JP2008255123A - Imidazole derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an imidazole derivative, a pharmaceutical composition containing the derivative and to provide a compound for treating a disease and condition with unusual cell proliferation and central nervous system. <P>SOLUTION: The compound indicates to have activity inhibiting cdk5, cdk2, and GSK-3. Pharmaceutical composition and method comprising the compound for treating and preventing disease and condition comprising abnormal cell growth, such as cancer, and neurodegenerative disease and condition and those affected by dopamine neurotransmission. Also described are pharmaceutical compositions comprising a compound for treating male fertility and sperm motility; diabetes mellitus; impaired glucose tolerance; metabolic syndrome or syndrome X; polycystic ovary syndrome; adipogenesis and obesity; myogenesis and frailty, for example, age-related decline in physical performance; acute sarcopenia, for example muscle atrophy and/or cachexia associated with burns, bed rest, limb immobilization, or immunodeficiency. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

Detailed Description of the Invention

FIELD OF THE INVENTION The present invention relates to imidazole derivatives, pharmaceutical compositions comprising such derivatives, and methods of using such derivatives to treat abnormal cell proliferation and certain diseases and conditions of the central nervous system. , Regarding. The compounds of the present invention act as inhibitors of the cyclin-dependent protein kinase enzymes cdk5 (cyclin-dependent protein kinase 5) and cdk2 (cyclin-dependent protein kinase 2). The compounds of the present invention are also inhibitors of the enzyme GSK-3 (glycogen synthase kinase-3) enzyme.

BACKGROUND OF THE INVENTION The serine / threonine kinase cdk5 is associated with neurodegenerative disorders along with its cofactor p25 (or longer cofactor, p35) and hence inhibition of cdk5 / p25 (or cdk5 / p35) The agent is useful in the treatment of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, stroke, Huntington's chorea. The treatment of such neurodegenerative disorders with cdk5 inhibitors is supported by the discovery that cdk5 is involved in tau protein phosphorylation (J. Biochem, 117, 741-749 (1995)). cdk5 also suggests that the 75th phosphorylates threonine dopamine and cyclic AMP-regulated phosphorprotein (DARPP-32) and thus has a role in dopaminergic neurotransmission. (Nature, 402, 669-671 (1999)).

The serine / threonine kinase cdk2 is essential for the normal cell cycle and plays a critical role in disorders caused by the abnormal cell cycle, a common feature of many oncological disorders. Inhibitors of cdk2 are therefore useful in the treatment of various types of cancer and other diseases or conditions associated with abnormal cell proliferation

GSK-3 is a serine / threonine protein kinase. It is one of several protein kinases that phosphorylate glycogen synthase (Embi, et al., Eur. J. Biochem. 107: 519-527 (1980); Hemmings et al., Eur. J. Biochem. 119: 443-451 (1982)). GSK-3 exists in two isoforms, α and β, which have been reported in vertebrates to have monomeric structures of 49 kD and 47 kD, respectively. Both isoforms phosphorylate muscle glycogen synthase (Cross, et al., Biochemical Journal 303: 21-26 (1994)). Amino acid identity between species homologs of GSK-3 has been suggested to be greater than 98% within the catalytic domain (Plyte, et al., Biochim. Biophys. Acta 1114: 147-162 (1992) ). Due to the remarkably high degree of conversion over the phylogenetic range, a fundamental role for GSK-3 in cellular processes has been suggested.

GSK-3 is associated with many different medical conditions and symptoms. For example, Chen, et al, Diabetes 43: 1234-1241 (1994) suggests that increased GSK-3 activity may be important in type 2 diabetes. Increased GSk-3 expression in diabetic muscle is also thought to contribute to impaired glycogen synthase activity and skeletal muscle insulin resistance present in type 2 diabetes (Nikoulina, et al., Diabetes 49: 263-271 (2000)). It was also suggested that the higher activity of type 1 protein phosphatase measured in immobile spermatozoa contributed to higher GSK-3 activity and was more important in maintaining sperm movement at rest. (Vijayaraghaven, et al. Biology of Reproduction 54: 709-718 (1996)). Vijayaraghaven et al. Suggest that such results suggest a biochemical basis for the development and control of sperm motility and a possible physiological role for the protein phosphatase 1 / inhibitor 2 / GSK-3 system. Pointed out. GSK-3 activity is also associated with Alzheimer's disease and mood disorders such as manic depression (WO 97/41854). Among other symptoms, GSK-3 is involved in alopecia, schizophrenia, and neurodegeneration, which are chronic neurodegenerative diseases (eg, Alzheimer's disease as described above) and neurotrauma such as stroke, traumatic Includes brain injury and spinal cord injury.

SUMMARY OF THE INVENTION
(Where R ¹ is linear or branched (C ₁ -C ₈ ) alkyl, linear or branched (C ₂ -C ₈ ) alkenyl, linear or branched (C ₂ -C ₈ ) alkynyl, ( C ₃ -C ₈₎ cycloalkyl, (C ₄ -C ₈₎ cycloalkenyl, (3-8 membered) heterocycloalkyl, (C ₅ -C ₁₁₎ bicycloalkyl, (C ₇ -C ₁₁₎ bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (C ₆ -C ₁₄ ) aryl, or (5-14 membered) heteroaryl; and in which R ¹ is optionally F, Cl, Br, I, nitro, cyano, —CF ₃ , —NR ⁷ R ⁸ , —NR ⁷ C (═O) R ⁸ , —NR ⁷ C (═O) OR ⁸ , —NR ⁷ C (═O) NR ⁸ R ⁹ , —NR ⁷ S (═O) ₂ R ⁸ , —NR ⁷ S (═O) ₂ NR ⁸ R ⁹ , —OR ⁷ , —OC (═O) R ⁷ , —OC (═O) OR ⁷ , —C (═O) OR ⁷ , —C (═O) R ⁷ , —C (═O) NR ⁷ R ⁸ , —OC (═O) NR ⁷ R ⁸ , —OC ( ═O) SR ⁷ , —SR ⁷ , —S (═O) R ⁷ , —S (═O) ₂ R ⁷ , —S (═O) ₂ NR ⁷ R ⁸ , —O—S (═O) ₂ Substituted by 1 to 6 substituents R ⁵ independently selected from R ⁷ , —N ₃ and R ⁷ ; R ² is H, F, CH ₃ , CN, or C (═O) OR ⁷ Yes; R ³ is —C (═O) NR ⁹ —, —C (═O) O—, —C (═O) (CR ¹⁰ R ¹¹ ) _n —, or — (CR ¹⁰ R ¹¹ ) _n —. Yes; R ⁴ is linear or branched (C ₁ -C ₈ ) alkyl, linear or branched (C ₂ -C ₈ ) alkenyl, linear or branched (C ₂ -C ₈ alkynyl), (C ₃ -C ₈₎ cycloalkyl, (C ₄ -C ₈₎ cycloalkenyl, (3-8 membered) Heteroshi Roarukiru, (C ₅ -C ₁₁₎ bicycloalkyl, (C ₇ -C ₁₁₎ bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (5-14 membered) (C ₆ -C ₁₄₎ aryl, or, And in which R ⁴ is optionally F, Cl, Br, I, nitro, cyano, —CF ₃ , —NR ⁷ R ⁸ , —NR ⁷ C (═O) R ⁸ , —NR ^{7 C (= O) OR 8} , -NR 7 C (= O) NR 8 R 9, -NR 7 S (= O) 2 R 8, -NR 7 S (= O) 2 NR 8 R 9, -OR ⁷ , —OC (═O) R ⁷ , —OC (═O) OR ⁷ , —C (═O) OR ⁷ , —C (═O) R ⁷ , —C (═O) NR ⁷ R ⁸ , − ^{OC (= O) NR 7 R} 8, -OC (= O) SR 7, -SR 7, -S (= O) R 7, -S (= O) 2 R 7, -S (= O) 2 NR ⁷ R ^8, or German from R ⁷ Substituted with 1-3 substituents R ⁶ which is selected; R ^7, R ^8, and R ⁹ are each, independently, H, linear or branched (C ₁ -C ₈₎ alkyl, straight chain or branched (C ₂ -C ₈₎ alkenyl, linear or branched (C ₂ -C ₈₎ alkynyl, (C ₃ -C ₈₎ cycloalkyl, (C ₄ -C ₈₎ cycloalkenyl, (3 8-membered) heterocycloalkyl, (C ₅ -C ₁₁₎ bicycloalkyl, (C ₇ -C ₁₁₎ bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (C ₆ -C ₁₄₎ aryl and ( Selected from 5-14 membered heteroaryl, in which R ⁷ , R ⁸ , and R ⁹ are F, Cl, Br, I, —NO ₂ , —CN, —CF ₃ , —NR ¹⁰ R ^{11, -NR 10 C (= O} ) R 11, -NR 10 C (= O) OR 11, -NR 10 C (= O) NR 11 R 12, -N _{^{10 S (= O) 2 R}} 11, -NR 10 S (= O) 2 NR 11 R 12, -OR 10, OC (= O) R 10, -OC (= O) OR 10, -OC (= O ) NR ¹⁰ R ¹¹ , —OC (═O) SR ¹⁰ , —SR ¹⁰ , —S (═O) R ¹⁰ , —S (═O) ₂ R ¹⁰ , —S (═O) ₂ NR ¹⁰ R ¹¹ , 1 to 6 substituents independently selected from —C (═O) R ¹⁰ , —C (═O) OR ¹⁰ , —C (═O) NR ¹⁰ R ¹¹ , and R ^10. Alternatively, when R ⁷ and R ⁸ are NR ⁷ R ⁸ , they are optionally instead of a 3-7 membered ring together with the nitrogen of NR ⁷ R ⁸ to which they are attached. A heterocycloalkyl moiety which may be joined to form a heterocycloalkyl optionally comprising one or more heteroatoms independently selected from N, O, and S; ; R ^10, R ^11, and R ¹² are each, independently, H, linear or branched (C ₁ -C ₈₎ alkyl, linear or branched (C ₂ -C ₈₎ alkenyl, straight chain or branched branch (C ₂ -C ₈₎ alkynyl, (C ₃ -C ₈₎ cycloalkyl, (C ₄ -C ₈₎ cycloalkenyl, (3-8 membered) heterocycloalkyl, (C ₅ -C ₁₁₎ bicycloalkyl , (C ₇ -C ₁₁ ) bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (C ₆ -C ₁₄ ) aryl, and (5-14 membered) heteroaryl, wherein R ¹⁰ , R ¹¹ , and R ¹² are F, Cl, Br, I, —NO ₂ , —CN, —CF ₃ , —NR ¹³ R, respectively.
¹⁴ , —NR ¹³ C (═O) R ¹⁴ , —NR ¹³ C (═O) OR ¹⁴ , —NR ¹³ C (═O) NR ¹⁴ R ¹⁵ , —NR ¹³ S (═O) ₂ R ¹⁴ , − NR ¹³ S (═O) ₂ NR ¹⁴ R ¹⁵ , —OR ¹³ , —OC (═O) R ¹³ , —OC (═O) OR ¹³ , —OC (═O) NR ¹³ R ¹⁴ , —OC (= ^{O) SR 13, -SR 13,} -S (= O) R 13, -S (= O) 2 R 13, -S (= O) 2 NR 13 R 14, -C (= O) R 13, - Independently substituted with 1 to 6 substituents independently selected from C (═O) OR ¹³ , —C (═O) NR ¹³ R ¹⁴ , and R ¹³ ; R ¹³ , R ¹⁴ And R ¹⁵ are each independently H, linear or branched (C ₁ -C ₈ ) alkyl, linear or branched (C ₂ -C ₈ ) alkenyl, linear or branched (C ₂ -C ₈₎ alkynyl, (C ₃ -C ₈₎ cycloalkyl, (C ₄ -C ₈₎ cycloalkenyl, (3-8 membered) heterocycloalkyl, (C ₅ -C ₁₁₎ bicycloalkyl, (C ₇ -C ₁₁₎ bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (C ₆ -C ₁₄₎ aryl, and (is selected from 5-14 membered) heteroaryl, wherein, R ^13, R ^14, and R ¹⁵ are each independently, F, Cl, Br, I , NO 2, - CN, —CF ₃ , —NR ¹⁶ R ¹⁷ , —NR ¹⁶ C (═O) R ¹⁷ , —NR ¹⁶ C (═O) OR ¹⁷ , —NR ¹⁶ C (═O) NR ¹⁷ R ¹⁸ , —NR ¹⁶ S (═O) ₂ R ¹⁷ , —NR ¹⁶ S (═O) ₂ NR ¹⁷ R ¹⁸ , —OR ¹⁶ , —OC (═O) R ¹⁶ , —OC (═O) OR ¹⁶ , —OC (═O ) NR ¹⁶ R ¹⁷ , —OC (═O) SR ¹⁶ , —SR ¹⁶ , —S (═O) R ¹⁶ , —S (═O) ₂ R ¹⁶ , —S (═O) ₂ NR 1 to 6 substituents independently selected from ¹⁶ R ¹⁷ , —C (═O) R ¹⁶ , —C (═O) OR ¹⁶ , —C (═O) NR ¹⁶ R ¹⁷ , and R ^16. R ¹⁶ , R ¹⁷ , and R ¹⁸ are each independently H, linear or branched (C ₁ -C ₈ ) alkyl, linear or branched (C ₂ -C ₈ ) alkenyl. , linear or branched (C ₂ -C ₈ alkynyl), (C ₃ -C ₈₎ cycloalkyl, (C ₄ -C ₈₎ cycloalkenyl, (3-8 membered) heterocycloalkyl, (C ₅ - Selected from C ₁₁ ) bicycloalkyl, (C ₇ -C ₁₁ ) bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (C ₆ -C ₁₄ ) aryl, and (5-14 membered) heteroaryl; n is 0, 1, 2 or 3; where -C (= O) (CR ¹⁰ R ¹¹ ) _n- and-(CR ¹⁰ R ¹¹ ) _n- Each of R ¹⁰ and R ¹¹ is a repeat of n, independently defined as listed above, and pharmaceutically acceptable salts thereof.

The compounds of formula 1 of the present invention are inhibitors of serine / threonine kinases, especially cyclin dependent kinases such as cdk5 and cdk2, and treatment of neurodegenerative disorders and other CNS disorders, as well as abnormal cell proliferation such as cancer. Useful for. The compounds of formula 1 are particularly useful for inhibiting cdk5. The compounds of formula 1 are also useful as inhibitors of GSK-3.

The term “alkyl”, as used herein, unless otherwise specified, includes saturated monovalent hydrocarbon radicals having straight or branched moieties. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, and t-butyl.

The term “alkenyl”, as used herein, unless otherwise stated, includes an alkyl moiety as defined above having at least one carbon-carbon double bond. Examples of alkenyl include, but are not limited to, ethenyl and propenyl.

The term “alkynyl”, as used herein, unless otherwise stated, includes an alkyl moiety as defined above having at least one carbon-carbon triple bond. Examples of alkynyl groups include, but are not limited to ethynyl and 2-propynyl.

The term “cycloalkyl”, as used herein, unless otherwise stated, includes saturated aromatic alkyl that is not aromatic, where alkyl is as defined above. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. A “bicycloalkyl” group is a saturated carbocyclic group consisting of two rings sharing one or two carbon atoms, which is not an aromatic ring. For the purposes of the present invention and unless otherwise specified, bicycloalkyl groups include spiro groups and fused ring groups. Examples of bicycloalkyl groups include, but are not limited to, bicyclo- [3.1.0] -hexyl, norbornyl, spiro [4.5] decyl, spiro [4.4] nonyl, spiro [4.3] octyl, and spiro [4.2] heptyl. “Cycloalkenyl” and “bicycloalkenyl” refer to non-aromatic, carbocyclic cycloalkyl and bicycloalkyl moieties as defined above, provided that 1 connects the carbocyclic members. Or a plurality of carbon-carbon double bonds (“intra-ring” double bonds) and / or carbon-carbon double bonds (“extra-ring” double bonds) that connect carbon other than the ring adjacent to the carbon ring member. Comprising. Examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl and cyclobutenyl, and a non-limiting example of a bicycloalkenyl group is norbornenyl. Cycloalkyl, cycloalkenyl, bicycloalkyl, and bicycloalkenyl groups also include groups that are substituted with one or more oxo moieties. Examples of such groups having an oxo moiety are oxocyclopentyl, oxocyclobutyl, oxocyclopentenyl, and norcamphoryl.

The term “aryl”, as used herein, unless otherwise stated, includes organic radicals derived from aromatic hydrocarbons by removal of one hydrogen, such as phenyl, naphthyl, indenyl, and fluorenyl.

The terms “heterocycle”, “heterocycloalkyl” and the like as used herein are any one selected from one or more heteroatoms, preferably 1 to 4, O, S and N Non-aromatic ring groups containing the heteroatoms of A “heterobicycloalkyl” group is a ring group with two non-aromatic rings, wherein the rings share one or two atoms and at least one of the rings is a heteroatom (O, S and N) Is included. For the purposes of the present invention and unless otherwise specified, heterobicycloalkyl groups include spiro groups and fused ring groups. In one embodiment, each ring of heterobicycloalkyl contains up to 4 heteroatoms (ie 0 to 4 heteroatoms, provided that at least one ring contains at least one heteroatom). The heterocyclic groups of this invention may also include ring systems substituted with one or more oxo moieties. Examples of non-aromatic heterocyclic groups are aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepinyl, piperazinyl, 1,2,3,6-tetrahydropyridinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydro Thiopyranyl, morpholino, thiomorpholino, thioxanyl, pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo [3.1.0] hexanyl, 3-azabicyclo [4.1.0] heptanyl, quinolizinyl, quinuclidinyl, 1,4-dioxaspiro [4.5] decyl, 1,4-dioxaspiro [4.4] nonyl, 1,4-dioxaspiro [ 4.3] Corruptible, and 1,4-dioxaspiro [4.2] heptyl.

“Heteroaryl” as used herein refers to an aromatic group containing one or more heteroatoms (O, S and N), preferably 1 to 4 heteroatoms. A polycyclic group containing one or more heteroatoms wherein at least one ring of the group is aromatic is a “heteroaryl” group. The heteroaryl groups of this invention may also contain ring systems substituted with one or more oxo moieties. Examples of heteroaryl groups are pyridinyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzfuranyl, benzfuranyl, Indazolyl, indolizinyl, phthalazinyl, triazinyl, isoindolyl, purinyl, oxadiazolyl, thiadiazolyl, furanyl, benzofurazanyl, benzothiophenyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, dihydroquinolyl, tetrahydroquinolyl, Dihydroisoquinolyl, tetrahydroisoquinolyl, ben Furyl, furopyridinyl, pyrolopyrimidinyl, and azaindolyl.

Such groups as derived from the compounds listed above may be C-bonded or N-bonded where possible. For example, a group derived from pyrrole may be pyrrol-1-yl (N-bonded) or pyrrol-3-yl (C-bonded). The term referring to the group also encompasses all possible tautomers.

In one embodiment, the present invention provides a compound of formula 1 wherein R ³ is C (═O) NR ⁹ — or —C (═O) (CR ¹⁰ R ¹¹ ) _n —. . In another embodiment, R ¹⁰ and R ¹¹ of —C (═O) (CR ¹⁰ R ¹¹ ) _n — are both hydrogen, each repeated n times. In another embodiment, R ⁹ of —C (═O) NR ⁹ — is hydrogen. In another embodiment, R ³ is —C (═O) NR ⁹ — or —C (═O) (CR ¹⁰ R ¹¹ ) _n —, and R ² is hydrogen.

In another embodiment of the present invention, the compound of formula 1 is R ¹ is optionally substituted (C ₃ -C ₈ ) cycloalkyl, or optionally substituted (C ₅ -C ₁₁ ) bicycloalkyl. Some are offered. In a preferred embodiment, R ¹ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or norbornyl, each as listed above (ie, F, Cl, Br, I, nitro, cyano, —CF ₃ , — NR ⁷ R ⁸ , —NR ⁷ C (═O) R ⁸ , —NR ⁷ C (═O) OR ⁸ , —NR ⁷ C (═O) NR ⁸ R ⁹ , —NR ⁷ S (═O) ₂ R
⁸ , —NR ⁷ S (═O) ₂ NR ⁸ R ⁹ , —OR ⁷ , —OC (═O) R ⁷ , —OC (═O) OR ⁷ , —C (═O) OR ⁷ , —C ( ^{= O) R 7, -C (} = O) NR 7 R 8, -OC (= O) NR 7 R 8, -OC (= O) SR 7, -SR 7, -S (= O) R 7, Optionally substituted with 1-6 substituents R ⁵ independently selected from —S (═O) ₂ R ⁷ , —S (═O) ₂ NR ⁷ R ⁸ , and R ⁷ . Is. In a more preferred embodiment, R ¹ is (C ₃ -C ₈ ) cycloalkyl or optionally substituted (C ₅ -C ₁₁ ) bicycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or norbornyl, and F , Cl, Br, I, nitro, _{^{cyano, -CF 3, -NR 7 R 8}} , -NR 7 C (= O) R 8, -OR 7, -C (= O) OR 7, -C (= O ) R ^7, and is optionally substituted with 1-3 substituents independently selected from R ^7. More preferably, R ¹ is (C ₃ -C ₈ ) cycloalkyl or optionally substituted (C ₅ -C ₁₁ ) bicycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or norbornyl, and R ¹ Is substituted with —NR ⁷ C (═O) R ⁸ , (C ₆ -C ₁₄ ) aryl, (3 to 8 membered) heterocycloalkyl, or (5 to 14 membered) heteroaryl, wherein Aryl, heterocycloalkyl, and heteroaryl are F, Cl, Br, I, NO ₂ , —CN, —CF ₃ , —NR ¹⁰ R ¹¹ , —NR ¹⁰ C (═O) R ¹¹ , —NR ¹⁰ C ( ^{= O) OR 11, -NR 10} C (= O) NR 11 R 12, -NR 10 S (= O) 2 R 11, -NR 10 S (= O) 2 NR 11 R 12, -OR 10, - ^{OC (= O) R 10,} -OC (= O) OR 10, -O ^{(= O) NR 10 R 11} , -OC (= O) SR 10, -SR 10, -S (= O) R 10, -S (= O) 2 R 10, -S (= O) 2 NR 10 1 to 6 substituents independently selected from R ¹¹ , —C (═O) R ¹⁰ , —C (═O) OR ¹⁰ , —C (═O) NR ¹⁰ R ¹¹ , and R ^10. Each is optionally substituted. In another embodiment of the present invention R ¹ is bicyclo [3.1.0] -hexyl and is optionally substituted as listed above (ie F, Cl, Br, I, nitro, cyano , —CF ₃ , —NR ⁷ R ⁸ , —NR ⁷ C (═O) R ⁸ , —NR ⁷ C (═O) OR ⁸ , —NR ⁷ C (═O) NR ⁸ R ⁹ , —NR ⁷ S ^{_{(= O) 2 R 8,}} -NR 7 S (= O) 2 NR 8 R 9, -OR 7, -OC (= O) R 7, -OC (= O) OR 7, -C (= O) ^{OR 7, -C (= O)} R 7, -C (= O) NR 7 R 8, -OC (= O) NR 7 R 8, -OC (= O) SR 7, -SR 7, -S ( ═O) R ⁷ , —S (═O) ₂ R ⁷ , —S (═O) ₂ NR ⁷ R ⁸ , and optionally substituted with 1 to 6 substituents independently selected from R ⁷ )

In another embodiment of the present invention, the compound of Formula 1 is a linear or branched (C ₁ -C ₈ ) alkyl optionally substituted with R ¹ , or an optionally substituted linear or branched (C _2). What is —C ₈ ) alkenyl is provided.

In another aspect of the invention, compounds of formula 1 are provided wherein R ² is not hydrogen. In a further embodiment, R ² is hydrogen and R ¹ is as partially limited in the previous section.

In another aspect, the present invention provides an R ⁴ is (C ₆ -C ₁₄₎ aryl or (5-14 membered) heteroaryl, each provides compounds of Formula 1, which is optionally substituted. In a preferred embodiment, R ⁴ is optionally substituted phenyl or optionally substituted pyridyl. In another preferred embodiment, R ⁴ is naphthyl, quinolyl, or isoquinolyl, each optionally substituted. In another embodiment, R ⁴ is naphthyl, quinolyl, or isoquinolyl and is not substituted.

In another embodiment, compounds of Formula 1 are provided such that R ² is specifically hydrogen and R ⁴ is partially limited in the previous section.

Examples of preferred compounds of formula 1 are: N- (1-cyclobutyl-1H-imidazol-4-yl) -2-quinolin-6-yl-acetamide; N- (1-cyclopentyl-1H-imidazol-4-yl) 2- (4-methoxy-phenyl) -acetamide; N- [1- (cis-3-phenyl-cyclobutyl) -1H-imidazol-4-yl] -2-quinolin-6-yl-acetamide; Cyclobutyl-1H-imidazol-4-yl) -carbamic acid phenyl ester; 1- (1-cyclobutyl-1H-imidazol-4-yl) -3-isoquinolin-5-yl-urea; N- [1- (cis- 3-amino-cyclobutyl) -1H-imidazol-4-yl] -2-naphthalen-1-yl-acetamide; 6-methyl-pyri 2-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide; 1H-imidazole-4-carboxylic acid {cis- 3- [4- (2-Naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide; 6-hydroxy-pyridine-2-carboxylic acid {cis-3- [4- (2 -Naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide; 3-methyl-pyridine-2-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-) Acetylamino) -imidazol-1-yl] -cyclobutyl} -amide; 2-pyridin-3-yl-thiazole-4-carboxylic acid {cis-3- [4 (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide; 6- {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazole- 1-yl] -cyclobutylcarbamoyl} -nicotinic acid methyl ester; pyrazine-2-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl } -Amide; N- {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -benzamide; 5-methyl-pyrazine-2-carboxylic acid { cis-3- [4- (2-Naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amino N- {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -isobutyramide; 6-chloro-pyridine-2-carboxylic acid {cis -3- [4- (2-Naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide; quinoline-2-carboxylic acid {cis-3- [4- (2-naphthalene- 1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide; 1H-pyrrole-2-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazole -1-yl] -cyclobutyl} -amide; N- {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazole-1- Yl] -cyclobutyl} -2-m-tolyl-acetamide; pyridine-2-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -Amide; 2- (3-hydroxy-phenyl) -N- {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -acetamide; piperidine- 4-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide hydrochloride; N- [1- (cis-3-acetyl Amino-cyclobutyl) -1H-imidazol-4-yl] -2-naphthalen-2-yl-acetamide; N- {cis-3- [4- (2- Isoquinolin-5-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -benzamide; and pyridine-2-carboxylic acid {cis-3- [4- (2-isoquinolin-5-yl-acetylamino)- Imidazol-1-yl] -cyclobutyl} -amide; and pharmaceutically acceptable salts of said compounds.

Examples of other specific compounds of the invention of formula 1 are: cis-N- (1-bicyclo [3.1.0] hex-3-yl-1H-imidazol-4-yl) -2-quinoline- 6-yl-acetamide; cis-N- {1- [trans-6- (pyridin-2-carbonyl) -bicyclo [3.1.0] hex-3-yl] -1H-imidazol-4-yl}- 2-quinolin-6-yl-acetamide; N- {1- [cis-3- (2-methoxy-phenyl) -cyclobutyl] -1H-imidazol-4-yl} -2-quinolin-6-yl-acetamide; N- {1- [cis-3- (2-fluoro-phenyl) -cyclobutyl] -1H-imidazol-4-yl} -2-quinolin-6-yl-acetamide; N- {1- [cis-3- (4-methoxy -Phenyl) -cyclobutyl] -1H-imidazol-4-yl} -2-quinolin-6-yl-acetamide; 2-quinolin-6-yl-N- [1- (cis-3-p-tolyl-cyclobutyl) -1H-imidazol-4-yl] -acetamide; N- {1- [cis-3- (2-ethoxy-phenyl) -cyclobutyl] -1H-imidazol-4-yl} -2-quinolin-6-yl- N- {1- [cis-3- (3-methoxy-phenyl) -cyclobutyl] -1H-imidazol-4-yl} -2-quinolin-6-yl-acetamide; and a pharmaceutically acceptable compound of said compound Salt.

Other examples of specific compounds of formula 1 are: N- {1- [3- (2-hydroxy-phenyl) -cyclobutyl] -1H-imidazol-4-yl} -2- (4-methoxy-phenyl) N- {1- [3- (3-hydroxy-phenyl) -cyclobutyl] -1H-imidazol-4-yl} -2- (4-methoxy-phenyl) -acetamide; N- {1- [3 -(2-amino-phenyl) -cyclobutyl] -1H-imidazol-4-yl} -2- (4-methoxy-phenyl) -acetamide; N- {1- [3- (3-amino-phenyl) -cyclobutyl ] -1H-imidazol-4-yl} -2- (4-methoxy-phenyl) -acetamide; N- {1- [3- (3-aminomethyl-phenyl) -cyclobutyl] -1H-imidazo R-4-yl} -2- (4-methoxy-phenyl) -acetamide; N- {1- [3- (3-dimethylaminomethyl-phenyl) -cyclobutyl] -1H-imidazol-4-yl} -2 -(4-methoxy-phenyl) -acetamide; and 2- (4-methoxy-phenyl) -N- {1- [3- (1-methyl-1H-pyrazol-3-yl) -cyclobutyl] -1H-imidazole -4-yl} -acetamide; and pharmaceutically acceptable salts of said compounds.

A salt of the compound of formula 1 can be obtained by forming a salt with any acidic or basic group present on the compound of formula 1. Examples of pharmaceutically acceptable salts of the compound of formula 1 are hydrochloric acid, p-toluenesulfonic acid, fumaric acid, citric acid, succinic acid, salicylic acid, oxalic acid, hydrobromic acid, phosphoric acid, methanesulfonic acid, tartaric acid , Maleic acid, di-p-toluoyl tartaric acid, acetic acid, sulfuric acid, hydroiodic acid, mandelic acid, sodium, potassium, magnesium, calcium, and lithium salts.

Compounds of formula 1 may have optical centers and therefore may occur in different enantiomers and other stereoisomeric configurations. The present invention includes all enantiomers, diastereomers, and other stereoisomers of such compounds of Formula 1, as well as racemic pairs and other mixtures thereof.

The present invention is also identical to those listed in Formula 1 except for the fact that one or more atoms are replaced by atoms having an atomic weight or mass number different from the atomic weight or mass number normally found in nature. Of isotopically labeled compounds. Examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, iodine, and chlorine, such as ³ H, ¹¹ C, ¹⁴ C, ¹⁸ F, ¹²³ I and Including ¹²⁵ I. Compounds of the present invention and pharmaceutically acceptable salts of said compounds that contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present invention. Isotopically labeled compounds of the present invention, such as those incorporating radioactive isotopes, such as ³ H and ¹⁴ C, are useful in drug and / or substrate tissue distribution assays. Tritiated, ie ³ H, and carbon-14, ie ¹⁴ C, isotopes are particularly preferred for their ease of preparation and detectability. ¹¹ C and ¹⁸ F isotopes are particularly useful in PET (position emission tomography), and ¹²⁵ I isotopes are particularly useful in SPECT (single photon emission computed tomography), all for brain imaging Useful. Furthermore, substitution with heavier isotopes, such as deuterium, i.e. ² H, may result in some therapeutic stability due to greater metabolic stability, e.g. increased in vivo stability or decreased dosage required. Can be beneficial and may be preferred in some circumstances. The isotope-labeled compounds of Formula 1 of the present invention can be performed according to the procedures disclosed in the schemes and / or examples below by replacing non-isotopically labeled reagents with readily available isotope-labeled reagents. Usually can be prepared.

The invention also provides a pharmaceutical composition for treating a disease or condition comprising abnormal cell growth in a mammal, wherein the compound is of an amount effective to inhibit abnormal cell growth, and A pharmaceutical composition comprising a pharmaceutically acceptable carrier is provided.

The present invention also provides a pharmaceutical composition for treating a disease or condition comprising abnormal cell proliferation in a mammal, wherein the compound is of an amount effective to inhibit cdk2 activity, and a medicament. Pharmaceutical compositions comprising an acceptable carrier are provided.

The present invention also provides a method for treating a disease or condition comprising abnormal cell growth in a mammal, wherein the mammal is administered an amount of a compound of Formula 1 effective to inhibit the abnormal cell growth. There is provided a method comprising:

The present invention is also a method for treating a disease or condition comprising abnormal cell proliferation in a mammal, comprising administering to the mammal an amount of a compound of formula 1 effective to inhibit cdk2 activity. A method comprising the steps of:

In the pharmaceutical composition or method of the invention for treating a disease or condition comprising abnormal cell growth, the disease or condition comprising abnormal cell growth is in one embodiment cancer. Cancers are malignant tumors such as bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lungs such as small cell lung cancer, esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid cancer, Prostate cancer, or skin cancer, eg squamous cell carcinoma; lymphoid hematopoietic tumors, eg leukemia, acute lymphocytic leukemia, B cell lymphoma, T cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hair cell Lymphoma, or Burquett lymphoma; hematopoietic cell tumors of myeloid lineage, such as acute and chronic myeloid leukemia, myelodysplastic syndrome, or promyelocytic leukemia; tumors derived from mesenchymal, such as fibrosarcoma or lateral Rhabdomyosarcoma; tumors of the central or peripheral nervous system, such as astrocytoma, neuroblastoma, glial or schwannoma; melanoma; seminoma; teratocarcinoma; osteosarcoma; color Sexually xerosis; keratoacanthoma; may be, or Kaposi's sarcoma; thyroid follicular cancer.

In another embodiment, the disease or condition comprising abnormal cell proliferation is benign. Such diseases and symptoms include benign prostatic hypertrophy, familial adenomatous polyposis, neurofibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis, hypertrophic scar formation, Inflammatory bowel disease, graft rejection, bacterial infection, and endotoxic shock.

The present invention also provides a pharmaceutical composition for treating a neurodegenerative disease or condition in a mammal, in an amount effective to treat said disease or condition, and a pharmaceutically acceptable carrier. A pharmaceutical composition is provided.

The present invention also provides a pharmaceutical composition for treating a neurodegenerative disease or condition in a mammal, comprising an amount of a compound of Formula 1 effective to inhibit cdk5 activity, and a pharmaceutically acceptable carrier. A pharmaceutical composition is provided.

The present invention also includes a method for treating a neurodegenerative disease or condition in a mammal, comprising administering to the mammal an amount of a compound of Formula 1 effective to inhibit cdk5 activity. provide.

The present invention also provides a method for treating a neurodegenerative disease or condition in a mammal comprising administering to the mammal an amount of a compound of Formula 1 effective to treat said disease or condition. Provide a method.

In one embodiment of the invention, the neurodegenerative disease or condition being treated is Huntington's disease, stroke, spinal cord injury, traumatic brain injury, multiple cerebral infarction dementia, epilepsy, amyotrophic lateral sclerosis, pain Virus-induced dementia such as AIDS-induced dementia, neurodegeneration associated with bacterial infection, migraine, hypoglycemia, urinary incontinence, cerebral ischemia, multiple sclerosis, Alzheimer's disease, Alzheimer's type senile dementia, Mild cognitive impairment, age-related cognitive decline, vomiting, cortical basal ganglia degeneration, fighting dementia, Down's syndrome, muscular dystrophy, Niemann-Pick disease, Pick's disease, prion disease with confusion, progressive supranuclear palsy, Selected from inferior lateral sclerosis and subacute sclerosing panencephalitis.

The present invention is also a pharmaceutical composition for treatment of a disease or condition, which can be achieved or facilitated by altering dopamine-mediated neurotransmission in a mammal, which treats the disease or condition. There is provided a pharmaceutical composition comprising an effective amount of a cdk5 inhibitor and a pharmaceutically acceptable carrier.

The present invention is also a pharmaceutical composition for treatment of a disease or condition that can be achieved or facilitated by altering dopamine-mediated neurotransmission in a mammal, which inhibits cdk5 activity. A pharmaceutical composition comprising an effective amount of a cdk5 inhibitor and a pharmaceutically acceptable carrier.

The present invention is also a method for treatment of a disease or condition that can be achieved or facilitated by altering dopamine-mediated neurotransmission in a mammal, effective for inhibiting cdk5 activity. There is provided a method comprising administering to a mammal an amount of a cdk5 inhibitor.

The present invention is also a method for treatment of a disease or condition that can be achieved or facilitated by altering dopamine-mediated neurotransmission in a mammal, wherein the method treats the disease or condition. A method comprising administering to a mammal an effective amount of a cdk5 inhibitor.

In one embodiment of the invention, the disease or condition that treatment can be achieved or facilitated by altering dopamine-mediated neurotransmission is Parkinson's disease; schizophrenia; schizophrenia-like disorder, eg, paranoid or depressed Paranoid disorders; substance-induced psychotic disorders such as psychosis induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhaled antigens, opioids, or phencyclidine; paranoid personality disorder; schizophrenic Personality disorder; drug addiction such as narcotics (eg heroin, opium and morphine), cocaine and alcohol dependence; drug withdrawal symptoms such as narcotic, cocaine and alcohol withdrawal symptoms; obsessive compulsive disorder; Tourette syndrome; depression Major depressive episodes, manic or mixed mood episodes, hypomania mood episodes Depressive, abnormal features, or depression with depressive or tonic features, mood episodes after the start of labor; depression after stroke, major depressive disorder, mood dysthymic disorder, mild depressive disorder, menstruation Pre-discomfort mood disorder, depressive disorder after psychosis of schizophrenia, mental disorders such as paranoid disorder or major depressive disorder overlapping with schizophrenia, bipolar disorder such as type I bipolar disorder, type II bipolar Selected from disorder, circulatory disorder; anxiety; attention deficit and hyperactivity disorder; and attention deficit disorder.

In another embodiment, a cdk5 inhibitor in a method or composition for treating a disease or condition that can be achieved or facilitated by altering dopamine-mediated neurotransmission is a compound of formula 1 or a pharmaceutically acceptable Is its salt.

The present invention also provides a pharmaceutical composition for the treatment of a disease or condition facilitated by cdk5 activity in a mammal, in an amount effective to inhibit cdk5 activity and a pharmaceutically acceptable carrier. A composition comprising: is provided.

The present invention is also a method for the treatment of a disease or condition facilitated by cdk5 activity in a mammal, comprising administering to the mammal an amount of a compound of Formula 1 effective to inhibit cdk5 activity. A method comprising:

We have also discovered that the compound of formula 1 has activity to inhibit GSK-3. Therefore, compounds of formula 1 can be expected to be useful in treating diseases or conditions where treatment can be achieved or facilitated by inhibition of GSK-3. Diseases or conditions for which treatment can be achieved or facilitated by inhibition of GSK-3 include diseases and conditions of neurodegeneration. Neurodegenerative diseases and symptoms are discussed above, and include, but are not limited to, for example, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, stroke, cerebral ischemia, Includes AIDS-related dementia, neurodegeneration associated with bacterial infection, multiple cerebral infarction dementia, traumatic brain injury, and spinal cord injury. Thus, the compounds of formula 1 are effective in treating neurodegenerative diseases and conditions based on both cdk5 activity and GSK-3 activity.

Other diseases and conditions that can be achieved or facilitated by inhibiting GSK-3 are psychiatric disorders and symptoms such as schizophrenia; schizophrenia-like disorders such as those of paranoid or depression type; Delusional disorders; substance-induced psychotic disorders such as psychosis induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhaled antigens, opioids, or phencyclidine; delusional personality disorder; and schizophrenic personality disorder including. Treatment of such diseases and conditions can also be achieved or facilitated by altering dopamine-mediated neurotransmission. Thus, the compounds of formula 1 are effective in treating such diseases and conditions based on both cdk5 activity and GSK-3 activity.

Other disorders and symptoms that can be achieved or facilitated by inhibiting GSK-3 are mood disorders and mood episodes, such as major depressive episodes, mania or mixed mood episodes, hypomania mood episodes Depression with abnormal characteristics, or depressed or tonic characteristics, mood episodes after the start of labor; depression after stroke, major depressive disorder, mood modulation disorder, mild depressive disorder, premenstrual Discomfort disorder, depressive disorder after psychosis in schizophrenia, mental disorders such as paranoid disorder or major depressive disorder overlapping with schizophrenia, bipolar disorder such as type I bipolar disorder, type II bipolar disorder And including circulatory disorders. Treatment of such mood disorders and episodes, such as depression, can also be achieved or facilitated by altering dopamine-mediated neurotransmission. Thus, compounds of formula 1 are effective in the treatment of certain mood disorders and episodes based on both cdk5 activity and GSK-3 activity.

Other disorders and symptoms that can be achieved or facilitated by inhibiting GSK-3 are: male fertility and sperm motility; diabetes mellitus; impaired glucose tolerance; metabolic syndrome or X syndrome; Cystic ovary syndrome; lipogenesis and obesity; myogenesis and brittleness, eg age-related decline in physical ability; acute sarcopenia, eg muscle atrophy and / or sunburn-related cachexia, bed rest, limbs Or general chest, abdominal, and / or orthopedic surgery; sepsis; spinal cord injury; hair loss, hair thinning and balding; immune deficiency; and cancer.

Thus, the present invention also includes male fertility and sperm motility; diabetes mellitus; glucose intolerance; metabolic syndrome or X syndrome; polycystic ovary syndrome; lipogenesis and obesity; Formation and fragility, eg age-related decline in physical ability; acute sarcopenia, eg muscle atrophy and / or sunburn-related cachexia, bed rest, limb fixation, or overall chest, abdomen And / or orthopedic surgery; sepsis; hair loss, hair thinning and balding; and a pharmaceutical composition for treating a disease or condition selected from immune deficiency, comprising: As an acceptable carrier and a composition comprising an amount of a compound of Formula 1 effective to treat said disease or condition.

The invention further includes male fertility and sperm motility; diabetes mellitus; impaired glucose tolerance; metabolic syndrome or syndrome X; polycystic ovary syndrome; lipogenesis and obesity; Fragility, eg age-related decline in physical ability; acute sarcopenia, eg muscle atrophy and / or sunburn related cachexia, bed rest, limb fixation, or overall chest, abdomen, and A pharmaceutical composition for treating a disease or symptom selected from septicemia; sepsis; hair loss, hair thinning and balding; and immune deficiency, pharmaceutically acceptable And a composition comprising an effective amount of a compound of Formula 1 to inhibit GSK-3.

The present invention also includes male fertility and sperm motility; diabetes mellitus; impaired glucose tolerance; metabolic syndrome or syndrome X; polycystic ovary syndrome; lipogenesis and obesity; Fragility, eg age-related decline in physical ability; acute sarcopenia, eg muscle atrophy and / or sunburn related cachexia, bed rest, limb fixation, or overall chest, abdomen, and A method for treating a disease or symptom selected from sepsis; hair loss, hair thinning and balding; and immune deficiency, comprising: There is provided a method comprising administering to the mammal an amount of a compound of Formula 1 effective to treat.

The present invention also includes male fertility and sperm motility; diabetes mellitus; impaired glucose tolerance; metabolic syndrome or syndrome X; polycystic ovary syndrome; lipogenesis and obesity; Fragility, eg age-related decline in physical ability; acute sarcopenia, eg muscle atrophy and / or sunburn related cachexia, bed rest, limb fixation, or overall chest, abdomen, and A method for treating a disease or symptom selected from sepsis; hair loss, hair thinning, and balding; and immune deficiency, which inhibits GSK-3 There is provided a method comprising administering to the mammal an effective amount of a compound of Formula 1.

The present invention is further a method for inhibiting GSK-3 in mammals, including humans, comprising administering to said mammal an amount of a compound of formula 1 effective to inhibit GSK-3. Provide a method.

The present invention further provides a pharmaceutical composition for treating a disorder selected from Alzheimer's disease, mild cognitive impairment, and age-related cognitive decline in a mammal, effective for treating said disorder. Provided is a composition comprising a cdk5 inhibitor and a COX-II inhibitor together in a sufficient amount and a pharmaceutically acceptable carrier. In one embodiment, the cdk5 inhibitor is a compound of Formula 1 or a pharmaceutically acceptable salt thereof.

The present invention also provides a method for treating a disorder selected from Alzheimer's disease, mild cognitive impairment, and age-related cognitive decline in a mammal comprising a cdk5 inhibitor and a COX-II inhibitor. Providing a method comprising administering to said mammal, wherein the combined amount of a cdk5 inhibitor and a COX-II inhibitor is effective to treat said disorder. In one embodiment, the cdk5 inhibitor is a compound of Formula 1 or a pharmaceutically acceptable salt thereof. The cdk5 inhibitor and the COX-II inhibitor can be administered to the mammal at the same time and / or at different times. Furthermore, they can be administered together in a single pharmaceutical composition or in separate pharmaceutical compositions.

Furthermore, a cdk-5 inhibitor, for example a compound of formula 1 according to the invention, or a pharmaceutically acceptable salt of a compound of formula 1, may be administered for the treatment or prevention of depression and / or anxiety. Or may be prepared into a pharmaceutical composition together with one or more antidepressants or anxiolytic compounds.

Accordingly, the present invention also provides a pharmaceutical composition for treating depression or anxiety in mammals, comprising an amount of a cdk5 inhibitor and an NK-1 receptor antagonist effective to treat depression or anxiety. A composition comprising the carrier and a pharmaceutically acceptable carrier is provided. In one embodiment, the cdk5 inhibitor is a compound of Formula 1 or a pharmaceutically acceptable salt thereof.

The present invention further provides a method for treating depression or anxiety in a mammal comprising administering a cdk5 inhibitor and an NK-1 receptor antagonist to said mammal, wherein the cdk5 inhibitor and NK-1 Provided are methods wherein the combined amount of receptor antagonist is effective to treat the disorder. In one embodiment, the cdk5 inhibitor is a compound of Formula 1 or a pharmaceutically acceptable salt thereof. The cdk5 inhibitor and the NK-1 receptor antagonist can be administered to the mammal at the same time and / or at different times. Furthermore, they can be administered together in a single pharmaceutical composition or in separate pharmaceutical compositions.

The present invention also provides a pharmaceutical composition for treating depression or anxiety in mammals, together with an amount of a cdk5 inhibitor and a 5HT _1D receptor antagonist effective to treat depression or anxiety, And a composition comprising a pharmaceutically acceptable carrier is provided. In one embodiment, the cdk5 inhibitor is a compound of Formula 1 or a pharmaceutically acceptable salt thereof.

The invention further provides a method for treating depression or anxiety in a mammal comprising administering a cdk5 inhibitor and a 5HT _1D receptor antagonist to the mammal, wherein the cdk5 inhibitor and the 5HT _1D receptor A method is provided wherein the combined amount of the antagonist is effective to treat the disorder. In one embodiment, the cdk5 inhibitor is a compound of Formula 1 or a pharmaceutically acceptable salt thereof. The cdk5 inhibitor and the 5HT _1D receptor antagonist can be administered to the mammal at the same time and / or at different times. Furthermore, they can be administered together in a single pharmaceutical composition or in separate pharmaceutical compositions.

The present invention also provides a pharmaceutical composition for treating depression or anxiety in mammals, wherein the cdk5 inhibitor and SSRI in an amount effective to treat depression or anxiety are combined and pharmaceutically acceptable. There is provided a composition comprising a supported carrier. In one embodiment, the cdk inhibitor is a compound of Formula 1 or a pharmaceutically acceptable salt thereof.

The present invention further provides a method for treating depression or anxiety in a mammal, comprising administering a cdk5 inhibitor and SSRI to the mammal, wherein the combined amount of the cdk5 inhibitor and SSRI is A method is provided that is effective in treating a disorder. In one embodiment, the cdk5 inhibitor is a compound of Formula 1 or a pharmaceutically acceptable salt thereof. The cdk5 inhibitor and SSRI can be administered to the mammal at the same time and / or at different times. Furthermore, they can be administered together in a single pharmaceutical composition or in separate pharmaceutical compositions.

The present invention also provides a pharmaceutical composition for treating schizophrenia in mammals, comprising a cdk5 inhibitor and ziprasidone, olanzapine, risperidone, L-745870, sonepiprazole, RP 62203, NGD 941, Provided is a composition comprising an antipsychotic agent selected from valperidone, flesinoxane, and gepirone, and a pharmaceutically acceptable carrier. In one embodiment, the cdk5 inhibitor is a compound of Formula 1 or a pharmaceutically acceptable salt thereof.

The present invention further provides a method for treating schizophrenia in a mammal, comprising a cdk5 inhibitor and ziprasidone, olanzapine, risperidone, L-745870, sonepiprazole, RP 62203, NGD 941, balaperidone, flesinoxane, and gepirone. A method comprising: administering to the mammal an antipsychotic agent selected from: wherein a combined amount of a cdk5 inhibitor and an antipsychotic agent is effective to treat the disorder. In one embodiment, the cdk5 inhibitor is a compound of Formula 1 or a pharmaceutically acceptable salt thereof. The cdk5 inhibitor and the antipsychotic can be administered to the mammal at the same time and / or at different times. Furthermore, they can be administered together in a single pharmaceutical composition or in separate pharmaceutical compositions.

The present invention is further a pharmaceutical composition for treating a disorder selected from mammalian Alzheimer's disease, mild cognitive impairment, and age-related cognitive impairment, which is effective for treating said disorder. Compositions comprising a cdk5 inhibitor and an acetylcholinesterase inhibitor together in an amount and a pharmaceutically acceptable carrier are provided. In one embodiment, the cdk5 inhibitor is a compound of Formula 1 or a pharmaceutically acceptable salt thereof.

The present invention also provides a method for treating a disorder selected from Alzheimer's disease, mild cognitive impairment, and age-related cognitive impairment in a mammal, comprising a cdk5 inhibitor and an acetylcholinesterase inhibitor as described above. Providing a method comprising administering to a mammal, wherein the combined amount of a cdk5 inhibitor and an acetylcholinesterase inhibitor is effective to treat the disorder. In one embodiment, the cdk5 inhibitor is a compound of Formula 1 or a pharmaceutically acceptable salt thereof. The cdk5 inhibitor and the acetylcholinesterase inhibitor can be administered to the mammal at the same time and / or at different times.

The present invention is also a pharmaceutical composition for treating stroke, spinal cord injury, traumatic brain injury, multiple cerebral infarction dementia, epilepsy, pain, Alzheimer's disease, and senile dementia, which treats the disorder A composition comprising an effective amount of a cdk5 inhibitor and TPA (tissue plasminogen activator, such as ACTIVASE), together with a pharmaceutically acceptable carrier is provided. In one embodiment, the cdk inhibitor is a compound of Formula 1 or a pharmaceutically acceptable salt thereof.

The invention further provides a method for treating mammalian stroke, spinal cord injury, traumatic brain injury, multiple cerebral infarction dementia, epilepsy, pain, Alzheimer's disease, and senile dementia, comprising a cdk5 inhibitor and a TPA. Is provided to the mammal, wherein a combined amount of a cdk5 inhibitor and TPA is effective to treat the disorder. In one embodiment, the cdk5 inhibitor is a compound of Formula 1 or a pharmaceutically acceptable salt thereof. The cdk5 inhibitor and TPA can be administered to the mammal at the same time and / or at different times. Furthermore, they can be administered together in a single pharmaceutical composition or in separate pharmaceutical compositions.

The present invention is also a pharmaceutical composition for treating stroke, spinal cord injury, traumatic brain injury, multiple cerebral infarct dementia, epilepsy, pain, Alzheimer's disease, and senile dementia, which treats the disorder A composition comprising an effective amount of a cdk5 inhibitor and NIF (neutrophil inhibitor) together with a pharmaceutically acceptable carrier is provided. In one embodiment, the cdk inhibitor is a compound of Formula 1 or a pharmaceutically acceptable salt thereof.

The present invention further provides a method for treating mammalian stroke, spinal cord injury, traumatic brain injury, multiple cerebral infarction dementia, epilepsy, pain, Alzheimer's disease, and senile dementia, comprising a cdk5 inhibitor and a NIF A combination of a cdk5 inhibitor and NIF is effective to treat the disorder. In one embodiment, the cdk5 inhibitor is a compound of Formula 1 or a pharmaceutically acceptable salt thereof. The cdk5 inhibitor and NIF can be administered to the mammal at the same time and / or at different times. Furthermore, they can be administered together in a single pharmaceutical composition or in separate pharmaceutical compositions.

The present invention also includes mammalian Huntington's disease, stroke, spinal cord injury, traumatic brain injury, multiple cerebral infarction dementia, epilepsy, amyotrophic lateral sclerosis, pain, virus-induced dementia, such as AIDS-induced dementia, Neurodegeneration associated with bacterial infection, migraine, hypoglycemia, urinary incontinence, cerebral ischemia, multiple sclerosis, Alzheimer's disease, senile dementia of Alzheimer type, mild cognitive impairment, age-related cognitive function Decline, vomiting, cortical basal ganglia degeneration, fighting dementia, Down syndrome, muscular dystrophy, Niemann-Pick disease, Pick's disease, prion with confusion, progressive supranuclear palsy, inferior lateral sclerosis, and subacute sclerosing panencephalitis A pharmaceutical composition for treating a disease or condition selected from the group consisting of a cdk5 inhibitor and an NMDA receptor antagonist in an amount effective to treat the disorder, and as a medicament Providing a composition comprising an acceptable carrier. In one embodiment, the cdk inhibitor is a compound of Formula 1 or a pharmaceutically acceptable salt thereof.

The present invention further includes Huntington's chorea, stroke, spinal cord injury, traumatic brain injury, multiple cerebral infarction dementia, epilepsy, amyotrophic lateral sclerosis, pain, virus-induced dementia such as AIDS-induced dementia, Neurodegeneration associated with bacterial infection, migraine, hypoglycemia, urinary incontinence, cerebral ischemia, multiple sclerosis, Alzheimer's disease, senile dementia of Alzheimer type, mild cognitive impairment, age-related cognitive function Decline, vomiting, cortical basal ganglia degeneration, fighting dementia, Down syndrome, muscular dystrophy, Niemann-Pick disease, Pick's disease, prion with confusion, progressive supranuclear palsy, inferior lateral sclerosis, and subacute sclerosing panencephalitis A combination of a cdk5 inhibitor and an NMDA receptor antagonist comprising administering to the mammal a cdk5 inhibitor and an NMDA receptor antagonist It is effective in treating said disorder, and a method. In one embodiment, the cdk5 inhibitor is a compound of Formula 1 or a pharmaceutically acceptable salt thereof. The cdk5 inhibitor and the NMDA receptor antagonist can be administered to the mammal at the same time and / or at different times. Furthermore, they can be administered together in a single pharmaceutical composition or in separate pharmaceutical compositions.

The present invention is also a pharmaceutical composition for treating stroke, spinal cord injury, traumatic brain injury, multiple cerebral infarct dementia, epilepsy, pain, Alzheimer's disease, and senile dementia, which treats the disorder A composition comprising an effective amount of a cdk5 inhibitor together with a potassium channel modulator and a pharmaceutically acceptable carrier is provided. In one embodiment, the cdk inhibitor is a compound of Formula 1 or a pharmaceutically acceptable salt thereof.

The present invention further provides a method for treating mammalian stroke, spinal cord injury, traumatic brain injury, multiple cerebral infarction dementia, epilepsy, pain, Alzheimer's disease, and senile dementia, comprising a cdk5 inhibitor and potassium There is provided a method comprising administering a channel modulator to the mammal, wherein the combined amount of a cdk5 inhibitor and a potassium channel modulator is effective to treat the disorder. In one embodiment, the cdk5 inhibitor is a compound of Formula 1 or a pharmaceutically acceptable salt thereof. The cdk5 inhibitor and the potassium channel modulator can be administered to the mammal at the same time and / or at different times. Furthermore, they can be administered together in a single pharmaceutical composition or in separate pharmaceutical compositions.

The terms “treatment”, “treating” and the like refer to reversing, reducing or inhibiting the progression of a disease or symptom to which such a term applies, or one or more symptoms of such a disease or symptom. To do. As used herein, these terms also depend on the patient's symptoms to prevent the onset of the disease or condition, or symptoms associated with the disease or condition, such as the disease or condition, or to them. It includes reducing the severity of the associated symptom prior to distress due to the disease or condition. Such prevention or alleviation prior to pain refers to the administration of a compound of the invention to a subject who is not suffering from the disease or condition at the time of administration. “Prevention” also encompasses preventing recurrence of the disease or condition, or symptoms associated therewith.

“Mammal” as used herein and means any mammal, unless otherwise specified. The term “mammal” includes, for example and without limitation, dogs, cats, and humans.

“Abnormal cell growth”, as used herein, is either malignant (eg, like cancer) or benign, ie independent of normal control mechanisms (eg, loss of contact inhibition). We refer to cell proliferation. Examples of benign proliferative diseases are psoriasis, benign prostatic hypertrophy, human papillomavirus (HPV), and restenosis.

“Neurodegenerative diseases and conditions” as used herein refers to diseases or conditions associated with neurodegeneration. Natural neurodegenerative symptoms and diseases are generally known to those skilled in the art.

Diseases and conditions that are referred to herein as “treatment can be achieved or facilitated by altering dopamine-mediated neurotransmission” are diseases or conditions caused at least in part by dopamine neurotransmission, or By disease or condition that results in abnormal dopamine neurotransmission that contributes to the symptom or manifestation of the disease or condition.

Diseases and conditions that are referred to herein as “treatment can be achieved or facilitated by reducing cdk5 activity” are diseases or conditions caused at least in part by cdk5 activity, or symptoms or symptoms of the disease or condition or It refers to a disease or condition that results in abnormal cdk5 activity used for expression.

“Effective amount for inhibiting cdk5 activity” as used herein refers to the amount of a compound sufficient to bind to the enzyme cdk5, which has the effect of reducing cdk5 activity.

“Effective amount for inhibiting cdk2 activity” as used herein refers to the amount of a compound sufficient to bind to the enzyme cdk2 having the effect of reducing cdk2 activity.

DETAILED DESCRIPTION OF THE INVENTION The compounds of formula 1 above and their pharmaceutically acceptable salts can be prepared according to the following reaction schemes and discussion. Unless otherwise specified, R ¹ , R ² , R ³ , and R ⁴ are as defined above. Product isolation and purification can be accomplished by standard procedures known to those skilled in the art.

As used herein, the expression “reactive inert solvent” refers to a solvent system in which the components do not react with the starting materials, reagents, or product intermediates to adversely affect the yield of the desired product. To mention.

During any of the following synthetic procedures it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules of interest. This means that conventional protecting group means such as
Can be achieved by the following.

Scheme 1 is a compound of Formula 1 where R ³ is —C (═O) NH—, —C (═O) O—, or —C (═O) (CR ¹⁰ R ¹¹ ) _n —. ) Illustrates a suitable method for preparing Referring to Scheme 1, 1,4-dinitroimidazole (J. Phys. Chem. (1995) Vol. 99, pp. 5009-1015) solution in dimethyl sulfoxide (DMSO), pyrimidine-water, water, acetonitrile-water, Primary alkyl or aryl at about -20 ° C to about 50 ° C, preferably about -5 ° C to 35 ° C in an alcohol or alcohol-water solvent system, preferably in a lower alcohol such as methanol Treatment with amine gives 1-N-substituted-4-nitroimidazole of formula 2. 1,4-dinitroimidazole is a high energy metastable material and should be stored in a freezer when not in use. Thermodynamic measurements have shown that it can potentially produce enough energy to explode vigorously at 35 ° C. under adiabatic conditions. Extreme care should always be used when using this material. Reduction of the nitro compound of formula 2 to the amine of formula 3 is carried out using a mixture of the compound of formula 2 and a noble metal catalyst in a solvent such as ethyl acetate, tetrahydrofuran, dioxane, or a mixture thereof at a pressure of about 1 to 100 atmospheres. (Wherein the preferred pressure of hydrogen gas is from about 1 to about 10 atmospheres). Palladium is a preferred noble metal catalyst. The metal can be conveniently suspended on an inert solid support such as charcoal. After the compound of formula 2 is consumed, the mixture is filtered and the resulting amine of formula 3 is immediately converted to the acid chloride ClC (═O) (CR ¹⁰ R ¹¹ ) _n R ⁴ , acid anhydride (R ⁴ ( CR ¹⁰ R ¹¹ ) _n C (═O)) ₂ O or an activated carboxylic acid derivative XC (═O) (CR ¹⁰ R ¹¹ ) _n —R ⁴ and a base such as triethylamine, diisopropylethylamine, pyridine, or 2 , 6-lutidine in the presence of about -78 ° C to 40 ° C. 1-propanephosphonic acid cyclic anhydride and triethylamine are a preferred combination. Activated carboxylic acid derivatives include carboxylic acid HOC (= O) (CR ¹⁰ R ¹¹ ) _n R ⁴ and known activating reagents such as dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride , Carbonyldiimidazole, 1-propanephosphonic acid cyclic anhydride, alkyl or aryl chloroformate, bis (2-oxo-3-oxazolidinyl) phosphine acid chloride, benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluoro Prepared from phosphate, or any other standard literature reagent. This procedure gives a compound of formula 1B where R ³ is —C (═O) (CR ¹⁰ R ¹¹ ) _n —.

Alternatively, after filtration, the amine of Formula 3 can be converted to a base such as triethylamine, diisopropylethylamine, pyridine, or 2,6-lutidine, and an alkyl or aryl chloroformate at about -78 ° C to 40 ° C (-78 ° C to- 40 ° C. is preferred), resulting in a compound of formula 1A where R ³ is —C (═O) O— and R ⁴ is phenyl. Diisopropylethylamine and phenyl chloroformate are a preferred combination. Subsequent treatment of the phenyl carbamate of formula 1A with a primary or secondary amine in a solvent such as dioxane, dimethylformamide, or acetonitrile at about 40 ° C. to 90 ° C. yields the corresponding urea product 1C. Where R ³ is —C (═O) NR ⁹ — and R ⁴ is phenyl or heteroaryl. A 1: 1 mixture of dioxane-dimethylformamide and 70 ° C. are preferred.

Compounds of formula 1 (wherein, R ¹ is substituted with R ^5, and R ⁵ is NHC (= O) a R ⁸⁾ demonstrates a method of preparing in Scheme 2. A compound of formula 4 (where R ⁵ is OH) is reacted with an alkyl- or arylsulfonyl chloride (p-toluenesulfonyl chloride (TosCl) is preferred), preferably in a reaction inert solvent such as tetrahydrofuran, methylene chloride. Or an amine base such as triethylamine, diisopropylethylamine, pyridine, or 2,6-lutidine (where triethylamine is preferred) at a temperature of about -10 ° C to about 30 ° C in chloroform (where methylene chloride is preferred). And a compound of formula 5 wherein R ⁵ is CH ₃ (C ₆ H ₄ ) SO ₃ (TosO) by treatment in the presence of catalytic 4-N, N-dimethylaminopyridine. ) Is given. A polar solvent such as dimethylformamide, dimethyl sulfoxide, lower alcohol, water, or a mixture of these solvents (wherein, with an alkali metal salt of an amide of the tosylate formed in this way, where sodium azide is preferred) Treatment at about 20 ° C. to 130 ° C. (preferably 90 ° C. to 110 ° C.) in an ethanol-water mixture is preferred to treat the compound of formula 6 where R ⁵ is N _3. Generate.

Under selective reduction conditions, for example with trialkyl- or triarylphosphine, where triphenylphosphine is preferred, in a solvent such as tetrahydrofuran, dioxane, acetonitrile, or a mixture thereof, where tetrahydrofuran is preferred. Treatment of with an azide gives a compound of formula 7 where R ⁵ is NH ₂ . The primary amino group of the compound of formula 7 thus formed (R ⁵ ═NH ₂ ) is a chloroformate, isocyanate, carbamoyl chloride, acid chloride, acid anhydride, or activated carbon It can be derivatized via reaction with an acid derivative. Activated carboxylic acid derivatives include carboxylic acids and known activating reagents such as dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, carbonyldiimidazole, 1-propanephosphonic acid cyclic anhydride, chloroformic acid. Alkyl, bis (2-oxo-3-oxazolidinyl) phosphine acid chloride, benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, or any other standard literature reagent etc. And optionally in the presence of an amine base, such as triethylamine, diisopropylethylamine, pyridine, or 2,6-lutidine, where 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride is preferred. -78 ° C 80 ° C. (where, 0 ° C. to 40 ° C. is preferred) are prepared by. Tetrahydrofuran and methylene chloride are preferred solvents.

A compound of formula 8 thus formed, wherein R ⁵ is —NHC (═O) R ⁸ , is a compound of formula 1D, where R ⁵ is NHC (═O) R ⁸ ; R ³ is The conversion of C (═O) (CR ¹⁰ R ¹¹ ) _n R ⁴ ) is preferably performed with a compound of formula 8 and a noble metal catalyst (where palladium is preferred) in a solvent such as ethyl acetate, tetrahydrofuran, dioxane, or mixtures thereof. A noble metal catalyst, wherein the metal can be conveniently suspended on an inert solid support, such as charcoal, in a hydrogen gas atmosphere at about 1-100 atmospheres (where the preferred pressure of hydrogen gas is about 1 To about 10 atmospheres). After consumption of the compound of formula 8, the mixture is filtered and the resulting amine is combined with an acid chloride, acid anhydride, or activated carboxylic acid derivative, if appropriate, an amine base such as triethylamine, diisopropyl. Immediately acylated by reaction at about −78 ° C. to 40 ° C. in the presence of ethylamine, pyridine, or 2,6-lutidine (where 1-propanephosphonic acid cyclic anhydride and triethylamine are the preferred combination); The N-acylated product of formula 1D is given. Activated carboxylic acid derivatives include carboxylic acids and known activating reagents such as dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, carbonyldiimidazole, 1-propanephosphinic acid cyclic anhydride, chloroformic acid. Alkyl, bis (2-oxo-3-oxazolidinyl) phosphine chloride, benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, or any other standard literature Prepared from

If aryl chloroformate or heteroaryl chloroformate is used in the above acylation in place of acid chloride, anhydride, or activated carboxylic acid derivative, aryl carbamate 1E is formed. The resulting aryl carbamate 1E (R ³ is C (═O) O— and R ⁴ is aryl or heteroaryl) is a solvent such as dioxane, dimethylformamide, or acetonitrile (where dioxane-dimethyl A 1: 1 mixture of formamide is preferred) and may be treated with an amine at a temperature of about 40 ° C. to 90 ° C., where 70 ° C. is preferred, resulting in the corresponding urea product of formula 1F ( R ³ gives (—C (═O) NR ⁹ —, R ⁴ is aryl or heteroaryl).

Another method for preparing compounds of formula 1 where R ⁵ is NHC (═O) R ⁸ is shown in Scheme 3. Reaction inert solvents such as tetrahydrofuran, methylene chloride or chloroform of compound 4 (where R ⁵ is OH) with alkyl- or aryl-sulfonyl chloride (p-toluenesulfonyl chloride (TosCl) is preferred) Amine bases such as triethylamine, diisopropylethylamine, pyridine, or 2,6-lutidine, and 4-N, N-dimethylamino at a temperature of about -10 ° C to about 30 ° C in methylene chloride Treatment in the presence of pyridine gives the compound of formula 5, where R ⁵ is CH ₃ (C ₆ H ₄ ) SO ₃ (TosO). Triethylamine is the preferred amine base. Conversion of a compound of formula 5 (R ⁵ is TosO) to a compound of formula 1G (R ⁵ is TosO and R ³ is C (═O) (CR ¹⁰ R ¹¹ ) _n R ⁴ ) A mixture of a compound of formula 5 (R ⁵ is TosO) and a noble metal catalyst in a solvent, such as ethyl acetate, tetrahydrofuran, dioxane, or a mixture thereof, at a hydrogen gas atmosphere (where hydrogen The preferred pressure of the gas is from about 1 to about 10 atmospheres). Palladium is a preferred noble metal catalyst. The metal can be conveniently suspended on an inert solid support such as charcoal. After compound 5 is consumed, the mixture is filtered and the resulting amine is immediately converted to the acid chloride, anhydride, or activated carboxylic acid derivative and, if appropriate, an amine base such as triethylamine, diisopropylethylamine, Reaction in the presence of pyridine, or 2,6-lutidine (where 1-propanephosphonic acid cyclic anhydride and triethylamine are a preferred combination) at about -78 ° C to 40 ° C to form an N-acyl of formula 1G Give the product. Activated carboxylic acid derivatives include carboxylic acids and known activating reagents such as dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, carbonyldiimidazole, 1-propanephosphonic acid cyclic anhydride, chloroformic acid. As described in alkyl, bis (2-oxo-3-oxazosodinyl) phosphine chloride, benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, or any other standard literature And so on.

According to an alkali metal salt of an azide of the compound of formula 1G (R ⁵ is TosO and R ³ is —C (═O) (CR ¹⁰ R ¹¹ ) _n —, where sodium azide is preferred) , In a polar solvent (eg dimethylformamide, dimethyl sulfoxide, lower alcohol, water, or a mixture of these solvents, where an ethanol-water mixture is preferred), about 20 ° C to 130 ° C (where 90 ° C Treatment at ˜110 ° C. may be used to produce compounds of formula 1H, where R ⁵ is N ₃ . Subsequent reduction of the azide of formula 1H (R ⁵ is N ₃ ) with a compound of formula 1H (R ⁵ is N ₃ ) in a solvent such as ethyl acetate, tetrahydrofuran, dioxane, or mixtures thereof A mixture of noble metal catalysts (where palladium is a preferred noble metal catalyst, which can be conveniently suspended on an inert solid support such as charcoal) in a hydrogen gas atmosphere at a pressure of about 1 to 100 atmospheres (Where the preferred pressure of hydrogen gas is from about 1 to about 10 atmospheres).

Alternatively, reduction of the azide of formula 1H (R ⁵ is N ₃ ) can be accomplished with a solvent such as tetrahydrofuran, dioxane, or acetonitrile (with triphenylphosphine being preferred) with a trialkyl- or triarylphosphine, where triphenylphosphine is preferred. Here, tetrahydrofuran is preferred). Compound of formula 1I (R
The primary amino group of ⁵ is NH ₂ is a chloroformate, isocyanate, carbamoyl chloride, acid chloride, acid anhydride, or activated carboxylic acid derivative (where the activated carboxylic acid derivative is a carboxylic acid Acids and known activating reagents such as dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, carbonyldiimidazole, 1-propanephosphinic acid cyclic anhydride, alkyl chloroformate, bis (2-oxo- 3-oxazolidinyl) phosphine acid chloride, benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, or any other standard literature reagent, etc., if necessary, an amine base such as Triethylamine, diisopropylethylamine -78 ° C to 80 ° C (where 0 ° C to 40 ° C) in the presence of pyridine or 2,6-lutidine (where 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride is preferred). Tetrahydrofuran and methylene chloride are preferred solvents.

Compounds of formula 1 wherein R ³ is — (CR ¹⁰ R ¹¹ ) _n — can be prepared according to Scheme 4. Referring to Scheme 4, a 4-bromoimidazole solution in a base such as sodium hydride, potassium hydride, lithium hydride, cesium carbonate, sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium diisopropylamide, sodium amide, Reaction inert solvents such as tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, dimethyl sulfoxide with potassium hexamethyldisilazide, sodium hexamethyldisilazide, sodium tert-butoxide, or potassium tert-butoxide, Or a phase transfer catalyst such as tetra-n-butylammonium chloride, tetra-n-butylammonium bromide in toluene at about −20 ° C. to 150 ° C. (where 20 ° C. to 100 ° C. is preferred). , Tetra-n-butylammonium iodide, benzyltrimethylammonium chloride, benzyltrimethylammonium bromide, or treatment with or without benzyltrimethylammonium fluoride, followed by alkyl, allyl, or benzyl chloride, bromide, iodide, The addition of alkyl sulfonate, aryl sulfonate, or triflate can be separated using methods known to those skilled in the art 1-substituted-4-bromoimidazole (9) and 1-substituted-5-bromo. A mixture of imidazole (10) is given.

Alternatively, a reaction inert solvent such as tetrahydrofuran, 1,2-dichloroethane, of 4-bromoimidazole with fluorinated, chlorinated, brominated, iodinated, acetic acid, or allyl carboxylate, where allyl carboxylate is preferred. , 1,4-dioxane, dimethyl sulfoxide, or N, N-dimethylformamide, where tetrahydrofuran is preferred, such as palladium (0) tetrakis (triphenylphosphine), palladium (II) acetate, Allyl palladium chloride dimer, tris (dibenzylideneacetone) dipalladium (0), tris (dibenzylideneacetone) (0) chloroform adduct, palladium (II) chloride (wherein palladium tetrakis (triphenylphosphine) or palladium (II Phosphine ligands such as triphenylphosphine, tri-o-triphosphine, tri-tert-butylphosphine, 1,2-bis (diphenylphosphino) ethane, or 1,3 in the presence of acetate) Treatment with about 0 ° C. to 100 ° C. (where 50 ° C. to 80 ° C. is preferred), irrespective of the presence or absence of bis (diphenylphosphino) propane, is carried out with 1-substituted-4-bromoimidazole (9) and 1 Provide a mixture of -substituted-5-bromoimidazole (10).

1-Substituted-4-bromoimidazole (9) of formula —NH ₂ (CR ¹⁰ R ¹¹ ) _n R ⁴ and a palladium catalyst such as palladium (II) acetate, allyl palladium chloride dimer, tris (dibenzylideneacetone) Dipalladium (0), tris (dibenzylideneacetone) dipalladium (0) chloroform adduct, or palladium (II) chloride, where palladium (II) acetate, tris (dibenzylideneacetone) dipalladium (0), and Tris (dibenzylideneacetone) dipalladium (0) chloroform adduct is preferred), and phosphine ligands such as BINAP, 2-biphenyldicyclohexylphosphine, 2-biphenyl-di-tert-butylphosphine, or 2-N, N -Dimethylamino-2'-diphenylphosphine Inobifeniru (where, 2-N, N-dimethylamino-2'-diphenylphosphino biphenyl is preferred), and a base such as sodium tert- butoxide, cesium carbonate, or potassium phosphate (K ₃ PO ₄₎ (wherein Treatment with a reaction inert solvent such as toluene, 1,4-dioxane, or tetrahydrofuran at about 0 ° C. to 150 ° C. (where 20 ° C. to 110 ° C. is preferred). Gives the binding product 1.

Another method for synthesizing compounds of Formula 1 wherein R ⁷ is —C (═O) (CR ¹⁰ R ¹¹ ) _n — is illustrated in Scheme 5 below. Ethyl-2-isocyano-3-N, N-dimethylaminoacrylate (11) with primary amine R ¹ —NH ₂ in a solvent such as n-butanol, n-propanol, I-propanol, or ethanol Or in the absence of a solvent (preferably n-propanol or no solvent). Treatment at about 23 ° C. to about 200 ° C. (where about 60 ° C. to about 150 ° C. is preferred) provides the imidazole of formula 12. Treatment of N, O-dimethylhydroxylamine hydrochloride with 1,2-dichloroethane with triethylaluminum followed by addition of 12 and about 30 ° C. to about 80 ° C. (where a temperature of about 50 ° C. is preferred) Heating gives imidazole 13. In a solvent such as tetrahydrofuran, methylene chloride, or diethyl ether of an organometallic reagent M- (CR ¹⁰ R ¹¹ ) _n R ⁴ (where M can be either lithium halide or magnesium, preferably magnesium halide) To a solution of 13 at a temperature of about −50 ° C. to about 30 ° C. (where about −20 ° C. to about 0 ° C. is preferred) gives 14. The addition of 14 at about 23 ° C. to a mixture of hydroxyamine hydrochloride and potassium acetate in a lower alcohol solvent, where ethanol is preferred, produces oxime 15 as a mixture of isomers. Treatment of a solution of oxime 15 in acetone at about 0 ° C. with sodium hydroxide solution followed by paratoluenesulfonyl chloride produces a mixture of O-sulfonyl compounds after the extraction operation. Dissolve the crude material in a non-polar solvent such as benzene, hexane, or toluene (here benzene is preferred) and apply to alumina column, 5 minutes later using chloroform-methanol (about 10: 1) The elution provides regioisomers from compound 1B and the Beckmann transition.

Compounds of formula 1J can also be prepared by the method illustrated in Scheme 6 below. The key starting materials for this synthesis are 1 to 3 groups selected from compounds containing a double bond substituted with the group ER ⁵ (compounds of formula X) and R ⁵ (X), where ER ⁵ is C (═O) R ⁷ , C (═O) OR ⁷ , C (═O) NR ⁷ R ⁸ , S (═O) ₂ R ⁷ , S (═O) ₂ NR ⁷ R ⁸ , Defined as an electron withdrawing group selected from S (═O) ₂ OR ⁷ , cyano and heteroaryl. Further, the compound of formula X is such that ER ⁵ is bonded to one of the groups R ⁵ or directly to a carbon-carbon double bond, and as a result, like 2-cyclopentan-1-one and 2-cyclohexane-1-one Such a compound may be included. Alternatively, compounds of formula X, where L is defined as Cl, Br, I, OC (═O) R ⁷ , or OS (═O) ₂ R ⁷ , may be used as starting materials. Examples of such compounds are 3-chloro-1-cyclopentane, 3-acetoxy-1-cyclobutanone. Referring to Scheme 6 as follows, 4 (5) -nitroimidazole, where the salt is sodium, potassium, cesium, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU ) Or tetraalkylammonium, where tetra n-butylammonium and DBU are the preferred salts), according to intermediate 16 or 17, such as acetonitrile, methylene chloride, 1,2-dichloroethane, or chloroform (where Treatment at a temperature of about −60 ° C. to about 50 ° C. (where −20 ° C. to 23 ° C. is a preferred range) in acetonitrile is a preferred solvent, to give an addition product of Formula 2A. Reduction of the nitro compound 2A involves the reaction of a mixture of 2A and a noble metal catalyst (palladium is the preferred noble metal catalyst, which can be conveniently suspended on an inert solid support such as charcoal) in a solvent such as acetic acid. Accomplished by exposure to a hydrogen gas atmosphere at a pressure of about 1 to 100 atmospheres (where the preferred pressure of hydrogen gas is about 1 to about 10 atmospheres) in ethyl, tetrahydrofuran, dioxane, or mixtures thereof. obtain. After 2A is consumed, the mixture is filtered and the resulting amine is immediately acid chloride, ClC (= O) (CR ¹⁰ R ¹¹ ) _n R ⁴ , acid anhydride (R ⁴ (CR ¹⁰ R ¹¹ ) _n C (═O)) ₂ O or activated carboxylic acid derivative × C (═O) (CR ¹⁰ R ¹¹ ) _n R ⁴ and a base such as triethylamine, diisopropylethylamine, pyridine, or 2,6-lutidine ( In the presence of 1-propanephosphinic acid cyclic anhydride and triethylamine here), it is reacted at −78 ° C. to about 40 ° C. to give 1J. Activated carboxylic acid derivatives include carboxylic acid HOC (= O) (CR ¹⁰ R ¹¹ ) _n R ⁴ and known activating reagents such as dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, Carbonyldiimidazole, 1-propanephosphonic acid cyclic anhydride, alkyl or aryl chloroformate, bis (2-oxo-3-oxazolidinyl) phosphine acid chloride, benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate Or prepared from any other standard literature or the like.

Alternatively, after filtration, the intermediate amine is a base such as triethylamine, diisopropylethylamine, pyridine, or 2,6-lutidine, and alkyl or aryl chloroformates (here diisopropylethylamine and phenyl chloroformate are preferred combinations). May be used at about −78 ° C. to about 40 ° C. (where about −78 ° C. to about −40 ° C. is preferred), resulting in 1K.

Subsequent treatment of 1K with a primary or secondary amine in a solvent such as dioxane, dimethylformamide, or acetonitrile (preferably a 1: 1 mixture of dioxane-dimethylformamide) is the corresponding urea Give 1 L of product.

Subsequent conversion of compounds 2A, 1J, 1K, and 1L using methods known to those skilled in the art may be performed to further provide compounds of formula 1 as described in this application.

The compounds of formula 1 described herein (wherein R ² is other than hydrogen) can be prepared using compounds well known to those of ordinary skill in the art (wherein R ² May be prepared by conversion of For example, a compound of formula 1 (where R ² is F) is a compound of formula 1 (where R ² is hydrogen), eg, formulas 1A, 1B referred to in Scheme 1 above. , And 1C can be prepared by treating with N-fluorobenzenesulfonimide in toluene, xylene, or dioxane at about room temperature to about 150 ° C, preferably about 100 ° C to about 120 ° C.

Pharmaceutically acceptable salts of the compounds of formula 1 can be conveniently prepared by treating the corresponding free base or acid with one chemical equivalent of a pharmaceutically acceptable acid or base. Conventional concentration or crystallization techniques can be applied to isolate the salt. Examples of suitable acids include acetic acid, lactic acid, succinic acid, maleic acid, tartaric acid, citric acid, gluconic acid, ascorbic acid, benzoic acid, cinnamic acid, fumaric acid, sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, iodine There are hydrofluoric acid, sulfamic acid, sulfonic acid such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and related acids. Exemplary bases are sodium, potassium, and calcium.

The compounds of the present invention may be administered either alone or in combination with a pharmaceutically acceptable carrier, either single or multiple doses. Suitable pharmaceutically acceptable carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. The pharmaceutical composition formed by combining the compound of formula 1 or a pharmaceutically acceptable salt thereof can then be easily administered in various dosage forms such as tablets, powders, lozenges, syrups, injection solutions, etc. . These pharmaceutical compositions may optionally contain additional ingredients such as perfumes, binders, excipients and the like. Thus, for oral administration, tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate bind various disintegrants such as starch, methylcellulose, alginic acid and certain complex silicates. It can be utilized with agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talc are often used for tableting. Similar types of solid compositions can also be utilized as fillers in soft and hard gelatin capsules. Preferred materials for this include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the essential active ingredients therein are various sweetening or flavoring agents, coloring substances or pigments and optionally emulsifying agents or suspending agents, diluents such as water. , Ethanol, propylene glycol, glycerin and combinations thereof.

For parenteral administration, solutions containing the compound of the invention or a pharmaceutically acceptable salt thereof in sesame oil or peanut oil, aqueous propylene glycol, or in a sterile aqueous solution may be utilized. Such aqueous solutions should be appropriately buffered if necessary, and the liquid diluent should be made isotonic with a sufficient amount of saline or glucose. These particular aqueous solutions are particularly suitable for intravenous or intramuscular, subcutaneous and intraperitoneal administration. All of the sterilized aqueous solutions used are readily available to those skilled in the art.

The compound of Formula 1 or a pharmaceutically acceptable salt thereof can be administered orally, transdermally (eg, through the use of a patch), parenterally (eg, intravenously), rectally, or topically. Usually, the daily dose to treat a disease or condition in which a neurodegenerative disease or condition or treatment can be achieved or facilitated by altering dopamine-mediated neurotransmission is usually per kg body weight of the patient to be treated It ranges from about 0.0001 to about 10.0 mg. The daily dose for treating a cancer or disease or condition involved in benign abnormal cell growth usually ranges from about 0.0001 to about 500 mg / kg body weight of the patient to be treated. For example, the compound of formula 1 or a pharmaceutically acceptable salt thereof is about 0.01 mg up to 1000 mg per day, preferably per day, for adults of average body weight (about 70 kg) for the treatment of neurodegenerative disorders. It can be administered in single or divided (ie, multiple) doses ranging from about 0.1 to about 500 mg. The daily dose for treating obesity, sperm motility, hair loss, or any other disease or condition that can be treated by inhibiting GSK-3 is usually about 1 kg / kg body weight of the patient to be treated. It ranges from 0.0001 to about 10.0 mg. Variations based on the aforementioned dose ranges will be made by the physician taking into account known considerations such as the weight, age and symptoms of the person being treated, the severity of the affliction, and the particular route of administration chosen. Sometimes.

The compound of formula 1 and their pharmaceutically acceptable salts are further one or more selected from an anti-angiogenic agent, a signal transduction inhibitor, and an anti-proliferative agent in an amount effective to inhibit abnormal cell growth. Or may be prepared in a pharmaceutical composition containing the substances.

Anti-angiogenic agents such as MMP-2 (matrix-metalloproteinase 2) inhibitor, MMP-9 (matrix-metalloproteinase 9) inhibitor, and COX-II (cyclooxygenase II) inhibitor are For the treatment of proliferation, it can be used in conjunction with a compound of formula 1 in the methods and pharmaceutical compositions described herein. Examples of useful COX-II inhibitors include CELEBREX ™ (celecoxib), valdecoxib, and rofecoxib. Examples of useful matrix metalloproteinase inhibitors are WO96 / 33172 (published 24 October 1996), WO96 / 27583 (published 7 March 1996), European Patent Application No. 9730497 (July 1997). European Patent Application No. 99308617.2 (filed on October 29, 1999), WO 98/07697 (published on February 26, 1998), WO 98/03516 (published on January 29, 1998), WO 98 / 34918 (August 13, 1998), WO98 / 34915 (published August 13, 1998), WO98 / 33768 (published August 6, 1998), WO98 / 30566 (published July 16, 1998), European Patent Publication No. 606,046 (issued July 13, 1994), European Patent Publication No. 931,788 (Issued July 28, 1999), WO 90/05719 (published March 31, 1990), WO 99/52910 (published October 21, 1999), WO 99/52889 (published October 21, 1999), WO 99 / 52889 (published October 21, 1999), WO99 / 29667 (published June 17, 1999), PCT International Application No. PCT / IB98 / 01113 (filed July 21, 1998), European Patent Application No. 993022232.1. (Filed March 25, 1999), UK patent application number 9912961.1 (filed June 3, 1999), US provisional patent application number 60 / 148,464 (filed August 12, 1999), US patent 5 863,949 (issued January 26, 1999), US Patent 5,861,510 (issued January 19, 1999) , And European are described in Patent Publication No. 780,386 (published Jun. 25, 1997), all in their entirety by reference are incorporated herein. Preferred MMP-2 and MMP-9 inhibitors are those that have little or no activity inhibiting MMP-1. Further preferred are other matrix-metalloproteinases (ie MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, It selectively inhibits MMP-2 and / or MMP-9 as compared with MMP-12 and MMP-13).

Some specific examples of MMP inhibitors useful in the present invention include AG-3340, RO32-3555, RS13-0830, and the following list: 3-[[4- (4-Fluoro-phenoxy) -benzenesulfonyl ]-(1-hydroxycarbamoyl-cyclopentyl) -amino] -propionic acid; 3-oxo-3- [4- (4-fluoro-phenoxy) -benzenesulfonylamino] -8-oxa-bicyclo [3.2.1] ] Octane-3-carboxylic acid hydroxyamide; (2R, 3R) 1- [4- (2-chloro-4-fluoro-benzyloxy) -benzenesulfonyl] -3-hydroxy-3-methyl-piperidine-2-carboxylic acid Acid hydroxyamide; 4- [4- (4-fluoro-phenoxy) -benzenesulfonylamino] -te Ravitro-pyran-4-carboxylic acid hydroxyamide; 3-[[4- (4-fluoro-phenoxy) -benzenesulfonyl]-(1-hydroxycarbamoyl-cyclobutyl) -amino] -propionic acid; 4- [4- ( 4-chloro-phenoxy) -benzenesulfonylamino] -tetrahydro-pyran-4-carboxylic acid hydroxyamide; (R) 3- [4- (4-chloro-phenoxy) -benzenesulfonylamino] -tetrahydro-pyran-3- (2R, 3R) 1- [4- (4-fluoro-2-methyl-benzyloxy) -benzenesulfonyl] -3-hydroxy-3-methyl-piperidine-2-carboxylic acid hydroxyamide; 3 -[[4- (4-Fluoro-phenoxy) -benzenesulfonyl]- 1-hydroxycarbamoyl-1-methyl-ethyl) -amino] -propionic acid; 3-[[4- (4-fluoro-phenoxy) -benzenesulfonyl]-(4-hydroxycarbamoyl-tetrahydro-pyran-4-yl) -Amino] -propionic acid; exo-3- [4- (4-chloro-phenoxy) -benzenesulfonylamino] -8-oxa-bicyclo [3.2.1] octane-3-carboxylic acid hydroxyamide; Endo-3- [4- (4-fluoro-phenoxy) -benzenesulfonylamino] -8-oxa-bicyclo [3.2.1] octane-3-carboxylic acid hydroxyamide; and (R) 3- [4- (4-Fluoro-phenoxy) -benzenesulfonylamino] -tetrahydro-furan-3-carboxylic acid hydroxyamido Compounds listed in, as well as acceptable salts and solvates as medicaments the compounds.

Other anti-angiogenic agents such as other COX-II inhibitors and other MMP inhibitors may also be used in the present invention.

An effective amount of a COX-II inhibitor when combined with a cdk5 inhibitor, eg, a compound of Formula 1, can generally be determined by one skilled in the art. The recommended daily effective range for a COX-II inhibitor when combined with a cdk5 inhibitor is about 0.1 to about 25 mg / kg body weight. An effective daily dose of a cdk5 inhibitor is usually about 0.0001 to about 10 mg / kg body weight. In some examples, the combined amount of COX-II inhibitor and / or cdk5 inhibitor is on an individual basis to achieve the same desired effect in inhibiting abnormal cell growth. There seems to be less than what is required.

Compounds of formula 1 are also signaling inhibitors, eg, substances that can inhibit the response of EGFR (epidermal growth factor receptor), eg, EGFR antibodies, EGF antibodies, and molecules that are EGFR inhibitors; VEGF (vascular endothelial growth factor ) Inhibitors; and erbB2 receptor inhibitors, eg, organic molecules or antibodies that bind to the erbB2 receptor, eg, HERCEPTIN ™ (Genentech, Inc. South San Francisco, California, USA). Such a combination is useful for treating and preventing abnormal cell proliferation, such as cancer, as described herein.

Examples of EGFR inhibitors include WO95 / 19970 (published on July 27, 1995), WO98 / 14451 (published on April 9, 1998), WO98 / 02434 (published on January 22, 1998), and US Pat. 747, 498 (issued May 5, 1998), and such materials may be used in the present invention as described herein. EGFR inhibitors include, but are not limited to, monoclonal antibody C225 and anti-EGFR 22 Mab (ImClore Systems Incorporated New York, New York, USA), Compound ZD-1839 (Astra Zeneca), BIBX-1382 (Boehringer Ingelheim) MDX-447 (Medarex Inc., Annandale, New Jersey, USA), and OLX-103 (Merck & Co., Whitehouse Station, New Jersey, USA), VRCTC-310 (Ventech Research) and EGF fusion toxin (Seragen Inc., Hopkinton, Massachusettes) including. These and other EGFR inhibitors can also be used in the present invention.

VEGF inhibitors such as SU-5416 and SU-6668 (Sugen Inc., South San Francisco, California, USA) may also be combined with the compound of formula 1. Examples of VEGF inhibitors include WO99 / 24440 (published on May 20, 1999), PCT international patent application PCT / IB99 / 00797 (filed on May 3, 1999), WO95 / 21613 (published on August 17, 1995). , WO99 / 61422 (published on December 2, 1999), US Patent 5,834,504 (issued on November 10, 1998), WO98 / 50356 (published on November 12, 1998), US Patent 5,883. 113 (issued March 16, 1999), US Patent 5,886,020 (issued March 23, 1999), US Patent 5,792,783 (issued August 17, 1998), WO99 / 10349 (1999). Published on March 4, 1997), WO97 / 32856 (published on September 12, 1997), WO97 / 22596 (on June 26, 1997) Open), WO 98/54093 (published December 3, 1998), WO 98/02438 (published January 22, 1998), WO 99/16755 (published April 8, 1999), and WO 98/02437 (1998 1). All of which are incorporated herein by reference in their entirety.

ErbBL receptor inhibitors such as GW-282974 (Glaxo Wellcome plc), and monoclonal antibodies AR-209 (Arorex Pharmaceuticals Inc., The Woodlands, Texas, USA) and 2B-1 (Chiron) are also combined with the compound of Formula 1. For example, WO98 / 02434 (published on January 22, 1998), WO99 / 35146 (published on July 15, 1999), WO99 / 35132 (published on July 15, 1999), WO98 / 02437 (1998) Published on Jan. 22), WO 97/13760 (published on Apr. 17, 1997), WO 95/19970 (published on Jul. 27, 1995), US Pat. No. 5,587,458 (issued on Dec. 24, 1996), And US Pat. No. 5,877,305 (issued March 2, 1999), all of which are incorporated by reference. Entirety by which is incorporated herein. ErbB2 receptor inhibitors useful in the present invention are also described in US Patent Application No. 60 / 117,341 (filed January 27, 1999), and US Provisional Patent Application No. 60 / 117,346 (January 27, 1999). Both of which are incorporated herein by reference in their entirety. The erbB2 receptor-inhibiting compounds and substances described in the PCT application, US patent, and US provisional patent application referred to above, as well as other compounds and substances that inhibit the erbB2 receptor, are combined with the compounds of formula 1 according to the present invention. Can be used.

The compounds of Formula 1 may also be used to treat other substances useful for treating abnormal cell proliferation or cancer, such as but not limited to substances that can enhance an anti-tumor immune response, such as CTLA4 (cytotoxic lymphocyte antigen) antibodies. , And other substances that can block CTLA4; and antiproliferative substances such as farnesyl protein transferase inhibitors. Specific CTLA4 antibodies that can be used in the present invention include those described in US Provisional Patent Application 60 / 113,647 (filed December 23, 1998), which is incorporated by reference in its entirety, but other CTLA4 antibodies may also be used. Can be used in the present invention.

The compound of formula 1 can also be administered in a method for inhibiting abnormal cell growth in a mammal in combination with radiation therapy. Techniques for administering radiation therapy are known in the art, and these techniques can be used in the treatment of combinations described herein. Administration of the compounds of the invention in this combination therapy can be determined as described herein.

A cdk5 inhibitor, eg, a compound of Formula 1, can also be administered with a COX-II inhibitor to treat Alzheimer's disease, mild cognitive impairment, or age-related cognitive decline. Specific examples of COX-II inhibitors useful in this aspect of the invention are given above, where the use of a COX-II inhibitor in combination with a compound of formula 1 for the treatment of abnormal cell proliferation Is described. An effective amount of a cdk5 inhibitor, eg, a COX-II inhibitor in combination with a compound of Formula 1, can usually be determined by one skilled in the art. The recommended effective daily dose range for a COX-II inhibitor in combination with a cdk5 inhibitor is about 0.1 to about 25 mg / kg body weight. An effective daily amount of a cdk5 inhibitor is about 0.0001 to about 10 mg / kg body weight. In some cases, the amount of COX-II inhibitor and / or cdk5 inhibitor when combined is the same desired in the treatment of Alzheimer's disease, mild cognitive impairment, or age-related cognitive decline. May be less than required based on individual criteria to achieve the desired effect.

A cdk5 inhibitor, eg, a compound of Formula 1, can also be administered in combination with an NK-1 receptor antagonist for the treatment of depression or anxiety. NK-1 receptor antagonists such as those listed herein can antagonize the NK-1 receptor, thereby inhibiting tachykinin-mediated responses, such as those mediated by substance P It is a substance. A variety of NK-1 receptor antagonists are known in the art, and any such NK-1 receptor antagonist may be used in combination with a cdk5 inhibitor, eg, a compound of formula 1, as described above. Can be used in the present invention. NK-1 receptor antagonists are, for example, US Pat. No. 5,716,965 (issued February 10, 1998); US Pat. No. 5,852,038 (issued December 22, 1998); WO 90/05729 (International Publication). US Patent 5,807,867 (issued September 15, 1998); US Patent 5,886,009 (issued March 23, 1999); US Patent 5,939,433 (Issued August 17, 1999); US Patent 5,773,450 (issued June 30, 1998); US Patent 5,744,480 (issued April 28, 1998); US Patent 5,232, 929 (issued August 3, 1993); US Patent 5,332,817 (issued July 26, 1994); US Patent 5,122,525 (issued June 16, 1992); , 843,966 (issued December 1, 1998); US Patent 5,703,240 (issued December 30, 1997); US Patent 5,719,147 (issued February 17, 1998); It is described in Patent 5,637,699 (issued on June 10, 1997). Each of the aforementioned US patents and the aforementioned published PCT international applications are hereby incorporated by reference in their entirety. The compounds described in the above literature having NK-1 receptor antagonistic activity can be used in the present invention. However, other NK-1 receptor antagonists can also be used in the present invention.

An effective amount of an NK-1 receptor antagonist when combined with a cdk5 inhibitor, eg, a compound of Formula 1, can usually be determined by one skilled in the art. The recommended effective daily dose range for an NK-1 receptor antagonist when combined with a cdk5 inhibitor is from about 0.07 to about 21 mg / kg body weight. In some cases, the amount of NK-1 receptor antagonist and / or cdk5 inhibitor when combined is on an individual basis to achieve the same desired effect in the treatment of depression or anxiety. May be less than required on the basis.

The invention also provides for combining a cdk5 inhibitor, eg, a compound of Formula 1, with a 5HT _1D receptor antagonist for the treatment of depression or anxiety. A 5HT _1D receptor antagonist as listed herein is an agent that antagonizes the 5HT _1D subtype of the serotonin receptor. Any such substance can be used in the present invention as described above in combination with a cdk5 inhibitor, eg, a compound of Formula 1. Substances having 5HT _1D receptor antagonistic activity are disclosed in WO98 / 14433 (International Publication Date April 9, 1998); WO97 / 36867 (International Publication Date October 9, 1997); WO94 / 21619 (International Publication Date 1994) US Patent 5,510,350 (issued 23 April 1996); US Patent 5,358,948 (issued 25 October 1994); and GB 2276162 A (21 September 1994); Published). These 5HT _1D receptor antagonists and others may also be used in the present invention. The foregoing published patent applications and patents are incorporated herein by reference in their entirety.

An effective amount of a 5HT1 _D receptor antagonist when combined with a cdk5 inhibitor, eg, a compound of Formula 1, can usually be determined by one skilled in the art. The recommended effective daily dose range for a 5HT1 _D receptor antagonist when combined with a cdk5 inhibitor is from about 0.01 to about 40 mg / kg body weight. An effective daily dose of a cdk5 inhibitor is about 0.0001 to about 10 mg / kg body weight. In some cases, the amount of 5HT1 _D receptor antagonist and / or the amount of cdk5 inhibitor when combined is an individual criterion for achieving the same desired effect in the treatment of depression or anxiety. May be less than required.

The present invention also provides pharmaceutical compositions and methods for treating depression or anxiety in mammals comprising a cdk5 inhibitor, such as a compound of formula 1, and an SSRI. Examples of SSRIs that may be combined with cdk5 inhibitors, such as compounds of Formula 1 and pharmaceutically acceptable salts thereof, in a method or pharmaceutical composition include, but are not limited to, fluoxetine, paroxetine, sertraline, and fluvoxamine. Other SSRIs may be combined with or administered with a cdk5 inhibitor, such as a compound of Formula 1 or a pharmaceutically acceptable salt thereof. Other antidepressants and / or anti-anxiety agents that can be combined with or administered with a cdk5 inhibitor, eg, a compound of Formula 1, include WELLBUTRIN, SERZONE, and EFFEXOR.

An effective amount of SSRI when combined with a cdk5 inhibitor, eg, a compound of Formula 1, can usually be determined by one of ordinary skill in the art. The recommended effective daily dose range for SSRIs in combination with a cdk5 inhibitor is about 0.01 to about 500 mg / kg body weight. An effective daily dose of a cdk5 inhibitor is usually about 0.0001 to about 10 mg / kg body weight. In some cases, the amount of SSRI and / or the amount of cdk5 inhibitor when combined is required based on individual criteria to achieve the same desired effect in the treatment of depression or anxiety. There may be less than what is done.

A cdk5 inhibitor, such as a compound of formula 1, or a pharmaceutically acceptable salt thereof, is achieved or facilitated by one or more antipsychotic agents, such as dopaminergic agents, and the treatment alters dopamine neurotransmission. Sometimes combined for the treatment of possible diseases or symptoms such as schizophrenia. An example of an antipsychotic that may be combined with the compounds of the present invention is ziprasidone (5- (2- (4- (1,2-benzisothiazol-3-yl) -1-piperazinyl) ethyl) -6- Chloro-1,3-dihydro-2H-indol-2-one; US Pat. No. 4,831,031 and US Pat. No. 5,312,925; Olanzapine (2-methyl-4- (4-methyl-1-piperazinyl-) 10H-thieno (2,3b) (1,5) benzodiazepine; U.S. Pat. No. 4,115,574 and U.S. Pat. No. 5,229,382); Risperidone (3- [2- [4- (6-fluoro-1,2, -Benzisoxazol-3-yl) -1-piperidinyl] ethyl] 6,7,8,9-tetrahydro-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one; rice Patent 4,804,663); L-745870 (3- (4- (4-chlorophenyl) piperazin-1-yl) methyl-1H-pyrrolo (2,3-b) pyridine; US Pat. No. 5,432,177) Sonepiperazole (S-4- (4- (2- (isochroman-1-yl) ethyl) piperazin-1-yl) benzenesulfonamide; US Pat. No. 5,877,317); RP 62203 (phananserin; 2- ( 3- (4- (4-fluorophenyl) -1-piperazinyl) propyl) naphtho (1,8-c, d) isothiazole-1,1-dioxide; US Pat. No. 5,021,420); NGD 941 (US Patent 5,633,376 and US Pat. No. 5,428,165); Balapperidone ((1α, 5α, 6α) -3- (2- (6- (4-fluorophenyl)- -Azabicyclo (3.2.0) hept-3-yl) ethyl) -2,4 (1H, 3H) -quinazolinedione; US Pat. No. 5,475,105); Fresinoxane ((+)-4-fluoro-N -[2- [4-5- (2-hydroxymethyl-1,4-benzodioxanyl)]-1-piperazinyl] ethyl] benzamide; U.S. Pat. No. 4,833,142); and gepirone (4,4- Dimethyl-1- (4- (4- (2-pyrimidinyl) -1-piperazinyl) butyl) -2,6-piperidinedione; U.S. Pat. No. 4,423,049) Patents listed above in this paragraph Each of which is incorporated herein by reference in its entirety The effective daily dose of a cdk inhibitor is usually from about 0.0001 to about 10 mg / kg body weight, a cdk5 inhibitor, eg, a compound of formula 1 The amount of any antipsychotics mentioned above to be considered to be used in combination with is an amount that is known in the art to be useful for treating mental symptoms. However, in some cases, the amount of antipsychotic drug and / or the amount of cdk5 inhibitor when combined is an individual criterion for achieving the same desired effect in the treatment of depression or anxiety. May be less than required. Furthermore, it should be understood that the present invention also encompasses combining cdk5 inhibitors, such as compounds of formula 1, with antipsychotic or dopaminergic drugs other than those listed above.

The recommended amount for Sonepiperazole in the above combination with a cdk5 inhibitor, eg a compound of Formula 1, is about 0.005 to about 50 mg / kg of patient body weight / day. The recommended amount of RP62203 in such a combination is about 0.20 to about 6 mg / kg of patient weight / day. The recommended amount of NGD941 in such a combination is about 0.1 to about 140 mg / kg of patient weight / day. The recommended amount of balaperidone in such combinations is from about 1 to about 100 mg / kg body weight / day. The recommended flesinoxane in such a combination is about 0.02 to about 1.6 mg / kg body weight / day. The recommended amount for gepirone in such combinations is about 0.01 to about 2 mg / kg body weight / day, preferably about 0.05 to about 100 mg / kg body weight / day. The recommended amount of L-745870 in such a combination is about 0.01 to about 250 mg / kg body weight / day, preferably about 0.05 to about 100 mg / kg body weight / day. The recommended amount of risperidone in such a combination is about 0.05 to about 50 mg / kg body weight / day. The recommended amount of olanzapine in such a combination is about 0.0005 to about 0.6 mg / kg body weight / day. The recommended amount of ziprasidone in such a combination is about 0.05 to about 10 mg / kg body weight / day. However, in some cases for each of the aforementioned combinations, the amount of each specific component in the combination is based on individual criteria to achieve the same desired effect in the treatment of mental symptoms. May be less than required.

The present invention also provides a pharmaceutical composition and method for treating Alzheimer's disease, mild cognitive impairment, or age-related cognitive decline, comprising a cdk5 inhibitor, such as a compound of formula 1, and acetylcholinesterase inhibition What comprises an agent is provided. Acetylcholinesterase is known in the art, and any such acetylcholinesterase inhibitor can be used in the pharmaceutical compositions or methods described above. Examples of acetylcholinesterases that can be used in the present invention are: ARICEPT (donepezil; US Pat. No. 4,895,841); EXELON (rivastigmine ((S)-[N-ethyl-3- [1- (dimethylamino) ethyl] phenyl) Carbamate); US Pat. No. 5,603,176 and US Pat. No. 4,948,807); metrifonate ((2,2,2-trichloro-1-hydroxyethyl) phosphonic acid dimethyl ester; US Pat. No. 2,701,225) And US Pat. No. 4,950,658); Galantamine (US Pat. No. 4,663,318); Physostigmine (Forest, USA); Tacrine (1,2,3,4-tetrahydro-9-acridinamine; US Pat. No. 4,816) , 456); Huperzine A (5R- (5α, 9β, 11E))-5-amino- 1-ethylidene-5,6,9,10-tetrahydro-7-methyl-5,9-methanecycloocta (b) pyridin-2- (1H) -one); and icopezil (5,7-dihydro -3- (2- (1- (phenylmethyl) -4-piperidinyl) ethyl) -6H-pyrrolo (3,2-f) -1,2-benzisoxazol-6-one; US Pat. No. 5,750 542 and WO 92/17475). The patents and patent applications listed above in this paragraph are hereby incorporated by reference in their entirety.

An effective amount of an acetylcholinesterase inhibitor when combined with a cdk5 inhibitor, eg, a compound of Formula 1, can usually be determined by one skilled in the art. The recommended effective daily range for an acetylcholinesterase inhibitor when combined with a cdk5 inhibitor is from about 0.01 to about 10 mg / kg body weight. An effective daily dose of a cdk5 inhibitor is about 0.0001 to about 10 mg / kg body weight. In some cases, the amount of acetylcholinesterase and / or the amount of cdk5 inhibitor when combined has the same desired effect in treating Alzheimer's disease, mild cognitive impairment, or age-related cognitive decline. May be less than required based on individual criteria to achieve.

The invention also includes Huntington's disease, stroke, spinal cord injury, traumatic brain injury, multiple cerebral infarction dementia, epilepsy, amyotrophic lateral sclerosis, pain, virus-induced dementia such as AIDS-induced dementia, bacterial infection Neurodegeneration, migraine, hypoglycemia, urinary incontinence, cerebral ischemia, multiple sclerosis, Alzheimer's disease, Alzheimer's type senile dementia, mild cognitive impairment, age-related cognitive decline, Treats vomiting, cortical basal ganglia degeneration, fist dementia, Down's syndrome, muscular dystrophy, Niemann-Pick disease, Pick's disease, confounded prion disease, progressive supranuclear palsy, inferior lateral sclerosis, and subacute sclerosing panencephalitis To do so, it is provided to combine a cdk5 inhibitor with a neuroprotective agent, such as an NMDA receptor antagonist. Examples of NMDA receptor antagonists that can be used in the present invention include (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol ( US Pat. No. 5,272,160), eliprozil (US Pat. No. 4,690,931), and gavesteinel (US Pat. No. 5,373,018). In addition, other NMDA receptor antagonists that can be used in the present invention are US Pat. No. 5,373,018; US Pat. No. 4,690,931; US Pat. No. 5,272,160; US Pat. No. 5,185,343; U.S. Pat. No. 5,744,483; WO 97/23216; WO 97/23215; WO 96/37214; WO 96/37222; WO 96/06081; WO 97/23458; WO 97/32581; No. 08 / 292,651 (filed Aug. 18, 1994). Each of the foregoing patents and patent applications is hereby incorporated by reference in its entirety.

An effective daily dose of a cdk5 inhibitor when combined with an NMDA receptor antagonist is usually about 0.0001 to about 10 mg / kg body weight. The amount of NMDA receptor antagonist contemplated for use in combination with a cdk5 inhibitor, eg, a compound of Formula 1, for the treatment of any of the aforementioned diseases, eg, Alzheimer's disease, is typically about 0.02 mg / kg / kg. Within the range of day to about 10 mg / kg / day. However, in some cases, the amount of NMDA antagonist and / or the amount of cdk5 inhibitor when combined is required based on individual criteria to achieve the same desired effect in the treatment of the disorder. There may be less than what is done.

The present invention also provides for combining cdk5 inhibitors with certain substances that can treat stroke or traumatic brain injury, such as TPA, NIF, or potassium channel modulators, such as BMS-204352. Such combinations are useful for treating neurodegenerative disorders such as stroke, spinal cord injury, traumatic brain injury, multiple cerebral infarct dementia, epilepsy, pain, Alzheimer's disease, senile dementia and the like.

Effective amounts of the compounds of the invention and other materials for the therapeutic and pharmaceutical compositions of the combinations described above are generally known to the effective amounts of the compounds described herein and other materials known in the art. Alternatively, it may be determined by one skilled in the art based on what is already described, for example, the quantities listed in the patents and patent applications listed above which are incorporated herein. Formulations and routes of administration for such treatments and compositions are combined with information and compositions described herein for compositions and treatments comprising the compounds of the invention as the sole active agent. May be based on information provided about other substances.

Specific compounds of Formula 1 that inhibit cdk2, cdk5, or GSK-3 can be determined using biological assays known to those of skill in the art, such as those described below.

The specific activity of the compound of formula 1 for inhibition of cdk5 or cdk2 can be confirmed, for example, by the following assay using materials available to those skilled in the art.

Enzymatic activity can be assayed as the incorporation of [33P] from the gamma phosphate of [33P] ATP (Amersham, cat. No. AH-9968) into the biotinylated peptide substrate PKTPKKAKKL. In such an assay, the reaction is performed in a buffer containing 50 mM Tris-HCl, pH 8.0; 10 mM MgCl ₂ , 0.1 mM Na ₃ UO ₄ , and 1 mM DTT. The final concentration of ATP is about 0.5 μM (final specific activity 4 μCi / nmol) and the final concentration of substrate is 0.75 μM. Reactions that are inhibited by the addition of either cdk5 and activated protein p25 or cdk2 and activated cyclin E can be performed at room temperature for about 60 minutes. The reaction was performed using 0.6 times the amount of SPA beads (Amersham cat. No. RPNQ 0007) is stopped by addition of a buffer containing. The radioactivity associated with the beads is quantified by a scintillation counter.

The specific activity of the compound of Formula 1 for inhibition of GSK-3 can be determined in both cell-free and cell-based assays, both described in the art (eg, WO 99/65897). Cell-free assays typically include GSK-3, peptide substrate, radiolabeled ATP (eg, γ ³³ P- or γ ³² P-ATP, both available from Amersham, Arlington Heights, Illinois), magnesium ions, and assays Can be carried out by incubating with the compound to be produced. The mixture is incubated for a period of time during which the radiolabeled phosphate is incorporated into the peptide substrate by GSK-3 activity. The reaction mixture is typically used to remove unreacted radiolabeled ATP after first transferring all or part of the enzyme reaction mixture to a well containing a uniform amount of ligand capable of binding to the peptide substrate. To be washed. The amount of ³³ P or ³² P remaining in each well after washing is subsequently quantified to determine the amount of radiolabeled phosphate incorporated into the peptide substrate. Inhibition is observed as a decrease in the incorporation of radiolabeled phosphate into the peptide substrate as compared to the control. An example of a GSK-3 peptide substrate suitable for the assay is the SGSG-binding CREB peptide sequence derived from CREB DNA-binding protein described in Wang, et al., Anal. Biochem., 220: 397-402 (1994). GSK-3 purified for the assay is obtained from cells transfected with a human GSK-3β expression plasmid, as described, for example, in Stambolic, et al., Current Biology 6: 1664-68 (1996). Obtainable. WO99 / 65897; Wang et al., And Stambolic et al., Are hereby incorporated by reference in their entirety.

Another example of a GSK-3 assay similar to that described above is as follows: gamma phosphorus of [33P] ATP (Amersham, cat. No. AH-9968) into the biotinylated peptide substrate PKTPKKAKKL It can be assayed as [33P] incorporation from the acid salt. In such an assay, the reaction is performed in a buffer containing 50 mM Tris-HCl, pH 8.0; 10 mM MgCl ₂ , 0.1 mM Na ₃ UO ₄ , and 1 mM DTT. The final concentration of ATP is about 0.5 μM (final specific activity 4 μCi / nmol) and the final concentration of substrate is 0.75 μM. Reactions that are inhibited by the addition of either cdk5 and activated protein p25 or cdk2 and activated cyclin E can be performed at room temperature for about 60 minutes. The reaction was performed using 0.6 times the amount of SPA beads (Amersham cat. No. RPNQ 0007) is stopped by addition of a buffer containing. The radioactivity associated with the beads is quantified by a scintillation counter.

All of the title compounds of the following examples have an IC ₅₀ that inhibits phosphorylation of peptide substrates less than about 50 μM when assayed for cdk5 inhibitors according to the foregoing assay.

Some of the title compounds in the examples below are assayed for GSK-3 inhibition using an assay as described above, and all tested are for inhibition of GSK-3β less than about 50 μM. It had an IC _50.

The following examples illustrate the invention. However, it is to be understood that the invention is not intended to be limited by the details of the following examples, as fully described herein and listed in the claims.

Example Preparation 11-Cyclobutyl-4-nitro-1H-imidazole 1,4-dinitroimidazole (237 mg, 1.5 mmol, J. Phys. Chem. 1995, 99, 5009-5015) and cyclobutylamine (107 mg, 1. 5 mmol) / methanol (10 mL) solution was added at 23 ° C. The reaction mixture was stirred (6 hours followed by removal of the solvent in vacuo and the resulting residue was purified by silica gel chromatography (1: 1 hexane-ethyl acetate) to yield 230 mg (92% yield) of 1- Cyclobutyl-4-nitro-1H-imidazole was given; 1H NMR (400 MHz, CDCl ₃ ) δ 7.81 (s, 1H), 7.45 (s, 1H), 4.64 (m, 1H), 2. . 6 (m, 2H), 2.4 (m, 2H), 2.0 (m, 2H); MS (AP / Cl): 168.2 (M + H) + Note: 1,4-nitroimidazole high It is an energetic metastable material and should always be stored in a freezer when not in use.The thermodynamic measurement shows the potential for energy to explode at 35 ° C under adiabatic conditions. Can be created Extreme care should always be taken when using this material.

Preparation 21-Cyclopentyl-4-nitro-1H-imidazole The reaction was carried out with cyclopentylamine and 1,4-dinitroimidazole using the procedure of Preparation 1, whereby 205 mg (75% yield) of 1-cyclopentyl-4-nitro-1H-imidazole was produced; 1H NMR (400 MHz, CDCl ₃ ) δ 7.77 (s, 1H), 7.45 (s, 1H), 4.49 (m, 1H), 2.25 (m, 2H), 2.0-1.7 (m, 6H); MS (AP / Cl): 182.2 (M + H) ⁺ .

Preparation 34-Nitro-1- (cis-3-phenyl-cyclobutyl) -1H-imidazole This reaction was performed using cis-3-phenylcyclobutylamine (J. Med. Pharm. Chem 1960, 2, 687-691; ACIEE 1981). , 20, 879-880) and 1,4-dinitroimidazole using the procedure for Preparation 1, whereby 46 mg (46% yield) of 4-nitro-1- (cis-3) -Phenyl-cyclobutyl) -1H-imidazole was produced; 1H NMR (300 MHz, CDCl ₃ ) δ 7.9 (s, 1H), 7.55 (s, 1H), 7.4-7.2 (m, 5H ), 4.73 (m, 1H), 3.48 (m, 1H), 3.12 (m, 2H), 2.54 (m, 2H); MS (AP / Cl): 244 (M + H) ⁺ .

Example 1 N- (1-Cyclobutyl-1H-imidazol-4-yl) -2-quinolin-6-yl-acetamide Parr hydrogenation bottle was prepared against 1-cyclobutyl-4-nitro-1H-imidazole (Preparation 1, 150 mg, 0.9 mmol) and ethyl acetate (10 mL) followed by 10% Pd-carbon (250 mg). The reaction mixture was placed in a Parr hydrogenation bottle apparatus and allowed to react at 23 ° C. and 50 psi for 6 hours. The contents of the bottle were rinsed with a nitrogen atmosphere in a flame-dried flask using filtered rice through a simple pad of Celite and dry methylene chloride (25 mL). Et ₃ N (626 μL, 4.5 mmol) was added and the reaction was cooled to −10 ° C. 6-Quinolylacetic acid (168 mg, 0.9 mmol) and tripropylphosphonic anhydride (530 μL, 1.7 M solution / acetic acid) were subsequently added and the mixture was stirred at −10 ° C. for 2 hours. The solution was diluted with methylene chloride (50 mL) and washed with water (2 ×). The aqueous phase was extracted with methylene chloride (3x) and the organic phases were combined and washed with salt solution (1x). The solvent is removed in vacuo, the residue is adsorbed on silica gel and chromatographed using a Biofage Flash 12 system with a SIM attachment (40: 1 methylene chloride-methanol), thereby yielding 130 mg (47% yield). N- (1-cyclobutyl-1H-imidazol-4-yl) -2-quinolin-6-yl-acetamide (title compound) was formed; 1H NMR (300 MHz, CDCl ₃ ) δ 9.48 (s, 1H) , 8.87 (dd, J = 1.6, 4.3 Hz, 1H), 8.11 (m, 2H), 7.76 (d, J = 1.8 Hz, 1H), 7.67 (dd, J = 2.0, 8.7 Hz, 1H), 7.44 (d, J = 1.6 Hz, 1H), 7.38 (m, 1H), 7.25 (d, J = 1.6 Hz, 1H) ), 4.5 (m, 1 H), 3.90 (s, 2H), 2.4 (m, 2H), 2.3 (m, 2H), 1.85 (m, 2H); MS (AP / Cl): 307.1 ( M + H) ⁺ .

Example 2 N- (1-Cyclopentyl-1H-imidazol-4-yl) -2- (4-methoxy-phenyl) -acetamide Carried out with -1H-imidazole (Preparation 2), whereby N- (1-cyclopentyl-1H-imidazol-4-yl) -2- (4-methoxy-phenyl) -acetamide in 32% yield (26.5 mg); 1H NMR (400 MHz, CDCl ₃ ) δ 8.54 (s, 1H), 7.35 (s, 1H), 7.24 (m, 2H), 6.87 (d , J = 1.7 Hz), 4.36 (m, 1H), 3.78 (s, 3H), 3.64 (s, 2H), 2.1 (m, 2H), 1.8 (m, 4H), 1.6 (m, 2H); MS (AP / l): 300.3 (M + H ) +.

Example 3 N- [1- (cis-3-Phenyl-cyclobutyl) -1H-imidazol-4-yl] -2-quinolin-6-yl-acetamide The procedure of Example 1 is 6-quinolylacetic acid and 4-nitro-1- Performed with (cis-3-phenylcyclobutyl) -1H-imidazole (Preparation 3), whereby N- [1- (cis-3-phenyl-cyclobutyl) -1H-imidazol-4-yl]- 2-Quinolin-6-yl-acetamide was prepared in 38% yield; 1H NMR (300 MHz, CDCl ₃ ) δ 8.93 (m, 1H), 8.12 (m, 2H), 7.79 ( d, J = 1.5 Hz, 1H), 7.71 (m, 1H), 7.55 (d, J = 1.5 Hz, 1H), 7.41 (dd, J = 4.3, 8.4 Hz) , 1H),
7.37-7.22 (m, 5H), 4.57 (m, 1H), 3.96 (s, 2H), 3.33 (m, 1H), 2.95 (m, 2H), 2 .49 (m, 2H); MS (AP / Cl): 383.0 (M + H) ⁺ .

Example 4 (1-Cyclobutyl-1H-imidazol-4-yl) -carbamic acid phenyl ester Parr in a hydrogenation bottle was charged with 1-cyclobutyl-4-nitro-1H-imidazole (preparation 1.3 g, 18 mmol) and ethyl acetate ( 70 mL) followed by 10% Pd-carbon (1.2 g) under a nitrogen atmosphere. The mixture was hydrogenated under 50 psi H ₂ at 23 ° C. for 6 hours. The mixture was then filtered through a pad of celite rinsed with methylene chloride (140 mL) into a flame-dried flask. The resulting solution was cooled to −78 ° C. and diisopropylethylamine (2.3 g, 18 mmol) was added followed by phenyl chloroformate (2.5 g, 16.2 mmol) dropwise. After 30 minutes, methanol containing acetic acid (1.8 mmol) was added. The reaction mixture was transferred to a separatory funnel, which was diluted with ethyl acetate (200 mL) and washed with water (2 ×). The aqueous phase was extracted with ethyl acetate (2 × 10 mL). The organic phases were combined, washed with salt solution (2 ×) and then dried (MgSO ₄ ), filtered and concentrated in vacuo. The crude product was adsorbed onto silica gel and purified by silica gel chromatography (1: 1 hexane-ethyl acetate), thereby 3 g (65% yield) of (1-cyclobutyl-1H-imidazol-4-yl) - carbamic acid phenyl ester _{occurs; 1H NMR (400MHz, CDCl 3} ) δ7.4-7.3 (m, 2H), 7.22-7.18 (m, 3H), 4.5 (m, 1H ), 2.46-2.30 (m, 4H), 1.83 (m, 2H); MS (AP / Cl): 258.2 (M + H) ⁺ .

Example 51-(1-Cyclobutyl-1H-imidazol-4-yl) -3-Isoquinolin-5-yl-urea One drum vial with septum and screw cap for (1-cyclobutyl-1H-imidazole-4- Yl) -carbamic acid phenyl ester (Example 4, 50 mg, 0.19 mmol), 5-aminoisoquinoline (30 mg, 0.21 mmol), and 1: 1 dioxane-DMF (1 mL) were added. The reaction mixture was heated at 70 ° C. for 2 hours. The reaction mixture was adsorbed onto silica gel and purified by silica gel chromatography (40: 1 chloroform-methanol), whereby 30 mg (52% yield) of 1- (1-cyclobutyl-1H-imidazol-4-yl) ) -3-Isoquinolin-5-yl-urea; 1H NMR (400 MHz, CD ₃ OD) δ 9.21 (d, J = 1.7 Hz, 1H), 8.45 (d, J = 6.2 Hz) , 1H), 8.24 (d, J = 7.5 Hz, 1H), 7.98 (d, J = 5.4 Hz, 1H), 7.84 (dd, J = 2.3, 8.3 Hz, 1H), 7.66 (m, 1H), 7.54 (s, 1H), 7.12 (brs, 1H), 4.66 (m, 1H), 2.5-2.3 (m, 4H) ), 1.9 (m, 2H); MS (AP / Cl): 308.0 M ⁺ H) +.

Preparation 4N- [1- (cis-3-Azido-cyclobutyl) -1H-imidazol-4-yl] -2-naphthalen-1-yl-acetamide Step 1 3-Benzyloxycyclobutylamine (43.4 mg, 24. 5 mmol, Chem. Ber. 1957, 90, 1424-1432) was dissolved in methanolic hydrogen chloride (saturated, 450 mL) followed by the addition of 10% Pd-carbon (4 g). The mixture was hydrogenated with 50 psi H ₂ for 6 hours. The mixture was filtered and concentrated in vacuo to give about 35 mg of oil. The oil was dissolved in methanol (600 mL), cooled to 0 ° C. and treated with potassium hydroxide (13.7 g, 245 mmol). When the pH was 10, a solution of 1,4-dinitroimidazole (42.7 g, 270 mmol) / methanol (200 mL) (prepared by dissolving 1,4-dinitroimidazole in methanol at 0 ° C.) was added ( caution : 1,4-dinitroimidazole is a high energy metastable material and should always be stored in a freezer when not in use.The thermodynamic measurement shows that it explodes at 35 ° C. under adiabatic conditions. It shows that it can potentially generate as much energy, and extreme care should always be taken when using this material). The resulting orange suspension was gradually warmed to 23 ° C. overnight. The solvent was removed in vacuo and the resulting residue was purified by passing through a large plug of silica gel (20: 1 chloroform-methanol), thereby 19 g (42% yield) of 3- (4-nitro -Imidazol-1-yl) -cyclobutanol formed as a 1: 1 mixture of cis-trans isomers; 1H NMR (400 MHz, CD ₃ OD) δ 8.29 (s, 1H), 8.27 (s, 1H ), 7.84 (s, 1H), 7.81 (s, 1H), 5.02 (m, 1H), 4.53 (m, 1H), 4.37 (m, 1H), 4.10 (M, 1H), 2.95 (m, 2H), 2.7 (m, 2H), 2.5 (m, 2H), 2.3 (m, 2H); MS (AP / Cl): 184 .0 (M + H) ⁺ .

Step 2 3- (4-Nitro-imidazol-1-yl) -cyclobutanol (Preparation 4, Step 1; 4 g, 22 mmol) was added Et ₃ N (7.7 mL, 55 mmol) / methylene chloride (150 mL) followed by Treated with p-toluenesulfonyl chloride (TsCl) (5 g, 26.4 mmol) and 4-N, N-dimethylaminopyridine (DMAP) (268 mg, 2.2 mmol). The resulting mixture was stirred at room temperature for 24 hours. Analysis by thin layer chromatography showed two new spots. The reaction mixture was diluted with methylene chloride and washed with water (1 ×) and brine (1 ×). The organic layer was dried (MgSo ₄ ), filtered and concentrated in vacuo. Purification by silica gel chromatography (1: 1 to 2: 1 hexane-ethyl acetate) allowed the separation of the trans and cis diastereomers. The first spot eluted (high Rf) is the trans isomer, trans-toluene-4-sulfonic acid 3- (4-nitro-imidazol-1-yl) -cyclobutyl ester (2.7 g, 37% yield). 1H NMR (400 MHz, CDCl ₃ ) δ 7.79 (s, 1H), 7.77 (m, 2H), 7.44 (d, J = 1.7 Hz, 1H), 7.36 (Dd, J = 0.5, 8.0 Hz, 2H), 5.034 (m, 1H), 4.94 (m, 1H), 2.9 (m, 2H), 2.7 (m, 2H) ); MS (AP / Cl): 338.1 (M + H) ⁺ . The second spot eluted is the yield of the cis isomer, cis-toluene-4-sulfonic acid 3- (4-nitro-imidazol-1-yl) -cyclobutyl ester (2.9 g, 39%). 1H NMR (400 MHz, CDCl ₃ ) δ7.8 (m, 3H), 7.43 (d, J = 1.4 Hz, 1H), 7.36 (dd, J = 0.6, 8.5 Hz) , 2H), 4.74 (m, 1H), 4.30 (m, 1H), 3.05 (m, 2H), 2.6-2.5 (m, 2H), 2.45 (s, 3H); MS (AP / Cl): 338.1 (M + H) ⁺ . The relative composition was determined by the nuclear overhauser effect.

Step 3 trans-Toluene-4-sulfonic acid 3- (4-nitro-imidazol-1-yl-cyclobutyl ester (Preparation 4, Step 2; 590 mg, 1.75 mmol) with 10% Pd-carbon (500 mg) Mixed in ethyl acetate (30 mL) The mixture was reacted for 6 hours at room temperature under 50 psi H _{2. The} mixture was filtered through celite into a flame-dried flask maintained in a nitrogen atmosphere. Et ₃ N (1.22 mL, 8.75 mmol) followed by 1-naphthylacetic acid (326 mg, 1.75 mmol) and tripropylphosphonic anhydride (1.1 mL, 1.7 M solution / ethyl acetate, 1.75 mmol) The mixture was stirred at room temperature for 1 hour and then diluted with ethyl acetate and washed with water and brine.The organic phase was dried, filtered and concentrated in vacuo. Siri Purification by gel chromatography (50: 1 chloroform-methanol) whereby 600 mg (72% yield) of trans-toluene-4-sulfonic acid-3- [4- (2-naphthalen-1-yl-acetyl) Amino) -imidazol-1-yl] -cyclobutyl ester was produced; 1H NMR (400 MHz, CDCl ₃ ) δ 7.9 (m, 2H), 7.85 (m, 2H), 7.76 (d, J = 8.3 Hz, 2H), 7.48 (m, 2H), 7.42 (m, 2H), 7.33 (m, 2H), 7.04 (s, 1H), 4.96 (m, 1H), 4.73 (m, 1H), 2.7 (m, 4H), 2.44 (s, 3H); MS (AP / Cl): 476.2 (M + H) ⁺ .

Step 4 trans-Toluene-4-sulfonic acid 3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl ester (Preparation 4, Step 3; 593 mg, 1. 25 mmol) was mixed with sodium azide (813 mg, 12.5 mmol) in ethanol (15 mL), water (5 mL), and chloroform (5 mL). The mixture was heated at reflux with stirring for 96 hours. The solvent was removed in vacuo and the residue was diluted with water and extracted with methylene chloride. The organic phase was dried (MgSO ₄ ), filtered and concentrated in vacuo. Purification by silica gel chromatography (50: 1 chloroform-methanol) gave 340 mg (79% yield) of N- [1- (cis-3-azido-cyclobutyl) 1H-imidazol-4-yl] -2-naphthalene- 1-yl-acetamide was produced; 1H NMR (400 MHz, CDCl ₃ ) δ 8.41 (s, 1H), 7.98 (d, J = 6.4 Hz, 1H), 7.87 (m, 1H) 7.82 (m, 1H), 7.5 (m, 2H), 7.45 (m, 3H), 7.08 (d, J = 1.7 Hz, 1H), 4.2 (m, 3H) ), 3.75 (m, 1H), 2.85 (m, 2H), 2.35 (m, 2H); MS (AP / Cl): 347.2 (M + H) ⁺ .

Example 6 N- [1- (cis-3-amino-cyclobutyl) -1H -imidazol-4-yl] -2-naphthalen-1-yl-acetamide N- [1- (cis-3-amino-cyclobutyl) -1H -Imidazol-4-yl] -2-naphthalen-1-yl-acetamide (Preparation 4, Step 4; 330 mg, 0.95 mmol) was added to triphenylphosphine (301 mg, 1.15 mmol) / tetrahydrofuran (10 mL) and water ( 1 mL) and 23 ° C. The solution was stirred at room temperature for 18 hours. The solvent was removed in vacuo and the resulting residue was purified by chromatography on silica gel (20: 1: 0.5 chloroform-methanol-ammonium hydroxide), whereby 289 mg (95% yield) of N- [1- (cis-3-amino-cyclobutyl) -1H-imidazol-4-yl] -2-naphthalen-1-yl-acetamide was formed; 1H NMR (400 MHz, CD ₃ OD) δ 8.05 (d, J = 7.5 Hz, 1H), 7.87 (d, J = 7.9 Hz, 1H), 7.79 (d, J = 9.0 Hz, 1H), 7.45 (m, 5H), 7. 35 (s, 1H), 4.26 (m, 1H), 4.16 (s, 2H), 3.29 (m, 2H), 3.16 (m, 1H), 2.75 (m, 2H) ), 2.1 (m, 2H); MS (AP / Cl): 321. (M + H) ^+.

Example 7a 6-Methyl-pyridine-2-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} amide 6- methylpicolinic acid (9. 4mg, 0.07mm
ol) / methylene chloride solution was treated with 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (84 mg) and DMAP (2 mg) at 23 ° C. After stirring for 10 minutes, N- [1- (cis-3-amino-cyclobutyl) -1H-imidazol-4-yl] -2-naphthalen-1-yl-acetamide (Example 6, 20 mg, 0.06 mmol) Was added. The resulting mixture was subsequently stirred for 3 hours. Water was added and the solution was neutralized with sodium hydroxide solution and extracted with ethyl acetate. The organic phase was dried (MgSO ₄ ), filtered and concentrated in vacuo. Purification by silica gel chromatography (20: 1 CHCl ₃ -MeOH) gave 26 mg (95% yield) of 6-methyl-pyridine-2-carboxylic acid {3- [4- (2-naphthalen-1-yl- Acetylamino) -imidazol-1-yl] -cyclobutyl} -amide; 1H NMR (400 MHz, CDCl ₃ ) δ 9.15 (s, 1H), 8.28 (d, J = 8.3 Hz, 1H) , 8.01 (d, J = 7.5 Hz, 1H), 7.96 (d, J = 7.5 Hz, 1H), 7.97 (d, J = 7.5 Hz, 1H), 7.81 ( dd, J = 2.4, 6.6 Hz, 1H), 7.72 (m, 1H), 7.5 (m, 5H), 7.2 (m, 1H), 7.16 (s, 1H) , 4.45 (m, 1H), 4.25 (m, 1H), 4.18 (s, 2H), 2. 8 (m, 2H), 2.60 (s, 3H), 2.40 (m, 2H); MS (AP / Cl): 440.3 (M + H) +.

Example 7b1H-imidazole-4-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide The title compound is as in Example 7a. Prepared; 1H NMR (400 MHz, CD ₃ OD) δ 8.06 (d, J = 7.9 Hz, 1H), 7.87 (m, 1H), 7.80 (d, J = 7.5 Hz, 1H) , 7.7 (s, 1H), 7.64 (s, 1H), 7.5 (m, 6H), 4.44 (m, 1H), 4.32 (m, 1H), 4.18 ( s, 2H), 2.9 (m, 2H), 2.45 (m, 2H); MS (AP / Cl): 415.3 (M + H) ⁺ .

Example 7c The title compound was prepared as in Example 7a; 1H NMR (400 MHz, CD ₃ OD) δ 8.02 (d, J = 7.9 Hz, 1H), 7.84 (d, J = 7.9 Hz, 1H), 7.79 (d, J = 7.5 Hz, 1H), 7.65 (s, 1H), 7.60 (m, 1H), 7.45 (m, 6H), 7.14 (brs) , 1H), 6.71 (d, J = 8.7 Hz, 1H), 4.4 (m, 1H), 4.32 (m, 1H), 4.17 (s, 2H), 2.93 ( m, 2H), 2.5 (m, 2H); MS (AP / Cl): 442.3 (M + H) ⁺ .

Example 7d 3-Methyl-pyridine-2-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} amide The title compound is as in Example 7a. 1H NMR (CD ₃ OD, 400 MHz) δ 8.39 (d, J = 4.2 Hz, 1H), 8.06 (d, J = 8.3 Hz, 1H), 7.87 (d, J = 7.5 Hz, 1 H), 7.80 (d, J = 7.5 Hz, 1 H), 7.69 (d, J = 7.9 Hz, 1 H), 7.5 (m, 7 H), 4.5 (M, 1H), 4.3 (m, 1H), 4.17 (s, 2H), 2.92 (m, 2H), 2.54 (s, 3H), 2.46 (m, 2H) MS (AP / Cl): 440.3 (M + H) ⁺ .

Example 7e 2-Pyridin-3-yl-thiazole-4-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} amide The title compound is Prepared as in Example 7a; 1H NMR (400 MHz, CD ₃ OD) δ 9.21 (d, J = 2.5 Hz, 1H), 8.61 (d, J = 5.0 Hz, 1H), 8.41 (Dd, J = 1.7, 7.9 Hz, 1H), 8.26 (s, 1H), 8.06 (d, J = 7.9 Hz, 1H), 7.86 (d, J = 7. 5 Hz, 1 H), 7.79 (d, J = 7.9 Hz, 1 H), 7.5 (m, 7 H), 4.44 (m, 2 H), 4.17 (s, 2 H), 2.9 (M, 2H), 2.6 (m, 2H); MS (AP / Cl): 509.3 (M + H) ⁺ .

Example 7 f6- {cis-3- [4- (2-Naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutylcarbamoyl} -nicotinic acid methyl ester The title compound was prepared analogously to Example 7a. 1H NMR (400 MHz, CD ₃ OD / CDCl ₃ ) δ 9.15 (d, J = 1.6 Hz, 1H), 9.12 (d, J = 8.0 Hz, 1H), 8.45 (dd, J = 2.0, 8.4 Hz, 1H), 8.16 (d, J = 8.0 Hz, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.48 (m, 6H), 4.45 (m, 2H), 3.96 (s, 3H), 2.94 (m, 2H), 2.58 (m, 2H); MS (AP / Cl): 484.3 (M + H) ⁺ .

EXAMPLE 7g Pyrazine-2-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide The title compound was prepared analogously to Example 7a. 1H NMR (400 MHz, CD ₃ OD) δ 9.23 (d, J = 2.0 Hz, 1H), 9.03 (d, J = 8.0 Hz, 1H), 8.73 (d, J = 2) .4 Hz, 1H), 8.63 (d, J = 1.6, 2.4 Hz, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 8. 0 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.49 (m, 6H), 4.44 (m, 2H), 4.16 (s, 2H), 2.95. (M, 2H), 2.56 (m, 2H); MS (AP / Cl): 427.3 (M + H) ⁺ .

Example 7 hN- {cis-3- [4- (2-Naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -benzamide The title compound was prepared analogously to Example 7a; 1H NMR ( 400 MHz, CD ₃ OD) δ 8.05 (d, J = 8.3 Hz, 1H), 7.99 (d, J = 7.1 Hz, 1H), 7.86 (d, J = 7.5 Hz, 1H) 7.80 (J = 7.1 Hz, 2H), 7.45 (m, 8H), 4.47 (m, 1H), 4.37 (m, 1H), 4.17 (s, 2H), 2.90 (m, 2H), 2.47 (m, 2H); MS (AP / Cl): 425.0 (M + H) ⁺ .

Example 7 i 5-Methyl-pyrazine-2-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide The title compound is Example 7a Prepared similarly; 1H NMR (400 MHz, CD ₃ OD) δ 9.07 (d, J = 1.2 Hz, 1H), 8.5 (d, J = 0.8 Hz, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 7.6 Hz, 1H), 7.79 (d, J = 7.6 Hz, 1H), 7.45 (m, 6H), 4. 40 (m, 2H), 4.16 (s, 2H), 2.93 (m, 2H), 2.61 (s, 3H), 2.54 (m, 2H); MS (AP / Cl): 441.3 (M + H) ⁺ .

Example 7 jN- {cis-3- [4- (2-Naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -isobutyramide The title compound was prepared analogously to Example 7a; 1H NMR (400 MHz, CD ₃ OD) δ 8.01 (d, J = 7.9 Hz, 1H), 7.84 (d, J = 7.5 Hz, 1H), 7.78 (d, J = 7.5 Hz, 1H) ), 7.45 (m, 6H), 4.35 (m, 1H), 4.15 (s, 2H), 4.11 (m, 2H), 2.84 (m, 2H), 2.35. (M, 1H), 2.28 (m, 2H), 1.06 (d, J = 6.6 Hz, 6H); MS (AP / Cl): 391.1 (M + H) ⁺ .

Example 7 k6-Chloro-pyridine-2-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide The title compound is the same as Example 7a Prepared similarly; 1H NMR (400 MHz, CD ₃ OD) δ 8.07 (d, J = 7.9 Hz, 1H), 8.03 (d, J = 7.5 Hz, 1H), 7.94 (m, 1H), 7.87 (d, J = 7.9 Hz, 1H), 7.81 (d, J = 7.9 Hz, 1H), 7.61 (d, J = 7.1 Hz, 1H), 7. 58 (s, 1H), 7.5 (m, 5H), 4.45 (m, 1H), 4.39 (m, 1H), 4.18 (s, 2H), 2.89 (m, 2H) ), 2.63 (m, 2H); MS (AP / Cl): 460.2, 462.2 (M + H) ⁺ .

Example 8 Acylation of N- [1- (cis-3-amino-cyclobutyl) -1H-imidazol-4-yl] -2-naphthalen-1-yl-acetamide (Example 6) with various carboxylic acids followed by Purification was carried out according to the following procedure: 1- (1- (cis-3-amino-cyclobutyl) against carboxylic acid (RCO ₂ H, 1 equivalent, 0.075 mmol) in a screw cap vial of 1 drum. -1H-imidazol-4-yl] -2-naphthalen-1-yl-acetamide (0.33 eq, 8 mg, 0.025 mmol) / methylene chloride (1 mL) was added. Next, PS-carbodiimide (Argonant Technologies, 0.5 eq, 39 mg, 0.038 mmol, 1 mmol / g) was added. The mixture was shaken at 23 ° C. for 24 hours. Note: If the acid was insoluble in methylene chloride, N, N-dimethylformamide (0.5 mL) was added. Each reaction mixture was transferred with methylene chloride (0.5 mL) to a 3 mL SPE cartridge (20 micron frit) with a tare weight of 2 drum vials to recover the solvent. The solvent was pushed through the frit and the polymer was washed with THF (0.5 mL), methylene chloride (0.5 mL), THF (0.5 mL), and methylene chloride (0.5 mL). The solution is concentrated under a stream of nitrogen and the crude product is LCMS (column: 3.9 × 150 mm Waters Symmetry C ₁₈ , 5 μM; flow = 1.0 ml / min; solvent system: A = 0.1% aqueous TFA B = acetonitrile; 10-100% linear gradient over 10 minutes). When the desired parent ion (M + H) was observed, the crude reaction mixture was prepared using preparative HPLC (column: 30 × 150 mm Waters Symmetry C ₁₈ 5 μM; flow = 20 mL / min; solvent system: A = 01% aqueous TFA; B = acetonitrile; 0-100% linear gradient over 15 minutes). The purity of the chromatographed compound was determined by analytical HPLC (column: 2.1 × 150 mm Waters Symmetry C ₁₈ 5 μM; flow: 0.5 mL / min; solvent system: UV: 254 nM and diode array for detection. A = 0.1% aqueous TFA; B = acetonitrile; 0-100% linear gradient over 10 minutes).

The following compounds were prepared by the method described above. Their mass spectrometric data and chromatographic retention times are listed in the table: Example 8a : Quinoline-2-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazole-1 -Yl] -cyclobutyl} -amide Example 8b : 1H-pyrrole-2-carboxylic acid {cis-
3- [4- (2-Naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide Example 8c : N- {cis-3- [4- (2-naphthalen-1-yl) -Acetylamino) -imidazol-1-yl] -cyclobutyl} -2-m-tolyl-acetamide Example 8d : Pyridine-2-carboxylic acid {cis-3- [4- (2-naphthalate-1-yl-acetylamino) ) -Imidazol-1-yl] -cyclobutyl} -amide Example 8e : 2- (3-hydroxy-phenyl) -N- {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazole -1-yl] -cyclobutyl} -acetamide

Preparation 54- {3- [4- (2-Naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutylcarbamoyl} -piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester Step 1 4-Piperidinecarboxylic acid (129 mg, 1 mmol) was treated with sodium hydroxide (80 mg, 2 mmol) in water / dioxane (1: 1, 10 mL). After stirring at room temperature for 30 minutes, 9-fluorenylmethyl chloroformate (259 mg, 1 mmol) / dioxane (2 mL) was added dropwise and the reaction solution was stirred for 4 hours. The solvent was removed in vacuo and diluted with water. The pH was adjusted to 1 with HCl (1N) and the aqueous solution was extracted with ethyl acetate. The organic phase was dried (MgSO ₄ ), filtered and concentrated in vacuo. Purification by silica gel chromatography (50: 1: 0.5 chloroform-methanol-acetic acid) gave 340 mg (97% yield) of N-1- (fluorenylmethyloxycarbonyl) -4-piperidinylcarboxylic acid 1H NMR (400 MHz, CDCl ₃ ) d7.75 (d, J = 7.1 Hz, 2H), 7.55 (d, J = 7.5 Hz, 2H), 7.39 (m, 2H) 7.30 (m, 2H), 4.4 (brs, 2H), 4.23 (t, J = 6.5 Hz, 1H), 3.9 (brd, 2H), 2.9 (brs, 2H) ), 2.52 (m, 1H), 1.90 (brs, 2H), 1.62 (brs, 2H); MS (AP / Cl): 352.0 (M + H) ⁺ .

Step 2 N-1- (Fluorenylmethyloxycarbonyl) -4-piperidinylcarboxylic acid (Preparation 5, Step 1; 77 mg) / methylene chloride solution was dissolved in 1- (3-dimethylaminopropyl) -3- Treated with ethyl carbodiimide hydrochloride (84 mg) and DMAP (5 mg). After stirring for 30 minutes, N- [1- (cis-3-amino-cyclobutyl) -1H-imidazol-4-yl] -2-naphthalen-1-yl-acetamide (Example 6) was added. The resulting mixture was subsequently stirred for 4 hours. Water was added to neutralize the solution and extracted with ethyl acetate. The organic phase was dried (MgSO ₄ ), filtered and concentrated in vacuo. Purification by silica gel chromatography (20: 1 chloroform-methanol) gave 101 mg (77% yield) of 4- {3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl. ] -Cyclobutylcarbamoyl} -piperidine-1-carboxylic acid 9H-fluoren-9ylmethyl ester; 1H NMR (400 MHz, CD ₃ OD) δ 8.0 (d, J = 8.3 Hz, 1H), 7 .83 (m, 1H), 7.78 (dd, J = 2.07, 7.5 Hz, 1H), 7.73 (d, J = 7.5 Hz, 2H), 7.53 (d, J = 6.6 Hz, 2H), 7.44 (m, 5H), 7.35 (m, 3H), 7.27 (m, 2H), 4.4 (brs, 2H), 4.2 (m, 1H) ), 4.15 (m, 5H), 2.85 (m 4H), 2.25 (m, 3H ), 1.7 (brs, 2H), 1.5 (brs, 2H); MS (AP / Cl): 654.8 (M + H) +.

Example 9 Piperidine-4-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide hydrochloride 4- {3- [4- (2-Naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutylcarbamoyl} -piperidin-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (Preparation 5, 100 mg, 0.15 mmol) ) / DMF (5 mL) was treated with piperidine (0.5 mL) and stirred at room temperature for 2 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (4: 1: 0.08 chloroform-methanol-ammonium hydroxide) to produce the free base. The free base was treated with diethyl ether and treated with 1N HCl / methanol to give the HCl salt (64 mg, 91% yield) of piperidine-4-carboxylic acid {cis-3- [4- (2-naphthalene- 1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amine hydrochloride was produced; 1H NMR (400 MHz, CD ₃ OD) δ 8.01 (d, J = 8.0 Hz, 1H), 7 .84 (d, J = 8.2 Hz, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.43 (m, 4H), 7.36 (s, 2H), 4.34 (M, 1H), 4.15 (s, 2H), 4.10 (m, 1H), 3.03 (m, 2H), 2.83 (m, 2H), 2.54 (m, 2H) , 2.24 (m, 3H), 1.69 (m, 2H), 1.55 (m, 2H); MS AP / Cl): 432 (M + H) +.

Preparation 6 Isoquinolin-5-yl-acetic acid Step 1 5-Aminoisoquinoline (5.0 g, 34.7 mmol) was mixed with 48% aqueous HBr (65 mL) at -78 ° C. for 15 minutes. Sodium nitrate (3.1 g, 45 mmol) / water (6 mL) was then added dropwise. After stirring at −78 ° C. for 15 minutes, the mixture was warmed to 0 ° C. Copper powder (0.3 g) was added very slowly to avoid excessive formation. After the addition was complete, the reaction vessel was secured to the reflux condenser and the mixture was heated to 100 ° C. for 4 hours. The mixture was poured onto ice (ca. 200 mg) and made basic (pH = 10) with KOH. The aqueous mixture was extracted with ethyl acetate and the combined organic phases were washed with brine and dried (MgSO ₄ ), filtered and concentrated in vacuo. Purification by silica gel chromatography (10: 1 hexane-ethyl acetate) produced 3.8 g (53% yield) of 5-bromoisoquinoline; 1H NMR (400 MHz, CD ₃ OD) δ 9.25 (s, 1H), 8.57 (d, J = 6.2 Hz, 1H), 8.1 (m, 3H), 7.60 (m, 1H); MS (AP / Cl): 208.0, 210.0 (M + H) ⁺ .

Step 2 5-Bromoisoquinoline (Preparation 6, Step 1, 1.04 g, 5.0 mmol) under nitrogen atmosphere with allyltributyltin (1.7 mL, 5.5 mmol) and dichloroperadium bis (triphenylphosphine) ) (176 mg, 0.25 mmol) in toluene (20 mL). After cooling to room temperature, a saturated aqueous solution of potassium fluoride (20 mL) is added with stirring, resulting in the formation of a precipitate. After stirring for 15 minutes, the mixture was filtered and the organic phase was separated from the aqueous phase, concentrated in vacuo, and generated by silica gel chromatography (6: 1 hexane-ethyl acetate), whereby 178 mg (92% Yield) of 5-allylisoquinoline; 1H NMR (400 MHz, CDCl ₃ ) δ 9.25 (s, 1H), 8.54 (d, J = 5.8 Hz, 1H), 7.85 ( m, 1H), 7.79 (d, J = 5.8 Hz, 1H), 7.56 (m, 2H), 6.1 (m, 1H), 5.15 (m, 1H), 5.05 (M, 1H), 3.81 (d, J = 6.2 Hz, 2H); MS (AP / Cl): 170.1 (M + H) ⁺ .

Step 3 5-Allylisoquinoline (Preparation 6, Step 2; 169 mg, 1.0 mmol) / methylene chloride (2 mL), acetic acid (0.5 mL), and water (0.5 mL) at 23 ° C. with dimethyl polyethylene glycol (number Average molecular weight was about 500, 95 μL, 100 mg, 0.2 mmol) / methylene chloride (1 mL). The mixture was cooled to 0 ° C. and powdered KMnO ₄ (521 mg, 3.3 mmol) was added in portions while maintaining the temperature below 30 ° C. After stirring vigorously for 18 hours, the solvent was removed in vacuo and methanolic hydrogen chloride (10 mL, 1N) was added and the mixture was refluxed for 4 hours. The methanol was removed in vacuo, the residue was diluted with water, and the mixture was basified with Na ₂ CO ₃ (pH = 9). The mixture is extracted with ethyl acetate and the resulting organic phase is washed with brine, dried (MgSO ₄ ), filtered, concentrated in vacuo and purified by silica gel chromatography (2: 1 hexane-ethyl acetate). Isoquinolin-5-yl-acetic acid was produced; 1H NMR (400 MHz, CDCl ₃ ) δ 9.28 (brs, 1H), 8.58 (d, J = 6.2 Hz, 1H), 7.95 (d, J = 7.9 Hz, 1H), 7.80 (d, J = 5.8 Hz, 1H), 7.66 (d, J = 5.8 Hz, 1H), 7.59 (t, J = 7.6 Hz, 1H), 4.06 (s, 2H), 3.70 (s, 3H); MS (AP / Cl): 202.1 (M + H) ⁺ . Note: An impurity of 5-isoquinolyl carboxaldehyde was present after silica gel chromatography (about 20%).

Step 4 Isoquinolin-5-yl-acetic acid methyl ester (Preparation 6, Step 3; 90 mg, 0.448 mmol) was treated with sodium hydroxide solution (4N, 3 mL) and the solution was heated at 50 ° C. for 4 hours. The solution was cooled to 0 ° C. and acetic acid (2 mL) was added dropwise, thereby forming a precipitate. The mixture was kept at 0 ° C. overnight (about 15 hours) and the precipitate was removed by filtration and washed with water. The solid was air dried to yield 35 mg (49% yield) of isoquinolin-5-yl-acetic acid; 1H NMR (400 MHz, CD ₃ OD) δ 9.24 (s, 1H), 8.47 (d, J = 6.2 Hz, 1H), 8.04 (d, J = 7.9 Hz, 1H), 7.96 (d, J = 6.2 Hz, 1H), 7.74 (d, J = 6.6 Hz) , 1H), 7.66 (t, J = 7.6 Hz, 1H), 4.11 (s, 2H); MS (AP / Cl): 188.3 (M + H) ⁺ .

Preparation 7N- [cis-3- (4-Nitro-imidazol-1H-yl) cyclobutylacetamide Step 1 trans-toluene-4-sulfonic acid 3- (4-nitro-imidazol-1-yl) -cyclobutyl ester (Preparation 1, Step 2; 3.6 g, 10.7 mmol) was mixed with sodium azide (7 g, 107 mmol) in ethanol (100 mL), water (35 mL), and chloroform (20 mL). The mixture was heated at reflux for 24 hours. Ethanol and chloroform were removed in vacuo and the resulting mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with brine, dried (MgSO ₄ ), filtered and concentrated in vacuo. Purification by silica gel chromatography (1: 1 to 3: 1 ethyl acetate-hexane) yielded 2.2 g (99%) of 1- (3-cis-azido-cyclobutyl) -4-nitro-1H-imidazole; 1H NMR (400 MHz, CDCl ₃ ) δ 7.85 (s, 1H), 7.49 (s, 1H), 4.42 (m, 1H), 3.91 (m, 1H), 3.07 (m, 2H), 2.43 (m, 1H); MS (AP / Cl): 208.5 (M + H) ⁺ .

Step 2 1- (3-cis-azido-cyclobutyl) -4-nitro-1H-imidazole (Preparation 7, Step 1; 2.2 g, 10.7 mmol) / THF (100 mL) was added to triphenylphosphine (3.36 g). , 12.8 mmol) and water (10 mL). The solution was removed in vacuo and the residue was purified by silica gel chromatography (20: 1: 0.4 chloroform-methanol-ammonium hydroxide) to yield 19.5 g (100% yield) of 1- (3- Cis-amino-cyclobutyl) -4-nitro-1H-imidazole was produced; 1H NMR (400 MHz, CD ₃ OD) δ 8.32 (s, 1H), 7.81 (s, 1H), 4.46 ( m, 1H), 3.29 (m, 1H), 2.87 (m, 2H), 2.17 (m, 2H); MS (AP / Cl): 183.1 (M + H) ⁺ .

Step 3 1- (3-cis-amino-cyclobutyl) -4-nitro-1H-imidazole (Preparation 7, Step 2; 500 mg, 2.75 mmol) was coupled with acetic acid and purified as in Example 7. To yield 594 mg (96% yield) of N- [cis-3- (4-nitro-imidazol-1H-yl) cyclobutyl] acetamide; 1H NMR (400 MHz, CD ₃ OD) δ 8.30 (s , 1H), 7.82 (s, 1H), 4.58 (m, 1H), 4.17 (m, 1H), 2.95 (m, 2H), 2.39 (m, 2H), 1 .93 (s, 3H); MS (AP / Cl): 225.1 (M + H) ⁺ .

Preparation 8 N- [cis-3- (4-nitro-imidazol-1-yl) cyclobutyl] -benzamide N- [cis-3- (4-nitro-imidazol-1-yl) cyclobutyl] -benzamide was prepared as Preparation 7 1H NMR (400 MHz, CD ₃ OD) δ 8.36 (s, 1H), 7.85 (m, 3H), 7.55 (m, 1H), 7.47 (m, 2H), 4.65 (m, 1H), 4.44 (m, 1H), 3.05 (m, 2H), 2.60 (m, 2H); MS (AP / Cl): 287.3 ( M + H) ⁺ .

Preparation 9 Pyridine-2-carboxylic acid [cis-3- (4-nitro-imidazol-1-yl) cyclobutyl] -amidopyridine-2-carboxylic acid [cis-3- (4-nitro-imidazol-1-yl) ) cyclobutyl] - amide was prepared similarly to the product of preparation 7; 1H NMR (400MHz, CDCl 3) δ8.55 (m, 1H), 8.35 (d, J = 7.0Hz, 1H), 8 .19 (d, J = 7.9 Hz, 1H), 8.01 (s, 1H), 7.88 (td, J = 1.65, 7.92 Hz, 1H), 7.57 (s, 1H) 7.47 (m, 1H), 4.5 (m, 2H), 3.17 (m, 2H), 2.72 (m, 2H); MS (AP / Cl): 288.1 (M + H) ⁺ .

EXAMPLE 9 aN- [1- (cis-3-acetylamino-cyclobutyl) -1H-imidazol-4-yl] -2-naphthalen-2-yl-acetamide N- [cis-3- (4-nitro-imidazole-1H -Yl) cyclobutyl] acetamide (Preparation 7; 50 mg, 0.22 mmol) was hydrogenated as in Example 1 and acylated with 2-naphthylacetic acid, whereby 35 mg (44% yield) of N- [1 -(Cis-3-acetylamino-cyclobutyl) -1H-imidazol-4-yl] -2-naphthalen-2-yl-acetamide was produced; 1H NMR (400 MHz, CD ₃ OD) δ 8.05 (d, J = 8.0 Hz, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.81 (d, J = 6.4 Hz, 1H), 7.46 (m, 5H), 7. 37 (s 1H), 4.41 (m, 1H), 4.17 (s, 2H), 4.12 (m, 1H), 2.84 (m, 2H), 2.27 (m, 2H), 1. 89 (s, 3H); MS (AP / Cl): 363.3 (M + H) ⁺ .

Example 9b N- {cis-3- [4- (2-Isoquinolin-5-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -benzamide The title compound was prepared in Preparation 8 and isoquinolin-5-ylacetic acid Prepared as in Example 9a using (Preparation 6); 1H NMR (400 MHz, CD ₃ OD) δ 9.24 (s, 1H), 8.45 (d, J = 6.2 Hz, 1H), 8 .05 (d, J = 7.9 Hz, 1H), 8.02 (J = 6.2 Hz, 1H), 7.82 (m, 3H), 7.67 (m, 1H), 7.52 (m , 2H), 7.45 (m, 3H), 4.5 (m, 1H), 4.4 (m, 1H), 4.21 (s, 2H), 2.95 (m, 2H), 2 .50 (m, 2H); MS (AP / Cl): 426.3 (M + H) ⁺ .

Example 9c Pyridine-2-carboxylic acid {cis-3- [4- (2-isoquinolin-5-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide The title compound was prepared as Preparation 9 and isoquinoline Prepared analogously to Example 9a using -5-ylacetic acid (Preparation 6); 1H NMR (400 MHz, CD ₃ OD) δ 9.23 (s, 1H), 8.60 (m, 1H), 8. 44 (d, J = 5.8 Hz, 1H), 8.03 (m, 3H), 7.92 (dt, J = 1.7, 7.5 Hz, 1H), 7.78 (d, J = 7 .1 Hz, 1 H), 7.66 (m, 1 H), 7.58 (s, 1 H), 7.5 (m, 1 H), 7.46 (s, 1 H), 4.45 (m, 1 H) , 4.40 (m, 1H), 4.20 (s, 2H), 2.85 (m, 2H), 2.6 (m, 2H); S (AP / Cl): 427.2 (M + H) +.

Example 10 N- {cis-3- [4- (3-naphthalen-1-yl) -ureido-1-yl] -cyclobutyl} -acetamide N- [cis-3- (4-nitro-imidazol-1H-yl) Cyclobutyl] acetamide (Preparation 7, 50 mg, 0.22 mmol) was reacted with phenyl chloroformate as described in Example 4. This resulted in a mixture of inseparable mono- and bis-phenylcarbamate products dissolved in 1: 1 DMF / dioxane (500 μL) after silica gel chromatography (20: 1: 2 chloroform-methanol-ammonium hydroxide). Generated. 1-Naphthylamine (31 mg, 0.22 mmol) was added and the mixture was heated at 70 ° C. for 16 hours. Two purifications by silica gel chromatography (20: 1: 0.02 chloroform-methanol-ammonium hydroxide) yielded 4.4 mg (5% yield) of N- {cis-3- [4- (3- Naphthalen-1-yl-ureido) -imidazol-1-yl] -cyclobutyl} -acetamide; 1H NMR (400 MHz, CD ₃ OD) δ 8.06 (d, J = 8.0 Hz, 1H), 7. 97 (d, J = 8.8 Hz, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.51 (m, 4H) ), 7.16 (s, 1H), 4.46 (m, 1H), 4.15 (m, 1H), 2.89 (m, 2H), 2.33 (m,
2H), 1.92 (s, 3H); MS (AP / Cl): 364.0 (M + H) ⁺ .

Claims (6)

formula
(Where R ¹ is linear or branched (C ₁ -C ₈ ) alkyl, linear or branched (C ₂ -C ₈ ) alkenyl, (C ₃ -C ₈ ) cycloalkyl, (C ₅ -C ₁₁₎ bicycloalkyl, (C ₆ -C ₁₄₎ aryl, or (5-14 membered) heteroaryl; and in this, R ¹ is optionally, F, Cl, Br, I, nitro, cyano, _{^{-CF 3, -NR 7 R 8,}} -NR 7 C (= O) R 8, -NR 7 C (= O) OR 8, -NR 7 C (= O) NR 8 R 9, -NR 7 S ( = O) ₂ R ⁸ , —NR ⁷ S (═O) ₂ NR ⁸ R ⁹ , —OR ⁷ , —SR ⁷ , —S (═O) R ⁷ , —S (═O) ₂ R ⁷ , —S Substituted by 1 to 6 substituents R ⁵ independently selected from (═O) ₂ NR ⁷ R ⁸ , —O—S (═O) ₂ R ⁷ , and —N ₃ ;
R ² is H;
R ³ is —C (═O) (CR ¹⁰ R ¹¹ ) _n —;
R ⁴ is linear or branched (C ₁ -C ₈ ) alkyl, linear or branched (C ₂ -C ₈ ) alkenyl, linear or branched (C ₂ -C ₈ ) alkynyl, (C ₃ -C ₈₎ cycloalkyl, (C ₄ -C ₈₎ cycloalkenyl, (3-8 membered) heterocycloalkyl, (C ₅ -C ₁₁₎ bicycloalkyl, (C ₇ -C ₁₁₎ bicycloalkenyl, (5-11 Membered) heterobicycloalkyl, (C ₆ -C ₁₄ ) aryl, or (5-14 membered) heteroaryl; and in which R ⁴ is optionally F, Cl, Br, I, nitro, cyano , —CF ₃ , —NR ⁷ R ⁸ , —NR ⁷ C (═O) R ⁸ , —NR ⁷ C (═O) OR ⁸ , —NR ⁷ C (═O) NR ⁸ R ⁹ , —NR ⁷ S (═O) ₂ R ⁸ , —NR ⁷ S (═O) ₂ NR ⁸ R ⁹ , —OR ⁷ , —OC (═O) R ⁷ , —OC (═O) OR ⁷ , —C (═O) OR ⁷ , —C (═O) R ⁷ , —C (═O) NR ⁷ R ⁸ , —OC (═O) NR ⁷ R ⁸ , —OC (═O) SR ⁷ , —SR ⁷ , —S (═O) R ⁷ , —S (═O) ₂ R ⁷ , —S (═O) ₂ NR ⁷ R ⁸ , or R ⁷ independently selected from R ⁷ Substituted with the substituent R ⁶ of
R ⁷ , R ⁸ , and R ⁹ are each independently H, linear or branched (C ₁ -C ₈ ) alkyl, linear or branched (C ₂ -C ₈ ) alkenyl, linear or branched (C ₂ -C ₈₎ alkynyl, (C ₃ -C ₈₎ cycloalkyl, (C ₄ -C ₈₎ cycloalkenyl, (3-8 membered) heterocycloalkyl, (C ₅ -C ₁₁₎ bicycloalkyl, (C ₇ -C ₁₁₎ bicycloalkenyl, (5-11 membered) heterobicycloalkyl, is selected from (C ₆ -C ₁₄₎ aryl, and (5-14 membered) heteroaryl, in this, R ⁷ , R ⁸ , and R ⁹ are F, Cl, Br, I, —NO ₂ , —CN, —CF ₃ , —NR ¹⁰ R ¹¹ , —NR ¹⁰ C (═O) R ¹¹ , —NR ¹⁰ C ( = O) OR ¹¹ , -NR ¹⁰ C (= O) NR ¹¹ R ¹² , -NR ¹⁰ S (= O) ₂ R ¹¹ , -NR ¹⁰ S (= O) ₂ NR ¹¹ R ¹² , —OR ¹⁰ , —OC (═O) R ¹⁰ , —OC (═O) OR ¹⁰ , —OC (═O) NR ¹⁰ R ¹¹ , —OC (═O) SR ¹⁰ , —SR ¹⁰ , ^{-S (= O) R 10,} -S (= O) 2 R 10, -S (= O) 2 NR 10 R 11, -C (= O) R 10, -C (= O) OR 10, - Each optionally substituted with 1 to 6 substituents independently selected from C (═O) NR ¹⁰ R ¹¹ and R ¹⁰ ;
Alternatively, when R ⁷ and R ⁸ are NR ⁷ R ⁸ , they are instead optionally, together with the NR ⁷ R ⁸ nitrogen to which they are attached, a 3-7 membered heterocycloalkyl. Moieties that may be joined to form a heterocycloalkyl optionally comprising one or more heteroatoms independently selected from N, O, and S;
R ¹⁰ , R ¹¹ , and R ¹² are each independently H, linear or branched (C ₁ -C ₈ ) alkyl, linear or branched (C ₂ -C ₈ ) alkenyl, linear or branched (C ₂ -C ₈₎ alkynyl, (C ₃ -C ₈₎ cycloalkyl, (C ₄ -C ₈₎ cycloalkenyl, (3-8 membered) heterocycloalkyl, (C ₅ -C ₁₁₎ bicycloalkyl, Selected from (C ₇ -C ₁₁ ) bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (C ₆ -C ₁₄ ) aryl, and (5-14 membered) heteroaryl, wherein R ¹⁰ , R ¹¹ and R ¹² are respectively F, Cl, Br, I, —NO ₂ , —CN, —CF ₃ , —NR ¹³ R ¹⁴ , —NR ¹³ C (═O) R ¹⁴ , —NR ¹³ C ( ═O) OR ¹⁴ , —NR ¹³ C (═O) NR ¹⁴ R ¹⁵ , —NR ¹³ S (═O) ₂ R ¹⁴ , —NR ¹³ S (= O) ₂ NR ¹⁴ R ¹⁵ , —OR ¹³ , —OC (═O) R ¹³ , —OC (═O) OR ¹³ , —OC (═O) NR ¹³ R ¹⁴ , —OC (═O) SR ¹³ , ^{-SR 13, -S (= O)} R 13, -S (= O) 2 R 13, -S (= O) 2 NR 13 R 14, -C (= O) R 13, -C (= O) Independently and optionally substituted with 1 to 6 substituents independently selected from OR ¹³ , —C (═O) NR ¹³ R ¹⁴ , and R ¹³ ;
R ¹³ , R ¹⁴ , and R ¹⁵ are each independently H, linear or branched (C ₁ -C ₈ ) alkyl, linear or branched (C ₂ -C ₈ ) alkenyl, linear or branched (C ₂ -C ₈₎ alkynyl, (C ₃ -C ₈₎ cycloalkyl, (C ₄ -C ₈₎ cycloalkenyl, (3-8 membered) heterocycloalkyl, (C ₅ -C ₁₁₎ bicycloalkyl, (C ₇ -C ₁₁₎ bicycloalkenyl, (5-11 membered) heterobicycloalkyl, is selected from (C ₆ -C ₁₄₎ aryl, and (5-14 membered) heteroaryl, wherein, R ^13, R ¹⁴ and R ¹⁵ are each independently F, Cl, Br, I, —NO ₂ , —CN, —CF ₃ , —NR ¹⁶ R ¹⁷ , —NR ¹⁶ C (═O) R ¹⁷ , —NR. ^{16 C (= O) OR 17} , -NR 16 C (= O) NR 17 R 18, -NR 16 S (= O) 2 R 17, -NR ¹⁶ S (═O) ₂ NR ¹⁷ R ¹⁸ , —OR ¹⁶ , —OC (═O) R ¹⁶ , —OC (═O) OR ¹⁶ , —OC (═O) NR ¹⁶ R ¹⁷ , —OC (═O ) SR ¹⁶ , -SR ¹⁶ , -S (= O) R ¹⁶ , -S (= O) ₂ R ¹⁶ , -S (= O) ₂ NR ¹⁶ R ¹⁷ , -C (= O) R ¹⁶ , -C Optionally substituted with 1 to 6 substituents independently selected from (═O) OR ¹⁶ , —C (═O) NR ¹⁶ R ¹⁷ , and R ¹⁶ ;
R ¹⁶ , R ¹⁷ , and R ¹⁸ are each independently H, straight chain or branched (C ₁ -C ₈ ) alkyl, straight chain or branched (C ₂ -C ₈ ) alkenyl, straight chain or branched (C ₂ -C ₈₎ alkynyl, (C ₃ -C ₈₎ cycloalkyl, (C ₄ -C ₈₎ cycloalkenyl, (3-8 membered) heterocycloalkyl, (C ₅ -C ₁₁₎ bicycloalkyl, (C ₇ -C ₁₁₎ bicycloalkenyl, (5-11 membered) heterobicycloalkyl, is selected from (C ₆ -C ₁₃₎ aryl, and (5-12 membered) heteroaryl;
n is 0, 1, 2 or 3;
Here, R ¹⁰ and R ¹¹ in —C (═O) (CR ¹⁰ R ¹¹ ) _n are each a repetition of n that is independently limited as listed above,
However, when R ¹ is optionally substituted (C ₃ -C ₈ ) cycloalkyl or optionally substituted (C ₅ -C ₁₁ ) bicycloalkyl, R ⁴ is optionally substituted (C ₆ -C ₁₄ ) Compounds that are not aryl or optionally substituted (5-14 membered) heteroaryl) and pharmaceutically acceptable salts thereof. R ¹ is optionally substituted substituted (C ₃ -C ₈₎ cycloalkyl or optionally a (C ₅ -C ₁₁₎ bicycloalkyl, compound of claim 1. 3. A compound according to claim 2, wherein R < ¹ > is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, or bicyclo- [3.1.0] -hexyl, each optionally substituted. R ¹ is optionally substituted linear or branched (C ₁ -C ₈₎ alkyl or optionally substituted straight or branched (C ₂ -C ₈₎ alkenyl compound of claim 1 . R ⁴ is a (C ₆ -C ₁₄₎ aryl or (5-14 membered) heteroaryl, each of which is optionally substituted, compound of Claim 1. R ⁴ is phenyl, pyridyl, naphthyl, quinolyl, or isoquinolyl, each of which is optionally substituted, A compound according to claim 5.