar manner to Example 118), 124 mg (0.557 mmol) of 4-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]benzonitrile ( intermediate) 8C) and 100 mg (0.46 mmol) of 2-(methylthio)quinoline-4-carboxylic acid (according to US6699879, 2004; page 17-18) The reaction was carried out to give a solid. After filtration, the solid was washed with EtOAc (EtOAc)

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.15 (s, 3H), 2.17 (s, 3H), 2.70 (s, 3H), 5.38 (s, 2H), 7.32 (d, 2H) , 7.55-7.63 (m, 2H), 7.75-7.80 (m, 1H), 7.85 (d, 2H), 7.96 (d, 1H), 8.08 (d, 1H), 9.96 (s, 1H).

Example 382 N-[1-(4-Cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(methylsulfide Quinoline-4-carboxamide

In a similar manner to Example 118), 1.41 g (5.02 mmol) of 4-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl The reaction of benzonitrile (intermediate 26C) and 1.00 g (4.56 mmol) of 2-(methylthio)quinoline-4-carboxylic acid (prepared according to US 6,699,879, 2004; pp. 17-18), thereby passing through the Biotage layer After two subsequent purifications of the system (50 g then 25 g of snap-on KP-Sil column, hexane / 0-100% ethyl acetate followed by ethyl acetate / 0-80% methanol) gave 1.25 g ( 54%) of the desired compound.

¹ H-NMR (400MHz, DMSO d ₆ ) δ (ppm) = 2.26 (s, 3H), 2.69 (s, 3H), 5.59 (s, 2H), 7.37 (d, 2H), 7.54 (s, 1H) , 7.57 (ddd, 1H), 7.77 (ddd, 1H), 7.88 (d, 2H), 7.96 (d, 1H), 8.01 (d, 1H), 10.28 (s, 1H).

Example 383 and example 384 (±)-N-[1-(4-Cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(methylsulfin Quinoline-4-carbamide and N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)- 1H-pyrazol-4-yl]-2-(methylsulfonyl)quinoline-4-carboxamide

To 150 mg (0.31 mmol) of N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]- at room temperature 2-(Methylthio)quinoline-4-carboxamide (Example 382) 108 mg (0.62 mmol) of m-chloroperoxybenzoic acid (MCPBA) was added portionwise in a stirred solution of 5.0 mL of dichloromethane. The mixture was then stirred at this temperature for a further two hours. After the mixture was diluted with 30 mL of water and the organic phase was separated, the aqueous phase was extracted three times with dichloromethane. The combined organic phases were then washed three times with 50 mL aq. NaHEtOAc. This material was purified via preparative HPLC (Method 5c) to give 32 mg (19%) of (+)-N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl) -1H-pyrazol-4-yl]-2-(methylsulfinyl)quinoline-4-carboxamide and 41 mg (24%) of N-[1-(4-cyanobenzyl)-5 -Methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(methylsulfonyl)quinoline-4-carboxamide as the desired compound.

(±)-N-[1-(4-Cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2- (Example 383) NMR of sulfinyl)quinoline-4-carboxamide: ¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.30 (s, 3H), 3.49 (s, 3H), 5.62 (s , 2H), 7.40 (d, 2H), 7.88-7.92 (m, 2H), 7.93-7.97 (m, 1H), 8.06 (ddd, 1H), 8.20-8.27 (m, 2H), 8.31 (d, 1H) ), 10.57 (s, 1H).

N-[1-(4-Cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(methylsulfonyl) as an example 384 NMR of quinoline-4-carboxamide: ¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.29 (s, 3H), 2.96 (s, 3H), 5.63 (s, 2H), 7.40 (d, 2H), 7.85 (ddd, 1H), 7.89-7.93 (m, 2H), 7.98 (ddd, 1H), 8.17 (s, 1H), 8.19 (d, 1H), 8.23 (d, 1H), 10.52 (s, 1H).

Example 385 (±)-N-[1-(4-Cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(N-cyanide s-S-methanesulfonimide fluorenyl)quinoline-4-carboxamide

To 1.00 g (2.08 mmol) of N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl] at 0 °C To a stirred solution of -2-(methylthio)quinoline-4-carboxamide (Example 382) and 175 mg (4.15 mmol) of cyanamine in 40 mL of dichloromethane was added 736 mg (2.29 mmol) of iodobenzenediacetate. The mixture was then stirred at this temperature for a further three hours. After evaporating the solvent, the residue was purified via a Biotage chromatography system (10 g, K K-Sil column, hexane / 0-100% ethyl acetate followed by ethyl acetate / 0 - 80% methanol) 1.06 g (95%) of the desired compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.29 (s, 3H), 3.34 (s, 3H), 5.61 (s, 2H), 7.38 (d, 2H), 7.87-7.94 (m, 3H), 8.03 (ddd, 1H), 8.19-8.27 (m, 3H), 10.55 (s, 1H).

Example 386 (±)-N-[1-(4-Cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(N-cyano -S-methanesulfonimide fluorenyl)quinoline-4-carboxamide

To a stirred solution of 1.74 g (8.13 mmol) of sodium metaperiodate at room temperature, 15 mL of dichloromethane containing 92 mg (0.41 mmol) of ruthenium chloride (III) hydrate was added dropwise over a period of 5 minutes. Containing 1.06 g (2.03 mmol) of (±)-N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]- 2-(N-Cyano-S-methanesulfinylimidinyl)quinoline-4-carboxamide (Example 385) in 8 mL of dichloromethane. The mixture was then stirred at this temperature for three hours. After filtering the solid, the liquid phase was diluted with 50 mL of dichloromethane and 30 mL of water. After extraction and separation of the organic phase, the aqueous phase was extracted with dichloromethane. The combined organic phases were then washed with brine, dried over sodium sulfate, filtered and evaporated. The resulting residue was purified via a Biotage chromatography system (25 g K K K K K K K K K K The title compound is required.

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 2.32 (s, 3H), 3.92 (s, 3H), 5.63 (s, 2H), 7.39 (d, 2H), 7.89-7.93 (m, 2H), 8.03 (ddd, 1H), 8.13 (ddd, 1H), 8.28 (d, 1H), 8.35-8.40 (m, 2H), 10.67 (s, 1H).

Example 387 (±)-N-[1-(4-Cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(S-A Sulfonimidomethyl)quinoline-4-carboxamide

To 440 mg (0.82 mmol) of (±)-N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole-4 at 0 °C -yl]-2-(N-cyano-S-methanesulfonimide fluorenyl)quinoline-4-carboxamide (Example 386) 347 μL (2.46 mmol) was added to a stirred solution of 47 mL dichloromethane. Trifluoroacetic anhydride. After stirring at room temperature for 2 hours, the mixture was evaporated to dryness. The residue was taken up in 7.45 mL of methanol and 566 mg (4.09 mmol) of potassium carbonate was added to this mixture and stirring was continued at room temperature for 2 hours. The mixture was then diluted with brine and extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and evaporated to dry. The resulting residue was purified via a Biotage chromatography system (10 g K K K K K K K K K K K K The title compound is required.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.24 (s, 3H), 3.33 (s, 3H), 5.60 (s, 2H), 6.68 (d, 1H), 7.25 (ddd, 1H) , 7.36-7.42 (m, 3H), 7.58 (ddd, 1H), 7.70 (d, 1H), 7.88-7.92 (m, 2H), 10.27 (s, 1H), 12.04 (s, 1H).

Example 388 N ⁴ -(1-{4-[(dimethylamino)methyl]benzyl}-3,5-dimethyl-1H-pyrazol-4-yl)-7-fluoroquin Porphyrin-2,4-dimethylamine

In a similar manner to Example 118), 79 mg (0.30 mmol) of 1-{4-[(dimethylamino)methyl]benzyl}-3,5-dimethyl-1H-pyrazole-4- The amine (intermediate 71C) and 59 mg (0.25 mmol) of 2-aminoformamido-7-fluoroquinoline-4-carboxylic acid (Intermediate 37A) were reacted to give 26 mg after purification via preparative HPLC (Method 5c) (20%) of the desired compound.

¹ H-NMR (400MHz, DMSO d ₆ ) δ (ppm) = 2.12 (s, 6H), 2.15 (s, 3H), 2.18 (s, 3H), 3.35 (s, 2H), 5.24 (s, 2H) , 7.15 (d, 2H), 7.27 (d, 2H), 7.78 (ddd, 1H), 7.92 (dd, 1H), 7.96 (d, 1H), 8.28 (s, 1H), 8.36 (dd, 1H), 8.39 (d, 1H), 10.12 (s, 1H).

Example 389 N ⁴ -[1-(4-cyanobenzyl)-3-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoroquinoline- 2,4-dimethylamine

In a manner similar to Example 118), 200 mg (0.71 mmol) of 4-{[4-amino-3- Methyl-5-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}benzonitrile (Intermediate 72C) and 139 mg (0.56 mmol) 2-Aminomethylmercapto-7-fluoroquinoline -4-carboxylic acid (Intermediate 37A) was reacted to give 136 mg (46%) of desired compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.25 (s, 3H), 5.60 (s, 2H), 7.34-7.38 (m, 2H), 7.81 (td, 1H), 7.87-7.91 ( m, 2H), 7.94 (dd, 1H), 7.99 (d, 1H), 8.27 (s, 1H), 8.32 (dd, 1H), 8.41 (d, 1H), 10.64 (s, 1H).

Example 390 N ⁴ -[1-(4-Cyano-2,6-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-7-fluoroquinoline- 2,4-dimethylamine

In a manner similar to Example 118), 101 mg (0.38 mmol) of 4-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]-3,5-di Fluorobenzonitrile (Intermediate 73C) and 75 mg (0.32 mmol) of 2-aminoformamido-7-fluoroquinoline-4-carboxylic acid (Intermediate 37A) were reacted after purification via preparative HPLC (Method 3) Yield 57 mg (36%) of the desired compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.06 (s, 3H), 2.32 (s, 3H), 5.32 (s, 2H), 7.78 (td, 1H), 7.84-7.90 (m, 2H), 7.92 (dd, 1H), 7.96 (d, 1H), 8.29 (s, 1H), 8.35 (dd, 1H), 8.40 (d, 1H), 10.12 (s, 1H).

Example 391 N ⁴ -[1-(4-Cyano-2,6-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine

109 mg (0.42 mmol) of 4-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]-3,5-di was obtained in a similar manner to Example 118) Fluorobenzonitrile (Intermediate 73C) and 75 mg (0.35 mmol) of 2-aminopyridylquinoline-4-carboxylic acid (Intermediate 4A) were reacted to give 45 mg after purification by preparative HPLC (Method 3) 27%) of the desired compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.07 (s, 3H), 2.33 (s, 3H), 5.32 (s, 2H), 7.82 (ddd, 1H), 7.85-7.90 (m, 2H), 7.91 (d, 1H), 7.95 (ddd, 1H), 8.22 (d, 1H), 8.26 (d, 1H), 8.29 (s, 1H), 8.40 (d, 1H), 10.07 (s, 1H) ).

Example 392 6-chloro-N ⁴ -[1-(4-Cyano-2,6-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-7-fluoroquin Porphyrin-2,4-dimethylamine

In a manner similar to Example 118), 88 mg (0.34 mmol) of 4-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]-3,5-di Fluorobenzonitrile (Intermediate 73C) and 75 mg (0.28 mmol) of 2-aminoformamido-6-chloro-7-fluoroquinoline-4-carboxylic acid (Intermediate 32A) are reacted via preparative HPLC (method 3) After purification, 17 mg (27%) of desired title compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.05 (s, 3H), 2.31 (s, 3H), 5.32 (s, 2H), 7.84-7.91 (m, 2H), 8.01 (d, 1H), 8.14 (d, 1H), 8.39 (s, 1H), 8.41 (d, 1H), 8.52 (d, 1H), 10.21 (s, 1H).

Example 393 N ⁴ -[1-(4-Cyano-2,6-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-5-fluoroquinoline- 2,4-dimethylamine

In a manner similar to Example 118), 101 mg (0.38 mmol) of 4-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]-3,5-di Fluorobenzonitrile (Intermediate 73C) and 75 mg (0.32 mmol) of 2-aminoformamido-5-fluoroquinoline-4-carboxylic acid (Intermediate 39A) were reacted after purification via preparative HPLC (Method 3) , 55 mg (35%) of the desired compound are obtained.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.06 (s, 3H), 2.32 (s, 3H), 5.31 (s, 2H), 7.78 (td, 1H), 7.84-7.90 (m, 2H), 7.92 (dd, 1H), 7.97 (d, 1H), 8.29 (s, 1H), 8.35 (dd, 1H), 8.40 (d, 1H), 10.12 (s, 1H).

Example 394 6-bromo-N ⁴ -[1-(4-Cyano-2,6-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline- 2,4-dimethylamine

In a manner similar to Example 118), 80 mg (0.31 mmol) of 4-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]-3,5-di Fluorobenzonitrile (Intermediate 73C) and 75 mg (0.25 mmol) of 6-bromo-2-amine-methylpyridyl quinoline-4-carboxylic acid (Intermediate 2A) were reacted after purification via preparative HPLC (Method 3) 19 mg (14%) of the desired title compound.

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 2.05 (s, 3H), 2.32 (s, 3H), 5.32 (s, 2H), 7.83-7.91 (m, 2H), 7.96 (d, 1H), 8.09 (dd, 1H), 8.15 (d, 1H), 8.37 (s, 1H), 8.43 (d, 1H), 8.48 (d, 1H), 10.17 (s, 1H).

Example 395 N ⁴ -[1-(4-Cyano-2,6-difluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoroquinoline -2,4-dimethylamine

In a similar manner to Example 118), 122 mg (0.38 mmol) of 4-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl} -3,5-Difluorobenzonitrile (Intermediate 74C) and 75 mg (0.32 mmol) of 2-Aminomethylmercapto-7-fluoroquinoline-4-carboxylic acid (Intermediate 37A) were reacted via preparative HPLC (Method 3) After purification, 52 mg (30%).

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.40 (s, 3H), 5.57 (s, 2H), 7.81 (ddd, 1H), 7.89-7.96 (m, 3H), 7.98 (d, 1H), 8.26-8.32 (m, 2H), 8.41 (d, 1H), 10.47 (s, 1H).

Example 396 N ⁴ -[1-(4-Cyano-2,6-difluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quina Porphyrin-2,4-dimethylamine

In a similar manner to Example 118), 132 mg (0.42 mmol) of 4-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl} -3,5-Difluorobenzonitrile (Intermediate 74C) and 75 mg (0.35 mmol) of 2-aminopyridylquinoline-4-carboxylic acid (Intermediate 4A) were reacted via preparative HPLC (Method 3) After purification, 46 mg (25%) of the desired compound was obtained.

¹ H-NMR (400MHz, DMSO d ₆ ) δ (ppm) = 2.40 (s, 3H), 5.57 (s, 2H), 7.83 (ddd, 1H), 7.89-8.00 (m, 4H), 8.17-8.30 ( m, 3H), 8.42 (d, 1H), 10.41 (s, 1H).

Example 397 N ⁴ -[1-(4-Cyano-2,6-difluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-5- Fluoroquinoline-2,4-dimethylamine

In a similar manner to Example 118), 122 mg (0.38 mmol) of 4-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl} -3,5-Difluorobenzonitrile (Intermediate 74C) and 75 mg (0.32 mmol) of 2-Aminomethylmercapto-5-fluoroquinoline-4-carboxylic acid (Intermediate 39A) were reacted via preparative HPLC (Method 3) After purification, 39 mg (22%).

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.40 (s, 3H), 5.57 (s, 2H), 7.81 (ddd, 1H), 7.89-7.96 (m, 3H), 7.98 (d, 1H), 8.26-8.32 (m, 2H), 8.41 (d, 1H), 10.47 (s, 1H).

Example 398 6-chloro-N ⁴ -[1-(4-cyano-2,6-difluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole-4- -7-fluoroquinoline-2,4-dimethylamine

In a similar manner to Example 118), 106 mg (0.34 mmol) of 4-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl} -3,5-difluorobenzonitrile (Intermediate 74C) and 75 mg (0.28 mmol) of 2-aminomethylmethyl-6-chloro-7-fluoroquinoline-4-carboxylic acid (Intermediate 32A) are reacted After purification by preparative HPLC (Method 3), 55 mg (33%)

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 2.39 (s, 3H), 5.57 (s, 2H), 7.89-7.96 (m, 2H), 8.02 (d, 1H), 8.15 (d, 1H), 8.37 (s, 1H), 8.40-8.46 (m, 2H), 10.55 (s, 1H).

Example 399 6-bromo-N ⁴ -[1-(4-cyano-2,6-difluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole-4- Quinoline-2,4-dimethylamine

96 mg (0.31 mmol) of 4-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl} was obtained in a manner analogous to Example 118) -3,5-Difluorobenzonitrile (Intermediate 74C) and 75 mg (0.25 mmol) of 6-bromo-2-amine-methylpyridylquinoline-4-carboxylic acid (Intermediate 2A) were reacted via preparative HPLC (Method 3) After purification, 58 mg (37%).

¹ H-NMR (400MHz, DMSO d ₆ ) δ (ppm) = 2.40 (s, 3H), 5.57 (s, 2H), 7.89-7.96 (m, 2H), 7.98 (d, 1H), 8.10 (dd, 1H), 8.16 (d, 1H), 8.36 (s, 1H), 8.41 (d, 1H), 8.44 (d, 1H), 10.50 (s, 1H).

Instance 400 7-fluoro-N ⁴ -{5-Methyl-1-[4-(1H-tetrazol-5-yl)benzyl]-3-(trifluoromethyl)-1H-pyrazole- 4-yl}quinoline-2,4-dimethylamine

100 mg (0.20 mmol) of N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoroquin A mixture of porphyrin-2,4-dimethylguanamine (Example 240), 48 mg (0.75 mmol) sodium azide and 48 mg (0.91 mmol) ammonium chloride in 1.0 mL DMF was heated to 115 ° C for 3 hours. After cooling to room temperature, 1 M aqueous hydrochloric acid was carefully added. The solid formed was isolated by filtration and purified by preparative HPLC (Method 5c) to afford 12 mg (10%)

¹ H-NMR (400MHz, DMSO d ₆ ) δ (ppm) = 2.31 (s, 3H), 5.56 (s, 2H), 7.39 (d, 2H), 7.80 (ddd, 1H), 7.93 (dd, 1H) , 7.98 (d, 1H), 8.04 (d, 2H), 8.14 (s, 1H), 8.27 (s, 1H), 8.28-8.33 (m, 1H), 8.40 (d, 1H), 10.47 (s, 1H) ).

Example 401 7-fluoro-N ⁴ -{1-[4-(Methoxymethyl)benzyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazole-4- Quinoline-2,4-dimethylamine

135 mg (0.45 mmol) of 1-[4-(methoxymethyl)benzyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazole in a similar manner to Example 118) 4-Amine (Intermediate 75C) and 88 mg (0.25 mmol) of 2-aminomethane-7-fluoroquinoline-4-carboxylic acid (Intermediate 37A) were reacted after purification via preparative HPLC (Method 5e) Yield 84 mg (42%) of the desired compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.26 (s, 3H), 3.27 (s, 3H), 4.39 (s, 2H), 5.46 (s, 2H), 7.22 (d, 2H) , 7.33 (d, 2H), 7.78 (ddd, 1H), 7.91 (dd, 1H), 7.95 (d, 1H), 8.25 (s, 1H), 8.28 (dd, 1H), 8.37 (d, 1H), 10.42 (s, 1H).

Example 402 5-fluoro-N ⁴ -{1-[4-(Methoxymethyl)benzyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazole-4- Quinoline-2,4-dimethylamine

135 mg (0.45 mmol) of 1-[4-(methoxymethyl)benzyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazole in a similar manner to Example 118) 4-Amine (Intermediate 75C) and 88 mg (0.25 mmol) of 2-aminocarbamido-5-fluoroquinoline-4-carboxylic acid (Intermediate 39A) were reacted after purification via preparative HPLC (Method 5e) , 82 mg (41%) of the desired title compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.28 (s, 3H), 3.29 (s, 3H), 4.41 (s, 2H), 5.48 (s, 2H), 7.24 (d, 2H) , 7.35 (d, 2H), 7.80 (ddd, 1H), 7.93 (dd, 1H), 7.98 (d, 1H), 8.27 (s, 1H), 8.30 (dd, 1H), 8.40 (d, 1H), 10.45 (s, 1H).

Example 403 N ⁴ -{1-[4-(Cyanomethyl)benzyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}-7-fluoro Quinoline-2,4-dimethylamine

In a similar manner to Example 118), 53 mg (0.18 mmol) of (4-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl }Phenyl)acetonitrile (intermediate 76C) and 35 mg (0.15 mmol) of 2-aminoformamido-7-fluoroquinoline-4-carboxylic acid (Intermediate 37A) were reacted to give purified via preparative HPLC (Method 5e) Thereafter, 40 mg (50%) of the desired title compound are obtained.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.28 (s, 3H), 4.05 (s, 2H), 5.49 (s, 2H), 7.29 (d, 2H), 7.39 (d, 2H) , 7.80 (ddd, 1H), 7.93 (dd, 1H), 7.98 (d, 1H), 8.26-8.27 (m, 1H), 8.30 (dd, 1H), 8.41 (d, 1H), 10.45 (s, 1H) ).

Example 404 6-bromo-N-(3,5-dimethyl-1-{[5-(methylaminemethanyl)-1,2,4-oxadiazol-3-yl]methyl}- 1H-pyrazol-4-yl)-2-(trifluoromethyl)quinoline-4-carboxamide

In a similar manner to Example 118), 100 mg (0.32 mmol) of 3-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]-N-methyl- 1,2,4-oxadiazol-5-carboxamide (intermediate 77C) and 85 mg (0.27 mmol) of 6-bromo-2-(trifluoromethyl)quinoline-4-carboxylic acid (intermediate 1A) Thus, after purification via preparative HPLC (Method 3), 85 mg (47%)

^{1 H NMR (400MHz, DMSO d} 6): δ (ppm) = 2.13 (s, 3H), 2.31 (s, 3H), 2.79 (d, 3H), 5.53 (s, 2H), 8.15 (dd, 1H) , 8.24 (d, 1H), 8.30 (s, 1H), 8.49 (d, 1H), 9.32 (br.q., 1H), 10.21 (s, 1H).

Example 405 4-[(4-{[(2-Aminocarboxyquinolin-4-yl)carbonyl]amino}-3,5-dimethyl-1H-pyrazol-1-yl) Methyl] piperidine-1-carboxylic acid tert-butyl ester

In a similar manner to Example 118), 1.58 g (4.61 mmol) of 4-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]piperidin-1- The third butyl formate (intermediate 78C) and 1.04 g (3.84 mmol) of 2-aminopyridylquinoline-4-carboxylic acid (Intermediate 4A) were reacted to afford after purification by preparative HPLC (Method 3) 1.34 g (65%) of the desired compound.

¹ H-NMR (300 MHz, DMSO d ₆ ) δ (ppm) = 1.11 (dddd, 2H), 1.39 (s, 9H), 1.51 (br.d., 2H), 2.00 (m, 1H), 2.13 (s) , 3H), 2.21 (s, 3H), 2.65 (m, 2H), 3.87 (d, 2H), 3.95 (br.d., 2H), 7.82 (br.dd., 1H), 7.89 (br.s .1H), 7.94 (br.dd., 1H), 8.21 (br.d., 1H), 8.26 (br.d., 1H), 8.27 (s, 1H), 8.38 (br.s., 1H) ), 10.01 (s, 1H).

Example 406 N ⁴ -[3,5-Dimethyl-1-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine

1.34 g (2.65 mmol) of 4-[(4-{[(2-aminocarbazinoquinolin-4-yl)carbonyl]amino}-3,5-dimethyl-1H-pyrazole-1- A solution of the tert-butyl methyl]piperidine-1-carboxylate (Example 405) in 18 mL of dichloromethane was stirred with 2.04 mL (26.5 mmol) of trifluoroacetic acid for 70 hours. NH ₂ The reaction was derivatized silica gel mixture was filtered, and the filtrate was evaporated to give 1.29g (96%) of the title compound desired.

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 1.40 (dddd, 2H), 1.72 (br.d., 2H), 2.11 (m, 1H), 2.13 (s, 3H), 2.23 (s) , 3H), 2.88 (m, 2H), 3.29 (br.d., 2H), 3.93 (d, 2H), 7.82 (br.dd., 1H), 7.92 (br.s., 1H), 7.95 ( Br.dd.,1H),8.21(br.d.,1H),8.24(br.d.,1H),8.28(s,1H),8.41(br.s.,1H),10.06(s,1H ).

Example 407 N ⁴ -(1-{[1-(ethylsulfonyl)piperidin-4-yl]methyl}-3,5-dimethyl-1H-pyrazol-4-yl)quinoline- 2,4-dimethylamine

100 mg (246 μmol) of N ⁴ -[3,5-dimethyl-1-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine (Example 406) A solution in 3 mL of DMF was stirred overnight with 32.6 μL (344 μmol) of ethanesulfonium chloride and 206 μL (1.48 mmol) of triethylamine. A saturated aqueous solution of sodium hydrogencarbonate and ethyl acetate were added to the reaction. The mixture was extracted with butanol and the combined organic phases were washed with brine, dried, filtered and evaporated. Purification by preparative HPLC (Method 3) gave 58 mg (47%)

¹ H-NMR (300MHz, DMSO d ₆ ) δ (ppm) = 1.20 (t, 3H), 1.27 (m, 2H), 1.61 (br.d., 2H), 1.98 (m, 1H), 2.13 (s) , 3H), 2.22 (s, 3H), 2.77 (m, 2H), 3.01 (q, 2H), 3.60 (br.d., 2H), 3.91 (d, 2H), 7.82 (br.dd., 1H) ), 7.92 (br.s., 1H), 7.95 (br.dd., 1H), 8.21 (br.d., 1H), 8.25 (br.d., 1H), 8.27 (s, 1H), 8.41 (br.s., 1H), 10.04 (s, 1H).

Example 408 6-chloro-7-fluoro-N ⁴ -{5-Methyl-1-[(5-methyl-1,2-oxazol-3-yl)methyl]-3-(trifluoromethyl)- 1H-pyrazol-4-yl}quinoline-2,4-dimethylamine

In a manner similar to Example 118), 100 mg (0.38 mmol) of 5-methyl-1-[(5-methyl-1,2-oxazol-3-yl)methyl]-3-(trifluoromethyl) -1H-pyrazole-4-amine (Intermediate 79C) and 86 mg (0.32 mmol) of 2-aminomethylmethyl-6-chloro-7-fluoroquinoline-4-carboxylic acid (Intermediate 32A) After purification via preparative HPLC (Method 4), 18 mg (9%)

^{1 H NMR (400MHz, DMSO d} 6): δ (ppm) = 2.32 (s, 3H), 2.41 (s, 3H), 5.54 (s, 2H), 6.21 (s, 1H), 8.02 (br.s. , 1H), 8.15 (d, 1H), 8.36 (s, 1H), 8.41 (br.s., 1H), 8.43 (d, 1H), 10.54 (s, 1H).

Example 409 6-chloro-N ⁴ -{1-[(5-ethyl-1,2,4-oxadiazol-3-yl)methyl]-5-methyl-3-(trifluoromethyl)- 1H-pyrazol-4-yl}-7-fluoroquinoline-2,4-dimethylamine

In a manner similar to Example 118), 100 mg (0.33 mmol) of 1-[(5-ethyl-) 1,2,4-oxadiazol-3-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazole-4-amine (Intermediate 80C) and 92 mg (0.27 mmol) 2-Aminomercapto-6-chloro-7-fluoroquinoline-4-carboxylic acid (Intermediate 32A) is reacted to give 30 mg (17%) of the desired compound after purification by preparative HPLC (Method 4) .

¹ H NMR (400 MHz, DMSO d ₆ ): δ (ppm) = 1.28 (t, 3H), 2.36 (s, 3H), 2.96 (q, 2H), 5.68 (s, 2H), 8.02 (br.s. , 1H), 8.15 (d, 1H), 8.37 (s, 1H), 8.41 (br.s., 1H), 8.43 (d, 1H), 10.57 (s, 1H).

Example 410 6-chloro-N ⁴ -{1-[(3-ethyl-1,2-oxazol-5-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyridyl Zin-4-yl}-7-fluoroquinoline-2,4-dimethylamine

In a manner similar to Example 118), 90 mg (0.33 mmol) of 1-[(3-ethyl-1,2-oxazol-5-yl)methyl]-5-methyl-3-(trifluoromethyl) -1H-pyrazole-4-amine (Intermediate 81C) and 73.5 mg (0.27 mmol) of 2-aminomethylmethyl-6-chloro-7-fluoroquinoline-4-carboxylic acid (Intermediate 32A), Thus, after purification via preparative HPLC (Method 3), 46 mg (27%)

^{1 H NMR (400MHz, DMSO d} 6): δ (ppm) = 1.19 (t, 3H), 2.37 (s, 3H), 2.64 (q, 2H), 5.68 (s, 2H), 6.50 (s, 1H) , 8.02 (br.s., 1H), 8.15 (d, 1H), 8.37 (s, 1H), 8.41 (br.s., 1H), 8.43 (d, 1H), 10.56 (s, 1H).

Example 411 6-chloro-N ⁴ -{3,5-Dimethyl-1-[(3-methyl-1,2-oxazol-5-yl)methyl]-1H-pyrazol-4-yl}-7-fluoroquinoline- 2,4-dimethylamine

In a manner similar to Example 118), 150 mg (0.73 mmol) of 3,5-dimethyl-1-[(3-methyl-1,2-oxazol-5-yl)methyl]-1H-pyridin Reaction of oxazol-4-amine (Intermediate 82C) and 163 mg (0.61 mmol) of 2-aminoformamido-6-chloro-7-fluoroquinoline-4-carboxylic acid (Intermediate 32A) over preparative HPLC Method 3) After purification, 77 mg (22%) of desired compound.

^{1 H NMR (400MHz, DMSO d} 6): δ (ppm) = 2.11 (s, 3H), 2.22 (s, 3H), 2.26 (s, 3H), 5.41 (s, 2H), 6.28 (s, 1H) , 7.99 (br.s., 1H), 8.13 (d, 1H), 8.39 (s, 1H), 8.39 (br.s., 1H), 8.52 (d, 1H), 10.22 (s, 1H).

Example 412 6-chloro-N ⁴ -{3,5-Dimethyl-1-[(5-methyl-1,2-oxazol-3-yl)methyl]-1H-pyrazol-4-yl}-7- Fluoroquinoline-2,4-dimethylamine

In a manner similar to Example 118), 92 mg (0.45 mmol) of 3,5-dimethyl-1-[(5-methyl-1,2-oxazol-3-yl)methyl]-1H-pyridin Reaction of oxazol-4-amine (Intermediate 83C) with 100 mg (0.37 mmol) of 2-aminoformamido-6-chloro-7-fluoroquinoline-4-carboxylic acid (Intermediate 32A) over preparative HPLC Method 4) After purification, 40 mg (19%) of desired compound.

^{1 H NMR (400MHz, DMSO d} 6): δ (ppm) = 2.11 (s, 3H), 2.22 (s, 3H), 2.38 (s, 3H), 5.28 (s, 2H), 6.09 (s, 1H) , 8.00 (br.s., 1H), 8.13 (d, 1H), 8.38 (s, 1H), 8.40 (br.s., 1H), 8.51 (d, 1H), 10.22 (s, 1H).

Example 413 6-chloro-N ⁴ -[1-{[1-(ethylsulfonyl)piperidin-4-yl]methyl}-5-methyl-3-(trifluoromethyl)-1H- Pyrazol-4-yl]-7-fluoroquinoline-2,4-dimethylamine

In a manner similar to Example 118), 120 mg (0.31 mmol) of 1-{[1-(ethanesulfonate) was obtained. Piperidin-4-yl]methyl}-5-methyl-3-(trifluoromethyl)-1H-pyrazole-4-amine (Intermediate 86C) and 85 mg (0.25 mmol) 2-A Reaction of decyl-6-chloro-7-fluoroquinoline-4-carboxylic acid (Intermediate 32A) afforded 81 mg (44%) of the desired compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 1.21. (t, 3H), 1.31 (m, 2H), 1.61 (br.d., 2H), 2.05 (m, 1H), 2.31 (s) , 3H), 2.81 (m, 2H), 3.02 (q, 2H), 3.62 (br.d., 2H), 4.13 (d, 2H), 8.00 (br.s., 1H), 8.15 (d, 1H) ), 8.36 (s, 1H), 8.40 (br.s., 1H), 8.43 (d, 1H), 10.49 (s, 1H).

Example 414 6-chloro-N ⁴ -{1-[(3-ethyl-1,2-oxazol-5-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-7- Fluoroquinoline-2,4-dimethylamine

In a manner similar to Example 118), 90 mg (0.38 mmol) of 1-[(3-ethyl-1,2-oxazol-5-yl)methyl]-3,5-dimethyl-1H-pyridin Reaction of oxazol-4-amine (intermediate 87C) with 84.1 mg (0.31 mmol) of 2-aminocarbamido-6-chloro-7-fluoroquinoline-4-carboxylic acid (Intermediate 32A) over preparative HPLC (Method 3) After purification, 39 mg (21.%)

¹ H NMR (400 MHz, DMSO d ₆ ): δ (ppm) = 1.18 (t, 3H), 2.11 (s, 3H), 2.27 (s, 3H), 2.61 (q, 2H), 5.41 (s, 2H) , 6.35 (s, 1H), 7.99 (br.s., 1H), 8.13 (d, 1H), 8.39 (s, 1H), 8.39 (br.s., 1H), 8.52 (d, 1H), 10.23 (s, 1H).

Example 415 6-chloro-N ⁴ -(1-{[1-(ethylsulfonyl)piperidin-4-yl]methyl}-3,5-dimethyl-1H-pyrazol-4-yl)- 7-fluoroquinoline-2,4-dimethylguanamine

In a manner similar to Example 118), 100 mg (0.31 mmol) of 1-{[1-(ethylsulfonyl)piperidin-4-yl]methyl}-3,5-dimethyl-1H-pyrazole 4-amine (intermediate 88C) and 72 mg (0.26 mmol) of 2-aminoformamido-6-chloro-7-fluoroquinoline-4-carboxylic acid (intermediate 32A) are reacted via preparative HPLC (method 3) After purification, 51 mg (29%) of desired title compound.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 1.20 (t, 3H), 1.27 (dddd, 2H), 1.61 (br.d., 2H), 1.99 (m, 1H), 2.11 (s) , 3H), 2.20 (s, 3H), 2.78 (m, 2H), 3.02 (q, 2H), 3.61 (br.d., 2H), 3.91 (d, 2H), 7.99 (br.s., 1H) ), 8.13 (d, 1H), 8.38 (s, 1H), 8.39 (br.s., 1H), 8.52 (d, 1H), 10.17 (s, 1H).

Example 416 6-chloro-N ⁴ -(3,5-Dimethyl-1-{[3-(propan-2-yl)-1,2-oxazol-5-yl]methyl}-1H-pyrazole-4- -7-fluoroquinoline-2,4-dimethylamine

In a manner similar to Example 118), 100 mg (0.41 mmol) of 3,5-dimethyl-1-{[3-(propan-2-yl)-1,2-oxazol-5-yl]methyl }-1H-pyrazole-4-amine (Intermediate 89C) and 90.8 mg (0.34 mmol) of 2-aminomethylmethyl-6-chloro-7-fluoroquinoline-4-carboxylic acid (Intermediate 32A) After purification via preparative HPLC (Method 3), 38 mg (18%)

¹ H NMR (400 MHz, DMSO d ₆ ): δ (ppm) = 1.21. (d, 6H), 2.11 (s, 3H), 2.27 (s, 3H), 2.99 (seven, peaks, 1H), 5.41 (s, 2H) ), 6.41 (s, 1H), 7.99 (br.s., 1H), 8.14 (d, 1H), 8.38 (br.s., 1H), 8.39 (s, 1H), 8.52 (d, 1H), 10.22 (s, 1H).

Example 417 6-chloro-N ⁴ -{1-[(5-cyclopropyl-1,2-oxazol-3-yl)methyl]-3,5-dimethyl-1H-pyrazole-4- -7-fluoroquinoline-2,4-dimethylamine

In a manner analogous to Example 118), 100 mg (0.34 mmol) of 1-[(5-cyclopropyl-1,2-oxazol-3-yl)methyl]-3,5-dimethyl-1H- Reaction of pyrazol-4-amine (Intermediate 90C) and 77 mg (0.29 mmol) of 2-aminoformamido-6-chloro-7-fluoroquinoline-4-carboxylic acid (Intermediate 32A) over preparative HPLC (Method 3) After purification, 45 mg (26%).

¹ H NMR (400 MHz, DMSO d ₆ ): δ (ppm) = 0.88 (m, 2H), 1.04 (m, 2H), 2.12 (s, 3H), 2.13 (m, 1H), 2.22 (s, 3H) , 5.25 (s, 2H), 6.08 (s, 1H), 7.99 (br.s., 1H), 8.14 (d, 1H), 8.38 (s, 1H), 8.38 (br.s., 1H), 8.51 (d, 1H), 10.21 (s, 1H).

Example 418 N ⁴ -{1-[(5-cyclopropyl-1,2-oxazol-3-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-7-fluoro Quinoline-2,4-dimethylamine

In a manner analogous to Example 118), 100 mg (0.34 mmol) of 1-[(5-cyclopropyl-1,2-oxazol-3-yl)methyl]-3,5-dimethyl-1H- Reaction of pyrazol-4-amine (Intermediate 90C) and 67 mg (0.29 mmol) of 2-aminoformamido-7-fluoroquinoline-4-carboxylic acid (Intermediate 37A) via preparative HPLC (Method 3) After purification, 109 mg (67%) of desired title compound.

¹ H NMR (400 MHz, DMSO d ₆ ): δ (ppm) = 0.88 (m, 2H), 1.03 (m, 2H), 2.12 (s, 3H), 2.12 (m, 1H), 2.23 (s, 3H) , 5.25 (s, 2H), 6.07 (s, 1H), 7.78 (ddd, 1H), 7.92 (dd, 1H), 7.95 (br.s., 1H), 8.28 (s, 1H), 8.38 (br. s., 1H), 8.35 (dd, 1H), 10.11 (s, 1H).

Example 419 N ⁴ -{1-[(5-Cyclopropyl-1,2-oxazol-3-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}quinoline-2,4 -dimethylguanamine

In a manner analogous to Example 118), 100 mg (0.34 mmol) of 1-[(5-cyclopropyl-1,2-oxazol-3-yl)methyl]-3,5-dimethyl-1H- Pyrazole-4-amine (Intermediate 90C) and 62 mg (0.29 mmol) of 2-aminopyridinylquinoline-4-carboxylic acid (Intermediate 4A) were reacted to give purified by preparative HPLC (Method 3) 100 mg (64%) of the desired compound.

¹ H NMR (400 MHz, DMSO d ₆ ): δ (ppm) = 0.88 (m, 2H), 1.03 (m, 2H), 2.12 (m, 1H), 2.13 (s, 3H), 2.24 (s, 3H) , 5.25 (s, 2H), 6.08 (s, 1H), 7.82 (ddd, 1H), 7.90 (br.s., 1H), 7.94 (ddd, 1H), 8.28 (s, 1H), 8.39 (br. s., 1H), 8.21 (dd, 1H), 8.26 (dd, 1H), 10.06 (s, 1H).

Example 420 6-chloro-7-fluoro-N ⁴ -{5-Methyl-1-[(3-methyl-1,2-oxazol-5-yl)methyl]-3-(trifluoromethyl)- 1H-pyrazol-4-yl}quinoline-2,4-dimethylamine

In a manner similar to Example 118), 100 mg (0.35 mmol) of 5-methyl-1-[(3-methyl-1,2-oxazol-5-yl)methyl]-3-(trifluoromethyl) -1H-pyrazole-4-amine (Intermediate 91C) and 82 mg (0.29 mmol) of 2-aminocarbamido-6-chloro-7-fluoroquinoline-4-carboxylic acid (Intermediate 32A) After purification via preparative HPLC (Method 3), 19 mg (10%)

¹ H NMR (400 MHz, DMSO d ₆ ): δ (ppm) = 2.24 (s, 3H), 2.36 (s, 3H), 5.68 (s, 2H), 6.43 (s, 1H), 8.1 (br.s. , 1H), 8.15 (d, 1H), 8.37 (s, 1H), 8.40 (br.s., 1H), 8.43 (d, 1H), 10.55 (s, 1H).

Example 421 6-chloro-N ⁴ -{1-[(5-Cyano-2-thienyl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazole-4- -7-fluoroquinoline-2,4-dimethylamine

In a manner similar to Example 118), 255 mg (0.58 mmol) of 5-{[4-amino-5- Methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}thiophene-2-carbonitrile (Intermediate 92C) and 136 mg (0.48 mmol) of 2-aminocarbazin-6- Chloro-7-fluoroquinoline-4-carboxylic acid (Intermediate 32A) was reacted to give 38 mg (12%) of the desired compound.

¹ H NMR (400 MHz, DMSO d ₆ ): δ (ppm) = 2.35 (s, 3H), 5.80 (s, 2H), 7.31 (d, 1H), 7.91 (d, 1H), 8.00 (br.s. , 1H), 8.15 (d, 1H), 8.37 (s, 1H), 8.40 (br.s., 1H), 8.43 (d, 1H), 10.55 (s, 1H).

Example 422 N ⁴ -{1-[(5-Cyano-2-thienyl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}-7- Fluoroquinoline-2,4-dimethylamine

In a manner similar to Example 118), 180 mg (0.50 mmol) of 5-[(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)methyl]thiophene-2-carbonitrile (Intermediate 93C) and 115 mg (0.42 mmol) of 2-aminocarbazin-7-fluoroquinoline-4-carboxylic acid (Intermediate 37A) were reacted to give 26 mg after purification by preparative HPLC (Method 3) 11%) of the desired compound.

^{1 H NMR (400MHz, DMSO d} 6): δ (ppm) = 2.15 (s, 3H), 2.25 (s, 3H), 5.55 (s, 2H), 7.23 (d, 1H), 7.88 (d, 1H) , 7.77 (ddd, 1H), 7.92 (dd, 1H), 7.95 (br.s., 1H), 8.28 (s, 1H), 8.38 (br.s., 1H), 8.35 (dd, 1H), 10.13 (s, 1H).

Example 423 N ⁴ -{1-[(5-Cyanopyrimidin-2-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}-7-fluoroquinoline- 2,4-dimethylamine

In a similar manner to Example 118), 145 mg (0.51 mmol, 50% purity) of 2-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl ]]methyl}pyrimidine-5-carbonitrile (Intermediate 94C) and 100 mg (0.43 mmol) of 2-aminoformamido-7-fluoroquinoline-4-carboxylic acid (Intermediate 37A) were reacted via preparative HPLC (Method 5c) After purification, 26 mg (11%).

¹ H-NMR (400MHz, DMSO d ₆ ) δ (ppm) = 2.29 (s, 3H), 5.87 (s, 2H), 7.82 (td, 1H), 7.94 (dd, 1H), 7.98 (s, 1H) , 8.27-8.35 (m, 2H), 8.41 (s, 1H), 9.34 (s, 2H), 10.49 (s, 1H).

Example 424 N ⁴ -{1-[(5-Cyanopyrimidin-2-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}-5- Fluoroquinoline-2,4-dimethylamine

In a manner similar to Example 118), 400 mg (0.71 mmol, purity 50%) of 2-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl ]methyl}pyrimidine-5-carbonitrile (Intermediate 94C) and 138 mg (0.59 mmol) of 2-aminoformamido-5-fluoroquinoline-4-carboxylic acid (Intermediate 39A) were reacted via preparative HPLC (Method 5c) After purification, 93 mg (31%).

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.27 (s, 3H), 5.85 (s, 2H), 7.80 (td, 1H), 7.78-7.99 (m, 2H), 8.25-8. m, 2H), 8.38 (s, 1H), 9.32 (s, 2H), 10.46 (s, 1H).

Example 425 N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-6-hydroxyquinoline -2,4-dimethylamine

In a manner similar to Example 164), 250 mg (0.49 mmol) of N4-[1-(4-cyano) Benzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-6-methoxyquinoline-2,4-dimethylamine (Example 245) Thus, after purifying the starting material sequentially via a Biotage chromatography system (25 g snap KP-Sil column, ethyl acetate / 40-100% methanol) and preparative HPLC (Method 5c), 32 mg (12%) of desired title was obtained. Compound.

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 2.27 (s, 3H), 5.62 (s, 2H), 7.39 (d, 2H), 7.44-7.51 (m, 2H), 7.78 (d, 1H), 7.88-7.95 (m, 2H), 8.04-8.08 (m, 1H), 8.17 (s, 1H), 8.26 (d, 1H), 10.34 (s, 1H), 10.55 (s, 1H).

Example 426 N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-N ² -(Methanesulfonate Quinoline-2,4-dimethylamine

In a similar manner to Example 118), 137 mg (0.492 mmol) of 4-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl} Benzoonitrile (Intermediate 26C) and 120 mg (0.41 mmol) of 2-[(methylsulfonyl)amine-carbamoyl]quinoline-4-carboxylic acid (Intermediate 60A) were reacted via preparative HPLC (Method 5d) After purification, 76 mg (30%) of the desired compound was obtained.

¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm) = 2.29 (s, 3H), 3.45 (s, 3H), 5.62 (s, 2H), 7.4 (d, 2H), 7.87-793 (m, 3H), 8.01 (dt, 1H), 8.22-8.27 (m, 2H), 8.33 (d, 1H), 10.47 (s, 1H), 11.76 (s, 1H).

Example 427 N ⁴ -{1-[(6-Cyanopyridazin-3-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}-7- Fluoroquinoline-2,4-dimethylamine

In a manner similar to Example 118), 80 mg (0.11 mmol, about 40% purity) of 6-{[4-amino-5-methyl-3-(trifluoromethyl)-1H-pyrazole-1- Reaction of methyl]pyridazine-3-carbonitrile (intermediate 95C) and 22 mg (0.094 mmol) of 2-aminoformamido-7-fluoroquinoline-4-carboxylic acid (intermediate 37A) After purification by HPLC (Method 5c), 12 mg (25%)

^{1 H-NMR (400MHz, DMSO} d 6) δ (ppm) = 2.37 (s, 3H), 5.96 (s, 2H), 7.82 (td, 1H), 7.90-7.96 (m, 2H), 8.00 (d, 1H), 8.27-8.33 (m, 2H), 8.41 - 8.46 (m, 2H), 10.53 (s, 1H).

Additional instance

In addition to the examples described in the synthetic schemes identified above, we have further produced the compounds listed in the table below using the schemes outlined above and in the general synthetic description or well known to those skilled in the art and synthetic methods. Compound.

Additionally, the compounds of formula (I) of the present invention can be converted to any of the salts described herein using any of the methods known to those skilled in the art. Similarly, any salt of a compound of formula (I) of the present invention can be converted to the free compound by any method known to those skilled in the art.

Biological in vitro analysis

The exemplary test experiments described herein are illustrative of the invention and the invention is not limited to the examples given.

Biological assessment

In order to better understand the present invention, the following examples will be set forth. The examples are for illustrative purposes only and are not to be considered as limiting the scope of the invention in any way. All publications mentioned herein are hereby incorporated by reference in their entirety. Confirmation of the activity of the compounds of the invention can be accomplished by in vitro and in vivo assays well known in the art. For example, to demonstrate the efficacy of the agent in inhibiting the glucose transporter GLUT1 and/or GLUT2, the following assays can be used.

Indirect measurement of GLUT1 and GLUT2 activity by quantitative intracellular ATP content

It is well known that small molecule inhibition of mitochondrial electron transport chain and glucose decomposition The combination of agents synergistically suppress ATP production and deplete cell viability (Ulanovskaya et al, 2008, 2011; Liu et al. 2001). Therefore, we used DLD1 or CHO-K1 cells and oxidative phosphorylation inhibitors to identify GLUT1 and GLUT2 inhibitors. Cell lines were maintained in DMEM medium supplemented with 10% FCS and 1% penicillin-streptomycin solution and 2% Glutamax. The cells were trypsinized and seeded in 384 plates at a density of 4000 cells/well. The cells were then incubated overnight in glucose-free medium containing 1% FCS to reduce intracellular ATP levels. After 24 hours, at each appropriate concentration of glucose (0.1 mM for GLUT1 activity) or fructose (10 mM for GLUT2 activity) at 37 ° C, with or without the use of the example compound and 1 μM of fish vine In the case, the cells were incubated for 15 minutes. The CellTiter-Glo® luminescence cell viability assay from Promega was then used to measure ATP content. The compounds which are believed to reduce the ATP content within 15 minutes of glucose/fructose application are glucose/fructose absorption inhibitors, respectively.

¹ DLD1 cells for measuring ATP levels, all values of IC ₅₀ values were normalized to cell delay element ₅₀ B IC; Table 2: fructose on ATP-induced increase in IC ₅₀ values of the compound (GLUT2 inhibition) of the measured

Bioanalysis: glucose absorption analysis

Cells are cultured under standard conditions (eg H460 or CHO-K1). 10,000 cells per well were seeded in clear 96-well tissue culture isoplate plates and grown overnight under standard conditions (PerkinElmer, 1450-516). The medium was removed and the cells were washed twice with 100 μL of KRP buffer and then each at 37 ° C (KRP buffer: 10 mM sodium hydrogen phosphate, 130 mM sodium chloride, 5 mM potassium chloride, 1.3 mM magnesium sulfate, 1.3 mM calcium chloride). (pH 7.5), 50 mM HEPES (pH 7.5), 4.7 mM potassium chloride, 1.25 mM magnesium sulfate, 1.25 mM calcium chloride) were incubated for 45 minutes. KRP wash buffer was removed and compound 126 (diluted in KRP buffer) was added and incubated for 30 minutes at 37 °C. 200 nM radioligand (radioactive ligand 2 [1,2] 3H-deoxy D -glucose in KRP buffer) was added and incubated for 5 minutes at room temperature. The supernatant was removed and the cells were washed twice with 100 μL of ice-cold KRP each. 25 μL of lysis buffer (1% Triton-X, 0.5 N sodium hydroxide) was added and incubated for 5 minutes at room temperature. 75 μL of scintillation solution (Microscint-20, PerkinElmer) was added and the plate was shaken for 1 minute. The plates were incubated for 3 hours at room temperature and counted by using a Wallace MicroBeta counter (60 seconds per well).

Bioanalysis: Proliferation analysis

Cultured tumor cells (MCF7, hormone-dependent human breast cancer cells, ATCC)

HTB22; NCI-H460, human non-small cell lung cancer cells, ATCC HTB-177; DU 145, hormone-independent human prostate cancer cells, ATCC HTB-81; HeLa-MaTu, human cervical cancer cells, EPO-GmbH, Berlin HeLa-MaTu-ADR, multi-drug human cervical cancer cells, EPO-GmbH, Berlin; HeLa human cervical cancer cells, ATCC CCL-2; B16F10 mouse melanoma cells, ATCC CRL-6475) Density of cells/well (MCF7, DU145, HeLa-MaTu-ADR), 3000 cells/well (NCI-H460, HeLa-MaTu, HeLA) or 1000 cells/well (B16F10) in a 96-well multi-well plate 200 μL of each growth medium supplemented with 10% fetal bovine serum. After 24 hours, cells of one plate (zero plate) were stained with crystal violet (see below), while media of other plates were replaced with fresh medium (200 μL), and various concentrations (0 μM, and 0.01 μM to 30 μM were added thereto). Test substance in the range; the final concentration of the solvent dimethyl sulfoxide is 0.5%). The cells were incubated for 4 days in the presence of the test substance. Cell proliferation was determined by staining cells with crystal violet: cells were fixed by adding 20 μL of 11% glutaraldehyde solution for 15 minutes at each measurement point at room temperature. After the fixed cells were washed with water for three cycles, the plates were dried at room temperature. The cells were stained by adding 100 μL of a 0.1% crystal violet solution (pH 3.0) at each measurement point. After the stained cells were washed with water for three cycles, the plates were dried at room temperature. The dye was dissolved by adding 100 μL of a 10% acetic acid solution to each measurement point. The extinction was measured by photometry at a wavelength of 595 nm. The change in the number of cells (%) was calculated by normalizing the measured values to the extinction value (=0%) of the zero-point culture plate and the extinction (=100%) of the untreated (0 μm) cells. ₅₀ by means of a 4 parameter fit measurement value IC.

Determination of in vitro metabolic stability

(including calculation of liver in vivo blood clearance (CL) and maximum oral bioavailability (F _max ))

In vitro metabolic stability of test compounds by suspension of liver microsomes in 1 μM with 100 mM phosphate buffer (NaH ₂ PO ₄ ×H ₂ O+Na ₂ HPO ₄ ×2H ₂ O) at pH 7.4 It was measured by incubating at a protein concentration of 0.5 mg/mL at 37 °C. By adding contain 1.2mg NADP, 3IU glucose-6-phosphate dehydrogenase, 14.6mg and glucose-6-phosphate ₂ in phosphate buffer pH 7.4 of the cofactor reaction mixture was 4.9mg MgCl activated. The organic solvent in the incubation was limited to <0.2% dimethyl hydrazine (DMSO) and <1% methanol. During incubation, the microsomal suspension was continuously vortexed and aliquots were taken at 2, 8, 16, 30, 45 and 60 minutes and an equal volume of cold methanol was immediately added to the aliquot. The samples were frozen overnight at -20 °C, then centrifuged at 3000 rpm for 15 minutes and the supernatant was analyzed using an Agilent 1200 HPLC system with LCMS/MS detection.

The half-life of the test compound was determined from the concentration-time curve. The intrinsic clearance rate is calculated from the half-life. The liver in vivo blood clearance (CL) and maximum oral bioavailability (F _max ) of different species were calculated along with additional parameters of liver blood flow, specific liver weight, and microsomal protein content. The following parameter values were used: liver blood flow - 1.3 L / h / kg (human), 2.1 L / h / kg (dog), 4.2 L / h / kg (rat); specific liver weight - 21 g / kg (person) 39 g/kg (dog), 32 g/kg (rat); microsomal protein content -40 mg/g. The analysis only reflects the first phase metabolism of the microsomes, for example, the redox reaction by cytochrome P450 enzyme and flavin monooxygenase (FMO) and the hydrolysis reaction by esterase (ester and guanamine). .

literature

Liu H, Hu YP, Savarai N, Priebe W, Lampadis T. Hypersensitization of tumor cells to glycolytic inhibitors. Biochemistry. 2001;40:5542-5547.

Ulanovskaya O, Janjic J, Matsumoto K, Schumacker PT, Kron SJ, Kozmin SA. Synthesis capable identification of the cellular target of leucascandrolide A and neopeltolide. Nat Chem Biol. 2008;4:418-424.

Ulanovskaya O, Jiayue Cui, Stephen J. Kron, and Sergey A. Kozmin. A pairwise chemical genetic screen labeled new inhibitors of glucose transport. Chem Biol. 2011 February 25; 18(2): 222-230.

Claims (25)

A compound of the formula (I): Wherein: R ¹ represents C ₁ -C ₃ alkyl-, halo-C ₁ -C ₃ alkyl-, cyano-, -C(=O)OR ¹⁰ or -C(=O)N(R ^10a ) R ^10b group; R ² represents C ₁ -C ₃ alkyl-, halo-C ₁ -C ₃ alkyl-, cyano-, -C(=O)OR ¹⁰ or -C(=O)N( R ^10a ) R ^10b group; R ³ represents a group selected from the group consisting of aryl-, heteroaryl-, C ₅ -C ₆ cycloalkyl- and 5- to 6-membered heterocycloalkyl-; The 5- to 6-membered heterocycloalkyl-group is optionally benzofused; wherein the aryl-, heteroaryl-, C ₅ -C ₆ cycloalkyl- and 5- to 6-membered heterocycloalkyl- The group is optionally substituted one or more times by -(L ² ) _p -R ⁷ ; and two of the -(L ² ) _p -R ⁷ groups, if present in the aryl- or heteroaryl group Where the base groups are ortho to each other, a bridge selected from the group consisting of *-C ₃ -C ₈ alkyl-*, *-O(CH ₂ ) ₂ O-*, *-O ( CH ₂ )O-*, *-O(CF ₂ )O-*, *-CH ₂ C(R ^10a )(R ^10b )O-*, *-C(=O)N(R ^10a )CH ₂ - *, *-N(R ^10a )C(=O)CH ₂ O-*, *-NHC(=O)NH-*; wherein each * represents a point of attachment to the aryl- or heteroaryl-group ; R ^4a represents a hydrogen atom or a halogen atom or a group selected from the group consisting of cyano-, hydroxy-, C _1- C ₃ alkyl-, halo-C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy-, halo-C ₁ -C ₃ alkoxy-, C ₃ -C ₇ naphthenic Base-, 4 to 7-membered heterocycloalkyl-, -C(=O)-OR ¹⁰ , -C(=O)N(R ^10a )R ^10b , -C(=O)-N(R ^10a ) -S(=O) ₂ -R ¹⁰ , -SR ¹⁰ , -S(=O)-R ¹⁰ , -S(=NR ¹¹ )-R ¹⁰ , -S(=O) ₂ -R ¹⁰ , -S( =O) ₂ -N(R ^10a )R ^10b , -S(=O)(=NR ¹¹ )-R ¹⁰ , -N(R ^10a )R ^10b ; R ^4b represents a hydrogen atom or a group selected from the group consisting of: C ₁ -C ₃ alkoxy-, C ₁ -C ₃ alkyl-, cyano-; or R ^4a and R ^4b together form a -C ₃ -C ₅ alkyl- group; R ^5a , R ^5b , R ^5c and R ^5d independently of each other represent a hydrogen atom, a halogen atom or a group selected from the group consisting of cyano-, -NO ₂ , C ₁ -C ₃ alkyl-, halo-C ₁ -C ₃ alkyl- , C ₁ -C ₃ alkoxy-, halo-C ₁ -C ₃ alkoxy-, phenyl-, heteroaryl-, -C(=O)R ¹⁰ , -C(=O)N( H) R ¹⁰ , -C(=O)N(R ^10a )R ^10b , -C(=O)OR ¹⁰ , -N(R ^10a )R ^10b , -N(H)C(=O)R ¹⁰ , -N(R ^10a )C(=O)R ^10b , -N(H)C(=O)N(R ^10a )R ^10b , -N(R ^10a )C(=O)N(R ^10b )R ^10c , -N(R ^10a )C(=O)C(=O)N(R ^10b )R ^10c , -N(H)C(=O)OR ¹⁰ , -N(R ^10a )C(=O)OR ^10b , -N(H)S(=O) ₂ R ¹⁰ , -N(R ^10a )S(=O) ₂ R ^10b , -OR ¹⁰ , -O(C=O)R ¹⁰ , -O(C=O N(R ^10a )R ^10b , -O(C=O)OR ¹⁰ , -SR ¹⁰ , -S(=O)R ¹⁰ , -S(=O) ₂ R ¹⁰ , -S(=O) ₂ N (H) R ¹⁰ , -S(=O) ₂ N(R ^10a )R ^10b or -S(=O)(=NR ^10a )R ^10b , the phenyl- or heteroaryl-group is optionally selected Substituting one or more of the following groups identically or differently: halo-, cyano-, C ₁ -C ₃ alkyl-, halo-C ₁ -C ₃ alkyl-, C ₁ -C ₃ Alkoxy-; R ⁶ represents a hydrogen atom or a group selected from the group consisting of C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy-(L ² )-, hydroxy-C ₁ -C ₃ alkane Base-, aryl-(L ² )-, heteroaryl-(L ² )-; R ⁷ represents a group selected from the group consisting of pendant oxy, C ₁ -C ₆ alkyl-, C ₃ -C ₇ Cycloalkyl-, 4- to 7-membered heterocycloalkyl-, halo-C ₁ -C ₄ alkyl-, hydroxy-C ₁ -C ₄ alkyl-, cyano-C ₁ -C ₄ alkyl- , C ₂ -C ₄ alkenyl-, C ₂ -C ₄ alkynyl-, C ₁ -C ₄ alkoxy-, halo-C ₁ -C ₄ alkoxy-, -OH, -CN, halo -, -C(=O)R ⁸ , -C(=O)-OR ⁸ , -C(=O)N(R ^8a )R ^8b , -N(R ^10a )R ^10b , -S(=O) ^{_{2 R 8, -S (= O}} ) (= NR 11) -R 10, phenyl -, heteroaryl 5-6 Group -; R ⁸ represents a hydrogen atom or a C ₁ -C ₆ alkyl -, halo -C ₁ -C ₃ alkyl -, cyano, -C ₁ -C ₄ alkyl -, C ₁ -C ₃ alkoxy -C ₁ -C ₃ alkyl-, C ₃ -C ₇ cycloalkyl-, phenyl-, 5- to 6-membered heteroaryl- or benzyl-group; R ^8a , R ^8b are independently of each other Hydrogen atom or C ₁ -C ₁₀ alkyl-, C ₃ -C ₇ cycloalkyl-, (C ₃ -C ₇ cycloalkyl)-(L ³ )-, C ₃ -C ₆ alkenyl-, C ₃ -C ₆ alkynyl-, 4 to 10 membered heterocycloalkyl-, (4 to 10 membered heterocycloalkyl)-(L ³ )-, phenyl-, heteroaryl-, phenyl-(L ³⁾ - (phenyl) -O- (L ³⁾ -, heteroaryl - (L ³⁾ - or (aryl) - (4-10 heterocycloalkyl) - group; the C ₁ -C ₁₀ alkyl-, C ₃ -C ₇ cycloalkyl-, (C ₃ -C ₇ cycloalkyl)-(L ³ )-, C ₃ -C ₆ alkenyl-, C ₃ -C ₆ alkynyl - 4 to 10 membered heterocycloalkyl-, (4 to 10 membered heterocycloalkyl)-(L ³ )-, phenyl-, heteroaryl-, phenyl-(L ³ )-, ( Phenyl)-O-(L ³ )-, heteroaryl-(L ³ )-, and (aryl)-(4 to 10 membered heterocycloalkyl)- groups are optionally the same or different via R ⁹ substituted one or more times; or R ^8a and R ^8b represents a 4-10 heterocyclyl group together with the nitrogen atom they are attached - group, the 4 Heterocycloalkyl 10 - group optionally substituted one or more times with R ⁹ identically or differently; R ⁹ represents a halogen atom or oxo, C ₁ -C ₃ alkyl -, halo -C ₁ - C ₃ alkyl-, hydroxy-C ₁ -C ₃ alkyl-, -CN, -C(=O)R ¹⁰ , -C(=O)N(H)R ¹⁰ , -C(=O)N( R ^10a )R ^10b , -C(=O)OR ¹⁰ , -N(R ^10a )R ^10b , -NO ₂ , -N(H)C(=O)R ¹⁰ , -N(R ^10a )C(= O) R ^10b , -N(H)C(=O)N(R ^10a )R ^10b , -N(R ^10a )C(=O)N(R ^10b )R ^10c , -N(H)C(= O) OR ¹⁰ , -N(R ^10a )C(=O)OR ^10b , -N(H)S(=O) ₂ R ¹⁰ , -N(R ^10a )S(=O) ₂ R ^10b , -OR ¹⁰ , -O(C=O)R ¹⁰ , -O(C=O)N(R ^10a )R ^10b , -O(C=O)OR ¹⁰ , -SR ¹⁰ , -S(=O)R ¹⁰ , -S(=O) ₂ R ¹⁰ , -S(=O) ₂ N(H)R ¹⁰ , -S(=O) ₂ N(R ^10a )R ^10b , -S(=O)(=NR ^10a ) R ^10b or a tetrazolyl- group; or two R ⁹ groups present adjacent to each other on the phenyl- or heteroaryl-ring form a bridge selected from the group consisting of: *-C ₃ -C ₅ Alkyl-*, *-O(CH ₂ ) ₂ O-*, *-O(CH ₂ )O-*, *-O(CF ₂ )O-*, *-CH ₂ C(R ^10a )(R ^10b )O-*, *-C(=O)N(R ^10a )CH ₂ -*, *-N(R ^10a )C(=O)CH ₂ O-*, *-NHC(=O)NH- *; each of which represents the phenyl- or hetero-aryl - connection point of the ^{ring; R 10, R 10a, R} 10b, R 10c each independently represents a hydrogen atom or a group selected from the group: C ₁ -C ₃ alkyl -, halo -C ₁ -C ₃ alkyl -, hydroxy-C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl-, C ₃ -C ₇ cycloalkyl-, C ₁ -C ₃ alkyl- The group is optionally substituted once with -N(R ¹² )R ^12a ; or R ^10a and R ^10b together with the nitrogen atom to which it is attached represent a 4 to 7 membered heterocycloalkyl- group, which is from 4 to 7 members. The cycloalkyl-group is optionally substituted one or more times by R ¹³ ; R ¹¹ represents a hydrogen atom or a cyano-, C ₁ -C ₃ alkyl-, -C(=O)R ¹⁰ , -C(=O)N(H)R ¹⁰ , -C(=O)N(R ^10a )R ^10b or -C(=O)OR ¹⁰ group; R ¹² and R ^12a independently of each other represent a hydrogen atom or a C ₁ -C ₃ alkyl-group, or R ¹² , R ^12a together with the nitrogen atom to which it is attached represent a 4 to 7 membered heterocycloalkyl- group; R ¹³ represents a halogen atom or a cyano group, a hydroxy group, a side An oxy group, a C ₁ -C ₃ alkyl-, trifluoromethyl-, -C(=O)R ¹⁰ or -C(=O)OR ¹⁰ group; L ¹ represents a group selected from the group consisting of -C _1- C ₄ alkylene-, -CH ₂ -CH=CH-, -C(phenyl)(H)-, -CH ₂ -CH ₂ -O-, -CH ₂ -C(=O -N(H)-, -CH ₂ -C(=O)-N(R ^10a )-; L ² represents a group selected from the group consisting of -CH ₂ -, -CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -CH ₂ -; L ³ represents a -C ₁ -C ₆ alkylene group; p is an integer 0 or 1; or a tautomer, stereoisomer, N-oxide, hydrated , solvate or salt or a mixture thereof. The compound of claim 1, wherein at least one of R ¹ and R ² is different from isopropyl-. The compound of claim 1 or 2, wherein R ¹ represents a C ₁ -C ₃ alkyl-, trifluoromethyl- or cyano- group, and wherein R ² represents methyl-, ethyl- or trifluoromethyl Base-group. The compound of claim 1 or 2, wherein R ³ represents a group selected from phenyl- or 5- to 6-membered heteroaryl-; wherein the phenyl- or 5- to 6-membered heteroaryl-group is considered The case is substituted one or more times by -(L ² ) _p -R ⁷ identically or differently, or wherein R ³ represents the following group Where * indicates the point of attachment to the rest of the molecule. The compound of claim 1 or 2, wherein R ^4a represents a group selected from the group consisting of C ₁ -C ₃ alkyl-, fluoro-C ₁ -C ₃ alkyl-, C ₁ -C ₃ alkoxy-, C ₃ -C ₅ cycloalkyl, -C(=O)N(R ^10a )R ^10b , -SR ¹⁰ , -S(=O)-R ¹⁰ , -S(=NR ¹¹ )-R ¹⁰ , -S (=O) ₂ -R ¹⁰ , -S(=O) ₂ -N(R ^10a )R ^10b , -N(R ^10a )R ^10b . The compound of claim 1 or 2, wherein R ^4a represents a group selected from the group consisting of isopropyl-, trifluoromethyl-, methoxy-, cyclopropyl-, -C(=O)-NH ₂ . The compound of claim 1 or 2, wherein R ^4b represents a hydrogen atom. The compound of claim 1 or 2, wherein R ^5a , R ^5b , R ^5c and R ^5d independently of each other represent a hydrogen atom, a halogen atom or a group selected from the group consisting of cyano-, C ₁ -C ₃ alkyl- C ₁ -C ₃ alkoxy-, -N(R ^10a )R ^10b , -OR ¹⁰ . A compound according to claim 1 or 2, wherein R ⁶ represents a hydrogen atom. The compound of claim 1 or 2, wherein R ⁷ represents a group selected from the group consisting of C ₁ -C ₃ alkyl-, cyclopropyl-, trifluoromethyl-, C ₁ -C ₃ alkoxy-, Trifluoromethoxy-, -CN, fluoro-, chloro-, -C(=O)-C ₁ -C ₃ alkyl, -C(=O)N(R ^8a )R ^8b , -S(=O ₂ )-C ₁ -C ₃ alkyl. The compound of claim 1 or 2, wherein R ⁸ represents a hydrogen atom or a C ₁ -C ₆ alkyl- group. The compound of claim 1 or 2, wherein R ^8a and R ^8b independently of each other represent a hydrogen atom or a C ₁ -C ₄ alkyl-, C ₃ -C ₅ cycloalkyl-, 4 to 7 membered heterocycloalkyl group - (4 to 7 membered heterocycloalkyl)-(L ³ )-, phenyl- or heteroaryl-(L ³ )- group; C ₁ -C ₄ alkyl-, C ₃ -C _5- Cycloalkyl-, 4- to 7-membered heterocycloalkyl-, (4 to 7 membered heterocycloalkyl)-(L ³ )-, phenyl- or heteroaryl-(L ³ )- group Substituting one or more times with R ⁹ as such or differently; or wherein R ^8a and R ^8b together with the nitrogen atom to which they are attached represent a 4 to 7 membered heterocycloalkyl- group. The compound of claim 1 or 2, wherein R ⁹ represents a halogen atom or a C ₁ -C ₃ alkyl-, fluoro-C ₁ -C ₃ alkyl-, hydroxy-C ₁ -C ₃ alkyl-, -CN, -C(=O)R ¹⁰ , -C(=O)N(H)R ¹⁰ , -C(=O)N(R ^10a )R ^10b , -N(R ^10a )R ^10b , -N(H) C(=O)R ¹⁰ , -N(R ^10a )C(=O)R ^10b , -OR ¹⁰ groups. The compound of claim 1 or 2, wherein L ¹ represents a group selected from the group consisting of -CH ₂ -, -C(CH ₃ )(H)-. The compound of claim 1, which is selected from the group consisting of 2-methoxy-N-[1-(4-methoxybenzyl)-3,5-dimethyl-1H-pyrazole 4-yl]quinoline-4-carboxamide, 6-bromo-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]- 2-(propan-2-yl)quinoline-4-carboxamide, 6-bromo-N-[1-(4-methoxybenzyl)-3,5-dimethyl-1H-pyrazole 4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, N-[1-(4-methoxybenzyl)-3,5-dimethyl-1H-pyridyl Zin-4-yl]-2,6-dimethylquinoline-4-carboxamide, 6-bromo-N-[1-(4-cyanobenzyl)-3,5-dimethyl- 1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-[1-(2-cyanobenzyl)-3,5- Dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, 2-cyclopropyl-N-[1-(4-fluorobenzyl) -3,5-dimethyl-1H-pyrazol-4-yl]-6-methylquinoline-4-carboxamide, 6,8-dichloro-N-[1-(4-methoxy Benzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-[1-( 4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, 2-cyclopropyl-6 -Fluoro-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyridyl 4-yl]quinoline-4-carboxamide, 6,8-dichloro-N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazole-4 -yl]-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-2-cyclopropyl-N-[1-(4-fluorobenzyl)-3,5-di Methyl-1H-pyrazol-4-yl]quinoline-4-carboxamide, 6-bromo-N-[1-(2,6-difluorobenzyl)-3,5-dimethyl- 1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, 6-chloro-N-[1-(4-fluorobenzyl)-3,5-di Methyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, N-[1-(4-cyanobenzyl)-3,5-di Methyl-1H-pyrazol-4-yl]-2-methoxyquinoline-4-carboxamide, 8-bromo-2-cyclopropyl-N-[1-(4-fluorobenzyl) -3,5-Dimethyl-1H-pyrazol-4-yl]quinoline-4-carboxamide, N-[1-(2,4-difluorobenzyl)-3,5-dimethyl -1H-pyrazol-4-yl]-2-methoxyquinoline-4-carboxamide, 8-bromo-N-[1-(4-fluorobenzyl)-3,5-dimethyl -1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, 2-cyclopropyl-N-[1-(4-fluorobenzyl)-3 ,5-Dimethyl-1H-pyrazol-4-yl]quinoline-4-carboxamide, 6,8-dichloro-N-[1-(2,6-difluorobenzyl)-3 ,5-Dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, 8-bromo-N-[1-(4-fluorobenzene -3,5-Dimethyl-1H-pyrazol-4-yl]-6-methyl-2-(trifluoromethyl)quinoline-4-carboxamide, 5,6-dichloro- N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, N -{3,5-Dimethyl-1-[4-(trifluoromethoxy)benzyl]-1H-pyrazol-4-yl}-2-methoxyquinoline-4-carboxamide ,6-bromo-N-[3,5-dimethyl-1-(2-methylbenzyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4 -Procarbamide, 6,8-dichloro-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl) Quinoline-4-carbamide, 5-fluoro-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-( Trifluoromethyl)quinoline-4-carboxamide, N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-methoxy Quinoline-4-carbamide, 6,8-dichloro-N-[3,5-dimethyl-1-(3-methylbenzyl)-1H-pyrazol-4-yl]- 2-(Trifluoromethyl)quinoline-4-carboxamide, 7-fluoro-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazole-4- 2-(trifluoromethyl)quinoline-4-carboxamide, 6-fluoro-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazole 4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, 6,8-dichloro-N-[3,5-dimethyl-1-(4-methyl Benzyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-[1-(4-fluorobenzyl)- 5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, N-(1-benzyl- 3,5-Dimethyl-1H-pyrazol-4-yl)-6-bromo-2-(trifluoromethyl)quinoline-4-carboxamide, 5-bromo-N-[1-(4 -fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, 6,8-dichloro-N -[1-(3,4-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide ,2-bromo-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-4-carboxamide, 7-bromo-N -[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-1,2,3,4-tetrahydroacridine-9-carboxamide, 6,8-Dichloro-N-[1-(4-fluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(trifluoro) Methyl)quinoline-4-carboxamide, 6,7-difluoro-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl] -2-(trifluoromethyl)quinoline-4-carboxamide, 2-cyclopropyl-8-fluoro-N-[1-(4-fluorobenzyl)-3,5-dimethyl- 1H-pyrazol-4-yl]quinoline-4-carboxamide, 6-bromo-N-[1-(2,4-difluorobenzyl)-3,5-dimethyl-1H-pyridyl Azole 4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, N-[1-(2,6-difluorobenzyl)-3,5-dimethyl-1H-pyridyl Zin-4-yl]-2-methoxyquinoline-4-carboxamide, 6-bromo-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyridyl Zin-4-yl]-2-methylquinoline-4-carboxamide, N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazole-4- -2,6-dimethylquinoline-4-carboxamide, N-[3,5-dimethyl-1-(4-methylbenzyl)-1H-pyrazol-4-yl -2,6-Dimethylquinoline-4-carboxamide, 2-cyclopropyl-5-fluoro-N-[1-(4-fluorobenzyl)-3,5-dimethyl- 1H-pyrazol-4-yl]quinoline-4-carboxamide, 6-bromo-N-[1-(3,4-difluorobenzyl)-3,5-dimethyl-1H-pyridyl Zin-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, 6,8-dichloro-N-[1-(2,4-difluorobenzyl)-3, 5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-[3,5-dimethyl-1- (2,4,6-trifluorobenzyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, N-[3,5-dimethyl 1-(2,4,6-trifluorobenzyl)-1H-pyrazol-4-yl]-2-methoxyquinoline-4-carboxamide, N-[3,5-di Methyl-1-(2-methylbenzyl)-1H-pyrazol-4-yl]-2-methoxyquinoline-4-carboxamide, 6-bromo-N-[3,5- two Methyl-1-(3-methylbenzyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, 8-bromo-N-[1 -(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-methylquinoline-4-carboxamide, 6-bromo-N-[3, 5-Dimethyl-1-(4-methylbenzyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, N-[1- (3,4-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-methoxyquinoline-4-carboxamide, 6-bromo-N- {3,5-Dimethyl-1-[4-(trifluoromethoxy)benzyl]-1H-pyrazol-4-yl}-2-(trifluoromethyl)quinoline-4-methyl Indoleamine, 6,8-dichloro-N-[3,5-dimethyl-1-(2,4,6-trifluorobenzyl)-1H-pyrazol-4-yl]-2-( Trifluoromethyl)quinoline-4-carboxamide, N-{3,5-dimethyl-1-[4-(trifluoromethoxy)benzyl]-1H-pyrazol-4-yl }-2,6-Dimethylquinoline-4-carboxamide, N-(1-benzylmethyl-3,5-dimethyl-1H-pyrazol-4-yl)-6,8-di Chloro-2-(trifluoromethyl)quinoline-4-carboxamide, 6,8-dichloro-N-{3,5-dimethyl-1-[4-(trifluoromethoxy)benzene Methyl]-1H-pyrazol-4-yl}-2-(trifluoromethyl)quinoline-4-carboxamide, N-[3,5-dimethyl-1-(4-methylbenzene Methyl)-1H-pyrazol-4-yl]-2-methoxyquinoline-4-carboxamide, N-[1-(4-fluorobenzyl)-3, 5-dimethyl-1H-pyrazol-4-yl]-2,6-dimethylquinoline-4-carboxamide, N-[1-(4-fluorobenzyl)-3,5- Dimethyl-1H-pyrazol-4-yl]-6-(trifluoromethoxy)-2-(trifluoromethyl)quinoline-4-carboxamide, N-[1-(3,4 -difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2,6-dimethylquinoline-4-carboxamide, N-(1-benzyl group -3,5-Dimethyl-1H-pyrazol-4-yl)-2-methoxyquinoline-4-carboxamide, 6,8-dichloro-N-[3,5-dimethyl -1-(pyridin-2-ylmethyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, 6,8-dichloro-N-[ 1-(3-Methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, 6, 8-Dichloro-N-[1-(2-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4 -Procarbamide, 2-ethyl-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-4-carboxamide, 6-Bromo-N-[3,5-dimethyl-1-(pyridin-2-ylmethyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4- Formamide, 6-bromo-N-[1-(3-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quina Benzyl-4-carbamide, 6-bromo-N-[1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]- 2-(Trifluoromethyl)quinoline-4-carboxamide, N-[1-(4-fluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole- 4-yl]-2,6-dimethylquinoline-4-carboxamide, 6-bromo-N-[1-(2-fluorobenzyl)-3,5-dimethyl-1H-pyridyl Zin-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazole 4-yl]-2-hydroxy-6-methoxyquinoline-4-carboxamide, N-[3,5-dimethyl-1-(3-methylbenzyl)-1H-pyridyl Zin-4-yl]-2-methoxyquinoline-4-carboxamide, N-[1-(2-fluorobenzyl)-3,5-dimethyl-1H-pyrazole-4- 2-methoxyquinolin-4-carboxamide, 2-cyano-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazole-4 -yl]quinoline-4-carboxamide, 2-cyclopropyl-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]- 6-(Trifluoromethyl)quinoline-4-carboxamide, N-[1-(2-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]- 2-methoxyquinoline-4-carboxamide, 2-methoxy-N-[1-(3-methoxybenzyl)-3,5-dimethyl-1H-pyrazole-4 -yl]quinoline-4-carboxamide, 6,8-dichloro-N-{3,5-dimethyl-1-[(3-methylpyridin-2-yl)methyl]-1H- Pyrazol-4-yl}-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-{3,5-dimethyl 1-[2-(trifluoromethoxy)benzyl]-1H-pyrazol-4-yl}-2-(trifluoromethyl)quinoline-4-carboxamide, N-[1- (2,6-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2,6-dimethylquinolin-4-carboxamide, 8-fluoro- N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, N -[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2,8-dimethylquinolin-4-carboxamide, N-[ 1-(3-Fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-methoxyquinoline-4-carboxamide, 7-bromo-N-[ 1-(4-Fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, 6,8- Dichloro-N-[3,5-dimethyl-1-(2-methylbenzyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-methyl Indoleamine, 6-fluoro-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-methylquinoline-4-carboxamidine Amine, 6,8-dichloro-N-[1-(3-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl) Quinoline-4-carboxamide, N-(1-benzyl-3,5-dimethyl-1H-pyrazol-4-yl)-2,6-dimethylquinoline-4-carboxamidine Amine, 6,8-dichloro-N-{3,5-dimethyl-1-[3-(trifluoromethoxy)benzyl]-1H-pyrazol-4-yl}-2 -(Trifluoromethyl)quinoline-4-carboxamide, 6,8-dichloro-N-[1-(2-fluorobenzyl)-3,5-dimethyl-1H-pyrazole- 4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazole-4 -yl]-3-methoxy-2-methylquinoline-4-carboxamide, N-[1-(2,4-difluorobenzyl)-3,5-dimethyl-1H- Pyrazol-4-yl]-2,6-dimethylquinoline-4-carboxamide, 6-bromo-N-[1-(3-methoxybenzyl)-3,5-dimethyl -1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, N-[1-(4-fluorobenzyl)-3,5-dimethyl -1H-pyrazol-4-yl]-2,6-bis(trifluoromethyl)quinoline-4-carboxamide, 2-chloro-N-[1-(4-fluorobenzyl)-3 ,5-Dimethyl-1H-pyrazol-4-yl]quinoline-4-carboxamide, 7-bromo-2-cyclopropyl-N-[1-(4-fluorobenzyl)-3 ,5-Dimethyl-1H-pyrazol-4-yl]quinoline-4-carboxamide, N-[3,5-dimethyl-1-(3-methylbenzyl)-1H- Pyrazol-4-yl]-2,6-dimethylquinoline-4-carboxamide, 8-cyano-N-[1-(4-fluorobenzyl)-3,5-dimethyl -1H-pyrazol-4-yl]-6-methyl-2-(trifluoromethyl)quinoline-4-carboxamide, 6-cyano-N-[1-(4-fluorobenzyl) -3,5-Dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, 6,8-dichloro-N -[1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, N- [1-(4-Fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-methylquinoline-4-carboxamide, 6,7-dichloro- N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, N -{3,5-Dimethyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrazol-4-yl}-2,6-dimethylquinolin-4-carboxamidine Amine, 2-cyclopropyl-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-8-(trifluoromethyl)quinoline 4-carbamamine, N-[1-(3-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2,6-dimethylquinoline 4-carbamamine, N-[3,5-dimethyl-1-(pyridin-2-ylmethyl)-1H-pyrazol-4-yl]-2-methoxyquinolin-4- Formamide, N-[3,5-dimethyl-1-(2-methylbenzyl)-1H-pyrazol-4-yl]-2,6-dimethylquinoline-4-methyl Indoleamine, N-[1-(2-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2,6-dimethylquinoline-4-carboxamide ,6-Bromo-N-{3,5-dimethyl-1-[3-(trifluoromethoxy)benzyl]-1H-pyrazol-4-yl}-2-(trifluoromethyl Quinoline-4-carboxamide, N-[1-(2-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2,6 - dimethylquinoline-4-carboxamide, N-{3,5-dimethyl-1-[3-(trifluoromethoxy)benzyl]-1H-pyrazol-4-yl} 2-methoxyquinolin-4-carboxamide, 6-bromo-N-{3,5-dimethyl-1-[(3-methylpyridin-2-yl)methyl]-1H- Pyrazol-4-yl}-2-(trifluoromethyl)quinoline-4-carboxamide, N-{3,5-dimethyl-1-[3-(trifluoromethoxy)benzene -1H-pyrazol-4-yl}-2,6-dimethylquinolin-4-carboxamide, 6-bromo-N-[1-(2-cyanobenzyl)-3, 5-dimethyl-1H-pyrazol-4-yl]-2-(propan-2-yl)quinoline-4-carboxamide, 6-bromo-N ⁴ -[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, 6,7-difluoro-N ⁴ -[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, 6-chloro-7-fluoro- N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, N ⁴ -[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, 6-bromo-2-cyclopropane -N-[1-(3,4-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-4-carboxamide, 6-bromo-7 -Fluoro-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamidine Amine, 6-chloro-2-cyclopropyl-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-4-carboxamidine Amine, N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, 6 , 8-dichloro-N ⁴ -[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, N ⁴ -[1-(3,4-Difluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine , 6-Bromo-N-[1-(3,4-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(propan-2-yl)quina Porphyrin-4-carbamamine, N ⁴ -[1-(4-fluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, 4- {[4-({[6-Bromo-2-(trifluoromethyl)quinolin-4-yl)carbonyl}amino)-3,5-dimethyl-1H-pyrazol-1-yl]- Methyl benzoate, 4-{[4-({[6-bromo-2-(trifluoromethyl)quinolin-4-yl]carbonyl}amino)-3,5-dimethyl-1H -pyrazol-1-yl]methyl}benzoic acid,6-bromo-N-[1-(4-aminoformamidobenzyl)-3,5-dimethyl-1H-pyrazole-4- 2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-{3,5-dimethyl-1-[4-(phenylaminemethanyl)benzene -1H-pyrazol-4-yl}-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-{3,5-dimethyl-1-[4- (methylamine-mercapto)benzyl}-1H-pyrazol-4-yl}-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-[3,5 -Dimethyl-1-(4-{[2-(morpholin-4-yl)ethyl]aminemethanyl}benzyl)-1H-pyrazol-4-yl]-2-(trifluoro) Methyl)quinoline-4-carboxamide, 6-bromo-N-(1-{4-[(2-methoxyethyl)aminemethanyl]benzyl}-3,5-dimethyl -1H-pyrazol-4-yl)-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-(3,5-dimethyl-1-{4-[ (pyridin-3-ylmethyl)amine-methylmethyl]benzyl}-1H-pyrazol-4-yl)-2-(trifluoro) Quinoline-4-carboxamide, 6-bromo-N-(1-{4-[(2-hydroxyethyl)aminemethanyl]benzyl}-3,5-dimethyl-1H -pyrazol-4-yl)-2-(trifluoromethyl)quinoline-4-carboxamide, N-{1-[4-(benzylaminocarbamimidyl)benzyl]-3, 5-dimethyl-1H-pyrazol-4-yl}-6-bromo-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-{3,5-dimethyl 1-[4-(morpholin-4-ylcarbonyl)benzyl]-1H-pyrazol-4-yl}-2-(trifluoromethyl)quinoline-4-carboxamide, 6- Bromo-N-[1-(4-{[2-(dimethylamino)ethyl]aminemethanyl}benzyl)-3,5-dimethyl-1H-pyrazol-4-yl] -2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-{1-[4-(dimethylaminecarbamimido)benzyl]-3,5-dimethyl -1H-pyrazol-4-yl}-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-2-cyclobutyl-N-[1-(3,4-di Fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-4-carboxamide, 6-chloro-2-cyclopropyl-N-[1-(3, 4-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-4-carboxamide, 6-bromo-2-cyclobutyl-N-[1- (4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-4-carboxamide, 6-bromo-N-{1-[(6-cyano) Pyridin-3-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-2-(trifluoromethyl) Phenyl-4-carbamide, 6-bromo-N-[1-(4-chlorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl) Quinoline-4-carboxamide, 4-{[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]aminecarbenyl}-2 -(Trifluoromethyl)quinoline-6-carboxylic acid methyl ester, (4-{[4-({[6-bromo-2-(trifluoromethyl)quinolin-4-yl)carbonyl}amino) Methyl -3,5-dimethyl-1H-pyrazol-1-yl]methyl}phenyl)acetate, (4-{[4-({[6-bromo-2-(trifluoromethyl))) Quinoline-4-yl]carbonyl}amino)-3,5-dimethyl-1H-pyrazol-1-yl]methyl}phenyl)acetic acid, N-{1-[4-(2-amine 2-ethyloxyethyl)benzyl]-3,5-dimethyl-1H-pyrazol-4-yl}-6-bromo-2-(trifluoromethyl)quinoline-4- Formamide, 6-bromo-N-(3,5-dimethyl-1-{4-[2-(methylamino)-2-yloxyethyl]benzyl}-1H-pyridyl Zin-4-yl)-2-(trifluoromethyl)quinoline-4-carboxamide, N-(1-{4-[2-(benzylamino)-2-oxoethyl Benzyl}-3,5-dimethyl-1H-pyrazol-4-yl)-6-bromo-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N -(3,5-Dimethyl-1-{4-[2-o-oxy-2-(phenylamino)ethyl]benzyl}-1H-pyrazol-4-yl)-2- (trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-(1-{4-[2-(dimethylamino)-2- Oxyethylethyl]benzyl}-3,5-dimethyl-1H-pyrazol-4-yl)-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo- N-[3,5-Dimethyl-1-(4-{2-o-oxy-2-[(pyridin-3-ylmethyl)amino]ethyl}benzyl)-1H-pyrazole 4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-(3,5-dimethyl-1-{4-[2-(morpholine- 4-yl)-2-yloxyethyl]benzyl}-1H-pyrazol-4-yl)-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N -[1-(4-{2-[(2-hydroxyethyl)amino]-2-oxoethyl}benzyl)-3,5-dimethyl-1H-pyrazole-4- 2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-[3,5-dimethyl-1-(pyridin-4-ylmethyl)-1H-pyridyl Zin-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-[1-(4-cyanobenzyl)-5-methyl-3- (trifluoromethyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, 2-cyclopropyl-N-[1-(3,4- Difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-6-fluoroquinoline-4-carboxamide, 2-(dimethylamino)-N-[1 -(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-4-carboxamide, 6-bromo-N-[1-(4-hydroxybenzene Methyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide 6-Chloro-N-[1-(3,4-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline- 4-Proline, N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-6-phenyl-2-(trifluoromethyl Quinoline-4-carboxamide, 6,8-dichloro-N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole 4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, N-[1-(3,4-difluorobenzyl)-3,5-dimethyl-1H- Pyrazol-4-yl]-7-fluoro-2-(trifluoromethyl)quinoline-4-carboxamide, N-[1-(4-cyanobenzyl)-3,5-dimethyl -1H-pyrazol-4-yl]-6,7-difluoro-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-[1-(cyclohexylmethyl) -3,5-Dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-[3,5-dimethyl 1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, N ⁴ -[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-N ² -methylquinoline-2,4-dimethylamine, N-[1-(3,4-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]- 5-fluoro-2-(trifluoromethyl)quinoline-4-carboxamide, N-[1-(3,4-difluorobenzyl)-3,5-dimethyl-1H-pyrazole 4-yl]-6-fluoro-2-(trifluoromethyl)quinoline-4-carboxamide, N-[1-(2-cyanobenzyl)-3,5-dimethyl- 1H-pyrazol-4-yl]-6,7-difluoro-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-ethyl-N-[1-(4 -fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, N-[1-(3, 4-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-6,7-difluoro-2-(trifluoromethyl)quinoline-4-carboxamide ,N ⁴ -[1-(4-fluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-N2-methylquinoline-2,4-dimethyl Indoleamine, 6-bromo-N-[1-(2,4-difluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2- (trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-{1-[(5-chlorothien-2-yl)methyl]-3,5-dimethyl-1H-pyridyl Zin-4-yl}-2-(trifluoromethyl)quinoline-4-carboxamide, N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazole 4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl) -1H-pyrazol-4-yl]-6,7-difluoro-2-(trifluoromethyl)quinoline-4-carboxamide, N-{1-[(6-cyanopyridine-3) -yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-6,7-difluoro-2-(trifluoromethyl)quinoline-4-carboxamide, 6 -Bromo-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-4-carboxamide, 6-bromo-N-[ 1-(3,4-Difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-methylquinoline-4-carboxamide, N-[1- (3-Chloro-4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2,6-dimethylquinolin-4-carboxamide, 6-bromo -N-{3,5-Dimethyl-1-[(1-methyl-1H-pyrazol-3-yl)methyl]-1H-pyrazol-4-yl}-2-(trifluoromethyl) base) Benzyl-4-carbamide, N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2,6 - dimethylquinoline-4-carboxamide, 7-bromo-N-[1-(3,4-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl ]-2-(Trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-[1-(3-chloro-4-fluorobenzyl)-3,5-dimethyl-1H -pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, N-[1-(3-chloro-4-fluorobenzyl)-3,5-dimethyl -1H-pyrazol-4-yl]-6,7-difluoro-2-(trifluoromethyl)quinoline-4-carboxamide, N-[1-(4-fluorobenzyl)- 3,5-Dimethyl-1H-pyrazol-4-yl]-6-methoxyquinoline-4-carboxamide, 6,7-difluoro-N-[1-(4-fluorophenyl) 5-)methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N- [1-(4-Fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-N-(2-methoxyethyl)-2-(trifluoromethyl) Quinoline-4-carboxamide, N-[1-(cyclohexylmethyl)-3,5-dimethyl-1H-pyrazol-4-yl]-6,7-difluoro-2-(three Fluoromethyl)quinoline-4-carboxamide, N-[3,5-dimethyl-1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl]-6,7- Difluoro-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-[1-(3,4-difluorobenzyl)-5-methyl-3- (trifluoromethyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, N-[1-(4-fluorobenzyl)-3, 5-dimethyl-1H-pyrazol-4-yl]-2-(morpholin-4-yl)quinoline-4-carboxamide, 6,8-dichloro-N-[1-(3, 4-difluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, N-Benzyl-6-bromo-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl) Quinoline-4-carboxamide, N-{1-[(6-cyanopyridin-3-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-2, 6-Dimethylquinoline-4-carboxamide, N-(1-{4-[(2-hydroxyethyl)aminemethanyl]benzyl}-3,5-dimethyl-1H- Pyrazol-4-yl)-2,6-dimethylquinolin-4-carboxamide, N-[1-(3,4-difluorobenzyl)-5-methyl-3-(three Fluoromethyl)-1H-pyrazol-4-yl]-2,6-dimethylquinolin-4-carboxamide, N-[1-(2,4-difluorobenzyl)-5- Methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2,6-dimethylquinolin-4-carboxamide, 6,8-dichloro-N-[1- (2,4-Difluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-methyl Indoleamine N-[1-(cyclohexylmethyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2,6-dimethylquinolin-4- Indoleamine, N-[1-(3,4-difluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-6,7-difluoro -2-(Trifluoromethyl)quinoline-4-carboxamide, N-[3,5-dimethyl-1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl] -2,6-dimethylquinoline-4-carboxamide, N ⁴ -[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-N ² ,N ² - dimethylquinoline-2,4-dimethylamine, N-[1-(2,4-difluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyridyl Zin-4-yl]-6,7-difluoro-2-(trifluoromethyl)quinoline-4-carboxamide, N-[1-(4-fluorobenzyl)-3,5-di Methyl-1H-pyrazol-4-yl]quinoline-4-carboxamide, 6-chloro-N ⁴ -[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-dimethylamine, 6-chloro -N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-dimethyl Indoleamine, 6-chloro-7-fluoro-N ⁴ -[1-(4-Methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, 6-chloro-N ⁴ -[1-(2-Cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-dimethylamine, N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-6,7-difluoroquinoline-2,4 -dimethylamine,6-bromo-N-{3,5-dimethyl-1-[4-(methylsulfonyl)benzyl]-1H-pyrazol-4-yl}-2-( Trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-[1-(4-cyano-3-fluorobenzyl)-3,5-dimethyl-1H-pyrazole- 4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-6-fluoroquinoline-2,4-dimethyl Guanamine, N ⁴ -{1-[(2-Cyanopyridin-3-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-6,7-difluoroquinoline-2,4 -dimethylamine, N ⁴ -[1-(2-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-6-fluoroquinoline-2,4-dimethylamine, N ⁴ -{1-[(3-Cyanopyridin-2-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-6,7-difluoroquinoline-2,4 -dimethylamine, N ⁴ -{1-[(2-Cyanopyridin-3-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}quinoline-2,4-dimethylamine, N ⁴ -{3,5-Dimethyl-1-[4-(methylsulfonyl)benzyl]-1H-pyrazol-4-yl}quinoline-2,4-dimethylamine, N ⁴ -{1-[(6-Cyanopyridin-3-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}quinoline-2,4-dimethylamine, 6 ,7-difluoro-N ⁴ -[1-(4-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, 6-fluoro-N ⁴ -[1-(4-Methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, N ⁴ -[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-6-fluoroquinoline-2,4-dimethylamine, 6-fluoro -N ⁴ -[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, N ⁴ -[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-6,7-difluoroquinoline-2,4-dimethylamine, N ⁴ -{3,5-Dimethyl-1-[4-(methylsulfonyl)benzyl]-1H-pyrazol-4-yl}-6,7-difluoroquinoline-2,4-di Formamide, N ⁴ -[1-(2-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, 2-cyclopropyl-N -[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-6-methoxyquinoline-4-carboxamide, 6-bromo-N -{1-[(3-Cyanopyridin-2-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-2-(trifluoromethyl)quinoline-4 -carbamamine, N ⁴ -[1-(2-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-6,7-difluoroquinoline-2,4-dimethylamine, 6,7-difluoro-N ⁴ -[1-(3-Fluoro-4-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, 6- Chloro-7-fluoro-N ⁴ -[1-(3-Fluoro-4-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, N ⁴ -[1-(3-Fluoro-4-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, N- [1-(3-Fluoro-4-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-methoxyquinoline-4-carboxamide, N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-dimethyl Indoleamine, 6-chloro-N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-8-fluoroquinoline-2,4-dimethyl Guanamine, N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoro-6-methoxyquinoline- 2,4-dimethylamine, N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-5,7-difluoroquinoline-2,4 -dimethylamine, N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-5-methylquinoline-2,4-di Formamide, N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-6-methoxyquinoline-2,4- Dimethylamine, 7-chloro-N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-8-fluoroquinoline-2,4-dimethyl Indoleamine, 6-chloro-N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-5-fluoroquinoline-2,4-dimethyl Guanamine, N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-5-fluoroquinoline-2,4-dimethyl Guanamine, N ⁴ -[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-dimethylamine, 6-chloro -N ⁴ -[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-8-fluoroquinoline-2,4-dimethylamine, N ⁴ -[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-5,7-difluoroquinoline-2,4-dimethylamine, N ⁴ -[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-7-fluoro-6-methoxyquinoline-2,4-dimethyl Guanamine, 8-chloro-N ⁴ -[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, N ⁴ -[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-7-fluoro-6-methylquinoline-2,4-dimethylhydrazine Amine, N ⁴ -[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-5-methylquinoline-2,4-dimethylamine, N ⁴ -[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-6-methoxyquinoline-2,4-dimethylamine, N ⁴ -[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, 7-chloro-N ⁴ -[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, 6-chloro-N ⁴ -[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, N ⁴ -[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-5-fluoroquinoline-2,4-dimethylamine, N ⁴ -[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-8-fluoroquinoline-2,4-dimethylamine, N ⁴ -[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-6-methylquinoline-2,4-dimethylamine, N- [1-(4-Cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-6-fluoro-2-methoxyquinoline-4-carboxamide, N ⁴ -[1-(2-Cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-dimethylamine, N ⁴ -[1-(2-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-5-fluoroquinoline-2,4-dimethylamine, 6-bromo -N ⁴ -[1-(2-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, 6-chloro-N ⁴ -[1-(2-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-8-fluoroquinoline-2,4-dimethylamine, 6-chloro -N ⁴ -[1-(2-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-dimethyl Guanamine, N ⁴ -[1-(2-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, N ⁴ -[1-(2-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-dimethyl Guanamine, N ⁴ -[1-(2-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-5-fluoroquinoline-2,4-dimethyl Indoleamine, 6-bromo-N ⁴ -[1-(2-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, 7 -Fluorine-N ⁴ -[1-(4-Methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, 6-chloro-8- Fluorine-N ⁴ -[1-(4-Methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, N ⁴ -[1-(4-Methoxybenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, 6-chloro-7-fluoro-N ⁴ -[1-(4-Methoxybenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, 6,7-difluoro-N ⁴ -[1-(4-Methoxybenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, N ⁴ -{1-[(6-Methoxypyridin-3-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}quinoline-2,4 -dimethylamine, 6-chloro-7-fluoro-N ⁴ -{1-[(6-Methoxypyridin-3-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}quinoline-2,4 -dimethylamine, N ⁴ -{1-[(6-Methoxypyridin-3-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}quinoline-2,4-dimethylamine, 6-chloro-7-fluoro-N ⁴ -{1-[(6-Methoxypyridin-3-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}quinoline-2,4-dimethylamine, N ⁴ -{1-[3-(4-Methoxyphenyl)propyl]-3,5-dimethyl-1H-pyrazol-4-yl}quinoline-2,4-dimethylamine, 6 -chloro-N ⁴ -{1-[(3-Cyanopyridin-4-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-7-fluoroquinoline-2,4-dimethyl Guanamine, N ⁴ -{1-[(3-Cyanopyridin-4-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}quinoline-2,4-dimethylamine, 6 -chloro-N ⁴ -{1-[(3-Cyanopyridin-4-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}-7-fluoroquinoline- 2,4-dimethylamine, N ⁴ -{1-[(3-Cyanopyridin-4-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}quinoline-2,4- Dimethylamine, N ⁴ -{1-[(6-Cyanopyridin-3-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}quinoline-2,4- Dimethylamine, N ⁴ -{1-[(6-Cyanopyridin-3-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}-7-fluoroquinoline- 2,4-dimethylamine, N ⁴ -{1-[(6-Cyanopyridin-3-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}-5-fluoroquinoline- 2,4-dimethylamine, N ⁴ -{1-[(6-Cyanopyridin-3-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-7-fluoroquinoline-2,4-dimethyl Indoleamine, 6-bromo-N ⁴ -{1-[(6-Cyanopyridin-3-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}quinoline-2,4-dimethylamine, 6 -chloro-N ⁴ -{1-[2-(4-Cyanophenoxy)ethyl]-3,5-dimethyl-1H-pyrazol-4-yl}-7-fluoroquinoline-2,4-dimethyl Guanamine, N ⁴ -{1-[2-(4-Cyanophenoxy)ethyl]-3,5-dimethyl-1H-pyrazol-4-yl}quinoline-2,4-dimethylamine, 6 -chloro-N ⁴ -[1-(4-Cyano-2-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-dimethylamine ,N ⁴ -[1-(4-Cyano-2-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, N ⁴ -[1-(4-Cyano-2-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-6,7-difluoroquinoline-2,4-di Formamide, 6-bromo-N ⁴ -[1-(4-Cyano-2-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, N ⁴ -[1-(4-Cyano-2-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-dimethylamine ,N ⁴ -[1-(4-Cyano-2-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-5-fluoroquinoline-2,4-dimethylamine ,N ⁴ -[1-(4-Cyano-2-fluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethyl Indoleamine, 6-chloro-N ⁴ -[1-(4-Cyano-2-fluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoroquinolin-2, 4-dimethylamine, N ⁴ -[1-(4-Cyano-2-fluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-6,7-difluoroquinoline -2,4-dimethylamine, 6-bromo-N ⁴ -[1-(4-Cyano-2-fluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethyl Guanamine, N ⁴ -[1-(4-Cyano-2-fluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-5-fluoroquinoline-2, 4-dimethylamine, 6-chloro-N ⁴ -[3-Cyano-1-(4-fluorobenzyl)-5-methyl-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-dimethylamine, N ⁴ -[3-cyano-1-(4-fluorobenzyl)-5-methyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, 6-bromo-N- [1-(4-Cyanobenzyl)-3,5-diethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, N ⁴ -[1-(4-cyanobenzyl)-3,5-diethyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, 6-chloro-N ⁴ -[1-(4-cyanobenzyl)-3,5-diethyl-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-dimethylamine, N ⁴ -[1-(4-cyanobenzyl)-3,5-diethyl-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-dimethylamine, 7-chloro -N ⁴ -[1-(4-cyanobenzyl)-3,5-diethyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, 6-chloro-N ⁴ -[1-(4-cyanobenzyl)-5-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-dimethyl Guanamine, N ⁴ -[1-(4-cyanobenzyl)-5-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-dimethyl Guanamine, N ⁴ -[1-(4-cyanobenzyl)-5-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-5-fluoroquinoline-2,4-dimethyl Guanamine, N ⁴ -[1-(4-cyanobenzyl)-5-isopropyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, N ⁴ -[1-(4-cyanobenzyl)-5-isopropyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-di Formamide, N ⁴ -[1-(4-Cyanobenzyl)-3-isopropyl-5-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, N ⁴ -[1-(4-cyanobenzyl)-3-isopropyl-5-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-di Formamide, N ⁴ -[1-(4-cyanobenzyl)-3-isopropyl-5-methyl-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-dimethylamine, N ⁴ -[1-(4-cyanobenzyl)-3-isopropyl-5-methyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, N ⁴ -[1-(4-cyanobenzyl)-5-isopropyl-3-methyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, 6-chloro- N ⁴ -[1-(4-cyanobenzyl)-3-isopropyl-5-methyl-1H-pyrazol-4-yl]-7-fluoroquinolin-2,4-dimethylamine, N ⁴ -[1-(4-cyanobenzyl)-3-ethyl-5-methyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, N ⁴ -[1-(4-cyanobenzyl)-5-ethyl-3-methyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, N ⁴ -[1-(4-cyanobenzyl)-3-ethyl-5-methyl-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-dimethylamine, N ⁴ -[1-(4-cyanobenzyl)-5-ethyl-3-methyl-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-dimethylamine, ( ±)-N ⁴ -{1-[1-(4-Cyanophenyl)ethyl]-3,5-dimethyl-1H-pyrazol-4-yl}quinoline-2,4-dimethylamine, (± )-6-chloro-N ⁴ -{1-[1-(4-Cyanophenyl)ethyl]-3,5-dimethyl-1H-pyrazol-4-yl}-7-fluoroquinoline-2,4-dimethylhydrazine Amine, (±)-N ⁴ -{1-[1-(4-cyanophenyl)ethyl]-3,5-dimethyl-1H-pyrazol-4-yl}-8-fluoroquinoline-2,4-dimethylhydrazine Amine, (±)-N ⁴ -{1-[1-(4-cyanophenyl)ethyl]-3,5-dimethyl-1H-pyrazol-4-yl}-8-fluoroquinoline-2,4-dimethylhydrazine Amine, (±)-N ⁴ -{1-[1-(4-Cyanophenyl)ethyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}quinoline-2,4-di Formamide, (±)-7-fluoro-N ⁴ -[5-Methyl-1-(1-phenylethyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, ( R )-7-fluoro-N ⁴ -[5-Methyl-1-(1-phenylethyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, ( S )-7-fluoro-N ⁴ -[5-Methyl-1-(1-phenylethyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, 6-cyanide base-N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, 8 -chloro-N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-methoxyquinoline-2,4- Dimethylamine, 2-(azetidin-1-ylcarbonyl)-N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H- Pyrazol-4-yl]-7-fluoroquinoline-4-carboxamide, N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoro-N ² -(3-hydroxypropyl)quinoline-2,4-dimethylamine, N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoro-N ² -[2-(morpholin-4-yl)ethyl]quinoline-2,4-dimethylamine, N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoro-6-methylquinoline-2 , 4-dimethylamine, N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-6-[(2-methoxyethyl) Amino]quinoline-2,4-dimethylamine, N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-6-(piperidin-1-yl)quinoline -2,4-dimethylamine, 6-chloro-N ⁴ -{1-[3-(4-Cyanophenyl)propyl]-3,5-dimethyl-1H-pyrazol-4-yl}-7-fluoroquinoline-2,4-dimethylhydrazine Amine, N ⁴ -{1-[3-(4-Cyanophenyl)propyl]-3,5-dimethyl-1H-pyrazol-4-yl}quinoline-2,4-dimethylamine, 6- Bromo-N-{1-[3-(4-cyanophenyl)propyl]-3,5-dimethyl-1H-pyrazol-4-yl}-2-(trifluoromethyl)quinoline 4-carbamamine, N-{1-[3-(4-cyanophenyl)propyl]-3,5-dimethyl-1H-pyrazol-4-yl}-2-methoxy Quinoline-4-carboxamide, 6-bromo-N ⁴ -{1-[(5-Cyanopyridin-2-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}quinoline-2,4-dimethylamine, 6 -chloro-N ⁴ -{1-[(5-Cyanopyridin-2-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-7-fluoroquinoline-2,4-dimethyl Guanamine, N ⁴ -{1-[(5-Cyanopyridin-2-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-5-fluoroquinoline-2,4-dimethyl Indoleamine, 6-bromo-N-{1-[(5-cyanopyridin-2-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-2-(three Fluoromethyl)quinoline-4-carboxamide, N ⁴ -{1-[(5-Cyanopyridin-2-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-6,7-difluoroquinoline-2,4 -dimethylamine, N ⁴ -{1-[(5-Cyanopyridin-2-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}quinoline-2,4-dimethylamine, N ⁴ -{1-[(5-Cyanopyridin-2-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-7-fluoroquinoline-2,4-dimethyl Indoleamine, N-{1-[(5-cyanopyridin-2-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-2-methoxyquinoline- 4-carbamamine, 6-bromo-N ⁴ -{1-[(5-Cyanopyridin-2-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}quinoline-2,4- Dimethylamine, 6-chloro-N ⁴ -{1-[(5-Cyanopyridin-2-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}-7-fluoroquinoline- 2,4-dimethylamine, N ⁴ -{1-[(5-Cyanopyridin-2-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}-7-fluoroquinoline- 2,4-dimethylamine, N ⁴ -{1-[(5-Cyanopyridin-2-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}quinoline-2,4- Dimethylamine, 6-bromo-N-{1-[(5-cyanopyridin-2-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazole-4 -yl}-2-(trifluoromethyl)quinoline-4-carboxamide, N ⁴ -{1-[(5-Cyanopyridin-2-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazole-4-yl}-5-fluoroquinoline- 2,4-dimethylamine, N ⁴ -{1-[(5-Cyanopyridin-2-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}-6,7-difluoro Quinoline-2,4-dimethylamine, N-{1-[(5-cyanopyridin-2-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyridyl Zin-4-yl}-2-methoxyquinoline-4-carboxamide, N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-6-methylquinoline-2,4-di Formamide, 4-{[4-{[(2-aminocarbamimid-7-fluoroquinolin-4-yl)carbonyl]amino}-5-methyl-3-(trifluoromethyl)- Methyl 1H-pyrazol-1-yl]methyl}benzoate, 4-{[4-{[(2-aminocarbamido-7-fluoroquinolin-4-yl)carbonyl]amino}-5 -methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}benzoic acid, N ⁴ -[1-(4-Aminomethylbenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4- Dimethylamine, 7-fluoro-N ⁴ -{5-Methyl-1-[4-(methylamine-mercapto)benzyl]-3-(trifluoromethyl)-1H-pyrazol-4-yl}quinoline-2,4- Dimethylamine, N ⁴ -{1-[4-(Dimethylaminocarbamimidyl)benzyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}-7-fluoroquinoline -2,4-dimethylamine, N ⁴ -{1-[4-(azetidin-1-ylcarbonyl)benzyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}-7-fluoro Quinoline-2,4-dimethylamine, 7-fluoro-N ⁴ -[1-{4-[(2-methoxyethyl)aminemethanyl]benzyl}-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl] Quinoline-2,4-dimethylamine, N ⁴ -[1-(4-{[2-(Dimethylamino)ethyl]aminemethanyl}benzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole-4 -yl]-7-fluoroquinoline-2,4-dimethylamine, 7-fluoro-N ⁴ -[1-{4-[(2-hydroxyethyl)aminemethanyl]benzyl}-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline -2,4-dimethylamine, (±)-[{4-[(4-{[(2-aminocarbazinoquinolin-4-yl)carbonyl]amino}-3,5-dimethyl -1H-pyrazol-1-yl)methyl]phenyl}(methyl)oxyl-yl ⁶ -sulfinyl]ethyl carbamate, (±)-N ⁴ -{3,5-Dimethyl-1-[4-(S-methanesulfonimide) benzyl]-1H-pyrazol-4-yl}quinoline-2,4-dimethylhydrazine amine,( S )-7-fluoro-N ⁴ -[5-Methyl-1-(1-phenylethyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, ( R )-7-fluoro-N ⁴ -[5-Methyl-1-(1-phenylethyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, 2-bromo -N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-4-carboxamide, N-[1-(4- Cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(methylthio)quinoline-4-carboxamide, N-[1-(4- Cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(methylthio)quinoline-4-carboxamide, (± )-N-[1-(4-Cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(methylsulfinyl) Quinoline-4-carboxamide, N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2- (Methanesulfonyl)quinoline-4-carboxamide, (±)-N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H- Pyrazol-4-yl]-2-(N-cyano-S-methylsulfinyliminium)quinoline-4-carboxamide, (±)-N-[1-(4-cyano) Benzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(N-cyano-S-methanesulfonimide fluorenyl)quinoline- 4-Protonamine, (±)-N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2 -(S-Methanesulfonimide fluorenyl)quinoline-4-carboxamide, N ⁴ -(1-{4-[(dimethylamino)methyl]benzyl}-3,5-dimethyl-1H-pyrazol-4-yl)-7-fluoroquinoline-2,4- Dimethylamine, N ⁴ -[1-(4-cyanobenzyl)-3-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-dimethyl Guanamine, N ⁴ -[1-(4-Cyano-2,6-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-di Formamide, N ⁴ -[1-(4-Cyano-2,6-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, 6-chloro-N ⁴ -[1-(4-Cyano-2,6-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-di Formamide, N ⁴ -[1-(4-Cyano-2,6-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-5-fluoroquinoline-2,4-di Formamide, 6-bromo-N ⁴ -[1-(4-Cyano-2,6-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, N ⁴ -[1-(4-Cyano-2,6-difluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoroquinoline -2,4-dimethylamine, N ⁴ -[1-(4-Cyano-2,6-difluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4 -dimethylamine, N ⁴ -[1-(4-Cyano-2,6-difluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-5-fluoroquinoline -2,4-dimethylamine, 6-chloro-N ⁴ -[1-(4-Cyano-2,6-difluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoroquinoline -2,4-dimethylamine, 6-bromo-N ⁴ -[1-(4-Cyano-2,6-difluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4 -dimethylamine,7-fluoro-N ⁴ -{5-Methyl-1-[4-(1H-tetrazol-5-yl)benzyl]-3-(trifluoromethyl)-1H-pyrazol-4-yl}quinoline-2, 4-dimethylamine, 7-fluoro-N ⁴ -{1-[4-(Methoxymethyl)benzyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}quinoline-2,4-di Formamide, 5-fluoro-N ⁴ -{1-[4-(Methoxymethyl)benzyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}quinoline-2,4-di Formamide, N ⁴ -{1-[4-(Cyanomethyl)benzyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}-7-fluoroquinoline-2, 4-dimethylamine, 6-bromo-N-(3,5-dimethyl-1-{[5-(methylaminemethanyl)-1,2,4-oxadiazol-3-yl ]methyl}-1H-pyrazol-4-yl)-2-(trifluoromethyl)quinoline-4-carboxamide, 4-[(4-{[(2-aminoformylquinoline)- 3-butyl)carbonyl]amino}-3,5-dimethyl-1H-pyrazol-1-yl)methyl]piperidine-1-carboxylic acid tert-butyl ester, N ⁴ -[3,5-Dimethyl-1-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, N ⁴ -(1-{[1-(ethylsulfonyl)piperidin-4-yl]methyl}-3,5-dimethyl-1H-pyrazol-4-yl)quinoline-2,4-di Formamide, 6-chloro-7-fluoro-N ⁴ -{5-Methyl-1-[(5-methyl-1,2-oxazol-3-yl)methyl]-3-(trifluoromethyl)-1H-pyrazol-4-yl}quin Porphyrin-2,4-dimethylamine, 6-chloro-N ⁴ -{1-[(5-ethyl-1,2,4-oxadiazol-3-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazole-4- -7-fluoroquinoline-2,4-dimethylamine, 6-chloro-N ⁴ -{1-[(3-ethyl-1,2-oxazol-5-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}- 7-fluoroquinoline-2,4-dimethylamine, 6-chloro-N ⁴ -{3,5-Dimethyl-1-[(3-methyl-1,2-oxazol-5-yl)methyl]-1H-pyrazol-4-yl}-7-fluoroquinoline- 2,4-dimethylamine, 6-chloro-N ⁴ -{3,5-Dimethyl-1-[(5-methyl-1,2-oxazol-3-yl)methyl]-1H-pyrazol-4-yl}-7-fluoroquinoline- 2,4-dimethylamine, 6-chloro-N ⁴ -[1-{[1-(ethylsulfonyl)piperidin-4-yl]methyl}-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7 -fluoroquinoline-2,4-dimethylamine, 6-chloro-N ⁴ -{1-[(3-ethyl-1,2-oxazol-5-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-7-fluoroquinoline- 2,4-dimethylamine, 6-chloro-N ⁴ -(1-{[1-(ethylsulfonyl)piperidin-4-yl]methyl}-3,5-dimethyl-1H-pyrazol-4-yl)-7-fluoroquinoline-2 , 4-dimethylamine, 6-chloro-N ⁴ -(3,5-Dimethyl-1-{[3-(propan-2-yl)-1,2-oxazol-5-yl]methyl}-1H-pyrazol-4-yl)-7 -fluoroquinoline-2,4-dimethylamine, 6-chloro-N ⁴ -{1-[(5-Cyclopropyl-1,2-oxazol-3-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-7-fluoroquinoline -2,4-dimethylamine, N ⁴ -{1-[(5-Cyclopropyl-1,2-oxazol-3-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-7-fluoroquinoline -2,4-dimethylamine, N ⁴ -{1-[(5-Cyclopropyl-1,2-oxazol-3-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}quinoline-2,4 -dimethylamine, 6-chloro-7-fluoro-N ⁴ -{5-Methyl-1-[(3-methyl-1,2-oxazol-5-yl)methyl]-3-(trifluoromethyl)-1H-pyrazol-4-yl}quin Porphyrin-2,4-dimethylamine, 6-chloro-N ⁴ -{1-[(5-Cyano-2-thienyl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}-7-fluoroquinoline- 2,4-dimethylamine, N ⁴ -{1-[(5-Cyano-2-thienyl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}-7-fluoroquinoline- 2,4-dimethylamine, N ⁴ -{1-[(5-Cyanopyrimidin-2-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}-7-fluoroquinoline- 2,4-dimethylamine, N ⁴ -{1-[(5-Cyanopyrimidin-2-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}-5-fluoroquinoline- 2,4-dimethylamine, N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-6-hydroxyquinoline-2,4-dimethyl Guanamine, N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-N ² -(Methanesulfonyl)quinoline-2,4-dimethylamine, N ⁴ -{1-[(6-Cyanopyridazin-3-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}-7-fluoroquinoline -2,4-dimethyl decylamine, N-{1-[4-(allylaminemethanyl)benzyl]-3,5-dimethyl-1H-pyrazol-4-yl}- 6-bromo-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-[1-(4-{[(2R)-2-hydroxypropyl]aminecarbamyl} Benzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-(3,5 -Dimethyl-1-{4-[(pyridin-4-ylmethyl)aminemethanyl]benzyl}-1H-pyrazol-4-yl)-2-(trifluoromethyl)quinoline 4-carbamamine, 6-bromo-N-(1-{4-[(cyanomethyl)aminemethanyl]benzyl}-3,5-dimethyl-1H-pyrazole-4 -yl)-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-{1-[4-(cyclopropylaminemethanyl)benzyl]-3,5 -Dimethyl-1H-pyrazol-4-yl}-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-{1-[(6-methoxypyridine- 3-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-{ 1-[(6-Methoxypyridin-3-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}-2-(trifluoromethyl Quinoline-4-carboxamide, 6-bromo-N-{1-[4-(ethylaminemethylmercapto)benzyl]-3, 5-dimethyl-1H-pyrazol-4-yl}-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-[3,5-dimethyl-1- (4-{[(1-Methyl-1H-pyrazol-3-yl)methyl]amine-methylmethyl}benzyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl) Quinoline-4-carboxamide, 6-bromo-N-(1-{4-[(2-fluoroethyl)aminemethanyl]benzyl}-3,5-dimethyl-1H- Pyrazol-4-yl)-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-{3,5-dimethyl-1-[4-(pyrrolidin-1 -ylcarbonyl)benzyl]-1H-pyrazol-4-yl}-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-[1-(4-methoxy Benzomethyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo -N-[1-(4-fluorobenzyl)-3-methyl-5-(methylaminemethanyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinaquin Phenyl-4-carbamide, N-{1-[4-(azetidin-1-ylcarbonyl)benzyl]-3,5-dimethyl-1H-pyrazol-4-yl}- 6-bromo-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-(1-{4-[(2-aminomethylphenyl)aminomethane]benzene Methyl}-3,5-dimethyl-1H-pyrazol-4-yl)-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-[1-(3 -fluoro-4-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoro Methyl)quinoline-4-carboxamide, 6-bromo-N-(1-{4-[(2-chlorophenyl)aminecarbamyl]benzyl}-3,5-dimethyl- 1H-pyrazol-4-yl)-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-(3,5-dimethyl-1-{[5-(benzene) Hydrazinyl)pyridin-2-yl]methyl}-1H-pyrazol-4-yl)-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-( 3,5-Dimethyl-1-{[5-(phenylamine-mercapto)pyridin-2-yl]methyl}-1H-pyrazol-4-yl)-2-(trifluoromethyl) Quinoline-4-carboxamide, 6-bromo-N-{3,5-dimethyl-1-[4-({2-[methyl(methylaminomethylmethyl)amino]ethyl} Aminomethyl) benzyl]-1H-pyrazol-4-yl}-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-[1-(4-{ [4-(Dimethylamino)-4-oxobutyl]aminemethylmercapto}benzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(three Fluoromethyl)quinoline-4-carboxamide, 6-bromo-N-{3,5-dimethyl-1-[4-(pyridin-3-ylaminocarbamoyl)benzyl]-1H -pyrazol-4-yl}-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-[1-(4-{[(2S)-2-hydroxypropyl] Aminomethyl benzyl}benzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N -{3,5-Dimethyl-1-[4-(1,3-thiazol-2-ylaminemethanyl)benzene -1H-pyrazol-4-yl}-2-(trifluoromethyl)quinoline-4-carboxamide, 6,8-dichloro-N-[1-(4-hydroxybenzyl)- 3,5-Dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-[1-(4-{[2 -(1,1-dioxa-yl-1-thia-6-azaspiro[3.3]hept-6-yl)ethyl]aminemethylmercapto}benzyl)-3,5-dimethyl -1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-(1-{4-[(3-hydroxypropyl)amine A Mercapto]benzyl}},5-dimethyl-1H-pyrazol-4-yl)-2-(trifluoromethyl)quinoline-4-carboxamide, N-{3,5- Dimethyl-1-[4-(methylsulfonyl)benzyl]-1H-pyrazol-4-yl}-2-methoxyquinoline-4-carboxamide, 6-bromo-N- (1-{4-[(trans-4-hydroxycyclohexyl)aminemethanyl]benzyl}-3,5-dimethyl-1H-pyrazol-4-yl)-2-(trifluoromethyl) Quinoline-4-carboxamide, 6-bromo-N-(1-{4-[(2-cyanoethyl)(2-methoxyethyl)aminemethanyl]benzyl}- 3,5-Dimethyl-1H-pyrazol-4-yl)-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-{3,5-dimethyl- 1-[4-(1H-pyrazol-3-ylaminecarbamimidyl)benzyl]-1H-pyrazol-4-yl}-2-(trifluoromethyl)quinoline-4-carboxamide ,6-bromo-N-{1-[(6-cyanopyridin-3-yl)methyl]-5-methyl-3-(three Methyl)-1H-pyrazol-4-yl}-2-(trifluoromethyl)quinoline-4-carboxamide, rel-6-bromo-N-[1-(4-{[(2R, 3R)-3-hydroxybutan-2-yl]amine-methylmethyl}benzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline 4-carboxamide, 6-bromo-N-(3,5-dimethyl-1-{4-[(tetrahydrofuran-2-ylmethyl)aminecarbamyl]benzyl}-1H-pyridyl Zin-4-yl)-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-(3,5-dimethyl-1-{4-[(2,2, 2-Trifluoroethyl)amine-methylmethyl]benzyl}-1H-pyrazol-4-yl)-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N- [3,5-Dimethyl-1-(4-{[4-(1H-tetrazol-5-yl)benzyl]amine-methylmethyl}benzyl)-1H-pyrazol-4-yl ]-2-(Trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-(3,5-dimethyl-1-{4-[(tetrahydro-2H-pyran-2) -ylmethyl)amine-methylmethyl]benzyl}-1H-pyrazol-4-yl)-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-(1 -{4-[(cis-4-hydroxycyclohexyl)amine-carbamoyl]benzyl}-3,5-dimethyl-1H-pyrazol-4-yl)-2-(trifluoromethyl) Quinoline-4-carboxamide, 6-bromo-N-[1-(4-{[2-(4-methoxyphenyl)ethyl]aminemethanyl}benzyl)-3,5 - Dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide 6-bromo-N-{3,5-dimethyl-1-[4-(pyridin-2-ylaminocarbamimidyl)benzyl]-1H-pyrazol-4-yl}-2-(three Fluoromethyl)quinoline-4-carboxamide, 6-bromo-N-[1-({5-[(2-hydroxyethyl))aminomethane]pyridin-2-yl}methyl)-5 -methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-(1-{ 4-[(3-Chlorophenyl)aminemethanyl]benzyl}-3,5-dimethyl-1H-pyrazol-4-yl)-2-(trifluoromethyl)quinoline-4 -carbamamine, N-(1-{4-[(3-amino-3-oxopropyl)aminecarbamyl]benzyl}-3,5-dimethyl-1H-pyrazole 4-yl)-6-bromo-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-(3,5-dimethyl-1-{4-[(pyridine) -2-ylmethyl)amine-methylmethyl]benzyl}-1H-pyrazol-4-yl)-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N- [1-(4-{[4-(Dimethylamino)phenyl]aminemethanyl}benzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-( Trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-(3,5-dimethyl-1-{[5-(methylamine-mercapto)pyridin-2-yl]- -1}-1H-pyrazol-4-yl)-2-(trifluoromethyl)quinoline-4-carboxamide, 6,8-dichloro-N-[1-(2-hydroxybenzyl) -3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-methyl Amine, 6-bromo-N-(3,5-dimethyl-1-{[1-(methylsulfonyl)piperidin-4-yl]methyl}-1H-pyrazol-4-yl)- 2-(Trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-[1-({5-[(cyclopropylmethyl)aminemethanyl)pyridin-2-yl}- -3,5-Dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-{1-[(3 -cyanopyridin-4-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-2-(trifluoromethyl)quinoline-4-carboxamide, N- [1-(4-Cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-methoxyquinoline-4-carboxamide ,6-Bromo-N-{1-[(5-Aminomethylpyridin-2-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl }-2-(Trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-(1-{4-[(5-hydroxypentyl)aminecarbamyl]benzyl}-3 ,5-Dimethyl-1H-pyrazol-4-yl)-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-[5-methyl-1-{[ 5-(Methylamine-mercapto)pyridin-2-yl]methyl}-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline- 4-carboxamide, 6-bromo-N-(1-{4-[(cyclopropylmethyl)aminemethanyl]benzyl}-3,5-dimethyl-1H-pyrazole-4 -yl)-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-(1-{4-[(2,2- Difluoroethyl)amine,mercapto]benzyl}},5-dimethyl-1H-pyrazol-4-yl)-2-(trifluoromethyl)quinoline-4-carboxamide, 6-Bromo-N-[1-(4-{[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]carbonyl}benzyl)-3,5-dimethyl-1H-pyridyl Zin-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, N ⁴ -{1-[(3-Cyanopyridin-2-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}quinoline-2,4-dimethylamine, 6 -Bromo-N-(1-{4-[(4-hydroxybutyl)aminemethanyl]benzyl}-3,5-dimethyl-1H-pyrazol-4-yl)-2-( Trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-[1-(4-{[2-(2-fluorophenoxy)ethyl]aminemethanyl}benzyl) -3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-(1-{4-[( 2-hydroxy-2-methylpropyl)amine-methylmethyl]benzyl}-3,5-dimethyl-1H-pyrazol-4-yl)-2-(trifluoromethyl)quinoline- 4-carbamamine, N ⁴ -{1-[(6-Cyanopyridin-3-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-6-fluoroquinoline-2,4-dimethyl Indoleamine, 6-bromo-N-(1-{4-[(1,1-dioxalyl-1-thia-6-azaspiro[3.3]hept-6-yl)carbonyl]benzyl }-3,5-Dimethyl-1H-pyrazol-4-yl)-2-(trifluoromethyl)quinoline-4-carboxamide, N-[1-(4-fluorobenzyl) -3,5-dimethyl-1H-pyrazol-4-yl]-6-nitro-2-(trifluoromethyl)quinoline-4-carboxamide, 2-methoxy-N-[ 1-(4-Methoxybenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-4-carboxamide, 6-bromo-N -[1-(4-{[3-(1H-imidazol-1-yl)propyl]aminemethanyl}benzyl)-3,5-dimethyl-1H-pyrazol-4-yl] -2-(Trifluoromethyl)quinoline-4-carboxamide, N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl] -2-(dimethylamino)quinoline-4-carboxamide, 6-bromo-N-[1-({5-[(2-hydroxyethyl)aminemethanyl]pyridin-2-yl} Methyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, N ⁴ -(3,5-Dimethyl-1-{[1-(methylsulfonyl)piperidin-4-yl]methyl}-1H-pyrazol-4-yl)quinoline-2,4-di Formamide, 6-bromo-N-(1-{4-[(1,3-dihydroxy-2-methylpropan-2-yl)aminemethanyl]benzyl}-3,5-di Methyl-1H-pyrazol-4-yl)-2-(trifluoromethyl)quinoline-4-carboxamide, N-[3,5-dimethyl-1-(4-vinyl phenyl) -1H-pyrazol-4-yl]-2,6-dimethylquinolin-4-carboxamide, 6-bromo-N-{1-[4-({2-[(cyclopropyl) Carbonyl)amino]ethyl}amine-mercapto)benzyl]-3,5-dimethyl-1H-pyrazol-4-yl}-2-(trifluoromethyl)quinoline-4-methyl Indoleamine, 6-bromo-N-[1-(4-{[4-(hydroxymethyl)piperidin-1-yl]carbonyl}benzyl)-3,5-dimethyl-1H-pyrazole 4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, N ⁴ -{1-[2-(4-Fluorophenyl)ethyl]-3,5-dimethyl-1H-pyrazol-4-yl}quinoline-2,4-dimethylamine, 6-bromo -N-[1-(4-{[(2S)-1-hydroxypropan-2-yl]aminemethanyl}benzyl)-3,5-dimethyl-1H-pyrazol-4-yl ]-2-(Trifluoromethyl)quinoline-4-carboxamide, N-{1-[(3-cyanopyridin-2-yl)methyl]-3,5-dimethyl-1H- Pyrazol-4-yl}-2-methoxyquinoline-4-carboxamide, N ⁴ -[1-(2,3-dihydro-1,4-benzodioxan-2-ylmethyl)-3,5-dimethyl-1H-pyrazol-4-yl]quina -2,4-dimethylguanamine, N-(4-{[4-({[6-bromo-2-(trifluoromethyl)quinolin-4-yl)carbonyl}amino)-3, Methyl 5-dimethyl-1H-pyrazol-1-yl]methyl}benzylidene)-L-threonate, 6-bromo-N-{1-[(3-cyanopyridine-4) -yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}-2-(trifluoromethyl)quinoline-4-carboxamide, 6- Bromo-N-[3,5-dimethyl-1-(4-{[2-(1H-pyrazol-1-yl)ethyl]aminemethanoyl}benzyl)-1H-pyrazole- 4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-(1-{4-[(5-hydroxy-4,4-dimethylpentyl)) Aminomethyl]benzyl}},5-dimethyl-1H-pyrazol-4-yl)-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N -(3,5-Dimethyl-1-{4-[(4-methylbenzyl)amine-methylmethyl]benzyl}-1H-pyrazol-4-yl)-2-(trifluoro) Methyl)quinoline-4-carboxamide, 2-methoxy-N-{1-[3-(4-methoxyphenyl)propyl]-3,5-dimethyl-1H-pyridyl Zin-4-yl}quinoline-4-carboxamide, 6-bromo-N-(3,5-dimethyl-1-{4-[(2-thienylmethyl)aminecarboxylidene]benzene Methyl}-1H-pyrazol-4-yl)-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-( 3,5-Dimethyl-1-{[1-(methylamine-mercapto)piperidin-4-yl]methyl}-1H-pyrazol-4-yl)-2-(trifluoromethyl Quinoline-4-carboxamide, 6-bromo-N-[1-(4-{[(2S)-2,3-dihydroxypropyl]aminemethanyl}benzyl)-3,5 -Dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, N-[1-(4-bromobenzyl)-3,5- Dimethyl-1H-pyrazol-4-yl]-2,6-dimethylquinolin-4-carboxamide, 6-bromo-N-[3,5-dimethyl-1-(tetrahydrogen) -2H-piperazin-4-ylmethyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-[1-( {5-[(2-Methoxyethyl)amine-carbamoyl]pyridin-2-yl}methyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl ]-2-(Trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-[1-(4-{[2-(1H-imidazol-1-yl)ethyl]aminecarboxamide Benzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, 6-amino-N-[ 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo- N-{1-[(2-Cyanopyridin-3-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-2-(trifluoromethyl)quinoline- 4-carboxamide, 6-bromo-N-(1-{4-[(4-fluorobenzyl)aminomethane]benzyl}-3,5-di Methyl-1H-pyrazol-4-yl)-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-(1-{4-[(3-methoxypropane) Aminomethyl benzyl] benzyl}-3,5-dimethyl-1H-pyrazol-4-yl)-2-(trifluoromethyl)quinoline-4-carboxamide, N-{ 1-[4-({2-[bis(2-hydroxyethyl)amino]ethyl}amine-methylmethyl)benzyl]-3,5-dimethyl-1H-pyrazol-4-yl }-6-bromo-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-(1-{4-[(1,3-dihydroxypropan-2-yl)amine Methyl benzyl] benzyl}-3,5-dimethyl-1H-pyrazol-4-yl)-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N- [1-(4-{[(2,2-Difluorocyclopropyl)methyl]aminemethanyl}benzyl)-3,5-dimethyl-1H-pyrazol-4-yl]- 2-(Trifluoromethyl)quinoline-4-carboxamide, (±)-6-bromo-N-[3,5-dimethyl-1-({5-[(oxetane-2) -ylmethyl)amine-mercapto]pyridin-2-yl}methyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo -N-[3,5-Dimethyl-1-(4-{[(1-methyl-1H-imidazol-4-yl)methyl]aminemethanyl}benzyl)-1H-pyrazole 4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-[1-(4-fluorobenzyl)-5-methyl-3-(A Hydrazinyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide N-[1-(4-Cyano-3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2,6-dimethylquinoline-4-methyl Indoleamine, N-{1-[(6-cyanopyridin-3-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}-2- Methoxyquinoline-4-carboxamide, 6-bromo-N-{1-[2-(4-fluorophenyl)ethyl]-3,5-dimethyl-1H-pyrazole-4- }--2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-(3,5-dimethyl-1-{4-[(1,3-thiazole-2- Methyl)aminomethane]benzyl}}H-pyrazol-4-yl)-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-[1- ({5-[(3-hydroxypropyl)amine-carbamoyl]pyridin-2-yl}methyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoro Methyl)quinoline-4-carboxamide, 6-bromo-N-(1-{4-[(3-methoxybenzyl)aminomethane]benzyl}-3,5-di Methyl-1H-pyrazol-4-yl)-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-[3,5-dimethyl-1-(4- {[3-(Morpholin-4-yl)propyl]amine-methylmethyl}benzyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamidine Amine, 6-bromo-N-(1-{4-[(3-hydroxy-2,2-dimethylpropyl)aminemethanyl]benzyl}-3,5-dimethyl-1H- Pyrazol-4-yl)-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-[3-aminemethanyl-1-(4) -fluorobenzyl)-5-methyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-[1-(4 -{[1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl]amine-methylmethyl}benzyl)-3,5-dimethyl-1H-pyrazol-4-yl] -2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-(3,5-dimethyl-1-{4-[(2-phenoxyethyl)amine A Mercapto]benzyl}}H-pyrazol-4-yl)-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-{1-[(5-amino-methyl) Nonylpyridin-2-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo -N-[3,5-Dimethyl-1-(4-{[2-(pyridin-2-yl)ethyl]aminemethanyl}benzyl)-1H-pyrazol-4-yl] -2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-(3,5-dimethyl-1-{4-[(2-phenylethyl)aminecarbamyl) Benzyl}-1H-pyrazol-4-yl)-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-{3,5-dimethyl-1- [4-(prop-2-yn-1-ylaminocarbamimidyl)benzyl]-1H-pyrazol-4-yl}-2-(trifluoromethyl)quinoline-4-carboxamide, 6-Bromo-N-[3,5-dimethyl-1-(4-{[(1-methyl-1H-imidazol-5-yl)methyl]amine-methylhydrazino}benzyl)-1H -pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, 6,8-dichloro-N-[3,5- Methyl-1-(tetrahydro-2H-piperazin-4-ylmethyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, 6- Bromo-N-[1-(4-{[2-(2-hydroxyethoxy)ethyl]aminemethanyl}benzyl)-3,5-dimethyl-1H-pyrazole-4- 2-(trifluoromethyl)quinoline-4-carboxamide, N-(1-{4-[bis(2-hydroxyethyl)aminemethanyl]benzyl}-3,5 -Dimethyl-1H-pyrazol-4-yl)-6-bromo-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-[1-(4-{[ 2-(1-Hydroxycyclopentyl)ethyl](methyl)aminemethane}}benzyl}-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoro Methyl)quinoline-4-carboxamide, 6-bromo-N-(1-{4-[(3-cyanoazetidin-1-yl)carbonyl]benzyl}-3,5- Dimethyl-1H-pyrazol-4-yl)-2-(trifluoromethyl)quinoline-4-carboxamide, N ⁴ -{1-[2-(3-Fluorophenyl)ethyl]-3,5-dimethyl-1H-pyrazol-4-yl}quinoline-2,4-dimethylamine, 6-bromo -N-(1-{4-[(2-fluorobenzyl)aminemethanyl]benzyl}-3,5-dimethyl-1H-pyrazol-4-yl)-2-(three Fluoromethyl)quinoline-4-carboxamide, 6-bromo-N-[3,5-dimethyl-1-(4-{[2-(piperidin-1-yl)ethyl]amine A Mercapto}benzyl}-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, N-(1-{[5-(phenylmethylamine) Mercapto)pyridin-2-yl]methyl}-3,5-dimethyl-1H-pyrazol-4-yl)-6-bromo-2-(trifluoromethyl)quinoline-4-carboxamidine Amine, 6-bromo-N-[1-(4-{[(2R)-2,3-dihydroxypropyl]aminemethanyl}benzyl)-3,5-dimethyl-1H-pyridyl Zin-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, N-{1-[(2-cyanopyridin-3-yl)methyl]-3,5-di Methyl-1H-pyrazol-4-yl}-2-methoxyquinoline-4-carboxamide, 6-bromo-N-[3,5-dimethyl-1-(4-{[( 1-methyl-1H-pyrazol-4-yl)methyl]amine-methylmethyl}benzyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4- Methionamine, 4-[(4-{[(2-aminopyridylquinolin-4-yl)carbonyl]amino}-3,5-dimethyl-1H-pyrazol-1-yl) A Methyl] piperidine-1-carboxylate, N-{1-[(1-ethylhydrazinopiperidin-4-yl)methyl]-3,5-dimethyl -1H-pyrazol-4-yl}-6-bromo-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-[3,5-dimethyl-1- (4-{[3-(Methylamino)-3-oxopropyl)aminemethylmercapto}benzyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl) Quinoline-4-carboxamide, 6-bromo-N-{3,5-dimethyl-1-[4-(pyrimidin-4-ylaminemethanyl)benzyl]-1H-pyrazole- 4-yl}-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-{3,5-dimethyl-1-[(5-{[(3-methyl) Oxetidin-3-yl)methyl]amine-methylmethyl}pyridin-2-yl)methyl]-1H-pyrazol-4-yl}-2-(trifluoromethyl)quinoline-4- Methionamine, 6-bromo-N-(1-{4-[(2-cyanoethyl)(methyl)aminemethanyl]benzyl}-3,5-dimethyl-1H-pyrazole 4-yl)-2-(trifluoromethyl)quinoline-4-carboxamide, (±)-6-bromo-N-(1-{4-[(3-hydroxypyrrolidin-1-yl) )carbonyl]benzyl}},5-dimethyl-1H-pyrazol-4-yl)-2-(trifluoromethyl)quinoline-4-carboxamide, (±)-6-bromo -N-(1-{4-[(3-hydroxypiperidin-1-yl)carbonyl]benzyl}-3,5-dimethyl-1H-pyrazol-4-yl)-2-(three Fluoromethyl)quinoline-4-carboxamide, 6-bromo-N-(1-{4-[(3-fluorobenzyl)aminomethane]benzyl}-3,5-dimethyl -1H-pyrazol-4-yl)-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-[3 ,5-dimethyl-1-(4-{[(2) S )-tetrahydrofuran-2-ylmethyl]amine-methylmethyl}benzyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo -N-{1-[3-(4-methoxyphenyl)propyl]-3,5-dimethyl-1H-pyrazol-4-yl}-2-(trifluoromethyl)quinoline 4-carbamamine, (±)-6-bromo-N-(3,5-dimethyl-1-{4-[(2-o-oxypyrrolidin-3-yl)amine-methyl) Benzyl}-1H-pyrazol-4-yl)-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-[1-(4-{[3-(two Methylamino)propyl]amine-methylmethyl}benzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamidine Amine, N-(1-{4-[(2-acetamidoethyl)aminemethylmercapto]benzyl}-3,5-dimethyl-1H-pyrazol-4-yl)-6 -Bromo-2-(trifluoromethyl)quinoline-4-carboxamide, 6-acetamido-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H -pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-[3,5-dimethyl-1-({5-[(pyridine) -3-ylmethyl)amine-mercapto]pyridin-2-yl}methyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, 4 -{[4-({[6-bromo-2-(trifluoromethyl)quinolin-4-yl]carbonyl}amino)-3,5-dimethyl-1H-pyrazol-1-yl] Methyl}piperidine-1-carboxylic acid methyl ester, N-[3,5-dimethyl-1-(4- Vinylbenzyl)-1H-pyrazol-4-yl]-2-methoxyquinolin-4-carboxamide, 6-bromo-N-{3,5-dimethyl-1-[4 -(pyridin-4-ylaminocarbamimidyl)benzyl]-1H-pyrazol-4-yl}-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N- {1-[4-(Tertiary Butyrylcarbamimidyl)benzyl]-3,5-dimethyl-1H-pyrazol-4-yl}-2-(trifluoromethyl)quinoline- 4-Proline, 6-bromo-N-[3,5-dimethyl-1-(tetrahydrofuran-2-ylmethyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl Quinoline-4-carboxamide, N-[3,5-dimethyl-1-(tetrahydro-2H-piperazin-4-ylmethyl)-1H-pyrazol-4-yl]-2 ,6-dimethylquinolin-4-carboxamide, 6-bromo-N-{1-[(5-{[2-(dimethylamino)ethyl]aminemethanyl}pyridine-2- Methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo -N-(3,5-Dimethyl-1-{4-[(3-phenylpropyl)aminemethanyl]benzyl}-1H-pyrazol-4-yl)-2-(trifluoro) Methyl)quinoline-4-carboxamide, 6-bromo-N-[1-(4-{[(2R)-1-hydroxypropan-2-yl]aminemethanyl}benzyl)-3 ,5-Dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-[5-(dimethylaminecarbamidine) -1(4-fluorobenzyl)-3-methyl-1H-pyrazol-4-yl]-2 -(trifluoromethyl)quinoline-4-carboxamide, N-{1-[2-(4-fluorophenyl)ethyl]-3,5-dimethyl-1H-pyrazole-4- }]-2-methoxyquinoline-4-carboxamide, 6-bromo-N-{1-[4-(cyclopentylaminemethylhydrazino)benzyl]-3,5-dimethyl -1H-pyrazol-4-yl}-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-(1-{4-[(2-methoxybenzyl) Aminomethyl] benzyl}-3,5-dimethyl-1H-pyrazol-4-yl)-2-(trifluoromethyl)quinoline-4-carboxamide, 4-[( 4-{[(2-Aminomethylsulfonyl-4-yl)carbonyl]amino}-3,5-dimethyl-1H-pyrazol-1-yl)methyl]piperidine-1-carboxylic acid Third butyl ester, 6-bromo-N-(1-{4-[(3-aminomethylphenyl)aminomethane]benzyl}-3,5-dimethyl-1H-pyrazole 4-yl)-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-(1-{4-[(2-hydroxyethyl)(methyl)aminecarboxamide Benzyl}-3,5-dimethyl-1H-pyrazol-4-yl)-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-[3 ,5-Dimethyl-1-(4-{methyl[2-(methylamino)-2-oxoethyl]aminemethanyl}benzyl)-1H-pyrazole-4- 2-(trifluoromethyl)quinoline-4-carboxamide, N-{1-[(3-cyanopyridin-4-yl)methyl]-5-methyl-3-(three Fluoromethyl)-1H-pyrazol-4-yl}-2-methoxyquinolin-4- Formamide, N-{1-[(3-cyanopyridin-4-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-2-methoxyquinoline 4-carboxamide, 6-bromo-N-(3,5-dimethyl-1-{4-[(3-methylbenzyl)aminecarbamyl]benzyl}-1H-pyridyl Zin-4-yl)-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-{3,5-dimethyl-1-[(5-{[2-( Morpholin-4-yl)ethyl]aminemethylmercapto}pyridin-2-yl)methyl]-1H-pyrazol-4-yl}-2-(trifluoromethyl)quinoline-4-carboxamidine Amine, 6-bromo-N-[1-(4-{[4-(2-hydroxyethyl)piperazin-1-yl]carbonyl}benzyl)-3,5-dimethyl-1H-pyridyl Zin-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-(3,5-dimethyl-1-{4-[(tetrahydro-2H) -piperazin-4-ylmethyl)amine-methylmethyl]benzyl}-1H-pyrazol-4-yl)-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo -N-[1-{[5-(dimethylaminocarbamimidyl)pyridin-2-yl]methyl}-5-methyl-3-(trifluoromethyl)-1H-pyrazole-4- 2-(trifluoromethyl)quinoline-4-carboxamide, N-[1-(2-chloro-4-fluorobenzyl)-3,5-dimethyl-1H-pyrazole 4-yl]-2,6-dimethylquinoline-4-carboxamide, N-{3,5-dimethyl-1-[(5-methyl-1,2-oxazole-3 -yl)methyl]-1H-pyrazol-4-yl}-2-methoxyquinoline-4-carboxamide, 6-bromo-N-[5-amine Mercapto-1-(4-fluorobenzyl)-3-methyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, N-[ 1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-6-(3,5-dimethyl-1,2-oxazole-4- 2-(trifluoromethyl)quinoline-4-carboxamide, N-[1-(2,4-dichlorobenzyl)-3,5-dimethyl-1H-pyrazole- 4-yl]-2,6-dimethylquinoline-4-carboxamide, 6-bromo-N-[5-methyl-1-{[5-(morpholin-4-ylcarbonyl)pyridine- 2-yl]methyl}-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, 4-{[4- ({[6-Bromo-2-(trifluoromethyl)quinolin-4-yl]carbonyl}amino)-3,5-dimethyl-1H-pyrazol-1-yl]methyl}piperidine 1-butylic acid tert-butyl ester, N-{1-[2-(3-fluorophenyl)ethyl]-3,5-dimethyl-1H-pyrazol-4-yl}-2-methoxy Quinoquinoline-4-carboxamide, 6-bromo-N-{1-[4-(diethylaminomethylmethyl)benzyl]-3,5-dimethyl-1H-pyrazole-4 -yl}-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-(1-{4-[(3-hydroxy-3-methylbutyl)aminecarbamyl) Benzyl}-3,5-dimethyl-1H-pyrazol-4-yl)-2-(trifluoromethyl)quinoline-4-carboxamide, N-{1-[(7- Fluorin-2,1,3-benzothiathiazol-4-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-2,6- Methylquinoline-4-carboxamide, 6-bromo-N-{3,5-dimethyl-1-[(2-o-oxy-1,3-oxazolidin-5-yl)methyl -1H-pyrazol-4-yl}-2-(trifluoromethyl)quinoline-4-carboxamide, N ⁴ -{1-[(5-Aminomethylpyridin-2-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-6-fluoroquinoline-2,4- Dimethylamine, 6-bromo-N-[1-(2,3-dihydro-1,4-benzodioxan-2-ylmethyl)-3,5-dimethyl- 1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-(1-{4-[(3-hydroxybenzyl)amine A Mercapto]benzyl}},5-dimethyl-1H-pyrazol-4-yl)-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-[ 3,5-Dimethyl-1-(4-{[2-(4-methylphenyl)ethyl]aminemethanyl}benzyl)-1H-pyrazol-4-yl]-2- (trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-(1-{4-[(3-hydroxybutyl)aminemethanyl]benzyl}-3,5-di Methyl-1H-pyrazol-4-yl)-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-(3,5-dimethyl-1-{4- [(4-Methylpiperazin-1-yl)carbonyl]benzyl}-1H-pyrazol-4-yl)-2-(trifluoromethyl)quinoline-4-carboxamide, N ⁴ -{1-[(1-Ethylpiperidin-4-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}quinoline-2,4-dimethylamine ,N ⁴ -[3-(Dimethylaminocarbamimidyl)-1-(4-fluorobenzyl)-5-methyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine ,6-bromo-N-[1-(4-{[(1S,2S)-2-hydroxycyclohexyl]amine-carbamoyl}benzyl)-3,5-dimethyl-1H-pyrazole- 4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-[3,5-dimethyl-1-(4-{[2-(1-) Pyrrrolidin-2-yl)ethyl]amine-methylmethyl}benzyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, 6- Bromo-N-(1-{4-[(4-hydroxypiperidin-1-yl)carbonyl]benzyl}-3,5-dimethyl-1H-pyrazol-4-yl)-2-( Trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-{3,5-dimethyl-1-[2-(morpholin-4-yl)ethyl]-1H-pyrazole 4-yl}-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-{1-(4-fluorobenzyl)-5-[(2-hydroxyethyl) Aminomethyl]-3-methyl-1H-pyrazol-4-yl}-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-{3,5- Dimethyl-1-[2-(piperidin-1-yl)ethyl]-1H-pyrazol-4-yl}-2-(trifluoromethyl)quinoline-4-carboxamide, 6- Bromo-N-(1-{[5-(dimethylaminocarbamimidyl)pyridin-2-yl]methyl}-3,5-dimethyl-1H-pyrazol-4-yl)-2- (trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-[3,5-dimethyl-1-(piperidin-4-yl) -1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, N-(1-{4-[(2-amino-2-yloxy) Aminomethyl benzyl] benzyl}-3,5-dimethyl-1H-pyrazol-4-yl)-6-bromo-2-(trifluoromethyl)quinoline-4-carboxamide ,6-bromo-N-[1-(4-{[2-(dimethylamino)ethyl](methyl)aminemethanyl}benzyl)-3,5-dimethyl-1H- Pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, 4-({[6-bromo-2-(trifluoromethyl)quinolin-4-yl]carbonyl) }Amino)-1-(4-fluorobenzyl)-5-methyl-1H-pyrazole-3-carboxylic acid ethyl ester, N-{3,5-dimethyl-1-[(2E)- 3-phenylprop-2-en-1-yl]-1H-pyrazol-4-yl}-2,6-dimethylquinolin-4-carboxamide, 6-bromo-N-(1- {4-[(2,2-Dimethylpropyl)aminemethanyl]benzyl}-3,5-dimethyl-1H-pyrazol-4-yl)-2-(trifluoromethyl) Quinoline-4-carboxamide, 6-bromo-N-(1-{4-[(2-hydroxyethyl)(pentyl)aminecarbamyl]benzyl}-3,5-dimethyl -1H-pyrazol-4-yl)-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-(1-{4-[(4-methoxyphenyl) Aminomethyl benzyl] benzyl}-3,5-dimethyl-1H-pyrazol-4-yl)-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo -N-[1-({5-[(1,3-dihydroxypropan-2-yl))aminomethyl)pyridin-2-yl}A ) -3,5-dimethyl--1H- pyrazol-4-yl] -2- (trifluoromethyl) quinoline-4-acyl amine, N ⁴ -[1-(4-Fluorobenzyl)-5-methyl-3-(methylaminemethanyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, N-[1-(2-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2,6-dimethylquinoline-4-carboxamide, 6-Bromo-N-{1-[2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-3,5-dimethyl-1H-pyrazol-4-yl }-2-(Trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-(3,5-dimethyl-1-{[5-(morpholin-4-ylcarbonyl)pyridine -2-yl]methyl}-1H-pyrazol-4-yl)-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-{1-(4-fluorobenzene Methyl)-3-[(2-hydroxyethyl)aminemethanyl]-5-methyl-1H-pyrazol-4-yl}-2-(trifluoromethyl)quinoline-4-carboxamidine Amine, N-[1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2,6-dimethylquinoline-4-carboxamide, 6-Cyano-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-methylquinoline-4-carboxamide, 6-Bromo-N-[1-(2,5-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline- 4-Protonamine, 6-bromo-N-(1-{[5-({[3-(hydroxymethyl)oxetan-3-yl)methyl)aminecarboxamido)pyridine-2- Methyl}-3,5-dimethyl-1H-pyrazol-4-yl)-2-(trifluoromethyl)quinoline-4-carboxamide, 6- -N-{3,5-dimethyl-1-[4-(2-{[2-(morpholin-4-yl)ethyl]amino}-2-oxoethyl)benzyl -1H-pyrazol-4-yl}-2-(trifluoromethyl)quinoline-4-carboxamide, N ⁴ -[3,5-dimethyl-1-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, N-[4-{ [1-(4-Fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]aminecarbenyl}-2-(trifluoromethyl)quinolin-6-yl] Ethylenediamine, 6,8-dichloro-N-{3,5-dimethyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrazol-4-yl}-2 -(trifluoromethyl)quinoline-4-carboxamide, 6,8-dichloro-N-[1-(3,5-difluorobenzyl)-3,5-dimethyl-1H- Pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, N-[5-(dimethylaminocarbazyl)-1-(4-fluorobenzyl) -3-methyl-1H-pyrazol-4-yl]-2-methoxyquinoline-4-carboxamide, 6-fluoro-N ⁴ -[1-({5-[(2-hydroxyethyl)aminemethanyl]pyridin-2-yl}methyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline -2,4-dimethylamine, N ⁴ -(3,5-Dimethyl-1-{[1-(methylamine-mercapto)piperidin-4-yl]methyl}-1H-pyrazol-4-yl)quinoline-2,4 -dimethylamine, N-{3,5-dimethyl-1-[(3-methylpyridin-2-yl)methyl]-1H-pyrazol-4-yl}-2-methoxy Quinoline-4-carboxamide, N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2,3-dihydro-1H- Cyclopenta[b]quinoline-9-carboxamide, N ⁴ -[5-(dimethylaminocarbazyl)-1-(4-fluorobenzyl)-3-methyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine ,6-Bromo-N-(1-{4-[(cyclohexylmethyl)aminemethanyl]benzyl}-3,5-dimethyl-1H-pyrazol-4-yl)-2- (trifluoromethyl)quinoline-4-carboxamide, N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-3-methyl Quinoline-4-carbamide, N-[1-(4-fluorobenzyl)-5-methyl-3-(methylaminecarbamimidyl)-1H-pyrazol-4-yl]- 2-methoxyquinoline-4-carboxamide, 6-bromo-N-{1-[4-(2-{[2-(dimethylamino)ethyl]amino}-2- side oxygen Benzyl)benzyl]-3,5-dimethyl-1H-pyrazol-4-yl}-2-(trifluoromethyl)quinoline-4-carboxamide, 4-({[6 -Bromo-2-(trifluoromethyl)quinolin-4-yl]carbonyl}amino)-1-(4-fluorobenzyl)-3-methyl-1H-pyrazole-5-carboxylic acid ethyl ester ,6-Bromo-N-[1-(3,5-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline 4-Metformamide, N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-6-[(methylsulfonyl)amino ]-2-(trifluoromethyl)quinoline-4-carboxamide, N ⁴ -[1-(4-fluorobenzyl)-3-methyl-5-(methylamine-mercapto)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, 6-Bromo-N-[3-(dimethylaminecarbamimido)-1-(4-fluorobenzyl)-5-methyl-1H-pyrazol-4-yl]-2-(trifluoro Methyl)quinoline-4-carboxamide, N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-hydroxyquinoline- 4-Proline, N-[3,5-dimethyl-1-(pyridin-2-ylmethyl)-1H-pyrazol-4-yl]-2,6-dimethylquinolin-4 -Proline, N-[3,5-dimethyl-1-(tetrahydro-2H-piperazin-4-ylmethyl)-1H-pyrazol-4-yl]-6,7-difluoro -2-(Trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-[1-({5-[(2,3-dihydroxypropyl)aminemethanyl]pyridine-2 -yl}methyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, 3-cyano-N-[ 1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-methylquinoline-4-carboxamide, N-[3-(dimethyl Hydrazinyl)-1-(4-fluorobenzyl)-5-methyl-1H-pyrazol-4-yl]-2-methoxyquinoline-4-carboxamide, 6-bromo -N-(3,5-dimethyl-1-{[(2S)-5-oxooxypyrrolidin-2-yl]methyl}-1H-pyrazol-4-yl)-2-(three Fluoromethyl)quinoline-4-carboxamide, 4-{[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyridyl Zin-4-yl]amine-methylmethyl}-2-(trifluoromethyl)quinoline-6-carboxylic acid, 8-cyano-N-[1-(4-fluorobenzyl)-3,5- Dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, N-{3,5-dimethyl-1-[4-(trifluoro Methyl)benzyl]-1H-pyrazol-4-yl}-2-methoxyquinoline-4-carboxamide, 6,7-difluoro-N-[1-(2-methoxy Benzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, 4-({[6-bromo-2 -(trifluoromethyl)quinolin-4-yl]carbonyl}amino)-1-(4-fluorobenzyl)-5-methyl-1H-pyrazole-3-carboxylic acid, N-[1- (4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-hydroxy-3-methylquinoline-4-carboxamide, N-{1-[ (3,5-Dimethyl-1,2-oxazol-4-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-2-methoxyquinoline- 4-Proline, 6-bromo-N-[1-(2-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl) Quinoline-4-carbamide, 6-[(4-{[(2-aminocarbamimido-6-fluoroquinolin-4-yl)carbonyl]amino}-3,5-dimethyl -1H-pyrazol-1-yl)methyl]nicotinic acid, N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2 ,7-bis(trifluoromethyl)quinoline-4-carboxamide, 7-bromo-N-[1-(4-fluorobenzyl)-3,5- Dimethyl-1H-pyrazol-4-yl]-2-methylquinoline-4-carboxamide, N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H -pyrazol-4-yl]-2,7-dimethylquinoline-4-carboxamide, 6-bromo-N-{3,5-dimethyl-1-[2-(4-methyl Piperazin-1-yl)ethyl]-1H-pyrazol-4-yl}-2-(trifluoromethyl)quinoline-4-carboxamide, N-{3,5-dimethyl-1 -[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methyl]-1H-pyrazol-4-yl}-2,6-di Methylquinoline-4-carboxamide, N-[1-(2,5-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2,6- Dimethylquinoline-4-carboxamide, 6-bromo-N-{1-[2-(3-fluorophenyl)ethyl]-3,5-dimethyl-1H-pyrazole-4- }--2-(trifluoromethyl)quinoline-4-carboxamide, N-[1-(3-cyanobenzyl)-3,5-dimethyl-1H-pyrazole-4- -2,6-dimethylquinoline-4-carboxamide, N-[1-(3,5-difluorobenzyl)-3,5-dimethyl-1H-pyrazole-4 -yl]-2-methoxyquinoline-4-carboxamide, N-{3,5-dimethyl-1-[(3-methylpyridin-2-yl)methyl]-1H-pyridyl Zin-4-yl}-2,6-dimethylquinolin-4-carboxamide, N-[1-(3-cyanobenzyl)-3,5-dimethyl-1H-pyrazole 4-yl]-2-methoxyquinoline-4-carboxamide, N-{3,5-dimethyl-1-[2-(trifluoromethoxy)benzyl]-1H- Pyrazole 4-yl}-2,6-dimethylquinolin-4-carboxamide, 6,8-dichloro-N-{3,5-dimethyl-1-[2-(trifluoromethoxy) Benzyl]-1H-pyrazol-4-yl}-2-(trifluoromethyl)quinoline-4-carboxamide, N-{3,5-dimethyl-1-[2- (trifluoromethoxy)benzyl]-1H-pyrazol-4-yl}-2-methoxyquinoline-4-carboxamide, N-[1-(4-t-butylphenyl) -3,5-Dimethyl-1H-pyrazol-4-yl]-2,6-dimethylquinolin-4-carboxamide, N-{3,5-dimethyl-1- [2-(morpholin-4-yl)ethyl]-1H-pyrazol-4-yl}-2-methoxyquinoline-4-carboxamide, 6-bromo-N-{1-[( 5-{[2-(dimethylamino)ethyl]amine-methylmethyl}pyridin-2-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-2- (trifluoromethyl)quinoline-4-carboxamide, N-[1-(3,5-dimethoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl ]-2,6-dimethylquinoline-4-carboxamide, N ⁴ -[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4,6-dimethylguanamine ,6,8-Dichloro-N-[1-(2,5-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl Quinoline-4-carboxamide, N-[1-(3,5-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2,6-di Methylquinoline-4-carboxamide, 6-bromo-N-{3,5-dimethyl-1-[3-(trifluoromethyl)benzyl]-1H-pyrazol-4-yl }-2-(Trifluoromethyl)quinoline-4-carboxamide, N-{3,5-dimethyl-1-[2-(trifluoromethyl)benzyl]-1H-pyrazole 4-yl}-2,6-dimethylquinolin-4-carboxamide, 6,8-dichloro-N-{3,5-dimethyl-1-[2-(trifluoromethyl) Benzyl]-1H-pyrazol-4-yl}-2-(trifluoromethyl)quinoline-4-carboxamide, N-{3,5-dimethyl-1-[3-( Trifluoromethyl)benzyl]-1H-pyrazol-4-yl}-2,6-dimethylquinolin-4-carboxamide, 6-bromo-N-{3,5-dimethyl 1-[2-(trifluoromethyl)benzyl]-1H-pyrazol-4-yl}-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N- {3,5-Dimethyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrazol-4-yl}-2-(trifluoromethyl)quinoline-4-carboxamidine Amine, N-{3,5-dimethyl-1-[3-(trifluoromethyl)benzyl]-1H-pyrazol-4-yl}-2-methoxyquin Benzyl-4-carbamide, N-[1-(2,5-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-methoxyquinoline 4-carbamamine, N-{3,5-dimethyl-1-[2-(trifluoromethyl)benzyl]-1H-pyrazol-4-yl}-2-methoxyquin Benzyl-4-carbamide, 6,8-dichloro-N-{3,5-dimethyl-1-[3-(trifluoromethyl)benzyl]-1H-pyrazol-4-yl }-2-(Trifluoromethyl)quinoline-4-carboxamide, N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl] -2,8-bis(trifluoromethyl)quinoline-4-carboxamide, 8-cyano-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H- Pyrazol-4-yl]-2-methylquinoline-4-carboxamide, 7-cyano-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H- Pyrazol-4-yl]-2-methylquinoline-4-carboxamide, 3-cyano-N-[1-(4-fluorobenzyl)-3,5-dimethyl-1H- Pyrazol-4-yl]-2-hydroxyquinoline-4-carboxamide, 6-bromo-N-[1-(2-cyanobenzyl)-3,5-dimethyl-1H-pyridyl Zin-4-yl]-2-cyclopropylquinoline-4-carboxamide, N-[3,5-dimethyl-1-(2-naphthylmethyl)-1H-pyrazol-4-yl ]-2-methoxyquinoline-4-carboxamide, N-[1-(2-chlorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2- Methoxyquinoline-4-carboxamide, N-[1-(biphenyl-2-ylmethyl)-3,5-dimethyl-1H-pyrazol-4-yl ]-2-methoxyquinoline-4-carboxamide, N-[1-(biphenyl-4-ylmethyl)-3,5-dimethyl-1H-pyrazol-4-yl]- 2-methoxyquinoline-4-carboxamide, N-[1-(2,4-dichlorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2 -methoxyquinolin-4-carboxamide, N-[1-(2-bromobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-methoxy Quinoline-4-carboxamide, N-[3,5-dimethyl-1-(quinolin-8-ylmethyl)-1H-pyrazol-4-yl]-2,6-dimethyl Quinoline-4-carboxamide, N-[1-(2,6-dichlorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2,6-dimethyl Quinoline-4-carbamide, N-{1-[4-fluoro-2-(trifluoromethyl)benzyl]-3,5-dimethyl-1H-pyrazol-4-yl} -2,6-dimethylquinolin-4-carboxamide, N-[3,5-dimethyl-1-(quinolin-8-ylmethyl)-1H-pyrazol-4-yl] -2-methoxyquinoline-4-carboxamide, N-[1-(4-t-butylbenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]- 2-methoxyquinoline-4-carboxamide, N-[1-(3-chloro-2-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]- 2-methoxyquinoline-4-carboxamide, N-[1-(4-bromobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-methoxy Quinoline-4-carbamide, N-[1-(biphenylmethyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-methyl Oxyquinoline-4-carboxamide, N-[1-(3,5-dimethylbenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-methyl Oxyquinoline-4-carboxamide, N-[3,5-dimethyl-1-(quinolin-2-ylmethyl)-1H-pyrazol-4-yl]-2-methoxy Quinoline-4-carboxamide, N-{1-[(3,5-dimethyl-1,2-oxazol-4-yl)methyl]-3,5-dimethyl-1H-pyridyl Zin-4-yl}-2,6-dimethylquinolin-4-carboxamide, N-[1-(3,4-dichlorobenzyl)-3,5-dimethyl-1H- Pyrazol-4-yl]-2-methoxyquinoline-4-carboxamide, N-[3,5-dimethyl-1-(pyridin-4-ylmethyl)-1H-pyrazole- 4-yl]-2,6-dimethylquinolin-4-carboxamide, N-{1-[3-fluoro-5-(trifluoromethyl)benzyl]-3,5-dimethyl -1H-pyrazol-4-yl}-2,6-dimethylquinolin-4-carboxamide, N-[1-(2,1,3-benzothiadiazole-4-yl) -3,5-Dimethyl-1H-pyrazol-4-yl]-2-methoxyquinoline-4-carboxamide, N-{3,5-dimethyl-1-[( 5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methyl]-1H-pyrazol-4-yl}-2-methoxyquinoline- 4-carboxamide, N-{1-[2-(1H-indol-3-yl)ethyl]-3,5-dimethyl-1H-pyrazol-4-yl}-2-methoxy Quinoline-4-carbamide, N-{3,5-dimethyl-1-[2-(1H-pyrrol-1-yl)ethyl]-1H-pyrazol-4-yl}-2 -methoxy Quinoline-4-carboxamide, N-[1-(2-chloro-4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-methoxy Quinoline-4-carboxamide, N-[1-(3,5-dimethoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-methoxy Quinoline-4-carbamide, 6-bromo-N-[3-cyano-1-(4-fluorobenzyl)-5-methyl-1H-pyrazol-4-yl]-2- (trifluoromethyl)quinoline-4-carboxamide, N ⁴ -[3,5-Dimethyl-1-(1,3-thiazol-4-ylmethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, 2-A Oxy-N-{1-[2-(4-methoxyphenyl)ethyl]-3,5-dimethyl-1H-pyrazol-4-yl}quinoline-4-carboxamide, 6-Bromo-N-{1-[(1,5-dimethyl-1H-pyrazol-4-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}- 2-(Trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-{1-[2-(4-cyanophenoxy)ethyl]-3,5-dimethyl- 1H-pyrazol-4-yl}-2-(trifluoromethyl)quinoline-4-carboxamide, 6-chloro-7-fluoro-N ⁴ -{1-[2-(4-Methoxyphenyl)ethyl]-3,5-dimethyl-1H-pyrazol-4-yl}quinoline-2,4-dimethylamine, N ⁴ -{3,5-Dimethyl-1-[(2-o-oxy-1,3-oxazolidin-5-yl)methyl]-1H-pyrazol-4-yl}quinoline-2, 4-dimethylamine, N-{1-[2-(4-cyanophenoxy)ethyl]-3,5-dimethyl-1H-pyrazol-4-yl}-2-methoxy Quinoline-4-carbamide, 6-bromo-N-[1-(4-cyano-2-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl] -2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-{1-[2-(4-methoxyphenyl)ethyl]-3,5-dimethyl -1H-pyrazol-4-yl}-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-[3,5-dimethyl-1-(1,3- Thiazol-4-ylmethyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, N-[1-(4-cyano-2-fluoro Benzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-methoxyquinoline-4-carboxamide, N ⁴ -{1-[2-(4-Methoxyphenyl)ethyl]-3,5-dimethyl-1H-pyrazol-4-yl}quinoline-2,4-dimethylamine, 6 -Bromo-N-{3,5-dimethyl-1-[(2-methyl-1,3-thiazol-4-yl)methyl]-1H-pyrazol-4-yl}-2-( Trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-[1-(4-fluorobenzyl)-3,5-di(propan-2-yl)-1H-pyrazole- 4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, N-[1-(4-fluorobenzyl)-3,5-di(propan-2-yl)-1H -pyrazol-4-yl]-2,6-dimethylquinolin-4-carboxamide, 6,7-difluoro-N-[1-(4-fluorobenzyl)-3,5- Di(propan-2-yl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, 6-bromo-N-[1-(4-cyano) 2-fluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, N-[1-(4-Cyano-2-fluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-methoxyquinoline -4-carboxamide, (±)-6-bromo-N-[3,5-dimethyl-1-(1-phenylethyl)-1H-pyrazol-4-yl]-2-(three Fluoromethyl)quinoline-4-carboxamide, (±)-N-[3,5-dimethyl-1-(1-phenylethyl)-1H-pyrazol-4-yl]-2- Methoxyquinoline-4-carboxamide, (±)-N ⁴ -[3,5-Dimethyl-1-(1-phenylethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, (±)-6-chloro-N ⁴ -[3,5-Dimethyl-1-(1-phenylethyl)-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-dimethylamine, (±)-N ⁴ -{1-[1-(4-fluorophenyl)ethyl]-3,5-dimethyl-1H-pyrazol-4-yl}quinoline-2,4-dimethylamine, 6-bromo -N-[5-methyl-1-(pyridin-4-ylmethyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline 4-carbamamine, 2-methoxy-N-[5-methyl-1-(pyridin-4-ylmethyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl Quinoline-4-carboxamide, N ⁴ -[5-Methyl-1-(pyridin-4-ylmethyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, 6 -chloro-7-fluoro-N ⁴ -[5-Methyl-1-(pyridin-4-ylmethyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, N ⁴ -[1-(4-Tertibutylbenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, N ⁴ -[1-(4-Tertibutylbenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine ,N ⁴ -{1-[2-(4-Fluorophenyl)ethyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}quinoline-2,4-dimethyl Indoleamine, N-{1-[2-(4-fluorophenyl)ethyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}-2-methoxy Quinoline-4-carbamide, 6-bromo-N-{1-[2-(4-fluorophenyl)ethyl]-5-methyl-3-(trifluoromethyl)-1H-pyridyl Zin-4-yl}-2-(trifluoromethyl)quinoline-4-carboxamide, (±)-6-bromo-N-{1-[1-(4-fluorophenyl)ethyl] -3,5-Dimethyl-1H-pyrazol-4-yl}-2-(trifluoromethyl)quinoline-4-carboxamide, N-{1-[1-(4-fluorophenyl) Ethyl]-3,5-dimethyl-1H-pyrazol-4-yl}-2-methoxyquinoline-4-carboxamide, N-[1-(4-cyanobenzyl) -5-Methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-6-fluoro-2-methoxyquinoline-4-carboxamide, N ⁴ -[1-(4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-6-methylquinoline-2,4-dimethylamine, (±) -6-bromo-N-{1-[4-(4-fluorophenyl)butan-2-yl]-3,5-dimethyl-1H-pyrazole-4-yl}-2-(trifluoro Methyl)quinoline-4-carboxamide, (±)-N ⁴ -{1-[4-(4-Fluorophenyl)butan-2-yl]-3,5-dimethyl-1H-pyrazol-4-yl}quinoline-2,4-dimethylamine, (±)-6-chloro-7-fluoro-N ⁴ -{1-[4-(4-Fluorophenyl)butan-2-yl]-3,5-dimethyl-1H-pyrazol-4-yl}quinoline-2,4-dimethylamine, N ⁴ -[1-(4-Tertibutylbenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4- Dimethylamine, N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-6-amine sulfonylquinoline-2,4 -dimethylamine, N ⁴ -[1-(4-Tertibutylbenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-dimethylamine, N ⁴ -[3,5-diethyl-1-(4-fluorobenzyl)-1H-pyrazol-4-yl]-8-fluoroquinoline-2,4-dimethylamine, N ⁴ -[3,5-diethyl-1-(4-fluorobenzyl)-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-dimethylamine, 6-chloro- N ⁴ -[3,5-diethyl-1-(4-fluorobenzyl)-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-dimethylamine, N ⁴ -[3,5-diethyl-1-(4-fluorobenzyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, 6-bromo-N-[3 ,5-Diethyl-1-(4-fluorobenzyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamide, N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-6-(methylsulfonyl)quinoline-2 , 4-dimethylguanamine, 4-{[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]aminecarbenyl}-7-A Methyl oxyquinoline-2-carboxylate, 7-chloro-N ⁴ -[3,5-diethyl-1-(4-fluorobenzyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, N ⁴ -{1-[(3-Cyanopyridin-2-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}-7-fluoroquinoline- 2,4-dimethylamine, N ⁴ -{1-[(3-Cyanopyridin-2-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}quinoline-2,4- Dimethylamine, N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-6-(4-methylpiperazin-1- Base) quinoline-2,4-dimethylamine, N ⁴ -{1-[(3-Cyanopyridin-2-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}-5-fluoroquinoline- 2,4-dimethylamine, N ⁴ -[1-(3,4-Difluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4- Dimethylamine, (±)-N ⁴ -[5-Methyl-1-(1-phenylethyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, (±) -6-bromo-N-[5-methyl-1-(1-phenylethyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl) Quinoline-4-carboxamide, N ⁴ -[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-7-fluoro-N ² -(2-hydroxyethyl)quinoline-2,4-dimethylamine, N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-N ² -[2-(dimethylamino)ethyl]-7-fluoroquinoline-2,4-dimethylamine, N ⁴ -[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-N ² -[2-(dimethylamino)ethyl]-7-fluoroquinoline-2,4-dimethylamine, N ⁴ -[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-7-fluoro-N ² -[2-(morpholin-4-yl)ethyl]quinoline-2,4-dimethylamine, N ⁴ -[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-7-fluoro-N ² -[2-(morpholin-4-yl)ethyl]quinoline-2,4-dimethylamine, N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoro-N ² -(2-hydroxyethyl)quinoline-2,4-dimethylamine, 7-fluoro-N ⁴ -[1-(4-isopropylbenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, N ⁴ -[1-(4-isopropylbenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, 7-fluoro-N ⁴ -[1-(4-isopropylbenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, N ⁴ -[1-(4-isopropylbenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, 6-bromo-N ⁴ -{1-[(3-Cyanopyridin-2-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}quinoline-2,4-dimethylamine, N ⁴ -{1-[(3-Cyanopyridin-2-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-7-fluoroquinoline-2,4-dimethyl Guanamine, N ⁴ -{1-[(3-Cyanopyridin-2-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-5-fluoroquinoline-2,4-dimethyl Indoleamine, 6-chloro-N ⁴ -{1-[(3-Cyanopyridin-2-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-7-fluoroquinoline-2,4-dimethyl Guanamine, N ⁴ -[1-(4-Ethylbenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-dimethyl Guanamine, N ⁴ -[1-(4-ethylbenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, 6 -bromo-N ⁴ -[1-(4-ethylbenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, 6 -chloro-N ⁴ -[1-(4-Ethylbenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-dimethyl Indoleamine, 6-bromo-N-[3,5-dimethyl-1-(pyrimidin-4-ylmethyl)-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline -4-carbamamine, N ⁴ -[3,5-Dimethyl-1-(pyrimidin-4-ylmethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, N-[3-cyano 1-(4-fluorobenzyl)-5-methyl-1H-pyrazol-4-yl]-2-methoxyquinoline-4-carboxamide, N ⁴ -{1-[4-(azetidin-1-ylcarbonyl)benzyl]-3,5-dimethyl-1H-pyrazol-4-yl}-7-fluoroquinoline-2,4 -dimethylamine,7-fluoro-N ⁴ -(1-{4-[(2-hydroxyethyl)aminemethanyl]benzyl}-3,5-dimethyl-1H-pyrazol-4-yl)quinoline-2,4-di Formamide, 7-fluoro-N ⁴ -(1-{4-[(2-methoxyethyl)aminemethanyl]benzyl}-3,5-dimethyl-1H-pyrazol-4-yl)quinoline-2,4 -dimethylamine, N ⁴ -[1-(4-{[2-(Dimethylamino)ethyl]aminemethanyl}benzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-7- Fluoroquinoline-2,4-dimethylamine, 4-[(4-{[(2-aminocarbamimid-7-fluoroquinolin-4-yl)carbonyl]amino}-3,5-di Methyl-1H-pyrazol-1-yl)methyl]benzoic acid, N ⁴ -[1-(4-Aminomethylmercaptobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-dimethylamine, N ⁴ -{3,5-Dimethyl-1-[4-(methylamine-mercapto)benzyl]-1H-pyrazol-4-yl}-7-fluoroquinoline-2,4-dimethyl Guanamine, N ⁴ -{1-[4-(Dimethylaminocarbamimidyl)benzyl]-3,5-dimethyl-1H-pyrazol-4-yl}-7-fluoroquinoline-2,4-di Formamide, (±)-6-bromo-N-{3,5-dimethyl-1-[4-(S-methanesulfonimide)methyl]-1H-pyrazole-4 -yl}-2-(trifluoromethyl)quinoline-4-carboxamide, 2-(azetidin-1-ylcarbonyl)-N-[1-(4-cyanobenzyl)- 3,5-Dimethyl-1H-pyrazol-4-yl]-7-fluoroquinoline-4-carboxamide, 7-fluoro-N ⁴ -{5-Methyl-1-[4-(methylsulfonyl)benzyl]-3-(trifluoromethyl)-1H-pyrazol-4-yl}quinoline-2,4-dimethyl Indoleamine, 6-bromo-N-{5-methyl-1-[4-(methylsulfonyl)benzyl]-3-(trifluoromethyl)-1H-pyrazol-4-yl}- 2-(Trifluoromethyl)quinoline-4-carboxamide, 2-methoxy-N-{5-methyl-1-[4-(methylsulfonyl)benzyl]-3-( Trifluoromethyl)-1H-pyrazol-4-yl}quinoline-4-carboxamide, N ⁴ -{5-Methyl-1-[4-(methylsulfonyl)benzyl]-3-(trifluoromethyl)-1H-pyrazol-4-yl}quinoline-2,4-dimethyl Indoleamine, (±)-[(4-{[4-({[6-bromo-2-(trifluoromethyl)quinolin-4-yl)carbonyl}amino)-3,5-dimethyl -1H-pyrazol-1-yl]methyl}phenyl)(methyl)oxyl-yl-λ ⁶ - sulfiliyl] urethane, N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-6-{[2-(dimethylamino) Ethyl]amino}quinoline-2,4-dimethylamine, N ⁴ -[1-(2,4-difluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4- Dimethylamine, N-[1-(4-fluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-methoxyquinoline -4-carboxamide, 5-fluoro-N ⁴ -{5-Methyl-1-[4-(methylsulfonyl)benzyl]-3-(trifluoromethyl)-1H-pyrazol-4-yl}quinoline-2,4-dimethyl Indoleamine, 6-chloro-7-fluoro-N ⁴ -{5-Methyl-1-[4-(methylsulfonyl)benzyl]-3-(trifluoromethyl)-1H-pyrazol-4-yl}quinoline-2,4-dimethyl Indoleamine, 6-bromo-N ⁴ -{5-Methyl-1-[4-(methylsulfonyl)benzyl]-3-(trifluoromethyl)-1H-pyrazol-4-yl}quinoline-2,4-dimethyl Guanamine, N ⁴ -[1-(2,4-difluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-5-fluoroquinoline-2,4- Dimethylamine, 6-chloro-N ⁴ -[1-(2,4-difluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4- Dimethylamine, 6-bromo-N ⁴ -[1-(2,4-difluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine ,N ⁴ -[1-(3,4-difluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-5-fluoroquinoline-2,4- Dimethylamine, 6-chloro-N ⁴ -[1-(3,4-Difluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4- Dimethylamine, 6-bromo-N ⁴ -[1-(3,4-Difluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine ,6-chloro-7-fluoro-N ⁴ -[1-(3-Methoxybenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, 7-fluoro-N ⁴ -[1-(3-Methoxybenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, N ⁴ -[1-(3-Methoxybenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, 5-fluoro-N ⁴ -[1-(3-Methoxybenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, 6-bromo-N ⁴ -[1-(3-Methoxybenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, 5-fluoro-N ⁴ -[1-(3-Methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, N ⁴ -[1-(3-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, 6-chloro-7- Fluorine-N ⁴ -[1-(3-Methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, N ⁴ -[1-(3-Cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-dimethylamine, N ⁴ -[1-(3-Cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, 6-chloro-N ⁴ -[1-(3-Cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-dimethylamine, N ⁴ -[1-(3-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-5-fluoroquinoline-2,4-dimethylamine, 6-bromo -N ⁴ -[1-(3-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, 7-fluoro-N ⁴ -[1-(3-Methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, N ⁴ -{3,5-Dimethyl-1-[4-(trifluoromethoxy)benzyl]-1H-pyrazol-4-yl}quinoline-2,4-dimethylamine, N ⁴ -{3,5-Dimethyl-1-[4-(trifluoromethoxy)benzyl]-1H-pyrazol-4-yl}-7-fluoroquinoline-2,4-dimethylhydrazine Amine, N ⁴ -{3,5-Dimethyl-1-[4-(trifluoromethoxy)benzyl]-1H-pyrazol-4-yl}-5-fluoroquinoline-2,4-dimethylhydrazine Amine, 6-chloro-N ⁴ -{3,5-Dimethyl-1-[4-(trifluoromethoxy)benzyl]-1H-pyrazol-4-yl}-7-fluoroquinoline-2,4-dimethylhydrazine Amine, 6-bromo-N ⁴ -{3,5-Dimethyl-1-[4-(trifluoromethoxy)benzyl]-1H-pyrazol-4-yl}quinoline-2,4-dimethylamine, N ⁴ -{5-Methyl-1-[4-(trifluoromethoxy)benzyl]-3-(trifluoromethyl)-1H-pyrazol-4-yl}quinoline-2,4-di Formamide, 7-fluoro-N ⁴ -{5-Methyl-1-[4-(trifluoromethoxy)benzyl]-3-(trifluoromethyl)-1H-pyrazol-4-yl}quinoline-2,4-di Formamide, 5-fluoro-N ⁴ -{5-Methyl-1-[4-(trifluoromethoxy)benzyl]-3-(trifluoromethyl)-1H-pyrazol-4-yl}quinoline-2,4-di Formamide, 6-chloro-7-fluoro-N ⁴ -{5-Methyl-1-[4-(trifluoromethoxy)benzyl]-3-(trifluoromethyl)-1H-pyrazol-4-yl}quinoline-2,4-di Formamide, 6-bromo-N ⁴ -[1-(3,4-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, N ⁴ -[1-(3,4-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-dimethylamine, N ⁴ -[1-(3,4-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-5-fluoroquinoline-2,4-dimethylamine, 6 -chloro-N ⁴ -[1-(3,4-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-dimethylamine, 6 -chloro-N ⁴ -[3,5-Dimethyl-1-(3-methylbenzyl)-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-dimethylamine, N ⁴ -[3,5-Dimethyl-1-(3-methylbenzyl)-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-dimethylamine, N ⁴ -[3,5-Dimethyl-1-(3-methylbenzyl)-1H-pyrazol-4-yl]-5-fluoroquinoline-2,4-dimethylamine, 6-chloro -N ⁴ -[3,5-Dimethyl-1-(3-methylbenzyl)-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-dimethylamine, 6-bromo -N ⁴ -[3,5-Dimethyl-1-(3-methylbenzyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, N ⁴ -[5-Methyl-1-(3-methylbenzyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, 5 -Fluorine-N ⁴ -[5-Methyl-1-(3-methylbenzyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, 7 -Fluorine-N ⁴ -[5-Methyl-1-(3-methylbenzyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, 6 -chloro-7-fluoro-N ⁴ -[5-Methyl-1-(3-methylbenzyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, 6 -bromo-N ⁴ -[5-Methyl-1-(3-methylbenzyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, N ⁴ -{3,5-Dimethyl-1-[4-(methylsulfonyl)benzyl]-1H-pyrazol-4-yl}-7-fluoroquinoline-2,4-dimethylamine ,N ⁴ -{3,5-Dimethyl-1-[4-(methylsulfonyl)benzyl]-1H-pyrazol-4-yl}-5-fluoroquinoline-2,4-dimethylamine ,6-chloro-N ⁴ -{3,5-Dimethyl-1-[4-(methylsulfonyl)benzyl]-1H-pyrazol-4-yl}-7-fluoroquinoline-2,4-dimethylamine ,6-bromo-N ⁴ -{3,5-Dimethyl-1-[4-(methylsulfonyl)benzyl]-1H-pyrazol-4-yl}quinoline-2,4-dimethylamine, N ⁴ -[1-(2,4-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-dimethylamine, N ⁴ -[1-(2,4-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-5-fluoroquinoline-2,4-dimethylamine, 6 -chloro-N ⁴ -[1-(2,4-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-dimethylamine, 6 -bromo-N ⁴ -[1-(2,4-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, 6-chloro-7 -Fluorine-N ⁴ -[1-(2-Methoxybenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, N ⁴ -[1-(2-Methoxybenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, 5-fluoro-N ⁴ -[1-(2-Methoxybenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, N ⁴ -[5-Methyl-1-(2-methylbenzyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, 7 -Fluorine-N ⁴ -[5-Methyl-1-(2-methylbenzyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, 5 -Fluorine-N ⁴ -[5-Methyl-1-(2-methylbenzyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, 6 -chloro-7-fluoro-N ⁴ -[5-Methyl-1-(2-methylbenzyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, 6 -bromo-N ⁴ -{5-Methyl-1-[4-(trifluoromethoxy)benzyl]-3-(trifluoromethyl)-1H-pyrazol-4-yl}quinoline-2,4-di Methionamine, 6-bromo-N-{1-[(5-ethyl-1,2,4-oxadiazol-3-yl)methyl]-3,5-dimethyl-1H-pyrazole 4-yl}-2-(trifluoromethyl)quinoline-4-carboxamide, N ⁴ -{1-[(5-ethyl-1,2,4-oxadiazol-3-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}quinoline-2 , 4-dimethylamine, N ⁴ -{1-[(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}quinoline- 2,4-dimethylamine, 6-bromo-N-{1-[(3-cyclopropyl-1,2,4-oxadiazol-5-yl)methyl]-3,5-dimethyl -1H-pyrazol-4-yl}-2-(trifluoromethyl)quinoline-4-carboxamide, N ⁴ -{3,5-Dimethyl-1-[(5-methyl-1,2-oxazol-3-yl)methyl]-1H-pyrazol-4-yl}quinoline-2,4- Dimethylamine, N ⁴ -[3,5-Dimethyl-1-(1,3-oxazol-2-ylmethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, 6- Bromo-N-(1-{[3-(methoxymethyl)-1,2,4-oxadiazol-5-yl]methyl}-3,5-dimethyl-1H-pyrazole- 4-yl)-2-(trifluoromethyl)quinoline-4-carboxamide, N ⁴ -(1-{[3-(methoxymethyl)-1,2,4-oxadiazol-5-yl]methyl}-3,5-dimethyl-1H-pyrazol-4-yl Quinoline-2,4-dimethylamine, N ⁴ -(3,5-Dimethyl-1-{[5-(methylamine-mercapto)-1,2,4-oxadiazol-3-yl]methyl}-1H-pyrazole-4- Base) quinoline-2,4-dimethylamine, N ⁴ -(3,5-Dimethyl-1-{[1-(propylsulfonyl)piperidin-4-yl]methyl}-1H-pyrazol-4-yl)quinoline-2,4- Dimethylamine, N ⁴ -(1-{[1-(butylsulfonyl)piperidin-4-yl]methyl}-3,5-dimethyl-1H-pyrazol-4-yl)quinoline-2,4- Dimethylamine, N ⁴ -[1-({1-[(3-cyanopropyl)sulfonyl]piperidin-4-yl}methyl)-3,5-dimethyl-1H-pyrazol-4-yl]quina Porphyrin-2,4-dimethylamine, N ⁴ -[1-({1-[(3-methoxypropyl)sulfonyl]piperidin-4-yl}methyl)-3,5-dimethyl-1H-pyrazol-4-yl] Quinoline-2,4-dimethylamine, N ⁴ -(3,5-Dimethyl-1-{[1-(pyridin-3-ylsulfonyl)piperidin-4-yl]methyl}-1H-pyrazol-4-yl)quinoline-2 , 4-dimethylamine, N ⁴ -{3,5-Dimethyl-1-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]-1H-pyrazol-4-yl}quinoline-2 , 4-dimethylamine, N ⁴ -(1-{[1-(cyclopropylsulfonyl)piperidin-4-yl]methyl}-3,5-dimethyl-1H-pyrazol-4-yl)quinoline-2,4 -dimethylamine, N ⁴ -(1-{[1-(isopropylsulfonyl)piperidin-4-yl]methyl}-3,5-dimethyl-1H-pyrazol-4-yl)quinoline-2,4 -dimethylamine, N ⁴ -(1-{[1-(cyclopentylsulfonyl)piperidin-4-yl]methyl}-3,5-dimethyl-1H-pyrazol-4-yl)quinoline-2,4 -dimethylamine, N ⁴ -(3,5-Dimethyl-1-{[1-(phenylsulfonyl)piperidin-4-yl]methyl}-1H-pyrazol-4-yl)quinoline-2,4- Dimethylamine, 6-bromo-N-{3,5-dimethyl-1-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]-1H-pyridyl Zin-4-yl}-2-(trifluoromethyl)quinoline-4-carboxamide, N ⁴ -(1-{[5-(dimethylaminocarbamimido)-1,2,4-oxadiazol-3-yl]methyl}-3,5-dimethyl-1H-pyrazole-4 -yl)quinoline-2,4-dimethylamine, 6-bromo-N-(1-{[5-(dimethylaminocarbamimidyl)-1,2,4-oxadiazol-3- Methyl}-3,5-dimethyl-1H-pyrazol-4-yl)-2-(trifluoromethyl)quinoline-4-carboxamide, N ⁴ -{3,5-Dimethyl-1-[(1-methyl-1H-imidazol-2-yl)methyl]-1H-pyrazol-4-yl}quinoline-2,4-dimethylhydrazine Amine, 6-bromo-N-{3,5-dimethyl-1-[(1-methyl-1H-imidazol-2-yl)methyl]-1H-pyrazol-4-yl}-2- (trifluoromethyl)quinoline-4-carboxamide, N-{3,5-dimethyl-1-[(2-o-oxy-1,3-oxazolidine-5-yl)methyl -1H-pyrazol-4-yl}-2-methoxyquinoline-4-carboxamide, N-{3,5-dimethyl-1-[(1-methyl-1H-pyrazole) -3-yl)methyl]-1H-pyrazol-4-yl}-2-methoxyquinoline-4-carboxamide, N-[1-(imidazo[1,2-a]pyridine- 2-ylmethyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-methoxyquinoline-4-carboxamide, 6-bromo-N-[1-(imidazole And [1,2-a]pyridin-2-ylmethyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(trifluoromethyl)quinoline-4-carboxamidine Amine, 7-fluoro-N ⁴ -[5-methyl-1-(1,3-oxazol-2-ylmethyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-di Formamide, N-(3,5-dimethyl-1-{[2-(morpholin-4-yl)-1,3-thiazol-4-yl]methyl}-1H-pyrazole-4 -yl)-2-methoxyquinoline-4-carboxamide, N ⁴ -{1-[(3-ethyl-1,2-oxazol-5-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}quinoline-2,4- Dimethylamine, N ⁴ -{1-[(3-ethyl-1,2-oxazol-5-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-7-fluoroquinoline- 2,4-dimethylamine, 6-bromo-N-(1-{[1-(ethylsulfonyl)piperidin-4-yl]methyl}-3,5-dimethyl-1H-pyridyl Zin-4-yl)-2-(trifluoromethyl)quinoline-4-carboxamide, N ⁴ -(1-{[1-(ethylsulfonyl)piperidin-4-yl]methyl}-3,5-dimethyl-1H-pyrazol-4-yl)-7-fluoroquinoline-2 , 4-dimethyl decylamine, N ⁴ -{1-[(5-ethyl-1,2,4-oxadiazol-3-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazole-4- }}quinoline-2,4-dimethylamine, N ⁴ -{1-[(3-ethyl-1,2,4-oxadiazol-5-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazole-4- }}quinoline-2,4-dimethylamine, N ⁴ -{1-[(3-ethyl-1,2,4-oxadiazol-5-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazole-4- -7-fluoroquinoline-2,4-dimethylamine, N ⁴ -{5-Methyl-1-[(5-methyl-1,2-oxazol-3-yl)methyl]-3-(trifluoromethyl)-1H-pyrazol-4-yl}quin Porphyrin-2,4-dimethylamine, 7-fluoro-N ⁴ -{5-Methyl-1-[(5-methyl-1,2-oxazol-3-yl)methyl]-3-(trifluoromethyl)-1H-pyrazol-4-yl}quin Porphyrin-2,4-dimethylamine, N ⁴ -[5-methyl-1-(1,3-oxazol-2-ylmethyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-di Formamide, N ⁴ -{3,5-Dimethyl-1-[(5-methyl-1,2-oxazol-3-yl)methyl]-1H-pyrazol-4-yl}-7-fluoroquinoline- 2,4-dimethylamine, 7-fluoro-N ⁴ -{5-Methyl-1-[(3-methyl-1,2-oxazol-5-yl)methyl]-3-(trifluoromethyl)-1H-pyrazol-4-yl}quin Porphyrin-2,4-dimethylamine, N ⁴ -{5-Methyl-1-[(3-methyl-1,2-oxazol-5-yl)methyl]-3-(trifluoromethyl)-1H-pyrazol-4-yl}quin Porphyrin-2,4-dimethylamine, 6-chloro-N ⁴ -{1-[(3-ethyl-1,2,4-oxadiazol-5-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazole-4- -7-fluoroquinoline-2,4-dimethylamine, N ⁴ -[1-{[1-(ethylsulfonyl)piperidin-4-yl]methyl}-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7 -fluoroquinoline-2,4-dimethylamine, N ⁴ -[1-{[1-(ethylsulfonyl)piperidin-4-yl]methyl}-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline -2,4-dimethylamine, 6-chloro-7-fluoro-N ⁴ -[5-methyl-1-(1,3-oxazol-2-ylmethyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-di Formamide, N ⁴ -{1-[(5-ethyl-1,2,4-oxadiazol-3-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazole-4- -7-fluoroquinoline-2,4-dimethylamine, N ⁴ -{1-[(5-Cyclopropyl-1,2-oxazol-3-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl} Quinoline-2,4-dimethylamine, N ⁴ -{1-[(5-Cyclopropyl-1,2-oxazol-3-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl} -7-fluoroquinoline-2,4-dimethylamine, 6-chloro-N ⁴ -{1-[(5-Cyclopropyl-1,2-oxazol-3-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl} -7-fluoroquinoline-2,4-dimethylamine, N ⁴ -{1-[(3-isopropyl-1,2-oxazol-5-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl} Quinoline-2,4-dimethylamine, 7-fluoro-N ⁴ -{1-[(3-isopropyl-1,2-oxazol-5-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl} Quinoline-2,4-dimethylamine, 6-chloro-7-fluoro-N ⁴ -{1-[(3-isopropyl-1,2-oxazol-5-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl} Quinoline-2,4-dimethylamine, N ⁴ -{1-[(3-ethyl-1,2-oxazol-5-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}quin Porphyrin-2,4-dimethylamine, N ⁴ -{1-[(3-ethyl-1,2-oxazol-5-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}- 7-fluoroquinoline-2,4-dimethylamine, N ⁴ -[5-methyl-1-{[5-(methylaminemethanyl)-1,2,4-oxadiazol-3-yl]methyl}-3-(trifluoromethyl)-1H -pyrazol-4-yl]quinoline-2,4-dimethylamine, 6-chloro-7-fluoro-N ⁴ -[5-methyl-1-{[5-(methylaminemethanyl)-1,2,4-oxadiazol-3-yl]methyl}-3-(trifluoromethyl)-1H -pyrazol-4-yl]quinoline-2,4-dimethylamine, 7-fluoro-N ⁴ -[5-methyl-1-{[5-(methylaminemethanyl)-1,2,4-oxadiazol-3-yl]methyl}-3-(trifluoromethyl)-1H -pyrazol-4-yl]quinoline-2,4-dimethylamine, N ⁴ -{3,5-Dimethyl-1-[(3-methyl-1,2-oxazol-5-yl)methyl]-1H-pyrazol-4-yl}quinoline-2,4- Dimethylamine, N ⁴ -{3,5-Dimethyl-1-[(3-methyl-1,2-oxazol-5-yl)methyl]-1H-pyrazol-4-yl}-7-fluoroquinoline- 2,4-dimethylamine, N ⁴ -{1-[(3-isopropyl-1,2-oxazol-5-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}quinoline-2,4 -dimethylamine,7-fluoro-N ⁴ -{1-[(3-isopropyl-1,2-oxazol-5-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}quinoline-2,4 -Dimethylguanamine, N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-6-fluoro-2 -(morpholin-4-ylcarbonyl)quinoline-4-carboxamide, N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-5-hydroxyquinoline-2,4-dimethyl Guanamine, N ⁴ -{1-[(3-Cyano-1,2-oxazol-5-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-7-fluoroquinoline- 2,4-dimethylamine, N ⁴ -{1-[(1,5-Dimethyl-1H-pyrazol-4-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}quinoline-2,4 -dimethylamine, N ⁴ -{3,5-Dimethyl-1-[(2-methyl-1,3-thiazol-4-yl)methyl]-1H-pyrazol-4-yl}quinoline-2,4-di Formamide, N ⁴ -{3,5-Dimethyl-1-[(1-methyl-1H-pyrazol-3-yl)methyl]-1H-pyrazol-4-yl}quinoline-2,4-dimethyl Indoleamine, 6-bromo-N-{1-[(3-ethyl-1,2,4-oxadiazol-5-yl)methyl]-3,5-dimethyl-1H-pyrazole- 4-yl}-2-(trifluoromethyl)quinoline-4-carboxamide, N ⁴ -{1-[(3-ethyl-1,2,4-oxadiazol-5-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}quinoline-2 , 4-dimethylguanamine, N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2-amine Sulfomethylquinoline-4-carboxamide, N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-amine sulfonate Quinoline-4-carbamide, N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-2 -(Methylamine sulfonyl)quinoline-4-carboxamide, N-[1-(4-cyanobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl] -2-(Methylamine sulfonyl)quinoline-4-carboxamide, N-[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H -pyrazol-4-yl]-2-(dimethylaminesulfonyl)quinoline-4-carboxamide, N-[1-(4-cyanobenzyl)-3,5-dimethyl -1H-pyrazol-4-yl]-2-(dimethylaminesulfonyl)quinoline-4-carboxamide, N ⁴ -[1-(3-Cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-dimethyl Guanamine, N ⁴ -[1-(3-Cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, 6 -chloro-N ⁴ -[1-(3-Cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-dimethyl Guanamine, N ⁴ -[1-(3-Cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-5-fluoroquinoline-2,4-dimethyl Guanamine, 7-fluoro-N ⁴ -{1-[4-(Methoxymethyl)benzyl]-3,5-dimethyl-1H-pyrazol-4-yl}quinoline-2,4-dimethylamine, 6- Chlorine-N ⁴ -{3,5-Dimethyl-1-[3-(trifluoromethoxy)benzyl]-1H-pyrazol-4-yl}-7-fluoroquinoline-2,4-dimethylhydrazine Amine, 5-fluoro-N ⁴ -{5-Methyl-1-[3-(trifluoromethoxy)benzyl]-3-(trifluoromethyl)-1H-pyrazol-4-yl}quinoline-2,4-di Formamide, N ⁴ -{3,5-Dimethyl-1-[3-(trifluoromethoxy)benzyl]-1H-pyrazol-4-yl}quinoline-2,4-dimethylamine, N ⁴ -{3,5-Dimethyl-1-[3-(trifluoromethoxy)benzyl]-1H-pyrazol-4-yl}-7-fluoroquinoline-2,4-dimethylhydrazine Amine, N ⁴ -{3,5-Dimethyl-1-[3-(trifluoromethoxy)benzyl]-1H-pyrazol-4-yl}-5-fluoroquinoline-2,4-dimethylhydrazine Amine, 7-fluoro-N ⁴ -[1-(2-Methoxybenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, 6-chloro-7-fluoro-N ⁴ -{5-Methyl-3-(trifluoromethyl)-1-[4-(trifluoromethyl)benzyl]-1H-pyrazol-4-yl}quinoline-2,4-dimethyl Guanamine, 7-fluoro-N ⁴ -{5-Methyl-3-(trifluoromethyl)-1-[4-(trifluoromethyl)benzyl]-1H-pyrazol-4-yl}quinoline-2,4-dimethyl Guanamine, 5-fluoro-N ⁴ -{5-Methyl-3-(trifluoromethyl)-1-[4-(trifluoromethyl)benzyl]-1H-pyrazol-4-yl}quinoline-2,4-dimethyl Guanamine, N ⁴ -{1-[4-(Cyanomethyl)benzyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}quinoline-2,4-dimethyl Guanamine, N ⁴ -{1-[4-(Cyanomethyl)benzyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}-5-fluoroquinoline-2, 4-dimethylamine, 6-chloro-N ⁴ -{1-[4-(Cyanomethyl)benzyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}-7-fluoroquinoline-2, 4-dimethylamine, 6-bromo-N ⁴ -{1-[4-(Cyanomethyl)benzyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}quinoline-2,4-dimethyl Guanamine, N ⁴ -{1-[4-(2-Cyanopropan-2-yl)benzyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}-7-fluoro Quinoline-2,4-dimethylamine, N ⁴ -{1-[4-(2-Cyanopropan-2-yl)benzyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}-5-fluoro Quinoline-2,4-dimethylamine, 6-chloro-N ⁴ -{3,5-Dimethyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrazol-4-yl}-7-fluoroquinoline-2,4-dimethylamine ,N ⁴ -{3,5-Dimethyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrazol-4-yl}-7-fluoroquinoline-2,4-dimethylamine , N ⁴ -{3,5-Dimethyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrazol-4-yl}-5-fluoroquinoline-2,4-dimethylamine ,N ⁴ -[1-(3-Aminomethylbenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4- Dimethylamine, N ⁴ -[1-(3-Aminomethylbenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-5-fluoroquinoline-2,4- Dimethylamine, N ⁴ -[1-(3-Aminomethylbenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-6-chloro-7-fluoroquinoline- 2,4-dimethylamine, N ⁴ -[1-(4-Ethylbenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, N ⁴ -[1-(4-Ethylbenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-di Formamide, N ⁴ -[1-(4-Ethylbenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-5-fluoroquinoline-2,4-di Formamide, N ⁴ -[1-(4-Ethylbenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, N ⁴ -[1-(4-Ethylbenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-dimethylamine, N ⁴ -[1-(4-Ethylbenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-5-fluoroquinoline-2,4-dimethylamine, N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-methylquinoline-2,4-di Formamide, 6-bromo-N ⁴ -[1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-dimethyl Guanamine, N ⁴ -{1-[4-(Cyanomethyl)benzyl]-3,5-dimethyl-1H-pyrazol-4-yl}-5-fluoroquinoline-2,4-dimethylamine , N ⁴ -{1-[4-(Cyanomethyl)benzyl]-3,5-dimethyl-1H-pyrazol-4-yl}-7-fluoroquinoline-2,4-dimethylamine ,N ⁴ -{1-[4-(Cyanomethyl)benzyl]-3,5-dimethyl-1H-pyrazol-4-yl}quinoline-2,4-dimethylamine, (±) -N ⁴ -{1-[4-(1-hydroxyethyl)benzyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}quinoline-2,4-di Formamide, N ⁴ -[1-(4-Cyclobutylbenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-di Formamide, N ⁴ -[1-(4-Cyclobutylbenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, N ⁴ -[1-(4-Cyclobutylbenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-5-fluoroquinoline-2,4-di Formamide, N ⁴ -[1-(3-Ethylbenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-di Formamide, N ⁴ -[1-(3-Ethylbenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-5-fluoroquinoline-2,4-di Formamide, N ⁴ -[1-(3-Ethylbenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-6-chloro-7-fluoroquinoline-2 , 4-dimethylamine, N ⁴ -[1-(3-Ethylbenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, N ⁴ -[1-(3-Ethylbenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-6-chloro-7-fluoroquinoline-2,4-dimethylhydrazine Amine, N ⁴ -[1-(3-Ethylbenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-5-fluoroquinoline-2,4-dimethylamine, N ⁴ -[1-(3-Ethylbenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-dimethylamine, N ⁴ -[1-(3-Ethylbenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, N ⁴ -[1-(2,6-difluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4- Dimethylamine, N ⁴ -[1-(2,6-difluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine ,N ⁴ -[1-(2,6-difluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-5-fluoroquinoline-2,4- Dimethylamine, 6-chloro-N ⁴ -[1-(2,6-difluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4- Dimethylamine, N ⁴ -[1-(2,6-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-dimethylamine, N ⁴ -[1-(2,6-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, N ⁴ -[1-(2,6-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-5-fluoroquinoline-2,4-dimethylamine, 6 -chloro-N ⁴ -[1-(2,6-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-dimethylamine, ±)-N ⁴ -{1-[4-(1-hydroxyethyl)benzyl]-3,5-dimethyl-1H-pyrazol-4-yl}quinoline-2,4-dimethylamine, N ⁴ -{5-Methyl-1-[3-(methylsulfonyl)benzyl]-3-(trifluoromethyl)-1H-pyrazol-4-yl}quinoline-2,4-dimethyl Guanamine, 7-fluoro-N ⁴ -{5-Methyl-1-[3-(methylsulfonyl)benzyl]-3-(trifluoromethyl)-1H-pyrazol-4-yl}quinoline-2,4-dimethyl Indoleamine, 6-chloro-7-fluoro-N ⁴ -{5-Methyl-1-[3-(methylsulfonyl)benzyl]-3-(trifluoromethyl)-1H-pyrazol-4-yl}quinoline-2,4-dimethyl Guanamine, 5-fluoro-N ⁴ -{5-Methyl-1-[3-(methylsulfonyl)benzyl]-3-(trifluoromethyl)-1H-pyrazol-4-yl}quinoline-2,4-dimethyl Guanamine, N ⁴ -{3,5-Dimethyl-1-[3-(methylsulfonyl)benzyl]-1H-pyrazol-4-yl}-7-fluoroquinoline-2,4-dimethylamine ,N ⁴ -{3,5-Dimethyl-1-[3-(methylsulfonyl)benzyl]-1H-pyrazol-4-yl}-5-fluoroquinoline-2,4-dimethylamine ,N ⁴ -{3,5-Dimethyl-1-[3-(methylsulfonyl)benzyl]-1H-pyrazol-4-yl}quinoline-2,4-dimethylamine, 6-chloro -N ⁴ -{3,5-Dimethyl-1-[3-(methylsulfonyl)benzyl]-1H-pyrazol-4-yl}-7-fluoroquinoline-2,4-dimethylamine , (±)-N ⁴ -{1-[3-(1-hydroxyethyl)benzyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}quinoline-2,4-di Formamide, (±)-N ⁴ -{1-[3-(1-hydroxyethyl)benzyl]-3,5-dimethyl-1H-pyrazol-4-yl}quinoline-2,4-dimethylamine, N ⁴ -[1-(4-Cyano-2-methoxybenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoroquinoline- 2,4-dimethylamine, N ⁴ -[1-(4-Cyano-2-methoxybenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-5-fluoroquinoline- 2,4-dimethylamine, 6-chloro-N ⁴ -[1-(4-Cyano-2-methoxybenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoroquinoline- 2,4-dimethylamine, N ⁴ -[1-(4-Cyano-2-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-dimethyl Guanamine, N ⁴ -[1-(4-Cyano-2-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-5-fluoroquinoline-2,4-dimethyl Indoleamine, 6-chloro-N ⁴ -[1-(4-Cyano-2-methoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-dimethyl Guanamine, N ⁴ -[1-(2-Cyano-5-fluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethyl Guanamine, N ⁴ -[1-(2-Cyano-5-fluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoroquinoline-2, 4-dimethylamine, N ⁴ -[1-(2-Cyano-5-fluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-5-fluoroquinolin-2, 4-dimethylamine, 6-chloro-N ⁴ -[1-(2-Cyano-5-fluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoroquinoline-2, 4-dimethylamine, N ⁴ -[1-(2-Cyano-4-fluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-5-fluoroquinolin-2, 4-dimethylamine, 6-chloro-N ⁴ -[1-(2-Cyano-4-fluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoroquinoline-2, 4-dimethylamine, N ⁴ -[1-(2-Cyano-4-fluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoroquinoline-2, 4-dimethylamine, N ⁴ -[1-(2-Cyano-4-fluorobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethyl Guanamine, N ⁴ -[1-(2-Cyano-4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-dimethylamine ,N ⁴ -[1-(2-Cyano-4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]quinoline-2,4-dimethylamine, N ⁴ -[1-(2-Cyano-4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-5-fluoroquinoline-2,4-dimethylamine ,6-chloro-N ⁴ -[1-(2-Cyano-4-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-dimethylamine ,N ⁴ -[1-(4-Cyano-3-methoxybenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoroquinoline- 2,4-dimethylamine, N ⁴ -[1-(4-Cyano-3-methoxybenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-5-fluoroquinoline- 2,4-dimethylamine, 6-chloro-N ⁴ -[1-(4-Cyano-3-methoxybenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoroquinoline- 2,4-dimethylamine, N ⁴ -{1-[4-(2-Cyanopropan-2-yl)benzyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}quinoline-2 , 4-dimethylamine, N ⁴ -[1-(4-Cyano-2-hydroxybenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoroquinoline-2, 4-dimethylamine, N ⁴ -{1-[(3-Cyano-1,2-oxazol-5-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}- 7-fluoroquinoline-2,4-dimethylamine, 5-[(4-{[(2-aminocarbamimid-7-fluoroquinolin-4-yl)carbonyl]amino}-3,5 -Ethyl dimethyl-1H-pyrazol-1-yl)methyl]-1,2-oxazole-3-carboxylate, N ⁴ -[1-{2-[(2-hydroxyphenyl)amino]-2-oxoethyl}-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl Quinoline-2,4-dimethylamine, N ⁴ -{1-[(3-Cyano-1,2-oxazol-5-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}quin Porphyrin-2,4-dimethylamine, 6-chloro-N ⁴ -{1-[(3-Cyano-1,2-oxazol-5-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}- 7-fluoroquinoline-2,4-dimethylamine, N ⁴ -{1-[(2-Cyano-1,3-thiazol-4-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}-7 -fluoroquinoline-2,4-dimethylamine, N ⁴ -{1-[(5-Cyano-2-thienyl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}-7-fluoroquinoline- 2,4-dimethylamine, 6-chloro-7-fluoro-N ⁴ -[5-methyl-1-{[5-(morpholin-4-ylmethyl)-1,2-oxazol-3-yl]methyl}-3-(trifluoromethyl)-1H- Pyrazol-4-yl]quinoline-2,4-dimethylamine, 5-{[4-{[(2-aminocarbamimid-7-fluoroquinolin-4-yl)carbonyl]amino} -5-Methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}-1,2-oxazole-3-carboxylic acid ethyl ester, N ⁴ -[1-(1,3-benzoxazol-2-ylmethyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoroquinoline -2,4-dimethylamine, N ⁴ -{1-[(5-Cyano-2-thienyl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}quinoline-2,4- Dimethylamine, 2-{[4-{[(2-aminopyridylquinolin-4-yl)carbonyl]amino}-5-methyl-3-(trifluoromethyl)-1H-pyridyl Methyl oxazol-1-yl]methyl}-1,3-oxazole-4-carboxylate, 2-{[4-{[(2-aminocarbazino-7-fluoroquinolin-4-yl)carbonyl Amino}-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}-1,3-oxazole-4-carboxylic acid methyl ester, 2-{[4 -{[(2-Aminomethylamino-6-chloro-7-fluoroquinolin-4-yl)carbonyl]amino}-5-methyl-3-(trifluoromethyl)-1H-pyrazole- Methyl 1-yl]methyl}-1,3-oxazole-4-carboxylate, 5-{[4-{[(2-aminocarbamido-6-chloro-7-fluoroquinolin-4-yl) Ethyl carbonyl]amino}-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}-1,2-oxazole-3-carboxylic acid ethyl ester, 2-{ [4-{[(2-Aminoformylquinolin-4-yl)carbonyl]amino}-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl }-1,3-oxazole-4-carboxylic acid, 2-{[4-{[(2-aminomethylindol-7-fluoroquinolin-4-yl)carbonyl]amino}-5-methyl- 3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}-1,3-oxazole-4-carboxylic acid, 2-{[4-{[(2-aminocarbamido-6) -chloro-7-fluoroquinolin-4-yl)carbonyl]amino}-5-methyl-3-(trifluoromethyl)-1H-pyrazole- 1-yl]methyl}-1,3-oxazole-4-carboxylic acid, N ⁴ -{1-[(6-Cyanopyridin-2-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}-7-fluoroquinoline- 2,4-dimethylamine, N ⁴ -{1-[(6-Cyanopyridin-2-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}-5-fluoroquinoline- 2,4-dimethylamine, 6-chloro-N ⁴ -{1-[(6-Cyanopyridin-2-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}-7-fluoroquinoline- 2,4-dimethylamine, N ⁴ -{1-[(6-Cyanopyridin-2-yl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}quinoline-2,4- Dimethylamine, N ⁴ -(1-{2-[(3-cyanophenyl)amino]-2-oxoethyl}-3,5-dimethyl-1H-pyrazol-4-yl)quinoline-2 , 4-dimethylamine, N ⁴ -(1-{2-[(4-fluorophenyl)amino]-2-oxoethyl}-3,5-dimethyl-1H-pyrazol-4-yl)quinoline-2, 4-dimethylamine, N ⁴ -(1-{2-[(4-fluorophenyl)(methyl)amino]-2-oxoethyl}-3,5-dimethyl-1H-pyrazol-4-yl)quina Porphyrin-2,4-dimethylamine, N ⁴ -[1-(4-Cyano-3-methylbenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-5-fluoroquinoline-2 , 4-dimethylamine, N ⁴ -[1-(4-Cyano-3-methylbenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoroquinoline-2 , 4-dimethylamine, 6-chloro-N ⁴ -[1-(4-Cyano-3-methylbenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-dimethylhydrazine Amine, N ⁴ -[1-(4-Cyano-3-methylbenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-5-fluoroquinoline-2,4-dimethylhydrazine Amine, N ⁴ -[1-(4-Cyano-3-methylbenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-dimethylhydrazine Amine, 6-chloro-N ⁴ -[1-(2-Cyano-5-methylbenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-7-fluoroquinoline-2,4-dimethylhydrazine Amine, N ⁴ -[1-(2-Cyano-5-methylbenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-fluoroquinoline-2 , 4-dimethylamine, N ⁴ -(1-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-3,5-dimethyl-1H-pyrazol-4-yl)quinoline-2, 4-dimethylamine, N ⁴ -[5-methyl-1-{[5-(morpholin-4-ylmethyl)-1,2-oxazol-3-yl]methyl}-3-(trifluoromethyl)-1H- Pyrazol-4-yl]quinoline-2,4-dimethylamine, 7-fluoro-N ⁴ -{5-Methyl-1-[2-(trifluoromethoxy)benzyl]-3-(trifluoromethyl)-1H-pyrazol-4-yl}quinoline-2,4-di Formamide, 6-chloro-7-fluoro-N ⁴ -{5-Methyl-1-[2-(trifluoromethoxy)benzyl]-3-(trifluoromethyl)-1H-pyrazol-4-yl}quinoline-2,4-di Formamide, N ⁴ -{5-Methyl-1-[2-(trifluoromethoxy)benzyl]-3-(trifluoromethyl)-1H-pyrazol-4-yl}quinoline-2,4-di Formamide, 5-fluoro-N ⁴ -{5-Methyl-1-[2-(trifluoromethoxy)benzyl]-3-(trifluoromethyl)-1H-pyrazol-4-yl}quinoline-2,4-di Formamide, N ⁴ -{1-[(6-Cyanopyridin-2-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-7-fluoroquinoline-2,4-dimethyl Guanamine, N ⁴ -{1-[(6-Cyanopyridin-2-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}quinoline-2,4-dimethylamine, N ⁴ -{1-[(6-Cyanopyridin-2-yl)methyl]-3,5-dimethyl-1H-pyrazol-4-yl}-5-fluoroquinoline-2,4-dimethyl Guanamine, 7-fluoro-N ⁴ -[1-(4-fluoro-2-methylbenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethyl Guanamine, 5-fluoro-N ⁴ -[1-(4-fluoro-2-methylbenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethyl Indoleamine, 6-chloro-7-fluoro-N ⁴ -[1-(4-fluoro-2-methylbenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethyl Guanamine, N ⁴ -[1-(4-fluoro-2-methylbenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]quinoline-2,4-dimethyl Guanamine, 7-fluoro-N ⁴ -{5-Methyl-1-[4-(2,2,2-trifluoroethyl)benzyl]-3-(trifluoromethyl)-1H-pyrazol-4-yl}quinoline- 2,4-dimethylamine, 5-fluoro-N ⁴ -{5-Methyl-1-[4-(2,2,2-trifluoroethyl)benzyl]-3-(trifluoromethyl)-1H-pyrazol-4-yl}quinoline- 2,4-dimethylamine, 6-chloro-7-fluoro-N ⁴ -{5-Methyl-1-[4-(2,2,2-trifluoroethyl)benzyl]-3-(trifluoromethyl)-1H-pyrazol-4-yl}quinoline- 2,4-dimethylamine, N ⁴ -{5-Methyl-1-[4-(2,2,2-trifluoroethyl)benzyl]-3-(trifluoromethyl)-1H-pyrazol-4-yl}quinoline- 2,4-dimethylguanamine, or a tautomer thereof, an N-oxide, a hydrate, a solvate or a salt thereof or a mixture thereof. A process for the preparation of a compound of the formula (I) according to any one of claims 1 to 15, in which an intermediate of the formula (II) is obtained Wherein R ¹ , R ² , R ³ , R ⁶ and L ¹ are as defined in any one of claims 1 to 15; reacting with a compound of the formula (III) Wherein R ^4a , R ^4b , R ^5a , R ^5b , R ^5c and R ^5d are as defined in any one of claims 1 to 15; thereby obtaining a compound of the formula (I) Wherein R ¹ , R ² , R ³ , R ^4a , R ^4b , R ^5a , R ^5b , R ^5b , R ^5d , R ⁶ and L ¹ are as defined in any one of claims 1 to 15. a compound of the general formula (II) Wherein R ¹ , R ² , R ³ , R ⁶ and L ¹ are as defined in any one of claims 1 to 15. a compound of formula (III) Wherein R ^4a , R ^4b , R ^5a , R ^5b , R ^5c and R ^5d are as defined in any one of claims 1 to 15. Use of a compound of the formula: (i) formula (II) Wherein R ¹ , R ² , R ³ , R ⁶ and L ^{1 are} as defined for the compound of the formula (I) according to any one of claims 1 to 15; or (ii) the formula (III) Wherein R ^4a , R ^4b , R ^5a , R ^5b , R ^5c and R ^{5b are} as defined in relation to the compound of formula (I) according to any one of claims 1 to 15, which are used in the preparation of claims 1 to 15 A compound of the formula (I) as defined in any one of the formulae. A compound according to any one of claims 1, 2 and 15 or a tautomer, N-oxide, hydrate, solvate or salt thereof, in particular a pharmaceutically acceptable salt thereof, or a mixture suitable for the treatment or prevention of a disease. The compound of claim 20, wherein the disease is a disease of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response, or inappropriate cell inflammatory response, in particular, the uncontrolled cell growth, proliferation and/or survival, inappropriate cells An immune response or an inappropriate cell inflammatory response is mediated by GLUT1, more specifically, the disease in which the uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response, or inappropriate cell inflammatory response is a hematological tumor, a solid tumor, and/or Metastasis, such as leukemia and myelodysplastic syndromes; malignant lymphoma; head and neck tumors, including brain tumors and brain metastases; chest tumors, including non-small cell lung tumors and small cell lung tumors; gastrointestinal tumors; endocrine tumors; Other gynecological tumors; urinary tumors, including kidney tumors, bladder tumors, and prostate tumors; skin tumors; and sarcomas; and/or their metastases. A pharmaceutical composition comprising a compound of formula (I) as defined in any one of claims 1 to 15, or a tautomer, N-oxide, hydrate, solvate or salt thereof, in particular A pharmaceutically acceptable salt thereof, or a mixture thereof, and a pharmaceutically acceptable diluent or carrier. A pharmaceutical combination comprising: one or more compounds of formula (I) according to any one of claims 1 to 15, or tautomers, N-oxides, hydrates, solvates or salts thereof, in particular a pharmaceutically acceptable salt thereof, or a mixture thereof; and one or more agents selected from the group consisting of taxanes such as docetaxel, paclitaxel or taxol; Epothilone, such as Ixabepilone, Patugilone or Sagopilone; Mitoxantrone; Predinisolone; Dexamethasone; Estramustin; Vinblastin; Vincristin; Doxorubicin; Adriamycin; Idarubicin; Daunorubicin; Bleomycin; Etoposide; Cyclophosphamide; Ifosfamide; Procarbazine; Melphalan ( Melphalan); 5-fluorourouracil; capecitabine; Fludarabine; Cytarabine; Ara-C; 2-Chloro-2'-deoxyadenosine; Thioguanine; Antiandrogen, such as Flutamide, Cyproterone acetate or Bicalutamide; Bortezomib; platinum derivatives such as Cisplatin or Carboplatin; Chlorambucil Methotrexate; and rituximab (Rituximab). A compound as defined in any one of claims 1 to 15, or a tautomer thereof, an N-oxide, a hydrate, a solvate or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or The use of a mixture for the preparation of a medicament for the prevention or treatment of a disease. The use of claim 24, wherein the disease is a disease of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response, or inappropriate cellular inflammatory response, in particular, the uncontrolled cell growth, proliferation and/or survival, inappropriate cells An immune response or an inappropriate cell inflammatory response is mediated by GLUT1, more specifically, the disease in which the uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response, or inappropriate cell inflammatory response is a hematological tumor, a solid tumor, and/or Metastasis, such as leukemia and myelodysplastic syndromes; malignant lymphoma; head and neck tumors, including brain tumors and brain metastases; chest tumors, including non-small cell lung tumors and small cell lung tumors; gastrointestinal tumors; endocrine tumors; Other gynecological tumors; urinary tumors, including kidney tumors, bladder tumors, and prostate tumors; skin tumors; and sarcomas; and/or their metastases.