RU2787994C2 - Substituted pyrazole compounds and methods for their use for treatment of hyperproliferative diseases - Google Patents

Abstract

FIELD: organic chemistry; medicine.

SUBSTANCE: group of inventions relates to the field of organic chemistry and medicine, and it is aimed to the treatment of hematopoietic cancer. In particular, a compound is presented, having a structural formula (Ia): optionally in the form of pharmaceutically acceptable salt, where values of radicals L¹, R¹, L², L³, R³, L⁴, R⁴, L⁵, R⁵, and R⁶ are such as it is specified in cl. 1, in addition, specific compounds are presented. The group of inventions also relates to a method for the treatment of hematopoietic cancer, including the administration of the specified compounds.

EFFECT: providing an effective therapy of hematopoietic cancer.

(Ia)

22 cl, 5 dwg, 4 tbl, 72 ex

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[1] This application claims priority over U.S. Provisional Application No. 62/428271, filed Nov. 30, 2016, which is incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

Technical field

[2] This invention relates to the field of compounds, pharmaceutical compositions containing them, and methods of using said compounds and compositions. This invention relates more specifically to methods of using certain compounds for the treatment of hyperproliferative disorders such as cancer.

Technical rationale

Cancer, being an uncontrolled cell proliferation, is a multifactorial disease characterized by tumor formation, growth and, in some cases, metastasis. This year, more than 1.5 million people will be diagnosed with cancer in the United States, with more than 500,000 people dying from cancer. Overall, it is estimated that at least one in three individuals will develop some form of cancer during their lifetime. There are more than 200 different histopathological types of cancer, with breast, lung, colorectal, and prostate cancers accounting for more than half of all new cases in the US. Current cancer treatments vary depending on the location and stage of the cancer, but in most cases involve a combination of surgery, systemic therapy, radiation therapy, and chemotherapy. Despite efforts that have been made to develop anti-cancer strategies, many remain ineffective for specific types of cancer.

Uncontrolled cell proliferation, which is the essence of cancer, includes not only unregulated control of cell proliferation, but also corresponding changes in energy metabolism to stimulate cell growth and division. The reprogramming of cellular metabolism is becoming an important molecular signature of cancer cells. Under aerobic conditions, normal cells convert glucose, first to pyruvate via glycolysis in the cytosol and then to carbon dioxide in the mitochondria; under anaerobic conditions, glycolysis is preferred, and relatively little pyruvate enters the oxygen-consuming mitochondria. When growth factors and nutrients are abundant, oncogenic signaling pathways promote increased metabolism, leading to increased synthesis of macromolecules such as lipids, proteins, and nucleic acids. The overall effect is to support cell growth and proliferation. However, during tumor formation, there is a harsh, anoxic, nutrient-deprived environment that interferes with the cell's ability to maintain its metabolic homeostasis. Cancer cells can reprogram their glucose metabolism, and therefore their energy production, by limiting their energy metabolism mainly to glycolysis, which was previously considered primitive and inefficient by biochemists. Despite these early beliefs, the metabolic profiles of cancer cells are not passive responses to damaged mitochondria, but are the result of oncogene-targeted metabolic reprogramming necessary to support anabolic growth. Oncogenic mutations that allow increased and more efficient use of deficient nutrients represent unique targets in cancer treatment.

SUMMARY OF THE INVENTION

In one aspect of the present invention, compounds are provided having any of the structural formulas (Ia)-(Ie):

(Ia),

(Ia)

(Ia),

(Ia)

(Ic)

(ic)

(Id),

(Id)

(Ie),

(Ie)

optionally in the form of a pharmaceutically acceptable salt or N-oxide and/or solvate or hydrate, where

L ¹ is selected from the group consisting of bond, C(O), S, S(O) ₁₂ , O, NR ⁶ , C(O)NR ⁶ , NR ⁶ C(O), C(S)NR ⁶ , NR ⁶ C(S), C(O)O, OC(O), C(O)S, SC(O), C(S)O, OC(S), C(S)S, SC(S), S(O) ₁₂ O, OS(O) ₁₂ , S(O) ₁₂ NR ⁶ and NR ⁶ S(O) ₁₂ ;

R ¹ is selected from the group consisting of

hydrogen,

C ₁ C ₈ alkyl, C ₁ -C ₈ alkenyl and C ₁ -C ₈ alkynyl, each unsubstituted or fluorinated,

cycloalkyl and heterocycloalkyl, each of which is optionally substituted with 1–2 R ^1E , and

phenyl and monocyclic heteroaryl, each of which is optionally substituted with 1–5 R ^1E ,

where

each R ^1E is independently selected from oxo, optionally substituted C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, halogen, CN, SF ₅ , N ₃ , C(O)R ^1F , SR ^1F , S(O) ₁₂ R ^1F , OR ^1F , –(OCH ₂ CH ₂ O) _n –R ^1G , where n is 1–4, N(R ^1G )C(O)CH ₂ –O–(CH ₂ CH ₂ O) _n R ^1G, , where n is 0–3, C(O)NR ^1G (CH ₂ CH ₂ O) _n R ^1G , NR ^1G R ^1F and C(O)R ^1F ;

each R ^1F is independently selected from H, C ₁ -C ₃ alkyl and C ₁ -C ₃ fluoroalkyl, and

each R ^1G is independently selected from H and C ₁ -C ₃ alkyl;

L ² is selected from the group consisting of bond, -CH ₂ -, -CH(CH ₃ ) - or -CH ₂ CH ₂ -;

Q is selected from the group consisting of H, CH ₂ OH, C(O)OH, C(O)OR ^2A , C(O)NR ^2B R ^2A , C(O)NR ^2B S(O) ₂ R ^2A , C (O)NR ^2B S(O) ₂ NR ^2B R ^2A , C(O)R ^2A , S(O) ₂ OH, P(O)(OH) ₂ , C(OH)(CF ₃ ) ₂ , S( O) ₂ R ^2A , N(R ^2B )S(O) ₂ R ^2A , S(O) ₂ NR ^2B R ^2A , C(O)NHOH, C(O)NH–O(C ₁ –C ₃ alkyl) , and CO(NH)CN, where

each R ^2A is independently selected from H and C ₁ C ₃ alkyl and

each R ^2B is independently selected from H and C ₁ -C ₃ alkyl;

L ³ is a bond, C(O), S, S(O) ₁₂ , O, ‌NR ⁶ , –CH ₂ –, –CH(CH ₃ )(OH)– or –CH(OH)–;

R ³ is aryl or heteroaryl each (i) optionally substituted with one substituent selected from -L ^3C -(aryl optionally substituted with 1-5 R ^3D ), -L ^3C -(heteroaryl optionally substituted with 1-5 R ^3D ) , -L ^3C -(cycloalkyl optionally substituted with 1-5 R ^3D ), -L ^3C -(heterocycloalkyl optionally substituted with 1-5 R ^3D ) and (ii) optionally substituted with 1-5 R ^3E ,

where

each L ^3C is a bond, methylene, ethylene, C(O), S, S(O) ₁₂ , O or NR ^3G ;

each R ^3D is independently selected from oxo optionally substituted C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, halogen, CN, SF ₅ , N ₃ , C(O)R ^3F , SR ^3F , S(O) ₁₂ R ^3F , OR ^3F , NR ^3G R ^3F , C(O)R ^3F , C(O)NR ^3G R ^3F , NR ^3G C(O)R ^3F , C(S)NR ^3G R ^3F , NR ^3G C(S)R ^3F , C(O)OR ^3F , OC(O)R ^3F , C(O)SR ^3F , SC(O)R ^3F , C(S)OR ^3F , OC(S)R ^3F , C(S)SR ^3F , SC(S)R ^3F , S(O) ₁₂ OR ^3F , OS(O) ₁₂ R ^3F , S(O) ₁₂ NR ^3G R ^3F and NR ^3G S(O) ₁₂ R ^3F ;

each R ^3E is independently selected from oxo optionally substituted C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, halogen, CN, SF ₅ , N ₃ , C(O)R ^3F , SR ^3F , S(O) ₁₂ R ^3F , OR ^3F , NR ^3G R ^3F , C(O)R ^3F , C(O)NR ^3G R ^3F , NR ^3G C(O)R ^3F , C(S)NR ^3G R ^3F , NR ^3G C(S)R ^3F , C(O)OR ^3F , OC(O)R ^3F , C(O)SR ^3F , SC(O)R ^3F , C(S)OR ^3F , OC(S)R ^3F , C(S)SR ^3F , SC(S)R ^3F , S(O) ₁₂ OR ^3F , OS(O) ₁₂ R ^3F , S(O) ₁₂ NR ^3G R ^3F , NR ^3G S(O) ₁₂ R ^3F ;

each R ^3F is independently selected from H, C ₁ -C ₃ alkyl and C ₁ -C ₃ fluoroalkyl, and

each R ^3G is independently selected from H, C ₁ -C ₃ alkyl and C ₁ -C ₃ fluoroalkyl;

L ⁴ is selected from the group consisting of bond, C(O), S, S(O) ₁₂ , O, NR ⁶ , C(O)NR ⁶ , NR ⁶ C(O), C(S)NR ⁶ , NR ⁶ C(S), C(O)O, OC(O), C(O)S, SC(O), C(S)O, OC(S), C(S)S, SC(S), S(O) ₁₂ O, OS(O) ₁₂ , S(O) ₁₂ NR ⁶ and NR ⁶ S(O) ₁₂ ;

R ⁴ is selected from the group consisting of hydrogen, optionally substituted C ₁ -C ₈ alkyl, optionally substituted C ₁ -C ₈ alkenyl, and optionally substituted C ₁ -C ₈ alkynyl;

L ⁵ is a bond, C(O), S, S(O) ₁₂ , O, NR ⁶ , –CH ₂ CH ₂ –, –CH=CH–, C≡C, –CH ₂ –, CH(CH ₃ )(OH)– or –CH(OH)–; and

R ⁵ is aryl, heteroaryl, cycloalkyl or heterocycloalkyl, each (i) optionally substituted with one substituent selected from -L ^5C - (phenyl optionally substituted with 1-5 R ^5D ), -L ^5C - (monocyclic heteroaryl optionally substituted with 15 R ^5D ) and -L ^5C - (monocyclic cycloalkyl optionally substituted with 1-5 R ^5D ), -L ^5C - (monocyclic heterocycloalkyl optionally substituted with 1-5 R ^5D ) and (ii) optionally substituted with 1-5 R ^5E ,

where

each L ^5C is a bond, methylene, ethylene, C(O), S, S(O) ₁₂ , O or NR ^3G ;

each R ^5D is independently selected from oxo, optionally substituted C ₁ C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, halogen, CN, SF ₅ , N ₃ , C(O)R ^3F , SR ^3F , S(O) ₁₂ R ^3F , OR ^3F , NR ^3G R ^3F , C(O)R ^3F , C(O)NR ^3G R ^3F , NR ^3G C(O)R ^3F , C(S)NR ^3G R ^3F , NR ^3G C(S)R ^3F , C(O)OR ^3F , OC(O)R ^3F , C(O)SR ^3F , SC(O)R ^3F , C(S)OR ^3F , OC(S)R ^3F , C(S)SR ^3F , SC(S)R ^3F , S(O) ₁₂ OR ^3F , OS(O) ₁₂ R ^3F , S(O) ₁₂ NR ^3G R ^3F and NR ^3G S(O) ₁₂ R ^3F ;

each R ^5E is independently selected from oxo, optionally substituted C ₁ C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, halogen, CN, SF ₅ , N ₃ , C(O)R ^5F , SR ^5F , S(O) ₁₂ R ^5F , OR ^5F , NR ^5G R ^5F , C(O)R ^5F , C(O)NR ^5G R ^5F , NR ^5G C(O)R ^5F , C(S)NR ^5G R ^5F , NR ^1G C(S)R ^5F , C(O)OR ^5F , OC(O)R ^5F , C(O)SR ^5F , SC(O)R ^5F , C(S)OR ^5F , OC(S)R ^5F , C(S)SR ^5F , SC(S)R ^5F , S(O) ₁₂ OR ^5F , OS(O) ₁₂ R ^5F , S(O) ₁₂ NR ^5G R ^5F and NR ^5G S(O) ₁₂ R ^5F ;

each R ^5F is independently selected from H, C ₁ -C ₃ alkyl and C ₁ -C ₃ fluoroalkyl, and

each R ^5G is independently selected from H, C ₁ -C ₃ alkyl;

where

each R ⁶ is selected from the group consisting of hydrogen, C ₁ -C ₃ alkyl and -C(O)(C ₁ C ₃ alkyl);

each optionally substituted alkyl, alkenyl, and alkynyl is unsubstituted, fluorinated, or substituted with one or two hydroxyl groups;

each cycloalkyl has 3-10 ring carbons and is unsaturated or partially unsaturated and optionally includes one or two fused cycloalkyl rings, with each fused ring containing 3-8 ring members;

each heterocycloalkyl has 3-10 ring members and 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, is unsaturated or partially unsaturated, and optionally includes one or two fused cycloalkyl rings each having 3-8 ring members;

each aryl is phenyl or naphthyl and optionally includes one or two fused cycloalkyl or heterocycloalkyl rings, with each fused cycloalkyl or heterocycloalkyl ring having 4-8 ring members;

each heteroaryl is a 5-6 membered monocyclic heteroaryl ring with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or an 8-10-membered bicyclic heteroaryl with 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur, and optionally includes one or two fused cycloalkyl or heterocycloalkyl rings, with each fused cycloalkyl or heterocycloalkyl ring having 4 to 8 ring members.

In some such embodiments of this invention, each optionally substituted alkyl, alkylene, alkenyl, alkenylene, alkynyl, and alkynylene is unsubstituted or fluorinated. For example, in some such embodiments of this invention, each optionally substituted alkyl, alkylene, alkenyl, alkenylene, alkynyl, and alkynylene is unsubstituted.

[4] In another aspect of the present invention, pharmaceutical compositions are provided that contain a compound as described herein.

[5] In another aspect, the present invention provides a method for treating a hyperproliferative disorder, such as cancer, in a subject in need thereof. Said method comprises administering to a subject an effective amount of a compound as described herein.

[6] In another aspect of the invention, the compounds described herein are provided for use in the treatment of hyperproliferative disorders such as cancer.

[7] In another aspect of the present invention, the use of a compound described herein for the preparation of a medicament for the treatment of a hyperproliferative disorder such as cancer is provided.

[8] In certain embodiments of various aspects of the present invention, the hyperproliferative disorder is a hematopoietic cancer. In some alternative embodiments of the present invention, the hyperproliferative disorder is a solid tumor.

[9] In some embodiments of various aspects of the present invention, the hyperproliferative disorder is a cancer (e.g., a solid tumor such as colorectal cancer, lung cancer, or pancreatic cancer) having a mutant KRAS gene, e.g., a heterozygous mutant KRAS gene.

[10] In another aspect of the present invention, there is provided a method for inhibiting cell cycle progression in a cancer cell. Said method includes contacting the cancer cell with an effective amount of a compound as described herein. In some such embodiments of the present invention, the cancer cell is a hematopoietic cancer cell. In other such embodiments of the present invention, the cancer cell is a cancer cell of a solid tumor (eg, pancreatic cancer, lung cancer, or colorectal cancer). In some such embodiments of the present invention, the cancer cell has a heterozygous mutant KRAS gene. Cell cycle progression can be inhibited, for example, in the G0/G1 phase.

[11] In another aspect of the present invention, a method for inducing apoptosis of a cancer cell is provided. Said method includes contacting the cancer cell with an effective amount of a compound as described herein. In some such embodiments of the present invention, the cancer cell is a hematopoietic cancer cell.

[12] In another aspect of the present invention, a method is provided for inducing the cytotoxic effect of a cancer cell. Said method includes contacting the cancer cell with an effective amount of a compound as described herein. In some such embodiments of the present invention, the cancer cell is a hematopoietic cancer cell. In other such embodiments of the present invention, the cancer cell is a cancer cell of a solid tumor (eg, pancreatic cancer, lung cancer, or colorectal cancer). In some such embodiments of the present invention, the cancer cell has a heterozygous mutant KRAS gene.

[13] In another aspect of the present invention, there is provided a method for inhibiting glutathione synthesis in a cancer cell. Said method includes contacting the cancer cell with an effective amount of a compound as described herein. In some such embodiments of the present invention, the cancer cell is a hematopoietic cancer cell. In other such embodiments of the present invention, the cancer cell is a cancer cell of a solid tumor (eg, pancreatic cancer, lung cancer, or colorectal cancer). In some such embodiments of the present invention, the cancer cell has a heterozygous mutant KRAS gene.

[14] In certain embodiments of this invention, the compound used in the methods, compounds and uses described herein is a compound of any of the structural formulas (I) below:

[15] Other aspects and embodiments of this invention are described, which are obvious in view of the detailed description provided in this document.

[16] All publications referenced in this document are incorporated herein by reference in their entirety to the extent that they do not conflict with the specific description provided in this document.

BRIEF DESCRIPTION OF GRAPHICS

1 is a bar graph showing the reactivity of cell lines to test compound exposure as fully described, taking into account the KRAS genotype and zygosity of the KRAS cell lines.

2 is a graph showing glutathione levels in three cell lines (BJAB, HCT116 and NHFL) after exposure to a test compound. BJAB is represented by a dark gray (bottom) line, HCT116 is represented by a black (middle) line, and NHFL is represented by a light gray (top) line.

3 is a pair of histograms demonstrating the decrease in glutathione levels in HCT-116 cells after exposure to test compound (top) and exposure to menadione (bottom) in both the presence and absence of N-acetylcysteine (NAC).

Fig. 4A is a set of graphs representing flow cytometry data obtained from representative cell cycle experiments on HCT116 cells following test compound exposure. Fig. 4B is a histogram of the data of FIG. 4A as percentage of cells in each phase of the cell cycle.

DETAILED DESCRIPTION

[17] In one aspect, the invention provides methods, compounds, and uses for the treatment of a variety of hyperproliferative disorders with a compound described herein. Said compound may be defined generally in accordance with any of formulas (Ia), (Ib), (Ic) and (Id) above or in various subgeneral compounds in which the structural formula, R ¹ , L ¹ , L ² , Q, L ³ , R ³ , L ⁴ , R ⁴ , L ⁵ and R ⁵ are optionally independently selected from groups (Ia) et seq., (1a) et seq. , (2a) et seq., (3a) et seq. , (4a) ff., (5a) ff., (6a) ff., (7a) ff., (8a) ff., (9a) ff. And (10a) et seq., as defined herein below ( e.g. , where the compound has the structural formula as defined in any combination of the embodiments below):

[18] In certain embodiments of the compounds described herein, the compound has one of the following structural formulas:

(Ia);

(Ib);

(Ic);

(id);

(Ie).

[19] In certain embodiments of the compounds described herein, R ¹ is selected from one of the following groups (1a)-(1k):

(1a) R ¹ is selected from the group consisting of hydrogen, optionally substituted C ₁ -C ₈ alkyl and cycloalkyl optionally substituted with 1-5 R ^1E;

(1b) R ¹ is hydrogen;

(1c) R ¹ is an optionally substituted C ₁ -C ₈ alkyl;

(1d) R ¹ is unsubstituted C ₁ -C ₈ alkyl or fluorinated C ₁ -C ₈ alkyl, eg propyl or butyl;

(1e) R ¹ is unsubstituted cycloalkyl;

(1f) R ¹ is an optionally substituted C ₁ -C ₈ alkenyl;

(1g) R ¹ is phenyl optionally substituted with 1-5 R ^E;

(1h) R ¹ is propyl, butyl, or butenyl;

(1i) R ¹ is trifluoromethyl-substituted phenyl, methoxy-substituted phenyl or fluoro-substituted phenyl.

(1j) R ¹ is phenyl substituted with –(OCH ₂ CH ₂ O) _n –R ^1G , where n is 1–4, N(R ^1G )C(O)CH ₂ –O–(CH ₂ CH ₂ O ) _n R ^1G , where n is 0–3, or ‌C(O)NR ^1G (CH ₂ CH ₂ O) _n R ^1G ;

(1k) R ¹ is hydroxymethyl, methoxymethyl, hydroxyethyl or methoxyethyl.

In certain such embodiments of this invention, each optionally substituted R ¹ alkyl (including R ^1E alkyls) is unsubstituted or fluorinated. For example, in some such embodiments of this invention, each optionally substituted alkyl, alkenyl, and alkynyl from R ¹ (including those from R ^1E ) is unsubstituted.

[20] In certain embodiments of the compounds described herein, L ¹ is selected from one of the following groups (2a)-(2e)

(2a) L ¹ is a bond, –S–, –S(O)– or –S(O) ₂ –;

(2b) L ¹ is selected from the bond, –CH ₂ –, –CH(CH ₃ )–, CH ₂ CH ₂ –, C(O), ‌S, ‌S(O) ₁₂ , ‌O, and ‌NR ⁶ ;

(2c) L ¹ is O– or –S–.

(2d) L ¹ is a bond (eg when R ¹ is (1d), (1f), (1g), (1i), (1j) or (1k) above);

(2e) L ¹ is -NR ⁶ -.

[21] In certain embodiments of the compounds described herein, L ² is selected from one of the following groups (3a)-(3c)

(3a) L ² is -CH ₂ -, -CH(CH ₃ ) - or CH ₂ CH ₂ -;

(3b) L ² is a bond;

(3c) L ² is a bond or -CH ₂ -.

[22] In certain embodiments of the compounds described herein, Q is selected from one of the following groups (4a)-(4d)

(4a) Q is selected from the group consisting of CH ₂ OH, C(O)OH, C(O)OR ^2A , C(O)NR ^2B R ^2A , C(O)NR ^2B S(O) ₂ R ^2A , C(O)NR ^2B S(O) ₂ NR ^2B R ^2A , C(O)R ^2A , S(O) ₂ OH, P(O)(OH) ₂ , C(OH)(CF ₃ ) ₂ , S (O) ₂ R ^2A , N(R ^2B )S(O) ₂ R ^2A , S(O) ₂ NR ^2B R ^2A , C(O)NH–O(C ₁ –C ₃ alkyl), C(O) NHOH and CO(NH)CN;

(4b) Q is selected from the group consisting of CH ₂ OH, C(O)OH, C(O)OR ^2A , C(O)NR ^2B R ^2A , C(O)NR ^2B S(O) ₂ R ^2A , C(O)NR ^2B S(O) ₂ NR ^2B R ^2A , C(O)R ^2A , S(O) ₂ OH, P(O)(OH) ₂ .

(4c) Q is CH ₂ OH, C(O)OH or C(O)OR ^2A ;

(4d) Q is -COOH.

[23] In certain embodiments of the compounds described herein, L ³ is selected from one of the following groups (5a)-(5c)

(5a) L ³ is a bond, C(O), S, S(O) ₁₂ , O, NR ⁶ , –CH ₂ –, –CH(CH ₃ )(OH)– or –CH(OH)–;

(5b) L ³ is a bond;

(5c) L ³ is a bond, –CH ₂ –, –CH(CH ₃ )(OH)– or –CH(OH)–.

[24] In certain embodiments of the compounds described herein, R ³ is selected from one of the following groups (6a)-(6k)

(6a) R ³ is aryl (eg phenyl) or heteroaryl (eg monocyclic heteroaryl) each (i) optionally substituted with one substituent selected from -L- ^3C -(aryl optionally substituted with 1-5 R ^3D) . -L ^3C -(heteroaryl optionally substituted with 1-5 R ^3D ), L ^3C (cycloalkyl optionally substituted with 1-5 R ^3D ), -L ^3C -(heterocycloalkyl optionally substituted with 1-5 R ^3D ) and (ii) optional substituted 1–5 R ^3E ;

(6b) R ³ is aryl (eg phenyl, benzodioxole, or dihydro-1H-isoquinoline) optionally substituted with 15 R ^3E ;

(6c) R ³ is aryl (e.g. phenyl, benzodioxole or dihydro-1H-isoquinoline) (i) substituted with one substituent selected from –L ^3C (aryl optionally substituted with 15 R ^3D ), –L3C– (heteroaryl, optionally substituted with 15 R ^3D ), L ^3C (cycloalkyl optionally substituted with 15 R ^3D ), L ^3C (heterocycloalkyl optionally substituted with 15 R ^3D ) and (ii) optionally substituted with 15 R ^3E ;

(6d) R ³ is aryl (e.g. phenyl, benzodioxole, or dihydro-1H-isoquinoline) (i) substituted with one substituent selected from L ^3C (phenyl optionally substituted with 1-5 R ^3D) , –L ^3C – (monocyclic heteroaryl optionally substituted with 1-5 R ^3D ), -L ^3C - (monocyclic cycloalkyl optionally substituted with 1-5 R ^3D ), -L ^3C - (monocyclic heterocycloalkyl optionally substituted with 1-5 R ^3D ) and (ii) optionally substituted 1-5 R ^3E ;

(6e) R ³ as defined in (6a)-(6d), where aryl is not substituted with any R ^3E;

(6f) R ³ is heteroaryl (e.g., isothiazole, pyridone, thiadiazole, pyrazine, pyrazolopyrimidine, pyrazolopyridine, imidazole, benzofuran, indole, imidazopyridine, pyridine, pyrazole, isoxazole, triazolopyridine, benzimidazole, thiophene, benzothiophene, furan, or pyrimidine), optionally substituted 1-5 R ^3E ;

(6g) R ³ is heteroaryl (e.g., isothiazole, pyridone, thiadiazole, pyrazine, pyrazolopyrimidine, pyrazolopyridine, imidazole, benzofuran, indole, imidazopyridine, pyridine, pyrazole, isoxazole, triazolopyridine, benzimidazole, thiophene, benzothiophene, furan, or pyrimidine) ( i) substituted with one substituent selected from -L ^3C -(aryl optionally substituted with 1-5 R ^3D ), -L ^3C -(heteroaryl optionally substituted with 1-5 R ^3D ), -L ^3C -(cycloalkyl optionally substituted with 1 –5 R ^3D ), –L ^3C –(heterocycloalkyl optionally substituted with 1-5 R ^3D ) and (ii) optionally substituted with 1-5 R ^3E ;

(6h) R ³ is heteroaryl (e.g., isothiazole, pyridone, thiadiazole, pyrazine, pyrazolopyrimidine, pyrazolopyridine, imidazole, benzofuran, indole, imidazopyridine, pyridine, pyrazole, isoxazole, triazolopyridine, benzimidazole, thiophene, benzothiophene, furan, or pyrimidine) ( i) substituted with one substituent selected from -L ^3C - (phenyl optionally substituted with 1-5 R ^3D ), -L ^3C - (monocyclic heteroaryl optionally substituted with 1-5 R ^3D ), -L ^3C - (monocyclic cycloalkyl, optionally substituted with 1-5 R ^3D ), -L ^3C - (monocyclic heterocycloalkyl optionally substituted with 1-5 R ^3D ) and (ii) optionally substituted with 15 R ^3E ;

(6i) R ³ is as defined in (6f) to (6h), where heteroaryl is not substituted by any R ^3E;

(6j) R ³ is selected from the group consisting of: phenyl, benzodioxolyl, dihydro-1H-isoquinolinyl, imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, pyridinyl and pyrazinyl, pyridonyl, thiadiazolyl, pyrazolopyrimidinyl, pyrazolopyridinyl, benzofuranyl, indolyl, imidazopyridinyl, pyrazolyl, triazolopyridinyl, benzimidazolyl, benzimidazolyl, thienyl, benzothienyl, furanyl and pyrimidinyl, each (i) optionally substituted with one substituent selected from –L ^3C –(aryl, optionally substituted 1-5 R ^3D ), –L ^3C – (heteroaryl, optionally substituted 1–5 R ^3D ), –L ^3C – (cycloalkyl optionally substituted 1–5 R ^3D ), –L ^3C – (heterocycloalkyl optionally substituted 1–5 R ^3D ) and (ii) optionally substituted 1–5 R ^3E .

(6k) R ³ is selected from the group consisting of phenyl and monocyclic heteroaryl (eg pyridyl, pyrazolyl) optionally substituted with 1-5 R ^3E.

In some such embodiments of this invention, each optionally substituted alkyl, alkenyl, and alkynyl R ³ (including R ³ and R ^3E ) is unsubstituted or fluorinated. For example, in some such embodiments of this invention, each optionally substituted alkyl, alkenyl, and alkynyl R ³ (including R ³ and R ^3E ) is unsubstituted. In some such embodiments of this invention, L ^3C is methylene or -O-. In some such embodiments of this invention, the optional number of R ^3E substituents is 1-3 or 1-2.

[25] In certain embodiments of the compounds described herein, R ⁴ is selected from one of the following groups (7a)-(7d)

(7a) R ⁴ is hydrogen;

(7b) R ⁴ is optionally substituted C ₁ -C ₈ alkyl, optionally substituted C ₁ C ₈ alkenyl, or optionally substituted C ₁ C ₈ alkynyl;

(7c) R ⁴ is hydrogen or unsubstituted C ₁ -C ₆ alkyl;

(7d) R ⁴ is unsubstituted C ₁ -C ₃ alkyl.

In some such embodiments of this invention, each optionally substituted alkyl, alkenyl, and alkynyl R ⁴ is unsubstituted or fluorinated. For example, in some such embodiments of this invention, each optionally substituted alkyl, alkenyl, and alkynyl R ⁴ is unsubstituted.

[26] In certain embodiments of the compounds described herein, L ⁴ is selected from one of the following groups (8a)-(8c)

(8a) L ⁴ is selected from the bond, –C(O), S, S(O) ₁₂ , O, and NR ⁶ ;

(8b) L ⁴ is a bond;

(8c) L ⁴ is -O- (eg when R ⁴ is any of (7a), (7b), (7c) or (7d) above).

[27] In certain embodiments of the compounds described herein, L ⁵ is selected from one of the following groups (9a)-(9c)

(9a) L ⁵ is a bond, C(O), S, S(O) ₁₂ , O, NR ⁶ , CH ₂ CH ₂ –, CH ₂ –, CH(CH ₃ )(OH)– or CH(OH )–;

(9b) L ⁵ is a bond;

( 9c) L ⁵ is a bond, O–, S–, C(O) or S(O) ₁₂ .

[28] In certain embodiments of the compounds described herein, R ⁵ is selected from one of the following groups (21o)-(21q)

(10a) R ⁵ is aryl (eg phenyl) or heteroaryl (eg isoxazolyl, pyridyl, imidazopyridyl, pyrazolyl), each of which is optionally substituted with 1-5 R ^5E;

(10b) R ⁵ is phenyl optionally substituted with 1-5 R ^5E;

(10c) R ⁵ is selected from the group consisting of phenyl, isoxazolyl, pyridyl, imidazopyridyl and pyrazolyl, each of which is optionally substituted with 1-5 R ^5E.

(10d) R ⁵ is phenyl substituted with one substituent selected from -L ^5C - (phenyl optionally substituted with 1-5 R ^5D), -L ^5C - (monocyclic heteroaryl optionally substituted with 1-5 R ^5D), and - L ^5C - (monocyclic cycloalkyl, optionally substituted with 1-5 R ^5D ) -L ^5C - (monocyclic heterocycloalkyl, optionally substituted with 1-5 R ^5D ), and (ii) optionally substituted with 1-5 R ^5E ;

(10e) R ⁵ is phenyl substituted with one substituent L ^5C (monocyclic heteroaryl optionally substituted with 1-5 R ^5D ) and (ii) optionally substituted with 1-5 R ^5E ;

(10f) R ⁵ is phenyl substituted with one substituent -L ^5C - (monocyclic heterocycloalkyl optionally substituted with 1-5 R ^5D ), and (ii) optionally substituted with 1-5 R ^5E ;

(10g) (10d), (10e) or (10f) above, where L ^5C is a bond;

(10h) (10d), (10e) or (10f) above, where L ^5C is -O- or -C(O)-;

(10h) R ⁵ is heterocycloalkyl optionally substituted with 1-5 R ^5E;

(10i) R ⁵ is heterocycloalkyl optionally substituted with one -L ^5C - substituent (monocyclic cycloalkyl optionally substituted with 1-5 R ^5D ). and (ii) optionally substituted with 1-5 R ^5E ;

(10j) (10h) or (10i) above, where heterocycloalkyl is a nitrogen-containing heterocycloalkyl attached to -L5- via a nitrogen atom;

(10k) (10h), (10i) or (10j) above, wherein the heterocycloalkyl is monocyclic;

(10l) (10h), (10i) or (10j) above, where heterocycloalkyl is bicyclic;

(10m) any of (10h)-(10l) above, where heterocycloalkyl is saturated;

(10n) R ⁵ is cycloalkyl optionally substituted with 1-5 R ^5E ;

(10o) (10n) above, where cycloalkyl is substituted with 1-5 R ^5E ;

(10p) (10n) or (10o) above, where cycloalkyl is monocyclic;

( 10q) - any of (10n), (10o) or (10p) above, where cycloalkyl is saturated;

In some such embodiments of this invention, each optionally substituted alkyl, alkenyl, and alkynyl R ⁵ (including R ^5D and R ^5E ) is unsubstituted or fluorinated. For example, in some such embodiments of this invention, each optionally substituted alkyl, alkenyl, and alkynyl R ⁵ (including R ^5D and R ^5E ) is unsubstituted.

[29] Various specific embodiments of compounds Nos. 1-1024 for uses in the methods, compounds and uses of this invention include compounds of formula (I), each of which is defined in each of the following rows (or its pharmaceutically acceptable salt or its N- oxide, or solvate, or hydrate), where each entry is a group number as defined above:

I L ¹ R ¹ L ² Q L ³ R ³ L ^four R ^four L ^five R ^five 1 (Ia) - (Id) (1a) (2a) (3c) (4a) (5b) (6a) (7a), (7b) (8a) (9a) (10a) 2 (Ia) - (Id) (1a) (2a) (3c) (4a) (5b) (6a) (7a), (7b) (8a) (9a) (10c) 3 (Ia) - (Id) (1a) (2a) (3c) (4a) (5b) (6a) (7a), (7b) (8a) (9b) (10a) four (Ia) - (Id) (1a) (2a) (3c) (4a) (5b) (6a) (7a), (7b) (8a) (9b) (10c) five (Ia) - (Id) (1a) (2a) (3c) (4a) (5b) (6a) (7d) (8a) (9a) (10a) 6 (Ia) - (Id) (1a) (2a) (3c) (4a) (5b) (6a) (7d) (8a) (9a) (10c) 7 (Ia) - (Id) (1a) (2a) (3c) (4a) (5b) (6a) (7d) (8a) (9b) (10a) 8 (Ia) - (Id) (1a) (2a) (3c) (4a) (5b) (6a) (7d) (8a) (9b) (10c) nine (Ia) - (Id) (1a) (2a) (3c) (4a) (5b) (6k) (7a), (7b) (8a) (9a) (10a) 10 (Ia) - (Id) (1a) (2a) (3c) (4a) (5b) (6k) (7a), (7b) (8a) (9a) (10c) eleven (Ia) - (Id) (1a) (2a) (3c) (4a) (5b) (6k) (7a), (7b) (8a) (9b) (10a) 12 (Ia) - (Id) (1a) (2a) (3c) (4a) (5b) (6k) (7a), (7b) (8a) (9b) (10c) 13 (Ia) - (Id) (1a) (2a) (3c) (4a) (5b) (6k) (7d) (8a) (9a) (10a) fourteen (Ia) - (Id) (1a) (2a) (3c) (4a) (5b) (6k) (7d) (8a) (9a) (10c) 15 (Ia) - (Id) (1a) (2a) (3c) (4a) (5b) (6k) (7d) (8a) (9b) (10a) sixteen (Ia) - (Id) (1a) (2a) (3c) (4a) (5b) (6k) (7d) (8a) (9b) (10c) 17 (Ia) - (Id) (1a) (2a) (3c) (4a) (5a) (6a) (7a), (7b) (8a) (9a) (10a) eighteen (Ia) - (Id) (1a) (2a) (3c) (4a) (5a) (6a) (7a), (7b) (8a) (9a) (10c) nineteen (Ia) - (Id) (1a) (2a) (3c) (4a) (5a) (6a) (7a), (7b) (8a) (9b) (10a) 20 (Ia) - (Id) (1a) (2a) (3c) (4a) (5a) (6a) (7a), (7b) (8a) (9b) (10c) 21 (Ia) - (Id) (1a) (2a) (3c) (4a) (5a) (6a) (7d) (8a) (9a) (10a) 22 (Ia) - (Id) (1a) (2a) (3c) (4a) (5a) (6a) (7d) (8a) (9a) (10c) 23 (Ia) - (Id) (1a) (2a) (3c) (4a) (5a) (6a) (7d) (8a) (9b) (10a) 24 (Ia) - (Id) (1a) (2a) (3c) (4a) (5a) (6a) (7d) (8a) (9b) (10c) 25 (Ia) - (Id) (1a) (2a) (3c) (4a) (5a) (6k) (7a), (7b) (8a) (9a) (10a) 26 (Ia) - (Id) (1a) (2a) (3c) (4a) (5a) (6k) (7a), (7b) (8a) (9a) (10c) 27 (Ia) - (Id) (1a) (2a) (3c) (4a) (5a) (6k) (7a), (7b) (8a) (9b) (10a) 28 (Ia) - (Id) (1a) (2a) (3c) (4a) (5a) (6k) (7a), (7b) (8a) (9b) (10c) 29 (Ia) - (Id) (1a) (2a) (3c) (4a) (5a) (6k) (7d) (8a) (9a) (10a) thirty (Ia) - (Id) (1a) (2a) (3c) (4a) (5a) (6k) (7d) (8a) (9a) (10c) 31 (Ia) - (Id) (1a) (2a) (3c) (4a) (5a) (6k) (7d) (8a) (9b) (10a) 32 (Ia) - (Id) (1a) (2a) (3c) (4a) (5a) (6k) (7d) (8a) (9b) (10c) 33 (Ia) - (Id) (1a) (2a) (3c) (4d) (5b) (6a) (7a), (7b) (8a) (9a) (10a) 34 (Ia) - (Id) (1a) (2a) (3c) (4d) (5b) (6a) (7a), (7b) (8a) (9a) (10c) 35 (Ia) - (Id) (1a) (2a) (3c) (4d) (5b) (6a) (7a), (7b) (8a) (9b) (10a) 36 (Ia) - (Id) (1a) (2a) (3c) (4d) (5b) (6a) (7a), (7b) (8a) (9b) (10c) 37 (Ia) - (Id) (1a) (2a) (3c) (4d) (5b) (6a) (7d) (8a) (9a) (10a) 38 (Ia) - (Id) (1a) (2a) (3c) (4d) (5b) (6a) (7d) (8a) (9a) (10c) 39 (Ia) - (Id) (1a) (2a) (3c) (4d) (5b) (6a) (7d) (8a) (9b) (10a) 40 (Ia) - (Id) (1a) (2a) (3c) (4d) (5b) (6a) (7d) (8a) (9b) (10c) 41 (Ia) - (Id) (1a) (2a) (3c) (4d) (5b) (6k) (7a), (7b) (8a) (9a) (10a) 42 (Ia) - (Id) (1a) (2a) (3c) (4d) (5b) (6k) (7a), (7b) (8a) (9a) (10c) 43 (Ia) - (Id) (1a) (2a) (3c) (4d) (5b) (6k) (7a), (7b) (8a) (9b) (10a) 44 (Ia) - (Id) (1a) (2a) (3c) (4d) (5b) (6k) (7a), (7b) (8a) (9b) (10c) 45 (Ia) - (Id) (1a) (2a) (3c) (4d) (5b) (6k) (7d) (8a) (9a) (10a) 46 (Ia) - (Id) (1a) (2a) (3c) (4d) (5b) (6k) (7d) (8a) (9a) (10c) 47 (Ia) - (Id) (1a) (2a) (3c) (4d) (5b) (6k) (7d) (8a) (9b) (10a) 48 (Ia) - (Id) (1a) (2a) (3c) (4d) (5b) (6k) (7d) (8a) (9b) (10c) 49 (Ia) - (Id) (1a) (2a) (3c) (4d) (5a) (6a) (7a), (7b) (8a) (9a) (10a) 50 (Ia) - (Id) (1a) (2a) (3c) (4d) (5a) (6a) (7a), (7b) (8a) (9a) (10c) 51 (Ia) - (Id) (1a) (2a) (3c) (4d) (5a) (6a) (7a), (7b) (8a) (9b) (10a) 52 (Ia) - (Id) (1a) (2a) (3c) (4d) (5a) (6a) (7a), (7b) (8a) (9b) (10c) 53 (Ia) - (Id) (1a) (2a) (3c) (4d) (5a) (6a) (7d) (8a) (9a) (10a) 54 (Ia) - (Id) (1a) (2a) (3c) (4d) (5a) (6a) (7d) (8a) (9a) (10c) 55 (Ia) - (Id) (1a) (2a) (3c) (4d) (5a) (6a) (7d) (8a) (9b) (10a) 56 (Ia) - (Id) (1a) (2a) (3c) (4d) (5a) (6a) (7d) (8a) (9b) (10c) 57 (Ia) - (Id) (1a) (2a) (3c) (4d) (5a) (6k) (7a), (7b) (8a) (9a) (10a) 58 (Ia) - (Id) (1a) (2a) (3c) (4d) (5a) (6k) (7a), (7b) (8a) (9a) (10c) 59 (Ia) - (Id) (1a) (2a) (3c) (4d) (5a) (6k) (7a), (7b) (8a) (9b) (10a) 60 (Ia) - (Id) (1a) (2a) (3c) (4d) (5a) (6k) (7a), (7b) (8a) (9b) (10c) 61 (Ia) - (Id) (1a) (2a) (3c) (4d) (5a) (6k) (7d) (8a) (9a) (10a) 62 (Ia) - (Id) (1a) (2a) (3c) (4d) (5a) (6k) (7d) (8a) (9a) (10c) 63 (Ia) - (Id) (1a) (2a) (3c) (4d) (5a) (6k) (7d) (8a) (9b) (10a) 64 (Ia) - (Id) (1a) (2a) (3c) (4d) (5a) (6k) (7d) (8a) (9b) (10c) 65 (Ia) - (Id) (1a) (2a) (3b) (4a) (5b) (6a) (7a), (7b) (8a) (9a) (10a) 66 (Ia) - (Id) (1a) (2a) (3b) (4a) (5b) (6a) (7a), (7b) (8a) (9a) (10c) 67 (Ia) - (Id) (1a) (2a) (3b) (4a) (5b) (6a) (7a), (7b) (8a) (9b) (10a) 68 (Ia) - (Id) (1a) (2a) (3b) (4a) (5b) (6a) (7a), (7b) (8a) (9b) (10c) 69 (Ia) - (Id) (1a) (2a) (3b) (4a) (5b) (6a) (7d) (8a) (9a) (10a) 70 (Ia) - (Id) (1a) (2a) (3b) (4a) (5b) (6a) (7d) (8a) (9a) (10c) 71 (Ia) - (Id) (1a) (2a) (3b) (4a) (5b) (6a) (7d) (8a) (9b) (10a) 72 (Ia) - (Id) (1a) (2a) (3b) (4a) (5b) (6a) (7d) (8a) (9b) (10c) 73 (Ia) - (Id) (1a) (2a) (3b) (4a) (5b) (6k) (7a), (7b) (8a) (9a) (10a) 74 (Ia) - (Id) (1a) (2a) (3b) (4a) (5b) (6k) (7a), (7b) (8a) (9a) (10c) 75 (Ia) - (Id) (1a) (2a) (3b) (4a) (5b) (6k) (7a), (7b) (8a) (9b) (10a) 76 (Ia) - (Id) (1a) (2a) (3b) (4a) (5b) (6k) (7a), (7b) (8a) (9b) (10c) 77 (Ia) - (Id) (1a) (2a) (3b) (4a) (5b) (6k) (7d) (8a) (9a) (10a) 78 (Ia) - (Id) (1a) (2a) (3b) (4a) (5b) (6k) (7d) (8a) (9a) (10c) 79 (Ia) - (Id) (1a) (2a) (3b) (4a) (5b) (6k) (7d) (8a) (9b) (10a) 80 (Ia) - (Id) (1a) (2a) (3b) (4a) (5b) (6k) (7d) (8a) (9b) (10c) 81 (Ia) - (Id) (1a) (2a) (3b) (4a) (5a) (6a) (7a), (7b) (8a) (9a) (10a) 82 (Ia) - (Id) (1a) (2a) (3b) (4a) (5a) (6a) (7a), (7b) (8a) (9a) (10c) 83 (Ia) - (Id) (1a) (2a) (3b) (4a) (5a) (6a) (7a), (7b) (8a) (9b) (10a) 84 (Ia) - (Id) (1a) (2a) (3b) (4a) (5a) (6a) (7a), (7b) (8a) (9b) (10c) 85 (Ia) - (Id) (1a) (2a) (3b) (4a) (5a) (6a) (7d) (8a) (9a) (10a) 86 (Ia) - (Id) (1a) (2a) (3b) (4a) (5a) (6a) (7d) (8a) (9a) (10c) 87 (Ia) - (Id) (1a) (2a) (3b) (4a) (5a) (6a) (7d) (8a) (9b) (10a) 88 (Ia) - (Id) (1a) (2a) (3b) (4a) (5a) (6a) (7d) (8a) (9b) (10c) 89 (Ia) - (Id) (1a) (2a) (3b) (4a) (5a) (6k) (7a), (7b) (8a) (9a) (10a) 90 (Ia) - (Id) (1a) (2a) (3b) (4a) (5a) (6k) (7a), (7b) (8a) (9a) (10c) 91 (Ia) - (Id) (1a) (2a) (3b) (4a) (5a) (6k) (7a), (7b) (8a) (9b) (10a) 92 (Ia) - (Id) (1a) (2a) (3b) (4a) (5a) (6k) (7a), (7b) (8a) (9b) (10c) 93 (Ia) - (Id) (1a) (2a) (3b) (4a) (5a) (6k) (7d) (8a) (9a) (10a) 94 (Ia) - (Id) (1a) (2a) (3b) (4a) (5a) (6k) (7d) (8a) (9a) (10c) 95 (Ia) - (Id) (1a) (2a) (3b) (4a) (5a) (6k) (7d) (8a) (9b) (10a) 96 (Ia) - (Id) (1a) (2a) (3b) (4a) (5a) (6k) (7d) (8a) (9b) (10c) 97 (Ia) - (Id) (1a) (2a) (3b) (4d) (5b) (6a) (7a), (7b) (8a) (9a) (10a) 98 (Ia) - (Id) (1a) (2a) (3b) (4d) (5b) (6a) (7a), (7b) (8a) (9a) (10c) 99 (Ia) - (Id) (1a) (2a) (3b) (4d) (5b) (6a) (7a), (7b) (8a) (9b) (10a) one hundred (Ia) - (Id) (1a) (2a) (3b) (4d) (5b) (6a) (7a), (7b) (8a) (9b) (10c) 101 (Ia) - (Id) (1a) (2a) (3b) (4d) (5b) (6a) (7d) (8a) (9a) (10a) 102 (Ia) - (Id) (1a) (2a) (3b) (4d) (5b) (6a) (7d) (8a) (9a) (10c) 103 (Ia) - (Id) (1a) (2a) (3b) (4d) (5b) (6a) (7d) (8a) (9b) (10a) 104 (Ia) - (Id) (1a) (2a) (3b) (4d) (5b) (6a) (7d) (8a) (9b) (10c) 105 (Ia) - (Id) (1a) (2a) (3b) (4d) (5b) (6k) (7a), (7b) (8a) (9a) (10a) 106 (Ia) - (Id) (1a) (2a) (3b) (4d) (5b) (6k) (7a), (7b) (8a) (9a) (10c) 107 (Ia) - (Id) (1a) (2a) (3b) (4d) (5b) (6k) (7a), (7b) (8a) (9b) (10a) 108 (Ia) - (Id) (1a) (2a) (3b) (4d) (5b) (6k) (7a), (7b) (8a) (9b) (10c) 109 (Ia) - (Id) (1a) (2a) (3b) (4d) (5b) (6k) (7d) (8a) (9a) (10a) 110 (Ia) - (Id) (1a) (2a) (3b) (4d) (5b) (6k) (7d) (8a) (9a) (10c) 111 (Ia) - (Id) (1a) (2a) (3b) (4d) (5b) (6k) (7d) (8a) (9b) (10a) 112 (Ia) - (Id) (1a) (2a) (3b) (4d) (5b) (6k) (7d) (8a) (9b) (10c) 113 (Ia) - (Id) (1a) (2a) (3b) (4d) (5a) (6a) (7a), (7b) (8a) (9a) (10a) 114 (Ia) - (Id) (1a) (2a) (3b) (4d) (5a) (6a) (7a), (7b) (8a) (9a) (10c) 115 (Ia) - (Id) (1a) (2a) (3b) (4d) (5a) (6a) (7a), (7b) (8a) (9b) (10a) 116 (Ia) - (Id) (1a) (2a) (3b) (4d) (5a) (6a) (7a), (7b) (8a) (9b) (10c) 117 (Ia) - (Id) (1a) (2a) (3b) (4d) (5a) (6a) (7d) (8a) (9a) (10a) 118 (Ia) - (Id) (1a) (2a) (3b) (4d) (5a) (6a) (7d) (8a) (9a) (10c) 119 (Ia) - (Id) (1a) (2a) (3b) (4d) (5a) (6a) (7d) (8a) (9b) (10a) 120 (Ia) - (Id) (1a) (2a) (3b) (4d) (5a) (6a) (7d) (8a) (9b) (10c) 121 (Ia) - (Id) (1a) (2a) (3b) (4d) (5a) (6k) (7a), (7b) (8a) (9a) (10a) 122 (Ia) - (Id) (1a) (2a) (3b) (4d) (5a) (6k) (7a), (7b) (8a) (9a) (10c) 123 (Ia) - (Id) (1a) (2a) (3b) (4d) (5a) (6k) (7a), (7b) (8a) (9b) (10a) 124 (Ia) - (Id) (1a) (2a) (3b) (4d) (5a) (6k) (7a), (7b) (8a) (9b) (10c) 125 (Ia) - (Id) (1a) (2a) (3b) (4d) (5a) (6k) (7d) (8a) (9a) (10a) 126 (Ia) - (Id) (1a) (2a) (3b) (4d) (5a) (6k) (7d) (8a) (9a) (10c) 127 (Ia) - (Id) (1a) (2a) (3b) (4d) (5a) (6k) (7d) (8a) (9b) (10a) 128 (Ia) - (Id) (1a) (2a) (3b) (4d) (5a) (6k) (7d) (8a) (9b) (10c) 129 (Ia) - (Id) (1a) (2b) (3c) (4a) (5b) (6a) (7a), (7b) (8a) (9a) (10a) 130 (Ia) - (Id) (1a) (2b) (3c) (4a) (5b) (6a) (7a), (7b) (8a) (9a) (10c) 131 (Ia) - (Id) (1a) (2b) (3c) (4a) (5b) (6a) (7a), (7b) (8a) (9b) (10a) 132 (Ia) - (Id) (1a) (2b) (3c) (4a) (5b) (6a) (7a), (7b) (8a) (9b) (10c) 133 (Ia) - (Id) (1a) (2b) (3c) (4a) (5b) (6a) (7d) (8a) (9a) (10a) 134 (Ia) - (Id) (1a) (2b) (3c) (4a) (5b) (6a) (7d) (8a) (9a) (10c) 135 (Ia) - (Id) (1a) (2b) (3c) (4a) (5b) (6a) (7d) (8a) (9b) (10a) 136 (Ia) - (Id) (1a) (2b) (3c) (4a) (5b) (6a) (7d) (8a) (9b) (10c) 137 (Ia) - (Id) (1a) (2b) (3c) (4a) (5b) (6k) (7a), (7b) (8a) (9a) (10a) 138 (Ia) - (Id) (1a) (2b) (3c) (4a) (5b) (6k) (7a), (7b) (8a) (9a) (10c) 139 (Ia) - (Id) (1a) (2b) (3c) (4a) (5b) (6k) (7a), (7b) (8a) (9b) (10a) 140 (Ia) - (Id) (1a) (2b) (3c) (4a) (5b) (6k) (7a), (7b) (8a) (9b) (10c) 141 (Ia) - (Id) (1a) (2b) (3c) (4a) (5b) (6k) (7d) (8a) (9a) (10a) 142 (Ia) - (Id) (1a) (2b) (3c) (4a) (5b) (6k) (7d) (8a) (9a) (10c) 143 (Ia) - (Id) (1a) (2b) (3c) (4a) (5b) (6k) (7d) (8a) (9b) (10a) 144 (Ia) - (Id) (1a) (2b) (3c) (4a) (5b) (6k) (7d) (8a) (9b) (10c) 145 (Ia) - (Id) (1a) (2b) (3c) (4a) (5a) (6a) (7a), (7b) (8a) (9a) (10a) 146 (Ia) - (Id) (1a) (2b) (3c) (4a) (5a) (6a) (7a), (7b) (8a) (9a) (10c) 147 (Ia) - (Id) (1a) (2b) (3c) (4a) (5a) (6a) (7a), (7b) (8a) (9b) (10a) 148 (Ia) - (Id) (1a) (2b) (3c) (4a) (5a) (6a) (7a), (7b) (8a) (9b) (10c) 149 (Ia) - (Id) (1a) (2b) (3c) (4a) (5a) (6a) (7d) (8a) (9a) (10a) 150 (Ia) - (Id) (1a) (2b) (3c) (4a) (5a) (6a) (7d) (8a) (9a) (10c) 151 (Ia) - (Id) (1a) (2b) (3c) (4a) (5a) (6a) (7d) (8a) (9b) (10a) 152 (Ia) - (Id) (1a) (2b) (3c) (4a) (5a) (6a) (7d) (8a) (9b) (10c) 153 (Ia) - (Id) (1a) (2b) (3c) (4a) (5a) (6k) (7a), (7b) (8a) (9a) (10a) 154 (Ia) - (Id) (1a) (2b) (3c) (4a) (5a) (6k) (7a), (7b) (8a) (9a) (10c) 155 (Ia) - (Id) (1a) (2b) (3c) (4a) (5a) (6k) (7a), (7b) (8a) (9b) (10a) 156 (Ia) - (Id) (1a) (2b) (3c) (4a) (5a) (6k) (7a), (7b) (8a) (9b) (10c) 157 (Ia) - (Id) (1a) (2b) (3c) (4a) (5a) (6k) (7d) (8a) (9a) (10a) 158 (Ia) - (Id) (1a) (2b) (3c) (4a) (5a) (6k) (7d) (8a) (9a) (10c) 159 (Ia) - (Id) (1a) (2b) (3c) (4a) (5a) (6k) (7d) (8a) (9b) (10a) 160 (Ia) - (Id) (1a) (2b) (3c) (4a) (5a) (6k) (7d) (8a) (9b) (10c) 161 (Ia) - (Id) (1a) (2b) (3c) (4d) (5b) (6a) (7a), (7b) (8a) (9a) (10a) 162 (Ia) - (Id) (1a) (2b) (3c) (4d) (5b) (6a) (7a), (7b) (8a) (9a) (10c) 163 (Ia) - (Id) (1a) (2b) (3c) (4d) (5b) (6a) (7a), (7b) (8a) (9b) (10a) 164 (Ia) - (Id) (1a) (2b) (3c) (4d) (5b) (6a) (7a), (7b) (8a) (9b) (10c) 165 (Ia) - (Id) (1a) (2b) (3c) (4d) (5b) (6a) (7d) (8a) (9a) (10a) 166 (Ia) - (Id) (1a) (2b) (3c) (4d) (5b) (6a) (7d) (8a) (9a) (10c) 167 (Ia) - (Id) (1a) (2b) (3c) (4d) (5b) (6a) (7d) (8a) (9b) (10a) 168 (Ia) - (Id) (1a) (2b) (3c) (4d) (5b) (6a) (7d) (8a) (9b) (10c) 169 (Ia) - (Id) (1a) (2b) (3c) (4d) (5b) (6k) (7a), (7b) (8a) (9a) (10a) 170 (Ia) - (Id) (1a) (2b) (3c) (4d) (5b) (6k) (7a), (7b) (8a) (9a) (10c) 171 (Ia) - (Id) (1a) (2b) (3c) (4d) (5b) (6k) (7a), (7b) (8a) (9b) (10a) 172 (Ia) - (Id) (1a) (2b) (3c) (4d) (5b) (6k) (7a), (7b) (8a) (9b) (10c) 173 (Ia) - (Id) (1a) (2b) (3c) (4d) (5b) (6k) (7d) (8a) (9a) (10a) 174 (Ia) - (Id) (1a) (2b) (3c) (4d) (5b) (6k) (7d) (8a) (9a) (10c) 175 (Ia) - (Id) (1a) (2b) (3c) (4d) (5b) (6k) (7d) (8a) (9b) (10a) 176 (Ia) - (Id) (1a) (2b) (3c) (4d) (5b) (6k) (7d) (8a) (9b) (10c) 177 (Ia) - (Id) (1a) (2b) (3c) (4d) (5a) (6a) (7a), (7b) (8a) (9a) (10a) 178 (Ia) - (Id) (1a) (2b) (3c) (4d) (5a) (6a) (7a), (7b) (8a) (9a) (10c) 179 (Ia) - (Id) (1a) (2b) (3c) (4d) (5a) (6a) (7a), (7b) (8a) (9b) (10a) 180 (Ia) - (Id) (1a) (2b) (3c) (4d) (5a) (6a) (7a), (7b) (8a) (9b) (10c) 181 (Ia) - (Id) (1a) (2b) (3c) (4d) (5a) (6a) (7d) (8a) (9a) (10a) 182 (Ia) - (Id) (1a) (2b) (3c) (4d) (5a) (6a) (7d) (8a) (9a) (10c) 183 (Ia) - (Id) (1a) (2b) (3c) (4d) (5a) (6a) (7d) (8a) (9b) (10a) 184 (Ia) - (Id) (1a) (2b) (3c) (4d) (5a) (6a) (7d) (8a) (9b) (10c) 185 (Ia) - (Id) (1a) (2b) (3c) (4d) (5a) (6k) (7a), (7b) (8a) (9a) (10a) 186 (Ia) - (Id) (1a) (2b) (3c) (4d) (5a) (6k) (7a), (7b) (8a) (9a) (10c) 187 (Ia) - (Id) (1a) (2b) (3c) (4d) (5a) (6k) (7a), (7b) (8a) (9b) (10a) 188 (Ia) - (Id) (1a) (2b) (3c) (4d) (5a) (6k) (7a), (7b) (8a) (9b) (10c) 189 (Ia) - (Id) (1a) (2b) (3c) (4d) (5a) (6k) (7d) (8a) (9a) (10a) 190 (Ia) - (Id) (1a) (2b) (3c) (4d) (5a) (6k) (7d) (8a) (9a) (10c) 191 (Ia) - (Id) (1a) (2b) (3c) (4d) (5a) (6k) (7d) (8a) (9b) (10a) 192 (Ia) - (Id) (1a) (2b) (3c) (4d) (5a) (6k) (7d) (8a) (9b) (10c) 193 (Ia) - (Id) (1a) (2b) (3b) (4a) (5b) (6a) (7a), (7b) (8a) (9a) (10a) 194 (Ia) - (Id) (1a) (2b) (3b) (4a) (5b) (6a) (7a), (7b) (8a) (9a) (10c) 195 (Ia) - (Id) (1a) (2b) (3b) (4a) (5b) (6a) (7a), (7b) (8a) (9b) (10a) 196 (Ia) - (Id) (1a) (2b) (3b) (4a) (5b) (6a) (7a), (7b) (8a) (9b) (10c) 197 (Ia) - (Id) (1a) (2b) (3b) (4a) (5b) (6a) (7d) (8a) (9a) (10a) 198 (Ia) - (Id) (1a) (2b) (3b) (4a) (5b) (6a) (7d) (8a) (9a) (10c) 199 (Ia) - (Id) (1a) (2b) (3b) (4a) (5b) (6a) (7d) (8a) (9b) (10a) 200 (Ia) - (Id) (1a) (2b) (3b) (4a) (5b) (6a) (7d) (8a) (9b) (10c) 201 (Ia) - (Id) (1a) (2b) (3b) (4a) (5b) (6k) (7a), (7b) (8a) (9a) (10a) 202 (Ia) - (Id) (1a) (2b) (3b) (4a) (5b) (6k) (7a), (7b) (8a) (9a) (10c) 203 (Ia) - (Id) (1a) (2b) (3b) (4a) (5b) (6k) (7a), (7b) (8a) (9b) (10a) 204 (Ia) - (Id) (1a) (2b) (3b) (4a) (5b) (6k) (7a), (7b) (8a) (9b) (10c) 205 (Ia) - (Id) (1a) (2b) (3b) (4a) (5b) (6k) (7d) (8a) (9a) (10a) 206 (Ia) - (Id) (1a) (2b) (3b) (4a) (5b) (6k) (7d) (8a) (9a) (10c) 207 (Ia) - (Id) (1a) (2b) (3b) (4a) (5b) (6k) (7d) (8a) (9b) (10a) 208 (Ia) - (Id) (1a) (2b) (3b) (4a) (5b) (6k) (7d) (8a) (9b) (10c) 209 (Ia) - (Id) (1a) (2b) (3b) (4a) (5a) (6a) (7a), (7b) (8a) (9a) (10a) 210 (Ia) - (Id) (1a) (2b) (3b) (4a) (5a) (6a) (7a), (7b) (8a) (9a) (10c) 211 (Ia) - (Id) (1a) (2b) (3b) (4a) (5a) (6a) (7a), (7b) (8a) (9b) (10a) 212 (Ia) - (Id) (1a) (2b) (3b) (4a) (5a) (6a) (7a), (7b) (8a) (9b) (10c) 213 (Ia) - (Id) (1a) (2b) (3b) (4a) (5a) (6a) (7d) (8a) (9a) (10a) 214 (Ia) - (Id) (1a) (2b) (3b) (4a) (5a) (6a) (7d) (8a) (9a) (10c) 215 (Ia) - (Id) (1a) (2b) (3b) (4a) (5a) (6a) (7d) (8a) (9b) (10a) 216 (Ia) - (Id) (1a) (2b) (3b) (4a) (5a) (6a) (7d) (8a) (9b) (10c) 217 (Ia) - (Id) (1a) (2b) (3b) (4a) (5a) (6k) (7a), (7b) (8a) (9a) (10a) 218 (Ia) - (Id) (1a) (2b) (3b) (4a) (5a) (6k) (7a), (7b) (8a) (9a) (10c) 219 (Ia) - (Id) (1a) (2b) (3b) (4a) (5a) (6k) (7a), (7b) (8a) (9b) (10a) 220 (Ia) - (Id) (1a) (2b) (3b) (4a) (5a) (6k) (7a), (7b) (8a) (9b) (10c) 221 (Ia) - (Id) (1a) (2b) (3b) (4a) (5a) (6k) (7d) (8a) (9a) (10a) 222 (Ia) - (Id) (1a) (2b) (3b) (4a) (5a) (6k) (7d) (8a) (9a) (10c) 223 (Ia) - (Id) (1a) (2b) (3b) (4a) (5a) (6k) (7d) (8a) (9b) (10a) 224 (Ia) - (Id) (1a) (2b) (3b) (4a) (5a) (6k) (7d) (8a) (9b) (10c) 225 (Ia) - (Id) (1a) (2b) (3b) (4d) (5b) (6a) (7a), (7b) (8a) (9a) (10a) 226 (Ia) - (Id) (1a) (2b) (3b) (4d) (5b) (6a) (7a), (7b) (8a) (9a) (10c) 227 (Ia) - (Id) (1a) (2b) (3b) (4d) (5b) (6a) (7a), (7b) (8a) (9b) (10a) 228 (Ia) - (Id) (1a) (2b) (3b) (4d) (5b) (6a) (7a), (7b) (8a) (9b) (10c) 229 (Ia) - (Id) (1a) (2b) (3b) (4d) (5b) (6a) (7d) (8a) (9a) (10a) 230 (Ia) - (Id) (1a) (2b) (3b) (4d) (5b) (6a) (7d) (8a) (9a) (10c) 231 (Ia) - (Id) (1a) (2b) (3b) (4d) (5b) (6a) (7d) (8a) (9b) (10a) 232 (Ia) - (Id) (1a) (2b) (3b) (4d) (5b) (6a) (7d) (8a) (9b) (10c) 233 (Ia) - (Id) (1a) (2b) (3b) (4d) (5b) (6k) (7a), (7b) (8a) (9a) (10a) 234 (Ia) - (Id) (1a) (2b) (3b) (4d) (5b) (6k) (7a), (7b) (8a) (9a) (10c) 235 (Ia) - (Id) (1a) (2b) (3b) (4d) (5b) (6k) (7a), (7b) (8a) (9b) (10a) 236 (Ia) - (Id) (1a) (2b) (3b) (4d) (5b) (6k) (7a), (7b) (8a) (9b) (10c) 237 (Ia) - (Id) (1a) (2b) (3b) (4d) (5b) (6k) (7d) (8a) (9a) (10a) 238 (Ia) - (Id) (1a) (2b) (3b) (4d) (5b) (6k) (7d) (8a) (9a) (10c) 239 (Ia) - (Id) (1a) (2b) (3b) (4d) (5b) (6k) (7d) (8a) (9b) (10a) 240 (Ia) - (Id) (1a) (2b) (3b) (4d) (5b) (6k) (7d) (8a) (9b) (10c) 241 (Ia) - (Id) (1a) (2b) (3b) (4d) (5a) (6a) (7a), (7b) (8a) (9a) (10a) 242 (Ia) - (Id) (1a) (2b) (3b) (4d) (5a) (6a) (7a), (7b) (8a) (9a) (10c) 243 (Ia) - (Id) (1a) (2b) (3b) (4d) (5a) 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(Id) (1d) (2a) (3c) (4a) (5b) (6k) (7d) (8a) (9b) (10c) 273 (Ia) - (Id) (1d) (2a) (3c) (4a) (5a) (6a) (7a), (7b) (8a) (9a) (10a) 274 (Ia) - (Id) (1d) (2a) (3c) (4a) (5a) (6a) (7a), (7b) (8a) (9a) (10c) 275 (Ia) - (Id) (1d) (2a) (3c) (4a) (5a) (6a) (7a), (7b) (8a) (9b) (10a) 276 (Ia) - (Id) (1d) (2a) (3c) (4a) (5a) (6a) (7a), (7b) (8a) (9b) (10c) 277 (Ia) - (Id) (1d) (2a) (3c) (4a) (5a) (6a) (7d) (8a) (9a) (10a) 278 (Ia) - (Id) (1d) (2a) (3c) (4a) (5a) (6a) (7d) (8a) (9a) (10c) 279 (Ia) - (Id) (1d) (2a) (3c) (4a) (5a) (6a) (7d) (8a) (9b) (10a) 280 (Ia) - (Id) (1d) (2a) (3c) (4a) (5a) (6a) (7d) (8a) (9b) (10c) 281 (Ia) - (Id) (1d) (2a) (3c) (4a) (5a) (6k) (7a), (7b) (8a) (9a) (10a) 282 (Ia) - (Id) (1d) (2a) (3c) (4a) (5a) (6k) (7a), (7b) (8a) (9a) (10c) 283 (Ia) - (Id) (1d) (2a) (3c) (4a) (5a) (6k) (7a), (7b) (8a) (9b) (10a) 284 (Ia) - (Id) (1d) (2a) (3c) (4a) (5a) (6k) (7a), (7b) (8a) (9b) (10c) 285 (Ia) - (Id) (1d) (2a) (3c) (4a) (5a) (6k) (7d) (8a) (9a) (10a) 286 (Ia) - (Id) (1d) (2a) 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315 (Ia) - (Id) (1d) (2a) (3c) (4d) (5a) (6k) (7a), (7b) (8a) (9b) (10a) 316 (Ia) - (Id) (1d) (2a) (3c) (4d) (5a) (6k) (7a), (7b) (8a) (9b) (10c) 317 (Ia) - (Id) (1d) (2a) (3c) (4d) (5a) (6k) (7d) (8a) (9a) (10a) 318 (Ia) - (Id) (1d) (2a) (3c) (4d) (5a) (6k) (7d) (8a) (9a) (10c) 319 (Ia) - (Id) (1d) (2a) (3c) (4d) (5a) (6k) (7d) (8a) (9b) (10a) 320 (Ia) - (Id) (1d) (2a) (3c) (4d) (5a) (6k) (7d) (8a) (9b) (10c) 321 (Ia) - (Id) (1d) (2a) (3b) (4a) (5b) (6a) (7a), (7b) (8a) (9a) (10a) 322 (Ia) - (Id) (1d) (2a) (3b) (4a) (5b) (6a) (7a), (7b) (8a) (9a) (10c) 323 (Ia) - (Id) (1d) (2a) (3b) (4a) (5b) (6a) (7a), (7b) (8a) (9b) (10a) 324 (Ia) - (Id) (1d) (2a) (3b) (4a) (5b) (6a) (7a), (7b) (8a) (9b) (10c) 325 (Ia) - (Id) (1d) (2a) (3b) (4a) (5b) (6a) (7d) (8a) (9a) (10a) 326 (Ia) - (Id) (1d) (2a) (3b) (4a) (5b) (6a) (7d) (8a) (9a) (10c) 327 (Ia) - (Id) (1d) (2a) (3b) (4a) (5b) (6a) (7d) (8a) (9b) (10a) 328 (Ia) - (Id) (1d) (2a) (3b) (4a) (5b) (6a) (7d) (8a) (9b) (10c) 329 (Ia) - (Id) (1d) (2a) 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(6a) (7d) (8a) (9b) (10a) 344 (Ia) - (Id) (1d) (2a) (3b) (4a) (5a) (6a) (7d) (8a) (9b) (10c) 345 (Ia) - (Id) (1d) (2a) (3b) (4a) (5a) (6k) (7a), (7b) (8a) (9a) (10a) 346 (Ia) - (Id) (1d) (2a) (3b) (4a) (5a) (6k) (7a), (7b) (8a) (9a) (10c) 347 (Ia) - (Id) (1d) (2a) (3b) (4a) (5a) (6k) (7a), (7b) (8a) (9b) (10a) 348 (Ia) - (Id) (1d) (2a) (3b) (4a) (5a) (6k) (7a), (7b) (8a) (9b) (10c) 349 (Ia) - (Id) (1d) (2a) (3b) (4a) (5a) (6k) (7d) (8a) (9a) (10a) 350 (Ia) - (Id) (1d) (2a) (3b) (4a) (5a) (6k) (7d) (8a) (9a) (10c) 351 (Ia) - (Id) (1d) (2a) (3b) (4a) (5a) (6k) (7d) (8a) (9b) (10a) 352 (Ia) - (Id) (1d) (2a) (3b) (4a) (5a) (6k) (7d) (8a) (9b) (10c) 353 (Ia) - (Id) (1d) (2a) (3b) (4d) (5b) (6a) (7a), (7b) (8a) (9a) (10a) 354 (Ia) - (Id) (1d) (2a) (3b) (4d) (5b) (6a) (7a), (7b) (8a) (9a) (10c) 355 (Ia) - (Id) (1d) (2a) (3b) (4d) (5b) (6a) (7a), (7b) (8a) (9b) (10a) 356 (Ia) - (Id) (1d) (2a) (3b) (4d) (5b) (6a) (7a), (7b) (8a) (9b) (10c) 357 (Ia) - (Id) (1d) (2a) (3b) (4d) (5b) (6a) (7d) (8a) (9a) (10a) 358 (Ia) - (Id) (1d) (2a) (3b) (4d) (5b) (6a) (7d) (8a) (9a) (10c) 359 (Ia) - (Id) (1d) (2a) (3b) (4d) (5b) (6a) (7d) (8a) (9b) (10a) 360 (Ia) - (Id) (1d) (2a) (3b) (4d) (5b) (6a) (7d) (8a) (9b) (10c) 361 (Ia) - (Id) (1d) (2a) (3b) (4d) (5b) (6k) (7a), (7b) (8a) (9a) (10a) 362 (Ia) - (Id) (1d) (2a) (3b) (4d) (5b) (6k) (7a), (7b) (8a) (9a) (10c) 363 (Ia) - (Id) (1d) (2a) (3b) (4d) (5b) (6k) (7a), (7b) (8a) (9b) (10a) 364 (Ia) - (Id) (1d) (2a) (3b) (4d) (5b) (6k) (7a), (7b) (8a) (9b) (10c) 365 (Ia) - (Id) (1d) (2a) (3b) (4d) (5b) (6k) (7d) (8a) (9a) (10a) 366 (Ia) - (Id) (1d) (2a) (3b) (4d) (5b) (6k) (7d) (8a) (9a) (10c) 367 (Ia) - (Id) (1d) (2a) (3b) (4d) (5b) (6k) (7d) (8a) (9b) (10a) 368 (Ia) - (Id) (1d) (2a) (3b) (4d) (5b) (6k) (7d) (8a) (9b) (10c) 369 (Ia) - (Id) (1d) (2a) (3b) (4d) (5a) (6a) (7a), (7b) (8a) (9a) (10a) 370 (Ia) - (Id) (1d) (2a) (3b) (4d) (5a) (6a) (7a), (7b) (8a) (9a) (10c) 371 (Ia) - (Id) (1d) (2a) (3b) (4d) (5a) (6a) (7a), (7b) (8a) (9b) (10a) 372 (Ia) - (Id) (1d) (2a) (3b) (4d) (5a) (6a) (7a), (7b) (8a) (9b) (10c) 373 (Ia) - (Id) (1d) (2a) (3b) (4d) (5a) (6a) (7d) (8a) (9a) (10a) 374 (Ia) - (Id) (1d) (2a) (3b) (4d) (5a) (6a) (7d) (8a) (9a) (10c) 375 (Ia) - (Id) (1d) (2a) (3b) (4d) (5a) (6a) (7d) (8a) (9b) (10a) 376 (Ia) - (Id) (1d) (2a) (3b) (4d) (5a) (6a) (7d) (8a) (9b) (10c) 377 (Ia) - (Id) (1d) (2a) (3b) (4d) (5a) (6k) (7a), (7b) (8a) (9a) (10a) 378 (Ia) - (Id) (1d) (2a) (3b) (4d) (5a) (6k) (7a), (7b) (8a) (9a) (10c) 379 (Ia) - (Id) (1d) (2a) (3b) (4d) (5a) (6k) (7a), (7b) (8a) (9b) (10a) 380 (Ia) - (Id) (1d) (2a) (3b) (4d) (5a) (6k) (7a), (7b) (8a) (9b) (10c) 381 (Ia) - (Id) (1d) (2a) (3b) (4d) (5a) (6k) (7d) (8a) (9a) (10a) 382 (Ia) - (Id) (1d) (2a) (3b) (4d) (5a) (6k) (7d) (8a) (9a) (10c) 383 (Ia) - (Id) (1d) (2a) (3b) (4d) (5a) (6k) (7d) (8a) (9b) (10a) 384 (Ia) - (Id) (1d) (2a) (3b) (4d) (5a) (6k) (7d) (8a) (9b) (10c) 385 (Ia) - (Id) (1d) (2b) (3c) (4a) (5b) (6a) (7a), (7b) (8a) (9a) (10a) 386 (Ia) - (Id) (1d) (2b) (3c) (4a) (5b) (6a) (7a), (7b) (8a) (9a) (10c) 387 (Ia) - (Id) (1d) (2b) (3c) (4a) (5b) (6a) (7a), (7b) (8a) (9b) (10a) 388 (Ia) - (Id) (1d) (2b) (3c) (4a) (5b) (6a) (7a), (7b) (8a) (9b) (10c) 389 (Ia) - (Id) (1d) (2b) (3c) (4a) (5b) (6a) (7d) (8a) (9a) (10a) 390 (Ia) - (Id) (1d) (2b) (3c) (4a) (5b) (6a) (7d) (8a) (9a) (10c) 391 (Ia) - (Id) (1d) (2b) (3c) (4a) (5b) (6a) (7d) (8a) (9b) (10a) 392 (Ia) - (Id) (1d) (2b) (3c) (4a) (5b) (6a) (7d) (8a) (9b) (10c) 393 (Ia) - (Id) (1d) (2b) (3c) (4a) (5b) (6k) (7a), (7b) (8a) (9a) (10a) 394 (Ia) - (Id) (1d) (2b) (3c) (4a) (5b) (6k) (7a), (7b) (8a) (9a) (10c) 395 (Ia) - (Id) (1d) (2b) (3c) (4a) (5b) (6k) (7a), (7b) (8a) (9b) (10a) 396 (Ia) - (Id) (1d) (2b) (3c) (4a) (5b) (6k) (7a), (7b) (8a) (9b) (10c) 397 (Ia) - (Id) (1d) (2b) (3c) (4a) (5b) (6k) (7d) (8a) (9a) (10a) 398 (Ia) - (Id) (1d) (2b) (3c) (4a) (5b) (6k) (7d) (8a) (9a) (10c) 399 (Ia) - (Id) (1d) (2b) (3c) (4a) (5b) (6k) (7d) (8a) (9b) (10a) 400 (Ia) - (Id) (1d) (2b) (3c) (4a) (5b) (6k) (7d) (8a) (9b) (10c) 401 (Ia) - (Id) (1d) (2b) (3c) (4a) (5a) (6a) (7a), (7b) (8a) (9a) (10a) 402 (Ia) - (Id) (1d) (2b) (3c) (4a) (5a) (6a) (7a), (7b) (8a) (9a) (10c) 403 (Ia) - (Id) (1d) (2b) (3c) (4a) (5a) (6a) (7a), (7b) (8a) (9b) (10a) 404 (Ia) - (Id) (1d) (2b) (3c) (4a) (5a) (6a) (7a), (7b) (8a) (9b) (10c) 405 (Ia) - (Id) (1d) (2b) (3c) (4a) (5a) (6a) (7d) (8a) (9a) (10a) 406 (Ia) - (Id) (1d) (2b) (3c) (4a) (5a) (6a) (7d) (8a) (9a) (10c) 407 (Ia) - (Id) (1d) (2b) (3c) (4a) (5a) (6a) (7d) (8a) (9b) (10a) 408 (Ia) - (Id) (1d) (2b) (3c) (4a) (5a) (6a) (7d) (8a) (9b) (10c) 409 (Ia) - (Id) (1d) (2b) (3c) (4a) (5a) (6k) (7a), (7b) (8a) (9a) (10a) 410 (Ia) - (Id) (1d) (2b) (3c) (4a) (5a) (6k) (7a), (7b) (8a) (9a) (10c) 411 (Ia) - (Id) (1d) (2b) (3c) (4a) (5a) (6k) (7a), (7b) (8a) (9b) (10a) 412 (Ia) - (Id) (1d) (2b) (3c) (4a) (5a) (6k) (7a), (7b) (8a) (9b) (10c) 413 (Ia) - (Id) (1d) (2b) (3c) (4a) (5a) (6k) (7d) (8a) (9a) (10a) 414 (Ia) - (Id) (1d) (2b) (3c) (4a) (5a) (6k) (7d) (8a) (9a) (10c) 415 (Ia) - (Id) (1d) (2b) (3c) (4a) (5a) (6k) (7d) (8a) (9b) (10a) 416 (Ia) - (Id) (1d) (2b) (3c) (4a) (5a) (6k) (7d) (8a) (9b) (10c) 417 (Ia) - (Id) (1d) (2b) (3c) (4d) (5b) (6a) (7a), (7b) (8a) (9a) (10a) 418 (Ia) - (Id) (1d) (2b) (3c) (4d) (5b) (6a) (7a), (7b) (8a) (9a) (10c) 419 (Ia) - (Id) (1d) (2b) (3c) (4d) (5b) (6a) (7a), (7b) (8a) (9b) (10a) 420 (Ia) - (Id) (1d) (2b) (3c) (4d) (5b) (6a) (7a), (7b) (8a) (9b) (10c) 421 (Ia) - (Id) (1d) (2b) (3c) (4d) (5b) (6a) (7d) (8a) (9a) (10a) 422 (Ia) - (Id) (1d) (2b) (3c) (4d) (5b) (6a) (7d) (8a) (9a) (10c) 423 (Ia) - (Id) (1d) (2b) (3c) (4d) (5b) (6a) (7d) (8a) (9b) (10a) 424 (Ia) - (Id) (1d) (2b) (3c) (4d) (5b) (6a) (7d) (8a) (9b) (10c) 425 (Ia) - (Id) (1d) (2b) (3c) (4d) (5b) (6k) (7a), (7b) (8a) (9a) (10a) 426 (Ia) - (Id) (1d) (2b) (3c) (4d) (5b) (6k) (7a), (7b) (8a) (9a) (10c) 427 (Ia) - (Id) (1d) (2b) (3c) (4d) (5b) (6k) (7a), (7b) (8a) (9b) (10a) 428 (Ia) - (Id) (1d) (2b) (3c) (4d) (5b) (6k) (7a), (7b) (8a) (9b) (10c) 429 (Ia) - (Id) (1d) (2b) (3c) (4d) (5b) (6k) (7d) (8a) (9a) (10a) 430 (Ia) - (Id) (1d) (2b) (3c) (4d) (5b) (6k) (7d) (8a) (9a) (10c) 431 (Ia) - (Id) (1d) (2b) (3c) (4d) (5b) (6k) (7d) (8a) (9b) (10a) 432 (Ia) - (Id) (1d) (2b) (3c) (4d) (5b) (6k) (7d) (8a) (9b) (10c) 433 (Ia) - (Id) (1d) (2b) (3c) (4d) (5a) (6a) (7a), (7b) (8a) (9a) (10a) 434 (Ia) - (Id) (1d) (2b) (3c) (4d) (5a) (6a) (7a), (7b) (8a) (9a) (10c) 435 (Ia) - (Id) (1d) (2b) (3c) (4d) (5a) (6a) (7a), (7b) (8a) (9b) (10a) 436 (Ia) - (Id) (1d) (2b) (3c) (4d) (5a) (6a) (7a), (7b) (8a) (9b) (10c) 437 (Ia) - (Id) (1d) (2b) (3c) (4d) (5a) (6a) (7d) (8a) (9a) (10a) 438 (Ia) - (Id) (1d) (2b) (3c) (4d) (5a) (6a) (7d) (8a) (9a) (10c) 439 (Ia) - (Id) (1d) (2b) (3c) (4d) (5a) (6a) (7d) (8a) (9b) (10a) 440 (Ia) - (Id) (1d) (2b) (3c) (4d) (5a) (6a) (7d) (8a) (9b) (10c) 441 (Ia) - (Id) (1d) (2b) (3c) (4d) (5a) (6k) (7a), (7b) (8a) (9a) (10a) 442 (Ia) - (Id) (1d) (2b) (3c) (4d) (5a) (6k) (7a), (7b) (8a) (9a) (10c) 443 (Ia) - (Id) (1d) (2b) (3c) (4d) (5a) (6k) (7a), (7b) (8a) (9b) (10a) 444 (Ia) - (Id) (1d) (2b) (3c) (4d) (5a) (6k) (7a), (7b) (8a) (9b) (10c) 445 (Ia) - (Id) (1d) (2b) (3c) (4d) (5a) (6k) (7d) (8a) (9a) (10a) 446 (Ia) - (Id) (1d) (2b) (3c) (4d) (5a) (6k) (7d) (8a) (9a) (10c) 447 (Ia) - (Id) (1d) (2b) (3c) (4d) (5a) (6k) (7d) (8a) (9b) (10a) 448 (Ia) - (Id) (1d) (2b) (3c) (4d) (5a) (6k) (7d) (8a) (9b) (10c) 449 (Ia) - (Id) (1d) (2b) (3b) (4a) (5b) (6a) (7a), (7b) (8a) (9a) (10a) 450 (Ia) - (Id) (1d) (2b) (3b) (4a) (5b) (6a) (7a), (7b) (8a) (9a) (10c) 451 (Ia) - (Id) (1d) (2b) (3b) (4a) (5b) (6a) (7a), (7b) (8a) (9b) (10a) 452 (Ia) - (Id) (1d) (2b) (3b) (4a) (5b) (6a) (7a), (7b) (8a) (9b) (10c) 453 (Ia) - (Id) (1d) (2b) (3b) (4a) (5b) (6a) (7d) (8a) (9a) (10a) 454 (Ia) - (Id) (1d) (2b) (3b) (4a) (5b) (6a) (7d) (8a) (9a) (10c) 455 (Ia) - (Id) (1d) (2b) (3b) (4a) (5b) (6a) (7d) (8a) (9b) (10a) 456 (Ia) - (Id) (1d) (2b) (3b) (4a) (5b) (6a) (7d) (8a) (9b) (10c) 457 (Ia) - (Id) (1d) (2b) (3b) (4a) (5b) (6k) (7a), (7b) (8a) (9a) (10a) 458 (Ia) - (Id) (1d) (2b) (3b) (4a) (5b) (6k) (7a), (7b) (8a) (9a) (10c) 459 (Ia) - (Id) (1d) (2b) (3b) (4a) (5b) (6k) (7a), (7b) (8a) (9b) (10a) 460 (Ia) - (Id) (1d) (2b) (3b) (4a) (5b) (6k) (7a), (7b) (8a) (9b) (10c) 461 (Ia) - (Id) (1d) (2b) (3b) (4a) (5b) (6k) (7d) (8a) (9a) (10a) 462 (Ia) - (Id) (1d) (2b) (3b) (4a) (5b) (6k) (7d) (8a) (9a) (10c) 463 (Ia) - (Id) (1d) (2b) (3b) (4a) (5b) (6k) (7d) (8a) (9b) (10a) 464 (Ia) - (Id) (1d) (2b) (3b) (4a) (5b) (6k) (7d) (8a) (9b) (10c) 465 (Ia) - (Id) (1d) (2b) (3b) (4a) (5a) (6a) (7a), (7b) (8a) (9a) (10a) 466 (Ia) - (Id) (1d) (2b) (3b) (4a) (5a) (6a) (7a), (7b) (8a) (9a) (10c) 467 (Ia) - (Id) (1d) (2b) (3b) (4a) (5a) (6a) (7a), (7b) (8a) (9b) (10a) 468 (Ia) - (Id) (1d) (2b) (3b) (4a) (5a) (6a) (7a), (7b) (8a) (9b) (10c) 469 (Ia) - (Id) (1d) (2b) (3b) (4a) (5a) (6a) (7d) (8a) (9a) (10a) 470 (Ia) - (Id) (1d) (2b) (3b) (4a) (5a) (6a) (7d) (8a) (9a) (10c) 471 (Ia) - (Id) (1d) (2b) (3b) (4a) (5a) (6a) (7d) (8a) (9b) (10a) 472 (Ia) - (Id) (1d) (2b) (3b) (4a) (5a) (6a) (7d) (8a) (9b) (10c) 473 (Ia) - (Id) (1d) (2b) (3b) (4a) (5a) (6k) (7a), (7b) (8a) (9a) (10a) 474 (Ia) - (Id) (1d) (2b) (3b) (4a) (5a) (6k) (7a), (7b) (8a) (9a) (10c) 475 (Ia) - (Id) (1d) (2b) (3b) (4a) (5a) (6k) (7a), (7b) (8a) (9b) (10a) 476 (Ia) - (Id) (1d) (2b) (3b) (4a) (5a) (6k) (7a), (7b) (8a) (9b) (10c) 477 (Ia) - (Id) (1d) (2b) (3b) (4a) (5a) (6k) (7d) (8a) (9a) (10a) 478 (Ia) - (Id) (1d) (2b) (3b) (4a) (5a) (6k) (7d) (8a) (9a) (10c) 479 (Ia) - (Id) (1d) (2b) (3b) (4a) (5a) (6k) (7d) (8a) (9b) (10a) 480 (Ia) - (Id) (1d) (2b) (3b) (4a) (5a) (6k) (7d) (8a) (9b) (10c) 481 (Ia) - (Id) (1d) (2b) (3b) (4d) (5b) (6a) (7a), (7b) (8a) (9a) (10a) 482 (Ia) - (Id) (1d) (2b) (3b) (4d) (5b) (6a) (7a), (7b) (8a) (9a) (10c) 483 (Ia) - (Id) (1d) (2b) (3b) (4d) (5b) (6a) (7a), (7b) (8a) (9b) (10a) 484 (Ia) - (Id) (1d) (2b) (3b) (4d) (5b) (6a) (7a), (7b) (8a) (9b) (10c) 485 (Ia) - (Id) (1d) (2b) (3b) (4d) (5b) (6a) (7d) (8a) (9a) (10a) 486 (Ia) - (Id) (1d) (2b) (3b) (4d) (5b) (6a) (7d) (8a) (9a) (10c) 487 (Ia) - (Id) (1d) (2b) (3b) (4d) (5b) (6a) (7d) (8a) (9b) (10a) 488 (Ia) - (Id) (1d) (2b) (3b) (4d) (5b) (6a) (7d) (8a) (9b) (10c) 489 (Ia) - (Id) (1d) (2b) (3b) (4d) (5b) (6k) (7a), (7b) (8a) (9a) (10a) 490 (Ia) - (Id) (1d) (2b) (3b) (4d) (5b) (6k) (7a), (7b) (8a) (9a) (10c) 491 (Ia) - (Id) (1d) (2b) (3b) (4d) (5b) (6k) (7a), (7b) (8a) (9b) (10a) 492 (Ia) - (Id) (1d) (2b) (3b) (4d) (5b) (6k) (7a), (7b) (8a) (9b) (10c) 493 (Ia) - (Id) (1d) (2b) (3b) (4d) (5b) (6k) (7d) (8a) (9a) (10a) 494 (Ia) - (Id) (1d) (2b) (3b) (4d) (5b) (6k) (7d) (8a) (9a) (10c) 495 (Ia) - (Id) (1d) (2b) (3b) (4d) (5b) (6k) (7d) (8a) (9b) (10a) 496 (Ia) - (Id) (1d) (2b) (3b) (4d) (5b) (6k) (7d) (8a) (9b) (10c) 497 (Ia) - (Id) (1d) (2b) (3b) (4d) (5a) (6a) (7a), (7b) (8a) (9a) (10a) 498 (Ia) - (Id) (1d) (2b) (3b) (4d) (5a) (6a) (7a), (7b) (8a) (9a) (10c) 499 (Ia) - (Id) (1d) (2b) (3b) (4d) (5a) (6a) (7a), (7b) (8a) (9b) (10a) 500 (Ia) - (Id) (1d) (2b) (3b) (4d) (5a) (6a) (7a), (7b) (8a) (9b) (10c) 501 (Ia) - (Id) (1d) (2b) (3b) (4d) (5a) (6a) (7d) (8a) (9a) (10a) 502 (Ia) - (Id) (1d) (2b) (3b) (4d) (5a) (6a) (7d) (8a) (9a) (10c) 503 (Ia) - (Id) (1d) (2b) (3b) (4d) (5a) (6a) (7d) (8a) (9b) (10a) 504 (Ia) - (Id) (1d) (2b) (3b) (4d) (5a) (6a) (7d) (8a) (9b) (10c) 505 (Ia) - (Id) (1d) (2b) (3b) (4d) (5a) (6k) (7a), (7b) (8a) (9a) (10a) 506 (Ia) - (Id) (1d) (2b) (3b) (4d) (5a) (6k) (7a), (7b) (8a) (9a) (10c) 507 (Ia) - (Id) (1d) (2b) (3b) (4d) (5a) (6k) (7a), (7b) (8a) (9b) (10a) 508 (Ia) - (Id) (1d) (2b) (3b) (4d) (5a) (6k) (7a), (7b) (8a) (9b) (10c) 509 (Ia) - (Id) (1d) (2b) (3b) (4d) (5a) (6k) (7d) (8a) (9a) (10a) 510 (Ia) - (Id) (1d) (2b) (3b) (4d) (5a) (6k) (7d) (8a) (9a) (10c) 511 (Ia) - (Id) (1d) (2b) (3b) (4d) (5a) (6k) (7d) (8a) (9b) (10a) 512 (Ia) - (Id) (1d) (2b) (3b) (4d) (5a) (6k) (7d) (8a) (9b) (10c) 513 (Id) (1a) (2a) (3c) (4a) (5b) (6a) (7a), (7b) (8a) (9a) (10a) 514 (Id) (1a) (2a) (3c) (4a) (5b) (6a) (7a), (7b) (8a) (9a) (10c) 515 (Id) (1a) (2a) (3c) (4a) (5b) (6a) (7a), (7b) (8a) (9b) (10a) 516 (ID) (1a) (2a) (3c) (4a) (5b) (6a) (7a), (7b) (8a) (9b) (10c) 517 (Id) (1a) (2a) (3c) (4a) (5b) (6a) (7d) (8a) (9a) (10a) 518 (Id) (1a) (2a) (3c) (4a) (5b) (6a) (7d) (8a) (9a) (10c) 519 (Id) (1a) (2a) (3c) (4a) (5b) (6a) (7d) (8a) (9b) (10a) 520 (Id) (1a) (2a) (3c) (4a) (5b) (6a) (7d) (8a) (9b) (10c) 521 (Id) (1a) (2a) (3c) (4a) (5b) (6k) (7a), (7b) (8a) (9a) (10a) 522 (Id) (1a) (2a) (3c) (4a) (5b) (6k) (7a), (7b) (8a) (9a) (10c) 523 (Id) (1a) (2a) (3c) (4a) (5b) (6k) (7a), (7b) (8a) (9b) (10a) 524 (Id) (1a) (2a) (3c) (4a) (5b) (6k) (7a), (7b) (8a) (9b) (10c) 525 (Id) (1a) (2a) (3c) (4a) (5b) (6k) (7d) (8a) (9a) (10a) 526 (Id) (1a) (2a) (3c) (4a) (5b) (6k) (7d) (8a) (9a) (10c) 527 (Id) (1a) (2a) (3c) (4a) (5b) (6k) (7d) (8a) (9b) (10a) 528 (Id) (1a) (2a) (3c) (4a) (5b) (6k) (7d) (8a) (9b) (10c) 529 (Id) (1a) (2a) (3c) (4a) (5a) (6a) (7a), (7b) (8a) (9a) (10a) 530 (Id) (1a) (2a) (3c) (4a) (5a) (6a) (7a), (7b) (8a) (9a) (10c) 531 (Id) (1a) (2a) (3c) (4a) (5a) (6a) (7a), (7b) (8a) (9b) (10a) 532 (Id) (1a) (2a) (3c) (4a) (5a) (6a) (7a), (7b) (8a) (9b) (10c) 533 (Id) (1a) (2a) (3c) (4a) (5a) (6a) (7d) (8a) (9a) (10a) 534 (Id) (1a) (2a) (3c) (4a) (5a) (6a) (7d) (8a) (9a) (10c) 535 (Id) (1a) (2a) (3c) (4a) (5a) (6a) (7d) (8a) (9b) (10a) 536 (Id) (1a) (2a) (3c) (4a) (5a) (6a) (7d) (8a) (9b) (10c) 537 (Id) (1a) (2a) (3c) (4a) (5a) (6k) (7a), (7b) (8a) (9a) (10a) 538 (Id) (1a) (2a) (3c) (4a) (5a) (6k) (7a), (7b) (8a) (9a) (10c) 539 (Id) (1a) (2a) (3c) (4a) (5a) (6k) (7a), (7b) (8a) (9b) (10a) 540 (Id) (1a) (2a) (3c) (4a) (5a) (6k) (7a), (7b) (8a) (9b) (10c) 541 (Id) (1a) (2a) (3c) (4a) (5a) (6k) (7d) (8a) (9a) (10a) 542 (Id) (1a) (2a) (3c) (4a) (5a) (6k) (7d) (8a) (9a) (10c) 543 (Id) (1a) (2a) (3c) (4a) (5a) (6k) (7d) (8a) (9b) (10a) 544 (Id) (1a) (2a) (3c) (4a) (5a) (6k) (7d) (8a) (9b) (10c) 545 (Id) (1a) (2a) (3c) (4d) (5b) (6a) (7a), (7b) (8a) (9a) (10a) 546 (Id) (1a) (2a) (3c) (4d) (5b) (6a) (7a), (7b) (8a) (9a) (10c) 547 (Id) (1a) (2a) (3c) (4d) (5b) (6a) (7a), (7b) (8a) (9b) (10a) 548 (Id) (1a) (2a) (3c) (4d) (5b) (6a) (7a), (7b) (8a) (9b) (10c) 549 (Id) (1a) (2a) (3c) (4d) (5b) (6a) (7d) (8a) (9a) (10a) 550 (Id) (1a) (2a) (3c) (4d) (5b) (6a) (7d) (8a) (9a) (10c) 551 (Id) (1a) (2a) (3c) (4d) (5b) (6a) (7d) (8a) (9b) (10a) 552 (Id) (1a) (2a) (3c) (4d) (5b) (6a) (7d) (8a) (9b) (10c) 553 (Id) (1a) (2a) (3c) (4d) (5b) (6k) (7a), (7b) (8a) (9a) (10a) 554 (Id) (1a) (2a) (3c) (4d) (5b) (6k) (7a), (7b) (8a) (9a) (10c) 555 (Id) (1a) (2a) (3c) (4d) (5b) (6k) (7a), (7b) (8a) (9b) (10a) 556 (Id) (1a) (2a) (3c) (4d) (5b) (6k) (7a), (7b) (8a) (9b) (10c) 557 (Id) (1a) (2a) (3c) (4d) (5b) (6k) (7d) (8a) (9a) (10a) 558 (Id) (1a) (2a) (3c) (4d) (5b) (6k) (7d) (8a) (9a) (10c) 559 (Id) (1a) (2a) (3c) (4d) (5b) (6k) (7d) (8a) (9b) (10a) 560 (Id) (1a) (2a) (3c) (4d) (5b) (6k) (7d) (8a) (9b) (10c) 561 (Id) (1a) (2a) (3c) (4d) (5a) (6a) (7a), (7b) (8a) (9a) (10a) 562 (Id) (1a) (2a) (3c) (4d) (5a) (6a) (7a), (7b) (8a) (9a) (10c) 563 (Id) (1a) (2a) (3c) (4d) (5a) (6a) (7a), (7b) (8a) (9b) (10a) 564 (Id) (1a) (2a) (3c) (4d) (5a) (6a) (7a), (7b) (8a) (9b) (10c) 565 (Id) (1a) (2a) (3c) (4d) (5a) (6a) (7d) (8a) (9a) (10a) 566 (Id) (1a) (2a) (3c) (4d) (5a) (6a) (7d) (8a) (9a) (10c) 567 (Id) (1a) (2a) (3c) (4d) (5a) (6a) (7d) (8a) (9b) (10a) 568 (Id) (1a) (2a) (3c) (4d) (5a) (6a) (7d) (8a) (9b) (10c) 569 (Id) (1a) (2a) (3c) (4d) (5a) (6k) (7a), (7b) (8a) (9a) (10a) 570 (Id) (1a) (2a) (3c) (4d) (5a) (6k) (7a), (7b) (8a) (9a) (10c) 571 (Id) (1a) (2a) (3c) (4d) (5a) (6k) (7a), (7b) (8a) (9b) (10a) 572 (Id) (1a) (2a) (3c) (4d) (5a) (6k) (7a), (7b) (8a) (9b) (10c) 573 (Id) (1a) (2a) (3c) (4d) (5a) (6k) (7d) (8a) (9a) (10a) 574 (Id) (1a) (2a) (3c) (4d) (5a) (6k) (7d) (8a) (9a) (10c) 575 (Id) (1a) (2a) (3c) (4d) (5a) (6k) (7d) (8a) (9b) (10a) 576 (Id) (1a) (2a) (3c) (4d) (5a) (6k) (7d) (8a) (9b) (10c) 577 (Id) (1a) (2a) (3b) (4a) (5b) (6a) (7a), (7b) (8a) (9a) (10a) 578 (Id) (1a) (2a) (3b) (4a) (5b) (6a) (7a), (7b) (8a) (9a) (10c) 579 (Id) (1a) (2a) (3b) (4a) (5b) (6a) (7a), (7b) (8a) (9b) (10a) 580 (Id) (1a) (2a) (3b) (4a) (5b) (6a) (7a), (7b) (8a) (9b) (10c) 581 (Id) (1a) (2a) (3b) (4a) (5b) (6a) (7d) (8a) (9a) (10a) 582 (Id) (1a) (2a) (3b) (4a) (5b) (6a) (7d) (8a) (9a) (10c) 583 (Id) (1a) (2a) (3b) (4a) (5b) (6a) (7d) (8a) (9b) (10a) 584 (Id) (1a) (2a) (3b) (4a) (5b) (6a) (7d) (8a) (9b) (10c) 585 (Id) (1a) (2a) (3b) (4a) (5b) (6k) (7a), (7b) (8a) (9a) (10a) 586 (Id) (1a) (2a) (3b) (4a) (5b) (6k) (7a), (7b) (8a) (9a) (10c) 587 (Id) (1a) (2a) (3b) (4a) (5b) (6k) (7a), (7b) (8a) (9b) (10a) 588 (Id) (1a) (2a) (3b) (4a) (5b) (6k) (7a), (7b) (8a) (9b) (10c) 589 (Id) (1a) (2a) (3b) (4a) (5b) (6k) (7d) (8a) (9a) (10a) 590 (Id) (1a) (2a) (3b) (4a) (5b) (6k) (7d) (8a) (9a) (10c) 591 (Id) (1a) (2a) (3b) (4a) (5b) (6k) (7d) (8a) (9b) (10a) 592 (Id) (1a) (2a) (3b) (4a) (5b) (6k) (7d) (8a) (9b) (10c) 593 (Id) (1a) (2a) (3b) (4a) (5a) (6a) (7a), (7b) (8a) (9a) (10a) 594 (Id) (1a) (2a) (3b) (4a) (5a) (6a) (7a), (7b) (8a) (9a) (10c) 595 (Id) (1a) (2a) (3b) (4a) (5a) (6a) (7a), (7b) (8a) (9b) (10a) 596 (Id) (1a) (2a) (3b) (4a) (5a) (6a) (7a), (7b) (8a) (9b) (10c) 597 (Id) (1a) (2a) (3b) (4a) (5a) (6a) (7d) (8a) (9a) (10a) 598 (Id) (1a) (2a) (3b) (4a) (5a) (6a) (7d) (8a) (9a) (10c) 599 (Id) (1a) (2a) (3b) (4a) (5a) (6a) (7d) (8a) (9b) (10a) 600 (Id) (1a) (2a) (3b) (4a) (5a) (6a) (7d) (8a) (9b) (10c) 601 (Id) (1a) (2a) (3b) (4a) (5a) (6k) (7a), (7b) (8a) (9a) (10a) 602 (Id) (1a) (2a) (3b) (4a) (5a) (6k) (7a), (7b) (8a) (9a) (10c) 603 (Id) (1a) (2a) (3b) (4a) (5a) (6k) (7a), (7b) (8a) (9b) (10a) 604 (Id) (1a) (2a) (3b) (4a) (5a) (6k) (7a), (7b) (8a) (9b) (10c) 605 (Id) (1a) (2a) (3b) (4a) (5a) (6k) (7d) (8a) (9a) (10a) 606 (Id) (1a) (2a) (3b) (4a) (5a) (6k) (7d) (8a) (9a) (10c) 607 (Id) (1a) (2a) (3b) (4a) (5a) (6k) (7d) (8a) (9b) (10a) 608 (Id) (1a) (2a) (3b) (4a) (5a) (6k) (7d) (8a) (9b) (10c) 609 (Id) (1a) (2a) (3b) (4d) (5b) (6a) (7a), (7b) (8a) (9a) (10a) 610 (Id) (1a) (2a) (3b) (4d) (5b) (6a) (7a), (7b) (8a) (9a) (10c) 611 (Id) (1a) (2a) (3b) (4d) (5b) (6a) (7a), (7b) (8a) (9b) (10a) 612 (Id) (1a) (2a) (3b) (4d) (5b) (6a) (7a), (7b) (8a) (9b) (10c) 613 (Id) (1a) (2a) (3b) (4d) (5b) (6a) (7d) (8a) (9a) (10a) 614 (Id) (1a) (2a) (3b) (4d) (5b) (6a) (7d) (8a) (9a) (10c) 615 (Id) (1a) (2a) (3b) (4d) (5b) (6a) (7d) (8a) (9b) (10a) 616 (Id) (1a) (2a) (3b) (4d) (5b) (6a) (7d) (8a) (9b) (10c) 617 (Id) (1a) (2a) (3b) (4d) (5b) (6k) (7a), (7b) (8a) (9a) (10a) 618 (Id) (1a) (2a) (3b) (4d) (5b) (6k) (7a), (7b) (8a) (9a) (10c) 619 (Id) (1a) (2a) (3b) (4d) (5b) (6k) (7a), (7b) (8a) (9b) (10a) 620 (Id) (1a) (2a) (3b) (4d) (5b) (6k) (7a), (7b) (8a) (9b) (10c) 621 (Id) (1a) (2a) (3b) (4d) (5b) (6k) (7d) (8a) (9a) (10a) 622 (Id) (1a) (2a) (3b) (4d) (5b) (6k) (7d) (8a) (9a) (10c) 623 (Id) (1a) (2a) (3b) (4d) (5b) (6k) (7d) (8a) (9b) (10a) 624 (Id) (1a) (2a) (3b) (4d) (5b) (6k) (7d) (8a) (9b) (10c) 625 (Id) (1a) (2a) (3b) (4d) (5a) (6a) (7a), (7b) (8a) (9a) (10a) 626 (Id) (1a) (2a) (3b) (4d) (5a) (6a) (7a), (7b) (8a) (9a) (10c) 627 (Id) (1a) (2a) (3b) (4d) (5a) (6a) (7a), (7b) (8a) (9b) (10a) 628 (Id) (1a) (2a) (3b) (4d) (5a) (6a) (7a), (7b) (8a) (9b) (10c) 629 (Id) (1a) (2a) (3b) (4d) (5a) (6a) (7d) (8a) (9a) (10a) 630 (Id) (1a) (2a) (3b) (4d) (5a) (6a) (7d) (8a) (9a) (10c) 631 (Id) (1a) (2a) (3b) (4d) (5a) (6a) (7d) (8a) (9b) (10a) 632 (Id) (1a) (2a) (3b) (4d) (5a) (6a) (7d) (8a) (9b) (10c) 633 (Id) (1a) (2a) (3b) (4d) (5a) (6k) (7a), (7b) (8a) (9a) (10a) 634 (Id) (1a) (2a) (3b) (4d) (5a) (6k) (7a), (7b) (8a) (9a) (10c) 635 (Id) (1a) (2a) (3b) (4d) (5a) (6k) (7a), (7b) (8a) (9b) (10a) 636 (Id) (1a) (2a) (3b) (4d) (5a) (6k) (7a), (7b) (8a) (9b) (10c) 637 (Id) (1a) (2a) (3b) (4d) (5a) (6k) (7d) (8a) (9a) (10a) 638 (Id) (1a) (2a) (3b) (4d) (5a) (6k) (7d) (8a) (9a) (10c) 639 (Id) (1a) (2a) (3b) (4d) (5a) (6k) (7d) (8a) (9b) (10a) 640 (Id) (1a) (2a) (3b) (4d) (5a) (6k) (7d) (8a) (9b) (10c) 641 (Id) (1a) (2b) (3c) (4a) (5b) (6a) (7a), (7b) (8a) (9a) (10a) 642 (Id) (1a) (2b) (3c) (4a) (5b) (6a) (7a), (7b) (8a) (9a) (10c) 643 (Id) (1a) (2b) (3c) (4a) (5b) (6a) (7a), (7b) (8a) (9b) (10a) 644 (Id) (1a) (2b) (3c) (4a) (5b) (6a) (7a), (7b) (8a) (9b) (10c) 645 (Id) (1a) (2b) (3c) (4a) (5b) (6a) (7d) (8a) (9a) (10a) 646 (Id) (1a) (2b) (3c) (4a) (5b) (6a) (7d) (8a) (9a) (10c) 647 (Id) (1a) (2b) (3c) (4a) (5b) (6a) (7d) (8a) (9b) (10a) 648 (Id) (1a) (2b) (3c) (4a) (5b) (6a) (7d) (8a) (9b) (10c) 649 (Id) (1a) (2b) (3c) (4a) (5b) (6k) (7a), (7b) (8a) (9a) (10a) 650 (Id) (1a) (2b) (3c) (4a) (5b) (6k) (7a), (7b) (8a) (9a) (10c) 651 (Id) (1a) (2b) (3c) (4a) (5b) (6k) (7a), (7b) (8a) (9b) (10a) 652 (Id) (1a) (2b) (3c) (4a) (5b) (6k) (7a), (7b) (8a) (9b) (10c) 653 (Id) (1a) (2b) (3c) (4a) (5b) (6k) (7d) (8a) (9a) (10a) 654 (Id) (1a) (2b) (3c) (4a) (5b) (6k) (7d) (8a) (9a) (10c) 655 (Id) (1a) (2b) (3c) (4a) (5b) (6k) (7d) (8a) (9b) (10a) 656 (Id) (1a) (2b) (3c) (4a) (5b) (6k) (7d) (8a) (9b) (10c) 657 (Id) (1a) (2b) (3c) (4a) (5a) (6a) (7a), (7b) (8a) (9a) (10a) 658 (Id) (1a) (2b) (3c) (4a) (5a) (6a) (7a), (7b) (8a) (9a) (10c) 659 (Id) (1a) (2b) (3c) (4a) (5a) (6a) (7a), (7b) (8a) (9b) (10a) 660 (Id) (1a) (2b) (3c) (4a) (5a) (6a) (7a), (7b) (8a) (9b) (10c) 661 (Id) (1a) (2b) (3c) (4a) (5a) (6a) (7d) (8a) (9a) (10a) 662 (Id) (1a) (2b) (3c) (4a) (5a) (6a) (7d) (8a) (9a) (10c) 663 (Id) (1a) (2b) (3c) (4a) (5a) (6a) (7d) (8a) (9b) (10a) 664 (Id) (1a) (2b) (3c) (4a) (5a) (6a) (7d) (8a) (9b) (10c) 665 (Id) (1a) (2b) (3c) (4a) (5a) (6k) (7a), (7b) (8a) (9a) (10a) 666 (Id) (1a) (2b) (3c) (4a) (5a) (6k) (7a), (7b) (8a) (9a) (10c) 667 (Id) (1a) (2b) (3c) (4a) (5a) (6k) (7a), (7b) (8a) (9b) (10a) 668 (Id) (1a) (2b) (3c) (4a) (5a) (6k) (7a), (7b) (8a) (9b) (10c) 669 (Id) (1a) (2b) (3c) (4a) (5a) (6k) (7d) (8a) (9a) (10a) 670 (Id) (1a) (2b) (3c) (4a) (5a) (6k) (7d) (8a) (9a) (10c) 671 (Id) (1a) (2b) (3c) (4a) (5a) (6k) (7d) (8a) (9b) (10a) 672 (Id) (1a) (2b) (3c) (4a) (5a) (6k) (7d) (8a) (9b) (10c) 673 (Id) (1a) (2b) (3c) (4d) (5b) (6a) (7a), (7b) (8a) (9a) (10a) 674 (Id) (1a) (2b) (3c) (4d) (5b) (6a) (7a), (7b) (8a) (9a) (10c) 675 (Id) (1a) (2b) (3c) (4d) (5b) (6a) (7a), (7b) (8a) (9b) (10a) 676 (Id) (1a) (2b) (3c) (4d) (5b) (6a) (7a), (7b) (8a) (9b) (10c) 677 (Id) (1a) (2b) (3c) (4d) (5b) (6a) (7d) (8a) (9a) (10a) 678 (Id) (1a) (2b) (3c) (4d) (5b) (6a) (7d) (8a) (9a) (10c) 679 (Id) (1a) (2b) (3c) (4d) (5b) (6a) (7d) (8a) (9b) (10a) 680 (Id) (1a) (2b) (3c) (4d) (5b) (6a) (7d) (8a) (9b) (10c) 681 (Id) (1a) (2b) (3c) (4d) (5b) (6k) (7a), (7b) (8a) (9a) (10a) 682 (Id) (1a) (2b) (3c) (4d) (5b) (6k) (7a), (7b) (8a) (9a) (10c) 683 (Id) (1a) (2b) (3c) (4d) (5b) (6k) (7a), (7b) (8a) (9b) (10a) 684 (Id) (1a) (2b) (3c) (4d) (5b) (6k) (7a), (7b) (8a) (9b) (10c) 685 (Id) (1a) (2b) (3c) (4d) (5b) (6k) (7d) (8a) (9a) (10a) 686 (Id) (1a) (2b) (3c) (4d) (5b) (6k) (7d) (8a) (9a) (10c) 687 (Id) (1a) (2b) (3c) (4d) (5b) (6k) (7d) (8a) (9b) (10a) 688 (Id) (1a) (2b) (3c) (4d) (5b) (6k) (7d) (8a) (9b) (10c) 689 (Id) (1a) (2b) (3c) (4d) (5a) (6a) (7a), (7b) (8a) (9a) (10a) 690 (Id) (1a) (2b) (3c) (4d) (5a) (6a) (7a), (7b) (8a) (9a) (10c) 691 (Id) (1a) (2b) (3c) (4d) (5a) (6a) (7a), (7b) (8a) (9b) (10a) 692 (Id) (1a) (2b) (3c) (4d) (5a) (6a) (7a), (7b) (8a) (9b) (10c) 693 (Id) (1a) (2b) (3c) (4d) (5a) (6a) (7d) (8a) (9a) (10a) 694 (Id) (1a) (2b) (3c) (4d) (5a) (6a) (7d) (8a) (9a) (10c) 695 (Id) (1a) (2b) (3c) (4d) (5a) (6a) (7d) (8a) (9b) (10a) 696 (Id) (1a) (2b) (3c) (4d) (5a) (6a) (7d) (8a) (9b) (10c) 697 (Id) (1a) (2b) (3c) (4d) (5a) (6k) (7a), (7b) (8a) (9a) (10a) 698 (Id) (1a) (2b) (3c) (4d) (5a) (6k) (7a), (7b) (8a) (9a) (10c) 699 (Id) (1a) (2b) (3c) (4d) (5a) (6k) (7a), (7b) (8a) (9b) (10a) 700 (Id) (1a) (2b) (3c) (4d) (5a) (6k) (7a), (7b) (8a) (9b) (10c) 701 (Id) (1a) (2b) (3c) (4d) (5a) (6k) (7d) (8a) (9a) (10a) 702 (Id) (1a) (2b) (3c) (4d) (5a) (6k) (7d) (8a) (9a) (10c) 703 (Id) (1a) (2b) (3c) (4d) (5a) (6k) (7d) (8a) (9b) (10a) 704 (Id) (1a) (2b) (3c) (4d) (5a) (6k) (7d) (8a) (9b) (10c) 705 (Id) (1a) (2b) (3b) (4a) (5b) (6a) (7a), (7b) (8a) (9a) (10a) 706 (Id) (1a) (2b) (3b) (4a) (5b) (6a) (7a), (7b) (8a) (9a) (10c) 707 (Id) (1a) (2b) (3b) (4a) (5b) (6a) (7a), (7b) (8a) (9b) (10a) 708 (Id) (1a) (2b) (3b) (4a) (5b) (6a) (7a), (7b) (8a) (9b) (10c) 709 (Id) (1a) (2b) (3b) (4a) (5b) (6a) (7d) (8a) (9a) (10a) 710 (Id) (1a) (2b) (3b) (4a) (5b) (6a) (7d) (8a) (9a) (10c) 711 (Id) (1a) (2b) (3b) (4a) (5b) (6a) (7d) (8a) (9b) (10a) 712 (Id) (1a) (2b) (3b) (4a) (5b) (6a) (7d) (8a) (9b) (10c) 713 (Id) (1a) (2b) (3b) (4a) (5b) (6k) (7a), (7b) (8a) (9a) (10a) 714 (Id) (1a) (2b) (3b) (4a) (5b) (6k) (7a), (7b) (8a) (9a) (10c) 715 (Id) (1a) (2b) (3b) (4a) (5b) (6k) (7a), (7b) (8a) (9b) (10a) 716 (Id) (1a) (2b) (3b) (4a) (5b) (6k) (7a), (7b) (8a) (9b) (10c) 717 (Id) (1a) (2b) (3b) (4a) (5b) (6k) (7d) (8a) (9a) (10a) 718 (Id) (1a) (2b) (3b) (4a) (5b) (6k) (7d) (8a) (9a) (10c) 719 (Id) (1a) (2b) (3b) (4a) (5b) (6k) (7d) (8a) (9b) (10a) 720 (Id) (1a) (2b) (3b) (4a) (5b) (6k) (7d) (8a) (9b) (10c) 721 (Id) (1a) (2b) (3b) (4a) (5a) (6a) (7a), (7b) (8a) (9a) (10a) 722 (Id) (1a) (2b) (3b) (4a) (5a) (6a) (7a), (7b) (8a) (9a) (10c) 723 (Id) (1a) (2b) (3b) (4a) (5a) (6a) (7a), (7b) (8a) (9b) (10a) 724 (Id) (1a) (2b) (3b) (4a) (5a) (6a) (7a), (7b) (8a) (9b) (10c) 725 (Id) (1a) (2b) (3b) (4a) (5a) (6a) (7d) (8a) (9a) (10a) 726 (Id) (1a) (2b) (3b) (4a) (5a) (6a) (7d) (8a) (9a) (10c) 727 (Id) (1a) (2b) (3b) (4a) (5a) (6a) (7d) (8a) (9b) (10a) 728 (Id) (1a) (2b) (3b) (4a) (5a) (6a) (7d) (8a) (9b) (10c) 729 (Id) (1a) (2b) (3b) (4a) (5a) (6k) (7a), (7b) (8a) (9a) (10a) 730 (Id) (1a) (2b) (3b) (4a) (5a) (6k) (7a), (7b) (8a) (9a) (10c) 731 (Id) (1a) (2b) (3b) (4a) (5a) (6k) (7a), (7b) (8a) (9b) (10a) 732 (Id) (1a) (2b) (3b) (4a) (5a) (6k) (7a), (7b) (8a) (9b) (10c) 733 (Id) (1a) (2b) (3b) (4a) (5a) (6k) (7d) (8a) (9a) (10a) 734 (Id) (1a) (2b) (3b) (4a) (5a) (6k) (7d) (8a) (9a) (10c) 735 (Id) (1a) (2b) (3b) (4a) (5a) (6k) (7d) (8a) (9b) (10a) 736 (Id) (1a) (2b) (3b) (4a) (5a) (6k) (7d) (8a) (9b) (10c) 737 (Id) (1a) (2b) (3b) (4d) (5b) (6a) (7a), (7b) (8a) (9a) (10a) 738 (Id) (1a) (2b) (3b) (4d) (5b) (6a) (7a), (7b) (8a) (9a) (10c) 739 (Id) (1a) (2b) (3b) (4d) (5b) (6a) (7a), (7b) (8a) (9b) (10a) 740 (Id) (1a) (2b) (3b) (4d) (5b) (6a) (7a), (7b) (8a) (9b) (10c) 741 (Id) (1a) (2b) (3b) (4d) (5b) (6a) (7d) (8a) (9a) (10a) 742 (Id) (1a) (2b) (3b) (4d) (5b) (6a) (7d) (8a) (9a) (10c) 743 (Id) (1a) (2b) (3b) (4d) (5b) (6a) (7d) (8a) (9b) (10a) 744 (Id) (1a) (2b) (3b) (4d) (5b) (6a) (7d) (8a) (9b) (10c) 745 (Id) (1a) (2b) (3b) (4d) (5b) (6k) (7a), (7b) (8a) (9a) (10a) 746 (Id) (1a) (2b) (3b) (4d) (5b) (6k) (7a), (7b) (8a) (9a) (10c) 747 (Id) (1a) (2b) (3b) (4d) (5b) (6k) (7a), (7b) (8a) (9b) (10a) 748 (Id) (1a) (2b) (3b) (4d) (5b) (6k) (7a), (7b) (8a) (9b) (10c) 749 (Id) (1a) (2b) (3b) (4d) (5b) (6k) (7d) (8a) (9a) (10a) 750 (Id) (1a) (2b) (3b) (4d) (5b) (6k) (7d) (8a) (9a) (10c) 751 (Id) (1a) (2b) (3b) (4d) (5b) (6k) (7d) (8a) (9b) (10a) 752 (Id) (1a) (2b) (3b) (4d) (5b) (6k) (7d) (8a) (9b) (10c) 753 (Id) (1a) (2b) (3b) (4d) (5a) (6a) (7a), (7b) (8a) (9a) (10a) 754 (Id) (1a) (2b) (3b) (4d) (5a) (6a) (7a), (7b) (8a) (9a) (10c) 755 (Id) (1a) (2b) (3b) (4d) (5a) (6a) (7a), (7b) (8a) (9b) (10a) 756 (Id) (1a) (2b) (3b) (4d) (5a) (6a) (7a), (7b) (8a) (9b) (10c) 757 (Id) (1a) (2b) (3b) (4d) (5a) (6a) (7d) (8a) (9a) (10a) 758 (Id) (1a) (2b) (3b) (4d) (5a) (6a) (7d) (8a) (9a) (10c) 759 (Id) (1a) (2b) (3b) (4d) (5a) (6a) (7d) (8a) (9b) (10a) 760 (Id) (1a) (2b) (3b) (4d) (5a) (6a) (7d) (8a) (9b) (10c) 761 (Id) (1a) (2b) (3b) (4d) (5a) (6k) (7a), (7b) (8a) (9a) (10a) 762 (Id) (1a) (2b) (3b) (4d) (5a) (6k) (7a), (7b) (8a) (9a) (10c) 763 (Id) (1a) (2b) (3b) (4d) (5a) (6k) (7a), (7b) (8a) (9b) (10a) 764 (Id) (1a) (2b) (3b) (4d) (5a) (6k) (7a), (7b) (8a) (9b) (10c) 765 (Id) (1a) (2b) (3b) (4d) (5a) (6k) (7d) (8a) (9a) (10a) 766 (Id) (1a) (2b) (3b) (4d) (5a) (6k) (7d) (8a) (9a) (10c) 767 (Id) (1a) (2b) (3b) (4d) (5a) (6k) (7d) (8a) (9b) (10a) 768 (Id) (1a) (2b) (3b) (4d) (5a) (6k) (7d) (8a) (9b) (10c) 769 (Id) (1d) (2a) (3c) (4a) (5b) (6a) (7a), (7b) (8a) (9a) (10a) 770 (Id) (1d) (2a) (3c) (4a) (5b) (6a) (7a), (7b) (8a) (9a) (10c) 771 (Id) (1d) (2a) (3c) (4a) (5b) (6a) (7a), (7b) (8a) (9b) (10a) 772 (Id) (1d) (2a) (3c) (4a) (5b) (6a) (7a), (7b) (8a) (9b) (10c) 773 (Id) (1d) (2a) (3c) (4a) (5b) (6a) (7d) (8a) (9a) (10a) 774 (Id) (1d) (2a) (3c) (4a) (5b) (6a) (7d) (8a) (9a) (10c) 775 (Id) (1d) (2a) (3c) (4a) (5b) (6a) (7d) (8a) (9b) (10a) 776 (Id) (1d) (2a) (3c) (4a) (5b) (6a) (7d) (8a) (9b) (10c) 777 (Id) (1d) (2a) (3c) (4a) (5b) (6k) (7a), (7b) (8a) (9a) (10a) 778 (Id) (1d) (2a) (3c) (4a) (5b) (6k) (7a), (7b) (8a) (9a) (10c) 779 (Id) (1d) (2a) (3c) (4a) (5b) (6k) (7a), (7b) (8a) (9b) (10a) 780 (Id) (1d) (2a) (3c) (4a) (5b) (6k) (7a), (7b) (8a) (9b) (10c) 781 (Id) (1d) (2a) (3c) (4a) (5b) (6k) (7d) (8a) (9a) (10a) 782 (Id) (1d) (2a) (3c) (4a) (5b) (6k) (7d) (8a) (9a) (10c) 783 (Id) (1d) (2a) (3c) (4a) (5b) (6k) (7d) (8a) (9b) (10a) 784 (Id) (1d) (2a) (3c) (4a) (5b) (6k) (7d) (8a) (9b) (10c) 785 (Id) (1d) (2a) (3c) (4a) (5a) (6a) (7a), (7b) (8a) (9a) (10a) 786 (Id) (1d) (2a) (3c) (4a) (5a) (6a) (7a), (7b) (8a) (9a) (10c) 787 (Id) (1d) (2a) (3c) (4a) (5a) (6a) (7a), (7b) (8a) (9b) (10a) 788 (Id) (1d) (2a) (3c) (4a) (5a) (6a) (7a), (7b) (8a) (9b) (10c) 789 (Id) (1d) (2a) (3c) (4a) (5a) (6a) (7d) (8a) (9a) (10a) 790 (Id) (1d) (2a) (3c) (4a) (5a) (6a) (7d) (8a) (9a) (10c) 791 (Id) (1d) (2a) (3c) (4a) (5a) (6a) (7d) (8a) (9b) (10a) 792 (Id) (1d) (2a) (3c) (4a) (5a) (6a) (7d) (8a) (9b) (10c) 793 (ID) (1d) (2a) (3c) (4a) (5a) (6k) (7a), (7b) (8a) (9a) (10a) 794 (ID) (1d) (2a) (3c) (4a) (5a) (6k) (7a), (7b) (8a) (9a) (10c) 795 (Id) (1d) (2a) (3c) (4a) (5a) (6k) (7a), (7b) (8a) (9b) (10a) 796 (Id) (1d) (2a) (3c) (4a) (5a) (6k) (7a), (7b) (8a) (9b) (10c) 797 (Id) (1d) (2a) (3c) (4a) (5a) (6k) (7d) (8a) (9a) (10a) 798 (Id) (1d) (2a) (3c) (4a) (5a) (6k) (7d) (8a) (9a) (10c) 799 (Id) (1d) (2a) (3c) (4a) (5a) (6k) (7d) (8a) (9b) (10a) 800 (Id) (1d) (2a) (3c) (4a) (5a) (6k) (7d) (8a) (9b) (10c) 801 (Id) (1d) (2a) (3c) (4d) (5b) (6a) (7a), (7b) (8a) (9a) (10a) 802 (Id) (1d) (2a) (3c) (4d) (5b) (6a) (7a), (7b) (8a) (9a) (10c) 803 (Id) (1d) (2a) (3c) (4d) (5b) (6a) (7a), (7b) (8a) (9b) (10a) 804 (Id) (1d) (2a) (3c) (4d) (5b) (6a) (7a), (7b) (8a) (9b) (10c) 805 (Id) (1d) (2a) (3c) (4d) (5b) (6a) (7d) (8a) (9a) (10a) 806 (Id) (1d) (2a) (3c) (4d) (5b) (6a) (7d) (8a) (9a) (10c) 807 (Id) (1d) (2a) (3c) (4d) (5b) (6a) (7d) (8a) (9b) (10a) 808 (Id) (1d) (2a) (3c) (4d) (5b) (6a) (7d) (8a) (9b) (10c) 809 (Id) (1d) (2a) (3c) (4d) (5b) (6k) (7a), (7b) (8a) (9a) (10a) 810 (Id) (1d) (2a) (3c) (4d) (5b) (6k) (7a), (7b) (8a) (9a) (10c) 811 (Id) (1d) (2a) (3c) (4d) (5b) (6k) (7a), (7b) (8a) (9b) (10a) 812 (Id) (1d) (2a) (3c) (4d) (5b) (6k) (7a), (7b) (8a) (9b) (10c) 813 (Id) (1d) (2a) (3c) (4d) (5b) (6k) (7d) (8a) (9a) (10a) 814 (Id) (1d) (2a) (3c) (4d) (5b) (6k) (7d) (8a) (9a) (10c) 815 (Id) (1d) (2a) (3c) (4d) (5b) (6k) (7d) (8a) (9b) (10a) 816 (Id) (1d) (2a) (3c) (4d) (5b) (6k) (7d) (8a) (9b) (10c) 817 (Id) (1d) (2a) (3c) (4d) (5a) (6a) (7a), (7b) (8a) (9a) (10a) 818 (Id) (1d) (2a) (3c) (4d) (5a) (6a) (7a), (7b) (8a) (9a) (10c) 819 (Id) (1d) (2a) (3c) (4d) (5a) (6a) (7a), (7b) (8a) (9b) (10a) 820 (Id) (1d) (2a) (3c) (4d) (5a) (6a) (7a), (7b) (8a) (9b) (10c) 821 (Id) (1d) (2a) (3c) (4d) (5a) (6a) (7d) (8a) (9a) (10a) 822 (Id) (1d) (2a) (3c) (4d) (5a) (6a) (7d) (8a) (9a) (10c) 823 (Id) (1d) (2a) (3c) (4d) (5a) (6a) (7d) (8a) (9b) (10a) 824 (Id) (1d) (2a) (3c) (4d) (5a) (6a) (7d) (8a) (9b) (10c) 825 (Id) (1d) (2a) (3c) (4d) (5a) (6k) (7a), (7b) (8a) (9a) (10a) 826 (Id) (1d) (2a) (3c) (4d) (5a) (6k) (7a), (7b) (8a) (9a) (10c) 827 (Id) (1d) (2a) (3c) (4d) (5a) (6k) (7a), (7b) (8a) (9b) (10a) 828 (Id) (1d) (2a) (3c) (4d) (5a) (6k) (7a), (7b) (8a) (9b) (10c) 829 (Id) (1d) (2a) (3c) (4d) (5a) (6k) (7d) (8a) (9a) (10a) 830 (Id) (1d) (2a) (3c) (4d) (5a) (6k) (7d) (8a) (9a) (10c) 831 (Id) (1d) (2a) (3c) (4d) (5a) (6k) (7d) (8a) (9b) (10a) 832 (Id) (1d) (2a) (3c) (4d) (5a) (6k) (7d) (8a) (9b) (10c) 833 (Id) (1d) (2a) (3b) (4a) (5b) (6a) (7a), (7b) (8a) (9a) (10a) 834 (Id) (1d) (2a) (3b) (4a) (5b) (6a) (7a), (7b) (8a) (9a) (10c) 835 (Id) (1d) (2a) (3b) (4a) (5b) (6a) (7a), (7b) (8a) (9b) (10a) 836 (Id) (1d) (2a) (3b) (4a) (5b) (6a) (7a), (7b) (8a) (9b) (10c) 837 (Id) (1d) (2a) (3b) (4a) (5b) (6a) (7d) (8a) (9a) (10a) 838 (Id) (1d) (2a) (3b) (4a) (5b) (6a) (7d) (8a) (9a) (10c) 839 (Id) (1d) (2a) (3b) (4a) (5b) (6a) (7d) (8a) (9b) (10a) 840 (Id) (1d) (2a) (3b) (4a) (5b) (6a) (7d) (8a) (9b) (10c) 841 (Id) (1d) (2a) (3b) (4a) (5b) (6k) (7a), (7b) (8a) (9a) (10a) 842 (Id) (1d) (2a) (3b) (4a) (5b) (6k) (7a), (7b) (8a) (9a) (10c) 843 (Id) (1d) (2a) (3b) (4a) (5b) (6k) (7a), (7b) (8a) (9b) (10a) 844 (Id) (1d) (2a) (3b) (4a) (5b) (6k) (7a), (7b) (8a) (9b) (10c) 845 (Id) (1d) (2a) (3b) (4a) (5b) (6k) (7d) (8a) (9a) (10a) 846 (Id) (1d) (2a) (3b) (4a) (5b) (6k) (7d) (8a) (9a) (10c) 847 (Id) (1d) (2a) (3b) (4a) (5b) (6k) (7d) (8a) (9b) (10a) 848 (Id) (1d) (2a) (3b) (4a) (5b) (6k) (7d) (8a) (9b) (10c) 849 (ID) (1d) (2a) (3b) (4a) (5a) (6a) (7a), (7b) (8a) (9a) (10a) 850 (Id) (1d) (2a) (3b) (4a) (5a) (6a) (7a), (7b) (8a) (9a) (10c) 851 (Id) (1d) (2a) (3b) (4a) (5a) (6a) (7a), (7b) (8a) (9b) (10a) 852 (Id) (1d) (2a) (3b) (4a) (5a) (6a) (7a), (7b) (8a) (9b) (10c) 853 (Id) (1d) (2a) (3b) (4a) (5a) (6a) (7d) (8a) (9a) (10a) 854 (Id) (1d) (2a) (3b) (4a) (5a) (6a) (7d) (8a) (9a) (10c) 855 (Id) (1d) (2a) (3b) (4a) (5a) (6a) (7d) (8a) (9b) (10a) 856 (Id) (1d) (2a) (3b) (4a) (5a) (6a) (7d) (8a) (9b) (10c) 857 (Id) (1d) (2a) (3b) (4a) (5a) (6k) (7a), (7b) (8a) (9a) (10a) 858 (Id) (1d) (2a) (3b) (4a) (5a) (6k) (7a), (7b) (8a) (9a) (10c) 859 (Id) (1d) (2a) (3b) (4a) (5a) (6k) (7a), (7b) (8a) (9b) (10a) 860 (Id) (1d) (2a) (3b) (4a) (5a) (6k) (7a), (7b) (8a) (9b) (10c) 861 (Id) (1d) (2a) (3b) (4a) (5a) (6k) (7d) (8a) (9a) (10a) 862 (Id) (1d) (2a) (3b) (4a) (5a) (6k) (7d) (8a) (9a) (10c) 863 (Id) (1d) (2a) (3b) (4a) (5a) (6k) (7d) (8a) (9b) (10a) 864 (Id) (1d) (2a) (3b) (4a) (5a) (6k) (7d) (8a) (9b) (10c) 865 (Id) (1d) (2a) (3b) (4d) (5b) (6a) (7a), (7b) (8a) (9a) (10a) 866 (Id) (1d) (2a) (3b) (4d) (5b) (6a) (7a), (7b) (8a) (9a) (10c) 867 (Id) (1d) (2a) (3b) (4d) (5b) (6a) (7a), (7b) (8a) (9b) (10a) 868 (Id) (1d) (2a) (3b) (4d) (5b) (6a) (7a), (7b) (8a) (9b) (10c) 869 (Id) (1d) (2a) (3b) (4d) (5b) (6a) (7d) (8a) (9a) (10a) 870 (Id) (1d) (2a) (3b) (4d) (5b) (6a) (7d) (8a) (9a) (10c) 871 (Id) (1d) (2a) (3b) (4d) (5b) (6a) (7d) (8a) (9b) (10a) 872 (Id) (1d) (2a) (3b) (4d) (5b) (6a) (7d) (8a) (9b) (10c) 873 (Id) (1d) (2a) (3b) (4d) (5b) (6k) (7a), (7b) (8a) (9a) (10a) 874 (Id) (1d) (2a) (3b) (4d) (5b) (6k) (7a), (7b) (8a) (9a) (10c) 875 (Id) (1d) (2a) (3b) (4d) (5b) (6k) (7a), (7b) (8a) (9b) (10a) 876 (Id) (1d) (2a) (3b) (4d) (5b) (6k) (7a), (7b) (8a) (9b) (10c) 877 (Id) (1d) (2a) (3b) (4d) (5b) (6k) (7d) (8a) (9a) (10a) 878 (Id) (1d) (2a) (3b) (4d) (5b) (6k) (7d) (8a) (9a) (10c) 879 (Id) (1d) (2a) (3b) (4d) (5b) (6k) (7d) (8a) (9b) (10a) 880 (Id) (1d) (2a) (3b) (4d) (5b) (6k) (7d) (8a) (9b) (10c) 881 (Id) (1d) (2a) (3b) (4d) (5a) (6a) (7a), (7b) (8a) (9a) (10a) 882 (Id) (1d) (2a) (3b) (4d) (5a) (6a) (7a), (7b) (8a) (9a) (10c) 883 (Id) (1d) (2a) (3b) (4d) (5a) (6a) (7a), (7b) (8a) (9b) (10a) 884 (Id) (1d) (2a) (3b) (4d) (5a) (6a) (7a), (7b) (8a) (9b) (10c) 885 (Id) (1d) (2a) (3b) (4d) (5a) (6a) (7d) (8a) (9a) (10a) 886 (Id) (1d) (2a) (3b) (4d) (5a) (6a) (7d) (8a) (9a) (10c) 887 (Id) (1d) (2a) (3b) (4d) (5a) (6a) (7d) (8a) (9b) (10a) 888 (Id) (1d) (2a) (3b) (4d) (5a) (6a) (7d) (8a) (9b) (10c) 889 (Id) (1d) (2a) (3b) (4d) (5a) (6k) (7a), (7b) (8a) (9a) (10a) 890 (Id) (1d) (2a) (3b) (4d) (5a) (6k) (7a), (7b) (8a) (9a) (10c) 891 (Id) (1d) (2a) (3b) (4d) (5a) (6k) (7a), (7b) (8a) (9b) (10a) 892 (Id) (1d) (2a) (3b) (4d) (5a) (6k) (7a), (7b) (8a) (9b) (10c) 893 (Id) (1d) (2a) (3b) (4d) (5a) (6k) (7d) (8a) (9a) (10a) 894 (Id) (1d) (2a) (3b) (4d) (5a) (6k) (7d) (8a) (9a) (10c) 895 (Id) (1d) (2a) (3b) (4d) (5a) (6k) (7d) (8a) (9b) (10a) 896 (Id) (1d) (2a) (3b) (4d) (5a) (6k) (7d) (8a) (9b) (10c) 897 (Id) (1d) (2b) (3c) (4a) (5b) (6a) (7a), (7b) (8a) (9a) (10a) 898 (Id) (1d) (2b) (3c) (4a) (5b) (6a) (7a), (7b) (8a) (9a) (10c) 899 (Id) (1d) (2b) (3c) (4a) (5b) (6a) (7a), (7b) (8a) (9b) (10a) 900 (Id) (1d) (2b) (3c) (4a) (5b) (6a) (7a), (7b) (8a) (9b) (10c) 901 (Id) (1d) (2b) (3c) (4a) (5b) (6a) (7d) (8a) (9a) (10a) 902 (Id) (1d) (2b) (3c) (4a) (5b) (6a) (7d) (8a) (9a) (10c) 903 (Id) (1d) (2b) (3c) (4a) (5b) (6a) (7d) (8a) (9b) (10a) 904 (Id) (1d) (2b) (3c) (4a) (5b) (6a) (7d) (8a) (9b) (10c) 905 (Id) (1d) (2b) (3c) (4a) (5b) (6k) (7a), (7b) (8a) (9a) (10a) 906 (Id) (1d) (2b) (3c) (4a) (5b) (6k) (7a), (7b) (8a) (9a) (10c) 907 (Id) (1d) (2b) (3c) (4a) (5b) (6k) (7a), (7b) (8a) (9b) (10a) 908 (Id) (1d) (2b) (3c) (4a) (5b) (6k) (7a), (7b) (8a) (9b) (10c) 909 (Id) (1d) (2b) (3c) (4a) (5b) (6k) (7d) (8a) (9a) (10a) 910 (Id) (1d) (2b) (3c) (4a) (5b) (6k) (7d) (8a) (9a) (10c) 911 (Id) (1d) (2b) (3c) (4a) (5b) (6k) (7d) (8a) (9b) (10a) 912 (Id) (1d) (2b) (3c) (4a) (5b) (6k) (7d) (8a) (9b) (10c) 913 (ID) (1d) (2b) (3c) (4a) (5a) (6a) (7a), (7b) (8a) (9a) (10a) 914 (Id) (1d) (2b) (3c) (4a) (5a) (6a) (7a), (7b) (8a) (9a) (10c) 915 (Id) (1d) (2b) (3c) (4a) (5a) (6a) (7a), (7b) (8a) (9b) (10a) 916 (Id) (1d) (2b) (3c) (4a) (5a) (6a) (7a), (7b) (8a) (9b) (10c) 917 (Id) (1d) (2b) (3c) (4a) (5a) (6a) (7d) (8a) (9a) (10a) 918 (Id) (1d) (2b) (3c) (4a) (5a) (6a) (7d) (8a) (9a) (10c) 919 (Id) (1d) (2b) (3c) (4a) (5a) (6a) (7d) (8a) (9b) (10a) 920 (Id) (1d) (2b) (3c) (4a) (5a) (6a) (7d) (8a) (9b) (10c) 921 (Id) (1d) (2b) (3c) (4a) (5a) (6k) (7a), (7b) (8a) (9a) (10a) 922 (Id) (1d) (2b) (3c) (4a) (5a) (6k) (7a), (7b) (8a) (9a) (10c) 923 (Id) (1d) (2b) (3c) (4a) (5a) (6k) (7a), (7b) (8a) (9b) (10a) 924 (Id) (1d) (2b) (3c) (4a) (5a) (6k) (7a), (7b) (8a) (9b) (10c) 925 (Id) (1d) (2b) (3c) (4a) (5a) (6k) (7d) (8a) (9a) (10a) 926 (Id) (1d) (2b) (3c) (4a) (5a) (6k) (7d) (8a) (9a) (10c) 927 (Id) (1d) (2b) (3c) (4a) (5a) (6k) (7d) (8a) (9b) (10a) 928 (Id) (1d) (2b) (3c) (4a) (5a) (6k) (7d) (8a) (9b) (10c) 929 (Id) (1d) (2b) (3c) (4d) (5b) (6a) (7a), (7b) (8a) (9a) (10a) 930 (Id) (1d) (2b) (3c) (4d) (5b) (6a) (7a), (7b) (8a) (9a) (10c) 931 (Id) (1d) (2b) (3c) (4d) (5b) (6a) (7a), (7b) (8a) (9b) (10a) 932 (Id) (1d) (2b) (3c) (4d) (5b) (6a) (7a), (7b) (8a) (9b) (10c) 933 (Id) (1d) (2b) (3c) (4d) (5b) (6a) (7d) (8a) (9a) (10a) 934 (Id) (1d) (2b) (3c) (4d) (5b) (6a) (7d) (8a) (9a) (10c) 935 (Id) (1d) (2b) (3c) (4d) (5b) (6a) (7d) (8a) (9b) (10a) 936 (Id) (1d) (2b) (3c) (4d) (5b) (6a) (7d) (8a) (9b) (10c) 937 (Id) (1d) (2b) (3c) (4d) (5b) (6k) (7a), (7b) (8a) (9a) (10a) 938 (Id) (1d) (2b) (3c) (4d) (5b) (6k) (7a), (7b) (8a) (9a) (10c) 939 (Id) (1d) (2b) (3c) (4d) (5b) (6k) (7a), (7b) (8a) (9b) (10a) 940 (Id) (1d) (2b) (3c) (4d) (5b) (6k) (7a), (7b) (8a) (9b) (10c) 941 (Id) (1d) (2b) (3c) (4d) (5b) (6k) (7d) (8a) (9a) (10a) 942 (Id) (1d) (2b) (3c) (4d) (5b) (6k) (7d) (8a) (9a) (10c) 943 (Id) (1d) (2b) (3c) (4d) (5b) (6k) (7d) (8a) (9b) (10a) 944 (Id) (1d) (2b) (3c) (4d) (5b) (6k) (7d) (8a) (9b) (10c) 945 (Id) (1d) (2b) (3c) (4d) (5a) (6a) (7a), (7b) (8a) (9a) (10a) 946 (Id) (1d) (2b) (3c) (4d) (5a) (6a) (7a), (7b) (8a) (9a) (10c) 947 (Id) (1d) (2b) (3c) (4d) (5a) (6a) (7a), (7b) (8a) (9b) (10a) 948 (Id) (1d) (2b) (3c) (4d) (5a) (6a) (7a), (7b) (8a) (9b) (10c) 949 (Id) (1d) (2b) (3c) (4d) (5a) (6a) (7d) (8a) (9a) (10a) 950 (Id) (1d) (2b) (3c) (4d) (5a) (6a) (7d) (8a) (9a) (10c) 951 (Id) (1d) (2b) (3c) (4d) (5a) (6a) (7d) (8a) (9b) (10a) 952 (Id) (1d) (2b) (3c) (4d) (5a) (6a) (7d) (8a) (9b) (10c) 953 (Id) (1d) (2b) (3c) (4d) (5a) (6k) (7a), (7b) (8a) (9a) (10a) 954 (Id) (1d) (2b) (3c) (4d) (5a) (6k) (7a), (7b) (8a) (9a) (10c) 955 (Id) (1d) (2b) (3c) (4d) (5a) (6k) (7a), (7b) (8a) (9b) (10a) 956 (Id) (1d) (2b) (3c) (4d) (5a) (6k) (7a), (7b) (8a) (9b) (10c) 957 (Id) (1d) (2b) (3c) (4d) (5a) (6k) (7d) (8a) (9a) (10a) 958 (Id) (1d) (2b) (3c) (4d) (5a) (6k) (7d) (8a) (9a) (10c) 959 (Id) (1d) (2b) (3c) (4d) (5a) (6k) (7d) (8a) (9b) (10a) 960 (Id) (1d) (2b) (3c) (4d) (5a) (6k) (7d) (8a) (9b) (10c) 961 (Id) (1d) (2b) (3b) (4a) (5b) (6a) (7a), (7b) (8a) (9a) (10a) 962 (Id) (1d) (2b) (3b) (4a) (5b) (6a) (7a), (7b) (8a) (9a) (10c) 963 (Id) (1d) (2b) (3b) (4a) (5b) (6a) (7a), (7b) (8a) (9b) (10a) 964 (Id) (1d) (2b) (3b) (4a) (5b) (6a) (7a), (7b) (8a) (9b) (10c) 965 (Id) (1d) (2b) (3b) (4a) (5b) (6a) (7d) (8a) (9a) (10a) 966 (Id) (1d) (2b) (3b) (4a) (5b) (6a) (7d) (8a) (9a) (10c) 967 (Id) (1d) (2b) (3b) (4a) (5b) (6a) (7d) (8a) (9b) (10a) 968 (Id) (1d) (2b) (3b) (4a) (5b) (6a) (7d) (8a) (9b) (10c) 969 (Id) (1d) (2b) (3b) (4a) (5b) (6k) (7a), (7b) (8a) (9a) (10a) 970 (Id) (1d) (2b) (3b) (4a) (5b) (6k) (7a), (7b) (8a) (9a) (10c) 971 (Id) (1d) (2b) (3b) (4a) (5b) (6k) (7a), (7b) (8a) (9b) (10a) 972 (Id) (1d) (2b) (3b) (4a) (5b) (6k) (7a), (7b) (8a) (9b) (10c) 973 (Id) (1d) (2b) (3b) (4a) (5b) (6k) (7d) (8a) (9a) (10a) 974 (Id) (1d) (2b) (3b) (4a) (5b) (6k) (7d) (8a) (9a) (10c) 975 (Id) (1d) (2b) (3b) (4a) (5b) (6k) (7d) (8a) (9b) (10a) 976 (Id) (1d) (2b) (3b) (4a) (5b) (6k) (7d) (8a) (9b) (10c) 977 (Id) (1d) (2b) (3b) (4a) (5a) (6a) (7a), (7b) (8a) (9a) (10a) 978 (Id) (1d) (2b) (3b) (4a) (5a) (6a) (7a), (7b) (8a) (9a) (10c) 979 (Id) (1d) (2b) (3b) (4a) (5a) (6a) (7a), (7b) (8a) (9b) (10a) 980 (Id) (1d) (2b) (3b) (4a) (5a) (6a) (7a), (7b) (8a) (9b) (10c) 981 (Id) (1d) (2b) (3b) (4a) (5a) (6a) (7d) (8a) (9a) (10a) 982 (Id) (1d) (2b) (3b) (4a) (5a) (6a) (7d) (8a) (9a) (10c) 983 (Id) (1d) (2b) (3b) (4a) (5a) (6a) (7d) (8a) (9b) (10a) 984 (Id) (1d) (2b) (3b) (4a) (5a) (6a) (7d) (8a) (9b) (10c) 985 (Id) (1d) (2b) (3b) (4a) (5a) (6k) (7a), (7b) (8a) (9a) (10a) 986 (Id) (1d) (2b) (3b) (4a) (5a) (6k) (7a), (7b) (8a) (9a) (10c) 987 (Id) (1d) (2b) (3b) (4a) (5a) (6k) (7a), (7b) (8a) (9b) (10a) 988 (Id) (1d) (2b) (3b) (4a) (5a) (6k) (7a), (7b) (8a) (9b) (10c) 989 (Id) (1d) (2b) (3b) (4a) (5a) (6k) (7d) (8a) (9a) (10a) 990 (Id) (1d) (2b) (3b) (4a) (5a) (6k) (7d) (8a) (9a) (10c) 991 (Id) (1d) (2b) (3b) (4a) (5a) (6k) (7d) (8a) (9b) (10a) 992 (Id) (1d) (2b) (3b) (4a) (5a) (6k) (7d) (8a) (9b) (10c) 993 (Id) (1d) (2b) (3b) (4d) (5b) (6a) (7a), (7b) (8a) (9a) (10a) 994 (Id) (1d) (2b) (3b) (4d) (5b) (6a) (7a), (7b) (8a) (9a) (10c) 995 (Id) (1d) (2b) (3b) (4d) (5b) (6a) (7a), (7b) (8a) (9b) (10a) 996 (Id) (1d) (2b) (3b) (4d) (5b) (6a) (7a), (7b) (8a) (9b) (10c) 997 (Id) (1d) (2b) (3b) (4d) (5b) (6a) (7d) (8a) (9a) (10a) 998 (Id) (1d) (2b) (3b) (4d) (5b) (6a) (7d) (8a) (9a) (10c) 999 (Id) (1d) (2b) (3b) (4d) (5b) (6a) (7d) (8a) (9b) (10a) 1000 (Id) (1d) (2b) (3b) (4d) (5b) (6a) (7d) (8a) (9b) (10c) 1001 (Id) (1d) (2b) (3b) (4d) (5b) (6k) (7a), (7b) (8a) (9a) (10a) 1002 (Id) (1d) (2b) (3b) (4d) (5b) (6k) (7a), (7b) (8a) (9a) (10c) 1003 (Id) (1d) (2b) (3b) (4d) (5b) (6k) (7a), (7b) (8a) (9b) (10a) 1004 (Id) (1d) (2b) (3b) (4d) (5b) (6k) (7a), (7b) (8a) (9b) (10c) 1005 (Id) (1d) (2b) (3b) (4d) (5b) (6k) (7d) (8a) (9a) (10a) 1006 (Id) (1d) (2b) (3b) (4d) (5b) (6k) (7d) (8a) (9a) (10c) 1007 (Id) (1d) (2b) (3b) (4d) (5b) (6k) (7d) (8a) (9b) (10a) 1008 (Id) (1d) (2b) (3b) (4d) (5b) (6k) (7d) (8a) (9b) (10c) 1009 (Id) (1d) (2b) (3b) (4d) (5a) (6a) (7a), (7b) (8a) (9a) (10a) 1010 (Id) (1d) (2b) (3b) (4d) (5a) (6a) (7a), (7b) (8a) (9a) (10c) 1011 (Id) (1d) (2b) (3b) (4d) (5a) (6a) (7a), (7b) (8a) (9b) (10a) 1012 (Id) (1d) (2b) (3b) (4d) (5a) (6a) (7a), (7b) (8a) (9b) (10c) 1013 (Id) (1d) (2b) (3b) (4d) (5a) (6a) (7d) (8a) (9a) (10a) 1014 (Id) (1d) (2b) (3b) (4d) (5a) (6a) (7d) (8a) (9a) (10c) 1015 (Id) (1d) (2b) (3b) (4d) (5a) (6a) (7d) (8a) (9b) (10a) 1016 (Id) (1d) (2b) (3b) (4d) (5a) (6a) (7d) (8a) (9b) (10c) 1017 (Id) (1d) (2b) (3b) (4d) (5a) (6k) (7a), (7b) (8a) (9a) (10a) 1018 (ID) (1d) (2b) (3b) (4d) (5a) (6k) (7a), (7b) (8a) (9a) (10c) 1019 (Id) (1d) (2b) (3b) (4d) (5a) (6k) (7a), (7b) (8a) (9b) (10a) 1020 (Id) (1d) (2b) (3b) (4d) (5a) (6k) (7a), (7b) (8a) (9b) (10c) 1021 (Id) (1d) (2b) (3b) (4d) (5a) (6k) (7d) (8a) (9a) (10a) 1022 (Id) (1d) (2b) (3b) (4d) (5a) (6k) (7d) (8a) (9a) (10c) 1023 (Id) (1d) (2b) (3b) (4d) (5a) (6k) (7d) (8a) (9b) (10a) 1024 (Id) (1d) (2b) (3b) (4d) (5a) (6k) (7d) (8a) (9b) (10c)

[30] Certain specific embodiments of the compounds of this invention are the compounds of embodiments 1-512 of the above table, in which the structural formula is (Ia).

[31] For example, some embodiments of the compounds described herein have any of the structural formulas (Ia)-(Ie) above, such as structural formula (Ia) or (Ie), where the variables are as described in any embodiment of this invention (for example, in relation to any of the alternative definitions of the variables L ¹ , L ² , Q, L ³ , R ³ , L ⁴ , R ⁴ , L ⁵ and R ⁵ as described herein, and in with respect to any of embodiments 1-1024 of the above table, if applicable) and where R ¹ is an unsubstituted or fluorinated C ₁ -C ₈ alkenyl. In certain such embodiments of this invention, L ¹ is a bond.

[32] For example, some embodiments of the compounds described herein have any of the structural formulas (Ia)-(Ie) above, such as structural formula (Ia) or (Ie), where the variables are as described in any embodiment of this invention (for example, in relation to any of the alternative definitions of the variables L ¹ , L ² , Q, L ³ , R ³ , L ⁴ , R ⁴ , L ⁵ and R ⁵ as described herein, and in with respect to any of embodiments 1-1024 of the above table, if applicable) and where R ¹ is phenyl optionally substituted with 1-5 R ^E. In certain such embodiments of this invention, L ¹ is a bond.

[33] Other embodiments of the compounds described herein described herein have any of the structural formulas (Ia)-(Ie) above, for example structural formula (Ia), where the variables are as described in any embodiment. implementation of this invention (for example, in relation to any of the alternative definitions of the variables L ¹ , L ² , Q, L ³ , R ³ , L ⁴ , R ⁴ , L ⁵ and R ⁵ as described herein, and in relation to any of embodiments 1-1024 of the above table, if applicable), and where R ¹ is phenyl substituted with one, two or three substituents each independently selected from fluorine, chlorine, nitro, methyl, methoxy, ethyl, ethoxy, trifluoromethyl , difluoromethyl, fluoromethyl, trifluoromethoxy, pentafluoroethyl and 2,2,2-trifluoroethoxy. In some such embodiments of this invention, L ¹ is a bond.

[34] Other embodiments of the compounds described herein have any of the structural formulas (Ia)-(Ie) above, for example, the structural formula (Ia), where the variables are as described in any embodiment as described in any embodiment of the present invention (for example, in relation to any of the alternative definitions of the variables L ¹ , L ² , Q, L ³ , R ³ , L ⁴ , R ⁴ , L ⁵ and R ⁵ as described herein, and in relation to any of embodiments 1-1024 of the above table, if applicable), and where R ¹ represents trifluoromethyl-substituted phenyl, methoxymethyl, hydroxymethyl, methoxy-substituted phenyl, or fluoro-substituted phenyl. In certain such embodiments of this invention, L ¹ is a bond.

[35] Other embodiments of the compounds described herein have any of the structural formulas (Ia)-(Ie) above, for example, the structural formula (Ia), where the variables are as described in any embodiment of the present invention (for example, in relation to any of the alternative definitions of the variables L ¹ , L ² , Q, L ³ , R ³ , L ⁴ , R ⁴ , L ⁵ and R ⁵ as described herein, and in relation to any of the embodiments 1 –1024 of the above table, if applicable), and where R ¹ is -phenyl substituted with -(OCH ₂ CH ₂ O) _n -R ^1G , where n is 1-4, N(R ^1G )C(O)CH ₂ –O–(CH ₂ CH ₂ O) _n R ^1G , where n is 0–3, or C(O)NR ^1G (CH ₂ CH ₂ O) _n R ^1G . In certain such embodiments of this invention, L ¹ is a bond.

Other embodiments of the compounds described herein have any of the structural formulas (Ia)-(Ie) above, for example, structural formula (Ia), where the variables are as described in any embodiment of this invention (for example, with respect to any of the alternative definitions of the variables L ¹ , L ² , Q, L ³ , R ³ , L ⁴ , R ⁴ , L ⁵ and R ⁵ as described herein, and with respect to any of embodiments 1-1024 of the above above table, if applicable), and where R ¹ represents hydroxymethyl, methoxymethyl, hydroxyethyl or methoxyethyl. In certain such embodiments of this invention, L ¹ is a bond.

[36] Other embodiments of the compounds described herein have any of the structural formulas (Ia)-(Ie) above, for example, the structural formula (Ia), where the variables are as described in any embodiment of the present invention. (for example, in relation to any of the alternative definitions of the variables L ¹ , R ¹ , Q, L ² , R ³ , L ³ , R ³ , L ⁵ and R ⁵ as described herein, and in relation to any of the embodiments 1 -1024 of the table above, if applicable), and where -L ⁴ -R ⁴ represents -OH or -O- (unsubstituted or fluorinated C ₁ -C ₈ -alkyl), for example, methoxy.

[37] Other embodiments of the compounds described herein have any of the structural formulas (Ia) - (Ie) above, for example, the structural formula (Ia), where the variables are as described in any embodiment of the present invention (for example, with respect to any of the alternative definitions of the variables L ¹ , R ¹ , L ² , Q, L ³ , R ³ , L ⁴ and R ⁴ , as described herein, and with respect to any of embodiments 1-1024 of the above above table if applicable) and where -L ⁵ -R ⁵ is phenyl substituted with one substituent selected from L ^5C (phenyl optionally substituted with 15 R ^5D ), L ^5C (monocyclic heteroaryl optionally substituted with 15 R ^5D ), and L ^5C (monocyclic cycloalkyl optionally substituted with 15 R ^5E ) L ^5C (monocyclic heterocycloalkyl optionally substituted with 15 R ^5E ) and (ii) optionally substituted with 15 R ^5E.

[38] Other embodiments of the compounds described herein have any of the structural formulas (Ia)-(Ie) above, for example, the structural formula (Ia), where the variables are as described in any embodiment of the present invention. (for example, with respect to any of the alternative definitions of the variables L ¹ , R ¹ , L ² , Q, L ³ , R ³ , L ⁴ and R ⁴ , as described herein, and with respect to any of embodiments 1-1024 of the above above table if applicable) and where -L ⁵ -R ⁵ is R ⁵ which is phenyl substituted with one L ^5C - (monocyclic heteroaryl optionally substituted with 15 R ^5D ) and (ii) optionally substituted with 15 R ^5E . Monocyclic heteroaryl may be, for example, oxadiazole.

[39] Other embodiments of the compounds described herein described herein have any of the structural formulas (Ia)-(Ie) above, for example structural formula (Ia), where the variables are as described in any embodiment. implementation of this invention (for example, in relation to any of the alternative definitions of the variables L ¹ , R ¹ , L ² , Q, L ³ , R ³ , L ⁴ and R ⁴ as described in this document, and in relation to any of the embodiments 1 –1024 of the above table, if applicable), and where –L ⁵ –R ⁵ is R ⁵ which is phenyl substituted with one L ^5C (monocyclic heterocycloalkyl optionally substituted with 15 R ^5E ) and (ii) optionally substituted with 15 ^R5E . The monocyclic heterocycloalkyl may be, for example, morpholinyl, eg morpholin-1-yl, or oxetanyl, eg oxetan-3-yl.

[40] Other embodiments of the compounds described herein have any of the structural formulas (Ia)-(Ie) above, for example, the structural formula (Ia), where the variables are as described in any embodiment of this invention (for example, with respect to any of the alternative definitions of the variables L ¹ , R ¹ , L ² , Q, L ³ , R ³ , L ⁴ and R ⁴ , as described herein, and with respect to any of embodiments 1-1024 of the above above table if applicable) and where -L ⁵ -R ⁵ is heterocycloalkyl optionally substituted with 15 R ^5E . The heterocycloalkyl may be, for example, a nitrogen-containing heterocycloalkyl attached to -L ⁵ - via a nitrogen atom. In some such embodiments of the invention, the heterocycloalkyl is monocyclic. In other such embodiments of the invention, the heterocycloalkyl is bicyclic. In some such embodiments of this invention, the heterocycloalkyl is saturated. In the various embodiments of the invention described herein, the heterocycloalkyl is morpholinyl (e.g., morpholin-1-yl), 1,4-dioxaspiro[4,5]dec-enyl (e.g., 1,4-dioxaspiro[4, 5]dec-en-8-yl), piperidinyl (e.g. piperidin-1-yl), azabicyclo[3.2.1]octanyl (e.g. azabicyclo[3.2.1]octan-8-yl), piperazinyl (e.g. piperazine -1-yl), pyrrolidinyl (for example, pyrrolidin-1-yl) or azaspiro[2.5]octanyl (for example, azaspiro[2.5]octan-6-yl).

[41] Other embodiments of the compounds described herein have any of the structural formulas (Ia) - (Ie) above, for example, the structural formula (Ia), where the variables are as described in any embodiment of this invention (for example, with respect to any of the alternative definitions of the variables L ¹ , R ¹ , L ² , Q, L ³ , R ³ , L ⁴ and R ⁴ , as described herein, and with respect to any of embodiments 1-1024 of the above above table if applicable) and where -L ⁵ -R ⁵ is heterocycloalkyl substituted with one L ^5C (monocyclic cycloalkyl optionally substituted with 15 R ^5E ) substituent, and (ii) optionally substituted with 15 R ^5E . The heterocycloalkyl may be, for example, a nitrogen-containing heterocycloalkyl attached to -L ⁵ - via a nitrogen atom. In some such embodiments of the invention, the heterocycloalkyl is monocyclic. In other such embodiments of the invention, the heterocycloalkyl is bicyclic. In some such embodiments of this invention, the heterocycloalkyl is saturated. In the various embodiments of the invention described herein, the heterocycloalkyl is morpholinyl (e.g., morpholin-1-yl), 1,4-dioxaspiro[4,5]dec-enyl (e.g., 1,4-dioxaspiro[4, 5]dec-en-8-yl), piperidinyl (e.g. piperidin-1-yl), azabicyclo[3.2.1]octanyl (e.g. azabicyclo[3.2.1]octan-8-yl), piperazinyl (e.g. piperazine -1-yl), pyrrolidinyl (for example, pyrrolidin-1-yl) or azaspiro[2.5]octanyl (for example, azaspiro[2.5]octan-6-yl). Cycloalkyl may be, for example, saturated cycloalkyl, such as saturated C ₃ -C ₅ cycloalkyl, eg cyclopropyl.

[42] Other embodiments of the compounds described herein described herein have any of the structural formulas (Ia)-(Ie) above, for example structural formula (Ia), where the variables are as described in any embodiment. implementation of this invention (for example, in relation to any of the alternative definitions of the variables L ¹ , R ¹ , L ² , Q, L ³ , R ³ , L ⁴ and R ⁴ as described in this document, and in relation to any of the embodiments 1 -1024 of the table above, if applicable), and where -L ⁵ -R ⁵ is cycloalkyl optionally substituted with 15 R ^5E . In certain such embodiments of this invention, the cycloalkyl is monocyclic. In other such embodiments of this invention, the cycloalkyl is bicyclic. In certain such embodiments of this invention, the cycloalkyl is saturated. In various embodiments of the invention described herein, cycloalkyl is cyclohexenyl (eg, cyclohexen-1-yl, eg, 4-trifluoromethylcyclohexen-1-yl) or cyclohexyl.

[43] Other embodiments of the compounds described herein described herein have any of the structural formulas (Ia)-(Ie) above, for example structural formula (Ia), where the variables are as described in any embodiment. implementation of this invention (for example, in relation to any of the alternative definitions of the variables ¹ , R ¹ , L ² , Q, L ³ , R ³ , L ⁴ and R ⁴ as described herein, and in relation to any of the embodiments 1– 1024 of the table above, if applicable), and where -L ⁵ -R ⁵ represents phenyl substituted with one, two or three substituents, each independently selected from fluorine, chlorine, nitro, methyl, methoxy, ethyl, ethoxy, trifluoromethyl , difluoromethyl, fluoromethyl, trifluoromethoxy, pentafluoroethyl and 2,2,2-trifluoroethoxy. In certain such embodiments of this invention, L ⁵ is a bond.

[44] In certain additional embodiments of this invention, including any of the embodiments described with reference to Formulas (I) and (Ia)-(If) and Embodiments 1-1024 above, each optionally substituted alkylene, alkenylene, and alkynylene , which is specified in any of the previous embodiments, is unsubstituted. In alternative additional embodiments of this invention, including any of the embodiments described with reference to Formulas (I)-(Io) and Embodiments 1-1024 above, each optionally substituted alkylene, alkenylene, and alkynylene that is specified in any of the preceding embodiments, is unsubstituted or fluorinated.

[45] In certain additional embodiments of this invention, including any of the embodiments described with reference to formulas (I) and (Ia)-(If), and embodiments 1-1024 above, and any embodiment described in paragraph immediately above, each optionally substituted alkyl, alkenyl, and alkynyl as defined in any of the previous embodiments is unsubstituted. In alternative additional embodiments of this invention, including any of the embodiments described with reference to Formulas (I)-(Io) and Embodiments 1-1024 above, and any embodiment described in the paragraph immediately above, each optionally substituted alkyl , alkenyl and alkynyl, which is specified in any of the previous embodiments, is unsubstituted.

[46] In certain additional embodiments of the present invention, including any of the embodiments described with reference to Formulas (I) and (Ia)-(If) and Embodiments 1-1024 above, and any of the embodiments described in the two paragraphs immediately above, each cycloalkyl referred to in any of the previous embodiments of this invention is a 3-7 membered monocyclic cycloalkyl. In certain additional embodiments of this invention, including any of the embodiments described with reference to Formulas (I) and (Ia) - If) and Embodiments 1-1024 above, and any embodiment described in the two paragraphs immediately above, each cycloalkyl referred to in any of the previous embodiments of this invention is cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl or cyclohexenyl.

[47] In certain additional embodiments of the present invention, including any of the embodiments described with reference to Formulas (I) and (Ia)-(If) and Embodiments 1-1024 above, and any of the embodiments described in the three paragraphs immediately above, each heterocycloalkyl referred to in any of the previous embodiments of this invention is a 4-7 membered monocyclic heterocycloalkyl having 1-2 heteroatoms selected from O, S and N. For example, in certain specific embodiments of this invention , including any of the embodiments described with reference to Formulas (I) and (Ia)-(If) and Embodiments 1-1024 above, and any embodiment described in the three paragraphs immediately above, each heterocycloalkyl specified in any from previous embodiments of this invention, is pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, piperazinyl, morphol inyl, thiomorpholinyl, tetrahydro-2H-pyranyl or tetrahydro-2H-thiopyranyl.

[48] In certain additional embodiments of the present invention, including any of the embodiments described with reference to Formulas (I) and (Ia)-(If) and Embodiments 1-1024 above, and any of the embodiments described in the four paragraphs immediately above, each heteroaryl is a 5-6 membered monocyclic heteroaryl having 1-3 heteroatoms selected from O, S, and N. For example, in certain specific embodiments of this invention, including any of the embodiments described with reference to formulas (I) and (Ia)-(If), and embodiments 1-1024 above, and any embodiment described in the four paragraphs immediately above, each heteroaryl is furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, or thiazolyl .

[49] In certain additional embodiments of the present invention, including any of the embodiments described with reference to Formulas (I) and (Ia)-(If) and Embodiments 1-1024 above, and any of the embodiments described in the four paragraphs immediately above, each aryl is a phenyl.

[50] In certain additional embodiments of this invention as described above, including any of the embodiments described with reference to formulas (I) and (Ia)-(If), and embodiments 1-1024 above, and any embodiment , described in the four paragraphs immediately above, R ⁵ is substituted with 1, 2 or 3 substituents selected from halogen (for example, chloro- or fluoro-) and fluorinated C ₁ -C ₃ -alkyl (for example, trifluoromethyl, difluoromethyl, fluoromethyl, pentafluoroethyl, trifluoroethyl). For example, in a certain embodiment of this invention as described above, R ⁵ is phenyl substituted (e.g., 3-substituted, 4-substituted, 3,4-disubstituted, 2,4-disubstituted, or 2,5-disubstituted) with one or two substituents selected from trifluoromethyl, fluorine and chlorine. For example, in specific embodiments of this invention, R ⁵ may be dichlorophenyl, eg 3,4-dichlorophenyl, or trifluoromethylphenyl, eg 4-trifluoromethylphenyl.

[51] In certain embodiments of this invention, said compound is one of the compounds in the table of compounds below, optionally presented as a pharmaceutically acceptable salt or N-oxide and/or solvate or hydrate. The table presents data on the proliferation of BJAB cells; "A" denotes a measured EC ₅₀ value less than or equal to 1 μM; "B" denotes a measured value of EC ₅₀ greater than 1 μm and less than or equal to 5 μm; "C" denotes a measured EC ₅₀ value greater than 5 μM and less than or equal to 10 μM; "D" denotes a measured EC ₅₀ value greater than 10 μM and less than or equal to 25 μM; "E" denotes a measured value of EC ₅₀ greater than 25 μm and less than or equal to 50 μm; "F" denotes a measured EC ₅₀ value greater than 50 μM and less than or equal to 100 μM; "G" means that in the experiments carried out there was no measured value of the EU ₅₀ less than or equal to 80 μm; "H" means that in the experiments carried out there was no measured value of the EU ₅₀ less than or equal to 50 μm; "I" means that in the experiments carried out there was no measured value of the EU ₅₀ less than or equal to 40 μm; "J" means that in the experiments carried out there was no measured value of the EU ₅₀ less than or equal to 25 μm; "K" means that in the experiments carried out there was no measured value of the EU ₅₀ less than or equal to 20 μm; and "L" means that in the experiments performed there was no measured value of the EC ₅₀ less than or equal to 5 μm.

Comm Composition Name BJAB 1

1–(4–(4–chloro–2–(oxetan–3–yloxy)phenyl)–5–(isopropylthio)thiazol–2–yl –3–methyl–1H–pyrazole–5–carboxylic acid I 2

1–(4–(4–chloro–3–(oxetan–3–yloxy)phenyl)–5–(isopropylthio)thiazol–2–yl –3–methyl–1H–pyrazole–5–carboxylic acid I 3

4–(3-fluorophenyl)–1–(5–(isopropylthio)–4–(4–(5–methyl–1,3,4–oxadiazol–2–yl)phenyl)thiazol–2–yl)–3– methyl-1H-pyrazole-5-carboxylic acid E four

4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-methylcyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid AT five

4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohexen-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazol- 5-carboxylic acid AND 6

1-(4-(4,4-dimethylcyclohex-1-en-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5 –carboxylic acid AND 7

4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(1,4-dioxaspiro [4,5]dec-7-en-8-yl)thiazol-2-yl)-3-methyl –1H-pyrazole-5-carboxylic acid E 8

1–(4–(4–chloro–3–(morpholine–4–carbonyl)phenyl)–5–(isopropylthio)thiazol–2–yl)–4–(3–fluorophenyl)–3–methyl–1H–pyrazole– 5-carboxylic acid I nine

4-(3,4-dichlorophenyl)-2-(4-(2,6-dimethylpyridin-4-yl)-3-methyl-1H-pyrazol-1-yl)-5-(isopropylthio)thiazole A, C, L 10

2-(4-(3-fluorophenyl)-3,5-dimethyl-1H-pyrazol-1-yl)-5-(isopropylthio)-4-(4-(trifluoromethyl)phenyl)thiazole I eleven

4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(piperidin-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid D 12

4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)piperidin-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid AND 13

4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methoxy-1H-pyrazole-5-carboxylic acid AT fourteen

4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-morpholinothiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid I 15

4-(3-fluorophenyl)-3-hydroxy-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-1H-pyrazole-5-carboxylic acid To sixteen

1-(5-(3,4-dichlorophenyl)-1-isobutyl-1H-1,2,4-triazol-3-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5- carboxylic acid To 17

1-(3-(3,4-dichlorophenyl)-1-isobutyl-1H-1,2,4-triazol-5-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5- carboxylic acid To eighteen

1-(4-(4,4-difluoropiperidin-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid AT nineteen

methyl 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole -5-carboxylate (enantiomerically pure - unknown stereochemistry) AND 20

methyl 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole -5-carboxylate (enantiomerically pure - unknown stereochemistry) AND 21

4-(3-fluorophenyl)-3-methyl-1-(4-(4-(trifluoromethyl)cyclohexyl)thiazol-2-yl)-1H-pyrazole-5-carboxylic acid To 22

4-(3-fluorophenyl)-1-(5-isobutyl-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid AND 23

4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)thiazol-2-yl)-3-methyl-1H- pyrazole-5-carboxylic acid FROM 24

1-(4-(4-cyanopiperidin-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid D 25

1–(4–(4–cyclopropylpiperazin–1–yl)–5–(isopropylthio)thiazol–2–yl)–4–(3–fluorophenyl)–3–methyl–1H–pyrazole–5–carboxylic acid FROM 26

1–(4–(4–ethylpiperazin–1–yl)–5–(isopropylthio)thiazol–2–yl)–4–(3–fluorophenyl)–3–methyl–1H–pyrazol–5–carboxylic acid To 27

1–(4–(4–acetylpiperazin–1–yl)–5–(isopropylthio)thiazol–2–yl)–4–(3–fluorophenyl)–3–methyl–1H–pyrazole–5–carboxylic acid To 28

4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-methylpiperidin-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid AT 29

4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-methylpiperazin-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid thirty

4-(3-fluorophenyl)-3-methyl-1-(5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)-1H-pyrazole-5-carboxylic acid To 31

4-(3-fluorophenyl)-1-(5-((2-methoxyethyl)(methyl)amino)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole- 5-carboxylic acid AT 32

1-(4-(4,4-dimethylpiperidin-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid AND 33

1–(4–(4–(tert–butoxycarbonyl)piperazin–1–yl)–5–(isopropylthio)thiazol–2–yl)–4–(3–fluorophenyl)–3–methyl–1H–pyrazol–5– carboxylic acid To 34

4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(3-(trifluoromethyl)pyrrolidin-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid AT 35

4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(piperazin-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid salt of hydrochloric acid To 36

4-(3-fluorophenyl)-3-methyl-1-(5-(2-methylprop-1-en-1-yl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-1H- pyrazole-5-carboxylic acid AND 37

4-(3-fluorophenyl)-3-methyl-1-(4-(2-methylprop-1-en-1-yl)-5-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-1H- pyrazole-5-carboxylic acid D 38

1-(4,5-bis(4-(trifluoromethyl)phenyl)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid AND 39

2-(4-(3-fluorophenyl)-3-methyl-1H-pyrazol-1-yl)-4,5-bis(4-(trifluoromethyl)phenyl)thiazole To 40

1-(4-(4-(tert-butyl)piperidin-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazol-5- carboxylic acid AND 41

4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(6-azaspiro[2,5]octan-6-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5 –carboxylic acid AT 42

4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-methoxy-4-(trifluoromethyl)piperidin-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole 5 –carboxylic acid AND 43

4-(3-fluorophenyl)-1-(4-(4-methoxyphenyl)-5(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid AT 44

1-(4,5-bis(4-methoxyphenyl)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid D 45

4-(3-fluorophenyl)-1-(5-(4-methoxyphenyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid AND 46

1–(4–(4–(tert-butyl)–3–oxo–1–yl)–5–(isopropylthio)thiazol–2–yl)–4–(3–fluorophenyl)–3–methyl–1H–pyrazole -5-carboxylic acid To 47

4-(3-fluorophenyl)-3-methyl-1-(5-(3-(methylamino)-3-oxopropyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-1H-pyrazol- 5-carboxylic acid To 48

4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(2-methoxyethoxy)-4-(trifluoromethyl)piperidin-1-yl)thiazol-2-yl)-3-methyl- 1H-pyrazole-5-carboxylic acid AT 49

4-(3-fluorophenyl)-1-(5-(4-((2-methoxyethyl)carbamoyl)phenyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H- pyrazole-5-carboxylic acid To 50

4-(3-fluorophenyl)-1-(5-(4-((2-methoxyethyl)(methyl)carbamoyl)phenyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl -1H-pyrazole-5-carboxylic acid To 51

4-(3-fluorophenyl)-1-(5-(4-(2-methoxyacetamido)phenyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5 –carboxylic acid D 52

4-(3-fluorophenyl)-1-(5-(4-(2-(2-methoxyethoxy)acetamido)phenyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl- 1H-pyrazole-5-carboxylic acid D 53

4-(3-fluorophenyl)-1-(5-(3-((2-methoxyethyl)amino)-3-oxopropyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl -1H-pyrazole-5-carboxylic acid To 54

4-(3-fluorophenyl)-1-(5-(3-((2-methoxyethyl)(methyl)amino)-3-oxopropyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)- 3-methyl-1H-pyrazole-5-carboxylic acid To 55

4-(3-fluorophenyl)-1-(5-(4-(2-methoxy-N-methylacetamido)phenyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H -pyrazole-5-carboxylic acid To 56

4-(3-fluorophenyl)-1-(5-(4-(2-(2-methoxyethoxy)-N-methylacetamido)phenyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3 –methyl–1H –pyrazole–5–carboxylic acid To 57

4-(3-fluorophenyl)-1-(5-(methoxymethyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid FROM 58

1–(5–(4–(2–(2–ethoxyethoxy)ethoxy)phenyl)–4–(4–(trifluoromethyl)phenyl)thiazol–2–yl)–4–(3–fluorophenyl)–3–methyl– 1H-pyrazole-5-carboxylic acid AT 59

4-(3-fluorophenyl)-1-(5-(3-fluorophenyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid AND 60

4-(3-fluorophenyl)-1-(5-(hydroxymethyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid To 61

4-(3-fluorophenyl)-3-methyl-1-(5-(4-(trifluoromethyl)phenyl)-4-(4-(trifluoromethyl)piperidin-1-yl)thiazol-2-yl)-1H-pyrazole -5-carboxylic acid AND 62

4-(3-fluorophenyl)-1-(4-(3-fluorophenyl)-5-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid FROM 63

4-(3-fluorophenyl)-1-(5-(1-hydroxyethyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid To 64

4-(3-fluorophenyl)-1-(5-(2-hydroxyethyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid To 65

4-(3-fluorophenyl)-1-(5-(4-(2-methoxyethoxy)phenyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5 –carboxylic acid AT 66

4-(3-fluorophenyl)-1-(5-1-methoxyethyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid FROM 67

4-(3-fluorophenyl)-1-(4-(4-isopropylpiperidin-1-yl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid AT 68

4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(3-methoxy-3-(trifluoromethyl)-8-azabicyclo[3.2.1]octan-8-yl)thiazol-2-yl) -3-methyl-1H-pyrazole-5-carboxylic acid -

The compounds described herein may, in certain embodiments of the present invention, contain one or more asymmetric carbon atoms, such that the compounds may exist in various stereoisomeric forms. These compounds may be, for example, racemates, chiral non-racemic compounds or diastereomers. In these situations, individual enantiomers, that is, optically active forms, can be obtained by asymmetric synthesis or resolution of racemates. Separation of racemates can be achieved, for example, by conventional methods such as crystallization in the presence of a separating agent; chromatography using, for example, a chiral HPLC column; or derivatizing the racemic mixture with a resolving agent to obtain diastereomers, separating the diastereomers by chromatography, and removing the resolving agent to give the parent compound in an enantiomerically enriched form. Any of the above procedures can be repeated to increase the enantiomeric purity of the compound.

When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry and, unless otherwise indicated, these compounds are meant to include cis, trans, Z- and E-configurations. Likewise, all tautomeric forms are also proposed for inclusion.

[52] In certain embodiments of the methods, compounds, and uses described herein, said compound is not one of the compounds listed below:

methyl 1-(4-(3,4-dichlorophenyl)thiazol-2-yl)-3-methyl-4-(2-nitrobenzyl)-1H-pyrazole-5-carboxylate;

1-(4-(3,4-dichlorophenyl)thiazol-2-yl)-3-methyl-4-(2-nitrobenzyl)-1H-pyrazole-5-carboxylic acid;

methyl 1-(4-(3,4-dichlorophenyl)-5-(ethylthio)thiazol-2-yl)-3-methyl-4-(2-nitrobenzyl)-1H-pyrazole-5-carboxylate;

1-(4-(3,4-dichlorophenyl)-5-(ethylthio)thiazol-2-yl)-3-methyl-4-(2-nitrobenzyl)-1H-pyrazole-5-carboxylic acid;

methyl 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4-(2-nitrobenzyl)-1H-pyrazole-5-carboxylate;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4-(2-nitrobenzyl)-1H-pyrazole-5-carboxylic acid;

methyl 1-(4-(3,4-dichlorophenyl)thiazol-2-yl)-3-methyl-4-(2-(methylsulfonamido)benzyl)-1H-pyrazole-5-carboxylate;

1-(4-(3,4-dichlorophenyl)thiazol-2-yl)-3-methyl-4-(2-(methylsulfonamido)benzyl)-1H-pyrazole-5-carboxylic acid;

methyl 1-(4-(3,4-dichlorophenyl)-5-(propylthio)thiazol-2-yl)-3-methyl-4-(2-nitrobenzyl)-1H-pyrazole-5-carboxylate;

1-(4-(3,4-dichlorophenyl)-5-(propylthio)thiazol-2-yl)-3-methyl-4-(2-nitrobenzyl)-1H-pyrazole-5-carboxylic acid;

methyl 1-(5-(butylthio)-4-(3,4-dichlorophenyl)thiazol-2-yl)-3-methyl-4-(2-nitrobenzyl)-1H-pyrazole-5-carboxylate;

1-(5-(butylthio)-4-(3,4-dichlorophenyl)thiazol-2-yl)-3-methyl-4-(2-nitrobenzyl)-1H-pyrazole-5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(propylthio)thiazol-2-yl)-3-methyl-4-(2-(methylsulfonamido)benzyl)-1H-pyrazole-5-carboxylic acid;

N–(2–((5–(4–(aminomethyl)piperidine–1–carbonyl)–1–(4–(3,4–dichlorophenyl)–5–(propylthio)thiazol–2–yl)–3–methyl -1H-pyrazol-4-yl)methyl)phenyl)methanesulfonamide;

4-bromo-1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(imidazo [1,2-a]pyridin-6-yl)-3-methyl-1H-pyrazole -5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4-phenyl-1H-pyrazole-5-carboxylic acid;

1-(5-(cyclohexylthio)-4-(3,4-dichlorophenyl)thiazol-2-yl)-3-methyl-4-(2-nitrobenzyl)-1H-pyrazole-5-carboxylic acid;

4-(benzofuran-2-yl)-1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(2-fluoropyridin-4-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

2–(4–(3,4–dichlorophenyl)–5–(isopropylthio)thiazol–2–yl)–2', 5,5'–trimethyl–4,4'–bi(2H–pyrazole)–3–carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(2,6-dimethylpyridin-4-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3,5-difluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(5-chloro-2-fluorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3,5-dichlorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1–(4–(5–chloro–2–fluorophenyl)–5–(isopropylthio)thiazol–2–yl)–4–(2,6–dimethylpyridin–4–yl)–3–methyl–1H–pyrazole–5 – carboxylic acid;

4-(3,5-dichlorophenyl)-1-(4-(3,5-dimethylisoxazol-4-yl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

4-(3,5-dichlorophenyl)-1-(5-(isopropylthio)-4-(1-methyl-1H-pyrazol-4-yl)thiazol-2-yl)-3-methyl-1H-pyrazol-5 – carboxylic acid;

4-(3,5-dichlorophenyl)-1-(5-(isopropylthio)-4-(pyridin-4-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

4-(3,5-dichlorophenyl)-1-(5-(isopropylthio)-4-(pyridin-3-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

4-(3,5-dichlorophenyl)-1-(4-(imidazo[1,2-a]pyridin-6-yl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole -5-carboxylic acid;

methyl 1-(5-(sec-butylthio)-4-(3,4-dichlorophenyl)thiazol-2-yl)-4-(3,5-dichlorophenyl)-3-methyl-1H-pyrazole-5-carboxylate;

1-(5-(sec-butylthio)-4-(3,4-dichlorophenyl)thiazol-2-yl)-4-(3,5-dichlorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid;

methyl 1-(5-(sec-butylthio)-4-(3,4-dichlorophenyl)thiazol-2-yl)-4-(2,6-dimethylpyridin-4-yl)-3-methyl-1H-pyrazol- 5-carboxylic acid;

1-(5-(sec-butylthio)-4-(3,4-dichlorophenyl)thiazol-2-yl)-4-(2,6-dimethylpyridin-4-yl)-3-methyl-1H-pyrazol-5 – carboxylic acid;

4-(2,6-dimethylpyridin-4-yl)-1-(5-(isopropylthio)-4-(2-methoxyphenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

4-(2,6-dimethylpyridin-4-yl)-1-(5-(isopropylthio)-4-(3-methoxyphenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

4-(2,6-dimethylpyridin-4-yl)-1-(5-(isopropylthio)-4-(4-methoxyphenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

4-(2,6-dimethylpyridin-4-yl)-1-(5-(isopropylthio)-4-phenylthiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1–(4–(3,4-dichlorophenyl)–5–(isopropylthio)thiazol–2–yl)–4–(3– (hydroxymethyl)–5–methylisoxazol–4–yl)–3–methyl–1H–pyrazole -5-carboxylic acid;

1–(4–(3,4-dichlorophenyl)–5–(isopropylthio)thiazol–2–yl)–4–(3– (methoxymethyl)–5–methylisoxazol–4–yl)–3–methyl–1H–pyrazole -5-carboxylic acid;

4-(2,6-dimethylpyridin-4-yl)-1-(5-(isopropylthio)-4-p-tolylthiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

4-(2,6-dimethylpyridin-4-yl)-1-(5-(isopropylthio)-4-m-tolylthiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

4-(2,6-dimethylpyridin-4-yl)-1-(5-(isopropylthio)-4-o-tolylthiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

4-(2,6-dimethylpyridin-4-yl)-1-(5-(isopropylthio)-4-(phenylethynyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4-(pyridin-3-yl)-1H-pyrazole-5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(methylthio)thiazol-2-yl)-3-methyl-4-(2-nitrobenzyl)-1H-pyrazole-5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3-(hydroxymethyl)phenyl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4-(pyridin-4-yl)-1H-pyrazole-5-carboxylic acid;

4-(3-(aminomethyl)phenyl)-1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(4-(hydroxymethyl)phenyl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4-(2-(trifluoromethyl)phenyl)-1H-pyrazole-5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4-(3-(trifluoromethyl)phenyl)-1H-pyrazole-5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4-(4-(trifluoromethyl)phenyl)-1H-pyrazole-5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(hydroxy(phenyl)methyl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylsulfinyl)thiazol-2-yl)-3-methyl-4-(2-nitrobenzyl)-1H-pyrazole-5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylsulfonyl)thiazol-2-yl)-3-methyl-4-(2-nitrobenzyl)-1H-pyrazole-5-carboxylic acid;

4–([1,2,4]triazolo[4,3–a]pyridin–3–yl)–1–(4–(3,4–dichlorophenyl)–5–(isopropylthio)thiazol–2–yl)– 3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3,5-dimethylisoxazol-4-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

4-(1H-benzo[d]imidazol-2-yl)-1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5 – carboxylic acid;

4-(3-chloro-2-methylphenyl)-1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

4-(3,5-bis(trifluoromethyl)phenyl)-1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3-isopropylphenyl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(2-methoxy-5-methylphenyl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(1H-imidazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4-(pyrazolo[1,5-a]pyridin-3-yl)-1H-pyrazol -5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4-(pyrazolo [1,5-a]pyrimidin-3-yl)-1H-pyrazol -5-carboxylic acid;

2-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-2', 5-dimethyl-4,4'-bi(2H-pyrazole)-3-carboxylic acid;

2-(4-(3,4-dichlorophenyl)-5-(isopropylsulfonyl)thiazol-2-yl)-2', 5-dimethyl-4,4'-bi(2H-pyrazole)-3-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4-(1-methyl-1H-benzo[d]imidazol-2-yl)-1H -pyrazole-5-carboxylic acid;

4-(5-cyanopyridin-3-yl)-1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(2-ethoxypyridin-3-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

2'-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-2,5,5'-trimethyl-3,4'-bi(2H-pyrazole)-3'- carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4-(pyrimidin-5-yl)-1H-pyrazole-5-carboxylic acid;

4-(3,5-bis(trifluoromethyl)phenyl)-1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(4,6-dimethylpyrimidin-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

4–(3,5–bis(trifluoromethyl)phenyl)–1–(4–(3,4–dichlorophenyl)–5–(isopropylthio)thiazol–2–yl)–3–methyl–N–(pyridine–2– ylmethyl)-1H-pyrazole-5-carboxamide;

4–(3,5–bis(trifluoromethyl)phenyl)–1–(4–(3,4–dichlorophenyl)–5–(isopropylthio)thiazol–2–yl)–N–(2–hydroxyethyl)–N, 3 dimethyl-1H-pyrazole-5-carboxamide;

4–(3,5–bis(trifluoromethyl)phenyl)–1–(4–(3,4–dichlorophenyl)–5–(isopropylthio)thiazol–2–yl)–N,3–dimethyl–N–(5– (trifluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-pyrazole-5-carboxamide;

(4–(3,5–bis(trifluoromethyl)phenyl)–1–(4–(3,4–dichlorophenyl)–5–(isopropylthio)thiazol–2–yl)–3–methyl–1H–pyrazole–5– yl)(3-(diethylamino)pyrrolidin-1-yl)methanone;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4-(pyrazin-2-yl)-1H-pyrazol-5-carboxylic acid;

4-(3-cyano-5-methylphenyl)-1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

4-(3,5-bis(trifluoromethyl)phenyl)-1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-N-(1H-tetrazole 5 –yl)–1H–pyrazole–5–carboxamide;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4-(5-methyl-1,3,4-thiadiazol-2-yl)-1H -pyrazole-5-carboxylic acid;

4-(3-cyano-5-methoxyphenyl)-1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

4–(3–cyano–5–(trifluoromethyl)phenyl)–1–(4–(3,4–dichlorophenyl)–5–(isopropylthio)thiazol–2–yl)–3–methyl–1H–pyrazole–5– carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3-(methoxymethyl)phenyl)-3-methyl-1H-pyrazole-5-carboxylic acid;

4-(3-benzyl-5-methylisoxazol-4-yl)-1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5 – carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3-((dimethylamino)methyl)phenyl)-3-methyl-1H-pyrazole-5-carboxylic acid;

(1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4-phenyl-1H-pyrazol-5-yl)methanol;

4–(benzo[d][1,3]dioxol–5–yl)–1–(4–(3,4–dichlorophenyl)–5–(isopropylthio)thiazol–2–yl)–3–methyl–1H– pyrazole-5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(4-methoxypyrimidin-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(isothiazol-4-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4-(3-methylisothiazol-5-yl)-1H-pyrazole-5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl) -1H-pyrazole-5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3 -methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluoro-5-methylphenyl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3-hydroxy-5-methylphenyl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3-isopropoxy-5-methylphenyl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4-(3-methyl-5-(oxetan-3-yloxy)phenyl)-1H- pyrazole-5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3-(dimethylamino)-5-methylphenyl)-3-methyl-1H-pyrazole-5-carboxylic acid;

4–(3–(1H-imidazol-1-yl)-5-methylphenyl)-1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H -pyrazole-5-carboxylic acid;

4-(2-(azetidin-1-yl)-6-methylpyridin-4-yl)-1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl -1H-pyrazole-5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4-(2-methyl-6-morpholinopyridin-4-yl)-1H-pyrazol-5 – carboxylic acid;

1-(5-(isopropylthio)-4-(3-methoxyphenyl)thiazol-2-yl)-3-methyl-4-(2-nitrobenzyl)-1H-pyrazole-5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopentylthio)thiazol-2-yl)-3-methyl-4-(2-nitrobenzyl)-1H-pyrazole-5-carboxylic acid;

1-(5-(isopropylthio)-4-(3-methoxyphenyl)thiazol-2-yl)-3-methyl-4-(2-(methylsulfonamido)benzyl)-1H-pyrazole-5-carboxylic acid;

1-(5-(sec-butylthio)-4-(3,4-dichlorophenyl)thiazol-2-yl)-3-methyl-4-(2-nitrobenzyl)-1H-pyrazole-5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(1H-indol-6-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4-(3-nitrophenyl)-1H-pyrazole-5-carboxylic acid;

2-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-5-methyl-4,4"-bi(2H-pyrazole)-3-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(1H-indol-3-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

4-(2-chlorophenyl)-1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

4-(3-chlorophenyl)-1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

4-(4-chlorophenyl)-1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(2-methoxyphenyl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3-methoxyphenyl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(4-methoxyphenyl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4-o-tolyl-1H-pyrazole-5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4-m-tolyl-1H-pyrazole-5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4-p-tolyl-1H-pyrazole-5-carboxylic acid;

4-(4-acetamidophenyl)-1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4-(2-(methylsulfonamido)benzyl)-1H-pyrazole-5-carboxylic acid;

1–(4–(3,4–dichlorophenyl)–5–(isopropylthio)thiazol–2–yl)–4–(2–(N, N–dimethylsulfamoylamino)benzyl)–3–methyl–1H–pyrazol–5– carboxylic acid;

4-(4-aminophenyl)-1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4-(4-(methylsulfonamido)phenyl)-1H-pyrazole-5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4-(3-(methylsulfonamido)phenyl)-1H-pyrazole-5-carboxylic acid;

2-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-2'-(2-methoxyethyl)-5-methyl-4,4'-bi(2H-pyrazole)- 3-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(1H-indol-7-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

2-(4-(1H-indol-7-yl)-3-methyl-1H-pyrazol-1-yl)-4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazole;

2-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-2'-ethyl-5-methyl-4,4'-bi(2H-pyrazole)-3-carboxylic acid ;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-N-(2-methoxyethyl)-3-methyl-4-m-tolyl-1H-pyrazole-5-carboxylic acid;

(4-(aminomethyl)piperidin-1-yl)(1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4-o-tolyl-1H- pyrazol-5-yl) methanone;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(5-methoxypyridin-3-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

2-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-2'-isobutyl-5-methyl-4,4'-bi(2H-pyrazole)-3-carboxylic acid ;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4-(2-(methylamino)pyridin-4-yl)-1H-pyrazol-5- carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-1'-(dimethylcarbamoyl)-3-methyl-1H,1'H-[4,4'-bipyrazole] -5-carboxylic acid;

(4-(aminomethyl)piperidin-1-yl)(4-(3,5-bis(trifluoromethyl)phenyl)-1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl )-3-methyl-1H-pyrazol-5-yl) methanone;

N-(2-aminoethyl)-4-(3,5-bis(trifluoromethyl)phenyl)-1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-N,3 -dimethyl-1H-pyrazole-5-carboxamide;

(3-aminoazetidin-1-yl)(4-(3,5-bis(trifluoromethyl)phenyl)-1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3 -methyl-1H-pyrazol-5-yl) methanone;

(4–(3,5–bis(trifluoromethyl)phenyl)–1–(4–(3,4–dichlorophenyl)–5–(isopropylthio)thiazol–2–yl)–3–methyl–1H–pyrazole–5– yl)(morpholino)methanone;

4-(3,5-bis(trifluoromethyl)phenyl)-1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-N, N, 3-trimethyl-1H-pyrazole –5–carboxamide;

(4–(3,5–bis(trifluoromethyl)phenyl)–1–(4–(3,4–dichlorophenyl)–5–(isopropylthio)thiazol–2–yl)–3–methyl–1H–pyrazole–5– yl)(4-(hydroxymethyl)piperidin-1-yl)methanone;

1-(4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-yl)-1', 3-dimethyl-1Н, 1'Н-[4,4'-bipyrazole]-5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3,5-dimethylphenyl)-3-methyl-1H-pyrazole-5-carboxylic acid;

4-(3,5-dichlorophenyl)-1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

4-(3-chloro-5-methoxyphenyl)-1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3-methoxy-5-(trifluoromethyl)phenyl)-3-methyl-1H-pyrazole-5- carboxylic acid;

4-(3-chloro-5-methylphenyl)-1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

4–(3,5–bis(trifluoromethyl)phenyl)–1–(4–(3,4–dichlorophenyl)–5–(isopropylthio)thiazol–2–yl)–3–methyl–N–(methylsulfonyl)–1H pyrazole-5-carboxamide;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(imidazo[1,2-а]pyridin-3-yl)-3-methyl-1H-pyrazole -5-carboxylic acid;

4-(3,5-dichlorophenyl)-1-(4-(3,5-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluoro-5-hydroxyphenyl)-3-methyl-1H-pyrazole-5-carboxylic acid;

4-(3-amino-5-methylphenyl)-1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

4-(3-chloro-5-hydroxyphenyl)-1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4-(1-methyl-1H-indol-7-yl)-1H-pyrazol-5 – carboxylic acid;

4-(3,4-dichlorophenyl)-5-(isopropylthio)-2-(1H-pyrazol-1-yl)thiazole;

1-(4-(2-chlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(2,6-dimethylpyridin-4-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(3-chlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(2,6-dimethylpyridin-4-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(4-chlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(2,6-dimethylpyridin-4-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(2,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(2,6-dimethylpyridin-4-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(2,5-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(2,6-dimethylpyridin-4-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

4-(2,6-dimethylpyridin-4-yl)-1-(5-(isopropylthio)-4-(phenylethynyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-benzyl-5-(isopropylthio)thiazol-2-yl)-4-(2,6-dimethylpyridin-4-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluoro-5-methoxyphenyl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3-methoxy-5-methylphenyl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(2-methoxypyridin-4-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4-(2-methylpyridin-4-yl)-1H-pyrazole-5-carboxylic acid;

1-(4-(1H-indol-4-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(3-fluorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(1H-indol-4-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(1H-indol-5-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(cyclopropylethynyl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid;

4-cyclopropyl-1-(4-cyclopropyl-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

4-cyclopropyl-1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

4-(3-chloro-5-isopropoxyphenyl)-1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

4–(3–chloro–5–(2–methoxyethoxy)phenyl)–1–(4–(3,4–dichlorophenyl)–5–(isopropylthio)thiazol–2–yl)–3–methyl–1H–pyrazole 5 – carboxylic acid;

1-(4-(3-chlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(4-chlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(2,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid;

4-bromo-1-(4-(6-(3-fluorophenyl)pyridin-3-yl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

(R)–1–(4–(3,4–dichlorophenyl)–5–(isopropylthio)thiazol–2–yl)–3–methyl–4–(2–methyl–6–((tetrahydrofuran–3–yl) hydroxy) pyridin-4-yl)-1H-pyrazole-5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(2-(2-methoxyethoxy)-6-methylpyridin-4-yl)-3-methyl-1H -pyrazole-5-carboxylic acid;

(S)–1–(4–(3,4–dichlorophenyl)–5–(isopropylthio)thiazol–2–yl)–3–methyl–4–(2–methyl–6–((tetrahydrofuran–3–yl) hydroxy) pyridin-4-yl)-1H-pyrazole-5-carboxylic acid;

1-(4-(cyclohex-1-en-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(cyclopent-1-en-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid;

4-(3-chloro-5-methoxyphenyl)-1-(5-(isopropylthio)-4-phenylthiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

4-(3-fluorophenyl)-1-(4-(4-fluorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-methoxyphenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(methylsulfonyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(4-fluoro-3-methoxyphenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1–(4–(4–chloro–3–methylphenyl)–5–(isopropylthio)thiazol–2–yl)–4–(2,6–dimethylpyridin–4–yl)–3–methyl–1H–pyrazole–5 – carboxylic acid;

1-(4-(4-chloro-3-methylphenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1–(4–(4–chloro–3,5–difluorophenyl)–5–(isopropylthio)thiazol–2–yl)–4–(2,6–dimethylpyridin–4–yl)–3–methyl–1H–pyrazole -5-carboxylic acid;

1-(4-(4-chloro-3,5-difluorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1–(4–(4–chloro–3–methoxyphenyl)–5–(isopropylthio)thiazol–2–yl)–4–(2,6–dimethylpyridin–4–yl)–3–methyl–1H–pyrazole–5 – carboxylic acid;

1-(4-(4-chloro-3-methoxyphenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid;

4-(2,6-dimethylpyridin-4-yl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5- carboxylic acid;

4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4-(3-methyl-5-(oxetan-3-yloxy)phenyl)-1H- pyrazole-5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(2-methoxy-6-methylpyridin-4-yl)-3-methyl-1H-pyrazole-5 – carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluoro-5-(oxetan-3-yloxy)phenyl)-3-methyl-1H- pyrazole-5-carboxylic acid;

4-(3-fluorophenyl)-1-(4-(3-fluorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(benzofuran-2-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid;

4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-phenylthiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1–(5–(isopropylthio)–4–phenylthiazol–2–yl)–1',3–dimethyl–1Н,1'Н– [4,4'–bipyrazole]–5–carboxylic acid;

4-(2,6-dimethylpyridin-4-yl)-1-(4-(4-fluorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(4-chloro-2-methoxyphenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1–(4–(4–chloro–2–methoxyphenyl)–5–(isopropylthio)thiazol–2–yl)–4–(2,6–dimethylpyridin–4–yl)–3–methyl–1H–pyrazole–5 – carboxylic acid;

1-(4-(3-chloro-4-methylphenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl -1H-pyrazole-5-carboxylic acid;

1–(4–(2–chloro–5–(trifluoromethoxy)phenyl)–5–(isopropylthio)thiazol–2–yl)–4–(3–fluorophenyl)–3–methyl–1H–pyrazole–5–carboxylic acid ;

1-(4-(5-cyanopyridin-3-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(1,3-dimethyl-1H-pyrazol-5-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazol-5 – carboxylic acid;

4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(pyrimidin-5-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(4-cyanophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(3-fluoro-4-methylphenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(2-cyanophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(4-chloro-2-methylphenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid;

4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(2-methyl-4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid ;

1-(4-(4-chloro-3-cyanophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid;

4-(3,5-dichlorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-((2-methoxyethyl)carbamoyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1–(4–(4–(dimethylcarbamoyl)phenyl)–5–(isopropylthio)thiazol–2–yl)–4–(3–fluorophenyl)–3–methyl–1H–pyrazole–5–carboxylic acid;

4-(3-chloro-5-methoxyphenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid ;

4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethoxy)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(2-methyl-4-(trifluoromethoxy)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid ;

4-(3-chloro-5-fluorophenyl)-1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(4-cyano-3-methylphenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-fluorothiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-isopropyl-1H-pyrazole-5-carboxylic acid;

1-(4-(4-(difluoromethyl)phenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(3,4-dichlorophenyl)-5-isopropoxythiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(4-ethylphenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid;

2-(4-(2,6-dimethylpyridin-4-yl)-3,5-dimethyl-1H-pyrazol-1-yl)-5-(isopropylthio)-4-(4-(trifluoromethyl)phenyl)thiazole;

4-(3-fluorophenyl)-1-(4-(5-fluoropyridin-3-yl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(benzofuran-3-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid;

4-(3,4-difluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

4-(4-fluoro-3-methylphenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid ;

4-(4-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

4-(4-fluoro-3-methoxyphenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid ;

1-(4-(4-chloro-2,6-dimethylphenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid;

1-(4-(4-(1,1-difluoroethyl)phenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid ;

4-(4-fluoro-3,5-dimethylphenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5- carboxylic acid;

4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(2-(trifluoromethyl)pyrimidin-5-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid ;

1–(4–(4–chloro–3–(ethylcarbamoyl)phenyl)–5–(isopropylthio)thiazol–2–yl)–4–(3–fluorophenyl)–3–methyl–1H–pyrazole–5–carboxylic acid ;

1–(4–(2–amino–4–(trifluoromethyl)phenyl)–5–(isopropylthio)thiazol–2–yl)–4–(3–fluorophenyl)–3–methyl–1H–pyrazole–5–carboxylic acid ;

4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-((4-(trifluoromethyl)phenyl)ethynyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(5-(trifluoromethyl)pyrimidin-2-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid ;

4-(3-fluorophenyl)-3-methyl-1-(4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-1H-pyrazole-5-carboxylic acid;

4–(3-fluorophenyl)–1–(5–(isopropylthio)–4–(4–(trifluoromethyl)phenyl)thiazol–2–yl)–N–(2–methoxyethyl)–N, 3–dimethyl–1H– pyrazole-5-carboxamide;

N–(2–(2–(2–(2–azidoethoxy)ethoxy)ethoxy)ethyl)–4–(3–fluorophenyl)–1–(5–(isopropylthio)–4–(4–(trifluoromethyl)phenyl) thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxamide;

4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-N-(2-methoxyethyl)-3-methyl-1H-pyrazole 5 – carboxamide;

4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-N-(propylsulfonyl)-1H-pyrazole-5- carboxamide;

4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(2-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(3-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

4-(3-fluorophenyl)-1-(5-(isopropylamino)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(pentafluoro-λ ⁶ -sulfanyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid;

4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-N-methoxy-3-methyl-1H-pyrazole-5-carboxamide;

4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(2,2,2-trifluoroethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5- carboxylic acid;

4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(6-(trifluoromethyl)pyridin-3-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid ; as well as

4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)thiazol-2-yl)-3-methyl -1H-pyrazole-5-carboxylic acid.

[53] In certain embodiments of the compounds described herein, said compound is in the N-oxide form. But in certain embodiments of the implementation of this invention, as described above, the specified connection is not in the form of N-oxide.

[54] In certain embodiments of the compounds described herein, said compound is in the form of a pharmaceutically acceptable salt of the compound or N-oxide as described herein. One of skill in the art will appreciate that various pharmaceutically acceptable salts may be provided, as described in more detail below. One of skill in the art will appreciate that the phrase "optionally in the form of a pharmaceutically acceptable salt or N-oxide or solvate or hydrate" includes compounds in the form of a pharmaceutically acceptable salt of the N-oxide. But in certain embodiments of the implementation of this invention, as described above, the specified connection is not in the form of a pharmaceutically acceptable salt.

[55] In certain embodiments of the compounds described herein, the compound is in the form of a solvate (eg, hydrate) of the compound, an N-oxide, or a salt, as described herein. One skilled in the art will appreciate that various solvates and/or hydrates may be formed. One of skill in the art will appreciate that the phrase "optionally in the form of a pharmaceutically acceptable salt or N-oxide or solvate or hydrate" includes compounds in the form of solvates and hydrates of base compounds, pharmaceutically acceptable salts and N-oxides as described above. But in certain embodiments of this invention, as described above, said compound is not in the form of a solvate or hydrate.

[56] A compound as described herein may usefully be provided in the form of a pharmaceutical composition comprising a compound, N-oxide, salt, solvate, or hydrate according to any of the previous aspects or embodiments of the invention described herein, together with a pharmaceutically acceptable excipient, diluent or carrier. The pharmaceutical composition may, for example, be in the form of a tablet, capsule, or parenteral formulation, but one of skill in the art will recognize that said compound may be present in a wide variety of pharmaceutical compositions.

As noted above, mutations that provide increased and more efficient use of deficient nutrients promote tumor formation. Oncogenic Ras stimulates both glucose uptake through increased GLUT1 expression and glucose utilization through anabolic pathways and conversion to glutathione, a key cellular antioxidant. Ras also regulates glutamine metabolism, specifically directing glucose and glutamine carbon into pathways that support biosynthesis, redox homeostasis, and ultimately cell survival and growth.

In addition to these effects on cell metabolism, Ras has also been described to influence cell progression throughout the cell cycle. In particular, Ras participates in transit through the limit point at the beginning of G1 and again at G2. Ras activity at the G1 stop point is particularly important as this event is a key integration point for growth factor signaling that causes the cell to further divide or enter G0 or the resting phase. Ras coordinates growth factor signaling to regulate levels of cyclins, cyclin-dependent kinases, and antagonistic inhibitors of cyclin-dependent kinases.

For more information, see outline Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674; Ward PS, Thompson CB (2012) Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate. Cancer Cell 21(3):297–308; Prabakaran S (2016) Kras rewires metabolic networks. Sci Signal 9(418):ec56–ec56; Kerr EM, Gaude E, Turrell FK, Frezza C, Martins CP (2016) Mutant Kras copy number defines metabolic reprogramming and therapeutic susceptibilities. Nature 531(7592):110–113; Flier JS, Mueckler MM, Usher P, Lodish HF (1987) Elevated levels of glucose transport and transporter messenger RNA are induced by ras or src oncogenes. Science 235(4795):1492–1495; Yun J, et al. (2009) Glucose Deprivation Contributes to the Development of KRAS Pathway Mutations in Tumor Cells. Science 325(5947):1555–1559; Son J, et al. (2013) Glutamine supports pancreatic cancer growth through a KRAS–regulated metabolic pathway. Nature 496(7443):101–105; Kim MH, Kim H (2013) Oncogenes and tumor suppressors regulate glutamine metabolism in cancer cells. J Cancer Prev 18(3):221–226; Gaglio D, et al. (2011) Oncogenic K–Ras decouples glucose and glutamine metabolism to support cancer cell growth. Mol Syst Biol 7:523; Hitomi M, Stacey DW (1999) Cellular ras and cyclin D1 are required during different cell cycle periods in cycling NIH 3T3 cells. Mol Cell Biol 19(7):4623–4632; Hitomi M, Stacey DW (2001) Ras-dependent cell cycle commitment during G2 phase. FEBS Lett 490(3):123–131; Foster DA, Yellen P, Xu L, Saqcena M (2010) Regulation of G1 Cell Cycle Progression: Distinguishing the Restriction Point from a Nutrient–Sensing Cell Growth Checkpoint(s). Genes Cancer 1(11):1124–1131; Massague J (2004) G1 cell-cycle control and cancer. Nature 432(7015):298-306; Pardee AB (1974) A restriction point for control of normal animal cell proliferation. Proc Natl Acad Sci U S A 71(4):1286–1290; Martinsson H–S, Starborg M, Erlandsson F, Zetterberg A (2005) Single cell analysis of G1 check points–the relationship between the restriction point and phosphorylation of pRb. Exp Cell Res 305(2):383–391; Larsson O, Zetterberg A (1995) Existence of a commitment program for mitosis in early G1 in tumor cells. Cell Prolif 28(1):33–43; Yen A, Pardee AB (1978) Exponential 3T3 cells escape in mid–G1 from their high serum requirement. Exp Cell Res 116(1):103–113; Novák B, Tyson JJ (2004) A model for restriction point control of the mammalian cell cycle. J Theor Biol 230(4):563–579; Weber JD, Hu W, Jefcoat SC, Raben DM, Baldassare JJ (1997) Ras-stimulated Extracellular Signal-related Kinase 1 and RhoA Activities Coordinate Platelet-derived Growth Factor-induced G1 Progression through the Independent Regulation of Cyclin D1 and p27KIP1. J Biol Chem 272(52):32966-32971; Kawada M, et al. (1997) Induction of p27Kip1 degradation and anchorage independence by Ras through the MAP kinase signaling pathway. Oncogene 15(6):629–637; Deng X, Mercer SE, Shah S, Ewton DZ, Friedman E (2004) The cyclin-dependent kinase inhibitor p27Kip1 is stabilized in G(0) by Mirk/dyrk1B kinase. J Biol Chem 279(21):22498–22504; Ladha MH, Lee KY, Upton TM, Reed MF, Ewen ME (1998) Regulation of exit from quiescence by p27 and cyclin D1–CDK4. Mol Cell Biol 18(11):6605–6615; Fan J, Bertino JR (1997) K-ras modulates the cell cycle via both positive and negative regulatory pathways. Oncogene 14(21):2595–2607.

Ras-associated oncogenes, KRAS (also known as homologues of the rat sarcoma viral oncogene k-Ras or V-Ki-ras2), in particular, also have a direct effect on cell metabolism. The result of this is a massive restructuring of metabolic circuits. KRAS has been noted to have pleiotropic effects on glucose utilization, glutathione synthesis, redox balance, and glutamine metabolism. Glutathione, a ubiquitous intracellular peptide, has a variety of functions including cell proliferation modulation, detoxification, and antioxidant protection (Lu, Shelly C., Mol Aspects Med . 2009; 30(1–2): 42–59). Increases in glutathione levels are associated with an early proliferative response (eg, by stimulating cells to transition from G0 to G1 phase of the cell cycle) and are also important for cell entry into S-phase ( Id .). Glutathione is also involved in the regulation of cell death, probably by modulating both apoptosis and necrosis (Id.). In addition, elevated levels of glutathione have been identified in many tumors and have been reported to play a role in conferring resistance to drug and/or radiation treatment, as well as preventing chemotherapy (Id.). Thus, glutathione synthesis inhibitors represent unique chemotherapeutic targets.

[57] Without wishing to be bound by any theory, the present inventors believe that the compounds described herein are active against cancer cells by arresting the cell cycle in the G0/G1 phase. Accordingly, as suggested above, the compounds described herein can be used in a variety of ways and applications. For example, in certain embodiments of this invention, a method of treating a hyperproliferative disorder in a subject in need thereof comprises administering to said subject an effective amount of a compound as described herein. In other embodiments of the invention, a compound as described herein is provided for use in the treatment of a hyperproliferative disorder. In other embodiments, this invention provides a compound described herein for the preparation of a medicament for the treatment of a hyperproliferative disorder. In each of these embodiments of the present invention, the hyperproliferative disorder may be, for example, cancer.

The inventors have determined that, in certain embodiments of the present invention, the currently described compounds inhibit cell cycle progression in cancer cells. Accordingly, in another embodiment, the present invention provides a method for inhibiting cell cycle progression in a cancer cell, said method comprising contacting the cancer cell with an effective amount of a compound as described herein. In certain such embodiments of the present invention, cell cycle progression is inhibited in the G0/G1 phase.

Inhibition of cell cycle progression in the G0/G1 phase may, in certain embodiments of the present invention, induce apoptosis of the cancer cell. Accordingly, in another embodiment, the present invention provides a method for inducing apoptosis in a cancer cell, such as a hematopoietic cancer cell. Said method includes contacting the cancer cell with an effective amount of a compound as described herein. However, in other embodiments of this invention, for example, in some solid tumors, apoptosis may not be necessary to achieve a significant therapeutic effect.

The present inventors have determined that the compounds described herein can, in certain embodiments, induce a cytotoxic effect on a cancer cell (eg, through the apoptosis mechanism described above, or through an alternative mechanism). Accordingly, in another embodiment, the present invention provides a method for inducing a cytotoxic effect on cancer cells. Said method includes contacting the cancer cell with an effective amount of a compound as described herein.

The present inventors have determined that the compounds described herein can, in certain embodiments, inhibit the synthesis of glutathione in a cancer cell. Accordingly, in another embodiment, the present invention provides a method for inhibiting glutathione synthesis in a cancer cell. Said method includes contacting the cancer cell with an effective amount of a compound as described herein.

The methods, compounds and uses described herein can be applied to many different types of cancer or to cells of many different types of cancer. For example, in certain embodiments of the methods, compounds, and uses described herein, the cancer is hematopoietic cancer. In other embodiments of this invention, the cancer is a solid tumor.

In certain embodiments of the methods, compounds, and uses described herein, the cancer is a lymphoma (e.g., Burkitt's lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, mantle cell lymphoma, T-cell lymphoma, cutaneous T-cell lymphoma, B-cell lymphoma, diffuse large B-cell lymphoma, double whammy lymphoma, Waldenström macroglobulinemia, primary central nervous system (CNS) lymphoma, and intravascular large B-cell lymphoma (ILCL). In other such embodiments of the present invention, the cancer is a leukemia (e.g., acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute myeloid leukemia, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic neutrophilic leukemia (CNL) ), chronic myelomonocytic leukemia (CMML), aggressive NK-cell leukemia, acute biphenotypic leukemia and polycythemia vera), acute and chronic T-cell and B-cell leukemia). In other such embodiments of the present invention, the cancer is a neoplasm of plasma cells (eg, multiple myeloma).

However, one of skill in the art will appreciate upon reading this disclosure that the methods, compounds, and uses described herein may be used in a variety of other cancers. For example, in certain embodiments of the methods, compounds, and uses described herein, the cancer is selected from cancer of the appendix, bone cancer (e.g., Ewing's sarcoma, osteosarcoma, and malignant fibrous histiocytoma), bronchial tumors, carcinoma of unknown primary site, chronic myeloproliferative neoplasms , colon and rectal cancer, head and neck cancer (including head and neck squamous cell carcinoma (SCCHN)), leukemia (eg, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute myeloid leukemia, chronic lymphocytic leukemia (CLL) ), chronic myelogenous leukemia (CML), chronic neutrophilic leukemia (CNL), chronic myelomonocytic leukemia (CMML), aggressive NK-cell leukemia, acute biphenotypic leukemia and polycythemia vera), acute and chronic T-cell and B-cell leukemia), lymphomas (eg, Burkitt's lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, l mantle cell lymphoma, T-cell lymphoma, cutaneous T-cell lymphoma, B-cell lymphoma, diffuse large B-cell lymphoma, double whammy lymphoma, Waldenström's macroglobulinemif, primary central nervous system (CNS) lymphoma, and intravascular large B-cell lymphoma (HPLN)), plasma cell neoplasms (eg, multiple myeloma), myelodysplastic syndrome, myelodysplastic/myeloproliferative neoplasms and chronic myeloproliferative neoplasms, pancreatic and neuroendocrine tumors of the pancreas (eg, islet cell tumors), small bowel cancer, soft tissue sarcomas and squamous cell carcinoma.

And in other embodiments of the methods, compounds, and uses described herein, the cancer is selected from adrenocortical carcinoma, adrenal cortex cancer, AIDS-associated cancer (e.g., Kaposi's sarcoma, AIDS-associated lymphoma, Burkitt's lymphoma, and primary CNS lymphoma) , anal canal cancer, appendix cancer, astrocytoma (eg, astrocytoma of the cerebellum or brain in childhood), bile duct cancer (eg, cholangiocarcinoma), bladder cancer, bone cancer (eg, Ewing's sarcoma, osteosarcoma, and malignant fibrous histiocytoma), brain tumors (eg, glioblastoma multiforme, cerebellar astrocytoma, cerebral astrocytoma/malignant glioma, ependymoma, medulloblastoma, oligodendroglioma, supratentorial primitive neuroectodermal tumors, glioma of the optic pathway and hypothalamus), brain gliomas, breast cancer, bronchial tumors, carcinoid tumors of the stomach -intestinal tract, karts inoidal tumors, carcinomas of unknown primary site, tumors of the heart (cardiac tumors), cancers of the central nervous system (eg, atypical teratoid/rhabdoid tumors, embryonic and germ cell tumors), cervical cancer, childhood cancers, chondrosarcoma, chronic myeloproliferative neoplasms , colorectal cancer, craniopharyngioma, desmoplastic small round cell tumor, ductal carcinoma in situ (PCIS), endometrial cancer, ependymoma, epithelioid hemangioendothelioma (EGE), esophageal cancer, esthesioneuroblastoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer ( e.g. intraocular melanoma and retinoblastoma), fallopian tube cancer, gallbladder cancer, gastric cancer (gastric cancer), stromal tumors of the gastrointestinal tract (GIT), gestational trophoblastic disease (GTD), glioma, hairy cell leukemia, head and neck cancer (for example, squamous head and neck cancer (SCCHN)), hepatocellular carcinoma (liver cancer), Langerhans cell histiocytosis, hypopharyngeal cancer, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, laryngeal cancer and papillomatosis, leukemia (eg, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute myeloblastic leukemia, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic neutrophilic leukemia (CNL), chronic myelomonocytic leukemia (CMML), aggressive NK-cell leukemia, acute biphenotypic leukemia and polycythemia vera) , acute and chronic T-cell and B-cell leukemia), lip and mouth cancer, liver cancer, lung cancer (eg, small cell lung cancer, non-small cell lung cancer (NSCLC), lung adenocarcinoma, lung carcinoma, and lung squamous cell carcinoma), lung carcinoid tumor, lymphomas (eg, Burkitt's lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, mantle cell lymphoma, T- cellular lymphoma, cutaneous T-cell lymphoma, B-cell lymphoma, diffuse large B-cell lymphoma, double whammy lymphoma, Waldenström's macroglobulinemif, primary central nervous system (CNS) lymphoma and intravascular large B-cell lymphoma (LBCL), breast cancer glands in men, meningiomas, mesothelioma, median NUT carcinoma, oral cancer, multiple endocrine neoplasia syndrome, plasma cell neoplasms (eg, multiple myeloma), mycosis fungoides, myelodysplastic syndrome, myelodysplastic/myeloproliferative neoplasms, and chronic myeloproliferative neoplasms, cancer nasal cavity and sinuses, nasopharyngeal cancer (NPC), neuroblastoma, oral cavity cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer and pancreatic neuroendocrine tumors (eg, islet cell tumors), paraganglioma, parathyroid cancer jelly cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary tumor, pleuropulmonary blastoma, primary peritoneal cancer, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, Cesari syndrome, skin cancer (eg, basal cell carcinoma, squamous cell carcinoma, Merkelak cell carcinoma and melanoma), small bowel cancer, soft tissue sarcoma, squamous cell carcinoma, gastric cancer (gastric cancer), testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, urethra cancer, cancer uterus and uterine sarcoma, vaginal cancer, vascular tumors, vulvar cancer and Wilms tumor.

For example, in several specific embodiments of the methods, compounds, and uses described herein, the cancer is a solid tumor. A solid tumor can be in various forms, such as lung cancer, colorectal cancer, or pancreatic cancer.

In one specific embodiment of the methods, compounds and uses described herein, the cancer is diffuse large B-cell lymphoma.

The data presented herein demonstrate that these compounds are particularly effective against cancers having a heterozygous mutant KRAS gene. KRAS mutations are found in > 90% of pancreatic cancers, 50% of colon cancers, and 25% of lung adenocarcinomas. Accordingly, in certain embodiments of the methods, compounds, and uses described herein, the cancer has a mutant KRAS gene, eg, a heterozygous mutant.

However, in certain embodiments of the methods, compounds, and uses described herein, the cancer or hyperproliferative disorder is not Burkitt's lymphoma.

One of skill in the art will determine effective amounts and dosages of the compounds described herein based on this description and in light of the state of the art.

Definitions

[58] The terms used herein may be preceded and/or followed by a single dash "-" or a double dash "=" to indicate the order of communication between the specified substituent and its original fragment; a single bar indicates a single bond and a double bar indicates a double bond or a pair of single bonds in the case of a spiro substituent. In the absence of a single or double bar, it is clear that a single bond is formed between the substituent and its original fragment; in addition, substituents are intended to be read "from left to right" with reference to the chemical structure in question, unless the bar indicates otherwise. For example, arylalkyl, arylalkyl- and -alkylaryl denote the same functionality.

[59] For simplicity, chemical moieties are defined and referred to throughout this document primarily as monovalent chemical moieties ( eg alkyl, aryl, etc.). However, such terms are also used to refer to the respective multivalent moieties under appropriate structural conditions understood by those skilled in the art. For example, while an "alkyl" moiety may refer to a monovalent radical ( e.g., CH ₃ -CH ₂ -), under certain conditions the divalent linking moiety may be "alkyl", in which case those skilled in the art will understand that alkyl would be a divalent radical ( eg , -CH ₂ -CH ₂ -), which is equivalent to the term "alkylene". (Similarly, under conditions where a divalent moiety is required and indicated to be "aryl", it will be understood by those skilled in the art that the term "aryl" refers to the corresponding divalent moiety, arylene). It is understood that all atoms have the normal number of valences to form a bond ( i.e. 4 for carbon, 3 for N, 2 for O, and 2, 4, or 6 for S, depending on the oxidation state of S). The nitrogens in the currently described compounds can be hypervalent, for example, a salt of an N-oxide or a tetrasubstituted ammonium. Sometimes a fragment can be defined, for example, as –B–(A) _a , where a is 0 or 1. In such cases, when a is 0, the fragment is –B, and when a is 1, the fragment is –B -A.

[60] In this context, the term "alkyl" includes a saturated hydrocarbon having a given number of carbon atoms, for example, from 1 to 10 carbon atoms (i.e., inclusive of 1 to 10), from 1 to 8 carbon atoms, from 1 to 6 carbon atoms, 1 to 3 carbon atoms, or 1, 2, 3, 4, 5, or 6. The alkyl group may be straight or branched, and depending on the context, may be a monovalent radical or a divalent radical (i.e., an alkylene group) . For example, the moiety “–(C ₁ C ₆ alkyl)O–” denotes the connection of oxygen through an alkylene bridge having from 1 to 6 carbon atoms, and C ₁ –C ₃ alkyl represents methyl, ethyl and propyl fragments. Examples of "alkyl" include, for example, methyl, ethyl, propyl, isopropyl, butyl, iso-, sec- and tert-butyl, pentyl and hexyl.

[61] The term "alkoxy" is an alkyl group with the specified number of carbon atoms, attached to the original molecular fragment through an oxygen bridge. Examples of "alkoxy" include, for example, methoxy, ethoxy, propoxy and isopropoxy.

[62] As used herein, the term "alkenyl" means an unsaturated hydrocarbon containing 2 to 10 carbon atoms (i.e., inclusive of 2 to 10), 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2, 3, 4 , 5 or 6, unless otherwise indicated, and containing at least one carbon-carbon double bond. The alkenyl group may be straight or branched and, depending on the context, may be a monovalent radical or a divalent radical (ie, an alkenylene group). For example, the fragment “–(C ₂ –C ₆ alkenyl)–O–” denotes an oxygen compound through an alkenylene bridge having from 2 to 6 carbon atoms. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, 3- decenyl and 3,7-dimethylocta-2,6-dienyl.

[63] As used herein, the term "alkynyl" means an unsaturated hydrocarbon containing 2 to 10 carbon atoms (i.e., inclusive of 2 to 10), 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2, 3, 4 , 5 or 6, unless otherwise indicated, and containing at least one carbon-carbon triple bond. The alkynyl group may be straight or branched and, depending on the context, may be a monovalent radical or a divalent radical (ie, an alkynylene group). For example, the fragment “(C ₂ –C ₆ alkynyl)–O–” denotes an oxygen compound through an alkynylene bridge having from 2 to 6 carbon atoms. Representative examples of alkynyl include, but are not limited to, acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.

[64] The term "aryl" refers to an aromatic ring system having a single ring (eg, phenyl) that is optionally fused to other aromatic hydrocarbon rings or non-aromatic hydrocarbon or heterocyclic rings. "Aryl" includes ring systems having multiple fused rings and in which at least one ring is carbocyclic and aromatic (eg, 1,2,3,4-tetrahydronaphthyl, naphthyl). Examples of aryl groups include phenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl, dihydronaphthyl, fluorenyl, tetralinyl, and 6,7,8,9-tetrahydro-5-benzo[a]cycloheptenyl. "Aryl" also includes ring systems having a first carbocyclic aromatic ring fused to a non-aromatic heterocycle, such as 1H-2,3-dihydrobenzofuranyl and tetrahydroisoquinolinyl. Aryl groups in this specification are unsubstituted or, if indicated as "optionally substituted", may be, unless otherwise indicated, substituted with various groups in one or more substitutable positions, as indicated.

[65] The terms "halogen" or "halogen" refer to fluorine, chlorine, bromine and iodine. In certain embodiments of each and every embodiment of this invention as described herein, the term "halogen" or "halo" refers to fluorine or chlorine. In certain embodiments of each and every embodiment of the invention described herein, the term "halogen" or "halo" refers to fluorine. The term "fluoroalkyl" means an alkyl group (ie, as described herein in another respect) that is substituted with at least one fluorine atom. "Fluoroalkyl" includes alkyl groups substituted with multiple fluorine atoms, such as perfluoroalkyl groups. Examples of fluoroalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 1,1,1,3,3,3-hexafluoroprop-2-yl, and 2,2,3,3,3-pentafluoroprop- 1–ill.

[66] The term "heteroaryl" refers to an aromatic ring system containing at least one aromatic heteroatom selected from nitrogen, oxygen and sulfur in the aromatic ring. Most often, heteroaryl groups will have 1, 2, 3, or 4 heteroatoms. Heteroaryl may be fused to one or more non-aromatic rings, such as cycloalkyl or heterocycloalkyl rings, with cycloalkyl and heterocycloalkyl rings described herein. In one embodiment of this invention, the heteroaryl group is linked to the rest of the structure through an atom in the aromatic ring of the heteroaryl group. In another embodiment of this invention, the heteroaryl group is linked to the rest of the structure through a non-aromatic ring atom. Examples of heteroaryl groups include, for example, pyridyl, pyrimidinyl, quinolinyl, benzothienyl, indolyl, indolinyl, pyridazinyl, pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl, benzothiazolyl , benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl, benzo[1,4] oxazinyl, triazolyl, tetrazolyl, isothiazolyl, naphthyridinyl, isochromanyl, chromanyl, isoindolinyl, isobenzothienyl, benzoxazolyl, pyridopyridinyl, purinyl, benzodioxolyl, triazinyl benzothiazolyl, pteridinyl, , imidazopyridinyl, imidazothiazolyl, benzisoxazinyl, benzoxazinyl, benzopyranyl, benzothiopyranyl, chromonyl, chromanonyl, pyridinyl-N-oxide, isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl N-oxide, pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinyl N-oxide, indolyl N-oxide, indolinyl N-oxide, isoquinolyl N-oxide, quinazolinyl N-oxide, quinoxalinyl N-oxide, phthalazinyl N-oxide, imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolyl N-oxide, indolizinyl N-oxide, indazolyl N-oxide, benzothiazolyl N-oxide, benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide, thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolyl N-oxide, benzothiopyranyl S-oxide, benzothiopyranyl S,S-dioxide. Preferred heteroaryl groups include pyridyl, pyrimidyl, quinolinyl, indolyl, pyrrolyl, furanyl, thienyl and imidazolyl, pyrazolyl, indazolyl, thiazolyl and benzothiazolyl. In some embodiments of this invention, each heteroaryl is selected from pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl, furanyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, isothiazolyl, pyridinyl- N -oxide, pyrrolyl N -oxide, pyrimidinyl N -oxide, pyridazinyl N -oxide, pyrazinyl N -oxide, imidazolyl N -oxide, isoxazolyl N -oxide, oxazolyl N -oxide, thiazolyl N -oxide, pyrrolyl N -oxide, oxadiazolyl N -oxide, thiadiazolyl N -oxide, triazolyl N -oxide and tetrazolyl N -oxide. Preferred heteroaryl groups include pyridyl, pyrimidyl, quinolinyl, indolyl, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, indazolyl, thiazolyl and benzothiazolyl. Heteroaryl groups in this specification are unsubstituted or, if indicated as "optionally substituted", may be, unless otherwise indicated, substituted with various groups in one or more substitutable positions, as indicated.

[67] The term "heterocycloalkyl" refers to a non-aromatic ring or ring system containing at least one heteroatom, which is preferably selected from nitrogen, oxygen and sulfur, while the specified heteroatom is in the non-aromatic ring. Heterocycloalkyl may have 1, 2, 3 or 4 heteroatoms. Heterocycloalkyl may be saturated (ie heterocycloalkyl) or partially unsaturated (ie heterocycloalkenyl). Heterocycloalkyl includes monocyclic groups of three to eight ring atoms, as well as bicyclic and polycyclic ring systems, including bridged and fused systems, with each ring containing from three to eight ring atoms. The heterocycloalkyl ring is optionally fused to other heterocycloalkyl rings and/or non-aromatic hydrocarbon rings. In certain embodiments of this invention, heterocycloalkyl groups have from 3 to 7 members in one ring. In other embodiments of this invention heterocycloalkyl groups have 5 or 6 members in one ring. In some embodiments of this invention, heterocycloalkyl groups have 3, 4, 5, 6 or 7 members in one ring. Examples of heterocycloalkyl groups include e.g. , thiomorpholinyl S-oxide, thiomorpholinyl S,S-dioxide, 2-oxazolidonyl, piperazinyl, homopiperazinyl, piperazinonyl, pyrrolidinyl, azepanyl, azetidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, tetrahydrofuranyl, tetrahydrothienyl, 3,4-dihydroisoquinoline-2(1 H) -yl, isoindolinedionyl, homopiperidinyl, homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydrofuryl, dihydropyranyl, imidazolidonyl, tetrahydrothienyl S-oxide, tetrahydromorpholinyl S,S-dioxide and S-dioxide -oxide. Particularly desirable heterocycloalkyl groups include morpholinyl, 3,4-dihydroisoquinolin-2( 1H )-yl, tetrahydropyranyl, piperidinyl, aza-bicyclo[2.2.2]octyl, γ-butyrolactonyl (i.e. oxo-substituted tetrahydrofuranyl), γ-butriolactamyl ( i.e. oxo-substituted pyrrolidine), pyrrolidinyl, piperazinyl, azepanil, azetidinyl, thiomorpholinyl, thiomorpholinyl S,S-dioxide, 2-oxazolidonyl, imidazolidonyl, isoindolindioneyl, piperazinonyl. Heterocycloalkyl groups in this specification are unsubstituted or, if indicated as "optionally substituted", may be, unless otherwise indicated, substituted with various groups in one or more substitutable positions, as indicated.

[68] The term "cycloalkyl" refers to a non-aromatic carbocyclic ring or ring system, which may be saturated (ie, cycloalkyl) or partially unsaturated (ie, cycloalkenyl). The cycloalkyl ring is optionally fused or otherwise attached (eg via bridge systems) to other cycloalkyl rings. Some examples of cycloalkyl groups present in the disclosed compounds have 3 to 7 members per ring, eg 5 or 6 members per ring. In some embodiments of this invention, the icloalkyl groups have 3, 4, 5, 6 or 7 members in one ring. Examples of cycloalkyl groups include, for example, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, tetrahydronaphthyl and bicyclo[2.2.1]heptane. Cycloalkyl groups in this specification are unsubstituted or, if indicated as "optionally substituted", may be, unless otherwise indicated, substituted with various groups in one or more substitutable positions, as indicated.

[69] The term "ring system" embraces monocycles as well as fused and/or bridged polycycles.

[70] The term "oxo" means that a double bonded oxygen, sometimes referred to as =O, or, for example, in the description of carbonyl "C(O)", can be used to indicate an oxo-substituted carbon.

[71] The term "substituted", when used to modify a specified group or radical, means that one or more hydrogen atoms of the specified group or radical, each independently of one another, are replaced by the same or different groups of substituents as defined below, unless otherwise indicated.

[72] As used herein, the phrase "pharmaceutically acceptable salt" refers to both pharmaceutically acceptable acid and base addition salts and solvates. Such pharmaceutically acceptable salts include acid salts such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic, alkanoic such as acetic, HOOC(CH ₂ ) _n COOH where n is 04 and the like. Non-toxic pharmaceutical base addition salts include base salts such as sodium, potassium, calcium, ammonium and the like. Those skilled in the art will recognize a wide variety of non-toxic, pharmaceutically acceptable additive salts.

[73] One of skill in the field of medicinal chemistry will also appreciate that the described structures are intended to include isotopically enriched forms of the described compounds. In this context, the term "isotopes" includes atoms having the same atomic number but different mass numbers. As is known to those skilled in the art, some atoms, such as hydrogen, occur in various isotopic forms. For example, hydrogen has three isotopic forms: protium, deuterium, and tritium. As will be apparent to those skilled in the art when considering the described compounds, some compounds may be enriched at a given position in a particular isotope of an atom at that position. For example, compounds having a fluorine atom can be synthesized in a form enriched in the radioactive isotope of fluorine ¹⁸ F. Similarly, compounds can be enriched in heavy hydrogen isotopes: deuterium and tritium; and similarly can be enriched in a radioactive isotope of carbon, such as ¹³ C. Such isotopic variants of the compounds pass through various metabolic pathways and may be useful, for example, in studying the ubiquitination pathway and its role in disease. Of course, in certain embodiments of the implementation of this invention, the specified connection has essentially the same isotopic characteristics as natural materials.

[74] In this context, the term "cell" refers to a cell that exists in vitro , ex vivo or in vivo . In some embodiments of the invention, said ex vivo cell may be part of a tissue sample excised from an organism, such as a mammal. In some embodiments of this invention, said cell in vitro may be a cell in cell culture. In some embodiments of this invention, the specified cell in vivo is a cell living in an organism, such as a mammal.

[75] In this context, the terms "individual", "patient" or "subject" are used interchangeably and refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep , horses or primates and most preferably humans.

[76] As used herein, the phrase “therapeutically effective amount” or “effective amount” refers to an amount of an active compound or pharmaceutical agent that elicits a biological or therapeutic response expected by a researcher, veterinarian, physician or other clinician in a tissue, system, animal. , individual or person.

[77] In certain embodiments of this invention, an effective amount may be an amount suitable for

(i) inhibition of disease progression;

(ii) prophylactic use, such as preventing or limiting the development of a disease, condition, or disorder in an individual who may be predisposed to or otherwise at risk for the disease, condition, or disorder, but not yet experiencing or exhibiting the disease process or symptoms of the disease;

(iii) disease inhibition; for example, inhibition of a disease, condition, or disorder in an individual who is experiencing or exhibiting a pathological process or symptoms of the disease, condition, or disorder;

(iv) alleviate the course of the described disease, for example, alleviate the disease, condition, or disorder in an individual who is experiencing or exhibiting the pathological process or symptoms of the disease, condition, or disorder (i.e., regression or reduction in the activity of the pathological process and/or symptoms) , such as reducing the severity of the disease; or

(v) obtaining the described biological effect.

[78] As used herein, the terms "treatment" and "treatment" mean (i) alleviating the course of a described disease, condition, or disorder (or a symptom thereof), such as, for example, alleviating a disease, condition, or disorder in an individual who is experiencing or demonstrates a pathological process or symptomatology of a disease, pathological condition or disorder (ie, regression or reduction in the activity of the pathological process and/or symptoms), such as reducing the severity of the disease or its symptom or inhibiting the progression of the disease; or (ii) obtaining the described biological effect (eg, induction of apoptosis or inhibition of glutathione synthesis).

Pharmaceutical formulations and dosage forms

[79] The compounds of this invention can be administered, for example, orally, topically, parenterally, by inhalation or spray or rectally in dosage forms containing one or more pharmaceutically acceptable carriers, diluents or excipients. In this context, the term "parenteral" includes methods of percutaneous, subcutaneous, intravascular (eg, intravenous), intramuscular or intrathecal injection or infusion, and the like. A drug comprising a compound of this invention may be provided in any suitable formulation and dosage form as described herein.

[80] Pharmaceutical compositions can be made using the compounds described herein. For example, in one embodiment of the present invention, the pharmaceutical composition comprises a pharmaceutically acceptable carrier, diluent or excipient, and a compound as described above with reference to any one of the structural formulae.

[81] In the pharmaceutical compositions described herein, one or more compounds of this invention may be present in combination with one or more pharmaceutically acceptable carriers, diluents or excipients, and, if necessary, with other active ingredients. Pharmaceutical compositions containing the compounds of this invention may be in a form suitable for oral administration, for example, in the form of tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. .

[82] Compositions intended for oral administration may be prepared in accordance with any suitable method for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavors, colors and preservatives to obtain pharmaceutically attractive and palatable preparations. The tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients can be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example corn starch or alginic acid; binding agents such as starch, gelatin or acacia; and lubricating agents such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated using known methods. In some cases, such coatings can be obtained using suitable methods to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained effect over a longer period. For example, a material having a disintegration and absorption time delay property such as glyceryl monostearate or glyceryl distearate can be used.

[83] Compositions for oral administration may also be presented in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or in the form of soft gelatin capsules in which the active ingredient is mixed with water or an oily medium such as peanut butter, liquid paraffin or olive oil.

[84] Formulations for oral administration can also be presented in the form of lozenges.

[85] Aqueous suspensions contain active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients may be suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum arabic; dispersing or wetting agents such as a naturally occurring phosphatide, e.g. lecithin, or condensates of alkylene oxide with fatty acids, e.g. polyoxyethylene stearate, or condensates of ethylene oxide with long chain aliphatic alcohols, e.g. esters derived from fatty acids and hexitol, such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, such as polyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate, one or more colorants, one or more flavors, and one or more sweeteners, such as sucrose or saccharin.

[86] Oil suspensions can be prepared by suspending the active ingredients in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweeteners and flavors may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

[87] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Examples of suitable dispersing or wetting agents or suspending agents have already been mentioned above. Additional excipients may also be present, such as sweeteners, flavors and colors.

[88] Pharmaceutical compositions may also be in the form of oil-in-water emulsions. The oil phase may be vegetable oil or mineral oil or mixtures thereof. Suitable emulsifying agents may be naturally occurring gums such as guar gum or tragacanth gum, naturally occurring phosphatides such as soybeans, lecithin and esters or partial esters derived from fatty acids and hexitol, anhydrides such as sorbitan monooleate, and condensation products of said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate. Emulsions may also contain sweeteners and flavors.

[89] In some embodiments of this invention, the pharmaceutically acceptable carrier, diluent or excipient is not water. In other embodiments of this invention, water is less than 50% of the composition. In some embodiments of this invention, compositions containing less than 50% water contain at least 1%, 2%, 3%, 4%, or 5% water. In other embodiments of this invention, the water content of the composition is determined in trace amounts.

[90] In some embodiments of this invention, the pharmaceutically acceptable carrier, diluent or excipient is not an alcohol. In other embodiments of this invention, the alcohol is less than 50% of the composition. In some embodiments of this invention, compositions containing less than 50% alcohol contain at least 1%, 2%, 3%, 4%, or 5% alcohol. In other embodiments of this invention, the alcohol content of the composition is determined in trace amounts.

[91] Syrups and elixirs can be formulated with sweeteners such as glycerol, propylene glycol, sorbitol, glucose or sucrose. Such formulations may also contain emollients, preservatives, flavoring and coloring agents. Pharmaceutical compositions may be in the form of a sterile injectable aqueous or oily suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents as mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic, parenterally acceptable diluent or solvent, for example in the form of a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fatty oils can be used as a solvent or suspending medium. Any bland fixed oil can be used for this purpose, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

[92] the Compounds of this invention can also be administered in the form of suppositories, for example, for rectal drug administration. These compositions can be prepared by mixing the compound with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols.

[93] The compounds of this invention can also be administered parenterally in a sterile environment. The drug, depending on the used carrier and concentration, can be either suspended or dissolved in the carrier. Preferably, adjuvants such as local anesthetics, preservatives and buffering agents may be dissolved in the carrier.

[94] These compositions can be formulated as a unit dosage form of the active ingredient. The term "unit dosage forms" refers to physically discrete units suitable as unit doses for humans and other mammals, each such unit containing a predetermined amount of active material calculated to produce the desired therapeutic effect, in combination with a suitable pharmaceutical excipient.

[95] The active compound may be effective over a wide dosage range and is usually administered in a pharmaceutically effective amount. However, it should be understood that the amount of compound actually administered is usually determined by the physician depending on the relevant circumstances, including the condition being treated, the chosen route of administration, the actual compound administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, and the like.

[96] For the preparation of solid compositions such as tablets, the main active ingredient is mixed with a pharmaceutical excipient to form a solid composition to form a dosage form containing a homogeneous mixture of the compound described herein. When these compositions are referred to as homogeneous before they are formulated into a dosage form, the active ingredient is usually evenly distributed throughout the composition so that said composition can be easily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid composition is then subdivided into unit dosage forms of the type described above, containing, for example, from 0.1 to about 500 mg of the active ingredient of the compound described herein, before being formulated into a dosage form.

[97] Tablets or pills can be coated or otherwise mixed to obtain a dosage form that provides the advantage of prolonged action. For example, a tablet or pill may contain an internal dose and an external dosage component, the latter being in the form of a shell over the former. The two components may be separated by an enteric layer which serves to resist disintegration in the stomach and allows the inner component to pass unaltered into the duodenum or be retained upon excretion. Various materials can be used for such enteric layers or coatings, such materials include a number of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol and cellulose acetate.

[98] The amount of a compound or composition administered to a patient will vary depending on what is being administered, the purpose of administration such as prophylaxis or treatment, the condition of the patient, the route of administration, and the like. In therapeutic applications, the compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially stop the development of the symptoms of the disease and its complications. Effective doses will depend on the course of the disease being treated, as well as the judgment of the attending physician, depending on such factors as the severity of the disease, the age, weight and general condition of the patient, and the like.

[99] the Compositions administered to the patient may be in the form of pharmaceutical compositions described above. These compositions may be sterilized by conventional sterilization techniques or may be sterile filtered. Aqueous solutions may be packaged for use as is or lyophilized, wherein the lyophilized preparation is combined with a sterile aqueous vehicle prior to administration. The pH of the compound preparations is usually 3 to 11, more preferably 5 to 9, and most preferably 7 to 8. It will be understood that the use of certain of the aforementioned excipients, carriers or stabilizers will result in the formation of pharmaceutical salts.

[100] The therapeutic dose of these compounds may vary depending on, for example, the specific application for which treatment is being carried out, the route of administration of the compound, the health and condition of the patient, and the judgment of the attending physician. The proportion or concentration of a compound described herein in a pharmaceutical composition may vary depending on a number of factors, including dose, chemical characteristics ( eg , hydrophobicity), and route of administration. For example, the compounds described herein can be provided in an aqueous physiological buffer solution containing from about 0.1 to about 10% wt./about. compounds for parenteral administration. Some typical dosage ranges are from about 1 μg/kg to about 1 g/kg of body weight per day. In some embodiments of this invention, the dosage range is from about 0.01 to about 100 mg/kg of body weight per day. The dose is likely to depend on variables such as the type and extent of progression of the disease or disorder, the general health of the individual patient, the relative bioavailability of the compound chosen, the composition of the excipient, and the route of administration of the compound. Effective doses can be extrapolated from dose-response curves obtained from in vitro test systems or animal models.

[101] The compounds described herein may also be formulated in combination with one or more additional active ingredients, which may include any pharmaceutical agent such as antiviral agents, vaccines, antibodies, immune enhancers, immunosuppressants, anti-inflammatory agents, etc. similar.

[102] One skilled in the art will formulate the compound as described in the pharmaceutical compositions provided herein, for example, based on the physicochemical properties of the compound, the amount of compound required for a pharmaceutically effective amount, and the desired route of administration.

EXAMPLES

General Synthesis Methods

[103] Many general references are available that present well-known chemical synthesis schemes and conditions suitable for the synthesis of the described compounds (see, for example, Smith and March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Fifth Edition, Wiley– Interscience, 2001; or Vogel, A Textbook of Practical Organic Chemistry, Including Qualitative Organic Analysis, Fourth Edition, New York: Longman, 1978).

[104] Compounds as described herein can be purified by any of the methods known in the art, including chromatographic techniques such as HPLC, preparative thin layer chromatography, flash column chromatography, and ion exchange chromatography. Any suitable stationary phase may be used, including normal and reversed phases, as well as ionic resins. In exemplary embodiments, the described compounds are purified by silica gel and/or alumina chromatography. See, for example, Introduction to Modern Liquid Chromatography, 2nd Edition, ed. L. R. Snyder and J. J. Kirkland, John Wiley and Sons, 1979; and Thin Layer Chromatography, ed E. Stahl, Springer-Verlag, New York, 1969.

[105] In the course of any of the methods for preparing the described compounds, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the described molecules. This can be achieved with conventional protecting groups as described in well-known works such as JFW McOmie, "Protective Groups in Organic Chemistry," Plenum Press, London and New York 1973, in TW Greene and PGM Wuts , "Protective Groups in Organic Synthesis ,” Third edition, Wiley, New York 1999, in "The Peptides"; Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981, in "Methoden der organischen Chemie," Houben–Weyl, 4.sup.th edition, Vol. 15/l, Georg Thieme Verlag, Stuttgart 1974, in H.–D. Jakubke and H. Jescheit, “Aminosauren, Peptide, Proteine,” Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982, and/or Jochen Lehmann, “Chemie der Kohlenhydrate: Monosaccharide and Derivate,” Georg Thieme Verlag, Stuttgart 1974. The protecting groups can be removed at a convenient subsequent step using methods known in the art.

[106] the Compounds described in this document can be obtained using procedures familiar to the person skilled in the art, taking into account the specific preparative procedures described in this document. One skilled in the art will be able to adapt the reaction sequences described in the examples below to suit the desired target molecule. Of course, in certain situations, one skilled in the art will use different reagents to affect one or more of the individual steps, or to use protected versions of some of the substituents. In addition, one skilled in the art should understand that the compounds of the present invention may be synthesized by various routes in general.

[107] Compounds suitable for use in the pharmaceutical compositions described herein include those in the table above. A variety of typical synthesis processes are given below; one skilled in the art will adapt the procedures described herein and/or other procedures familiar to one of skill in the art to obtain the compounds described herein.

[108] The following synthetic examples and biochemical data are intended to further illustrate certain embodiments of the present invention and are not intended to limit the scope of the compounds described herein.

Compound 1: 1–(4–(4–chloro–2–(oxetan–3–yloxy)phenyl)–5–(isopropylthio)thiazol–2–yl)–3–methyl–1H–pyrazole–5–carboxylic acid

3–(2–bromo–5–chlorophenoxy)oxetane

Diisopropyl diazocarboxylate (292 mg, 1.45 mmol) was added to a solution of 2-bromo-5-chlorophenol (200 mg, 0.964 mmol), oxetan-3-ol (89 mg, 1.2 mmol) and triphenylphosphine (379 mg, 1 .45 mmol) in THF (4.2 ml). The reaction mixture was stirred at room temperature for 18 hours. Ethyl acetate was added and the mixture was washed with 1N NaOH (3x). The organic layer was dried with sodium sulfate, filtered and evaporated under reduced pressure. The crude product was purified by silica gel flash chromatography using a solution of ethyl acetate in hexanes (10%) to give the title compound (208 mg, 0.789 mmol, 82%).

2–(4–chloro–2–(oxetan–3–yloxy)phenyl)–4,4,5,5–tetramethyl–1,3,2–dioxaborolane

Degassed dioxane was added to a mixture of 3-(2-bromo-5-chlorophenoxy)oxetane (100 mg, 0.379 mmol), pinacoldiborane (116 mg, 0.455 mmol), [1,1"-bis(diphenylphosphino)ferrocene]palladium (II) dichloride (28 mg, 0.038 mmol) and potassium acetate (112 mg, 1.14 mmol). The reaction mixture was heated at 85 ^° C. for 18 hours. The mixture was filtered on celite and the support washed with dioxane. The filtrate was evaporated to give the title compound (219 mg, 186%, 50% w/w from NMR analysis) which was used as is.

2-chloro-5-(isopropylthio)thiazole

A 2.5 M solution of n -BuLi in a mixture of hexanes (20.5 ml, 51.2 mmol) was added to a THF solution (117 ml) of 2-chlorothiazole (4.9 g, 41.0 mmol) at –78 ^° C. The reaction mixture was stirred at the same temperature for 30 minutes. Diisopropyl disulfide (13.1 ml, 82.0 mmol) was added to the reaction mixture and stirred at the same temperature for 1.5 hours. Water was added to quench the reaction and then Et ₂ O. The reaction mixture was transferred to a separating funnel and the aqueous layer was extracted with Et ₂ O (3x). The combined organic layers were dried with Na ₂ SO ₄ and concentrated in vacuo. The crude product was purified by silica gel flash chromatography (dry column fill) using EtOAc in hexanes (0 to 5% gradient) to give the title compound (2.31 g, 11.9 mmol, 29 %) as a yellow liquid.

4-bromo-2-chloro-5-(isopropylthio)thiazole

A 2 M solution of bromine (72.7 µl, 1.42 mmol) in dichloromethane ("DCM") was added dropwise to a solution of 2-chloro-5-(isopropylthio)thiazole (250 mg, 1.29 mmol) in DCM. The reaction mixture was stirred for 3 hours at room temperature. Na ₂ SO ₃ solution was added and the aqueous layer was extracted with DCM (3x). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by silica gel flash chromatography using a solution of DCM in hexanes (50 to 100% gradient) to give the title compound (271 mg, 0.99 mmol, 77%) as a colorless liquid.

4-bromo-2-hydrazinyl-5-(isopropylthio)thiazole

DIPEA (64 µl, 0.37 mmol) was added to a solution of hydrazine hydrochloride (13.0 mg, 0.18 mmol) and 4-bromo-2-chloro-5-(isopropylthio)thiazole (50.0 mg, 0.18 mmol) in NMP (2 ml) in a microwave glass vial. The vial was closed and heated to 150°C for 1 h using microwave radiation. The crude product was purified by reverse flash chromatography (C18 using a gradient of 0 to 40 to 70% MeCN in H ₂ O with 10 mM NH ₄ CO ₂ H buffer) to give the title compound (29.0 mg, 0. 11 mmol, 59%) as a yellow solid after extraction with Et ₂ O and concentration in vacuo.

methyl 2–(methoxyimino)–3–(2–nitrobenzyl)–4–oxopentanoate

Methylacetopyruvate (1.0 g, 6.94 mmol), methoxyhydroxylamine hydrochloride (0.58 g, 6.94 mmol) and molecular sieves (2.5 g) were placed in a flame-dried round bottom flask equipped with a nitrogen inlet. Dry DMF (23 ml) was added, the round bottom flask was covered with foil and stirred overnight at room temperature. The reaction mixture was diluted with EtOAc (150 ml) and the organic phase was washed with water (3 x 50 ml) and brine (1 x 50 ml), dried using Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (1 .07 g, 6.16 mmol, 89%) as a red liquid.

methyl 1-(4-bromo-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate

Methyl 2-(methoxyimino)-3-(2-nitrobenzyl)-4-oxopentanoate (4.00 g, 23.1 mmol) was dissolved in MeOH (115 ml). 4-Bromo-2-hydrazinyl-5-(isopropylthio)thiazole (6.19 g, 23.1 mmol) was added and then HCl 12 N (7.70 ml, 92.4 mmol) was added dropwise to the reaction mixture. The reaction mixture was heated under reflux overnight. The crude product was concentrated in vacuo and purified by flash chromatography on silica gel (dry column loading) using a solution of EtOAc in hexanes (5 to 20% gradient) and purified a second time by flash chromatography on silica gel (dry method). filling columns) using a solution of DCM in hexane (10 to 50% gradient) to give the title compound (1.89 g, 5.02 mmol, 22%) as an orange oil.

methyl 4-bromo-1-(4-bromo-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate

A 2 M solution of bromine (3.32 ml, 6.64 mmol) in MeCN was added dropwise to a solution of methyl 1-(4-bromo-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazol- 5-carboxylate (500 mg, 1.33 mmol) in DCM/MeCN solution (7 ml, 1:1). The reaction mixture was stirred for 5 hours at room temperature. Na ₂ SO ₃ solution was added and the aqueous layer was extracted using Et ₂ O (3x). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by silica gel flash chromatography using a solution of DCM in hexanes (20%) to give the title compound (421 mg, 0.93 mmol, 70%) as an orange solid.

methyl 1–(4–(4–chloro–2–(oxetan–3–yloxy)phenyl)–5–(isopropylthio)thiazol–2–yl)–3–methyl–1H–pyrazole–5–carboxylate

Degassed THF (2 ml) was added to a mixture of methyl 4-bromo-1-(4-bromo-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate (100 mg, 0.220 mmol ), 2–(4–chloro–2–(oxetan–3–yloxy)phenyl)–4,4,5,5–tetramethyl–1,3,2–dioxaborolane (137 mg, 0.220 mmol, 50% wt./ wt.], [1,1'-bis(di- tert -butylphosphino)ferrocene]dichloropalladium (II) (11 mg, 0.022 mmol) and potassium carbonate (152 mg, 1.10 mmol).The reaction mixture was heated at 90 ^° C for 18 hours The mixture was mixed with silica and the solvent was evaporated for flash chromatography on silica gel using a solution of ethyl acetate in hexanes (2 to 40%) to give the title compound (17 mg, 0.035 mmol , 16%) as a pale yellow oil.

1–(4–(4–chloro–2–(oxetan–3–yloxy)phenyl)–5–(isopropylthio)thiazol–2–yl –3–methyl–1H–pyrazole–5–carboxylic acid

Methyl 1-(4-(4-chloro-2-(oxetan-3-yloxy)phenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate (17 mg, 0.035 mmol) was diluted in a 1:1 solution of THF and MeOH (0.35 ml). 1M NaOH (0.070 ml, 0.070 mmol) was added and the reaction mixture was stirred for 18 hours at room temperature. 1N HCl (1 ml) was added followed by water (5 ml) and the mixture was extracted using EtOAc (3×5 ml). The combined organic layers were dried with sodium sulfate, filtered and evaporated under reduced pressure. The crude product was purified by semi-preparative HPLC-MS (X-Bridge 30×50 column) using a solution of MeCN in water (containing 10 mM ammonium formate) (50 to 70%). The product was lyophilized to give the title compound (2 mg, 0.004 mmol, 12%) as a pale yellow solid.

¹ H NMR (500 MHz, DMSO) δ 7.34 (d, J = 8.2 Hz, 1H), 7.14 (dd, J = 8.1, 1.9 Hz, 1H), 6.83 ( d, J = 1.9 Hz, 1H), 6.64 (s, 1H), 5.38–5.31 (m, 1H), 4.89 (t, J = 6.8 Hz, 2H), 4.49 (dd, J = 7.3, 5.1 Hz, 2H), 3.21 (m, J = 6.6 Hz, 1H), 2.25 (s, 3H), 1.14 (d , J =6.7 Hz, 6H); MS (m/z): 466.1 [M+1] ⁺ .

Compound 2: 1–(4–(4–chloro–3– (oxetan–3–yloxy)phenyl)–5–(isopropylthio)thiazol–2–yl)–3–methyl–1H–pyrazole–5–carboxylic acid

3– (5–bromo–2–chlorophenoxy)oxetane

Diisopropyl diazocarboxylate (292 mg, 1.45 mmol) was added to a solution of 5-bromo-2-chlorophenol (200 mg, 0.964 mmol), oxetan-3-ol (89 mg, 1.2 mmol) and triphenylphosphine (379 mg, 1 .45 mmol) in THF (4.2 ml). The reaction mixture was stirred at room temperature for 18 hours. Ethyl acetate was added and the mixture was washed with 1N NaOH (3x). The organic layer was dried with sodium sulfate, filtered and evaporated under reduced pressure. The crude product was purified by silica gel flash chromatography using a solution of ethyl acetate in hexanes (10%) to give the title compound (222 mg, 0.842 mmol, 87%).

2–(4–chloro–3– (oxetan–3–yloxy)phenyl)–4,4,5,5–tetramethyl–1,3,2–dioxaborolane

Degassed dioxane was added to a mixture of 3-(5-bromo-2-chlorophenoxy)oxetane (100 mg, 0.379 mmol), pinacoldiborane (116 mg, 0.455 mmol), [1,1"-bis(diphenylphosphino)ferrocene]palladium (II) dichloride (28 mg, 0.038 mmol) and potassium acetate (112 mg, 1.14 mmol). The reaction mixture was heated at 85 ^° C. for 18 hours. The mixture was filtered on celite and the support washed with dioxane. The filtrate was evaporated to give the title compound (238 mg, 202%, 50% w/w from NMR analysis) which was used as is.

methyl 1–(4–(4–chloro–3– (oxetan–3–yloxy)phenyl)–5–(isopropylthio)thiazol–2–yl)–3–methyl–1H–pyrazole–5–carboxylate

Degassed THF (2 ml) was added to a mixture of methyl 4-bromo-1-(4-bromo-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate (100 mg, 0.220 mmol ) prepared in Example 27, 2-(4-chloro-3-(oxetan-3-yloxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (137 mg, 0.220 mmol, 50% w/w), [1,1'-bis(di- tert -butylphosphino)ferrocene]dichloropalladium (II) (11 mg, 0.022 mmol) and potassium carbonate (152 mg, 1.10 mmol). The reaction mixture was heated at 90 ^° C for 18 hours. The mixture was mixed with silica and the solvent was evaporated for flash chromatography on silica gel using a solution of ethyl acetate in hexanes (2 to 40%) to give the title compound (6.2 mg, 0.013 mmol, 66%) as pale orange oils.

1–(4–(4–chloro–3– (oxetan–3–yloxy)phenyl)–5–(isopropylthio)thiazol–2–yl)–3–methyl–1H–pyrazole–5–carboxylic acid

methyl 1–(4–(4–chloro–3– (oxetan–3–yloxy)phenyl)–5–(isopropylthio)thiazol–2–yl)–3–methyl–1H–pyrazole–5–carboxylate (6.2 mg, 0.013 mmol) was diluted in a 1:1 solution of THF and MeOH (0.13 ml). 1M NaOH (0.026 ml, 0.026 mmol) was added and the reaction mixture was stirred for 18 hours at room temperature. 1N HCl (1 ml) was added followed by water (5 ml) and the mixture was extracted using EtOAc (3×5 ml). The combined organic layers were dried with sodium sulfate, filtered and evaporated under reduced pressure. The crude product was purified by semi-preparative HPLC-MS (X-Bridge 30×50 column) using a solution of MeCN in water (containing 10 mM ammonium formate) (50 to 70%). The product was lyophilized to give the title compound (1.2 mg, 0.003 mmol, 20%) as a pale yellow solid.

¹ H NMR (500 MHz, DMSO) δ 7.71-7.66 (m, 1H), 7.57 (d, J =8.3 Hz, 1H), 7.36 (d, J =1.8 Hz, 1H), 6.71 (s, 1H), 5.43–5.35 (m, 1H), 5.04 (t, J =6.8 Hz, 2H), 4.62 (dd, J =7.9, 4.9 Hz, 2H), 3.33 (sept, J=6.7 Hz, 1H), 2.27 (s, 3H), 1.22 (d, J =6.7 Hz , 6H); MS (m/z): 466.1 [M+1] ⁺ .

Compound 3: 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)thiazol-2-yl) -3-methyl-1H-pyrazole-5-carboxylic acid

methyl 4-bromo-1-(5-(isopropylthio)-4-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)thiazol-2-yl)-3-methyl-1H pyrazole-5-carboxylic acid

Methyl 4-bromo-1-(4-bromo-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H -pyrazole-5-carboxylate obtained as described above in relation to Compound 1 (100 mg, 0.220 mmol), (4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)boronic acid ( 38.1 mg 0.187 mmol) and K ₂ CO ₃ (152 mg, 1.10 mmol) _, nitrogen and vacuum cycles were performed (2x). Nitrogen gas was bubbled through the THF solution (2 mL) and then this solution was added to a microwave vial followed by Pd(dtbpf)Cl ₂ catalyst (14.3 mg, 0.022 mmol). The vial was closed and placed in an oil bath at 90°C for 16 hours. The solvent was evaporated in vacuo and the crude product was purified by silica gel flash chromatography (dry column fill) using EtOAc in hexanes (0 to 50% gradient) to give the title compound (57.8 g, 0.108 mmol, 49%) as a brown oil.

methyl 4–(3-fluorophenyl)–1–(5–(isopropylthio)–4–(4–(5–methyl–1,3,4–oxadiazol–2–yl)phenyl)thiazol–2–yl)–3 methyl-1H-pyrazole-5-carboxylic acid

Methyl 4-bromo-1-(5-(isopropylthio)-4-(4-(5-methyl-1,3,4 )-oxadiazol-2-yl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate (57.8 mg, 0.108 mmol), 3-fluorophenylboronic acid (18.2 mg, 0.130 mmol ) and Na ₂ CO ₃ (57.3 mg, 0.541 mmol), nitrogen and vacuum cycles were performed (2x). Nitrogen gas was bubbled through a dioxane/water solution (2 ml, 4:1) and then this solution was added to a microwave vial followed by Pd(PPh ₃ ) ₄ catalyst (12.5 mg, 0.011 mmol). The vial was closed and placed in an oil bath at 85°C for 16 hours. The crude product was purified by silica gel flash chromatography (dry column fill) using a solution of EtOAc in hexane (5 to 40% gradient) to give the title compound (25.4 mg, 0.046 mmol, 43%) in form of a yellow solid.

4–(3-fluorophenyl)–1–(5–(isopropylthio)–4–(4–(5–methyl–1,3,4–oxadiazol–2–yl)phenyl)thiazol–2–yl)–3– methyl-1H-pyrazole-5-carboxylic acid

Methyl 4–(3-fluorophenyl)–1–(5–(isopropylthio)–4–(4–(5–methyl–1,3,4–oxadiazol–2–yl)phenyl)thiazole was diluted in a 25 ml round bottom flask -2-yl)-3-methyl-1H-pyrazole-5-carboxylate (25.4 mg, 0.046 mmol) with a mixture of THF/MeOH (2 ml, 1:1). A 1 M NaOH solution (92.4 μl, 0.092 mmol) was added and the reaction mixture was stirred 16 hours at room temperature. The reaction mixture was acidified with 1 M HCl and the crude product was concentrated in vacuo. This product was purified by semi-preparative HPLC-MS (X-Bridge 30×50 column, eluted with 40-60% MeCN/NH ₄ CO ₂ H 10 mM, pH 3.8/flow 45 ml/min/11 min), whereby the title compound (3.99 mg, 0.007 mmol, 16%) was obtained as a white solid after lyophilization.

¹ H NMR (500 MHz, DMSO) δ 8.26 (d, J = 8.2 Hz, 2H), 8.06 (d, J = 8.5 Hz, 2H), 7.52–7.33 ( m, 3H), 7.12 (s, 2H), 3.37–3.24 (m, 1H), 2.61 (s, 3H), 2.30 (s, 3H), 1.24 (d , J =6.7Hz, 6H); MS (m/z): 536.1 [M+1] ⁺ .

Compound 4: 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-methylcyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole- 5-carboxylic acid

methyl 4-bromo-1-(5-(isopropylthio)-4-(4-methylcyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate

Methyl 4-bromo-1-(4-bromo-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H -pyrazole-5-carboxylate prepared as described above for Compound 1 (100 mg, 0.220 mmol), 4,4,5,5-tetramethyl-2- (4-methylcyclohex-1-en-1-yl) -1,3,2-dioxaborolane (41.5 mg, 0.187 mmol) and K ₂ CO ₃ (152 mg, 1.10 mmol), nitrogen and vacuum cycles were performed (2x). Nitrogen gas was bubbled through the THF solution (2 mL) and then this solution was added to a microwave vial followed by Pd(dtbpf)Cl ₂ catalyst (14.3 mg, 0.022 mmol). The vial was closed and placed in an oil bath at 90°C for 16 hours. The solvent was evaporated in vacuo and the crude product was purified by silica gel flash chromatography (dry column fill) using EtOAc in hexanes (0 to 10% gradient) to give the title compound (45.6 g, 0.097 mmol, 44%) as brown oil.

methyl 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-methylcyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazol-5- carboxylate

Methyl 4-bromo-1-(5-(isopropylthio)-4-(4-methylcyclohex-1-en-1-yl) thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate (44.6 mg, 0.085 mmol), 3-fluorophenylboronic acid (14.3 mg, 0.102 mmol) and Na ₂ CO ₃ (45.2 mg, 0.427 mmol), nitrogen and vacuum cycles were performed (2x). Nitrogen gas was bubbled through a dioxane/water solution (2 ml, 4:1) and then this solution was added to a microwave vial followed by Pd(PPh ₃ ) ₄ catalyst (9.86 mg, 0.009 mmol). The vial was closed and placed in an oil bath at 85°C for 16 hours. The crude product was purified by silica gel flash chromatography (wet-load with DCM) using a solution of EtOAc in hexanes (1% isocratic) to give the title compound (40.0 mg, 0.082 mmol, 97%) as an oil. yellow color.

4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-methylcyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid

Methyl 4–(3–fluorophenyl)–1–(5–(isopropylthio)–4–(4–(5–meth methyl 4–(3–fluorophenyl)–1–(5–(isopropylthio) )-4-(4-methylcyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate (40.0 mg, 0.082 mmol) with THF/MeOH (2 ml, 1:1) 1 M NaOH solution (165 µl, 0.165 mmol) was added and the reaction mixture was stirred for 16 h at room temperature. The reaction mixture was acidified with 1 M HCl and the crude product was concentrated in vacuo. MS (X-Bridge 30x50 column, eluted with 60-80% MeCN/NH ₄ CO ₂ H 10 mM, pH 3.8/flow 45 mL/min/11 min) to give the title compound (2.55 mg, 0.005 mmol, 7%) as a yellow solid after lyophilization.

¹ H NMR (500 MHz, DMSO) δ 7.50 (dd, J = 14.9, 7.8 Hz, 1H), 7.35–7.27 (m, 2H), 7.21 (s, 1H ), 6.35 (s, 1H), 3.32–3.16 (m, 1H), 2.57 (s, 1H), 2.45–2.35 (m, 1H), 2.32 ( s, 1H), 2.28 (s, 3H), 1.86–1.74 (m, 2H), 1.67 (s, 1H), 1.33–1.26 (m, 1H), 1 .24 (d, J =6.6 Hz, 6H), 0.98 (d, J =6.6 Hz, 3H); MS (m/z): 472.1 [M+1] ⁺ .

Compound 5: 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1Н -pyrazole-5-carboxylic acid

methyl 4-bromo-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate

Methyl 4-bromo-1-(4-bromo-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H -pyrazole-5-carboxylate prepared as described above for Compound 1 (100 mg, 0.220 mmol), 4,4,5,5-tetramethyl-2-(4-(trifluoromethyl)cyclohex-1-en-1 -yl)-1,3,2-dioxaborolane (51.6 mg, 0.187 mmol) and K ₂ CO ₃ (152 mg, 1.10 mmol), nitrogen and vacuum cycles were performed (2x). Nitrogen gas was bubbled through the THF solution (2 mL) and then this solution was added to a microwave vial followed by Pd(dtbpf)Cl ₂ catalyst (14.3 mg, 0.022 mmol). The vial was closed and placed in an oil bath at 90°C for 16 hours. The solvent was evaporated in vacuo and the crude product was purified by silica gel flash chromatography (dry column loading) using EtOAc in hexanes (0 to 10% gradient) to give the title compound (47.4 g, 0.090 mmol, 41%) as brown oil.

4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohexen-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazol- 5-carboxylic acid

Methyl 4-bromo-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-ene-1 -yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate (47.4 mg, 0.090 mmol), 3-fluorophenylboronic acid (15.2 mg, 0.108 mmol) and Na ₂ CO ₃ ( 47.9 mg, 0.452 mmol), nitrogen and vacuum cycles were performed (2x). Nitrogen gas was bubbled through a dioxane/water solution (2 ml, 4:1) and then this solution was added to a microwave vial followed by Pd(PPh ₃ ) ₄ catalyst (10.4 mg, 0.009 mmol). The vial was closed and placed in an oil bath at 85°C for 16 hours. The reaction mixture was diluted with EtOAc and transferred to an extraction funnel. The layers were separated and the aqueous layer was extracted using Et ₂ O (3x). The combined organic layers were dried with Na ₂ SO ₄ , filtered and concentrated in vacuo. THF/MeOH (2 ml, 1:1) and NaOH 1M (181 μl, 0.181 mmol) were added and the reaction mixture was stirred 16 h at room temperature. This product was purified by semi-preparative HPLC-MS (X-Bridge 30×50 column, eluted with 55-75% MeCN/NH ₄ CO ₂ H 10 mM, pH 3.8/flow 45 ml/min/11 min), whereby the title compound (12.8 mg, 0.024 mmol, 27%) was obtained as a yellow solid after lyophilization.

¹ H NMR (500 MHz, DMSO) δ 7.53–7.42 (m, 1H), 7.30–7.23 (m, 2H), 7.22–7.15 (m, 1H), 6 .41 (s, 1H), 3.32–3.22 (m, 1H), 2.74–2.60 (m, 1H), 2.50–2.33 (m, 3H), 2.26 (s, 3H), 2.23–2.15 (m, 1H), 2.07–1.97 (m, 1H), 1.57–1.46 (m, 1H), 1.23 (dd , J =6.7, 3.4 Hz, 6H); MS (m/z): 526.3 [M+1] ⁺ .

Compound 6: 1-(4-(4,4-dimethylcyclohex-1-en-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H- pyrazole-5-carboxylic acid

methyl 4-bromo-1-(4-(4,4-dimethylcyclohex-1-en-1-yl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate

Methyl 4-bromo-1-(4-bromo-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H -pyrazole-5-carboxylate prepared as described above for Compound 1 (100 mg, 0.220 mmol), 2-(4,4-dimethylcyclohex-2-en-1-yl)-4,4,5,5 -tetramethyl-1,3,2-dioxaborolane (52 mg, 0.22 mmol), K ₂ CO ₃ (152 mg, 1.10 mmol) and THF (2 ml). Nitrogen was bubbled into the solvent for 10 minutes followed by the addition of Pd(dtbpf)Cl ₂ catalyst (11 mg, 0.022 mmol). The vial was closed and placed in an oil bath at 90°C for 16 hours. The solvent was evaporated in vacuo and the crude product was purified by silica gel flash chromatography (dry column fill) using a gradient of 0 to 10% EtOAc in hexanes to give the title compound (57 mg, 0.12 mmol, 54%) as a yellow oil. MS (m/z): 484.0 [M+1]+.

1-(4-(4,4-dimethylcyclohex-1-en-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5 –carboxylic acid

Methyl 4-bromo-1-(4-(4,4-dimethylcyclohex-1-en-1-yl)-5-( isopropylthio) thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate (53 mg, 0.11 mmol), (3-fluorophenyl) boronic acid (18 mg, 0.13 mmol) and Na₂CO₃ (58 mg, 0.55 mmol). Nitrogen gas was bubbled through a solution of dioxane/water (2 ml, 4:1) and then this solution was added to a microwave vial followed by the addition of catalyst Pd(PPh₃)_four(13 mg, 0.011 mmol). The vial was closed and placed in an oil bath at 85°C for 16 hours. LiOH (13 mg, 0.55 mmol) was added to the reaction mixture and stirred under microwave at 110° C. for 15 minutes. The solvent was evaporated in vacuo and the indicated product was purified by semi-preparative HPLC-MS (X-Bridge column 30×50, eluted with 70-90% MeCN/NH_fourCO₂H 10 mM, pH 3.8/flow 45 mL/min/11 min) to give the title compound (13 mg, 0.027 mmol, 24%) as a yellow solid after lyophilization.

¹ H NMR (500 MHz, DMSO) δ 7.52–7.44 (m, 1H), 7.35–7.27 (m, 2H), 7.23–7.15 (m, 1H), 6 .33–6.27 (m, 1H), 3.28–3.19 (m, 1H), 2.48–2.42 (m, 2H), 2.28 (s, 3H), 2.00 –1.95 (m, 2H), 1.43 (t, J = 6.4 Hz, 2H), 1.23 (d, J = 6.7 Hz, 6H), 0.94 (s, 6H) . MS (m/z): 486.1 [M+1] ⁺ .

Compound 7: 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(1,4-dioxaspiro[4,5]deca-7-en-8-yl)thiazol-2-yl)- 3-methyl-1H-pyrazole-5-carboxylic acid

methyl 4-bromo-1-(5-(isopropylthio)-4-(1,4-dioxaspiro [4,5]dec-7-en-8-yl)thiazol-2-yl)-3-methyl-1H- pyrazole-5-carboxylic acid

Methyl 4-bromo-1-(4-bromo-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H -pyrazole-5-carboxylate prepared as described above for Compound 1 (100 mg, 0.220 mmol), 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec- 6-en-8-yl)-1,3,2-dioxaborolane (59 mg, 0.22 mmol), K ₂ CO ₃ (152 mg, 1.10 mmol) and THF (2 ml). Nitrogen was bubbled into the solvent for 10 minutes followed by the addition of Pd(dtbpf)Cl ₂ catalyst (11 mg, 0.022 mmol). The vial was closed and placed in an oil bath at 90°C for 16 hours. The solvent was evaporated in vacuo and the crude product was purified by silica gel flash chromatography (dry column fill) using a gradient of 0 to 20% EtOAc in hexanes to give the title compound (55 mg, 0.11 mmol, 49%) as a yellow oil. MS (m/z): 514.0 [M+1]+.

4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(1,4-dioxaspiro[4,5]dec-7-en-8-yl)thiazol-2-yl)-3-methyl –1H-pyrazole-5-carboxylic acid

Methyl 4-bromo-1-(5-(isopropylthio)-4-(1,4-dioxaspiro[4.5]dec- 7-en-8-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate (53 mg, 0.10 mmol), (3-fluorophenyl) boronic acid (17 mg, 0.12 mmol) and Na₂CO₃ (54 mg, 0.51 mmol). Nitrogen gas was bubbled through a solution of dioxane/water (2 ml, 4:1) and then this solution was added to a microwave vial followed by the addition of catalyst Pd(PPh₃)_four(12 mg, 0.010 mmol). The vial was closed and placed in an oil bath at 85°C for 16 hours. The reaction mixture was diluted with EtOAc, washed with water and brine. Dried MgSO_four, filtered and concentratedin a vacuum. The reaction mixture was dissolved in 1/1 THF/MeOH (2 ml) and treated with 1N NaOH (102 μl, 0.204 mmol). After 1 hour, more 1N NaOH (102 μl, 0.204 mmol) was added and stirring was continued for 16 hours. The solvent was evaporated in vacuo and the indicated product was purified by semi-preparative HPLC-MS (X-Bridge column 30×50, eluted with 55-75% MeCN/NH_fourCO₂H 10 mM, pH 3.8/flow 45 ml/min/10 min) to give the title compound (14 mg, 0.027 mmol, 26%) as a yellow solid after lyophilization.

¹ H NMR (500 MHz, DMSO) δ 7.53–7.45 (m, 1H), 7.34–7.27 (m, 2H), 7.25–7.16 (m, 1H), 6 .34–6.28 (m, 1H), 3.92 (s, 4H), 3.32–3.19 (m, 1H), 2.67–2.60 (m, 2H), 2.43 –2.36 (m, 2H), 2.28 (s, 3H), 1.77 (t, J = 6.5 Hz, 2H), 1.25 (d, J = 6.7 Hz, 6H) . MS (m/z): 516.1[M+1] ⁺ .

Compound 8: 1–(4–(4–chloro–3– (morpholine–4–carbonyl)phenyl)–5–(isopropylthio)thiazol–2–yl)–4–(3–fluorophenyl)–3–methyl–1Н -pyrazole-5-carboxylic acid

methyl 4-bromo-1-(4-(4-chloro-3-(morpholine-4-carbonyl)phenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate

Degassed THF (2 ml) was added to a mixture of methyl 4-bromo-1-(4-bromo-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate (75.0 mg 0.165 mmol) prepared using the above method for Compound 1, (4-chloro-3- (morpholine-4-carbonyl)phenyl)boronic acid (44 mg, 0.16 mmol), [1,1'-bis(di - tert) -butylphosphino)ferrocene]dichloropalladium (II) (8.2 mg, 0.016 mmol) and potassium carbonate (114 mg, 0.824 mmol). The reaction mixture was heated at 90 ^° C for 18 hours. Water was added and the mixture was extracted using ethyl acetate (2x). The combined organic layers were dried using sodium sulfate, filtered and evaporated. The crude product was purified by silica gel flash chromatography using a solution of ethyl acetate in hexanes (2% to 10%) to give the title compound (47 mg, 0.078 mmol, 47%) as a pale orange oil.

1–(4–(4–chloro–3–(morpholine–4–carbonyl)phenyl)–5–(isopropylthio)thiazol–2–yl)–4–(3–fluorophenyl)–3–methyl–1H–pyrazole– 5-carboxylic acid

A solution of methyl 4-bromo-1-(4-(4-chloro-3- (morpholine-4-carbonyl)phenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5- carboxylate (47 mg, 0.078 mmol), (3-fluorophenyl)boric acid (13 mg, 0.094 mmol), Pd (PPh ₃ ) ₄ (9 mg, 0.008 mmol), Na ₂ CO ₃ (41 mg, 0.39 mmol ) in degassed 1,4-dioxane and H ₂ O (4:1, 1.6 ml) was heated at 85 ^° C for 18 hours. LiOH hydrate (16 mg, 0.39 mmol) was added and the reaction mixture was heated at 95° C. under microwave radiation for 45 minutes. 1N HCl (1 ml) was added followed by water (5 ml) and the mixture was extracted using EtOAc (3×5 ml). The combined organic layers were dried with sodium sulfate, filtered and evaporated under reduced pressure. The crude product was purified by semi-preparative HPLC-MS (X-Bridge 30×50 column) using a solution of MeCN in water (containing 10 mM ammonium formate) (45 to 65%). The product was lyophilized to give the title compound (2 mg, 0.003 mmol, 4%) as an off-white solid.

¹ H NMR (500 MHz, DMSO) δ 8.06 (d, J =8.1 Hz, 1H), 7.99 (s, 1H), 7.65 (d, J =8.5 Hz, 1H) , 7.52-7.44 (m, 1H), 7.41-7.31 (m, 2H), 7.22-7.13 (m, 1H), 3.75-3.62 (m, 4H), 3.61–3.51 (m, 2H), 3.33 (1H, underwater signal), 3.22–3.15 (m, 2H), 2.30 (s, 3H), 1 .22 (d, J = 5.8 Hz, 6H); MS (m/z): 552.1 [M+1] ⁺ .

Compound 9: 4-(3,4-dichlorophenyl)-2-(4-(2,6-dimethylpyridin-4-yl)-3-methyl-1H-pyrazol-1-yl)-5-(isopropylthio)thiazole

1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(2,6-dimethylpyridin-4-yl)-3-methyl-1H-pyrazole-5-carboxylic acid (38.0 mg, 0.071 mmol), copper chromite (12.0 mg, 0.085 mmol) and quinoline (0.6 ml) were heated at 230°C for 15 minutes under microwave radiation. The crude product was purified by reverse chromatography on a C-18 column with MeCN in water (containing 10 mM NH ₄ CO ₂ H) (55 to 80 to 100%) to give the title compound (24.7 mg, 0.050 mmol 71%) as a beige solid after lyophilization.

¹ H NMR (500 MHz, DMSO) δ 9.05 (s, 1H), 8.32 (d, J =2.0 Hz, 1H), 8.14 (dd, J =8.4, 2.1 Hz, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.34 (s, 2H), 3.38–3.32 (m, J = 13.4, 6.7 Hz , 1H), 3.29 (s, 3H), 2.47 (s, 6H), 1.23 (d, J = 6.7 Hz). 6H); MS (m/z): 489.2 [M+1] ⁺ .

Compound 10: 2-(4-(3-fluorophenyl)-3,5-dimethyl-1H-pyrazol-1-yl)-5-(isopropylthio)-4-(4-(trifluoromethyl)phenyl)thiazole

4-iodine-3,5-dimethyl-1H-pyrazole

3,5-dimethyl-1H-pyrazole (100 mg, 1.04 mmol) was dissolved in 1.0 ml TFA. N-iodosuccinimide (234 mg, 1.04 mmol) was added in one portion. The reaction mixture was stirred at room temperature for 1 hour. LCMS showed a clean reaction. Water and EtOAc were added and the phases were separated. The organic phase was washed with an aqueous saturated sodium sulfite solution and dried over sodium sulfate, filtered and concentrated. 230 mg of crude product (1.04 mmol, 99%) was obtained as a white solid.

4-(3-fluorophenyl)-3,5-dimethyl-1H-pyrazole

4-iodine-3,5-dimethyl-1H-pyrazole (231 mg, 1.04 mmol), boronic acid (281 mg, 2.01 mmol), sodium carbonate (551 mg, 5.20 mmol), dioxane (5 .2 ml) and water (1.3 ml) were loaded into a screw cap vial. The mixture was degassed for 10 minutes and Pd(PPh ₃ ) ₄ (60 mg, 0.05 mmol) was added. The tube was closed and the mixture was heated to 85°C. There was no reaction after 1 hour. After 16 hours, the ratio of iodopyrazole:product was 1:6. The mixture was heated to 110°C. After 6 hours no iodopyrazole starting material remained, so the mixture was cooled to room temperature, diluted with water and EtOAc. The phases were separated and the aqueous phase was washed with brine. SiO2 was added to the organic phase and concentrated to dryness. The crude product on silica was purified on Isco with a gradient of hexanes to EtOAc. 144 mg (0.76 mmol, 73%) of the product was obtained as a colorless oil.

2-thiocyanato-1-(4-(trifluoromethyl)phenyl)ethanone

Potassium thiocyanate (9.55 g, 98.3 mmol) was added to a stirred solution of 2-bromo-1-(4-(trifluoromethyl)phenyl)ethanone (25.0 g, 93.6 mmol) in MeCN (178 ml) at room temperature. The reaction mixture was heated under reflux (90 ^o C) for 2 h, then cooled to room temperature and diluted with water and EtOAc. The aqueous layer was extracted with EtOAc (3 times). The combined organic layers were washed with brine, dried over MgSO ₄ , filtered and concentrated in vacuo to give the title compound (23.3 g, 94.9 mmol, 97%) which was used without further purification.

2-chloro-4-(4-(trifluoromethyl)phenyl)thiazole

A mixture of 2-thiocyanato-1-(4-(trifluoromethyl)phenyl)ethanone (23.3 g, 94.9 mmol) and 4 M HCl in dioxane (142 ml, 569 mmol) in dioxane (95 ml) was stirred for 16 h at room temperature. The reaction mixture was concentrated in vacuo and the residue was diluted with sat. aq. NaHCO ₃ solution and extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over MgSO ₄ , filtered and concentrated in vacuo to give the title compound (25.0 g, 94.8 mmol, 100%) as a brown solid.

2-chloro-5-(isopropylthio)-4-(4-(trifluoromethyl)phenyl)thiazole

A 2.5 M solution of n -BuLi in a mixture of hexanes (18.8 ml, 40.3 mmol) was added to a THF solution (107 ml) of 2-chloro-4-(4-(trifluoromethyl)phenyl)thiazole (10.0 g , 32.3 mmol) at –78 °С. The reaction mixture was stirred at the same temperature for 30 minutes. Diisopropyl disulfide (10.3 ml, 64.5 mmol) was added to the reaction mixture and stirred at the same temperature for 2 hours. Water was added to quench the reaction and then Et ₂ O. The reaction mixture was transferred to a separating funnel and the layers were separated. The aqueous layer was extracted using Et ₂ O (2x). The combined organic layers were dried with Na ₂ SO ₄ and concentrated in vacuo. The crude product was purified by silica gel flash chromatography (dry column fill) using a solution of EtOAc in hexanes (0 to 1% gradient) to give the title compound (3.05 g, 9.03 mmol, 28 %) as a yellow oil.

2-(4-(3-fluorophenyl)-3,5-dimethyl-1H-pyrazol-1-yl)-5-(isopropylthio)-4-(4-(trifluoromethyl)phenyl)thiazole

4-(3-Fluorophenyl)-3,5-dimethyl-1H-pyrazole (140 mg, 1.0 mmol), the thiazole obtained above (372 mg, 1.1 mmol), K ₂ CO ₃ (690 mg, 5.0 mmol) and DMSO (3.3 ml). Nitrogen was bubbled into DMSO for 10 minutes. And then CuI (57 mg, 0.30 mmol) was added. The resulting solution was covered with a lid and heated in a microwave oven at 100°C for 3 hours. LCMS showed 40% conversion (pyrazole:product ratio) and a clean reaction. The mixture was heated in an oil bath for 3 hours. LCMS showed 74% conversion. Heating was continued for 16 hours. LCMS showed complete conversion. The mixture was diluted with EtOAc and water, the phases were separated and the organic phase was washed 3 times with water and then brine. Silica gel was added to the organic phase and concentrated to dryness. The crude product on SiO2 was purified on Isco with a gradient of hexanes to 10% DCM. 151 mg (0.307 mmol, 31%) of product was obtained as a colorless oil. This mixture was repurified on Isco reversed phase using a C18 column eluting with a gradient of 50-100% MeCN/water (10 mM ammonium formate, pH 3.8). Fractions containing this product were concentrated to remove most of the acetonitrile, water was added, and the flask was frozen and lyophilized. The product (99 mg, 0.201 mmol, 20% yield) was obtained as a pale yellow solid.

¹ H NMR (500 MHz, DMSO) δ 8.24 (d, J =8.2 Hz, 2H), 7.87 (d, J =8.4 Hz, 2H), 7.53 (dd, J = 14.2, 7.9 Hz, 1H), 7.29-7.18 (m, 3H), 3.39-3.33 (m, 1H), 2.69 (s, 3H), 2.25 (s, 3H), 1.23 (d, J = 6.7 Hz, 6H); MS (m/z): 492.3 [M+1] ⁺ .

Compound 11: 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(piperidin-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid

methyl 4-bromo-1-(5-(isopropylthio)-4-(piperidin-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate

Methyl 4-bromo-1-(4-bromo-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H -pyrazole-5-carboxylate obtained as described above in relation to Compound 1 (100 mg, 0.220 mmol), XantPhos (12.7 mg, 0.022 mmol) and Cs ₂ CO ₃ (358 mg, 1.10 mmol) _, nitrogen and vacuum cycles were performed (2x). Nitrogen gas was bubbled through a solution of dioxane (2 ml) and piperidine (21.7 μl, 0.220 mmol), then this solution was added to a microwave vial followed by RuPhos Palladacycle catalyst (17.9 mg, 0.022 mmol). The vial was closed and placed in an oil bath at 105°C for 16 hours. The solvent was evaporated in vacuo and the crude product was purified by silica gel flash chromatography (dry column fill) using a solution of EtOAc in hexanes (1% isocratic) to give the title compound (41.0 mg, 0.089 mmol, 41%) as a yellow oil.

4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(piperidin-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid

Methyl 4-bromo-1-(5-(isopropylthio)-4-(piperidin-1-yl)thiazol-2-yl) -3-methyl-1H-pyrazole-5-carboxylate (41.0 mg, 0.089 mmol), 3-fluorophenylboronic acid (15.0 mg, 0.108 mmol) and Na ₂ CO ₃ (47.3 mg, 0.446 mmol), nitrogen and vacuum cycles were performed (2x). Nitrogen gas was bubbled through a dioxane/water solution (2 ml, 4:1) and then this solution was added to a microwave vial followed by Pd(PPh ₃ ) ₄ catalyst (10.3 mg, 0.009 mmol). The vial was closed and placed in an oil bath at 85°C for 16 hours. LiOH (18.7 mg, 0.446 mmol) was added to the reaction mixture and stirred under microwave at 120° C. for 10 min. The reaction mixture was diluted with EtOAc and 0.1 M HCl. The aqueous layer was extracted with EtOAc (2x) and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. This product was purified by semi-preparative HPLC-MS (X-Bridge 30×50 column, eluted with 55-75% MeCN/NH ₄ CO ₂ H 10 mM, pH 3.8/flow 45 ml/min/11 min), whereby the title compound (3.24 mg, 0.007 mmol, 8%) was obtained as a yellow solid after lyophilization.

¹ H NMR (500 MHz, DMSO) δ 7.55-7.40 (m, 1H), 7.41-7.24 (m, 2H), 7.23-7.05 (m, 1H), 3 .59–3.49 (m, 4H), 3.18–3.06 (m, 1H), 2.27 (s, 3H), 1.55 (s, 6H), 1.23 (d, J =6.7 Hz, 6H); MS (m/z): 461.2 [M+1] ⁺ .

Compound 12: 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)piperidin-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5 –carboxylic acid

methyl 4-bromo-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)piperidin-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate

Methyl 4-bromo-1-(4-bromo-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H -pyrazole-5-carboxylate prepared as above for Compound 1 (100 mg, 0.220 mmol), 4-(trifluoromethyl)piperidine (41.7 mg, 0.220 mmol), XantPhos (12.7 mg, 0.022 mmol ) and Cs ₂ CO ₃ (358 mg, 1.10 mmol) _, nitrogen, and vacuum cycles were performed (2x). Nitrogen gas was bubbled through dioxane (2 ml) which was then added to a microwave vial followed by RuPhos Palladacycle catalyst (17.9 mg, 0.022 mmol). The vial was closed and placed in an oil bath at 105°C for 16 hours. The solvent was evaporated in vacuo and the crude product was purified by silica gel flash chromatography (dry column fill) using a solution of EtOAc in hexanes (1% isocratic) to give the title compound (52.0 mg, 0.099 mmol, 45 %) as a yellow oil.

4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)piperidin-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid

Methyl 4-bromo-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)piperidin-1-yl)thiazole -2-yl)-3-methyl-1H-pyrazole-5-carboxylate (52.0 mg, 0.099 mmol), 3-fluorophenylboronic acid (16.6 mg, 0.118 mmol) and Na ₂ CO ₃ (52.3 mg , 0.493 mmol) _, nitrogen, and vacuum cycles were performed (2x). Nitrogen gas was bubbled through a dioxane/water solution (2 ml, 4:1) and then this solution was added to a microwave vial followed by Pd(PPh ₃ ) ₄ catalyst (11.4 mg, 0.010 mmol). The vial was closed and placed in an oil bath at 85°C for 16 hours. LiOH (42.0 mg, 0.493 mmol) was added to the reaction mixture and stirred under microwave at 120° C. for 10 min. The reaction mixture was diluted with EtOAc and 0.1 M HCl. The aqueous layer was extracted with EtOAc (2x) and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. This product was purified by semi-preparative HPLC-MS (X-Bridge 30×50 column, eluted with 55-75% MeCN/NH ₄ CO ₂ H 10 mM, pH 3.8/flow 45 ml/min/11 min), whereby the title compound (3.41 mg, 0.007 mmol, 7%) was obtained as a yellow solid after lyophilization.

¹ H NMR (500 MHz, DMSO) δ 7.52-7.43 (m, 1H), 7.36-7.26 (m, 2H), 7.19 (t, J =7.6 Hz, 1H ), 4.38 (d, J =12.8 Hz, 2H), 3.19–3.07 (m, 1H), 2.95–2.86 (m, 2H), 2.58–2, 51 (m, 1H), 2.28 (s, 3H), 1.80 (d, J = 10.7 Hz, 2H), 1.49 ( qd, J = 12.6, 4.1 Hz, 2H ), 1.24 (d, J =6.7 Hz, 6H); MS (m/z): 529.1 [M+1] ⁺ .

Compound 13: 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methoxy-1H-pyrazole-5-carboxylic acid

2-thiocyanato-1-(4-(trifluoromethyl)phenyl)ethanone

Potassium thiocyanate (9.55 g, 98.3 mmol) was added to a stirred solution of 2-bromo-1-(4-(trifluoromethyl)phenyl)ethanone (25.0 g, 93.6 mmol) in MeCN (178 ml) at room temperature. The reaction mixture was heated under reflux (90 ^o C) for 2 h, then cooled to room temperature and diluted with water and EtOAc. The aqueous layer was extracted with EtOAc (3 times). The combined organic layers were washed with brine, dried over MgSO ₄ , filtered and concentrated in vacuo to give the title compound (23.3 g, 94.9 mmol, 97%) which was used without further purification.

2-chloro-4-(4-(trifluoromethyl)phenyl)thiazole

A mixture of 2-thiocyanato-1-(4-(trifluoromethyl)phenyl)ethanone (23.3 g, 94.9 mmol) and 4 M HCl in dioxane (142 ml, 569 mmol) in dioxane (95 ml) was stirred for 16 h at room temperature. The reaction mixture was concentrated in vacuo and the residue was diluted with sat. aq. NaHCO ₃ solution and extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over MgSO ₄ , filtered and concentrated in vacuo to give the title compound (25.0 g, 94.8 mmol, 100%) as a brown solid.

2-chloro-5-(isopropylthio)-4-(4-(trifluoromethyl)phenyl)thiazole

A 2.5 M solution of n -BuLi in a mixture of hexanes (18.8 ml, 40.3 mmol) was added to a THF solution (107 ml) of 2-chloro-4-(4-(trifluoromethyl)phenyl)thiazole (10.0 g , 32.3 mmol) at –78 °С. The reaction mixture was stirred at the same temperature for 30 minutes. Diisopropyl disulfide (10.3 ml, 64.5 mmol) was added to the reaction mixture and stirred at the same temperature for 2 hours. Water was added to quench the reaction and then Et ₂ O. The reaction mixture was transferred to a separating funnel and the layers were separated. The aqueous layer was extracted using Et ₂ O (2x). The combined organic layers were dried with Na ₂ SO ₄ and concentrated in vacuo. The crude product was purified by silica gel flash chromatography (dry column fill) using a solution of EtOAc in hexanes (0 to 1% gradient) to give the title compound (3.05 g, 9.03 mmol, 28 %) as a yellow oil.

2-hydrazinyl-5-(isopropylthio)-4-(4-(trifluoromethyl)phenyl)thiazole

DIPEA (3.2 ml, 18.2 mmol) was added to a solution of hydrazine hydrochloride (1.2 g, 18.2 mmol) and 2-chloro-5-(isopropylthio)-4-(4-(trifluoromethyl)phenyl)thiazole (3.1 g, 9.1 mmol) in NMP (18 ml) in a round bottom flask. The flask was heated to 135° C. for 2 h in an oil bath. The reaction mixture was diluted with water and extracted with Et ₂ O. The combined organic layers were washed with brine (3x), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. This gave the title compound (2.85 g, 8.55 mmol, 95%) as a blue oil.

methyl 3-hydroxy-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-1H-pyrazole-5-carboxylate

A solution of 2-hydrazinyl-5-(isopropylthio)-4-(4-(trifluoromethyl)phenyl)thiazole (1.9 g, 5.76 mmol) in toluene (5 ml) was slowly added to a solution of dimethyl 2,5-dioxohex- 3-indioate (900 mg, 6.33 mmol) in toluene (3 ml) and AcOH (4 ml) at 0 °C. The reaction mixture was stirred at room temperature for 1 hour and refluxed for 4 hours. The reaction mixture was concentrated in vacuo and the crude product was purified by silica gel flash chromatography (dry column fill) using a solution of EtOAc in hexanes (5 to 30% gradient) to give the title compound (714 mg, 1 .61 mmol, 28%) as a yellow oil.

methyl 1–(5–(isopropylthio)–4–(4–(trifluoromethyl)phenyl)thiazol–2–yl)–3–methoxy–1H–pyrazole–5–carboxylate

In a round bottom flask equipped with a magnetic stirrer and nitrogen flow at room temperature, ADDP (171 mg, 0.677 mmol) and tributylphosphine (205 mg, 1.02 mmol) in THF (7 ml) were placed, followed by the addition of methyl 3-hydroxy-1- (5-(isopropylthio)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-1H-pyrazol-5-carboxylate (150 mg, 0.338 mmol) and MeOH (20.6 μl, 0.550 mmol). The reaction mixture was heated to 80°C for 3 hours. The reaction mixture was concentrated in vacuo and dissolved in Et ₂ O to filter the tributylphosphine oxide. The filtrate was concentrated in vacuo and the crude product was purified by silica gel flash chromatography (dry column fill) using a solution of EtOAc in hexanes (10 to 30% gradient) to give the title compound (115 mg, 0.251 mmol, 74 %) as a yellow oil.

methyl 4-bromo-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methoxy-1H-pyrazole-5-carboxylate

A 2 M solution of bromine in acetonitrile (0.45 mL, 0.900 mmol) was added to a solution of methyl 1–(5–(isopropylthio)–4–(4–(trifluoromethyl)phenyl)thiazol–2–yl)–3–methoxy–1H -pyrazole-5-carboxylate (137 mg, 0.300 mmol) in MeCN/DCM (4 ml, 1:1 ml). The reaction mixture was stirred for 3 hours at room temperature. A saturated aqueous solution of Na ₂ SO ₃ was added and the reaction mixture was extracted using Et ₂ O (3x). The combined organic layers were dried with sodium sulfate, filtered and evaporated under reduced pressure. The crude product was purified by silica gel flash chromatography (dry column fill) using a solution of EtOAc in hexanes (2 to 10%) to give the title compound (98.0 mg, 0.183 mmol, 61%) as yellow oils.

4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methoxy-1H-pyrazole-5-carboxylic acid

Methyl 4-bromo-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl )-3-methoxy-1H-pyrazole-5-carboxylate (98.0 mg, 0.183 mmol), 3-fluorophenylboronic acid (60.7 mg, 0.219 mmol) and Na ₂ CO ₃ (96.8 mg, 0.914 mmol) , nitrogen, and vacuum cycles were performed (2x). Nitrogen gas was bubbled through a dioxane/water solution (2 ml, 4:1) and then this solution was added to a microwave vial followed by Pd(PPh ₃ ) ₄ catalyst (21.1 mg, 0.018 mmol). The vial was closed and placed in an oil bath at 85°C for 16 hours. LiOH (38.3 mg, 0.914 mmol) was added to the reaction mixture and stirred under microwave at 120° C. for 10 min. The reaction mixture was diluted with EtOAc and 0.1 M HCl. The aqueous layer was extracted with EtOAc (2x) and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. This product was purified by semi-preparative HPLC-MS (X-Bridge 30×50 column, eluted with 40-60% MeCN/NH ₄ CO ₂ H 10 mM, pH 3.8/flow 45 ml/min/11 min), whereby the title compound (2.95 mg, 0.005 mmol, 3%) was obtained as a yellow solid after lyophilization.

¹ H NMR (500 MHz, MeOD) δ 8.31 (d, J=8.1 Hz, 2H), 7.76 (d, J=8.3 Hz, 2H), 7.60–7.55 ( m, 2H), 7.40–7.34 (m, 1H), 7.02–6.97 (m, 1H), 3.95 (s, 3H), 3.29–3.21 (m, 1H), 1.25 (d, J=6.7 Hz, 6H); MS (m/z): 538.2 [M+1] ⁺ .

Compound 14: 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-morpholinothiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid

methyl 4-bromo-1-(5-(isopropylthio)-4-morpholinothiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate

Methyl 4-bromo-1-(4-bromo-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H -pyrazole-5-carboxylate obtained as described above in relation to Compound 1 (300 mg, 0.659 mmol), XantPhos (38.1 mg, 0.066 mmol) and Cs ₂ CO ₃ (1.07 mg, 3.30 mmol) _, nitrogen and vacuum cycles were performed (2x). Nitrogen gas was bubbled through a solution of dioxane (3 mL) and morpholine (57.4 μL, 0.659 mmol) which was then added to a microwave vial followed by RuPhos Palladacycle catalyst (53.8 mg, 0.066 mmol). The vial was closed and placed in an oil bath at 105°C for 16 hours. The solvent was evaporated in vacuo and the crude product was purified by silica gel flash chromatography (dry column fill) using a solution of EtOAc in hexanes (5 to 20% gradient) to give the title compound (108 mg, 0.234 mmol, 36 %) as a yellow oil.

4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-morpholinothiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid

Methyl 4-bromo-1-(5-(isopropylthio)-4-morpholinothiazol-2-yl)-3-methyl-1H- performed pyrazole-5-carboxylate (108 mg, 0.234 mmol), 3-fluorophenylboronic acid (39.3 mg, 0.281 mmol) and Na ₂ CO ₃ (124 mg, 1.17 mmol), nitrogen and performed vacuum cycles (2x) . Nitrogen gas was bubbled through a dioxane/water solution (2 ml, 4:1) and then this solution was added to a microwave vial followed by Pd(PPh ₃ ) ₄ catalyst (27.0 mg, 0.023 mmol). The vial was closed and placed in an oil bath at 85°C for 16 hours. LiOH (49.1 mg, 1.17 mmol) was added to the reaction mixture and stirred under microwave at 110° C. for 15 min. The reaction mixture was diluted with EtOAc and 0.1 M HCl. The aqueous layer was extracted with EtOAc (2x) and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. This product was purified by semi-preparative HPLC-MS (X-Bridge 30×50 column, eluted with 30-50% MeCN/NH ₄ CO ₂ H 10 mM, pH 3.8/flow 45 ml/min/11 min), whereby the title compound (18.0 mg, 0.039 mmol, 16%) was obtained as a yellow solid after lyophilization.

¹ H NMR (500 MHz, DMSO) δ 7.46 (dd, J =14.4, 7.6 Hz, 1H), 7.39-7.29 (m, 2H), 3.70-3.63 (m, 4H), 3.58-3.51 (m, 4H) 3.16-3.07 (m, J =13.4, 6.7 Hz, 1H), 2.27 (s, 3H) , 1.24 (d, J = 6.7 Hz, 6H); MS (m/z): 463.2 [M+1] ⁺ .

Compound 15: 4-(3-fluorophenyl)-3-hydroxy-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-1H-pyrazole-5-carboxylic acid

2-thiocyanato-1-(4-(trifluoromethyl)phenyl)ethanone

Potassium thiocyanate (9.55 g, 98.3 mmol) was added to a stirred solution of 2-bromo-1-(4-(trifluoromethyl)phenyl)ethanone (25.0 g, 93.6 mmol) in MeCN (178 ml) at room temperature. The reaction mixture was heated under reflux (90 ^o C) for 2 h, then cooled to room temperature and diluted with water and EtOAc. The aqueous layer was extracted with EtOAc (3 times). The combined organic layers were washed with brine, dried over MgSO ₄ , filtered and concentrated in vacuo to give the title compound (23.3 g, 94.9 mmol, 97%) which was used without further purification.

2-chloro-4-(4-(trifluoromethyl)phenyl)thiazole

A mixture of 2-thiocyanato-1-(4-(trifluoromethyl)phenyl)ethanone (23.3 g, 94.9 mmol) and 4 M HCl in dioxane (142 ml, 569 mmol) in dioxane (95 ml) was stirred for 16 h at room temperature. The reaction mixture was concentrated in vacuo and the residue was diluted with sat. aq. NaHCO ₃ solution and extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over MgSO ₄ , filtered and concentrated in vacuo to give the title compound (25.0 g, 94.8 mmol, 100%) as a brown solid.

2-chloro-5-(isopropylthio)-4-(4-(trifluoromethyl)phenyl)thiazole

A 2.5 M solution of n -BuLi in a mixture of hexanes (18.8 ml, 40.3 mmol) was added to a THF solution (107 ml) of 2-chloro-4-(4-(trifluoromethyl)phenyl)thiazole (10.0 g , 32.3 mmol) at –78 °С. The reaction mixture was stirred at the same temperature for 30 minutes. Diisopropyl disulfide (10.3 ml, 64.5 mmol) was added to the reaction mixture and stirred at the same temperature for 2 hours. Water was added to quench the reaction and then Et ₂ O. The reaction mixture was transferred to a separating funnel and the layers were separated. The aqueous layer was extracted using Et ₂ O (2x). The combined organic layers were dried with Na ₂ SO ₄ and concentrated in vacuo. The crude product was purified by silica gel flash chromatography (dry column fill) using a solution of EtOAc in hexanes (0 to 1% gradient) to give the title compound (3.05 g, 9.03 mmol, 28 %) as a yellow oil.

2-hydrazinyl-5-(isopropylthio)-4-(4-(trifluoromethyl)phenyl)thiazole

Diisopropylethiamin (3.2 ml, 18.2 mmol) was added to a solution of hydrazine hydrochloride (1.2 g, 18.2 mmol) and 2-chloro-5-(isopropylthio)-4-(4-(trifluoromethyl)phenyl)thiazole (3.1 g, 9.1 mmol) in N-methylpyrrolidine ("NMP") (18 ml) in a round bottom flask. The flask was heated to 135° C. for 2 hours in an oil bath. The reaction mixture was diluted with water and extracted with Et ₂ O. The combined organic layers were washed with brine (3x), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. This gave the title compound (2.85 g, 8.55 mmol, 95%) as a blue oil.

methyl 3-hydroxy-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-1H-pyrazole-5-carboxylate

A solution of 2-hydrazinyl-5-(isopropylthio)-4-(4-(trifluoromethyl)phenyl)thiazole (1.9 g, 5.76 mmol) in toluene (5 ml) was slowly added to a solution of dimethyl 2,5-dioxohex- 3-indioate (900 mg, 6.33 mmol) in toluene (3 ml) and AcOH (4 ml) at 0 °C. The reaction mixture was stirred at room temperature for 1 hour and refluxed for 4 hours. The reaction mixture was concentrated in vacuo and the crude product was purified by silica gel flash chromatography (dry column fill) using a solution of EtOAc in hexanes (5 to 30% gradient) to give the title compound (714 mg, 1 .61 mmol, 28%) as a yellow oil.

methyl 4-bromo-3-hydroxy-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-1H-pyrazole-5-carboxylate

N-bromosuccinimide (188 mg, 1.06 mmol) was added in portions to a solution of methyl 3-hydroxy-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-1H-pyrazole -5-carboxylate (469 mg, 1.06 mmol) in MeCN/DCM (8 ml, 1:1). The reaction mixture was stirred for 5 minutes at room temperature. And then extinguished with water and drops of Na ₂ S ₂ O ₃ . The aqueous layer was extracted using EtOAc (2x) and the combined organic layers were dried with Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by silica gel flash chromatography (dry column fill) using a solution of EtOAc in hexanes (0 to 30% gradient) to give the title compound (139 mg, 0.266 mmol, 25%) as pink solid.

methyl 3-acetoxy-4-bromo-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-1H-pyrazole-5-carboxylate

methyl 4-bromo-3-hydroxy-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-1H-pyrazole-5-carboxylate (89 mg, 0.17 mmol ) was placed in acetic anhydride (5.00 ml) followed by the addition of pyridine (2 drops). The reaction mixture was stirred for 1 hour at room temperature and then evaporated to dryness. The crude product was purified by silica gel flash chromatography (dry column fill) using a solution of EtOAc in hexanes (5% isocratic) to give the title compound (50 mg, 0.089 mmol, 52%) as a white solid. colors.

methyl 4-(3-fluorophenyl)-3-hydroxy-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-1H-pyrazole-5-carboxylate

Methyl 3-acetoxy-4-bromo-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)phenyl)thiazole )-2-yl)-1H-pyrazol-5-carboxylate (30.0 mg, 0.053 mmol), 3-fluorophenylboronic acid (8.93 mg, 0.064 mmol) and KF (10.2 mg, 0.175 mmol), nitrogen and performed vacuum cycles (2x). Nitrogen gas was bubbled through the THF solution (0.5 ml) and then this solution was added to the microwave vial followed by the addition of Pd(P ^t Bu ₃ ) ₂ catalyst (2.72 mg, 0.005 mmol). The vial was closed and stirred at room temperature for 72 hours. The crude product was purified by reverse chromatography on a C-18 column with a solution of MeCN in water (containing 10 mM NH ₄ CO ₂ H) (40 to 80%) to give the title compound (4.00 mg, 0.007 mmol. 14 %) as a white solid.

4-(3-fluorophenyl)-3-hydroxy-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-1H-pyrazole-5-carboxylic acid

In a 10 ml round-bottom flask, methyl 4-(3-fluorophenyl)-3-hydroxy-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-1H-pyrazol-5 -carboxylate (4.00 mg, 0.007 mmol) was diluted with THF/MeOH (2 ml, 1:1). A solution of NaOH 1 M (15 μl, 0.015 mmol) was added and the reaction mixture was stirred overnight at room temperature. The crude product was purified by reverse chromatography on a C-18 column with MeCN in water (containing 10 mM NH ₄ CO ₂ H) (35 to 65%) to give the title compound (0.548 mg, 0.001 mmol, 14%) in the form of a pale green powder after lyophilization.

¹ H NMR (500 MHz, MeOD) δ 8.33-8.28 (m, 2H), 7.74-7.70 (m, 2H), 7.54-7.48 (m, 2H), 7 .29–7.20 (m, 1H), 6.82–6.75 (m, 1H), 4.57 (br s, 1H), 3.25–3.17 (m, 1H), 1, 22 (d, J =6.7 Hz, 6H); MS (m/z): 524.2 [M+1] ⁺ .

Compounds 16 and 17: 1-(5-(3,4-dichlorophenyl)-1-isobutyl-1Н-1,2,4-triazol-3-yl)-4-(3-fluorophenyl)-3-methyl-1Н -pyrazole-5-carboxylic acid and 1-(3-(3,4-dichlorophenyl)-1-isobutyl-1H-1,2,4-triazol-5-yl)-4-(3-fluorophenyl)-3- methyl-1H-pyrazole-5-carboxylic acid

3,4-dichlorobenzohydrazide

Hydrazine hydrate (20.2 ml, 324 mmol) was added to methyl 3,4-dichlorobenzoate (4.52 g, 21.6 mmol) in EtOH (108 ml). The reaction mixture was refluxed for 1.5 hours. LCMS showed completion of the reaction. Most of the ethanol was evaporated and the product was triturated in water. Drying under high vacuum gave the product (4.42 g, 21.6 mmol) as a white solid.

N-(5-(3,4-dichlorophenyl)-1H-1,2,4-triazol-3-yl)nitramide

Nitroguanidine (3.04 g, 29.3 mmol) was suspended in 1 N NaOH (19.5 ml, 19.5 mmol). 3,4-dichlorobenzohydrazide (2.00 g, 9.75 mmol) was added (it remained on the surface, but went into solution when heated). The reaction mixture was heated at 75°C for 3 hours. Added 1 n. HCl (20 ml) to acidify the mixture (the product was destroyed). The mixture was filtered and washed with water. With the help of LCMS, the product was identified as the main one. The product (2.36 g, 6.80 mmol, 70%) was obtained as an off-white solid after drying under high vacuum.

5-(3,4-dichlorophenyl)-3-hydrazinyl-1H-1,2,4-triazole

Acetic acid (4.56 ml ). The suspension was stirred at 10°C and a suspension of zinc powder (298 mg, 4.56 mmol) in water (4.56 ml) was added. After 16 hours the mixture was cooled to 0° C. and a solution of 8 M aqueous sodium hydroxide (15 ml) was added and the pH was checked to be basic (pH > 10). This mixture was used for the next step.

tert-butyl 2-(5-(3,4-dichlorophenyl)-1H-1,2,4-triazol-3-yl)hydrazinecarboxylate

In a flask containing a crude solution of 5-(3,4-dichlorophenyl)-3-hydrazinyl-1H-1,2,4-triazole in water (pH<10, aqueous phase from previous step, theoretical amount 223 mg. 0.91 mmol) was added THF (9 ml). Di-tert-butyl dicarbonate (499 mg, 2.28 mmol) was added. After 16 hours, LCMS showed no s.m. and many products. This mixture was transferred to an EtOAc separating funnel and the phases were separated. The aqueous phase was extracted using EtOAc. The combined organic phase was washed with brine and dried over sodium sulfate, filtered and concentrated. A mixture of Boc product and Boc impurities was obtained in the form of a light brown oil. This mixture was used directly in the next step.

Methyl 1-(5-(3,4-dichlorophenyl)-1H-1,2,4-triazol-3-yl)-3-methyl-1H-pyrazole-5-carboxylate

MeOH (9.1 ml) was added to the flask containing the crude Boc-protected material from the previous step (theoretical amount 314 mg, 0.91 mmol). Ketooxime (332 mg, 1.92 mmol) was added followed by conc. HCl 37% in water (0.33 ml, 4.0 mmol). The mixture was heated to 80°C in an oil bath and after 1 h and 3 h LCMS showed only a trace of the product. More conc. HCl 37% in water (0.33 ml, 4.0 mmol) and after 4 hours of heating s.m. did not have. The mixture was transferred to a separatory funnel using EtOAc and the organic phase was washed with saturated sodium bicarbonate solution and then with brine. The organic phase was dried with sodium sulfate, filtered and concentrated. The crude product was purified on Isco using a C18 column loading with DMSO, eluting with a gradient of 35-55% MeCN/water (containing 10 mM ammonium formate, pH 3.8). Fractions containing this product were lyophilized to give the product (72 mg, 0.20 mmol, 22%) as an off-white solid.

Methyl 1-(5-(3,4-dichlorophenyl)-1H-1,2,4-triazol-3-yl)-4-iodine-3-methyl-1H-pyrazole-5-carboxylate

TFA (1 ml) was added to the flask containing the triazolylpyrazole from the previous step (72 mg, 0.20 mmol). N-iodosuccinimide (115 mg, 0.51 mmol) was added and after stirring for 16 h, LCMS showed no starting material and no pure product. This mixture was transferred to a separating funnel using EtOAc, the organic phase was washed with water, then with saturated sodium bicarbonate solution, and then with brine. The organic phase was dried with sodium sulfate, filtered and concentrated. The crude product (98 mg, 0.20 mmol, 100%) was obtained as a light yellow oil and used as is in the next step.

Methyl 1-(3-(3,4-dichlorophenyl)-1-isobutyl-1H-1,2,4-triazol-5-yl)-4-iodine-3-methyl-1H-pyrazole-5-carboxylate and methyl 1-(5-(3,4-dichlorophenyl)-1-isobutyl-1H-1,2,4-triazol-3-yl)-4-iodine-3-methyl-1H-pyrazole-5-carboxylate

To a flask containing the product from the previous step (98 mg, 0.205 mmol) was added cesium carbonate (200 mg, 0.61 mmol), DMF (2 ml), then isobutyl iodide (189 μl, 302 mg, 1.64 mmol) . After 16 hours there was no s.m. pyrazole, and the ratio of products was 77:13. This mixture was added to a C18 column eluting with a gradient of 65-100% MeCN/water (containing 10 mM ammonium formate, pH 3.8). Fractions containing these products were combined and lyophilized to give a mixture of the ester product (110 mg, 0.205 mmol, 100%) as an off-white solid.

1-(5-(3,4-dichlorophenyl)-1-isobutyl-1H-1,2,4-triazol-3-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5- carboxylic acid and 1-(3-(3,4-dichlorophenyl)-1-isobutyl-1H-1,2,4-triazol-5-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole -5-carboxylic acid

Mix from previous step (5:1 ratio, 110 mg, 0.21 mmol), boronic acid (58 mg, 0.41 mmol), sodium carbonate (109 mg, 1.03 mmol), dioxane (2.1 ml) and water (0.5 ml) was placed in a test tube with a screw cap. The mixture was degassed for 10 minutes and Pd(PPh3)4 (24 mg, 0.021 mmol) was added. The tube was hermetically sealed and the mixture was heated to 85°C. After 16 hours, no product was detected by LCMS, so more boric acid (58 mg, 0.41 mmol), sodium carbonate (109 mg, 1.03 mmol) and degassed water (0.5 ml) were added. The mixture was degassed for 10 minutes and Pd(PPh3)4 (24 mg, 0.021 mmol) was added. After 4 h, no iodopyrazole s.m. was detected by LCMS, so the mixture was cooled to room temperature, neutralized with 2 ml of 1 M HCl in water, and added to a C18 column with DMSO. The mixture was purified on Isco using a gradient of 25-100% MeCN/water (containing 10 mM ammonium formate, pH 3.8). Lyophilization of the ester fractions gave a mixture of esters (38 mg, 0.076 mmol, 37%) as an off-white solid.

1-(5-(3,4-dichlorophenyl)-1-isobutyl-1H-1,2,4-triazol-3-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5- carboxylic acid and 1-(3-(3,4-dichlorophenyl)-1-isobutyl-1H-1,2,4-triazol-5-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole -5-carboxylic acid

Dioxane (0.70 ml), methanol (70 µl) and NaOH 1M in water 0.70 ml, 0.70 mmol). This mixture was heated in a microwave reactor to 100°C for 20 min. LCMS showed a complete reaction. A solution of 1 M HCl in water (0.70 mL, 0.70 mmol) was added and the mixture was purified on Isco reversed phase using a C18 column eluting with a gradient of 30-70% MeCN/water (10 mM ammonium formate, pH 3.8) . Pure fractions containing the ^1st eluted product were pooled, concentrated to remove most of the acetonitrile, frozen, and lyophilized. 1-(5-(3,4-dichlorophenyl)-1-isobutyl-1H-1,2,4-triazol-3-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5- carboxylic acid (5 mg, 0.010 mmol, 15% yield) was obtained as an off-white solid. Pure fractions containing the ^2nd eluted product were pooled, concentrated to remove most of the acetonitrile, frozen, and lyophilized. 1-(3-(3,4-dichlorophenyl)-1-isobutyl-1H-1,2,4-triazol-5-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5- carboxylic acid (8 mg, 0.016 mmol, 24% yield) was obtained as a white solid.

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.75 (s, 1H), 7.58 (d, J =8.2 Hz, 1H), 7.47 (d, J =7.1 Hz, 1H ), 7.33 (dd, J = 14.1, 7.7 Hz, 1H), 7.08 (d, J = 7.4 Hz, 1H), 7.06–6.98 (m, 2H) , 4.03 (d, J = 7.2 Hz, 2H), 2.38–2.31 (m, 1H), 2.28 (s, 3H), 0.87 (d, J = 6.6 Hz, 6H). The carboxylic acid OH signal was not observed or was hidden under the water signal (br s, 3.7–2.5 ppm); MS (m/z): 488.12 [M+1] ⁺ .

¹ H NMR (500 MHz, CDCl ₃ ) δ 8.07 (d, J =2.0 Hz, 1H), 7.77 (dd, J =8.4, 2.0 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.32 (td, J = 8.0, 6.0 Hz, 1H), 7.06–6.92 (m, 3H), 4.03 ( d, J = 7.3 Hz, 2H), 2.31–2.22 (m, 1H), 2.20 (s, 3H), 0.88 (d, J = 6.7 Hz, 6H); MS (m/z): 488.12 [M+1] ⁺ .

Compound 18: 1-(4-(4,4-difluoropiperidin-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazol-5- carboxylic acid

methyl 4-bromo-1-(4-(4,4-difluoropiperidin-1-yl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate

Methyl 4-bromo-1-(4-bromo-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H -pyrazole-5-carboxylate obtained using the above method (300 mg, 0.659 mmol), 4,4-difluoropiperidine (104 mg, 0.659 mmol), XantPhos (38.1 mg, 0.066 mmol) and Cs ₂ CO ₃ (1 .07 g, 3.30 mmol), nitrogen and vacuum cycles were performed (2x). Nitrogen gas was bubbled through dioxane (3 mL) which was then added to a microwave vial followed by RuPhos Palladacycle catalyst (53.8 mg, 0.066 mmol). The vial was closed and placed in an oil bath at 105°C for 16 hours. The solvent was evaporated in vacuo and the crude product was purified by silica gel flash chromatography (dry column fill) using a mixture of hexanes (100% isocratic) to give the title compound (173 mg, 0.350 mmol, 53%) as yellow oils.

methyl 1-(4-(4,4-difluoropiperidin-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylate

Methyl 4-bromo-1-(4-(4,4-difluoropiperidin-1-yl)-5-(isopropylthio)thiazole- 2-yl)-3-methyl-1H-pyrazole-5-carboxylate (173 mg, 0.349 mmol), 3-fluorophenylboronic acid (58.6 mg, 0.419 mmol) and Na ₂ CO ₃ (185 mg, 1.75 mmol ), nitrogen, and vacuum cycles were performed (2x). Nitrogen gas was bubbled through a dioxane/water solution (2 ml, 4:1) and then this solution was added to a microwave vial followed by Pd(PPh ₃ ) ₄ catalyst (40.4 mg, 0.035 mmol). The vial was closed and placed in an oil bath at 85°C for 16 hours. The reaction mixture was diluted with tOAc. The aqueous layer was extracted with EtOAc (2x) and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by silica gel flash chromatography (dry column fill) using a solution of EtOAc in hexanes (0 to 1% gradient) to give the title compound (150 g, 0.294 mmol, 84%) as yellow oils.

1-(4-(4,4-difluoropiperidin-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid

In a 25 ml round bottom flask, methyl 1–(4–(4,4–difluoropiperidin–1–yl)–5–(isopropylthio)thiazol–2–yl)–4–(3–fluorophenyl)–3–methyl–1H– pyrazole-5-carboxylate (150 mg, 0.294 mmol) was diluted with THF/MeOH (2 ml, 1:1). A solution of NaOH 1 M (588 μl, 0.588 mmol) was added and the reaction mixture was stirred for 16 hours at room temperature. HCl solution 1 M (588 μl, 0.588 mmol) and water (2 ml) were added. The reaction mixture was directly purified by reverse chromatography on a C-18 column with a solution of MeCN in water (containing 10 mM NH ₄ CO ₂ H) (40 to 70%) to give the title compound (31.5 mg, 0.064 mmol, 22%) as a yellow powder after lyophilization.

¹ H NMR (500 MHz, DMSO) δ 7.50 (dd, J =14.6, 7.9 Hz, 1H), 7.34-7.27 (m, 2H), 7.25-7.18 (m, 1H), 3.74-3.66 (m, 4H), 3.22-3.13 (m, 1H), 2.28 (s, 3H), 2.07-1.95 (m , 4H), 1.25 (d, J = 6.7 Hz, 6H); MS (m/z): 497.1 [M+1] ⁺ .

Compound 19: methyl 4–(3-fluorophenyl)–1–(5–(isopropylthio)–4–(4–(trifluoromethyl)cyclohex–1–en–1–yl)thiazol–2–yl)–3–methyl– 1H-pyrazole-5-carboxylate (enantiomerically pure - unknown stereochemistry)

In a 25 ml round bottom flask, methyl 4–(3–fluorophenyl)–1–(5–propylthio)–4–(4–(trifluoromethyl)cyclohex–1–en–1–yl)thiazol–2–yl)–3– methyl-1H-pyrazole-5-carboxylate (prepared as above and dissolved, enantiomerically pure (12.7 mg, 0.024 mmol) was diluted with THF/MeOH (2 mL, 1:1). NaOH solution 1 M ( 235 µl, 0.235 mmol) and the reaction mixture was stirred for 16 hours at a temperature of 60 ° C. HCl solution 1 M (235 µl, 0.235 mmol) and water (10 ml) were added. The reaction mixture was diluted with EtOAc and transferred to an extraction funnel. Layers was separated and the aqueous layer was extracted with Et ₂ O (3x) The combined organic layers were dried with Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (9.00 mg, 0.017 mmol, 73%) as yellow solid after lyophilization.

¹ H NMR (500 MHz, MeOD) δ 7.49-7.42 (m, 1H), 7.28-7.23 (m, 1H), 7.22-7.17 (m, 1H), 7 .15–7.09 (m, 1H), 6.53–6.44 (m, 1H), 3.30–3.21 (m, 1H), 2.80 (d, J = 18.1 Hz , 1Н), 2.59–2.40 (m, 3Н), 2.31 (s, 3Н), 2.18–2.10 (m, 1Н), 1.71–1.56 (m, 2H ), 1.30 (dd, J =6.7, 1.9 Hz, 6H); MS (m/z): 526.1 [M+1] ⁺ .

Compound 19: methyl 4–(3-fluorophenyl)–1–(5–(isopropylthio)–4–(4–(trifluoromethyl)cyclohex–1–en–1–yl)thiazol–2–yl)–3–methyl– 1H-pyrazole-5-carboxylate (enantiomerically pure - unknown stereochemistry)

In a 25 ml round bottom flask, methyl 4–(3–fluorophenyl)–1–(5–propylthio)–4–(4–(trifluoromethyl)cyclohex–1–en–1–yl)thiazol–2–yl)–3– methyl-1H-pyrazole-5-carboxylate enantiomerically pure (30.7 mg, 0.057 mmol) (prepared as described above and dissolved) was diluted with THF/MeOH (2 ml, 1:1). 1 M NaOH solution (569 µl, 0.569 mmol) was added and the reaction mixture was stirred for 16 hours at 60°C. A solution of HCl 1 M (569 μl, 0.569 mmol) and water (10 ml) was added. The reaction mixture was diluted with EtOAc and transferred to an extraction funnel. The layers were separated and the aqueous layer was extracted using Et ₂ O (3x). The combined organic layers were dried with Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (20.0 mg, 0.038 mmol, 67%) as a yellow solid after lyophilization.

¹ H NMR (500 MHz, MeOD) δ 7.36 (td, J = 8.0, 6.0 Hz, 1H), 7.18-7.13 (m, 1H), 7.11-7.07 (m, 1H), 7.05-6.99 (m, 1H) 6.41-3.34 (m, 1H), 3.21-3.11 (m, 1H), 2.70 (d, J = 18.3 Hz, 1H), 2.50-2.30 (m, 3H), 2.21 (s, 3H), 2.08-1.99. (m, 1H), 1.59–1.42 (m, 2H), 1.20 (dd, J =6.7, 1.9 Hz, 6H); MS (m/z): 526.1 [M+1] ⁺ .

Compound 20: 4-(3-fluorophenyl)-3-methyl-1-(4-(4-(trifluoromethyl)cyclohexyl)thiazol-2-yl)-1H-pyrazole-5-carboxylic acid

In a 10 ml glass vial equipped with a magnetic stirrer, Compound 5 (20.0 mg, 0.037 mmol) was dissolved in acetic acid (4 ml). Pd on activated charcoal (3.94 mg, 0.004 mmol) was added and the reaction mixture was stirred at 80° C. under a hydrogen atmosphere for 16 hours. The crude product was purified by reverse chromatography on a C-18 column with MeCN in water (containing 10 mM NH ₄ CO ₂ H) (35 to 65%) to give the title compound (3.00 mg, 0.007 mmol, 18 %) as a white powder after lyophilization.

¹ H NMR (500 MHz, MeOD) δ 7.47-7.40 (m, 1H), 7.30-7.25 (m, 1H), 7.24-7.18 (m, 1H), 7 .13–7.06 (m, 2H), 3.09–3.01 (m, 1H), 2.36–2.28 (m, 4H), 2.27–2.16 (m, 1H) , 2.05 (d, J = 11.6 Hz, 1H), 1.89–1.72 (m, 3H), 1.67–1.56 (m, 2H), 1.54–1.41 (m, 1H), 1.35–1.20 (m, 1H); MS (m/z): 454.1 [M+1] ⁺ .

Compound 22: 4-(3-fluorophenyl)-1-(5-isobutyl-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid

methyl 1–(5–iodine–4–(4–(trifluoromethyl)phenyl)thiazol–2–yl)–3–methyl–1H–pyrazole–5–carboxylate

Methyl 3-methyl-1-(4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-1H-pyrazol-5-carboxylate prepared in general as described above for the butylthio analog (100 mg, 0.272 mmol ), was dissolved in TFA (1.4 ml) and N -iodosuccinimide (73 mg, 0.33 mmol) was added. This reaction mixture was stirred for 45 minutes at room temperature. The reaction mixture was poured into water and extracted using EtOAc. The organic layer was washed successively with an aqueous solution saturated with NaHCO3, a 10% aqueous solution of Na ₂ S ₂ O ₃ and brine. The organic layers were dried with sodium sulfate, filtered and concentrated. The product was purified by silica gel flash chromatography (dry column fill) using a gradient of 0 to 10% EtOAc in hexanes to give the title compound (79 mg, 0.16 mmol, 59%) as a solid. Pink colour. MS (m/z): 493.9 [M+1]+.

methyl 3-methyl-1-(5-(2-methylprop-1-en-1-yl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-1H-pyrazole-5-carboxylate

Methyl 1–(5–iodo–4–(4–(trifluoromethyl)phenyl)thiazol–2–yl)–3–methyl– 1H-pyrazol-5-carboxylate (200 mg, 0.405 mmol), (2-methylprop-1-en-1-yl) boronic acid (49 mg, 0.49 mmol), K ₂ CO ₃ (280 mg, 2, 03 mmol) and THF (3 ml). Nitrogen was bubbled into the solvent for 10 minutes followed by the addition of Pd(dtbpf) catalyst (26 mg, 0.041 mmol). The vial was closed and placed in an oil bath at 90°C for 16 hours. The product was purified by silica gel flash chromatography (dry column fill) using a gradient of 0 to 10% EtOAc in hexanes to give the title compound (64 mg, 0.059 mmol, 38%) as a yellow oil. MS (m/z): 422.3 [M+1]+.

methyl 1–(5–isobutyl–4–(4–(trifluoromethyl)phenyl)thiazol–2–yl)–3–methyl–1H–pyrazole–5–carboxylate

Methyl 3-methyl-1-(5-(2-methylprop-1-en-1-yl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-1H-pyrazole-5-carboxylate (64 mg, 0.15 mmol) was dissolved in MeOH/AcOH (3 ml) and 20% Pd(OH) ₂ /C (16 mg) was added. This reaction mixture was purged and stirred under a hydrogen atmosphere for 16 hours. The reaction mixture was filtered through a ^Celite® pad and concentrated in vacuo . The crude reaction mixture was re-introduced to the reaction conditions for two additional cycles to give, after evaporation, the title compound (36 mg, 0.084 mmol, 55%) as a yellowish solid. MS (m/z): 424.2 [M+1]+.

methyl 4-bromo-1-(5-isobutyl-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate

Methyl 1-(5-isobutyl-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate (36 mg, 0.084 mmol) was dissolved in MeCN/DCM (1 ml) and a 2 M solution of bromine in MeCN (210 μl, 0.420 mmol) was added dropwise. This reaction mixture was stirred for 16 hours at room temperature. and extinguished with 10% aqueous solution of Na ₂ S ₂ O ₃ . The reaction mixture was diluted with EtOAc, washed with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated to give the title compound (36 mg, 0.072 mmol, 85%) as a yellow solid. MS (m/z): 502.0 [M+1]+.

4-(3-fluorophenyl)-1-(5-isobutyl-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid

Methyl 4-bromo-1-(5-isobutyl-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)– 3-methyl-1H-pyrazole-5-carboxylate (36 mg, 0.072 mmol), (3-fluorophenyl)boronic acid (12 mg, 0.086 mmol) and Na₂CO₃ (38 mg, 0.36 mmol). Nitrogen gas was bubbled through a solution of dioxane/water (2 ml, 4:1) and then this solution was added to a microwave vial followed by the addition of catalyst Pd(PPh₃)_four(8.3 mg, 0.0072 mmol). The vial was closed and placed in an oil bath at 85°C for 16 hours. LiOH (8.5 mg, 0.36 mmol) was added to the reaction mixture and stirred under microwave at 110° C. for 15 minutes. The product was purified by semi-preparative HPLC–MS (X–Bridge 30×50 column, eluted with 60–80% MeCN/NH_fourCO₂H 10 mM, pH 3.8/flow 45 mL/min/10 min) to give the title compound (7.5 mg, 0.015 mmol, 21%) as a white solid after lyophilization.

¹ H NMR (500 MHz, DMSO) δ 7.83 (s, 4H), 7.53-7.47 (m, 1H), 7.34-7.28 (m, 2H), 7.25-7 .18 (m, 1H), 2.89 (d,, J = 7.2 Hz, 2H), 2.30 (s, 3H), 1.96–1.83 (m, 1H), 0.93 (d, J =6.6 Hz, 6H). MS (m/z): 504.0 [M+1] ⁺ .

Compound 23: 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)thiazol-2-yl)-3-methyl -1H-pyrazole-5-carboxylic acid

tert-butyl 4-(2,2,2-trifluoroethyl)piperazine-1-carboxylate

Trifluoroiodoethane (0.794 ml, 8.05 mmol) was added to a stirred mixture of boc-piperazine (1.25 g, 6.71 mmol), DIPEA (6.25 ml, 33.6 mmol) and DMF (7 ml). This reaction mixture was stirred at room temperature for 72 hours. The reaction mixture was filtered and the filtrate was evaporated. The crude product was purified by silica gel flash chromatography (dry column fill) using a solution of EtOAc in hexanes (20 to 100% gradient) to give the title compound (253 g, 0.943 mmol, 14%) as yellow solid.

1-(2,2,2-trifluoroethyl)piperazine hydrochloride

tert-Butyl-4-(2,2,2-trifluoroethyl)piperazine-1-carboxylate (253 mg, 0.94 mmol) was dissolved in DCM (9 ml) and a solution of 4 M HCl in dioxane (4.72 ml, 18.9 mmol). This reaction mixture was stirred for 3 hours at room temperature. The product was then concentrated in vacuo and co-evaporated with DCM 3 times to give the title compound (200 mg, 0.977 mmol, 100%) as a beige solid.

methyl 4-bromo-1-(5-(isopropylthio)-4-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazol-5 carboxylate

Methyl 4-bromo-1-(4-bromo-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H -pyrazole-5-carboxylate prepared as described above for Compound 1 (300 mg, 0.659 mmol), 1-(2,2,2-trifluoroethyl)piperazine hydrochloride (135 mg, 0.659 mmol), XantPhos (38, 1 mg, 0.066 mmol) and Cs ₂ CO ₃ (1.07 g, 3.30 mmol), nitrogen and vacuum cycles were performed (2x). Nitrogen gas was bubbled through dioxane (3 mL) which was then added to a microwave vial followed by RuPhos Palladacycle catalyst (53.8 mg, 0.066 mmol). The vial was closed and placed in an oil bath at 105°C for 16 hours. The solvent was evaporated in vacuo and the crude product was purified by silica gel flash chromatography (dry column fill) using a solution of EtOAc in hexanes (10 to 30% gradient) to give the title compound (123 mg, 0.227 mmol, 34 %) as a yellow oil.

methyl 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)thiazol-2-yl)-3-methyl-1H pyrazole-5-carboxylic acid

Methyl 4-bromo-1-(5-(isopropylthio)-4-(4-(2,2,2-trifluoroethyl)piperazine ) -1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate (123 mg, 0.227 mmol), 3-fluorophenylborone. acid (38.1 mg, 0.272 mmol) and Na ₂ CO ₃ (120 mg, 1.13 mmol) _, nitrogen and vacuum cycles were performed (2x). Nitrogen gas was bubbled through a dioxane/water solution (2 ml, 4:1) and then this solution was added to a microwave vial followed by Pd(PPh ₃ ) ₄ catalyst (26.2 mg, 0.023 mmol). The vial was closed and placed in an oil bath at 85°C for 16 hours. The reaction mixture was diluted with tOAc. The aqueous layer was extracted with EtOAc (2x) and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (dry pack) using a solution of EtOAc in hexanes (0 to 15% gradient) to give the title compound (41.3 mg, 0.074 mmol, 33%) as a yellow oil. .

4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)thiazol-2-yl)-3-methyl-1H- pyrazole-5-carboxylic acid

In a 25 ml round bottom flask, methyl 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)thiazol-2-yl) -3-methyl-1H-pyrazole-5-carboxylate (41.3 mg, 0.076 mmol) was diluted with THF/MeOH (2 ml, 1:1). A solution of NaOH 1 M (381 μl, 0.381 mmol) was added and the reaction mixture was stirred 16 h at room temperature. HCl solution 1 M (381 μl, 0.381 mmol) and water (2 ml) were added. The reaction mixture was directly purified by reverse chromatography on a C-18 column with a solution of MeCN in water (containing 10 mM NH ₄ CO ₂ H) (40 to 70%) to give the title compound (32.0 mg, 0.059 mmol, 77%) as a yellow powder after lyophilization.

¹ H NMR (500 MHz, DMSO) δ 7.56-7.46 (m, J =14.4, 8.0 Hz, 1H), 7.28 (d, J =8.4 Hz, 2H), 7.26–7.19 (m, J =9.0 Hz, 1H), 3.59–3.53 (m, 4H), 3.21 (dd, J =20.5, 10.2 Hz, 2H), 3.17–3.07 (m, J =13.4, 6.7 Hz, 1H), 2.73–2.66 (m, 4H), 2.28 (s, 3H), 1 .24 (d, J = 6.7 Hz, 6H); MS (m/z): 544.1 [M+1] ⁺ .

Compound 24: 1-(4-(4-cyanopiperidin-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid

methyl 4-bromo-1-(4-(4-cyanopiperidin-1-yl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate

Methyl 4-bromo-1-(4-bromo-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H -pyrazole-5-carboxylate obtained as described above in relation to Compound 1 (150 mg, 0.330 mmol), piperidine-4-carbonitrile (36 mg, 0.33 mmol), Cs ₂ CO ₃ (537 mg, 1, 65 mmol), XantPhos (19 mg, 0.033 mmol) and dioxane (3 ml). Nitrogen was bubbled into the solvent for 10 minutes followed by the addition of RuPhos Pd G1 catalyst (27 mg, 0.033 mmol). The vial was closed and placed in an oil bath at 105°C for 16 hours. The solvent was evaporated in vacuo and the indicated product was purified by semi-preparative HPLC-MS (X-Bridge column 30×50, eluted with 70-90% MeCN/NH ₄ CO ₂ H 10 mM, pH 3.8/flow 45 ml/ min/10 min) to give the title compound (29 mg, 0.059 mmol, 18%) as a yellow solid after lyophilization. MS (m/z): 484.0 [M+1]+.

1-(4-(4-cyanopiperidin-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid

Methyl 4-bromo-1-(4-(4-cyanopiperidin-1-yl)-5-(isopropylthio)thiazol-2yl )-3-methyl-1H-pyrazole-5-carboxylate (29 mg, 0.059 mmol), (3-fluorophenyl)boronic acid (9.9 mg, 0.071 mmol) and Na₂CO₃(31 mg, 0.29 mmol). Nitrogen gas was bubbled through a solution of dioxane/water (2 ml, 4:1) and then this solution was added to a microwave vial followed by the addition of catalyst Pd(PPh₃)_four(6.8 mg, 0.0059 mmol). The vial was closed and placed in an oil bath at 85°C for 16 hours. LiOH (7.0 mg, 0.29 mmol) was added to the reaction mixture and stirred under microwave at 110° C. for 15 minutes. The product was purified by semi-preparative HPLC–MS (X–Bridge 30×50 column, eluted with 50–70% MeCN/NH_fourCO₂H 10 mM, pH 3.8/flow 45 ml/min/10 min) to give the title compound (2.3 mg, 0.0047 mmol, 8%) as a yellowish solid after lyophilization.

¹ H NMR (500 MHz, MeOD) δ 7.41 (td, J = 8.0, 6.1 Hz, 1H), 7.37-7.34 (m, 1H), 7.33-7.28 (m, 1H), 7.07-7.01 (m, 1H) 4.02-3.95 (m, 2H), 3.54-3.47 (m, 2H), 3.22-3, 10 (m, 1H), 3.01–2.91 (m, 1H), 2.32 (s, 3H), 2.09–1.98 (m, 2H), 1.93–1.80 ( m, 2H), 1.30 (d, J = 6.7 Hz, 6H). MS (m/z): 486.1 [M+1] ⁺ .

Compound 25: 1–(4–(4–cyclopropylpiperazin–1–yl)–5–(isopropylthio)thiazol–2–yl)–4–(3–fluorophenyl)–3–methyl–1H–pyrazole–5–carboxylic acid

methyl 4-bromo-1-(4-(4-cyclopropylpiperazin-1-yl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate

Methyl 4-bromo-1-(4-bromo-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H -pyrazole-5-carboxylate prepared as described above for Compound 1 (150 mg, 0.330 mmol), 1-cyclopropylpiperazine (42 mg, 0.33 mmol), Cs ₂ CO ₃ (537 mg, 1.65 mmol ), XantPhos (19 mg, 0.033 mmol) and dioxane (3 ml). Nitrogen was bubbled into the solvent for 10 minutes followed by the addition of RuPhos Pd G1 catalyst (27 mg, 0.033 mmol). The vial was closed and placed in an oil bath at 105°C for 16 hours. The product was purified by silica gel flash chromatography (dry column fill) using a gradient of 0 to 10% EtOAc in hexanes to give the title compound (28 mg, 0.055 mmol, 17%) as a yellow oil. MS (m/z): 500.0 [M+1]+.

1–(4–(4–cyclopropylpiperazin–1–yl)–5–(isopropylthio)thiazol–2–yl)–4–(3–fluorophenyl)–3–methyl–1H–pyrazole–5–carboxylic acid

Methyl 4-bromo-1-(4-(4-cyclopropylpiperazin-1-yl)-5-(isopropylthio)thiazol-2yl )-3-methyl-1H-pyrazole-5-carboxylate (28 mg, 0.055 mmol), (3-fluorophenyl)boronic acid (9.2 mg, 0.066 mmol) and Na₂CO₃(29 mg, 0.28 mmol). Nitrogen gas was bubbled through a solution of dioxane/water (2 ml, 4:1) and then this solution was added to a microwave vial followed by the addition of catalyst Pd(PPh₃)_four(6.3 mg, 0.0055 mmol). The vial was closed and placed in an oil bath at 85°C for 16 hours. LiOH (6.6 mg, 0.28 mmol) was added to the reaction mixture and stirred under microwave at 110° C. for 15 minutes. The product was purified by semi-preparative HPLC–MS (X–Bridge 30×50 column, eluted with 35–55% MeCN/NH_fourCO₂H 10 mM, pH 3.8/flow 45 mL/min/10 min, followed by 35-55% 35-55% MeCN/NH_fourCO₃H 10 mM, pH 10/flow 45 ml/min/10 min) to give the title compound (3.0 mg, 0.0060 mmol, 11%) as a yellow solid after lyophilization.

¹ H NMR (500 MHz, MeOD) δ 7.46-7.40 (m, 1H), 7.39-7.35 (m, 1H), 7.35-7.31 (m, 1H), 7 .09–7.03 (m, 1H), 3.93–3.75 (m, 4H), 3.40–3.32 (m, 4H), 3.26–3.15 (m, 1H) , 2.76–2.60 (m, 1H), 2.34 (s, 3H), 1.31 (d, J =6.7 Hz, 6H) 0.95–0.81 (s, 4H) . MS (m/z): 502.1 [M+1] ⁺ .

Compound 26: 1-(4-(4-ethylpiperazin-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid

methyl 4-bromo-1-(4-(4-ethylpiperazin-1-yl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate

Methyl 4-bromo-1-(4-bromo-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H -pyrazole-5-carboxylate prepared as described above for Compound 1 (150 mg, 0.330 mmol), 1-ethylpiperazine (38 mg, 0.33 mmol), Cs ₂ CO ₃ (537 mg, 1.65 mmol ), XantPhos (19 mg, 0.033 mmol) and dioxane (3 ml). Nitrogen was bubbled into the solvent for 10 minutes followed by the addition of RuPhos Pd G1 catalyst (27 mg, 0.033 mmol). The vial was closed and placed in an oil bath at 105°C for 16 hours. The indicated product was purified by semi-preparative HPLC-MS (X-Bridge 30×50 column, eluted once with 50-70% MeCN/NH ₄ CO ₂ H 10 mM, pH 3.8/flow 45 ml/min/10 min ) to give the title compound (49 mg, 0.10 mmol, 31%) as a yellow solid after lyophilization. MS (m/z): 488.0 [M+1]+.

1–(4–(4–ethylpiperazin–1–yl)–5–(isopropylthio)thiazol–2–yl)–4–(3–fluorophenyl)–3–methyl–1H–pyrazole–5–carboxylic acid

Methyl 4-bromo-1-(4-(4-ethylpiperazin-1-yl)-5-(isopropylthio)thiazol-2yl )-3-methyl-1H-pyrazole-5-carboxylate (49 mg, 0.10 mmol), (3-fluorophenyl)boronic acid (17 mg, 0.12 mmol) and Na₂CO₃ (53 mg, 0.50 mmol). Nitrogen gas was bubbled through a solution of dioxane/water (2 ml, 4:1) and then this solution was added to a microwave vial followed by the addition of catalyst Pd(PPh₃)_four(12 mg, 0.010 mmol). The vial was closed and placed in an oil bath at 85°C for 16 hours. LiOH (12 mg, 0.50 mmol) was added to the reaction mixture and stirred under microwave at 110° C. for 15 minutes. The product was purified by semi-preparative HPLC–MS (X–Bridge 30×50 column, eluted once with 35–55% MeCN/NH_fourCO₂H 10 mM, pH 3.8/flow 45 ml/min/10 min) to give the title compound (1.1 mg, 0.0022 mmol, 2%) as a white solid after lyophilization.

¹ H NMR (500 MHz, MeOD) δ 8.49 (s, 1H), 7.43 (td, J = 7.9, 6.0 Hz, 1H), 7.40–7.32 (m, 2H ), 7.09–7.02 (m, 1H), 4.06–3.63 (m, 4H), 3.40–3.27 (m, 4H), 3.27–3.12 (m , 3H), 2.34 (s, 3H), 1.36 (t, J = 7.3 Hz, 3H), 1.31 (d, J = 6.7 Hz, 6H). Ammonium formate salt. MS (m/z): 490.1 [M+1] ⁺ .

Compound 27: 1-(4-(4-acetylpiperazin-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid

methyl 1–(4–(4–acetylpiperazin–1–yl)–5–(isopropylthio)thiazol–2–yl)–4–bromo–3–methyl–1H–pyrazole–5–carboxylate

Methyl 4-bromo-1-(4-bromo-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H -pyrazole-5-carboxylate prepared as described above for Compound 1 (150 mg, 0.330 mmol), 1-(piperazin-1-yl)ethanone (42 mg, 0.33 mmol), Cs ₂ CO ₃ ( 537 mg 1.65 mmol), XantPhos (19 mg, 0.033 mmol) and dioxane (3 ml). Nitrogen was bubbled into the solvent for 10 minutes followed by the addition of RuPhos Pd G1 catalyst (27 mg, 0.033 mmol). The vial was closed and placed in an oil bath at 105°C for 16 hours. This product was purified by semi-preparative HPLC-MS (X-Bridge 30×50 column, eluted once with 65-85% MeCN/NH ₄ CO ₂ H 10 mM, pH 3.8/flow 45 ml/min/10 min ) to give the title compound (30 mg, 0.059 mmol, 18%) as a yellow oil after lyophilization.

MS (m/z): 502.0 [M+1]+.

1–(4–(4–acetylpiperazin–1–yl)–5–(isopropylthio)thiazol–2–yl)–4–(3–fluorophenyl)–3–methyl–1H–pyrazole–5–carboxylic acid

Methyl 1–(4–(4–acetylpiperazin–1–yl)–5–(isopropylthio)thiazol–2–yl)–4 -bromo-3-methyl-1H-pyrazole-5-carboxylate (30 mg, 0.059 mmol), (3-fluorophenyl)boronic acid (10 mg, 0.071 mmol) and Na₂CO₃(31 mg, 0.30 mmol). Nitrogen gas was bubbled through a solution of dioxane/water (2 ml, 4:1) and then this solution was added to a microwave vial followed by the addition of catalyst Pd(PPh₃)_four(12 mg, 0.010 mmol). The vial was closed and placed in an oil bath at 85°C for 16 hours. LiOH (7.1 mg, 0.30 mmol) was added to the reaction mixture and stirred under microwave at 110° C. for 15 minutes. The product was purified by semi-preparative HPLC–MS (X–Bridge 30×50 column, eluted once with 40–60% MeCN/NH_fourCO₂H 10 mM, pH 3.8/flow 45 mL/min/10 min) to give the title compound (4.1 mg, 0.0081 mmol, 14%) as a yellow solid after lyophilization.

¹ H NMR (500 MHz, MeOD) δ 7.43 (td, J = 8.0, 6.1 Hz, 1H), 7.36-7.32 (m, 1H), 7.31-7.27 (m, 1H), 7.09–7.03 (m, 1H), 3.74–3.60 (m, 8H), 3.26–3.13 (m, 1H), 2.34 (s , 3H), 2.14 (s, 3H), 1.31 (d, J = 6.7 Hz, 6H). MS (m/z): 504.1 [M+1] ⁺ .

Compound 28: 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-methylpiperidin-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid

methyl 4-bromo-1-(5-(isopropylthio)-4-(4-methylpiperidin-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate

Methyl 4-bromo-1-(4-bromo-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H -pyrazole-5-carboxylate prepared as described above for Compound 1 (150 mg, 0.330 mmol), 4-methylpiperidine (33 mg, 0.33 mmol), Cs ₂ CO ₃ (537 mg, 1.65 mmol ), XantPhos (19 mg, 0.033 mmol) and dioxane (3 ml). Nitrogen was bubbled into the solvent for 10 minutes followed by the addition of RuPhos Pd G1 catalyst (27 mg, 0.033 mmol). The vial was closed and placed in an oil bath at 105°C for 16 hours. The indicated product was purified by semi-preparative HPLC-MS (X-Bridge 30×50 column, eluted once with 80–100% MeCN/NH ₄ CO ₂ H 10 mM, pH 3.8/flow 45 ml/min/10 min ) to give the title compound (9.5 mg, 0.020 mmol, 6%) as a yellow oil after lyophilization. MS (m/z): 473.1 [M+1]+.

4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-methylpiperidin-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid

Methyl 4-bromo-1-(5-(isopropylthio)-4-(4-methylpiperidin-1-yl)thiazol-2yl )-3-methyl-1H-pyrazole-5-carboxylate (9.5 mg, 0.020 mmol), (3-fluorophenyl)boronic acid (3.4 mg, 0.024 mmol) and Na₂CO₃ (11 mg, 0.10 mmol). Nitrogen gas was bubbled through a solution of dioxane/water (2 ml, 4:1) and then this solution was added to a microwave vial followed by the addition of catalyst Pd(PPh₃)_four(2.3 mg, 0.0020 mmol). The vial was closed and placed in an oil bath at 85°C for 16 hours. LiOH (2.4 mg, 0.10 mmol) was added to the reaction mixture and stirred under microwave at 110° C. for 15 minutes. The product was purified by semi-preparative HPLC–MS (X–Bridge 30×50 column, eluted once with 65–85% MeCN/NH_fourCO₂H 10 mM, pH 3.8/flow 45 ml/min/10 min) to give the title compound (1.6 mg, 0.0034 mmol, 17%) as a yellow solid after lyophilization.

¹ H NMR (500 MHz, MeOD) δ 7.45-7.39 (m, 1H), 7.35-7.31 (m, 1H), 7.31-7.26 (m, 1H), 7.010 –7.03 (m, 1H), 4.43–4.34 (m, 2H), 3.23–3.10 (m, 1H), 2.95–2.86 (m, 2H), 2 .32 (s, 3H), 1.74–1.62 (m, 2H), 1.61–1.49 (m, 1H), 1.38–1.19 (m, 2H), 1.29 (d, J =6.7 Hz, 6H), 0.98 (d, J =6.6 Hz, 3H). MS (m/z): 475.2 [M+1] ⁺ .

Compound 29: 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-methylpiperazin-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid

The title compound was prepared in a manner analogous to Compound 12 as described above.

¹ H NMR (500 MHz, MeOD) δ 7.43 (td, J = 7.9, 6.1 Hz, 1H), 7.40-7.37 (m, 1H), 7.37-7.32 (m, 1H), 7.09-7.03 (m, 1H), 4.43-3.50 (m, 4H), 3.42-3.31 (m, 4H), 3.29-3 .14 (m, 1H), 2.91 (s, 3H), 2.35 (s, 3H), 1.31 (d, J = 6.7 Hz, 6H). MS (m/z): 476.1 [M+1]+.

Compound 30: 4-(3-fluorophenyl)-3-methyl-1-(5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)-1H-pyrazole-5-carboxylic acid

5–(4–(trifluoromethyl)phenyl)–1,3,4–thiadiazol–2–amine

Thiosemicarbazide (480 mg, 5.26 mmol) and 4-(trifluoromethyl)benzoic acid (1.00 g, 5.26 mmol) were suspended in phosphorus oxychloride (1.40 ml) and heated at 75°C for 30 minutes. After cooling to room temperature, water (5.5 ml) was added and the reaction mixture was refluxed for 4 hours. The reaction mixture was cooled to room temperature and basified to pH 8 by adding dropwise a solution of 6 N NaOH with stirring. The precipitate was filtered off and washed with water to give the title compound (1.09 g, 4.44 mmol, 85%) as a white solid.

2-chloro-5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazole

A stirred suspension of 5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-amine (700 mg, 2.85 mmol) and copper (18 mg, 0.29 mmol) in conc. hydrochloric acid (2.8 ml) and acetic acid (14 ml) were cooled to 0 ^o C. To this suspension was added in portions a solution of sodium nitrite (206 mg, 2.99 mmol) in water (0.94 ml) and then the reaction mixture stirred at room temperature for 16 hours. After cooling to 0° C., more sodium nitrite solution (41 mg, 0.59 mmol) in water (0.20 ml) was added and stirring was continued at room temperature for 3 hours. The reaction mixture was added dropwise to a cold water solution (150 ml) and the precipitate was filtered to give the title compound (627 mg, 2.37 mmol, 83%) as a yellow solid.

2-hydrazinyl-5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazole

2-chloro-5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazole (425 mg, 1.61 mmol) and hydrazine hydrate (176 mg, 1.93 mmol) were stirred in dioxane at 82 ^° C After 3 hours more hydrazine hydrate (65 mg, 0.71 mmol) was added and stirring was continued at 82° C. for 16 hours. More hydrazine hydrate (60 mg, 0.66 mmol) was added to the suspension, after which an additional 4 hours were required to complete the reaction. The yellow precipitate was filtered off and washed with Et ₂ O to give the title compound (346 mg, 1.33 mmol, 83%) as a yellow solid.

Methyl 3-methyl-1-(5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)-1H-pyrazole-5-carboxylate

Methyl 2-(methoxyimino)-4-oxopentanoate (127 mg, 0.734 mmol) was dissolved in MeOH (4 ml) and 2-hydrazinyl-5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazole (191 mg , 0.734 mmol), and then HCl 12 N (245 μl, 2.94 mmol) was added dropwise. The specified reaction mixture was heated under reflux for 5 hours. The reaction mixture was concentrated. Residual starting material was removed by trituration in DCM. The filtrate was concentrated and the crude product was purified by silica gel flash chromatography using a solution of ethyl acetate in hexanes (0% to 50% gradient) to give the title compound (55.6 mg, 0.151 mmol, 21%) as a yellow oil. colors.

Methyl 4-bromo-3-methyl-1-(5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)-1H-pyrazole-5-carboxylate

Methyl 3-methyl-1-(5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)-1H-pyrazol-5-carboxylate (88 mg, 0.24 mmol) was dissolved in TFA (1.2 ml) and N -bromosuccinimide (47 mg, 0.26 mmol) was added. This reaction mixture was stirred for 2 hours at room temperature followed by the addition of more N -bromosuccinimide (12 mg, 0.067 mmol) and continued stirring for 16 hours. More N -bromosuccinimide (12 mg, 0.067 mmol) was added and stirring was continued for another 16 hours. The reaction mixture was slowly added to ice water and the solid was filtered off, washed with water and dried to give the title compound (84 mg, 0.19 mmol, 78%) as a yellow solid.

4-(3-fluorophenyl)-3-methyl-1-(5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)-1H-pyrazole-5-carboxylic acid

Methyl 4-bromo-3-methyl-1-(5-(4-(trifluoromethyl)phenyl)-1,3,4 - thiadiazol-2-yl)-1H-pyrazole-5-carboxylate (42 mg, 0.094 mmol), (3-fluorophenyl)boronic acid (16 mg, 0.11 mmol) and Na₂CO₃(50 mg, 0.47 mmol). Nitrogen gas was bubbled through a solution of dioxane/water (1.2 ml, 4:1) and then this solution was added to a microwave vial followed by the addition of Pd(PPh₃)_four(11 mg, 0.00095 mmol). The vial was closed and placed in an oil bath at 85°C for 16 hours. LiOH (11 mg, 0.47 mmol) was added to the reaction mixture and stirred under microwave at 115° C. for 15 minutes. The product was purified by semi-preparative HPLC–MS (X–Bridge 30×50 column, eluted with 40–60% MeCN/NH_fourCO₂H 10 mM, pH 3.8/flow 45 mL/min/10 min) to give the title compound (6.4 mg, 0.014 mmol, 15%) as a white solid after lyophilization.

¹ H NMR (500 MHz, DMSO) δ 8.23 (d, J = 8.2 Hz, 2H), 7.95 (d, J = 8.2 Hz, 2H), 7.48–7.36 ( m, 3H), 7.18–7.09 (m, 1H) 2.32 (s, 3H); MS (m/z): 448.9 [M+1] ⁺

Compound 31: 4-(3-fluorophenyl)-1-(5-((2-methoxyethyl)(methyl)amino)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H -pyrazole-5-carboxylic acid

methyl 1-(4-(3,4-dichlorophenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate

Methyl 2-(methoxyimino)-4-oxopentanoate (1.00 g, 5.77 mmol) was dissolved in MeOH (60 ml) and 4-(3,4-dichlorophenyl)-2-hydrazinylthiazole (1.52 g, 5.77 mmol). 77 mmol), prepared as described, and then HCl 12 N (1.82 ml, 23.1 mmol) was added dropwise. The specified reaction mixture was heated under reflux overnight. The reaction mixture was diluted with EtOAc and transferred to an extraction funnel. The layers were separated and the aqueous layer was extracted using Et ₂ O (3x). The combined organic layers were dried with Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by silica gel flash chromatography (dry column fill) using 1:2:18 EtOAc/DCM/hexanes in 1:9 DCM/hexanes (gradient 0 to 100%) to give the indicated the title compound (1.23 mg, 2.19 mmol, 38%) as a yellow solid.

methyl 1-(4-(3,4-dichlorophenyl)-5-fluorothiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate

methyl 1-(4-(3,4-dichlorophenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate (500 mg, 1.36 mmol) was dissolved in MeCN/DCE (4 ml, 1 :1). SelectFluor (577 mg, 1.63 mmol) was added and the reaction mixture was stirred for 18 h at 80°C. The crude product was concentrated in vacuo and purified by silica gel flash chromatography (wet-loaded with DCM) using EtOAc in hexanes (5 to 20% gradient) to give the title compound (190 mg, 0.492 mmol, 36 %) as a white solid.

methyl 4-bromo-1-(4-(3,4-dichlorophenyl)-5-fluorothiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate

Bromine (0.126 ml, 2.46 mmol) was added to a solution of methyl 1-(4-(3,4-dichlorophenyl)-5-fluorothiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate (190 mg (0.492 mmol) in MeCN/DCM (5 ml, 1:1 ml) This reaction mixture was stirred for 5 hours at room temperature Saturated aqueous Na ₂ SO ₃ solution was added and the reaction mixture was extracted using Et ₂ O (3x) The combined organic layers were dried with sodium sulfate, filtered and evaporated under reduced pressure.The crude product was purified by flash chromatography on silica gel (dry column method) using a solution of DCM in hexanes (10 to 40%) to give the title the title compound (42.6 mg, 0.092 mmol, 19%) as a white solid.

1-(4-(3,4-dichlorophenyl)-5-fluorothiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid

Methyl 4-bromo-1-(4-(3,4-dichlorophenyl)-5-fluorothiazol-2-yl)-3- methyl-1H-pyrazole-5-carboxylate (42.6 mg, 0.092 mmol), 3-fluorophenylboronic acid (15.4 mg, 0.110 mmol) and Na ₂ CO ₃ (48.5 mg, 0.458 mmol), nitrogen and performed vacuum cycles (2x). Nitrogen gas was bubbled through a dioxane/water solution (2 ml, 4:1) and then this solution was added to a microwave vial followed by Pd(PPh ₃ ) ₄ catalyst (10.6 mg, 0.009 mmol). The vial was closed and placed in an oil bath at 85°C for 16 hours. LiOH (19.2 mg, 0.458 mmol) was added to the reaction mixture and stirred under microwave at 120° C. for 10 minutes. The product was purified by semi-preparative HPLC–MS (X–Bridge 30×50 column, eluted with 55–75% MeCN/NH ₄ CO ₂ H 10 mM, pH 3.8/flow 45 ml/min/11 min), in resulting in the title compound (8.93 mg, 0.019 mmol, 21%) as a white solid after lyophilization.

¹ H NMR (500 MHz, DMSO) δ 7.92 (t, J =1.1 Hz, 1H), 7.76 (d, J =1.1 Hz, 2H), 7.48 (dd, J = 14.4, 8.0 Hz, 1H), 7.41-7.30 (m, J =15.4, 9.1 Hz, 2H), 7.19 (t, J =7.6 Hz, 1H ), 3.33 (1H, signal below water level), 2.29 (s, 3H); MS (m/z): 466.9 [M+1] ⁺ .

4-(3-fluorophenyl)-1-(5-((2-methoxyethyl)(methyl)amino)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole- 5-carboxylic acid

1–(5–fluoro–4–(4–(trifluoromethyl)phenyl)thiazol–2–yl)–4–(3–fluorophenyl)–3–methyl -1H-pyrazole-5-carboxylic acid (10 mg, 0.021 mmol) and (2-methoxyethyl)methylamine (246 mg, 2.75 mmol). The vial was closed and placed in an oil bath at 80°C for 16 hours. This reaction mixture was heated to 90°C and stirred for another 3 days. This product was purified by semi-preparative HPLC-MS (X-Bridge 30x50 column, eluted with 55-75% MeCN/NH ₄ CO ₂ H 10 mM, pH 3.8/flow 45 ml/min/10 min), whereby the title compound (3.3 mg, 0.0062 mmol, 29%) was obtained as a yellowish solid after lyophilization.

¹ H NMR (500 MHz, MeOD) δ 8.38 (d, J = 8.3 Hz, 2H), 7.68 (d, J = 8.3 Hz, 2H), 7.50–7.44 ( m, 1H), 7.33–7.29 (m, 1H), 7.28–7.23 (m, 1H), 7.16–7.09 (m, 1H), 3.56 (t, J = 5.3 Hz, 2H), 3.28 (s, 3H), 3.20 (t, J = 5.3 Hz, 2H). 2.89 (s, 3H); 2.35 (s, 3H); MS (m/z): 535.1 [M+1] ⁺

Compound 32: 1-(4-(4,4-dimethylpiperidin-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazol-5- carboxylic acid

The title compound was obtained using a method similar to Compound 12 as described above. ¹ H NMR (500 MHz, DMSO) δ 7.47-7.46 (m, 1H), 7.34-7.30 (m, 2H), 7.17 (bs, 1H), 3.59-3 .53 (m, 4H), 3.11 (q, J =5.0 Hz, 1H), 2.27 (s, 3H), 1.38–1.34 (m, 4H), 1.23 ( d, J = 6.7 Hz, 6H), 0.95 (s, 6H). MS (m/z): 489.2 [M+1] ⁺ .

Compound 33: 1-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole -5-carboxylic acid

The title compound was prepared in a manner analogous to Compound 12 as described above. ¹ H NMR (500 MHz, DMSO) δ 7.53-7.48 (m, 1H), 7.30-7.28 (m, 2H), 7.24-7.21 (m, 1H), 3 .53–3.51 (m, 4H), 3.40 (bs, 4H), 3.19–3.14 (m, 1H), 2.28 (s, 3H), 1.41 (s, 9H ), 1.24 (d, J = 6.7 Hz, 6H). MS (m/z): 562.2 [M+1] ⁺ .

Compound 34: 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(3-(trifluoromethyl)pyrrolidin-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5 –carboxylic acid

The title compound was obtained using a method similar to Compound 12 as described above. ¹ H NMR (500 MHz, DMSO) δ 7.53-7.49 (m, 1H), 7.30-7.27 (m, 2H), 7.25-7.21 (m, 1H), 3 .82–3.70 (m, 3H), 3.64–3.59 (m, 1H), 3.06–3.01 (m, 1H), 2.28 (s, 3H), 2.25 –2.18 (m, 1H), 2.06–1.99 (m, 1H), 1.22 (d, J = 6.7, Hz, 6H). MS (m/z): 515.1 [M+1] ⁺ .

Compound 35: 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(piperazin-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid hydrochloric acid salt acids

The title compound was obtained using a method similar to Compound 12 as described above. ¹ H NMR (500 MHz, MeOD) δ 8.45 (bs, 1H), 7.44-7.39 (m, 1H), 7.37-7.31 (m, 2H), 7.06-7 .03 (m, 1H), 3.85–3.83 (m, 4H), 3.28–3.26 (m, 4H), 3.23–3.17 (m, 1H), 2.33 (s, 3H), 1.29 (d, J = 6.7 Hz, 6H). MS (m/z): 462.1 [M+1] ⁺ .

Compound 36: 4-(3-fluorophenyl)-3-methyl-1-(5-(2-methylprop-1-en-1-yl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl) -1H-pyrazole-5-carboxylic acid

Methyl 4-iodine-1-(5-iodine-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate

Methyl 3-methyl-1-(4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-1H-pyrazol-5-carboxylate, prepared as above (1.86 g, 5.06 mmol), was dissolved in TFA (25 ml) and N -iodosuccinimide (2.39 g, 10.6 mmol) was added. This reaction mixture was stirred 1 h 30 min at room temperature followed by the addition of more N -iodosuccinimide (190 mg, 0.844 mmol) and stirring was continued for 4 h. The reaction mixture was slowly added to ice water and the solid was filtered off, washed with water and dried to give the title compound (2.45 mg, 3.96 mmol, 78%) as a pink solid.

Methyl 4-iodine-3-methyl-1-(5-(2-methylprop-1-en-1-yl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-1H-pyrazol-5 carboxylate

Methyl 4-iodine-1-(5-iodine-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl -1H-pyrazole-5-carboxylate (800 mg, 1.29 mmol), (2-methylprop-1-en-1-yl)boronic acid (129 mg, 1.29 mmol) and K ₂ CO ₃ (893 mg , 6.46 mmol), nitrogen and vacuum cycles were performed (2x). Nitrogen gas was bubbled through the THF solution (13 mL) and then this solution was added to a microwave vial followed by Pd(dtbpf)Cl ₂ catalyst (84.2 mg, 0.129 mmol). The vial was closed and placed in an oil bath at 90°C for 16 hours. The reaction mixture was diluted with EtOAc, washed with water and brine. The organic layer was dried with magnesium sulfate, filtered and evaporated under reduced pressure. The crude product was purified by silica gel flash chromatography using ethyl acetate in hexanes (0% to 10% gradient) to give the title compound (172 mg, 0.314 mmol, 24%) as a yellow solid.

Methyl 4-(3-fluorophenyl)-3-methyl-1-(5-(2-methylprop-1-en-1-yl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-1H pyrazole-5-carboxylate

Methyl 4-iodine-3-methyl-1-(5-(2-methylprop-1-en-1-yl)-4 -(4-(trifluoromethyl)phenyl)thiazol-2-yl)-1H-pyrazol-5-carboxylate (172 mg, 0.314 mmol), 3-fluorophenylboronic acid (52.8 mg, 0.377 mmol) and Na ₂ CO ₃ ( 167 mg, 1.57 mmol), nitrogen and vacuum cycles were performed (2x). Nitrogen gas was bubbled through a dioxane/water solution (3 ml, 4:1) and then this solution was added to a microwave vial followed by the addition of Pd(PPh ₃ ) ₄ catalyst (36.3 mg, 0.0314 mmol). The vial was closed and placed in an oil bath at 85°C for 16 hours. The crude product was purified by silica gel flash chromatography using a solution of EtOAc in hexanes (0 to 10% gradient) to give the title compound (111 mg, 0.215 mmol, 69%) as a yellow solid.

4-(3-fluorophenyl)-3-methyl-1-(5-(2-methylprop-1-en-1-yl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-1H- pyrazole-5-carboxylic acid

Methyl 4-(3-fluorophenyl)-3-methyl-1-(5-(2-methylprop-1-en-1-yl)-4-(4-(trifluoromethyl) phenyl)thiazol-2-yl)-1H-pyrazole-5-carboxylate (20 mg, 0.039 mmol) and LiOH (4.6 mg, 0.19 mmol). A dioxane/water solution (2 ml, 4:1) was added. The vial was heated to 110°C under microwave radiation for 15 minutes. The crude product was purified by semi-preparative HPLC-MS (X-Bridge 30x50 column, eluted with 60-80% MeCN/AmForm 10 mM, pH 3.8/flow 45 mL/min/10 min) to give the title compound (8.2 mg, 0.016 mmol, 42%) as a yellow solid after lyophilization.

¹ H NMR (500 MHz, DMSO) δ 7.89 (d, J = 8.3 Hz, 2H), 7.81 (d, J = 8.3 Hz, 2H), 7.51–7.44 ( m, 1H), 7.39–7.30 (m, 2H), 7.22–7.14 (m, 1H), 6.41–6.36 (m, 1H), 2.30 (s, 3H), 1.95 (s, 3H), 1.90 (s, 3H); MS (m/z): 502.0 [M+1] ⁺

Compound 37: 4-(3-fluorophenyl)-3-methyl-1-(4-(2-methylprop-1-en-1-yl)-5-(4-(trifluoromethyl)phenyl)thiazol-2-yl) -1H-pyrazole-5-carboxylic acid

Methyl 4-bromo-1-(4,5-dibromothiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate

To a solution of methyl 1-(4-bromo-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate prepared as described above for Compound 1 (27.9 g, 74 .07 mmol) in MeCN (570 ml) at 0°C was added a solution of Br ₂ (21 ml) in MeCN (170 ml). This reaction mixture was allowed to warm to room temperature and stirred for 2.5 hours. The reaction mixture was filtered and the mother liquor was transferred to an extraction funnel. The layers were separated and the aqueous layer was extracted with DCM (3x). The combined organic layers were dried over MgSO _{4 ,} filtered and concentrated in vacuo to give the title compound (8.76 mg, 19.0 mmol, 26%) as a yellow solid.

Methyl 4-bromo-1-(4-bromo-5-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate

Methyl 4-bromo-1-(4,5-dibromothiazol-2-yl)-3-methyl-1H-pyrazol-5- carboxylate (1.50 g, 3.26 mmol), (4-(trifluoromethyl)phenyl)boronic acid (619 mg, 3.26 mmol) and K ₂ CO ₃ (2.25 g, 16.3 mmol), nitrogen and performed vacuum cycles (2x). Nitrogen gas was bubbled through the THF solution (11 ml) and then this solution was added to the microwave vial followed by the addition of Pd(dtbpf)Cl ₂ catalyst (212 mg, 0.326 mmol). The vial was closed and placed in an oil bath at 90°C for 16 hours. The solvent was evaporated in vacuo and the crude product was purified by flash chromatography on silica gel (dry column loading) using a solution of EtOAc in hexanes (1 to 5% gradient) and then purified again by reverse chromatography on column C– 18 with a solution of MeCN in water (containing 10 mM NH ₄ CO ₂ H) (60 to 100%) to give the title compound (490 mg, 0.933 mmol, 29%) as a white powder after lyophilization.

Methyl 4-bromo-3-methyl-1-(4-(2-methylprop-1-en-1-yl)-5-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-1H-pyrazol-5 carboxylate

Methyl 4-bromo-1-(4-bromo-5-(4-(trifluoromethyl)phenyl)thiazol-2-yl)– 3-methyl-1H-pyrazole-5-carboxylate (200 mg, 0.381 mmol), (2-methylprop-1-en-1-yl)boronic acid (38.0 mg, 0.381 mmol) and K ₂ CO ₃ (263 mg, 1.90 mmol), nitrogen and vacuum cycles were performed (2x). Nitrogen gas was bubbled through the THF solution (2 ml) and then this solution was added to the microwave vial followed by the addition of Pd(dtbpf)Cl ₂ catalyst (24.8 mg, 0.0381 mmol). The vial was closed and placed in an oil bath at 90°C for 16 hours. The solvent was evaporated in vacuo and the crude product was purified by silica gel flash chromatography (dry column fill) using a solution of EtOAc in hexanes (0 to 5% gradient) to give the title compound (62.0 mg, 0.124 mmol, 33%) as a white solid.

Methyl 4-(3-fluorophenyl)-3-methyl-1-(4-(2-methylprop-1-en-1-yl)-5-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-1H pyrazole-5-carboxylate

Methyl 4-bromo-3-methyl-1-(4-(2-methylprop-1-en-1-yl)-5 - (4-(trifluoromethyl)phenyl)thiazol-2-yl)-1H-pyrazol-5-carboxylate (62.0 mg, 0.124 mmol), 3-fluorophenylboronic acid (20.8 mg, 0.149 mmol) and Na ₂ CO ₃ (65.7 mg, 0.620 mmol), nitrogen and vacuum cycles were performed (2x). Nitrogen gas was bubbled through a dioxane/water solution (2 ml, 4:1) and then this solution was added to a microwave vial followed by Pd(PPh ₃ ) ₄ catalyst (13.8 mg, 0.012 mmol). The vial was closed and placed in an oil bath at 85°C for 16 hours. The crude product was purified by silica gel flash chromatography using a solution of EtOAc in hexanes (1% isocratic) to give the title compound (27.0 mg, 0.052 mmol, 42%) as a colorless oil.

4-(3-fluorophenyl)-3-methyl-1-(4-(2-methylprop-1-en-1-yl)-5-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-1H- pyrazole-5-carboxylic acid

In a 25 ml round-bottom flask, methyl 4-(3-fluorophenyl)-3-methyl-1-(4-(2-methylprop-1-en-1-yl)-5-(4-(trifluoromethyl)phenyl)thiazol- 2-yl)-1H-pyrazole-5-carboxylate (27.0 mg, 0.052 mmol) was diluted with THF/MeOH (2 ml, 1:1). A 1 M NaOH solution (262 μl, 0.262 mmol) was added and the reaction mixture was stirred for 16 hours at room temperature. HCl solution 1 M (262 μl, 0.262 mmol) and water (2 ml) were added. The reaction mixture was directly purified by reverse chromatography on a C-18 column with MeCN in water (containing 10 mM NH ₄ CO ₂ H) (35 to 75%) to give the title compound (3.00 mg, 0.006 mmol , 11%) as a white powder after lyophilization.

¹ H NMR (500 MHz, MeOD) δ 7.75 (d, J = 8.3 Hz, 2H), 7.69 (d, J = 8.2 Hz, 2H), 7.43–7.30 ( m, 3H), 7.06–6.99 (m, 1H), 6.14–6.09 (m, 1H), 2.33 (s, 3H), 2.14 (d, J = 1, 0 Hz, 3H), 1.88 (d, J =1.1 Hz, 3H); MS (m/z): 502.1 [M+1] ⁺ .

Compound 38: 1-(4,5-bis(4-(trifluoromethyl)phenyl)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid

The title compound was prepared in a manner similar to Compound 37 as described above. ¹ H NMR (500 MHz, DMSO) δ 7.82 (d, J =8.2 Hz, 2H), 7.73 (d, J =8.4 Hz, 2H), 7.65 (dd, J = 8.1, 3.6 Hz, 4H), 7.53-7.46 (m, 1H), 7.40-7.33 (m, 2H), 7.23-7.17 (m, 1H) , 2.32 (s, 3H). MS (m/z): 592.2 [M+1] ⁺ .

Compound 39: 2-(4-(3-fluorophenyl)-3-methyl-1H-pyrazol-1-yl)-4,5-bis(4-(trifluoromethyl)phenyl)thiazole

The title compound was prepared in a manner similar to Compound 37 as described above. ¹ H NMR (500 MHz, DMSO) δ 8.94 (s, 1H), 7.82 (d, J =8.3 Hz, 2H), 7.78 (d, J =8.3 Hz, 2H) , 7.73 (d, J = 8.2 Hz, 2H), 7.66 (d, J = 8.0 Hz, 2H), 7.54–7.48 (m, 3H), 7.22– 7.15 (m, 1H), 2.48 (s, 3H). MS (m/z): 548.2 [M+1] ⁺ .

Compound 40: 1-(4-(4-(tert-butyl)piperidin-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole -5-carboxylic acid

The title compound was obtained using a method similar to Compound 12 as described above. ¹ H NMR (500 MHz, DMSO) δ 7.53-7.48 (m, 1H), 7.29-7.21 (m, 3H), 4.37 (d, J =12.9 Hz, 2H ), 3.15–3.10 (m, 1H), 2.76 (t, J = 11.6 Hz, 2H), 2.28 (s, 3H), 1.66 (d, J = 12, 6 Hz, 2H), 1.27–1.20 (m, 8H), 1.18–1.14 (m, 1H), 0.85 (s, 9H). MS (m/z): 517.2 [M+1] ⁺ .

Compound 41: 4–(3-fluorophenyl)–1–(5–(isopropylthio)–4–(6–azaspiro [2,5]octan–6–yl)thiazol–2–yl)–3–methyl–1H– pyrazole-5-carboxylic acid

The title compound was prepared in a manner analogous to Compound 12 as described above. ¹ H NMR (500 MHz, DMSO) δ 7.47 (bs, 1H), 7.31 (bs, 2H), 7.18 (bs, 1H), 3.62-3.60 (m, 4H), 3.16-3.11 (m, 1H), 2.27 (s, 3H), 1.40-1.38 (m, 4H), 1.24 (d, J = 6.7 Hz, 6H) , 0.32 (s, 4H). MS (m/z): 487.2 [M+1] ⁺ .

Compound 42: 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-methoxy-4-(trifluoromethyl)piperidin-1-yl)thiazol-2-yl)-3-methyl-1H -pyrazole-5-carboxylic acid

The title compound was prepared in a manner analogous to Compound 12 as described above. ¹ H NMR (500 MHz, DMSO) δ 7.50-7.46 (m, 1H), 7.32-7.29 (m, 2H), 7.21-7.18 (m, 1H), 4 .24 (d, J = 13.1 Hz, 2H), 3.39 (s, 3H), 3.18–3.13 (m, 1H), 3.05 (t, J = 11.9 Hz, 2H), 2.28 (s, 3H), 1.91 (d, J =12.6 Hz, 2H), 1.76 (td, J =13.5, 4.4 Hz, 2H), 1, 24 (d, J =6.7 Hz, 6H). MS (m/z): 559.1 [M+1] ⁺ .

Compound 43: 4-(3-fluorophenyl)-1-(4-(4-methoxyphenyl)-5-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid

The title compound was prepared in a manner similar to Compound 37 as described above. ¹ H NMR (500 MHz, DMSO) δ 7.79 (d, J = 8.2 Hz, 2H), 7.64 (d, J = 8.2 Hz, 2H), 7.54–7.46 ( m, 1H), 7.41–7.36 (m, 2H). ), 7.36–7.31 (m, 2H), 7.26–7.17 (m, 1H), 6.95–6.90 (m, 2H), 3.77 (s, 3H), 2.32(s, 3H). MS (m/z): 554.0 [M+1]+.

Compound 44: 1-(4,5-bis(4-methoxyphenyl)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid

The title compound was prepared in a manner similar to Compound 37 as described above. ¹ H NMR (500 MHz, DMSO) δ 7.56-7.46 (m, 1H), 7.43-7.29 (m, 6H), 7.27-7.14 (m, 1H), 7 .03–6.97 (m, 2H), 6.92–6.85 (m, 2H), 3.80 (s, 3H), 3.75 (s, 3H), 2.30 (s, 3H ). MS (m/z): 516.4 [M+1]+.

Compound 45: 4-(3-fluorophenyl)-1-(5-(4-methoxyphenyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid

The title compound was prepared in a manner similar to Compound 37 as described above. ¹ H NMR (500 MHz, DMSO) δ 7.70 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 8.4 Hz, 2H), 7.54–7.47 ( m, 1H), 7.340–7.30 (m, 4H), 7.27–7.18 (m, 1H), 7.05–7.00 (m, 2H), 3.81 (s, 3H) , 2.32 (s, 3H). MS (m/z): 553.9 [M+1]+.

Compound 46: 1–(4–(4–(tert-butyl)–3–oxopiperazin–1–yl)–5–(isopropylthio)thiazol–2–yl)–4–(3–fluorophenyl)–3–methyl– 1H-pyrazole-5-carboxylic acid

The title compound was obtained using a method similar to Compound 12 as described above. ¹ H NMR (500 MHz, DMSO) δ 7.44-7.40 (m, 2H), 7.36-7.34 (m, 1H), 7.12-7.09 (m, 1H), 4 .19 (s, 2H), 3.77–3.75 (m, 2H), 3.46–3.44 (m, 2H), 3.12–3.07 (m, 1H), 2.26 (s, 3H), 1.38 (s, 9H), 1.23 (d, J = 6.7 Hz, 6H). MS (m/z): 532.1 [M+1] ⁺ .

Compound 47: 4-(3-fluorophenyl)-3-methyl-1-(5-(3-(methylamino)-3-oxopropyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-1H -pyrazole-5-carboxylic acid

Methyl 1-(5-(3-(tert-butoxy)-3-oxoprop-1-en-1-yl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-4-iodine-3 methyl-1H-pyrazole-5-carboxylic acid

Methyl 4-iodine-1-(5-iodine-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl -1H-pyrazole-5-carboxylate prepared according to the description of Compound 36 (500 mg, 0.807 mmol), tert-butyl acrylate (113 μl, 0.888 mmol), K ₂ CO ₃ (558 mg, 4.035 mmol) and catalyst Pd(dtbpf) Cl ₂ (53 mg, 0.0807 mmol). THF (8.1 ml, 0.1 M) was added to a microwave tube and a stream of nitrogen was bubbled through the brown mixture for 5 minutes. The flask was closed and stirred in an oil bath at 90°C for 16 hours. After 16 hours, the reaction mixture was purified on a silica gel column using a mobile phase of 0–5% EtOAc in a mixture of hexanes. Fractions containing product were evaporated under reduced pressure to give the title compound (215 mg, 0.347 mmol, 43%) as an off-white foam.

Methyl 1–(5–(3– (tert-butoxy)–3–oxoprop–1–en–1–yl)–4–(4–(trifluoromethyl)phenyl)thiazol–2–yl)–4–(3– fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid

Methyl 1–(5–(3–(tert–butoxy)–3–oxoprop–1–en–1–yl)–4–(4– (trifluoromethyl) phenyl) thiazol-2-yl)-4-iodine-3-methyl-1H-pyrazole-5-carboxylate (105 mg, 0.169 mmol), (3-fluorophenyl) boronic acid (24 mg, 0.169 mmol), Na ₂ CO ₃ (90 mg, 0.845 mmol) and Pd(PPh ₃ ) ₄ catalyst (20 mg, 0.0169 mmol). A mixture of THF:water (1.7 ml, 4:1, 0.1 M), which had been deoxygenated with a stream of nitrogen for 5 minutes, was added to a microwave tube. The flask was closed and stirred in an oil bath at 90°C for 16 hours. After 16 hours, the reaction mixture was purified on a silica gel column using a mobile phase of 0–5% EtOAc in a mixture of hexanes. Fractions containing product were evaporated under reduced pressure to give the title compound (69 mg, 0.117 mmol, 70%) as a colorless oil.

methyl 1–(5–(3–(tert-butoxy)–3–oxopropyl)–4–(4–(trifluoromethyl)phenyl)thiazol–2–yl)–4–(3–fluorophenyl)–3–methyl–1H pyrazole-5-carboxylic acid

Methyl 1–(5–(3– (tert-butoxy)–3–oxoprop–1–en–1–yl)–4–(4–(trifluoromethyl )phenyl)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylate (68 mg, 0.115 mmol), catalyst Pd (OH) ₂ (15 mg) and MeOH: AcOH (1 ml, 1:1, 0.1 M). The flask was equipped with a hydrogen cylinder. The reaction mixture was purged three times with hydrogen and vacuum. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. After 16 hours the reaction mixture was filtered through celite and the filter cake was washed with methanol. The reaction mixture was purified on a silica gel column using a mobile phase of 0–5% EtOAc in a mixture of hexanes. Fractions containing product were evaporated under reduced pressure to give the title compound (50 mg, 0.0848 mmol, 75%) as a yellow oil.

3-(2-(4-(3-fluorophenyl)-5-(methoxycarbonyl)-3-methyl-1H-pyrazol-1-yl)-4-(4-(trifluoromethyl)phenyl)thiazol-5-yl)propanoic acid

Methyl )-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylate (50 mg, 0.0848 mmol), CeCl ₃ ⋅ 7H ₂ O (47 mg, 0.127 mmol) NaI (16 mg, 0.110 mmol) and MeCN (0.7 ml, 0.1 M). The reaction mixture was heated under reflux for 2 hours. After 2 hours the reaction mixture was diluted with EtOAc and treated with 0.5 M HCl. The compound was extracted three times using EtOAc. The combined organic layers were dried with Na ₂ SO ₄ , filtered and evaporated under reduced pressure to give the title compound (38 mg, 0.0729 mmol, 86%) as an orange solid.

4-(3-fluorophenyl)-3-methyl-1-(5-(3-(methylamino)-3-oxopropyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-1H-pyrazol- 5-carboxylic acid

3– (2–(4–(3–fluorophenyl)–5–(methoxycarbonyl)–3–methyl–1H–pyrazol–1–yl) was placed at room temperature into a 10 mL round bottom flask equipped with a magnetic stirrer. ) – 4-(4-(trifluoromethyl)phenyl)thiazol-5-yl)propanoic acid (48 mg, 0.0899 mmol), HATU (51 mg, 0.134 mmol), MeNH ₂ (67 μl, 0.134 mmol) and Hunig's base ( 39 µl, 0.224 mmol) in DMF (0.9 ml, 0.1 M). The orange solution turned yellowish within 5 minutes. After 5 minutes, HPLC–MS analysis of the reaction mixture showed that the reaction was complete. The compound was evaporated to dryness. The yellowish residue was transferred to a microwave vial to which LiOH (21 mg, 0.899 mmol) and THF:water (4:1, 2 ml, 0.04 M) were added. The microwave vial was capped and heated at 110°C for 15 minutes under microwave radiation. The reaction mixture was filtered and the crude product was purified by semi-preparative HPLC-MS (X-Bridge 30×50 column, eluted with 40-60% MeCN/NH ₄ CO ₂ H 10 mM, pH 3.8/flow 45 ml/min/ 11 min) to give the title compound (8 mg, 0.015 mmol, 17%) as a white solid after lyophilization.

¹ H NMR (500 MHz, DMSO) δ 7.93-7.87 (m, 3H), 7.83-7.81 (m, 2H), 7.46-7.39 (m, 2H), 7 .36–7.34 (m, 1H), 7.13–7.10 ( m, 1H), 3.19 (t, J =7.2 Hz, 2H), 2.58 (d, J =4 .6 Hz, 3H), 2.53–2.51 (m, 2H), 2.28 (s, 3H); MS (m/z): 533.0 [M+1] ⁺ .

Compound 48: 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(2-methoxyethoxy)-4-(trifluoromethyl)piperidin-1-yl)thiazol-2-yl)-3 -methyl-1H-pyrazole-5-carboxylic acid

The title compound was obtained using a method similar to Compound 11 as described above. ¹ H NMR (500 MHz, DMSO) δ 14.16 (s, 1H), 7.54-7.47 (m, 1H), 7.28 (d, J =7.7 Hz, 2H), 7, 24 (t, J = 8.1 Hz, 1H), 4.22 (d, J = 13.2 Hz, 2H), 3.72–3.67 (m, 2H), 3.53–3.48 (m, 2H), 3.28 (s, 3H), 3.20–3.08 (m, 3H), 2.29 (s, 3H), 1.93 (d, J = 12.8 Hz, 2H), 1.77 (td, J =13.4, 4.4 Hz, 2H), 1.24 (d, J =6.7 Hz, 6H). MS (m/z): 603.3 [M+1] ⁺ .

Compound 49: 4-(3-fluorophenyl)-1-(5-(4-((2-methoxyethyl)carbamoyl)phenyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl -1H-pyrazole-5-carboxylic acid

The title compound was prepared in a manner analogous to Compound 36 as described above. ¹ H NMR (500 MHz, DMSO) δ 8.56 (t, J = 5.3 Hz, 1H), 7.87-7.81 (m, 2H), 7.65 (d, J = 8.3 Hz, 2H), 7.58 (d, J = 8.3 Hz, 2H), 7.49–7.40 (m, 3H), 7.33–7.25 (m, 2H), 7.19 –7.10 (m, 1H), 3.42–3.34 (m, 4H), 3.21 (s, 3H), 2.26 (s, 3H). MS (m/z): 625.2 [M+1]+.

Compound 50: 4-(3-fluorophenyl)-1-(5-(4-((2-methoxyethyl)(methyl)carbamoyl)phenyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)- 3-methyl-1H-pyrazole-5-carboxylic acid

The title compound was prepared in a manner analogous to Compound 36 as described above. ¹ H NMR (500 MHz, DMSO) δ 7.75-7.62 (m, 4H), 7.54-7.42 (m, 5H), 7.41-7.32 (m, 2H), 7 .26–7.16 (m, 1H), 3.69–3.35 (m, 4H), 3.17 (s, 3H), 2.98 (s, 3H), 2.32 (s, 3H ). MS (m/z): 639.2 [M+1] ⁺ .

Compound 51: 4-(3-fluorophenyl)-1-(5-(4-(2-methoxyacetamido)phenyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H- pyrazole-5-carboxylic acid

The title compound was prepared in a manner analogous to Compound 36 as described above. ¹ H NMR (500 MHz, DMSO) δ 9.92 (s, 1H), 7.72-7.66 (m, 2H), 7.66-7.57 (m, 4H), 7.44-7 .36 (m, 1H), 7.36–7.27 (m, 4H), 7.13–7.05 (m, 1H), 3.96 (s, 2H), 3.32 (s, 3H ), 2.24 (s, 3H). MS (m/z): 611.2 [M+1].

Compound 52: 4-(3-fluorophenyl)-1-(5-(4-(2-(2-methoxyethoxy)acetamido)phenyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3 -methyl-1H-pyrazole-5-carboxylic acid

The title compound was prepared in a manner analogous to Compound 36 as described above. ¹ H NMR (500 MHz, DMSO) δ 9.87 (s, 1H), 7.77-7.65 (m, 6H), 7.49-7.36 (m, 5H), 7.17-7 .07 (m, 1H), 4.11 (s, 2H), 3.72–3.65 (m, 2H), 3.57–3.51 (m, 2H), 3.31 (s, 3H ), 2.31 (s, 3H). MS (m/z): 655.1 [M+1] ⁺ .

Compound 53: 4-(3-fluorophenyl)-1-(5-(3-((2-methoxyethyl)amino)-3-oxopropyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)- 3-methyl-1H-pyrazole-5-carboxylic acid

The title compound was prepared in a similar manner to Compound 47 as described above. ¹ H NMR (500 MHz, DMSO) δ 8.49 (bs, 1H), 7.97-7.95 (m, 2H), 7.73-7.71 (m, 2H), 7.42-7 .30 (m, 3H), 7.04–7.00 (m, 1H), 3.44–3.42 (m, 2H), 3.38–3.32 (m, 4H), 3.32 (s, 3H), 2.64 (t, J =7.4 Hz, 2H), 2.33 (s, 3H). MS (m/z): 577.1 [M+1] ⁺ .

Compound 54: 4-(3-fluorophenyl)-1-(5-(3-((2-methoxyethyl)(methyl)amino)-3-oxopropyl)-4-(4-(trifluoromethyl)phenyl)thiazole-2- yl)-3-methyl-1H-pyrazole-5-carboxylic acid

The title compound was prepared in a similar manner to Compound 47 as described above. ¹ H NMR (500 MHz, MeOD) δ 7.91-7.90 (m, 2H), 7.75-7.74 (m, 2H), 7.47-7.42 (m, 1H), 7 .29–7.27 (m, 1H), 7.24–7.22 (m, 1H), 7.12–7.08 (m, 1H), 3.58–3.49 (m, 4H) , 3.35-3.32 (m, 2H), 3.33-3.29 (m, 3H), 3.07-2.96 (m, 3H), 2.91 (t, J = 7, 1 Hz, 1H), 2.85 (t, J =7.0 Hz, 1H), 2.32 (d, J =1.3 Hz, 3H). MS (m/z): 591.1 [M+1] ⁺ .

Compound 55: 4-(3-fluorophenyl)-1-(5-(4-(2-methoxy-N-methylacetamido)phenyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3- methyl-1H-pyrazole-5-carboxylic acid

The title compound was prepared in a manner analogous to Compound 36 as described above. ¹ H NMR (500 MHz, DMSO) δ 7.73-7.64 (m, 4H), 7.52-7.32 (m, 7H), 7.22-7.15 (m, 1H), 4 .02–3.86 (m, 2H), 3.23 (s, 3H), 3.22 (s, 3H), 2.33 (s, 3H). MS (m/z): 625.2 [M+1] ⁺ .

Compound 56: 4-(3-fluorophenyl)-1-(5-(4-(2-(2-methoxyethoxy)-N-methylacetamido)phenyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl )-3-methyl-1H-pyrazole-5-carboxylic acid

The title compound was prepared in a manner similar to Compound 36 as described above. ¹ H NMR (500 MHz, DMSO) δ 7.72-7.63 (m, 4H), 7.51-7.33 (m, 7H), 7.21-7.13 (m, 1H), 4 .08–3.91 (m, 2H), 3.55–3.44 (m, 2H), 3.42–3.35 (m, 2H), 3.22 (s, 3H), 3.20 (s, 3H), 2.31 (s, 3H). MS (m/z): 669.4 [M+1] ⁺ .

Compound 57: 4-(3-fluorophenyl)-1-(5-(methoxymethyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid

The title compound was prepared in a manner analogous to Compound 36 as described above. ¹ H NMR (500 MHz, DMSO) δ 7.90 –7.81 (m, 4H), 7.56–7.46 (m, 1H), 7.36–7.28 (m, 2H), 7 .25–7.18 (m, 1H), 4.77 (s, 2H), 3.42 (s, 3H), 2.31 (s, 3H). MS (m/z): 492.0 [M+1] ⁺ .

Compound 58: 1–(5–(4–(2–(2–ethoxyethoxy)ethoxy)phenyl)–4–(4–(trifluoromethyl)phenyl)thiazol–2–yl)–4–(3–fluorophenyl)–3 -methyl-1H-pyrazole-5-carboxylic acid

The title compound was prepared in a manner similar to Compound 36 as described above. ¹ H NMR (500 MHz, DMSO) δ 7.66-7.56 (m, 4H), 7.48-7.41 (m, 1H), 7.32-7.24 (m, 4H), 7 .20–7.11 (m, 1H), 7.00–6.94 (m, 2H), 4.08 (dd, J =5.4, 3.8 Hz, 2H), 3.69 (dd , J =5.4, 3.8 Hz, 2H), 3.52 (dd, J =5.8, 3.8 Hz, 2H), 3.43 (dd, J =5.8, 3.9 Hz, 2H), 3.37 (q, J =7.0 Hz, 2H), 2.25 (s, 3H), 1.03 (t, J =7.0 Hz, 3H). MS (m/z): 656.3 [M+1] ⁺ .

Compound 59: 4-(3-fluorophenyl)-1-(5-(3-fluorophenyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid

The title compound was prepared in a manner analogous to Compound 36 as described above. ¹ H NMR (500 MHz, DMSO) δ 7.70 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 8.4 Hz, 2H), 7.54–7.45 ( m, 2H), 7.41–7.34 (m, 2H), 7.33–7.28 (m, 2H), 7.27–7.24 (m, 1H), 7.23–7, 17(m, 1H), 2.32(s, 3H). MS (m/z): 542.0 [M+1] ⁺ .

Compound 60: 4-(3-fluorophenyl)-1-(5-(hydroxymethyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid

The title compound was prepared in a manner analogous to Compound 36 as described above. ¹ H NMR (500 MHz, DMSO) δ 7.91-7.80 (m, 4H), 7.57-7.45 (m, 1H), 7.36-7.27 (m, 2H), 7 .26–7.16 (m, 1H), 6.13 (s, 1H), 4.85 (d, J = 4.0 Hz, 2H), 2.31 (s, 3H). MS (m/z): 478.1 [M+1] ⁺ .

Compound 61: 4-(3-fluorophenyl)-3-methyl-1-(5-(4-(trifluoromethyl)phenyl)-4-(4-(trifluoromethyl)piperidin-1-yl)thiazol-2-yl)- 1H-pyrazole-5-carboxylic acid

Methyl 4-bromo-3-methyl-1-(5-(4-(trifluoromethyl)phenyl)-4-(4-(trifluoromethyl)piperidin-1-yl)thiazol-2-yl)-1H-pyrazol-5- carboxylate

Methyl 4-bromo-1-(4-bromo-5-(4-(trifluoromethyl)phenyl)thiazol-2-yl)– 3-methyl-1H-pyrazole-5-carboxylate prepared as above for Compound 37 (131 mg, 0.249 mmol), 4-(trifluoromethyl)piperidine (47.3 mg, 0.249 mmol), Cs ₂ CO ₃ (406 mg, 1.25 mmol), XantPhos (14 mg, 0.025 mmol) and dioxane (2.5 ml). Nitrogen was bubbled into the solvent for 10 minutes followed by the addition of RuPhos Pd G1 catalyst (20 mg, 0.025 mmol). The vial was closed and placed in an oil bath at 105°C for 16 hours. The crude product was purified by silica gel flash chromatography using a solution of ethyl acetate in hexanes (0 to 10% gradient) to give the title compound (74 mg, 0.12 mmol, 50%) as a yellow oil.

4-(3-fluorophenyl)-3-methyl-1-(5-(4-(trifluoromethyl)phenyl)-4-(4-(trifluoromethyl)piperidin-1-yl)thiazol-2-yl)-1H-pyrazole -5-carboxylic acid

Methyl 4-bromo-3-methyl-1-(5-(4-(trifluoromethyl)phenyl)-4-(4-) (trifluoromethyl)piperidin-1-yl)thiazol-2-yl)-1H-pyrazole-5-carboxylate (74 mg, 0.12 mmol), (3-fluorophenyl)boronic acid (21 mg, 0.15 mmol) and Na ₂ CO ₃ (66 mg, 0.62 mmol) _. Nitrogen gas was bubbled through a dioxane/water solution (2 ml, 4:1) and then this solution was added to a microwave vial followed by Pd(PPh ₃ ) ₄ catalyst (14 mg, 0.012 mmol). The vial was closed and placed in an oil bath at 85°C for 16 hours. LiOH (15 mg, 0.62 mmol) was added to the reaction mixture and stirred under microwave at 115° C. for 15 minutes. The product was purified by semi-preparative HPLC–MS (X–Bridge 30×50 column, eluted with 60–80% MeCN/NH ₄ CO ₂ H 10 mM, pH 3.8/flow 45 ml/min/10 min), in whereby the title compound (4.2 mg, 0.0070 mmol, 6%) was obtained as a yellowish solid after lyophilization.

¹ H NMR (500 MHz, MeOD) δ 7.91 (d, J = 8.2 Hz, 2H), 7.74 (d, J = 8.2 Hz, 2H), 7.50–7.43 ( m, 1H), 7.38–7.32 (m, 1H), 7.32–7.27 (m, 1H), 7.15–7.08 (m, 1H), 3.59–3, 50 (m, 2H), 3.00–2.91 (m, 2H), 2.36 (s, 3H), 2.39–2.25 (m, 1H), 1.95–1.88 ( m, 2H), 1.81–1.68 (m, 2H); MS (m/z): 599.1 [M+1] ⁺

Compound 62: 4-(3-fluorophenyl)-1-(4-(3-fluorophenyl)-5-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid

The title compound was prepared in a manner analogous to Compound 36 as described above. ¹ H NMR (500 MHz, MeOD) δ 7.76 (d, J = 8.2 Hz, 2H), 7.66 (d, J = 8.2 Hz, 2H), 7.51–7.45 ( m, 1H), 7.38–7.28 (m, 5H), 7.15–7.10 (m, 1H), 7.09–7.04 (m, 1H), 2.38 (s, 3H). MS (m/z): 542.1 [M+1] ⁺ .

Compound 63: 4-(3-fluorophenyl)-1-(5-(1-hydroxyethyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid

The title compound was prepared in a similar manner to Compound 64 as described below. ¹ H NMR (500 MHz, MeOD) δ 8.52 (bs, 1H), 7.96 (d, J =8.1 Hz, 2H), 7.72 (d, J =8.0 Hz, 2H) , 7.43–7.31 (m, 3H), 7.05–7.01 (m, 1H), 5.30 (q, J =6.2 Hz, 1H), 2.34 (s, 3H ), 1.61 (d, J = 6.3 Hz, 3H). MS (m/z): 492.1 [M+1] ⁺ .

Compound 64: 4-(3-fluorophenyl)-1-(5-(2-hydroxyethyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid

methyl 4-bromo-3-methyl-1-(4-(4-(trifluoromethyl)phenyl)-5-vinylthiazol-2-yl)-1H-pyrazole-5-carboxylate

Methyl 4-bromo-1-(5-bromo-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl -1H-pyrazole-5-carboxylate prepared as described above for Compound 36 (200 mg, 0.380 mmol), potassium vinyl trifluoroborate (51 mg, 0.380 mmol), K ₂ CO ₃ (158 mg, 1.14 mmol) and catalyst Pd(dtbpf)Cl ₂ (25 mg, 0.0380 mmol). THF (1.9 ml, 0.2 M) was added to a microwave tube and a stream of nitrogen was bubbled through the brown mixture for 5 minutes. The flask was closed and stirred in an oil bath at 90°C for 16 hours. After 16 hours, the reaction mixture was purified on a silica gel column using a mobile phase of 0–5% EtOAc in a mixture of hexanes. Fractions containing product were evaporated under reduced pressure to give the title compound (104 mg, 0.220 mmol, 58%) as an off-white solid.

methyl 4-(3-fluorophenyl)-3-methyl-1-(4-(4-(trifluoromethyl)phenyl)-5-vinylthiazol-2-yl)-1H-pyrazole-5-carboxylate

Methyl 4-bromo-3-methyl-1-(4-(4-(trifluoromethyl)phenyl)-5-vinylthiazol-2-yl)– 1H-pyrazole-5-carboxylate (101 mg, 0.213 mmol), (3-fluorophenyl)boronic acid (30 mg, 0.213 mmol), Na ₂ CO ₃ (68 mg, 0.639 mmol) and catalyst Pd (PPh ₃ ) ₄ ( 25 mg, 0.0213 mmol). A mixture of THF:water (2.1 ml, 4:1, 0.1 M), which had been deoxygenated with a stream of nitrogen for 5 minutes, was added to a microwave tube. The flask was closed and stirred in an oil bath at 90°C for 16 hours. After 16 hours, the reaction mixture was purified on a silica gel column using a mobile phase of 0–5% EtOAc in a mixture of hexanes. Fractions containing product were evaporated under reduced pressure to give the title compound (77 mg, 0.159 mmol, 75%) as a white solid.

4-(3-fluorophenyl)-1-(5-(2-hydroxyethyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid

Methyl 4-(3-fluorophenyl)-3-methyl-1-(4-(4-(trifluoromethyl)phenyl)-5-vinylthiazol-2-yl) was placed into a 10 ml round-bottom flask equipped with a magnetic stirrer at room temperature. -1H-pyrazole-5-carboxylate (22 mg, 0.0451 mmol) in dry THF (0.5 ml, 0.1 M). The solution was cooled to 0°C and borane DMS (225 μl, 0.451 mmol) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 16 hours under nitrogen. After 16 hours, 30% peroxide in water (250 µl) and NaOH (18 mg, 0.451 mmol) in water (250 µl) were added at 0°C. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was extracted three times with EtOAc. The combined organic layers were dried with Na ₂ SO ₄ , filtered and evaporated. A white solid was tolerated in a microwave vial to which LiOH (11 mg, 0.451 mmol) and THF:water (1.5 ml; 4:1, 0.03 M) were added. The microwave vial was capped and heated at 110°C for 15 minutes under microwave radiation. The reaction mixture was filtered and the crude product was purified by semi-preparative HPLC-MS (X-Bridge 30×50 column, eluted with 40-60% MeCN/NH ₄ CO ₂ H 10 mM, pH 3.8/flow 45 ml/min /11 min) to give the title compound (1 mg, 0.002 mmol, 5%) as a white solid after lyophilization.

¹ H NMR (500 MHz, MeOD) δ 7.96 (d, J = 8.1 Hz, 2H), 7.71 (d, J = 7.7 Hz, 2H), 7.42–7.30 ( m, 3H), 7.05–7.01 (m, 1H ), 3.86 (t, J = 6.2 Hz, 2H), 3.20 (t, J = 6.2 Hz, 2H), 2.33(s, 3H); MS (m/z): 492.1 [M+1] ⁺ .

Compound 65: 4-(3-fluorophenyl)-1-(5-(4-(2-methoxyethoxy)phenyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H- pyrazole-5-carboxylic acid

The title compound was prepared in a manner similar to Compound 36 as described above. ¹ H NMR (500 MHz, DMSO) δ 7.71-7.63 (m, 4H), 7.53-7.46 (m, 1H), 7.39-7.32 (m, 4H), 7 .24–7.16 (m, 1H), 7.06–7.00 (m,, 2H), 4.16–4.12 (m, 2H), 3.70–3.66 (m, 2H ), 3.32 (s, 3H), 2.31 (s, 3H). MS (m/z): 598.2 [M+1]+.

Compound 66: 4-(3-fluorophenyl)-1-(5-(1-methoxyethyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid

The title compound was prepared using a method similar to Compound 64 as described above. ¹ H NMR (500 MHz, MeOD) δ 7.88 (d, J = 7.9 Hz, 2H), 7.74 (d, J = 8.1 Hz, 2H), 7.44–7.39 ( m, 1H), 7.36–7.34 (m, 1H), 7.31–7.29 (m, 1H), 7.07–7.03 (m, 1H), 4.89–4, 87 (m, 1H), 3.26 (s, 3H), 2.34 (s, 3H), 1.63 (d, J = 6.3 Hz, 3H). MS (m/z): 506.1 [M+1] ⁺ .

Compound 67: 4-(3-fluorophenyl)-1-(4-(4-isopropylpiperidin-1-yl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid

The title compound was prepared in a manner analogous to Compound 12 as described above. ¹ H NMR (500 MHz, MeOD) δ 7.44-7.40 (m, 1H), 7.29 (d, J =7.6 Hz, 1H), 7.24 (d, J =9.7 Hz, 1H), 7.08–7.05 (m, 1H), 4.41 (d, J =12.8 Hz, 2H), 3.17–3.12 (m, 1H), 2.82 (t, J =12.3 Hz, 2H), 2.30 (s, 3H), 1.71 (d, J =12.2 Hz, 2H), 1.48–1.40 (m, 1H) , 1.37–1.31 (m, 2H), 1.28 (d, J = 6.7 Hz, 6H), 1.23–1.18 (m, 1H), 0.91 (d, J =6.7Hz, 6H). MS (m/z): 503.3 [M+1] ⁺ .

Compound 68: 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(3-methoxy-3-(trifluoromethyl)-8-azabicyclo[3.2.1]octan-8-yl)thiazol-2 yl)-3-methyl-1H-pyrazole-5-carboxylic acid

The title compound was prepared in a manner similar to Compound 47 as described above. ¹ H NMR (500 MHz, DMSO) δ 7.50-7.41 (m, 1H), 7.38-7.27 (m, 2H), 7.24-7.08 (m, 1H), 4 .77 (s, 2H), 3.37 (s, 3H) 3.16–3.07 (m, 1H), 2.28 (s, 3H), 2.09–1.82 (m, 8H) , 1.23 (d, J = 6.7 Hz, 6H). MS (m/z): 585.1 [M+1] ⁺ .

BJAB Data

BJAB (DSMZ) cells were maintained in RPMI 1640+10% FBS growth medium at 37°C/5% CO ₂ and used until passage 34. Cells were plated in white 96-well Corning Costar quantitation plates at 2500 cells/well per 50 µl of medium. Serial dilutions of test compounds were made in cell culture medium/FBS + 0.2% DMSO and transferred to 50 µl volume quantitation plates (DMSO at 0.1% final concentration). The plates were kept at 37°C for approximately 72 hours. The effect of the compounds on cell proliferation was assessed using the Cell Titer Glo reagent (Promega) according to the manufacturer's instructions. Briefly, 100 µl of the reagent was added to a well and after a 10 minute incubation, luminescence values were determined on a plate reader (Tecan F200PRO). The percentage of luminescence signal relative to untreated controls was calculated for each compound concentration, and EC ₅₀ values were determined from dose-response data using non-linear regression analysis using Prism software (GraphPad). The data is given in the connection table above. The mTor inhibitor Torin1 was used as a control (Liu, et al. (2010) J. Med. Chem. 53 , 7146.). The data are summarized in the compound table above.

Further studies of various test compounds demonstrated that cell viability decreased in a dose dependent manner and that the test compounds caused cell death in a dose dependent manner 48 hours after treatment.

Biological examples

The inventors of the present invention have determined that, despite initial data indicating that the described compounds inhibit the initiation of RNA translation, an important biological effect produced by the compounds as described herein is the inhibition of cell cycle progression as described by the data presented herein. Without intending to be bound by any theory, the authors of the present invention assume that the compounds described herein disrupt the cell cycle in the G0/G1 phase, preventing further proliferation of the cancer cell.

The examples below provide four measurements of the activity of the compounds of this invention, specifically against a test compound falling within the broad range of compounds described herein having an IC ₅₀ value in the "A" range. The test compound is expected to be representative of the active compounds as described herein. The first is the general sensitivity of tumor cell lines to the test compound. Second, the role of the KRAS genotype in cell sensitivity to the test compound. Third, the effect of the test compound on the key cellular metabolite, glutathione. And fourth, the effect of the test compound on the cell cycle.

Example 1 Anticancer activity

A panel of 96 tumor and 3 normal cell lines was analyzed for sensitivity to the test compound. Cell lines were cultured in standard media and pipetted into 96-well plates at the required seeding density. Cells were acclimatized for 24 hours prior to compound testing. This compound was prepared as a 20 mM stock in DMSO. To obtain dose-response curves, the compound was serially diluted in DMSO and dispensed into plate wells using a Tecan D300e digital dispenser. The final concentration of DMSO was 0.15%. After 72 hours of incubation, the number of cells was determined according to the protocol CellTiter-Glo® (Promega). In this quantitative assay, the ATP level will be measured as a surrogate for cell number. Compound activity was determined by comparing untreated cells with treated cells and calculating the % signal remaining. Compound activity was measured as EC ₅₀ maximum potency level and these two values were used to calculate the activity area curve.

Of 96 tumor cell lines, 39 tumors (40%) showed a significant response to the test compound (as determined by the ability to assess IC ₅₀ ; Table 1). Of these, hematopoietic tumors showed a higher response rate. More than 89% of all hematopoietic tumors responded to the compound, while among solid tumors, a response was observed in 28.5%.

Table 1 Summary of tumor responses

Type of tumor Number of responses Response Rate (%) No Yes Hematopoietic 2 17 89 Solid 55 22 28.5

Data for various cell lines are presented in Table 2 below:

Table 2. Responses of specific tumors

cell line Type of tumor Tumor category KRAS Zygosity KRAS Calculated IC50 Activity area Max. inhibition_% 143b Solid Sarcoma MUT NO Yes 2.00 63.84 786–0 Solid Bud wt HOMO Not 1.05 24.32 A204 Solid Sarcoma wt HOMO Not 1, 37 34.89 A2058 Solid Leather wt HOMO Not -0.08 6.18 A2780 Solid Ovary wt HOMO Yes 3, 88 70.89 A375 Solid Leather wt HOMO Not 1, 14 29.08 A498 Solid Bud wt HOMO Not 2, 29 46.35 A549 Solid Lung MUT HOMO Yes 3.92 81.53 A673 Solid Sarcoma wt HOMO Yes 2, 29 57.68 AU565 Solid Breast wt HOMO Yes 2, 82 84.45 BT-474 Solid Breast wt HOMO Not -,12 -1.00 BT-483 Solid Breast wt HOMO Not 0.22 6.13 BxPC-3 Solid Pancreas wt HOMO Not 1, 46 30.79 CaCo-2 Solid colorectal wt HOMO Not 0.07 22.11 CAL-27 Solid Head and neck wt HOMO Not –,05 23.28 COLO 205 Solid colorectal wt HOMO Not 2, 40 49.77 COLO-824 Solid Breast wt HOMO Not -0.06 29.16 Daudi Hematopoietic Hematopoietic wt HOMO Yes 4, 33 92.47 DOHH-2 Hematopoietic Hematopoietic wt HOMO Yes 5, 04 100.21 DU-145 Solid Prostate wt HOMO Not 1, 48 33.20 EFM-19 Solid Breast wt HOMO Not 0.51 29.01 FADU Solid Head and neck wt HOMO Not 2, 88 49.81 HCC1143 Solid Breast wt HOMO Not 0.95 19.79 HCC1187 Solid Breast wt HOMO Not 1, 38 31.76 HCC1395 Solid Breast wt HOMO Not 1, 08 33.13 HCC1419 Solid Breast wt HOMO Not 0.25 5.82 HCC1500 Solid Breast wt HOMO Not 0.82 55.17 HCC1569 Solid Breast wt HOMO Not –1, 27 26.60 HCC1806 Solid Breast wt HOMO Not 1.00 56.75 HCC1937 Solid Breast wt HOMO Not 1.12 40.02 HCC1954 Solid Breast wt HOMO Not 1, 08 21.92 HCC38 Solid Breast wt HOMO Not 0.13 9.67 NST-116 Solid colorectal MUT NO Yes 4, 13 86.23 Hep 3B2.1–7 Solid Liver wt HOMO Not 1.21 23.73 HepG2 Solid Liver wt HOMO Not 0.70 19.20 HL-60 Hematopoietic Hematopoietic wt HOMO Yes 2.45 103.55 Hs-445 Hematopoietic Hematopoietic wt HOMO Yes 2.76 57.67 HT-1080 Solid Sarcoma wt HOMO Yes 3, 03 77.72 HT-29 Solid colorectal wt HOMO Not 1.89 46.47 Jurkat Hematopoietic Hematopoietic wt HOMO Yes 4, 91 94.46 K–562 Hematopoietic Hematopoietic wt HOMO Not 0.30 30.94 Kasumi-1 Hematopoietic Hematopoietic wt HOMO Yes 2, 70 63.46 KHOS/NP Solid Sarcoma NA N/A Not 1.43 32.83 LoVo Solid colorectal MUT NO Yes 3, 70 61.30 Malme-3M Solid Leather wt HOMO Not –1, 41 29.79 MCF7 Solid Breast wt HOMO Yes 2, 43 54.45 MDA-MB-157 Solid Breast wt HOMO Not 1.77 31.44 MDA-MB-231 Solid Breast MUT NO Not 0.92 32.97 MDA-MB-435S Solid Breast wt HOMO Not 0.02 32.16 MDA-MB-436 Solid Breast wt HOMO Not 1, 33 28.79 MDA-MB-453 Solid Breast wt HOMO Not 0.83 42.71 MDA-MB-468 Solid Breast wt HOMO Yes 2.85 60.30 MFM-223 Solid Breast wt HOMO Not 1, 12 22.49 MG-63 Solid Sarcoma wt HOMO Not 0.59 55.53 MIA PaCa-2 Solid Pancreas MUT HOMO Yes 2.56 53.12 MOLT-4 Hematopoietic Hematopoietic wt HOMO Yes 3, 12 65.24 MV–4–11 Hematopoietic Hematopoietic wt HOMO Yes 2.97 74.31 NALM–6 Hematopoietic Hematopoietic wt HOMO Yes 2.95 66.29 NAMALWA Hematopoietic Hematopoietic wt HOMO Yes 4, 32 88.24 NCI-H1734 Solid Lung MUT NO Yes 2, 43 62.45 NCI-H2122 Solid Lung MUT NO Yes 3, 73 71.82 NCI-H2444 Solid Lung MUT HOMO Not -0.45 15.70 NCI-H460 Solid Lung MUT NO Yes 3.52 64.86 NCI-H929 Hematopoietic Hematopoietic wt HOMO Not 1.22 31.23 OCI-LY7 Hematopoietic Hematopoietic NA NA Yes 5.40 99.53 OVCAR-3 Solid Ovary wt HOMO Yes 2, 44 59.46 PANC-1 Solid Pancreas MUT NO Yes 2, 73 60.76 PC-3 Solid Prostate wt HOMO Not 0.27 15.52 PC–9 Solid Lung wt HOMO Yes 3.37 67.08 Raji Hematopoietic Hematopoietic wt HOMO Yes 3, 21 80.38 RL95-2 Solid Endometrial wt HOMO Not 2.38 45.56 RPMI-2650 Solid Head and neck wt HOMO Not 2.34 45.63 RPMI-8226 Hematopoietic Hematopoietic MUT NO Yes 2.94 60.91 SJSA-1 Solid Sarcoma MUT HOMO Not 0.46 36.32 SK-BR-3 Solid Breast NA NA Not 0.98 70.35 SK-ES-1 Solid Sarcoma wt HOMO Not 1.24 33.95 SK-HEP-1 Solid Liver wt HOMO Yes 2.72 60.08 SK-MEL-28 Solid Leather wt HOMO Not -1.15 8.99 SK-N-AC Solid Neuroblastoma wt HOMO Not -0.08 30.60 SK-NEP-1 Solid Bud wt HOMO Not 1.22 36.63 SK-OV-3 Solid Ovary wt HOMO Not 0.60 33.48 SU-DHL-10 Hematopoietic Hematopoietic MUT NO Yes 5, 37 100.83 SU-DHL-4 Hematopoietic Hematopoietic wt HOMO Yes 4, 08 99.94 SU-DHL-6 Hematopoietic Hematopoietic wt HOMO Yes 4, 76 100.72 SUM190PT Solid Breast wt HOMO Yes 2.69 77.18 SUP–B15 Hematopoietic Hematopoietic wt HOMO Yes 4, 21 100.03 SW48 Solid colorectal wt HOMO Not 0.06 11.53 SW480 Solid colorectal MUT HOMO Not 0.90 20.83 SW620 Solid colorectal MUT HOMO Not 2.04 47.00 T.Tn Solid Esophagus NA NA Yes 2.26 65.75 T47D Solid Breast wt HOMO Not 1.41 26.52 TK-71 Solid Sarcoma wt HOMO Yes 4, 23 80.00 U-118-MG Solid Brain wt HOMO Not –0.24 18.15 U–2OS Solid Sarcoma wt HOMO Yes 1.80 55.04 U–87–MG Solid Brain wt HOMO Not 0.82 24.25 ZR-75-30 Solid Breast wt HOMO Not 1.04 23.13

Example 2: Role KRAS in activity

The KRAS allele genotype was then determined for solid tumor lines. Using the COSMIC database, KRAS genotype and zygosity (homozygous or heterozygous) could be determined for 74 of 77 solid tumor cell lines (Table 3).

Table 3. Tumor response rate relative to KRAS genotype

KRAS genotype Number of responses Response Rate (%) Not Yes MUT five nine 65 NA 2 1 33 wt 48 12 20

Only 20% of cell types having the wild-type KRAS allele were sensitive to the test compound. In contrast, among cell types carrying a mutation in the KRAS allele, 65% were sensitive to the test compound. When the analysis extended to determine whether the KRAS allele is homozygous or heterozygous, a distinct split in the results was observed (Table 4). Cell lines carrying a heterozygous mutation in the KRAS allele demonstrated the highest response rate.

Table 4. Tumor response rate relative to KRAS zygosity

Number of responses KRAS MUT Response Rate (%) Not Yes NO 1 7 87.5 HOMO four 2 thirty NA 0 1

For the final analysis of the role of KRAS in the formation of response to the test compound used pooled data based on the area of activity of the compound. All cell line responses were included in the analysis using the Tukey's All Pairs HSD test. The data is presented in Fig. 1 as a plot of area of activity versus KRAS genotype and KRAS zygosity . The average frequency of response to the test compound in cell lines containing the mutant heterozygous KRAS genotype was significantly higher than in the corresponding WT cell lines.

Example 3 Cell Metabolism and Activity

Measurement of glutathione levels after treatment using three cell lines: BJAB, HCT116 and normal human lung fibroblasts (NHLF) was maintained in RPMI (Wisent), McCoy (Wisent) or FGM-2 (Lonza) medium, respectively. To measure total glutathione, 5000 cells/well (BJAB or HCT116) or 10000 cells/well (NHLF) were transferred to 96-well quantitation clear bottom plates (Thermo Fisher) in a volume of 50 μl. The plates were incubated overnight at 37°C in 5% CO ₂ in an unsealed plastic bag with wet paper. The test compound was serially diluted in medium plus 0.4% DMSO and 50 μl/well of each dilution was transferred to a quantitation plate. Quantitation plates were incubated at 37°C in 5% CO ₂ in an unsealed plastic bag with wet paper for the indicated time. To measure total glutathione, the GSH-Glo™ reagent (Promega) was prepared by diluting the provided luciferin-NT (1:100), glutathione-S-transferase (1:100) and DTT (1 mM, final concentration) in GSH- Glo™ and 100 µl were added to quantitation plates followed by a 30-minute incubation at room temperature, and then 100 µl of luciferin reagent was added. The plates were kept in the dark at room temperature for 10 min. Luminescence was measured with a Tecan Infinite 200Pro.

Fig. 2 represents data from a typical experiment demonstrating that the test compound reduced cellular glutathione levels in a dose-dependent manner. Cell lines whose growth and survival were sensitive to the test compound (BJAB and HCT116) showed a dose-dependent decrease in cellular glutathione levels, while cell lines that were not sensitive (NHLF) were not affected.

To assess proliferation (in parallel with the measurement of glutathione levels), 50 μl/well of cells in the medium described above was added to transparent 96-well plates (TPP). At the indicated time, cells were fixed by adding 50 µl of cold 50% trichloroacetic acid (TCA Sigma) and incubated at 4°C for at least 45 minutes before being washed with distilled water. Sulforodamine B 0.4% (w/v) (SRB, Sigma) at a volume of 50 μl/well in 1% acetic acid was added to the wells to determine the total protein content. The plates were washed several times with a large volume of 1% acetic acid to remove excess dye, then the total protein was dissolved in 200 μl of 10 mM unbuffered Tris base, stirring for 30 minutes. Absorbance was measured at 560 nm on a Tecan Infinite 200Pro.

Effect on glutathione levels: BJAB and HCT116 cells were maintained in RPMI medium (Wisent) or McCoy medium (Wisent), respectively. 5000 cells/well were transferred to 96-well assay plates with a transparent bottom (Thermo Fisher) in a volume of 50 µl. The plates were incubated overnight at 37°C in 5% CO ₂ in an unsealed plastic bag with wet paper. Menadione (Sigma) was dissolved in DMSO and diluted in 10% heat-inactivated FBS plus culture medium to 20 μM and 5 μM (0.2% DMSO for each). The culture medium was carefully aspirated from the cells and replaced with diluted menadione 50 μl or 0.2% DMSO as a control. Test compound was diluted to 80 µM (0.2% DMSO) in 10% heat-inactivated FBS plus culture medium, then further diluted to 5 µM, 1 µM, 0.5 µM and 0.05 µM (in 0.2% DMSO). 50 µl of test compound solution was added to each well with or without menadione. One μl of a solution of N-acetylcysteine (Sigma) at a concentration of 100 mM in water was added if indicated. Quantitation plates were incubated for the indicated time at 37°C, 5% CO ₂ in an open plastic bag with wet paper. Total glutathione levels were determined according to the procedure described above.

The inclusion of N-acetylcysteine in the medium prevents the decrease in the level of glutathione caused by menadione. On FIG. 3, top panel, test compound-mediated reduction in glutathione levels in HCT116 cells. There was no difference in glutathione levels in the presence or absence of N-acetylcysteine. Fig. 3, bottom panel, shows menadione-mediated reduction in glutathione levels in HCT116 cells. These data indicate that the test compound reduces cellular glutathione levels in a manner that is different from agents that affect mitochondrial function and induce cellular ROS. Without wishing to be bound by a particular theory, it is believed that because N-acetylcysteine does not restore glutathione levels, it is believed that the defect in glutathione levels in treated cells is caused by an inability to synthesize glutathione after treatment with the test compound.

Example 4 Cell Cycle Analysis of Compound Treated Cells

HCT116 cells (3 × 10 ⁵ cells) grown in McCoy medium supplemented with heat-inactivated fetal bovine serum were plated on 6-well plates and left overnight. Duplicate samples were prepared by treating cells for 24 hours with serum starvation (0% FBS), test compound 5 μM, or vehicle DMSO as a control. Two hours prior to collection, replicating DNA was labeled with EdU (5-ethynyl-2'-deoxyuridine, Thermo Fisher) at 10 μM. Both adherent and floating cells were collected and fixed in a solution of 4% paraformaldehyde in PBS for 15 minutes at room temperature. The cells were then permeabilized in a solution of 0.25% v/v. Triton X-100/0.5% BSA/PBS for 20 minutes at room temperature. This was followed by a short exposure reaction with OG488-azide to detect EdU incorporation as follows: cells were incubated for 30 minutes in a reaction mixture containing 100 mM Tris-HCl, pH 7.6, 4 mM CuSO4, 10 μM OG488-azide and 100 mM ascorbic acid. Excess reagent was removed by repeated washes in 0.5% BSA/PBS wash buffer. Cells were resuspended in 500 μl of DAPI staining solution (1 μg/ml DAPI and 50 μg/ml RNase A in PBS).

Flow cytometry analysis was performed on an LSRII flow cytometer (BD Biosciences) equipped with blue (488 nm), red (633 nm), and violet (405 nm) spectrum lasers. OG488 analysis was performed using 488 nm excitation and detection with a 505LP mirror and a 530/30BP filter. DAPI analysis was performed using 405 nm excitation and detection with a 442/16BP filter. The voltage settings were as follows: FSC=324, SSC=276, OG488=215, DAPI=351. Cell cycle analysis using DAPI was performed using a scale of linear axes. For EdU, a logarithmic scale was used. Data analysis was performed using FCS Express version 6 software (DeNovo Software).

On FIG. 4A shows flow cytometry data obtained from representative cell cycle experiments on HCT116 cells following test compound exposure. The data is presented as a scatter plot of cell labeling data, with each channel gated for detection and quantification. Fig. 4B is a histogram of the data from FIG. 4A as percentage of cells in each phase of the cell cycle. The data clearly demonstrate the effect of serum starvation on cells by arresting the development of cells in the G0/G1 phase. The test compound showed a similar distribution of cells in G1, S and G2/M, suggesting that the test compound arrests cell development in the G0/G1 phase.

It should be understood that the examples and embodiments described herein are for illustrative purposes only, and that various modifications or changes in light of this description will be made to those skilled in the art and should be included within the spirit and scope of this application and scope. the appended claims.

Claims (145)

1. A compound having the structural formula (Ia):

(Ia) optionally in the form of a pharmaceutically acceptable salt, where (a) L¹ selected from the group consisting of bond, S and O, and R¹ choose from C₁-C₈ alkyl and C₁-C₈ alkenyl, each unsubstituted or fluorinated; or (b) L ¹ is a bond and R ¹ is selected from the group consisting of phenyl and monocyclic heteroaryl, each of which is optionally substituted with 1–5 R ^1E , where each R ^1E is independently selected from oxo, optionally substituted C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, halogen, CN, SF ₅ , N ₃ , C(O)R ^1F , SR ^1F , S(O) _{1- 2} R ^1F , OR ^1F , –(OCH ₂ CH ₂ O) _n –R ^1G , where n is 1–4, N(R ^1G )C(O)CH ₂ –O–(CH ₂ CH ₂ O) _n R ^1G, where n is 0–3, C(O)NR ^1G (CH ₂ CH ₂ O) _n R ^1G , NR ^1G R ^1F and C(O)R ^1F ; each R ^1F is independently selected from H, C ₁ -C ₃ alkyl and C ₁ -C ₃ fluoroalkyl, and each R ^1G is independently selected from H and C ₁ -C ₃ alkyl; L ² is selected from the group consisting of bond, -CH ₂ - and -CH(CH ₃ )-; Q is selected from the group consisting of C(O)OH and C(O)OR ^2A where each R ^2A is independently selected from H and C1-C3 alkyl; L ³ is a bond; R ³ is phenyl or monocyclic heteroaryl, each optionally substituted with 1-5 R ^3E , where each R ^3E is independently selected from oxo, optionally substituted C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, halogen, CN, SF ₅ , N ₃ , C(O)R ^3F , SR ^3F , S(O) _{1- 2} R ^3F , OR ^3F , NR ^3G R ^3F , C(O)R ^3F ; each R ^3F is independently selected from H, C ₁ -C ₃ alkyl and C ₁ -C ₃ fluoroalkyl, and each R ^3G is independently selected from H, C ₁ -C ₃ alkyl and C ₁ -C ₃ fluoroalkyl; L ⁴ is a bond; R ⁴ is selected from the group consisting of hydrogen, optionally substituted C ₁ -C ₈ alkyl and optionally substituted C ₁ -C ₈ alkenyl; L ⁵ is a bond; and R ⁵ is phenyl, monocyclic heteroaryl, cycloalkyl, or heterocycloalkyl, each (i) optionally substituted with one substituent selected from -L ^5C - (monocyclic cycloalkyl optionally substituted with 1-5 R ^5D ), -L ^5C - (monocyclic heterocycloalkyl, optionally substituted with 1-5 R ^5D ) and (ii) optionally substituted with 1-5 R ^5E , where each L ^5C is a bond, methylene, C(O), S, S(O) ₁₂ , O or NR ^3G ; each R ^5D is independently selected from oxo, optionally substituted C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, halogen, CN, SF ₅ , N ₃ , C(O)R ^5F , SR ^5F , S(O) _{1- 2} R ^5F , OR ^5F , NR ^5G R ^5F , C(O)R ^5F ; each R ^5E is independently selected from oxo, optionally substituted C ₁ C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, halogen, CN, SF ₅ , N ₃ , C(O)R ^5F , SR ^5F , S(O) _1-2 R ^5F , OR ^5F , NR ^5G R ^5F , C(O)R ^5F ; each R ^5F is independently selected from H, C ₁ -C ₃ alkyl and C ₁ -C ₃ fluoroalkyl, and each R ^5G is independently selected from H, C ₁ -C ₃ alkyl; with the proviso that R ⁵ is cycloalkyl or heterocycloalkyl when L ¹ is selected from the group consisting of bond, S and O, and R ¹ is selected from C ₁ -C ₈ alkyl and C ₁ -C ₈ alkenyl; where each R ⁶ is selected from the group consisting of hydrogen, C ₁ -C ₃ alkyl and -C(O)(C ₁ C ₃ alkyl); each optionally substituted alkyl, alkenyl, and alkynyl is unsubstituted, fluorinated, or substituted with one or two hydroxyl groups; each cycloalkyl has 3-10 ring carbons and is unsaturated or partially unsaturated and optionally includes one or two fused cycloalkyl rings, with each fused ring containing 3-8 ring members; each heterocycloalkyl has 3-10 ring members and 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, is unsaturated or partially unsaturated, and optionally includes one or two fused cycloalkyl rings each having 3-8 ring members; each monocyclic heteroaryl is a 5-6 membered monocyclic heteroaryl ring with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and where the compound is not 1-(4-(cyclohex-1-en-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole 5-carboxylic acid or 1-(4-(cyclopent-1-en-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazol- 5-carboxylic acid. 2. A compound according to claim 1, wherein (a) L ¹ is selected from the group consisting of a bond, S and O, and R ¹ is selected from C ₁ -C ₈ alkyl and C ₁ -C ₈ alkenyl, each unsubstituted or fluorinated. 3. Connection according to any one of paragraphs. 1, 2, characterized in that R ¹ is an unsubstituted C ₁ -C ₈ alkyl or fluorinated C ₁ -C ₈ alkyl. 4. The connection according to any one of paragraphs. 1-3, characterized in that L ¹ represents -S-. 5. A compound according to claim 1, wherein (b) L ¹ is a bond and R ¹ is selected from the group consisting of phenyl and monocyclic heteroaryl, each of which is optionally substituted with 1-5 R ^1E . 6. A compound according to claim 5, characterized in that R ¹ is phenyl optionally substituted with 1-5 R ^1E . 7. Connection according to any one of paragraphs. 1-6, characterized in that L ² is a bond. 8. Connection according to any one of paragraphs. 1–7, characterized in that Q is –C(O)OH. 9. Connection according to any one of paragraphs. 1-7, characterized in that Q is C(O)OR ^2A . 10. Connection according to any one of paragraphs. 1-9, characterized in that R ³ is phenyl optionally substituted with 1-5 R ^3E . 11. The connection according to any one of paragraphs. 1-10, characterized in that R ³ is a monocyclic heteroaryl, optionally substituted with 1-5 R ^3E . 12. Connection according to any one of paragraphs. 1-11, characterized in that R ⁴ is hydrogen or unsubstituted C ₁ -C ₆ alkyl. 13. Connection according to any one of paragraphs. 1 and 5-12, characterized in that R ⁵ is phenyl optionally substituted with 1-5 R ^5E . 14. Connection according to any one of paragraphs. 1 and 5-12, characterized in that R ⁵ is a monocyclic heteroaryl optionally substituted with 1-5 R ^5E . 15. Connection according to any one of paragraphs. 1-12, characterized in that R ⁵ is a heterocycloalkyl optionally substituted with 1-5 R ^5E . 16. Connection according to any one of paragraphs. 1–12, characterized in that R ⁵ is heterocycloalkyl substituted with one substituent –L ^5C– (monocyclic cycloalkyl optionally substituted with 1–5 R ^5D ) and (ii) optionally substituted with 1–5 R ^5E . 17. Connection under item 1, characterized in that L ¹ is -S- or a bond; R ¹ is unsubstituted or fluorinated C ₁ -C ₈ alkyl, unsubstituted or fluorinated C ₁ -C ₈ alkenyl, unsubstituted or fluorinated C ₁ -C ₈ alkynyl or phenyl substituted with 1-5 R ^1E , where each R ^1E is independently selected from oxo, optionally substituted C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, halogen, CN, SF ₅ , N ₃ , C(O)R ^1F , SR ^1F , S(O) ₁₂ R ^1F , OR ^1F , –(OCH ₂ CH ₂ O) _n –R ^1G , where n is 1–4, N(R ^1G )C(O)CH ₂ –O–(CH ₂ CH ₂ O) _n R ^1G , where n is 0–3, C(O)NR ^1G (CH ₂ CH ₂ O) _n R ^1G , NR ^1G R ^1F and C(O)R ^1F ; each R ^1F is independently selected from H, C ₁ -C ₃ alkyl and C ₁ -C ₃ fluoroalkyl, and each R ^1G is independently selected from H and C ₁ -C ₃ alkyl; L ² is a bond or -CH ₂ -; Q is -COOH; R ³ is phenyl optionally substituted with 1-5 R ^3E , R ⁴ is unsubstituted C ₁ -C ₈ alkyl; R ⁵ is phenyl, monocyclic heteroaryl, monocyclic heterocycloalkyl or monocyclic cycloalkyl, each of which is optionally substituted with 1-5 R ^5E , where each cycloalkyl has 3–7 ring carbons and is unsaturated or partially unsaturated; each heterocycloalkyl has 3-7 ring members and 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur and is unsaturated or partially unsaturated; each monocyclic heteroaryl is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. 18. Connection selected from 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-methylcyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid; 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohexen-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazol- 5-carboxylic acid; 1-(4-(4,4-dimethylcyclohex-1-en-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5 – carboxylic acid; 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(1,4-dioxaspiro [4,5]dec-7-en-8-yl)thiazol-2-yl)-3-methyl –1H-pyrazole-5-carboxylic acid; 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(piperidin-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid; 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)piperidin-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid ; 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-morpholinothiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid; 1-(4-(4,4-difluoropiperidin-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid; methyl 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole –5–carboxylate; methyl 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole –5–carboxylate; 4-(3-fluorophenyl)-3-methyl-1-(4-(4-(trifluoromethyl)cyclohexyl)thiazol-2-yl)-1H-pyrazole-5-carboxylic acid; 4-(3-fluorophenyl)-1-(5-isobutyl-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid; 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)thiazol-2-yl)-3-methyl-1H- pyrazole-5-carboxylic acid; 1-(4-(4-cyanopiperidin-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid; 1-(4-(4-cyclopropylpiperazin-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid; 1-(4-(4-ethylpiperazin-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid; 1-(4-(4-acetylpiperazin-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid; 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-methylpiperidin-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid; 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-methylpiperazin-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid; 1-(4-(4,4-dimethylpiperidin-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid; 1–(4–(4–(tert–butoxycarbonyl)piperazin–1–yl)–5–(isopropylthio)thiazol–2–yl)–4–(3–fluorophenyl)–3–methyl–1H–pyrazol–5– carboxylic acid; 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(3-(trifluoromethyl)pyrrolidin-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid ; 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methoxy-1H-pyrazole-5-carboxylic acid; 1-(4,5-bis(4-(trifluoromethyl)phenyl)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid; 2-(4-(3-fluorophenyl)-3-methyl-1H-pyrazol-1-yl)-4,5-bis(4-(trifluoromethyl)phenyl)thiazol-1-(4-(4-(tert- butyl)piperidin-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid; 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(6-azaspiro[2,5]octan-6-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5 – carboxylic acid; 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-methoxy-4-(trifluoromethyl)piperidin-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole 5 – carboxylic acid; 4-(3-fluorophenyl)-1-(4-(4-methoxyphenyl)-5-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid; 1-(4,5-bis(4-methoxyphenyl)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid; 4-(3-fluorophenyl)-1-(5-(4-methoxyphenyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid; 1–(4–(4–(tert-butyl)–3–oxo–1–yl)–5–(isopropylthio)thiazol–2–yl)–4–(3–fluorophenyl)–3–methyl–1H–pyrazole -5-carboxylic acid; 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(2-methoxyethoxy)-4-(trifluoromethyl)piperidin-1-yl)thiazol-2-yl)-3-methyl- 1H-pyrazole-5-carboxylic acid; 4-(3-fluorophenyl)-1-(5-(4-((2-methoxyethyl)carbamoyl)phenyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H- pyrazole-5-carboxylic acid; 4-(3-fluorophenyl)-1-(5-(4-((2-methoxyethyl)(methyl)carbamoyl)phenyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl -1H-pyrazole-5-carboxylic acid; 4-(3-fluorophenyl)-1-(5-(4-(2-methoxyacetamido)phenyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5 – carboxylic acid; 4-(3-fluorophenyl)-1-(5-(4-(2-(2-methoxyethoxy)acetamido)phenyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl- 1H-pyrazole-5-carboxylic acid; 4-(3-fluorophenyl)-1-(5-(4-(2-methoxy-N-methylacetamido)phenyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H -pyrazole-5-carboxylic acid; 4-(3-fluorophenyl)-1-(5-(4-(2-(2-methoxyethoxy)-N-methylacetamido)phenyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3 -methyl-1H-pyrazole-5-carboxylic acid; 4-(3-fluorophenyl)-1-(5-(methoxymethyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid; 1–(5–(4–(2–(2–ethoxyethoxy)ethoxy)phenyl)–4–(4–(trifluoromethyl)phenyl)thiazol–2–yl)–4–(3–fluorophenyl)–3–methyl– 1H-pyrazole-5-carboxylic acid; 4-(3-fluorophenyl)-1-(5-(3-fluorophenyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid; 4-(3-fluorophenyl)-3-methyl-1-(5-(4-(trifluoromethyl)phenyl)-4-(4-(trifluoromethyl)piperidin-1-yl)thiazol-2-yl)-1H-pyrazole -5-carboxylic acid; 4-(3-fluorophenyl)-1-(4-(3-fluorophenyl)-5-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid; 4-(3-fluorophenyl)-1-(5-(4-(2-methoxyethoxy)phenyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5 – carboxylic acid; 4-(3-fluorophenyl)-1-(4-(4-isopropylpiperidin-1-yl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid; as well as 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(3-methoxy-3-(trifluoromethyl)-8-azabicyclo[3.2.1]octan-8-yl)thiazol-2-yl) -3-methyl-1H-pyrazole-5-carboxylic acid, optionally in the form of a pharmaceutically acceptable salt. 19. A method of treating hematopoietic cancer in a subject in need thereof, comprising administering to said subject an effective amount of a compound according to any one of paragraphs. 1–18. 20. The method of claim 19 wherein the compound is 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-methylcyclohexyl-1-en-1-yl)thiazol-2-yl) -3-methyl-1H-pyrazole-5-carboxylic acid, optionally in the form of a pharmaceutically acceptable acid. 21. The method of claim 19, wherein the compound is selected from 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-methylcyclohexyl-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acids; 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazol- 5-carboxylic acid; 1-(4-(4,4-dimethylcyclohex-1-en-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazol-5 - carboxylic acid; 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)piperidin-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid ; 1-(4-(4,4-difluoropiperidin-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid; methyl 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole -5-carboxylate; 4-(3-fluorophenyl)-1-(5-isobutyl-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid; 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-methylpiperidin-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid; and 1-(4-(4,4-dimethylpiperidin-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid, optionally in the form of a pharmaceutically acceptable acid. 22. The method of claim 19, wherein the compound is selected from 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(3-(trifluoromethyl)pyrrolidin-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid ; 1-(4,5-bis(4-(trifluoromethyl)phenyl)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid; 1-(4-(4-(tert-butyl)piperidin-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazol-5- carboxylic acid; 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(6-azaspiro[2.5]octan-6-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acids; 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-methoxy-4-(trifluoromethyl)piperidin-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazol- 5-carboxylic acid; 4-(3-fluorophenyl)-1-(4-(4-methoxyphenyl)-5-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid; 4-(3-fluorophenyl)-1-(5-(4-methoxyphenyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid; 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(2-methoxyethoxy)-4-(trifluoromethyl)piperidin-1-yl)thiazol-2-yl)-3-methyl- 1H-pyrazole-5-carboxylic acid; 1-(5-(4-(2-(2-ethoxyethoxy)ethoxy)phenyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl- 1H-pyrazole-5-carboxylic acid; 4-(3-fluorophenyl)-1-(5-(3-fluorophenyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid; 4-(3-fluorophenyl)-3-methyl-1-(5-(4-(trifluoromethyl)phenyl)-4-(4-(trifluoromethyl)piperidin-1-yl)thiazol-2-yl)-1H-pyrazole -5-carboxylic acid; 4-(3-fluorophenyl)-1-(5-(4-(2-methoxyethoxy)phenyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5 - carboxylic acid; and 4-(3-fluorophenyl)-1-(4-(4-isopropylpiperidin-1-yl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid, optionally in the form of a pharmaceutically acceptable acid.

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