 Imidazole Derivatives
专利摘要:
The present invention provides a compound of formula 1 and pharmaceutically acceptable salts thereof. Compounds of Formula 1 have been shown to have activity to inhibit cdk5, cdk2 and GSK-3. Pharmaceutical compositions for the treatment and prophylaxis of diseases and disorders, including those of abnormal cell growth and neurodegenerative diseases and disorders, such as cancer, and diseases and disorders affected by dopamine neurotransmission, including the compounds of Formula 1, and treatment and prophylaxis A method is provided. In addition, male fertility and sperm movement, including the compound of formula (1); diabetes; Impaired glucose tolerance; Metabolic syndrome or syndrome X; Polycystic ovary syndrome; Lipogenesis and obesity; Muscle development and weakness, eg, age-related poor physical performance; Acute myopathy, eg muscular dystrophy and / or cachexia associated with burns, bedside care, limb fixation, or chest, abdomen, and / or orthopedic major surgery; blood poisoning; Hair loss, hair softening and baldness; And pharmaceutical compositions and methods of treatment for the treatment of immunodeficiency. <Formula 1> Wherein R 1 , R 2 , R 3 and R 4 are as defined. 公开号:KR20030019644A 申请号:KR10-2003-7001455 申请日:2001-07-25 公开日:2003-03-06 发明作者:마이클 커크 알리자니안；크리스토퍼 블레어 쿠퍼；크리스토퍼 존 헬랄；리트-후이 라우；프랭크 사무엘 멘니티；마크 앨런 산너；패트리샤 앤 시모어；아나벨라 빌라로보스 申请人:화이자 프로덕츠 인크.； IPC主号:
专利说明:
Imidazole Derivatives [2] Since serine / threonine kinase cdk5 is associated with neurodegenerative disorders with its cofactor p25 (or longer cofactor, p35), the cdk5 / p25 (or cdk5 / p35) inhibitors may be associated with Alzheimer's disease, Parkinson's disease, stroke or Huntington. It is useful for the treatment of neurodegenerative disorders such as disease. Treatment of such neurodegenerative disorders with cdk5 inhibitors is supported by the discovery that cdk5 is associated with phosphorylation of tau protein (J. Biochem, 117, 741-749 (1995)). Cdk5 also phosphorylates dopamine and cyclic AMP-regulated phosphoroprotein (DARPP-32) in threonine 75, indicating that cdk5 plays an important role in dopaminergic neurotransmission (Nature, 402, 669-671 ( 1999)]). [3] Serine / threonine kinase cdk2 is essential for normal cell circulation and plays an important role in disorders caused by abnormal cell circulation, a common characteristic of many tumorous disorders. Therefore, cdk2 inhibitors are useful for the treatment of various types of cancer and other diseases or disorders associated with abnormal cell growth (Meijer, et al., Properties and Potential-applications of Chemical Inhibitors of Cyclin-dependent Kinases, Pharmacology & therapeutics). , 82 (2-3), 279-284 (1999); Sausville, et al., Cyclin-dependent Kinases: Initial Approaches to Exploit a Novel Therapeutic Target, Pharmacology & therapeutics 82 (2-3) 285-292 ( 1999)]). [4] 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 vertebrates in two isoforms, α and β, which have been reported to have monomeric structures of 49 kD and 47 kD, respectively. Both of these isoforms phosphorylate muscle glycogen synthase (Cross, et al., Biochemical Journal 303: 21-26 (1994)). Amino acid identity between GSK-3 species homologues was found in at least 98% in the catalytic domain (Plyte, et al., Biochim. Biophys. Acta 1114: 147-162 (1992)). Due to the very high degree of conservation in the phylogenetic spectrum, the basic role of GSK-3 in cellular processes has been proposed. [5] GSK-3 is associated with a number of different disease states and disorders. For example, Chen, et al, Diabetes 43: 1234-1241 (1994) suggested that increased GSK-3 activity may be important in type 2 diabetes. Increased GSK-3 expression in diabetic muscle also affects skeletal muscle insulin resistance and impaired glycogen synthase activity present in type 2 diabetes (Nikoulina, et al., Diabetes 49: 263-271 (2000)). . In addition, the higher activity of type 1 protein phosphatase measured in sperm without automatism is due to higher GSK-3 activity and has been shown to inhibit sperm motility (Vijayaraghavan, et al. Biology of Reproduction 54: 709 -718 (1996)]. Vijayaraghavan et al. Indicated that these results suggest a biochemical basis for the development and regulation of sperm motility and possible physiological roles for the protein phosphatase 1 / inhibitor 2 / GSK-3 system. GSK-3 activity is also associated with mood disorders such as Alzheimer's disease and bipolar disorder (WO 97/41854). Among other diseases, GSK-3 also has neurodegenerative disorders including hair loss, schizophrenia, and chronic neurodegenerative diseases (eg, Alzheimer's disease) and neurotraumas, such as stroke, traumatic brain injury, and spinal cord trauma. It is related. [6] (Summary of invention) [7] The present invention provides a compound of formula 1 and pharmaceutically acceptable salts thereof. [8] [9] Where [10] R 1 is straight or branched chain (C 1 -C 8 ) alkyl, straight or branched chain (C 2 -C 8 ) alkenyl, straight or branched chain (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 To 11-membered) heterobicycloalkyl, (C 6 -C 14 ) aryl or (5- to 14-membered) heteroaryl, wherein R 1 is F, Cl, Br, I, nitro, cyano, -CF 3 ,- NR 7 R 8 , -NR 7 C (= 0) R 8 , -NR 7 C (= 0) OR 8 , -NR 7 C (= 0) NR 8 R 9 , -NR 7 S (= 0) 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) to 2 R 7, -S (= O ) 2 NR 7 R 8, -OS (= O) 2 R 7, -N 3 , and R 7 independently of one to six substituents selected from R 5 Optionally substituted; [11] R 2 is H, F, CH 3 , CN or C (═O) OR 7 ; [12] R 3 is —C (═O) NR 9 —, —C (═O) O—, —C (═O) (CR 10 R 11 ) n -or-(CR 10 R 11 ) n- ; [13] R 4 is straight or branched chain (C 1 -C 8 ) alkyl, straight or branched chain (C 2 -C 8 ) alkenyl, straight or branched chain (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 To 11-membered) heterobicycloalkyl, (C 6 -C 14 ) aryl or (5- to 14-membered) heteroaryl, wherein R 4 is F, Cl, Br, I, nitro, cyano, -CF 3 ,- NR 7 R 8 , -NR 7 C (= 0) R 8 , -NR 7 C (= 0) OR 8 , -NR 7 C (= 0) NR 8 R 9 , -NR 7 S (= 0) 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 to 3 substituents R 6 independently selected from -S (= 0) 2 R 7 , -S (= 0) 2 NR 7 R 8 or R 7 ; [14] Each R 7 , R 8 and R 9 is independently H, straight or branched chain (C 1 -C 8 ) alkyl, straight or branched chain (C 2 -C 8 ) alkenyl, straight or branched chain (C 2 -C 8 ) alkynyl, (C 3 -C 8 ) cycloalkyl, (C 4 -C 8 ) cycloalkenyl, (3 to 8 membered) heterocycloalkyl, (C 5 -C 11 ) bicycloalkyl, (C 7 -C 11 ) bicycloalkenyl, (5- to 11-membered) heterobicycloalkyl, (C 6 -C 14 ) aryl and (5- to 14-membered) heteroaryl, wherein R 7 , R 8 and R 9 Are each independently 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 (= 0) NR 11 R 12 , -NR 10 S (= 0) 2 R 11 , -NR 10 S (= 0) 2 NR 11 R 12 , -OR 10 , -OC (= 0) 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 (= 0) 2 NR 10 R 11 , -C (= 0) R 10 , -C (= 0) OR 10 , -C (= 0) NR 10 R 11 and R 10 independently Optionally substituted with 1 to 6 substituents selected; [15] If R 7 and R 8 are present as NR 7 R 8 , they are instead 3 to 3 containing one or two additional heteroatoms independently selected from N, O and S together with the nitrogen of NR 7 R 8 to which they are attached; Optionally form a heterocycloalkyl moiety of a seven membered ring; [16] Each R 10 , R 11 and R 12 is independently H, straight or branched chain (C 1 -C 8 ) alkyl, straight or branched chain (C 2 -C 8 ) alkenyl, straight or branched chain (C 2 -C 8 ) alkynyl, (C 3 -C 8 ) cycloalkyl, (C 4 -C 8 ) cycloalkenyl, (3 to 8 membered) heterocycloalkyl, (C 5 -C 11 ) bicycloalkyl, (C 7 -C 11 ) bicycloalkenyl, (5- to 11-membered) heterobicycloalkyl, (C 6 -C 14 ) aryl and (5- to 14-membered) heteroaryl, wherein R 10 , R 11 and R 12 Are each independently F, Cl, Br, I, -NO 2 , -CN, -CF 3 , -NR 13 R 14 , -NR 13 C (= 0) R 14 , -NR 13 C (= 0) 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) OR 13 , -C (= O) NR 13 Independent from R 14 and R 13 Optionally substituted with 1 to 6 substituents selected from; [17] Each R 13 , R 14 and R 15 is independently H, straight or branched chain (C 1 -C 8 ) alkyl, straight or branched chain (C 2 -C 8 ) alkenyl, straight or branched chain (C 2 -C 8 ) alkynyl, (C 3 -C 8 ) cycloalkyl, (C 4 -C 8 ) cycloalkenyl, (3 to 8 membered) heterocycloalkyl, (C 5 -C 11 ) bicycloalkyl, (C 7 -C 11 ) bicycloalkenyl, (5- to 11-membered) heterobicycloalkyl, (C 6 -C 14 ) aryl and (5- to 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 (= 0) R 17 , -NR 16 C (= 0) OR 17 , -NR 16 C (= 0) NR 17 R 18 , -NR 16 S (= 0) 2 R 17 , -NR 16 S (= 0) 2 NR 17 R 18 , -OR 16 , -OC (= 0) 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 (= O) OR 16 , -C (= O) NR 16 Independent of R 17 and R 16 Optionally substituted with 1 to 6 substituents selected from; [18] Each R 16 , R 17 and R 18 is independently H, straight or branched chain (C 1 -C 8 ) alkyl, straight or branched chain (C 2 -C 8 ) alkenyl, straight or branched chain (C 2 -C 8 ) alkynyl, (C 3 -C 8 ) cycloalkyl, (C 4 -C 8 ) cycloalkenyl, (3 to 8 membered) heterocycloalkyl, (C 5 -C 11 ) bicycloalkyl, (C 7 -C 11 ) bicycloalkenyl, (5- to 11-membered) heterobicycloalkyl, (C 6 -C 14 ) aryl and (5- to 14-membered) heteroaryl; [19] n is 0, 1, 2 or 3; [20] Wherein R 10 and R 11 in —C (═O) (CR 10 R 11 ) n − and — (CR 10 R 11 ) n − are independently defined as above for each repeated n. [21] The compounds of formula 1 of the present invention are inhibitors of serine / threonine kinases, in particular cyclin-dependent kinases such as cdk5 and cdk2, and are useful for the treatment of abnormal cell growth, including neurodegenerative disorders and other CNS disorders, and cancer. Compounds of formula 1 are particularly useful for inhibiting cdk5. In addition, the compounds of formula 1 are useful as GSK-3 inhibitors. [22] As used herein, the term "alkyl" includes saturated monovalent hydrocarbon radicals having straight or branched chain residues unless otherwise indicated. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl and t-butyl. [23] As used herein, the term "alkenyl" includes alkyl moieties having one or more carbon-carbon double bonds unless otherwise specified, wherein alkyl is as defined above. Examples of alkenyl include but are not limited to ethenyl and propenyl. [24] As used herein, the term "alkynyl" includes alkyl moieties having one or more carbon-carbon triple bonds unless otherwise indicated, wherein alkyl is as defined above. Examples of alkynyl groups include, but are not limited to, ethynyl and 2-propynyl. [25] As used herein, the term "cycloalkyl" includes non-aromatic saturated cyclic alkyl moieties unless otherwise indicated, wherein 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 nonaromatic saturated carbocyclic group consisting of two rings, wherein the ring shares one or two carbon atoms. In the present invention, unless otherwise stated, 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 Do not. "Cycloalkenyl" and "bicycloalkenyl" are one or more carbon-carbon double bonds ("in-ring" double bonds) that link carbon ring members and / or one that link adjacent acyclic carbons with carbon ring members. It refers to non-aromatic carbocyclic cycloalkyl and bicycloalkyl moieties as defined above, except that the carbon-carbon double bonds above (“external” double bonds) are included. Examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl and cyclobutenyl, and non-limiting examples of bicycloalkenyl groups are norborneneyl. In addition, cycloalkyl, cycloalkenyl, bicycloalkyl and bicycloalkenyl groups include groups substituted with one or more oxo residues. Examples of such groups containing oxo residues are oxocyclopentyl, oxocyclobutyl, oxocyclopentenyl and norcamphoryl. [26] As used herein, the term "aryl" includes organic radicals derived from the removal of one hydrogen from an aromatic hydrocarbon, such as phenyl, naphthyl, indenyl and fluorenyl, unless otherwise indicated. [27] As used herein, the terms "heterocyclic" and "heterocycloalkyl" refer to non-aromatic cyclic groups containing one or more, preferably 1 to 4 heteroatoms, each selected from O, S and N. A "heterobicycloalkyl" group is a non-aromatic bicyclic cyclic group wherein the ring shares one or two atoms, and at least one of the rings contains heteroatoms (O, S or N). In the present invention, unless stated otherwise, heterobicycloalkyl groups include spiro groups and fused ring groups. In one embodiment, each ring of heterobicycloalkyl contains up to four heteroatoms (ie, 0 to 4 heteroatoms, with only one ring containing one or more heteroatoms). In addition, the heterocyclic group of the present invention may include a ring system substituted with one or more oxo residues. Examples of non-aromatic heterocyclic groups include aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azefinyl, piperazinyl, 1,2,3,6-tetrahydropyridinyl, oxiranyl, ox Cetanyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, 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, quinucridinyl, 1,4-dioxaspiro [4.5] decyl, 1,4-dioxaspiro [4.4] nonyl, 1,4-dioxaspiro [4.3] octyl and 1,4-dioxaspiro [4.2] heptyl. [28] As used herein, "heteroaryl" refers to an aromatic group containing one or more, preferably 1 to 4 heteroatoms (O, S or N). A multicyclic group containing at least one heteroatom, wherein at least one ring of the group is aromatic is a "heteroaryl" group. Heteroaryl groups of the invention may include ring systems substituted with one or more oxo residues. Examples of heteroaryl groups include pyridinyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thia Zolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolinyl, phthalazinyl, triazinyl, isoindolyl, purinyl, oxa Diazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, dihydroquinolyl, tetrahydroqui Noyl, dihydroisoquinolyl, tetrahydroisoquinolyl, benzofuryl, furopyridinyl, pyrrolopyrimidinyl and azaindolinyl. [29] The groups derived from the compounds listed above may be possible C- or N-bonds. For example, the group derived from pyrrole may be pyrrole-1-yl (N-linked) or pyrrole-3-yl (C-linked). The term referring to this group also includes all possible tautomers. [30] In one embodiment, the present invention provides a compound of Formula 1 wherein R 3 is -C (= 0) NR 9 -or -C (= 0) (CR 10 R 11 ) n- . In other embodiments, R 10 and R 11 of —C (═O) (CR 10 R 11 ) n − are both hydrogen for each repeated n. In other embodiments, R 9 of —C (═O) NR 9 — is hydrogen. In other embodiments, R 3 is —C (═O) NR 9 — or —C (═O) (CR 10 R 11 ) n — and R 2 is hydrogen. [31] In another embodiment of the invention, there is provided a compound of Formula 1, wherein R 1 is optionally substituted (C 3 -C 8 ) cycloalkyl or optionally substituted (C 5 -C 11 ) bicycloalkyl. R 1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or norbornyl, each of which is optionally substituted as mentioned above (ie F, Cl, Br, I, nitro, cyano, -CF 3 , -NR 7 R 8 , -NR 7 C (= 0) R 8 , -NR 7 C (= 0) OR 8 , -NR 7 C (= 0) NR 8 R 9 , -NR 7 S (= 0) 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 (= 0) 2 R 7 , -S (= 0) 2 NR 7 optionally substituted with 1 to 6 substituents R 5 independently selected from R 8 and R 7 ). In a more preferred embodiment, R 1 is (C 3 -C 8 ) cycloalkyl or optionally substituted (C 5 -C 11 ) bicycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or norbor Nyl, F, Cl, Br, I, nitro, cyano, -CF 3 , -NR 7 R 8 , -NR 7 C (= 0) R 8 , -OR 7 , -C (= 0) OR 7 , Is optionally substituted with 1 to 3 substituents independently selected from -C (= 0) R 7 and R 7 . More preferably, R 1 is (C 3 -C 8 ) cycloalkyl or optionally substituted (C 5 -C 11 ) bicycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or norbornyl 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 said aryl , Heterocycloalkyl and heteroaryl are F, Cl, Br, I, NO 2 , -CN, -CF 3 , -NR 10 R 11 , -NR 10 C (= 0) R 11 , -NR 10 C (= O) OR 11 , -NR 10 C (= 0) NR 11 R 12 , -NR 10 S (= 0) 2 R 11 , -NR 10 S (= 0) 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 (= 0) 2 R 10 , -S (= 0) 2 NR 10 R 11 , -C (= 0) R 10 , -C (= 0) OR 10 , -C (= 0) NR 10 R 11 and Optionally substituted with 1 to 6 substituents independently selected from R 10 . In another embodiment of the invention, R 1 is bicyclo- [3.1.0] -hexyl and optionally substituted as mentioned above (ie F, Cl, Br, I, nitro, cyano, -CF 3 , -NR 7 R 8 , -NR 7 C (= 0) R 8 , -NR 7 C (= 0) OR 8 , -NR 7 C (= 0) NR 8 R 9 , -NR 7 S (= 0) 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 (= 0) 2 R 7 , -S (= 0) 2 NR 7 optionally substituted with 1 to 6 substituents R 5 independently selected from R 8 and R 7 ). [32] In another embodiment of the invention, there is provided a compound of Formula 1, wherein R 1 is optionally substituted straight or branched chain (C 1 -C 8 ) alkyl or optionally substituted straight or branched chain (C 2 -C 8 ) alkenyl do. [33] In another embodiment of the invention, there is provided a compound of Formula 1, wherein R 2 is hydrogen. In other embodiments, R 2 is hydrogen and R 1 is as defined in the paragraphs above. [34] In another embodiment, the invention provides compounds of Formula 1, wherein R 4 is (C 6 -C 14 ) aryl or (5- to 14 membered) heteroaryl, each of 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 of which is optionally substituted. In other embodiments, R 4 is naphthyl, quinolyl or isoquinolyl, which is unsubstituted. [35] In another embodiment, there is provided a compound of Formula 1, wherein R 2 is specifically hydrogen and R 4 is as defined in the paragraphs above. [36] Examples of preferred compounds of formula 1 [37] N- (1-cyclobutyl-1H-imidazol-4-yl) -2-quinolin-6-yl-acetamide, [38] N- (1-cyclopentyl-1H-imidazol-4-yl) -2- (4-methoxy-phenyl) -acetamide, [39] N- [1- (cis-3-phenyl-cyclobutyl) -1H-imidazol-4-yl] -2-quinolin-6-yl-acetamide, [40] (1-cyclobutyl-1H-imidazol-4-yl) -carbamic acid phenyl ester, [41] 1- (1-cyclobutyl-1H-imidazol-4-yl) -3-isoquinolin-5-yl-urea, [42] N- [1- (cis-3-amino-cyclobutyl) -1H-imidazol-4-yl] -2-naphthalen-1-yl-acetamide, [43] 6-Methyl-pyridine-2-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide, [44] 1 H-imidazole-4-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide, [45] 6-hydroxy-pyridine-2-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide, [46] 3-Methyl-pyridine-2-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide, [47] 2-Pyridin-3-yl-thiazole-4-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide , [48] 6- {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutylcarbamoyl} -nicotinic acid methyl ester, [49] Pyrazine-2-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide, [50] N- {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -benzamide, [51] 5-Methyl-pyrazine-2-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide, [52] N- {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -isobutyramide, [53] 6-Chloro-pyridine-2-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide, [54] Quinoline-2-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide, [55] 1H-pyrrole-2-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide, [56] N- {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -2-m-tolyl-acetamide, [57] Pyridine-2-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide, [58] 2- (3-hydroxy-phenyl) -N- {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -acetamide, [59] Piperidine-4-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide hydrochloride, [60] N- [1- (cis-3-acetylamino-cyclobutyl) -1H-imidazol-4-yl] -2-naphthalen-2-yl-acetamide, [61] N- {cis-3- [4- (2-isoquinolin-5-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -benzamide, and [62] Pyridine-2-carboxylic acid {cis-3- [4- (2-isoquinolin-5-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide, and pharmaceutically acceptable of said compound It is a salt. [63] Examples of other specific compounds of formula 1 of the present invention [64] Cis-N- (1-bicyclo [3.1.0] hex-3-yl-1H-imidazol-4-yl) -2-quinolin-6-yl-acetamide, [65] Cis-N- {1- [trans-6- (pyridine-2-carbonyl) -bicyclo [3.1.0] hex-3-yl] -1H-imidazol-4-yl} -2-quinoline-6 -Yl-acetamide, [66] N- {1- [cis-3- (2-methoxy-phenyl) -cyclobutyl] -1H-imidazol-4-yl} -2-quinolin-6-yl-acetamide, [67] N- {1- [cis-3- (2-fluoro-phenyl) -cyclobutyl] -1H-imidazol-4-yl} -2-quinolin-6-yl-acetamide, [68] N- {1- [cis-3- (4-methoxy-phenyl) -cyclobutyl] -1H-imidazol-4-yl} -2-quinolin-6-yl-acetamide, [69] 2-quinolin-6-yl-N- [1- (cis-3-p-tolyl-cyclobutyl) -1H-imidazol-4-yl] -acetamide, [70] N- {1- [cis-3- (2-ethoxy-phenyl) -cyclobutyl] -1H-imidazol-4-yl} -2-quinolin-6-yl-acetamide, [71] N- {1- [cis-3- (3-methoxy-phenyl) -cyclobutyl] -1H-imidazol-4-yl} -2-quinolin-6-yl-acetamide, and a pharmaceutical composition of said compound Acceptable salts. [72] Other examples of certain compounds of Formula 1 include [73] N- {1- [3- (2-hydroxy-phenyl) -cyclobutyl] -1 H-imidazol-4-yl} -2- (4-methoxy-phenyl) -acetamide, [74] N- {1- [3- (3-hydroxy-phenyl) -cyclobutyl] -1 H-imidazol-4-yl} -2- (4-methoxy-phenyl) -acetamide, [75] N- {1- [3- (2-Amino-phenyl) -cyclobutyl] -1 H-imidazol-4-yl} -2- (4-methoxy-phenyl) -acetamide, [76] N- {1- [3- (3-amino-phenyl) -cyclobutyl] -1 H-imidazol-4-yl} -2- (4-methoxy-phenyl) -acetamide, [77] N- {1- [3- (3-Aminomethyl-phenyl) -cyclobutyl] -1 H-imidazol-4-yl} -2- (4-methoxy-phenyl) -acetamide, [78] N- {1- [3- (3-Dimethylaminomethyl-phenyl) -cyclobutyl] -1 H-imidazol-4-yl} -2- (4-methoxy-phenyl) -acetamide, and [79] 2- (4-methoxy-phenyl) -N- {1- [3- (1-methyl-1H-pyrazol-3-yl) -cyclobutyl] -1 H-imidazol-4-yl} -acetamide And pharmaceutically acceptable salts of these compounds. [80] Salts of compounds of formula (1) may be obtained by forming salts with acidic or basic groups present in compounds of formula (1). Examples of pharmaceutically acceptable salts of compounds of formula 1 include 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, Salts of acetic acid, sulfuric acid, iodic acid, mandelic acid, sodium, potassium, magnesium, calcium and lithium. [81] The compounds of formula (1) may have optical centers and therefore may take on different enantiomer and other stereoisomeric arrangements. The present invention includes all enantiomers, diastereomers and other stereoisomers of the compounds of formula 1 as well as racemic and other mixtures thereof. [82] The present invention also encompasses isotopically labeled compounds, which are identical to the compounds mentioned in Formula 1 except that one or more atoms are replaced by an atom having an atomic or mass number that is different from the atomic or mass number commonly found in nature. . Examples of isotopes that may 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 125 I Isotopes are included. Pharmaceutically acceptable salts of the compounds of the invention and of such compounds containing the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this invention. Isotopically labeled compounds of the invention, such as those incorporating radioisotopes such as 3 H and 14 C, are useful for drug and / or substrate tissue distribution analysis. Tritium, ie 3 H, and carbon-14, ie 14 C isotopes are particularly preferred in terms of ease of preparation and detectability. 11 C and 18 F isotopes are particularly useful for PET (positron emission tomography), while 125 I isotopes are particularly useful for SPECT (single photon emission computed tomography), all of which are useful for brain imaging. In addition, substitution with heavier isotopes such as deuterium, i.e. 2 H, may provide certain therapeutic advantages resulting from greater metabolic stability, such as an increase in half-life or a required dose reduction in vivo, and therefore in some cases It may be desirable. Isotopically Labeled Compounds of Formula 1 of the Invention can generally be prepared by replacing the isotopically labeled reagents with readily available isotopically labeled reagents by the methods described in the following schemes and / or Examples. . [83] The present invention also provides a pharmaceutical composition for treating a disease or disorder comprising abnormal cell growth in a mammal, comprising an inhibitory effective amount of a compound of formula 1 and a pharmaceutically acceptable carrier. [84] The present invention also provides a pharmaceutical composition for treating a disease or disorder comprising abnormal cell growth in a mammal, comprising an inhibitory effective amount of a cdk2 activity, a compound of formula 1 and a pharmaceutically acceptable carrier. [85] The present invention also provides a method of treating a disease or disorder comprising abnormal cell growth in a mammal comprising administering to the mammal an inhibitory effective amount of a compound of formula (1). [86] The present invention also provides a method of treating a disease or disorder comprising abnormal cell growth in a mammal comprising administering to the mammal an inhibitory effective amount of a cdk2 activity. [87] In the pharmaceutical composition or method for treating a disease or disorder comprising abnormal cell growth of the present invention, one embodiment of the disease or disorder comprising abnormal cell growth is cancer. Cancer is a carcinoma of the bladder, breast, large intestine, kidney, liver, lung (eg small cell lung cancer), esophagus, gallbladder, ovary, pancreas, stomach, cervix, thyroid, prostate or skin carcinoma, for example Squamous cell carcinoma; Lymphoid hematopoietic tumors such as leukemia, acute lymphocytic leukemia, B cell lymphoma, T cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hair cell lymphoma or Burkett's lymphoma; Myeloid hematopoietic tumors such as acute and chronic myeloid leukemia, myelodysplastic syndromes or promyelocytic leukemia; Mesenchymal origin tumors such as fibrosarcoma or rhabdomyosarcoma; Central or peripheral nervous system tumors, such as astrocytoma, neuroblastoma, glioma or neuromyoma; Melanoma; Germ cell tumor; Teratocarcinoma; Osteosarcoma; Pigmentary dry skin disease; Keratinocytes; Thyroid vesicle cancer; Or Kaposi's sarcoma. [88] In other embodiments, the disease or condition comprising abnormal cell growth is positive. These diseases and conditions include benign prostatic hyperplasia, familial adenomatous polyposis, neurofibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis, hypertrophic scar formation, inflammatory bowel disease, transplant rejection, fungal infections and endotoxins Is included. [89] The present invention also provides a pharmaceutical composition for treating said disease or disorder in a mammal comprising a therapeutically effective amount of a compound of formula 1 and a pharmaceutically acceptable carrier. [90] The present invention also provides a pharmaceutical composition for treating a neurodegenerative disease or disorder in a mammal, comprising an inhibitory effective amount of a cdk5 activity, a compound of formula 1 and a pharmaceutically acceptable carrier. [91] The present invention also provides a method of treating a neurodegenerative disease or condition in a mammal comprising administering to the mammal an inhibitory effective amount of a cdk5 activity. [92] The present invention also provides a method of treating a disease or disorder in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula 1 in a neurodegenerative disease or disorder. [93] In one embodiment of the invention, the neurodegenerative disease or condition to be treated is Huntington's disease, stroke, spinal cord injury, traumatic brain injury, multiple infarct, epilepsy, muscular dystrophy, pain, virus-induced dementia, eg AIDS induction Dementia, neurodegeneration associated with bacterial infection, migraine, hypoglycemia, urinary incontinence, cerebral ischemia, multiple infarction, Alzheimer's disease, Alzheimer's disease, cognitive impairment, age-related cognitive decline, vomiting, cortical hypoplasia, projectile dementia, Down syndrome , Muscle tone reduction axis, Niemann-Pick disease, Pick disease, prion disease caused by fiber concentrate, progressive nuclear palsy, lower lateral sclerosis and subacute sclerosing panencephalitis. [94] The invention also provides a pharmaceutical composition for treating said disease or disorder in a mammal comprising a therapeutically effective amount of a cdk5 inhibitor and a pharmaceutically acceptable carrier for the disease or disorder in which the treatment can be achieved or promoted by modifying dopamine mediated neurotransmission. To provide. [95] The present invention also provides a pharmaceutical composition for treating a disease or condition wherein the treatment can be achieved or promoted by modifying dopamine mediated neurotransmission in a mammal comprising an inhibitory effective amount of cdk5 inhibitory cdk5 inhibitor and a pharmaceutically acceptable carrier. . [96] The present invention also provides a method of treating a disease or condition in which treatment can be achieved or promoted by modifying dopamine mediated neurotransmission in a mammal comprising administering to the mammal an inhibitory effective amount of a cdk5 inhibitor of cdk5 activity. do. [97] In addition, the present invention includes administering to a mammal a therapeutically effective amount of a cdk5 inhibitor of a disease or condition in which the treatment can be achieved or promoted by modifying dopamine mediated neurotransmission. To provide. [98] In one embodiment of the invention, the disease or condition for which the treatment may be achieved or promoted by modifying dopamine mediated neurotransmission may include Parkinson's disease; Schizophrenia, schizophrenic disorders, schizophrenia affective disorders, eg delusional or depressive; Delusional disorder; Substance-induced psychotic disorders such as psychosis induced by alcohol, amphetamines, cannabis, cocaine, hallucinogens, inhalants, opioids or phencycline; Paranoid personality disorder; Schizotypal personality disorder; Drug addiction, including drugs (eg, heroin, opiates and morphine), cocaine and alcoholism; Drug withdrawal, including drug, cocaine and alcohol withdrawal; Obsessive compulsive disorder; Tourette syndrome; depression; Major depression, manic or mixed mood, hypomania, atypical or depressive or tonic depressed, postpartum segmentation; Major depressive disorders, bipolar disorders in addition to psychiatric disorders such as post-stroke depression, major depressive disorders, mood disorders, mild depressive disorders, premenstrual discomfort, depressive disorders of schizophrenia, delusions or schizophrenia, for example Bipolar disorder I, bipolar disorder II, cyclic mood disorder; Anxiety; Attention deficit and hyperactivity disorder; And attention deficit disorder. [99] In another embodiment, the cdk5 inhibitor is a compound of Formula 1 or a pharmaceutically acceptable salt thereof in a method of treating or treating a disease or condition for which treatment can be achieved or promoted by modifying dopamine mediated neurotransmission. [100] The present invention also provides a pharmaceutical composition for treating a disease or condition promoted by cdk5 activity in a mammal, comprising an inhibitory effective amount of a cdk5 activity, a compound of Formula 1 and a pharmaceutically acceptable carrier. [101] The present invention also provides a method of treating a disease or condition promoted by cdk5 activity in a mammal, comprising administering to said mammal an inhibitory effective amount of a cdk5 activity to a mammal. [102] In addition, the present inventors have found that the compound of formula 1 has an activity of inhibiting GSK-3. Therefore, the compounds of formula 1 can be expected to be useful for the treatment of diseases and disorders in which treatment can be achieved or promoted by GSK-3 inhibition. Diseases and disorders that can be achieved or promoted by GSK-3 inhibition include neurodegenerative diseases and disorders. Neurodegenerative diseases and disorders have been discussed above, for example Alzheimer's disease, Parkinson's disease, Huntington's disease, atrophic lateral sclerosis, multiple infarction, stroke, cerebral ischemia, AIDS related dementia, neurodegeneration associated with bacterial infections, multiple infarctions, Including but not limited to traumatic brain injury and spinal cord trauma. Therefore, the compound of formula 1 is effective for the treatment of neurodegenerative diseases and disorders based on both cdk5 activity and GSK-3 activity. [103] Other diseases and conditions for which treatment may be achieved or promoted by GSK-3 inhibition include psychotic disorders and diseases such as schizophrenia, schizophrenic disorders; Schizophrenic affective disorders, eg delusional or depressive; Delusional disorder; Substance-induced psychotic disorders such as psychosis induced by alcohol, amphetamines, cannabis, cocaine, hallucinogens, inhalants, opioids or phencycline; Paranoid personality disorder; And schizotypal personality disorder. In addition, treatment of such diseases and disorders can be achieved or facilitated by modifying dopamine mediated neurotransmission. Therefore, the compound of formula 1 is effective in the treatment of the above disorders and diseases based on both cdk5 activity and GSK-3 activity. [104] Other disorders and disorders in which treatment can be achieved or promoted by GSK-3 inhibition include mood disorders and mood episodes, such as major depression, manic or mixed mood episodes, hypomania, atypical or depressive or tonic depressive episodes. Postpartum fragmentation; Major depressive disorders, bipolar disorders in addition to psychiatric disorders such as post-stroke depression, major depressive disorders, mood disorders, mild depressive disorders, premenstrual discomfort, depressive disorders of schizophrenia, delusions or schizophrenia, for example Bipolar disorder I, bipolar disorder II, and cyclic mood disorder. In addition, the treatment of mood disorders and illustrations, such as depression, can be achieved or promoted by modifying dopamine mediated neurotransmission. Therefore, the compound of formula 1 is effective in the treatment of certain mood disorders and mood induction based on both cdk5 activity and GSK-3 activity. [105] Other disorders and diseases in which treatment can be achieved or promoted by GSK-3 inhibition include male fertility and sperm movement; diabetes; Impaired glucose tolerance; Metabolic syndrome or syndrome X; Polycystic ovary syndrome; Lipogenesis and obesity; Muscle development and weakness, eg, age-related poor physical performance; Acute myopathy, eg muscular dystrophy and / or cachexia associated with burns, bedside care, limb fixation, or chest, abdomen, and / or orthopedic major surgery; blood poisoning; Spinal cord injury; Hair loss, hair softening and baldness; Immunodeficiency; And cancer. [106] Thus, the present invention also relates to male fertility and sperm exercise; diabetes; Impaired glucose tolerance; Metabolic syndrome or syndrome X; Polycystic ovary syndrome; Lipogenesis and obesity; Muscle development and weakness, eg, age-related poor physical performance; Acute myopathy, eg muscular dystrophy and / or cachexia associated with burns, bedside care, limb fixation, or chest, abdomen, and / or orthopedic major surgery; blood poisoning; Hair loss, hair softening and baldness; And it provides a pharmaceutical composition for treating the disease or disorder in a mammal comprising a human, comprising a therapeutically effective amount of a compound of formula 1 and a pharmaceutically acceptable carrier for the disease or disorder selected from immunodeficiency. [107] In addition, the present invention provides a combination of male fertility and sperm motility in mammals, including humans, comprising an inhibitory effective amount of GSK-3, a compound of Formula 1 and a pharmaceutically acceptable carrier; diabetes; Impaired glucose tolerance; Metabolic syndrome or syndrome X; Polycystic ovary syndrome; Lipogenesis and obesity; Muscle development and weakness, eg, age-related poor physical performance; Acute myopathy, eg muscular dystrophy and / or cachexia associated with burns, bedside care, limb fixation, or chest, abdomen, and / or orthopedic major surgery; blood poisoning; Hair loss, hair softening and baldness; And pharmaceutical compositions for treating a disease or disorder selected from immunodeficiency. [108] In addition, the present invention provides male fertility and sperm exercise; diabetes; Impaired glucose tolerance; Metabolic syndrome or syndrome X; Polycystic ovary syndrome; Lipogenesis and obesity; Muscle development and weakness, eg, age-related poor physical performance; Acute myopathy, eg muscular dystrophy and / or cachexia associated with burns, bedside care, limb fixation, or chest, abdomen, and / or orthopedic major surgery; blood poisoning; Hair loss, hair softening and baldness; And administering to a mammal, including a human, a therapeutically effective amount of a compound of Formula 1 in a disease or disorder selected from immunodeficiency. [109] In addition, the present invention comprises administering an inhibitory effective amount of a compound of Formula 1 to a mammal, including human, male reproductive and sperm exercise in the mammal; diabetes; Impaired glucose tolerance; Metabolic syndrome or syndrome X; Polycystic ovary syndrome; Lipogenesis and obesity; Muscle development and weakness, eg, age-related poor physical performance; Acute myopathy, eg muscular dystrophy and / or cachexia associated with burns, bedside care, limb fixation, or chest, abdomen, and / or orthopedic major surgery; blood poisoning; Hair loss, hair softening and baldness; And methods for treating a disease or condition selected from immunodeficiency. [110] The present invention also provides a method of inhibiting GSK-3 in a mammal comprising administering an inhibitory effective amount of GSK-3 to a mammal, including a human. [111] The present invention also provides a pharmaceutical composition for treating said disorder in a mammal comprising a therapeutically effective amount of a cdk5 inhibitor and a COX-II inhibitor and a pharmaceutically acceptable carrier for a disorder selected from Alzheimer's disease, mild cognitive impairment and age-related cognitive decline. to provide. In one embodiment, the cdk5 inhibitor is a compound of Formula 1 or a pharmaceutically acceptable salt thereof. [112] Further, the present invention comprises administering to a mammal a cdk5 inhibitor and a COX-II inhibitor in a therapeutically effective amount for a disorder selected from Alzheimer's disease, mild cognitive impairment and age-related cognitive decline. Provide 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 COX-II inhibitor may be administered to the mammal simultaneously and / or at different times. In addition, they may be administered together in a single pharmaceutical composition or in separate pharmaceutical compositions. [113] In addition, a cdk5 inhibitor, for example a compound of Formula 1 or a pharmaceutically acceptable salt of Compound 1 of the present invention, may be administered or pharmaceuticaled with one or more antidepressant or anti-anxiety compounds for the treatment or prevention of depression and / or anxiety. It may be formulated into a composition. [114] Accordingly, the present invention also provides a pharmaceutical composition for treating depression or anxiety in a mammal, comprising a therapeutically effective amount of a cdk5 inhibitor and an NK-1 receptor antagonist, and a pharmaceutically acceptable carrier. In one embodiment, the cdk5 inhibitor is a compound of Formula 1 or a pharmaceutically acceptable salt thereof. [115] The present invention also provides a method of treating depression or anxiety in a mammal comprising administering to the mammal a cdk5 inhibitor and an NK-1 receptor antagonist combined in a therapeutically effective amount of depression or anxiety. In one embodiment, the cdk5 inhibitor is a compound of Formula 1 or a pharmaceutically acceptable salt thereof. The cdk5 inhibitor and NK-1 receptor antagonist may be administered to the mammal simultaneously and / or at different times. In addition, they may be administered together in a single pharmaceutical composition or in separate pharmaceutical compositions. [116] The present invention also provides a pharmaceutical composition for treating depression or anxiety in a mammal comprising a therapeutically effective amount of a cdk5 inhibitor and a 5HT 1D receptor antagonist, and a pharmaceutically acceptable carrier. In one embodiment, the cdk5 inhibitor is a compound of Formula 1 or a pharmaceutically acceptable salt thereof. [117] The present invention also provides a method of treating depression or anxiety in a mammal comprising administering to the mammal a cdk5 inhibitor and a 5HT 1D receptor antagonist combined in a therapeutically effective amount of depression or anxiety. In one embodiment, the cdk5 inhibitor is a compound of Formula 1 or a pharmaceutically acceptable salt thereof. The cdk5 inhibitor and 5HT 1D receptor antagonist may be administered to the mammal simultaneously and / or at different times. In addition, they may be administered together in a single pharmaceutical composition or in separate pharmaceutical compositions. [118] The present invention also provides a pharmaceutical composition for treating depression or anxiety in a mammal, comprising a therapeutically effective amount of a cdk5 inhibitor and SSRI, and a pharmaceutically acceptable carrier for depression or anxiety. In one embodiment, the cdk5 inhibitor is a compound of Formula 1 or a pharmaceutically acceptable salt thereof. [119] The present invention also provides a method of treating depression or anxiety in a mammal comprising administering to the mammal a cdk5 inhibitor and SSRI combined in a therapeutically effective amount of depression or anxiety. In one embodiment, the cdk5 inhibitor is a compound of Formula 1 or a pharmaceutically acceptable salt thereof. The cdk5 inhibitor and the SSRI may be administered to the mammal simultaneously and / or at different times. In addition, they may be administered together in a single pharmaceutical composition or in separate pharmaceutical compositions. [120] The present invention also provides a therapeutically effective amount of a cdk5 inhibitor of schizophrenia, and ziprasidone, olanzapine, risperidone, L-745870, sonepiprazole, RP 62203, NGD 941, A pharmaceutical composition for treating schizophrenia in a mammal is provided, comprising an antipsychotic selected from balaperidone, flesinoxan, 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. [121] The present invention is also selected from cdk5 inhibitors combined in a therapeutically effective amount of schizophrenia, and from ziprasidone, olanzapine, risperidone, L-745870, sonepyprazole, RP 62203, NGD 941, valericidone, plesinoxane and gepyron Provided is a method of treating schizophrenia in a mammal, comprising administering an antipsychotic to the mammal. In one embodiment, the cdk5 inhibitor is a compound of Formula 1 or a pharmaceutically acceptable salt thereof. cdk5 inhibitors and antipsychotics may be administered to the mammal simultaneously and / or at different times. In addition, they may be administered together in a single pharmaceutical composition or in separate pharmaceutical compositions. [122] The present invention also provides a pharmaceutical for treating said disorder in a mammal comprising a therapeutically effective amount of a cdk5 inhibitor and an acetylcholinesterase inhibitor and a pharmaceutically acceptable carrier for a disorder selected from Alzheimer's disease, mild cognitive impairment and age-related cognitive decline. To provide a composition. In one embodiment, the cdk5 inhibitor is a compound of Formula 1 or a pharmaceutically acceptable salt thereof. [123] The present invention also includes administering to a mammal a cdk5 inhibitor and an acetylcholinesterase inhibitor combined in a therapeutically effective amount of a disorder selected from Alzheimer's disease, mild cognitive impairment and age-related cognitive decline. Provides a method of treatment. 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 may be administered to the mammal simultaneously and / or at different times. [124] The invention also provides therapeutically effective amounts of cdk5 inhibitors and TPA (tissue plasminogen activators, such as strokes, spinal cord trauma, traumatic brain injury, multiple infarcts, epilepsy, pain, Alzheimer's disease and senile dementia). ACTIVASE), and a pharmaceutically acceptable carrier, to provide a pharmaceutical composition for treating the disease or disorder. In one embodiment, the cdk5 inhibitor is a compound of Formula 1 or a pharmaceutically acceptable salt thereof. [125] The invention also includes administering to a mammal a cdk5 inhibitor and TPA combined in a therapeutically effective amount of a disease or condition selected from stroke, spinal cord injury, traumatic brain injury, multiple infarction, epilepsy, pain, Alzheimer's disease and senile dementia. To provide a method of treating the disease or disorder in the mammal. 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 simultaneously and / or at different times. In addition, they may be administered together in a single pharmaceutical composition or in separate pharmaceutical compositions. [126] The invention also provides therapeutically effective amounts of cdk5 inhibitors and NIF (neutrophil inhibitors), and pharmaceutically acceptable amounts of a disease or condition selected from stroke, spinal cord injury, traumatic brain injury, multiple infarction, epilepsy, pain, Alzheimer's disease and senile dementia. It provides a pharmaceutical composition for treating the disease or disorder, comprising a carrier. In one embodiment, the cdk5 inhibitor is a compound of Formula 1 or a pharmaceutically acceptable salt thereof. [127] The invention also includes administering to a mammal a cdk5 inhibitor and a NIF in combination in a therapeutically effective amount of a disease or condition selected from stroke, spinal cord injury, traumatic brain injury, multiple infarction, epilepsy, pain, Alzheimer's disease and senile dementia. To provide a method of treating the disease or disorder in the mammal. In one embodiment, the cdk5 inhibitor is a compound of Formula 1 or a pharmaceutically acceptable salt thereof. The cdk5 inhibitor and the NIF may be administered to the mammal simultaneously and / or at different times. In addition, they may be administered together in a single pharmaceutical composition or in separate pharmaceutical compositions. [128] The invention also relates to Huntington's disease, stroke, spinal cord injury, traumatic brain injury, multiple infarct, epilepsy, muscular dystrophy, pain, virus-induced dementia, for example AIDS-induced dementia, migraine, hypoglycemia, urinary incontinence, cerebral ischemia. , Multiple infarction, Alzheimer's disease, Alzheimer's type senile dementia, mild cognitive impairment, age-related cognitive decline, vomiting, cortical hypoplasia, projectile dementia, Down's syndrome, myotonic dystrophy, Neimanpick disease, pick disease, prion disease caused by fiber concentrate, Provided is a pharmaceutical composition for treating a disease or condition comprising a therapeutically effective amount of a cdk5 inhibitor and an NMDA receptor antagonist, and a pharmaceutically acceptable carrier, for a disease or condition selected from advanced nuclear palsy, lower lateral sclerosis and subacute sclerosis panencephalitis . In one embodiment, the cdk5 inhibitor is a compound of Formula 1 or a pharmaceutically acceptable salt thereof. [129] The invention also relates to Huntington's disease, stroke, spinal cord injury, traumatic brain injury, multiple infarct, epilepsy, muscular dystrophy, pain, virus-induced dementia, for example AIDS-induced dementia, migraine, hypoglycemia, urinary incontinence, cerebral ischemia. , Multiple infarction, Alzheimer's disease, Alzheimer's type senile dementia, mild cognitive impairment, age-related cognitive decline, vomiting, cortical hypoplasia, projectile dementia, Down's syndrome, myotonic dystrophy, Neimanpick disease, pick disease, prion disease caused by fiber concentrate, Treatment of said disease or condition in said mammal comprising administering to said mammal a cdk5 inhibitor and an NMDA receptor antagonist combined in a therapeutically effective amount of a disease or condition selected from progressive nuclear palsy, lower lateral sclerosis and subacute sclerosis panencephalitis Provide a method. In one embodiment, the cdk5 inhibitor is a compound of Formula 1 or a pharmaceutically acceptable salt thereof. The cdk5 inhibitor and NMDA receptor antagonist may be administered to the mammal simultaneously and / or at different times. In addition, they may be administered together in a single pharmaceutical composition or in separate pharmaceutical compositions. [130] The invention also provides a therapeutically effective amount of a cdk5 inhibitor and a potassium channel modulator, and a pharmaceutically acceptable carrier for a disease or condition selected from stroke, spinal cord injury, traumatic brain injury, multiple infarction, epilepsy, pain, Alzheimer's disease and senile dementia. Provided, the pharmaceutical composition for treating the disease or disorder. In one embodiment, the cdk5 inhibitor is a compound of Formula 1 or a pharmaceutically acceptable salt thereof. [131] In addition, the present invention provides a mammal with a cdk5 inhibitor and a potassium channel modulator in combination with a therapeutically effective amount of a disease or disorder selected from stroke, spinal cord injury, traumatic brain injury, multiple infarction, epilepsy, pain, Alzheimer's disease and senile dementia. It provides a method of treating the disease or disorder in the mammal. 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 may be administered to the mammal simultaneously and / or at different times. In addition, they may be administered together in a single pharmaceutical composition or in separate pharmaceutical compositions. [132] The terms “treatment”, “treating”, etc. refer to the reversal, alleviation or inhibition of the disease or condition in which the term is used or the progression of one or more symptoms of such disease or condition. Also, as used herein, these terms, depending on the disease of the patient, may be used to determine a disease or condition, or symptoms associated with the disease or condition, including reducing the severity of the disease or condition, or symptoms associated therewith, prior to the suffering of the disease or condition. Preventing the outbreak. The pre-pain reduction or prevention refers to the administration of a compound of the present invention to a subject who does not suffer from the disease or condition at the time of administration. "Prevention" also includes preventing the recurrence of a disease or condition, or symptoms associated therewith. [133] As used herein, "mammal" means any mammal unless stated otherwise. The term "mammal" includes, but is not limited to, for example, dogs, cats, and humans. [134] As used herein, "abnormal cell growth" refers to malignant (eg cancer) or benign cell growth, which is independent of normal regulatory mechanisms (eg loss of contact inhibition). Examples of benign proliferative diseases are psoriasis, benign prostatic hyperplasia, human papilloma virus (HPV) and restenosis. [135] As used herein, "neurodegenerative diseases and disorders" refers to diseases and disorders associated with the degeneration of neurons. Diseases and diseases that are neurodegenerative in nature are generally known to those skilled in the art. [136] As used herein, a "disease or disease in which treatment can be achieved or promoted by modifying dopamine mediated neurotransmission" refers to a disease or disorder caused by dopamine neurotransmission, or an abnormal dopamine neuron that exhibits symptoms or signs of the disease or disorder. Refers to a disease or condition that causes delivery. [137] As used herein, a "disease or disease in which treatment can be achieved or promoted by reducing cdk5 activity" refers to a disease or condition caused at least in part by cdk5 activity, or to induce abnormal cdk5 activity that exhibits symptoms or signs of the disease or condition. Means a disease or condition. [138] As used herein, an "inhibitory effective amount of cdk5 activity" refers to an amount of a compound that is sufficient to bind the enzyme cdk5 to reduce cdk5 activity. [139] As used herein, "an inhibitory effective amount of cdk2 activity" refers to an amount of a compound that is sufficient to bind the enzyme cdk2 to reduce cdk2 activity. [1] The present invention relates to imidazole derivatives, pharmaceutical compositions comprising the derivatives, and methods of using these derivatives for the treatment of abnormal cell growth and certain diseases and disorders of the central nervous system. Compounds of the invention act as inhibitors of the cyclin-dependent protein kinase enzymes cdk5 (cyclin-dependent protein kinase 5) and cdk2 (cyclin-dependent protein kinase 2). In addition, the compounds of the present invention are inhibitors of the enzyme GSK-3 (glycogen synthase kinase-3) enzyme. [140] The compound of Formula 1 and pharmaceutically acceptable salts thereof may be prepared according to the following scheme and description. Unless stated otherwise, R 1 , R 2 , R 3 and R 4 are as defined above. Isolation and purification of the product is accomplished by standard methods known to those skilled in the art. [141] The expression "reactive inert solvent" as used herein refers to a solvent system in which the components do not interact with the starting materials, reagents or intermediates of the product in a manner that adversely affects the yield of the desired product. [142] During any of the following synthetic sequences, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules involved. This is described in T. W. Greene, Protective Groups in Organic Chemistry, John Wiley & Sons, 1981 and T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1991. [143] Scheme 1 illustrates a method suitable for the preparation of compounds of Formula 1 wherein R 3 is -C (= 0) NH-, -C (= 0) O- or -C (= 0) (CR 10 R 11 ) n-. do. Referring to Scheme 1, dimethyl sulfoxide (DMSO), pyridine-water, water, acetonitrile-water, alcohol or alcohol-water solvent at about −20 ° C. to about 50 ° C., preferably about −5 ° C. to 35 ° C. System, preferably a 1,4-dinitroimidazole solution (J. Phys. Chem. (1995) Vol. 99, pp. 5009-1015) in a lower alcohol such as methanol is used as primary alkyl or aryl amine Is treated to give 1-N-substituted-4-nitroimidazole of formula (2). 1,4-dinitroimidazole is a very powerful semi-stable substance that must be stored in the freezer when not in use. Thermodynamic measurements have shown that there is a possibility to generate enough energy at 35 ° C. under adiabatic conditions and explode violently. Reduction of the nitro compound of formula (2) to the amine of formula (3) is carried out in a solvent such as ethyl acetate, tetrahydrofuran, dioxane or mixtures thereof in a mixture of the compound of formula 2 and the noble metal catalyst in a hydrogen gas atmosphere at about 1-100 atmospheres, Preferably by exposure to hydrogen gas at about 1 to about 10 atmospheres. Palladium is the preferred noble metal catalyst. The metal can advantageously be supported on an inert solid support, such as charcoal. After the compound of formula 2 is consumed, the mixture is filtered and formula 3 produced at about -78 ° C to 40 ° C in the presence of a base such as triethylamine, diisopropylethylamine, pyridine or 2,6-lutidine Amines of 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 XC (= O React immediately with CR 10 R 11 and n R 4 . 1-propanephosphonic acid cyclic anhydride and triethylamine are preferred combinations. Activated carboxylic acid derivatives include carboxylic acid HOC (= 0) (CR 10 R 11 ) n R 4 and known activating reagents such as dicyclohexyl carbodiimide, 1- (3-dimethylaminopropyl) -3-ethyl Carbodiimide hydrochloride, carbonyl diimidazole, 1-propanephosphonic acid cyclic anhydride, alkyl or aryl chloroformate, bis (2-oxo-3-oxazolidinyl) phosphinic chloride, benzotriazole-1- It is prepared from yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, or any other standard literature reagent. This process affords a compound of Formula 1B wherein R 3 is -C (= 0) (CR 10 R 11 ) n- . [144] Alternatively, after filtration, the amine of formula 3 is reacted with a base such as triethylamine, diisopropylethylamine, pyridine or 2,6- at about −78 ° C. to 40 ° C., preferably at −78 ° C. to −40 ° C. Treatment with lutidine, and alkyl- or aryl-chloroformates can yield compounds of Formula 1A wherein R 3 is -C (= 0) O- and R 4 is phenyl. Diisopropylethylamine and phenyl chloroformate are preferred combinations. Subsequent treatment of phenyl carbamate of formula 1A with primary or secondary amine at about 40 ° C. to 90 ° C. in a solvent such as dioxane, dimethylformamide or acetonitrile, wherein R 3 is —C (═O) NR 9 To yield the corresponding urea product 1C, wherein-and R 4 is phenyl or heteroaryl. Preference is given to a 1: 1 mixture of dioxane-dimethylformamide and 70 ° C. [145] [146] Scheme 2 R 1 is substituted with R 5 and R 5 represents a NHC (= O) R 8 in the process for producing the compound of the formula (I). Amine bases such as triethylamine, diisopropylethylamine, pyridine or 2,6-ruti in a reaction inert solvent such as tetrahydrofuran, methylene chloride or chloroform, preferably methylene chloride at from about −10 ° C. to about 30 ° C. Dine, preferably triethylamine and a compound of formula 4 wherein R 5 is OH in the presence of the catalyst 4-N, N-dimethylaminopyridine, alkyl- or aryl-sulfonyl chloride, preferably p-toluenesulfonyl chloride Treatment with (TosCl) affords a compound of formula 5 wherein R 5 is CH 3 (C 6 H 4 ) SO 3 (TosO). Tosylate so formed at about 20 ° C. to 130 ° C., preferably 90 ° C. to 110 ° C. in polar solvents such as dimethylformamide, dimethyl sulfoxide, lower alcohols, water or mixtures of these solvents, preferably ethanol-water mixtures. Is treated with an alkali metal salt of an azide, preferably sodium azide, to give a compound of formula 6 wherein R 5 is N 3 . [147] Azides in a solvent such as tetrahydrofuran, dioxane, acetonitrile or mixtures thereof, preferably tetrahydrofuran, under selective reducing conditions such as trialkyl- or triarylphosphine and water, preferably triphenylphosphine Treatment yields a compound of formula 7 wherein R 5 is NH 2 . The primary amino group of the compound of formula 7 (R 5 = NH 2 ) thus formed can be derivatized via reaction with chloroformate, isocyanate, carbamoylyl chloride, acid chloride, acid anhydride or activated carboxylic acid derivative. . Activated carboxylic acid derivatives include carboxylic acids and known activating reagents such as dicyclohexyl carbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, carbonyl diimidazole, 1-propaneforce Phonic acid cyclic anhydride, alkyl chloroformate, bis (2-oxo-3-oxazolidinyl) phosphinic chloride, benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, or any From other standard literature reagents, if necessary, an amine base such as triethylamine, diisopropylethylamine, pyridine or 2,6-lutidine, preferably 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide It is prepared at about -78 ° C to 80 ° C, preferably 0 ° C to 40 ° C in the presence of hydrochloride. Tetrahydrofuran and methylene chloride are preferred solvents. [148] The compound of Formula 1D of the compound of Formula 8 wherein R 5 is —NHC (═O) R 8 (R 5 is NHC (═O) R 8 and R 3 is C (═O) (CR 10 R 11 ) n The conversion to R 4 is carried out in a solvent such as ethyl acetate, tetrahydrofuran, dioxane or mixtures thereof and the compound of formula 8 and a noble metal catalyst, preferably palladium (where the metal is advantageously on an inert solid support such as charcoal) May be supported by exposure to about 1 to 100 atmospheres of hydrogen gas atmosphere, preferably about 1 to about 10 atmospheres of hydrogen gas. After the compound of formula 8 has been consumed, the mixture is filtered and, if appropriate, an amine base such as triethylamine, diisopropylethylamine, pyridine or 2,6-lutidine, preferably 1-propanephosphonic acid cyclic anhydride And acylation of the resulting amine at about −78 ° C. to 40 ° C. immediately in the presence of a combination of triethylamine with an acid chloride, acid anhydride or activated carboxylic acid derivative to yield the N-acylated product of Formula 1D. do. Activated carboxylic acid derivatives include carboxylic acids and known activating reagents such as dicyclohexyl carbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, carbonyl diimidazole, 1-propaneforce Phonic acid cyclic anhydride, alkyl chloroformate, bis (2-oxo-3-oxazolidinyl) phosphinic chloride, benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, or any It is prepared from other standard literature reagents. [149] The use of aryl chloroformate or heteroaryl chloroformate in place of the acid chloride, acid anhydride or activated carboxylic acid derivative in the acylation yields aryl carbamate 1E. Aryl carbamate 1E (R) produced at about 40 ° C. to 90 ° C., preferably 70 ° C. in a 1: 1 mixture of a solvent such as dioxane, dimethylformamide or acetonitrile, preferably dioxane-dimethylformamide 3 is C (═O) O— and R 4 is aryl or heteroaryl) with an amine to give Formula 1F (R 3 is —C (═O) NR 9 — and R 4 is aryl or heteroaryl) Corresponding urea products of can be obtained. [150] [151] Scheme 3 shows another method for preparing a compound of Formula 1 wherein R 5 is -NHC (= 0) R 8 . Amine bases such as triethylamine, diisopropylethylamine, pyridine or 2,6-ruti in a reaction inert solvent such as tetrahydrofuran, methylene chloride or chloroform, preferably methylene chloride at from about −10 ° C. to about 30 ° C. Dine, and a compound of formula 4 wherein R 5 is OH in the presence of 4-N, N-dimethylaminopyridine, treated with alkyl- or aryl-sulfonyl chloride, preferably p-toluenesulfonyl chloride (TosCl), Obtain a compound of formula 5 wherein R 5 is CH 3 (C 6 H 4 ) SO 3 (TosO). Triethylamine is the preferred amine base. The 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 (= 0) (CR 10 R 11 ) n R 4 is a solvent such as ethyl acetate, In tetrahydrofuran, dioxane or mixtures thereof, a mixture of the compound of formula 5 (R 5 is TosO) and the noble metal catalyst is placed in a hydrogen gas atmosphere at about 1 to 100 atm, preferably at about 1 to about 10 atm. Can be achieved by exposure. Palladium is the preferred noble metal catalyst. The metal can advantageously be supported on an inert solid support, such as charcoal. After the compound of formula 5 has been consumed, the mixture is filtered and, if appropriate, an amine base such as triethylamine, diisopropylethylamine, pyridine or 2,6-lutidine, preferably 1-propanephosphonic acid cyclic anhydride And the amine produced at about −78 ° C. to 40 ° C. in the presence of a combination of triethylamine is immediately reacted with an acid chloride, acid anhydride or activated carboxylic acid derivative to obtain an N-acylated product of Formula 1G. Activated carboxylic acid derivatives include carboxylic acids and known activating reagents such as dicyclohexyl carbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, carbonyl diimidazole, 1-propaneforce Phonic acid cyclic anhydride, alkyl chloroformate, bis (2-oxo-3-oxazolidinyl) phosphinic chloride, benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, or any It is prepared from other standard literature reagents. [152] A compound of formula 1G at about 20 ° C to 130 ° C, preferably 90 ° C to 110 ° C in a polar solvent such as dimethylformamide, dimethylsulfoxide, lower alcohol, water or a mixture of these solvents, preferably an ethanol-water mixture (R 5 is TosO and R 3 is C (= O) (CR 10 R 11 ) n- ) with an alkali metal salt of an azide, preferably sodium azide, wherein R 5 is N 3 Compounds can be obtained. Subsequent reduction of the azide of formula 1H (R 5 is N 3 ) is carried out in a solvent such as ethyl acetate, tetrahydrofuran, dioxane or mixtures thereof, wherein the compound of formula 1H (R 5 is N 3 ) and a noble metal catalyst, preferably Preferably a mixture of palladium, where the metal can advantageously be supported on an inert solid support, such as charcoal, is exposed to about 1 to 100 atmospheres of hydrogen gas atmosphere, preferably about 1 to about 10 atmospheres of hydrogen gas. Can be achieved. [153] Alternatively, the reduction of the azide of formula 1H (R 5 is N 3 ) can be carried out by trialkyl- or triarylphosphine and water in a solvent such as tetrahydrofuran, dioxane or acetonitrile, preferably tetrahydrofuran, Preferably it can be achieved by treatment with triphenylphosphine. Primary amino groups of the compound of formula (I) (R 5 is NH 2 ) can be derivatized via reaction with chloroformate, isocyanate, carbamoylyl chloride, acid chloride, acid anhydride or activated carboxylic acid derivative, The activated carboxylic acid derivatives here are carboxylic acids and known activating reagents such as dicyclohexyl carbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, carbonyl diimidazole, 1-propane Phosphonic acid cyclic anhydride, alkyl chloroformate, bis (2-oxo-3-oxazolidinyl) phosphinic chloride, benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, or optional From other standard literature reagents, if necessary, an amine base such as triethylamine, diisopropylethylamine, pyridine or 2,6-lutidine, preferably 1- (3-dimethyl Aminopropyl) -3-ethylcarbodiimide hydrochloride is prepared at about -78 ° C to 80 ° C, preferably 0 ° C to 40 ° C. Tetrahydrofuran and methylene chloride are preferred solvents. [154] [155] Compounds of formula 1 wherein R 3 is-(CR 10 R 11 ) n -can be prepared according to Scheme 4. Referring to Scheme 4, in a reaction inert solvent such as tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, dimethylsulfoxide or toluene, about -20 ° C to 150 ° C, preferably 20 ° C to Phase transfer catalyst at 100 ° C., such as tetra-n-butylammonium chloride, tetra-n-butylammonium bromide, tetra-n-butylammonium iodide, benzyltrimethyl ammonium chloride, benzyltrimethyl ammonium bromide, or benzyltrimethyl ammonium fluoride The solution of 4-bromoimidazole in the absence or presence of a base such as sodium hydride, potassium hydride, lithium hydride, cesium carbonate, sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium diisopropyl amide, sodium amide, potassium hexamethyldi After treatment with silazide, sodium hexamethyldisilazide, sodium tert-butoxide, or potassium tert-butoxide, alkyl, allyl or 1-substituted-4-bromoimidazole (9) and 1-substituted-5-bromoimida by addition of chloride, bromide, iodide, alkyl sulfonate, aryl sulfonate, or triflate of benzyl A mixture of the sol 10 is obtained, which can be separated using methods known to those skilled in the art. [156] Alternatively, palladium catalysts such as palladium in a reaction inert solvent such as tetrahydrofuran, 1,2-dichloroethane, 1,4-dioxane, dimethylsulfoxide or N, N-dimethylformamide, preferably tetrahydrofuran (0) Tetrakis (triphenylphosphine), palladium (II) acetate, allyl palladium chloride dimer, tris (dibenzylideneacetone) dipalladium (0), tris (dibenzylideneacetone) dipalladium (0) chloroform addition Phosphine ligands such as triphenylphosphine, tri-o-tolylphosphine, tri-tert in the presence of a product, palladium (II) chloride, preferably palladium tetrakis (triphenylphosphine) or palladium (II) acetate About 0 ° C. to 100 ° C., preferably 50 ° C. to 80 ° C., with or without butylphosphine, 1,2-bis (diphenylphosphino) ethane or 1,3-bis (diphenylphosphino) propane 4-bromoimidazole in Treatment with allyl fluoride, chloride, bromide, iodide, acetate or carbonate, preferably allyl carbonate, results in 1-substituted-4-bromoimidazole (9) and 1-substituted-5 A mixture of bromoimidazole (10) is obtained. [157] Formulated 1-substituted-4-bromoimidazole (9) at about 0 ° C. to 150 ° C., preferably 20 ° C. to 110 ° C., in a reaction inert solvent such as toluene, 1,4-dioxane or tetrahydrofuran. Intermediates of -NH 2 (CR 10 R 11 ) n R 4 and palladium catalysts such as palladium (II) acetate, allyl palladium chloride dimer, tris (dibenzylideneacetone) dipalladium (0), tris (dibenzylideneacetone) Dipalladium (0) chloroform adduct, or palladium (II) chloride, preferably palladium (II) acetate, tris (dibenzylideneacetone) dipalladium (0), and tris (dibenzylideneacetone) dipalladium (0 ) Chloroform adducts, and phosphine ligands such as BINAP, 2-biphenyl dicyclohexylphosphine, 2-biphenyl di-tert-butylphosphine or 2-N, N-dimethylamino-2'-diphenylphosph Pino biphenyl, preferably 2-N, N-dimethylamino-2'-diphenylphosphino Phenyl, and a base such as sodium tert- butoxide, to give a cesium carbonate, or potassium phosphate (K 3 PO 4), preferably by treatment with potassium phosphate, coupled product 1. [158] [159] Another method for synthesizing the compound of Formula 1 wherein R 3 is -C (= 0) (CR 10 R 11 ) n -is shown in Scheme 5 below. From about 23 ° C. to about 200 ° C., preferably from about 60 ° C. to about 60 ° C. in a solvent such as n-butanol, n-propanol, i-propanol or ethanol or in the absence of a solvent, preferably in n-propanol or in the absence of a solvent Ethyl-2-isocyano-3-N, N-dimethylamino acrylate (11) is treated with primary amine R 1 -NH 2 at 150 ° C. to give the imidazole of formula 12. Treatment of N, 0-dimethyl hydroxyl amine hydrochloride with trimethylaluminum in 1,2-dichloroethane followed by addition of compound 12 and heating at about 30 ° C. to about 80 ° C., preferably about 50 ° C. Obtained dazole 13. Organometallic reagent M- (CR 10 R 11 ) n R 4 (at about −50 ° C. to about 30 ° C., preferably about −20 ° C. to about 0 ° C. in a solvent such as tetrahydrofuran, methylene chloride or diethyl ether. Wherein M may be lithium or magnesium halide, preferably magnesium halide) to a solution of compound 13 to yield compound 14. Compound 14 is added to a mixture of hydroxyl amine hydrochloride and potassium acetate at about 23 ° C. in a lower alcohol solvent, preferably ethanol, to give oxime 15 as a mixture of isomers. The acetone solution of oxime 15 at about 0 ° C. was treated with aqueous sodium hydroxide followed by paratoluenesulfonyl chloride to give a mixture of 0-sulfonyl compounds, followed by extraction. The crude material is dissolved in a nonpolar solvent such as benzene, hexane or toluene, preferably benzene, added to an alumina column, eluted with chloroform-methanol (about 10: 1) after approximately 5 minutes and subjected to Beckmann rearrangement. To yield compound 1B and the regio isomer. [160] [161] Compounds of Formula 1J may also be prepared by the method shown in Scheme 6 below. The key starting material in the synthesis is a double bond containing compound (X) substituted with 1 to 3 groups selected from ER 5 group and R 5 group (compound of formula X), wherein ER 5 is C (= 0) R 7 , C (= O) OR 7 , C (= O) NR 7 R 8 , S (= O) 2 R 7 , S (= O) 2 NR 7 R 8 , S (= O) 2 OR 7 , And an electron withdrawing group selected from cyano and heteroaryl. In addition, the compound of formula X may be that ER 5 is linked to one of the R 5 groups or directly to the carbon-carbon double bond to form a ring, 2-cyclopenten-l-one and 2-cyclohexene-1 Compounds such as -ones are included. Alternatively, compounds of formula (X) wherein L is defined as Cl, Br, I, OC (= 0) R 7 or OS (= 0) 2 R 7 can be used as starting materials, examples of which are 3-chloro -1-cyclopentanone and 3-acetoxy-1-cyclobutanone. Thus, referring to Scheme 6, about -60 ° C to about 50 ° C, preferably -20 ° C to 23 ° C in a solvent such as acetonitrile, methylene chloride, 1,2-dichloroethane or chloroform, preferably acetonitrile Salts of 4 (5) -nitroimidazole, such as sodium salts, potassium salts, cesium salts, 1,8-diazabicyclo [5.4.0] undes-7-ene (DBU) salts or tetraalkyl ammonium salts, preferably Preferably, tetra n-butylammonium salt and DBU salt are treated with intermediate 16 or 17 to obtain the addition product of formula 2A. Reduction of the nitro compound 2A can be carried out in a solvent such as ethyl acetate, tetrahydrofuran, dioxane or mixtures thereof, with compound 2A and a noble metal catalyst, preferably palladium (preferably the metal is supported on an inert solid support such as charcoal Can be achieved by exposure to about 1 to 100 atmospheres of hydrogen gas atmosphere, preferably about 1 to about 10 atmospheres of hydrogen gas. After compound 2A has been consumed, the mixture is filtered and a mixture of bases such as triethylamine, diisopropylethylamine, pyridine or 2,6-lutidine, preferably 1-propanephosphonic acid cyclic anhydride and triethylamine The amines produced at about −78 ° C. to about 40 ° C. in the presence of the combination were prepared with acid chloride ClC (═O) (CR 10 R 11 ) n R 4 , acid anhydride (R 4 (CR 10 R 11 ) n C (= 0) )) Immediately react with 2 O or an activated carboxylic acid derivative XC (= 0) (CR 10 R 11 ) n R 4 to give compound 1J. Activated carboxylic acid derivatives include carboxylic acid HOC (= 0) (CR 10 R 11 ) n R 4 and known activating reagents such as dicyclohexyl carbodiimide, 1- (3-dimethylaminopropyl) -3-ethyl Carbodiimide hydrochloride, carbonyl diimidazole, 1-propanephosphonic acid cyclic anhydride, alkyl or aryl chloroformate, bis (2-oxo-3-oxazolidinyl) phosphinic chloride, benzotriazole-1- It is prepared from yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, or any other standard literature reagent. [162] Alternatively, after filtration, the intermediate amine is reacted with a base such as triethylamine, diisopropylethylamine, pyridine or 2,6 at about -78 ° C to about 40 ° C, preferably at about -78 ° C to about -40 ° C. Treatment with -rutidine, and a combination of alkyl- or aryl-chloroformates, preferably diisopropylethylamine and phenyl chloroformate, affords compound 1K. [163] Compound 1K is first or second in a solvent such as dioxane, dimethylformamide or acetonitrile, preferably in a 1: 1 mixture of dioxane-dimethylformamide at about 40 ° C. to about 90 ° C., preferably about 70 ° C. Subsequent treatment with a tertiary amine yields 1 L of the corresponding urea product. [164] Compounds 2A, 1J, 1K and 1L may be subsequently modified using methods known to those skilled in the art to provide additional compounds of Formula 1 described herein. [165] The compounds of formula 1 R 2 is as described herein other than hydrogen can be prepared by transformation using methods known to those skilled in the art the compounds of the formula I described herein which R 2 is hydrogen. For example, a compound of Formula 1 wherein R 2 is F is a compound of Formula 1 wherein R 2 is hydrogen at about room temperature to about 150 ° C., preferably about 100 ° C. to about 120 ° C. in toluene, xylene or dioxane, eg For example, the compounds of Formulas 1A, 1B and 1C shown in Scheme 1 may be prepared by treating with N-fluorobenzenesulfonimide. [166] [167] Pharmaceutically acceptable salts of compounds of formula 1 may be prepared in a conventional manner by treating a solution or suspension of the corresponding free base or acid with one chemical equivalent of pharmaceutically acceptable acid or base. Salts can be isolated using conventional concentration or crystallization techniques. Examples of suitable acids are acetic acid, lactic acid, succinic, maleic acid, tartaric acid, citric acid, gluconic acid, ascorbic acid, benzoic acid, cinnamic acid, fumaric acid, sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfamic acid, sulfonic acid, such as Methanesulfonic acid, benzene sulfonic acid, p-toluenesulfonic acid and related acids. Examples of bases are sodium, potassium and calcium. [168] The compounds of the present invention may be administered in single or multiple doses, alone or in combination with pharmaceutically acceptable carriers. Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. Pharmaceutical compositions formed by combining the compound of Formula 1 or a pharmaceutically acceptable salt thereof can be easily administered in various dosage forms, such as tablets, powders, lozenges, syrups, injectable solutions, and the like. Depending on the purpose, these pharmaceutical compositions may contain additional ingredients such as flavorings, binders, excipients and the like. That is, for oral administration, tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate may be used in various disintegrating agents such as starch, methylcellulose, alginic acid and certain complex silicates, binders such as polyvinylpyrrolidone With sucrose, gelatin and acacia. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talc are often useful for the manufacture of tablets. Solid compositions of a similar type may also be used as fillers in soft and hard filled gelatin capsules. Preferred materials for this include lactose or lactose and high molecular weight polyethylene glycols. Where aqueous suspensions or elixirs are intended for oral administration, their essential active ingredients may be formulated into various sweetening or flavoring agents, colorants or dyes and, depending on the purpose, emulsifying or suspending agents and diluents such as water, ethanol, propylene Combinations with glycols, glycerin and combinations thereof. [169] For parenteral administration, solutions containing the compounds of the present invention or their pharmaceutically acceptable salts in sesame oil or peanut oil, aqueous propylene glycol, or in sterile aqueous solutions can be used. Such aqueous solutions should suitably be buffered as necessary and first make the liquid diluent isotonic with sufficient saline or glucose. These particular aqueous solutions are especially administered intravenously, intramuscularly, subcutaneously and intraperitoneally. All sterile aqueous media used are readily available by standard techniques known to those skilled in the art. [170] The compound of formula 1 or a pharmaceutically acceptable salt thereof may be administered orally, transdermally (eg with a patch), parenteral (eg intravenously), rectally or topically. In general, the daily dosage for the treatment of a neurodegenerative disease or condition, or disease or condition for which treatment may be achieved or promoted by modifying dopamine mediated neurotransmission, is generally from about 0.0001 to about 10.0 mg / body of the patient to be treated. will be kg. The daily dosage for the treatment of cancer or diseases or disorders associated with benign abnormal cell growth will also generally be from about 0.0001 to about 500 mg / kg body weight of the patient to be treated. For example, for the treatment of neurodegenerative disorders, the compound of Formula 1 or a pharmaceutically acceptable salt thereof may be administered in an amount of about 0.01 mg to about 1000 mg / day, preferably about 0.1 to about Administration may be in single or divided (ie, multiple) doses of 500 mg / day. The daily dosage for the treatment of diabetes, sperm movement, hair loss or any other disease or condition that can be treated by GSK-3 inhibition will generally be from about 0.0001 to about 10.0 mg / kg body weight of the patient to be treated. Known things such as the weight, age and condition of the patient to be treated, the severity of the condition, and the particular route of administration chosen may vary widely based on the dosage range by a physician of ordinary skill in the art. [171] The compounds of formula (1) and their pharmaceutically acceptable salts may also be administered or formulated into pharmaceutical compositions with an inhibitory effective amount of at least one substance selected from antiangiogenic agents, signaling inhibitors and antiproliferative agents. [172] Antiangiogenic agents such as MMP-2 (matrix-metalloproteinase 2) inhibitors, MMP-9 (matrix-metalloproteinase 9) inhibitors and COX-II (cyclooxygenase II) inhibitors And the compounds of formula 1 in the methods and pharmaceutical compositions described herein for the treatment of abnormal cell growth. Examples of useful COX-II inhibitors include CELEBREX ™ (celecoxib), valdecoxib and rofecoxib. Examples of useful matrix metalloproteinase inhibitors include WO 96/33172 published October 24, WO 96/27583 published March 7, 1996, European Patent Application 97304971.1 (1997). European Patent Application No. 99308617.2, filed October 29, 1999, WO 98/07697 published 26 February 1998, WO 98/03516, issued January 29, 1998. Published), WO 98/34918 published 13 August 1998, WO 98/34915 published 13 August 1998, WO 98/33768 published 6 August 1998, WO 98 / 30566, published July 16, 1998, European Patent Publication 606,046, published July 13, 1994, European Patent Publication 931,788, published July 28, 1999, WO 90/05719. (Published May 31, 1990), WO 99/52910 (published October 21, 1999), WO 99/52889 (published October 21, 1999), WO 99/29667 (June 1999) Published 17), PCT International Patent Application No. PCT / IB98 / 01113 (filed Jul. 21, 1998), European Patent Application No. 99302232.1 (filed March 25, 1999), U.S. Patent Application No. 992961.1 (filed June 3, 1999), U.S. Provisional Application No. 60 / 148,464 (filed August 12, 1999), U.S. Patent No. 5,863,949, issued January 26, 1999, U.S. Patent 5,861,510, issued January 19, 1999 and European Patent Publication No. 780,386, published June 25, 1997, all of which are incorporated herein by reference in their entirety. Preferred MMP-2 and MMP-9 inhibitors are those which have little or no activity inhibiting MMP-1. More preferred are other matrix-metalloproteinases (ie MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, Selective inhibition of MMP-2 and / or MMP-9 as compared to MMP-12 and MMP-13). [173] Some specific examples of MMP inhibitors useful in the present invention are AG-3340, RO 32-3555, RS 13-0830, and the compounds listed below and their pharmaceutically acceptable salts and solvates: [174] 3-[[4- (4-Fluoro-phenoxy) -benzenesulfonyl]-(1-hydroxycarbamoyl-cyclopentyl) -amino] -propionic acid; [175] 3-exo-3- [4- (4-fluoro-phenoxy) -benzenesulfonylamino] -8-oxa-bicyclo [3.2.1] octane-3-carboxylic acid hydroxyamide; [176] (2R, 3R) -1- [4- (2-Chloro-4-fluoro-benzyloxy) -benzenesulfonyl] -3-hydroxy-3-methyl-piperidine-2-carboxylic acid hydroxy amides; [177] 4- [4- (4-Fluoro-phenoxy) -benzenesulfonylamino] -tetrahydro-pyran-4-carboxylic acid hydroxyamide; [178] 3-[[4- (4-Fluoro-phenoxy) -benzenesulfonyl]-(1-hydroxycarbamoyl-cyclobutyl) -amino] -propionic acid; [179] 4- [4- (4-Chloro-phenoxy) -benzenesulfonylamino] -tetrahydro-pyran-4-carboxylic acid hydroxyamide; [180] (R) -3- [4- (4-chloro-phenoxy) -benzenesulfonylamino] -tetrahydro-pyran-3-carboxylic acid hydroxyamide; [181] (2R, 3R) -1- [4- (4-Fluoro-2-methyl-benzyloxy) -benzenesulfonyl] -3-hydroxy-3-methyl-piperidine-2-carboxylic acid hydroxy amides; [182] 3-[[4- (4-Fluoro-phenoxy) -benzenesulfonyl]-(1-hydroxycarbamoyl-1-methyl-ethyl) -amino] -propionic acid; [183] 3-[[4- (4-Fluoro-phenoxy) -benzenesulfonyl]-(4-hydroxycarbamoyl-tetrahydro-pyran-4-yl) -amino] -propionic acid; [184] 3-exo-3- [4- (4-chloro-phenoxy) -benzenesulfonylamino] -8-oxa-bicyclo [3.2.1] octane-3-carboxylic acid hydroxyamide; [185] 3-endo-3- [4- (4-fluoro-phenoxy) -benzenesulfonylamino] -8-oxa-bicyclo [3.2.1] octane-3-carboxylic acid hydroxyamide; And [186] (R) -3- [4- (4-Fluoro-phenoxy) -benzenesulfonylamino] -tetrahydro-furan-3-carboxylic acid hydroxyamide. [187] Other antiangiogenic agents can also be used in the present invention, including other COX-II inhibitors and other MMP inhibitors. [188] An effective amount of a cdk5 inhibitor, eg, a COX-II inhibitor in combination with a compound of Formula 1, can generally be determined by one skilled in the art. The suggested daily effective dose of a COX-II inhibitor in combination with a cdk5 inhibitor is about 0.1 to about 25 mg / kg body weight. The effective daily dose of the cdk5 inhibitor will generally be from about 0.0001 to about 10 mg / kg body weight. In some cases, the amount of COX-II inhibitor and / or cdk5 inhibitor in combination may be less than the amount needed for the individual criteria to achieve the same desired effect in inhibiting abnormal cell growth. [189] Compounds of Formula 1 may also contain signaling inhibitors, such as agents capable of inhibiting EGFR (epidermal growth factor receptor) responses, such as EGFR antibodies, EGF antibodies and EGFR inhibitor molecules; VEGF (vascular endothelial growth factor) inhibitors; And organic molecules or antibodies that bind to erbB2 receptor inhibitors, such as the erbB2 receptor, such as HERCEPTIN ™ (Genentech, Inc., South San Francisco, CA). Such combinations are useful for the treatment and prevention of abnormal cell growth, including cancer, as described herein. [190] EGFR inhibitors are described, for example, in WO 95/19970, published July 27, 1995, WO 98/14451, published April 9, 1998, WO 98/02434, published January 22, 1998. And US Pat. No. 5,747,498, issued May 5, 1998, which materials can be used in the present invention as described herein. EGFR-inhibitors include monoclonal antibody C225 and anti-EGFR 22Mab (ImClone Systems Incorporated, New York, NY), compound ZD-1839 (AstraZeneca), BIBX-1382 ( Boehringer Ingelheim, MDX-447 (Medarex Inc., Anadale, NJ), and OLX-103 (Merck & Company, Whitehouse Station, NJ, USA) Co.)), VRCTC-310 (Ventech Research) and EGF fusion toxin (Seragen, Hopkinton, Mass.). These and other EGFR-inhibitors can be used in the present invention. [191] VEGF inhibitors such as SU-5416 and SU-6668 (Sugen Inc., San Francisco, CA) may also be combined with the compound of Formula 1. VEGF inhibitors are described, for example, in WO 99/24440 (published May 20, 1999), PCT International Application PCT / IB99 / 00797 (filed May 3, 1999), WO 95/21613 (August 17, 1995). Published), WO 99/61422 published December 2, 1999, US Pat. No. 5,834,504 issued November 10, 1998, WO 98/50356 published November 12, 1998, United States Patent 5,883,113 issued March 16, 1999, US Patent 5,886,020 issued March 23, 1999, US Patent 5,792,783 issued August 11, 1998, WO 99/10349 Published March 4, 1999), WO 97/32856 (published September 12, 1997), WO 97/22596 (published June 26, 1997), WO 98/54093 (December 3, 1998). Published), WO 98/02438 published January 22, 1998, WO 99/16755 published April 8, 1999 and WO 98/02437 published January 22, 1998 (these). All documents are incorporated by reference in their entirety. Other examples of some specific VEGF inhibitors useful in the present invention include IM862 (Cytran Inc., Kirkland, USA); Anti-VEGF monoclonal antibodies (Genentech Inc., San Francisco, CA); And Angiozyme (synthetic ribozyme from Ribozyme, Boulder, Colorado) and Chiron, Emeryville, California. These and other VEGF inhibitors can be used in the present invention as described herein. [192] ErbB2 receptor inhibitors such as GW-282974 (Glaxo Welcome plc) and monoclonal antibody AR-209 (Aronex Pharmaceuticals Inc., Woodlands, TX) and 2B -1 (chiron) can also be combined with a compound of formula 1, for example WO 98/02434 (published January 22, 1998), WO 99/35146 (published July 15, 1999), WO 99/35132 published 15 July 1999, WO 98/02437 published 22 January 1998, WO 97/13760 published 17 April 1997, WO 95/19970. Published July 27, 1995, US Pat. No. 5,587,458 issued Dec. 24, 1996, and US Pat. No. 5,877,305 issued March 2, 1999, all of which are incorporated herein by reference in their entirety. ). ErbB2 receptor inhibitors useful in the present invention are also described in US Provisional Application No. 60 / 117,341, filed Jan. 27, 1999 and US Provisional Application No. 60 / 117,346, filed January 27, 1999, both of which are incorporated herein in their entirety. Inc., incorporated herein by reference. In addition to the erbB2 receptor inhibitor compounds and materials described in the PCT application, US patents and US provisional applications, other compounds and materials that inhibit the erbB2 receptor can be used with the compounds of formula 1 in accordance with the present invention. [193] Compounds of formula (1) can also contain agents that can enhance anti-tumor immune responses, such as CTLA4 (cytotoxic lymphocyte antigen 4) antibodies, and other agents that can block CTLA4; And other agents useful for the treatment of abnormal cell growth or cancer, including but not limited to antiproliferatives such as farnesyl protein transferase inhibitors. Specific CTLA4 antibodies that may be used in the present invention include those described in US Provisional Application No. 60 / 113,647 filed Dec. 23, 1998, which is incorporated herein by reference in its entirety, although other CTLA4 antibodies are described herein. Can be used. [194] The compound of formula 1 may also be administered in a method of inhibiting abnormal cell growth in combination with radiotherapy in a mammal. Radiotherapy administration techniques are known to those skilled in the art and these techniques can be used in the combination therapies described herein. Administration of the compounds of the invention in these combination therapies can be determined as described herein. [195] cdk5 inhibitors, such as compounds of Formula 1, may also be administered with COX-II inhibitors for the treatment of 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 set forth above and described for the use of a COX-II inhibitor in combination with a compound of Formula 1 for the treatment of abnormal cell growth. An effective amount of a cdk5 inhibitor, eg, a COX-II inhibitor in combination with a compound of Formula 1, can generally be determined by one skilled in the art. A suggested effective daily dose for a COX-II inhibitor in combination with a cdk5 inhibitor is about 0.1 to about 25 mg / kg body weight. A daily effective amount of a cdk5 inhibitor will generally be about 0.0001 to about 10 mg / kg body weight. In some cases, the amount of COX-II inhibitor and / or cdk5 inhibitor in combination is less than the amount required by the individual criteria to achieve the same desired effect in the treatment of Alzheimer's disease, mild cognitive impairment or age-related cognitive decline. Can be. [196] cdk5 inhibitors, such as compounds of Formula 1, may also be administered with NK-1 receptor antagonists for the treatment of depression or anxiety. The NK-1 receptor antagonists cited herein are substances that can antagonize the NK-1 receptor to inhibit tachykinin mediated responses, such as those mediated by substance P. Various NK-1 receptor antagonists are known in the art, and any such NK-1 receptor antagonists may be used in the present invention with cdk5 inhibitors, eg, compounds of Formula 1, as described above. NK-1 receptor antagonists are described, for example, in US Pat. No. 5,716,965, issued February 10, 1998; US Patent No. 5,852,038, issued Dec. 22, 1998; WO 90/05729, published May 31, 1990; U.S. Patent 5,807,867 issued September 15, 1998; US Patent No. 5,886,009, issued March 23, 1999; US Patent No. 5,939,433, issued August 17, 1999; US Patent No. 5,773,450 issued June 30, 1998; US Patent No. 5,744,480, issued April 28, 1998; U.S. Patent 5,232,929 (August 3, 1993); US Patent No. 5,332,817, issued July 26, 1994; US Patent No. 5,122,525, issued June 16, 1992; US Patent No. 5,843,966, issued December 1, 1998; U.S. Patent 5,703,240, issued December 30, 1997; US Patent No. 5,719,147, issued February 17, 1998; And US Pat. No. 5,637,699, issued June 10, 1997. The U.S. Patent and the PCT International Application are each incorporated herein in their entirety. Compounds described in this document 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. [197] Effective amounts of cdk5 inhibitors, for example NK-1 receptor antagonists in combination with compounds of Formula 1, can generally be determined by one skilled in the art. The suggested effective daily dose for NK-1 receptor antagonists in combination with cdk5 inhibitors is about 0.07 to about 21 mg / kg body weight. An effective amount of a cdk5 inhibitor is generally about 0.0001 to about 10 mg / kg body weight. In some cases, the amount of NK-1 receptor antagonist and / or cdk5 inhibitor in combination may be less than the amount required on an individual basis to achieve the same desired effect in the treatment of depression or anxiety. [198] The present invention also provides a combination of a cdk5 inhibitor, such as a compound of Formula 1, with a 5HT 1D receptor antagonist for the treatment of depression or anxiety. The 5HT 1D receptor antagonists cited herein are substances that antagonize the 5HT 1D subtype of serotonin receptors. Any such material can be used in the present invention with a cdk5 inhibitor, for example a compound of Formula 1, as described above. Materials having 5HT 1D receptor antagonistic activity can be determined by one skilled in the art. For example, 5HT 1D receptor antagonists include WO 98/14433 (published April 9, 1998); WO 97/36867 (October 9, 1997 international publication); WO 94/21619 (September 29, 1994 International Publication); US Patent No. 5,510,350, issued April 23, 1996; US Patent No. 5,358,948, issued October 25, 1994; And GB 2276162 A (published September 21, 1994). In addition to these 5HT 1D receptor antagonists, others may be used in the present invention. Such published patent applications and patents are incorporated herein by reference in their entirety. [199] An effective amount of a cdk5 inhibitor, for example a 5HT 1D receptor antagonist in combination with a compound of Formula 1, can generally be determined by one skilled in the art. The suggested effective daily dose for 5HT 1D receptor antagonists in combination with cdk5 inhibitors is about 0.01 to about 40 mg / kg body weight. A daily effective amount of a cdk5 inhibitor will generally be about 0.0001 to about 10 mg / kg body weight. In some cases, the amount of 5HT 1D receptor antagonist and / or cdk5 inhibitor in combination may be less than the amount required on an individual basis to achieve the same desired effect in the treatment of depression or anxiety. [200] The present invention also provides a pharmaceutical composition comprising a cdk5 inhibitor, for example a compound of Formula 1, and SSRI, and a method of treatment thereof for the treatment of depression or anxiety in a mammal. Examples of SSRIs that may be combined with cdk5 inhibitors, such as compounds of Formula 1 and pharmaceutically acceptable salts thereof, in the methods or pharmaceutical compositions include fluoxetine, paroxetine, sertraline and flu. Fluvoxamines include, but are not limited to. Other SSRIs can also be combined or administered with cdk5 inhibitors, such as a compound of Formula 1 or a pharmaceutically acceptable salt thereof. Other antidepressants and / or anti-anxiety agents that can be combined or administered with cdk5 inhibitors, such as the compound of Formula 1, include WELLBUTRIN, SERZONE and EFFEXOR. [201] An effective amount of an SSRI in combination with a cdk5 inhibitor, eg, a compound of Formula 1, can generally be determined by one skilled in the art. The suggested effective daily dose for SSRI in combination with a cdk5 inhibitor is about 0.01 to about 500 mg / kg body weight. A daily effective amount of a cdk5 inhibitor will generally be about 0.0001 to about 10 mg / kg body weight. In some cases, the amount of SSRI and / or cdk5 inhibitor in combination may be less than the amount required on an individual basis to achieve the same desired effect in the treatment of depression or anxiety. [202] A cdk5 inhibitor, eg, a compound of Formula 1, or a pharmaceutically acceptable salt thereof, may also be used to treat a disease or condition, such as schizophrenia, in which the treatment can be achieved or promoted by modifying dopamine mediated neurotransmission. Psychiatric agents, for example dopamine. Examples of antipsychotics that may be combined with the compounds of the present invention include ziprasidone [5- (2- (4- (1,2-benzisothiazol-3-yl) -1-piperazinyl) -ethyl ) -6-chloro-1,3-dihydro-2H-indol-2-one; U.S. Patent 4,831,031 and U.S. Patent 5,312,925; Olanzapine [2-methyl-4- (4-methyl-1-piperazinyl-10H-thieno (2,3b) (1,5) benzodiazepine; US Pat. No. 4,115,574 and US 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; US Patent No. 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]; Sonepprazole [S-4- (4- (2- (isochroman-1-yl) ethyl) -pipe Razin-1-yl) benzenesulfonamide; US Patent No. 5,877,317; RP 62203 [fananserin; 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 Pat. No. 5,633,376 and US Pat. No. 5,428,165]; Valaperidone [(1α , 5α, 6α) -3- (2- (6- (4-fluorophenyl) -3-azabicyclo (3.2.0) hept-3-yl) ethyl) -2,4 (1H, 3H) -Quinazolindione; US Pat. No. 5,475,105] Plesinoxane [(+)-4-fluoro-N- [2- [4- [5- (2-hydroxymethyl-1,4-benzodioxanyl )]-1-piperazinyl] ethyl] benzamide; US Pat. No. 4,833,142]; and gepyrone [4,4-dimethyl-1- (4- (4- (2-pyrimidinyl) -1-pi Ferrazinyl) butyl) -2,6-piperidinedione; U.S. Patent No. 4,423,049. The patents cited in this paragraph are each incorporated herein by reference in their entirety. Generally from about 0.0001 to about 10 mg / kg body weight.Daily effective dosages of any of the above antipsychotics used in combination with a cdk5 inhibitor, eg, a compound of Formula 1, are generally intended to be useful for the treatment of psychotic diseases. However, in some cases, the amount of antipsychotic and / or cdk5 inhibitor in combination will achieve the same desired effect in the treatment of depression or anxiety. Risk may be less than the amount required by the individual criteria. It will also be understood that the present invention also includes combining cdk5 inhibitors, eg, compounds of Formula 1, with antipsychotics or dopamine agents other than those listed above. [203] Suggested amounts of the above described sonepiprazole in combination with a cdk5 inhibitor, for example a compound of Formula 1, are from about 0.005 to about 50 mg / kg body weight per patient. The suggested amount of RP 62203 in the combination is about 0.20 to about 6 mg / kg body weight of the patient. The suggested amount of NGD 941 in the combination is about 0.1 to about 140 mg / kg body weight / day. Suggested amounts of valaperidone in the combination are about 1 to about 100 mg / kg body weight / day. The suggested amount of plesinoxane in the combination is about 0.02 to about 1.6 mg / kg body weight / day. The suggested amount of gepirone in the combination is about 0.01 to about 2 mg / kg body weight / day. The suggested amount of L-745870 in the 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 suggested amount of risperidone in the combination is about 0.05 to about 50 mg / kg body weight / day. The suggested amount of olanzapine in the combination is about 0.0005 to about 0.6 mg / kg body weight / day. The suggested amount of ziprasidone in the combination is about 0.05 to about 10 mg / kg body weight / day. However, in some cases, the amount of each particular component in each of the above combinations may be less than the amount required in the individual criteria to achieve the same desired effect in the treatment of psychotic diseases. [204] The present invention also provides a pharmaceutical composition comprising a cdk5 inhibitor, for example a compound of Formula 1, and an acetylcholinesterase inhibitor, and a method of treatment thereof for the treatment of Alzheimer's disease, mild cognitive impairment or age-related cognitive decline. Acetylcholinesterase inhibitors are known in the art and any of the above acetylcholinesterase inhibitors can be used in the pharmaceutical compositions or methods described above. Examples of acetylcholinesterase inhibitors that may be used in the present invention include ARICEPT [donepezil; US Patent No. 4,895,841; EXELON [rivastigmine, (S)-[N-ethyl-3- [1- (dimethylamino) ethyl] phenyl carbamate; U.S. Patent 5,603,176 and U.S. Patent 4,948,807; Metrifonate [(2,2,2-trichloro-1-hydroxyethyl) phosphonic acid dimethyl ester; US Patent No. 2,701,225 and US Patent No. 4,950,658; Galantamine (US Pat. No. 4,663,318); Physostigmine [US Forest]; Tacrine [1,2,3,4-tetrahydro-9-acridinamine; US Patent No. 4,816,456; Huperzine A [5R- (5α, 9β, 11E) -5-amino-11-ethylidene-5,6,9,10-tetrahydro-7-methyl-5,9-methanocyclo Octa (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; U.S. Patent Nos. 5,750,542 and WO 92/17475. The patents and patent applications cited above in this paragraph are hereby incorporated by reference in their entirety. [205] An effective amount of a cdk5 inhibitor, for example an acetylcholinesterase inhibitor in combination with a compound of Formula 1, can generally be determined by one skilled in the art. A suggested effective daily dose for an acetylcholinesterase inhibitor in combination with a cdk5 inhibitor is about 0.01 to about 10 mg / kg body weight. The daily effective amount of a cdk5 inhibitor is generally from about 0.0001 to about 10 mg / kg body weight. In some cases, the amount of acetylcholinesterase inhibitor in combination and / or the amount of cdk5 inhibitor is the amount required on an individual basis to achieve the same desired effect in the treatment of Alzheimer's disease, mild cognitive impairment or age-related cognitive decline. May be less. [206] The invention also relates to Huntington's disease, stroke, spinal cord trauma, traumatic brain injury, multiple infarct, epilepsy, muscular dystrophy, pain, virus-induced dementia, eg AIDS-induced dementia, migraine, hypoglycemia, urinary incontinence, cerebral ischemia, Multiple infarction, Alzheimer's disease, Alzheimer's type senile dementia, mild cognitive impairment, age-related cognitive decline, vomiting, cortical basal degeneration, projection type dementia, Down syndrome, myotonic dystonia, Neimanpick disease, pick disease, prion disease caused by fiber concentrate, progressive Combining cdk5 inhibitors with neuroprotective agents such as NMDA receptor antagonists for the treatment of nuclear palsy, lower lateral sclerosis or subacute sclerosing panencephalitis Examples of NMDA receptor antagonists that may 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), eliprodil (US Pat. No. 4,690,931) and gavestenel (US Pat. No. 5,373,018). In addition, other NMDA receptor antagonists that may be used in the present invention include US Pat. No. 5,373,018; US Patent No. 4,690,931; US Patent No. 5,272,160; US Patent No. 5,185,343; US Patent No. 5,356,905; US Patent No. 5,744,483; WO 97/23216; WO 97/23215; WO 97/23214; WO 96/37222; WO 96/06081; WO 97/23458; WO 97/32581; WO 98/18793; WO 97/23202; And US Application 08 / 292,651, filed August 18, 1994. The above patents and patent applications are each incorporated herein by reference in their entirety. [207] The daily effective amount of a cdk5 inhibitor in combination with an NMDA receptor antagonist will generally be from about 0.0001 to about 10 mg / kg body weight. The amount of NMDA receptor antagonist in combination with a cdk5 inhibitor, eg, a compound of Formula 1, for the treatment of any of the above diseases, such as Alzheimer's disease, is generally from about 0.02 mg / kg / day to about 10 mg / kg / day. to be. However, in some cases, the amount of NMDA antagonist and / or cdk5 inhibitor in combination may be less than the amount required on an individual basis to achieve the same desired effect in the treatment of the disorders. [208] The present invention also provides the combination of a cdk5 inhibitor with certain substances capable of treating stroke or traumatic brain injury, such as TPA, NIF or calcium channel modulators such as BMS-204352. Such combinations are useful in the treatment of neurodegenerative diseases such as stroke, spinal cord trauma, traumatic brain injury, multiple infarction, epilepsy, pain, Alzheimer's disease and senile dementia. [209] For the combination therapies and pharmaceutical compositions described above, an effective amount of a compound of the invention and other agents will generally be an effective amount of a compound described herein and an effective amount of other agents known in the art, such as those described herein It may be determined by one skilled in the art based on the amounts described in the cited patents and patent applications. Dosage forms and routes for such therapies and compositions may be based on the information described herein for compositions and therapies comprising the compounds of the invention as the sole active agent, and the information provided for other agents in combination with the compounds of the invention. Can be. [210] It can be measured using biological assays known to those skilled in the art, for example, the assays described below, that certain compounds of Formula 1 inhibit cdk2, cdk5 or GSK-3. [211] The specific activity of the compound of formula 1 that inhibits cdk5 or cdk2 can be assessed by the following assay using, for example, materials available to those skilled in the art. [212] Enzyme activity can be analyzed by introducing [33P] from the gamma phosphate of [33P] ATP (Amersham, List No. AH-9968) into the biotinylated peptide substrate PKTPKKAKKL. In this assay, the reaction is carried out in a buffer containing 50 mM Tris-HCl, pH 8.0, 10 mM MgCl 2 , 0.1 mM Na 3 V0 4 and 1 mM DTT. The final concentration of ATP is about 0.5 μM (final specific radioactivity 4 μCi / nmol) and the final concentration of substrate is 0.75 μM. The reaction initiated by the addition of cdk5 and activator protein p25, or cdk2 and activator cyclin E, can be performed at room temperature for about 60 minutes. The reaction is stopped by adding 0.6 volumes of buffer containing 2.5 mM EDTA, 0.05% Triton-X 100, 100 μM ATP and 1.25 mg / ml streptavidin coated SPA beads (Amersham List No. RPNQ0007) (final concentration). . Radioactivity associated with the beads is quantified by scintillation counting. [213] The specific activity of the compound of formula 1 that inhibits GSK-3 can be determined by cell-based and cell-based assays, both of which are described, for example, in WO 99/65897. Cell based assays generally obtain GSK-3 from peptide substrates, radiolabeled ATP (eg, γ 33 P- or γ 32 -P-ATP, both of Amersham, Arlington Heights, Ill.) ), Magnesium ions and the compound to be analyzed. The mixture is incubated for a time to allow radiolabeled phosphate to be introduced into the peptide substrate by GSK-3 activity. Typically all or part of the enzyme reaction mixture is first transferred to a well containing a certain amount of ligand capable of binding a peptide substrate, followed by washing the reaction mixture to remove unreacted radiolabeled ATP. After washing, 33 P or 32 P remaining in each well is quantified to determine the amount of radiolabeled phosphate introduced into the peptide substrate. Inhibition is observed as a reduction compared to the control in introducing radiolabeled phosphates into the peptide substrate. Examples of suitable GSK-3 peptide substrates for analysis are SGSG linked CREB peptide sequences derived from CREB DNA binding proteins, which are described in Wang, et al., Anal Biochem., 220: 397-402 (1994). It is. GSK-3 purified for analysis can be obtained from cells transfected with, for example, a human GSK-3β expression plasmid, for example, Stambolic, et al., Current Biology 6: 1664-68 (1996 )]. WO 99/65897; Wang et al. And Staambolic et al. Are incorporated herein by reference in their entirety. [214] Another example of a GSK-3 assay similar to that described in the previous paragraph is as follows: [33P] is introduced into the biotinylated peptide substrate PKTPKKAKKL from gamma phosphate of [33P] ATP (Amersham, List No. AH-9968). Enzyme activity is analyzed. The reaction is carried out in a buffer containing 50 mM Tris-HCl, pH 8.0, 10 mM MgCl 2 , 0.1 mM Na 3 V0 4 and 1 mM DTT. The final concentration of ATP is 0.5 μM (final specific radioactivity 4 μCi / nmol) and the final concentration of substrate is 0.75 μM. The reaction initiated by the addition of enzyme is carried out at room temperature for about 60 minutes. The reaction is stopped by adding 0.6 volumes of buffer containing 2.5 mM EDTA, 0.05% Triton-X 100, 100 μM ATP and 1.25 mg / ml streptavidin coated SPA beads (Amersham List No. RPNQ0007) (final concentration). . Radioactivity associated with the beads is quantified by scintillation counting. [215] All compounds of the examples below had an IC 50 of less than about 50 μM for inhibition of peptide substrate phosphorylation when analyzed for cdk5 inhibition according to the above assay. [216] Several title compounds of the following examples were analyzed for GSK-3 inhibition using the assay described above, and all compounds tested had an IC 50 of less than about 50 μM for GSK-3β inhibition. [217] The following examples illustrate the invention. However, it should be understood that the present invention as fully described in the specification and claims is not limited by the detailed description of the following examples. [218] Preparation Example 1 [219] 1-cyclobutyl-4-nitro-1H-imidazole [220] 1,4-dinitroimidazole (237 mg, 1.5 mmol, J. Phys. Chem. 1995, 99, 5009-5015) at 23 ° C. was cyclobutylamine (107 mg, 1.5) in methanol (10 mL). mmol) solution. The reaction mixture was stirred for 16 hours, then the solvent was removed in vacuo, and the resulting residue was purified by silica gel chromatography (1: 1 hexane-ethyl acetate) to yield 1-cyclobutyl-4-nitro-1H. 230 mg (92% yield) of imidazole were obtained. [221] [222] Note: 1,4-dinitroimidazole is a very powerful semi-stable substance and should be stored in the freezer when not in use. Thermodynamic measurements have shown that there is a possibility to generate enough energy at 35 ° C. under adiabatic conditions and explode violently. Extreme care should always be taken when using this material. [223] Preparation Example 2 [224] 1-cyclopentyl-4-nitro-1H-imidazole [225] The reaction was carried out according to the procedure of Preparation Example 1 using cyclopentyl amine and 1,4-dinitroimidazole to give 205 mg (75% yield) of 1-cyclopentyl-4-nitro-1H-imidazole. . [226] [227] Preparation Example 3 [228] 4-nitro-1- (cis-3-phenyl-cyclobutyl) -1H-imidazole [229] Cis-3-phenylcyclobutylamine (J. Med. Pharm. Chem 1960, 2, 687-691; [ACIEE 1981, 20, 879-880]) and 1,4-dinitroimidazole The reaction was carried out according to the procedure of Preparation Example 1, to obtain 46 mg (46% yield) of 4-nitro-1- (cis-3-phenyl-cyclobutyl) -1H-imidazole. [230] [231] Example 1 [232] N- (1-cyclobutyl-1H-imidazol-4-yl) -2-quinolin-6-yl-acetamide [233] To the Par hydrogenated bottle was added 1-cyclobutyl-4-nitro-1H-imidazole (Preparation Example 1, 150 mg, 0.9 mmol) and ethyl acetate (10 mL) followed by 10% Pd (250 mg) on carbon. . The reaction mixture was placed in a Parr hydrogenation apparatus and reacted at 23 ° C. under 50 psi H 2 for 6 hours. The contents of the bottle were filtered through a short pad of celite and washed with dry methylene chloride (25 mL) in a flame dried flask under nitrogen. Et 3 N (626 μl, 4.5 mmol) was added and the reaction solution was cooled to -10 ° C. Then 6-quinolyl acetic acid (168 mg, 0.9 mmol) and tripropylphosphonic acid anhydride (530 μl, 1.7 M solution in ethyl acetate) were 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 (2x). The aqueous layer was extracted with methylene chloride (3x) and the organic layers were combined and washed with brine (1x). The solvent is removed in vacuo, the residue is adsorbed on silica gel and chromatographed using a Biotage Flash 12 system with SIM (40: 1 methylene chloride-methanol), N- (1 130 mg (47% yield) of -cyclobutyl-1H-imidazol-4-yl) -2-quinolin-6-yl-acetamide (title compound) were obtained. [234] [235] Example 2 [236] N- (1-cyclopentyl-1H-imidazol-4-yl) -2- (4-methoxy-phenyl) -acetamide [237] By performing the procedure of Example 1 using para-methoxy-phenylacetic acid and 1-cyclopentyl-4-nitro-1H-imidazole (Preparation Example 2), N- (1-cyclopentyl-1H-imidazole -4-yl) -2- (4-methoxy-phenyl) -acetamide was obtained in 32% yield (26.5 mg). [238] [239] Example 3 [240] N- [1- (cis-3-phenyl-cyclobutyl) -1H-imidazol-4-yl] -2-quinolin-6-yl-acetamide [241] The procedure of Example 1 was carried out using 6-quinolylacetic acid and 4-nitro-1- (cis-3-phenylcyclobutyl) -1H-imidazole (Preparation Example 3), whereby N- [1- (cis 3-phenyl-cyclobutyl) -1H-imidazol-4-yl] -2-quinolin-6-yl-acetamide was obtained in 38% yield. [242] [243] Example 4 [244] (1-cyclobutyl-1H-imidazol-4-yl) -carbamic acid phenyl ester [245] Parr hydrogenation bottle under nitrogen atmosphere was prepared with 1-cyclobutyl-4-nitro-1H-imidazole (Preparation 1, 3 g, 18 mmol) and ethyl acetate (70 mL) followed by 10% Pd (1.2 g) on carbon Was charged. The mixture was hydrogenated at 23 ° C. under 50 psi H 2 for 6 hours. The mixture was then filtered through a pad of celite, which was washed with dry methylene chloride (140 mL) in a flame dried flask. The resulting solution was cooled to −78 ° C., diisopropylethylamine (2.3 g, 18 mmol) was added and then phenylchloroformate (2.5 g, 16.2 mmol) was added dropwise. After 30 minutes, methanol (9 mL) containing acetic acid (1.8 mmol) was added. The reaction mixture was transferred to a separatory funnel, diluted with ethyl acetate (200 mL) and washed with water (2 ×). The aqueous layer was extracted with ethyl acetate (2x10 mL). The organic layers were combined, washed with brine (2 ×), 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) to give 3 g (1-cyclobutyl-1H-imidazol-4-yl) carbamic acid phenyl ester % Yield) was obtained. [246] [247] Example 5 [248] 1- (1-cyclobutyl-1H-imidazol-4-yl) -3-isoquinolin-5-yl-urea [249] (1-cyclobutyl-1H-imidazol-4-yl) -carbamic acid phenyl ester (Example 4, 50 mg, 0.19 mmol), 5-aminoisoquinoline (30 mg) in 1 dram vial with septa screw cap , 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) to give 1- (1-cyclobutyl-1H-imidazol-4-yl) -3-isoquinoline-5 30 mg (52% yield) of -yl-urea were obtained. [250] [251] Preparation Example 4 [252] N- [1- (cis-3-azido-cyclobutyl) -1H-imidazol-4-yl] -2-naphthalen-1-yl-acetamide [253] Step 1 [254] 3-benzyloxycyclobutylamine (43.4 g, 245 mmol, Chem. Ber. 1957, 90, 1424-1432) was dissolved in methanolic hydrogen chloride (saturated, 450 mL) and then 10% Pd on carbon ( 4 g) was added. The mixture was hydrogenated at 50 psi H 2 for 6 hours. The mixture was filtered and concentrated in vacuo to give about 35 g of oil. The oil was taken up in methanol (600 mL), cooled to 0 ° C. and treated with potassium hydroxide (13.7 g, 245 mmol). When the pH reached 10, a solution of 1,4-dinitroimidazole (42.7 g, 270 mmol) in methanol (200 mL) (prepared by dissolving 1,4-dinitroimidazole in methanol at 0 ° C.) was prepared. Added. (Note: 1,4-dinitroimidazole is a very powerful semi-stable substance and should be stored in the freezer when not in use. Thermodynamic measurements have the potential to generate sufficient energy at 35 ° C under adiabatic conditions and explode violently. Extreme care should always be taken when using this material.) The resulting orange suspension is then slowly warmed to 23 ° C. overnight. The solvent is removed in vacuo and the resulting residue is purified by passage through large plugs of silica gel (20: 1 chloroform-methanol) to give 3- (4-nitro-imidazole as a 1: 1 mixture of cis-trans isomers. 19 g (42% yield) of 1-yl) -cyclobutanol were obtained. [255] [256] Step 2 [257] 3- (4-nitro-imidazol-1-yl) -cyclobutanol (Preparation 4, step 1; 4 g, 22 mmol) was added to Et 3 N (7.7 mL, 55 mmol) in methylene chloride (150 mL). Then 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 rt for 24 h. Thin layer chromatography analysis revealed two new spots. The reaction mixture was diluted with methylene chloride and washed with water (1x) and brine (1x). 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) separated the trans and cis diastereomers. The first spot eluted (high Rf) was the trans-isomer trans-toluene-4-sulfonic acid 3- (4-nitro-imidazol-1-yl) -cyclobutyl ester (2.7 g, 37% yield). [258] [259] The second spot eluted was cis-isomer cis-toluene-4-sulfonic acid 3- (4-nitro-imidazol-1-yl) -cyclobutyl ester (2.9 g, 39% yield). [260] [261] The relative structure was determined by measuring the nuclear Overhauser effect. [262] Step 3 [263] Trans-toluene-4-sulfonic acid 3- (4-nitro-imidazol-1-yl) -cyclobutyl ester (Preparation 4, step 2; 590 mg, 1.75 mmol) in ethyl acetate (30 mL) Mixed with% Pd (500 mg). The mixture was then reacted for 6 hours at room temperature under 50 psi H 2 . The mixture was filtered through celite into a flame dried flask, which was kept under a nitrogen atmosphere. Et 3 N (1.22 mL, 8.75 mmol) was added followed by 1-naphthylacetic acid (326 mg, 1.75 mmol) and tripropylphosphonic anhydride (1.1 mL, 1.7 M solution in ethyl acetate, 1.75 mmol). . The mixture was stirred at rt for 1 h, then diluted with ethyl acetate and washed with water and brine. The organic layer was dried (MgSO 4 ), filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (50: 1 chloroform-methanol) to give trans-toluene-4-sulfonic acid 3- [4- (2-naphthalen-1-yl-acetylamino) -imidazole- 600 mg (72% yield) of 1-yl] -cyclobutyl ester were obtained. [264] [265] Step 4 [266] Trans-toluene-4-sulfonic acid 3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] in ethanol (15 mL), water (5 mL) and chloroform (5 mL) -Cyclobutyl ester (Preparation 4, step 3; 593 mg, 1.25 mmol) was mixed with sodium azide (813 mg, 12.5 mmol). The mixture was then heated to reflux with stirring for 96 h. The solvent was removed in vacuo and the residue was diluted with water and extracted with methylene chloride. The organic layer was dried (MgSO 4 ), filtered and concentrated in vacuo. Purification by silica gel chromatography (50: 1 chloroform-methanol) gave N- [1- (cis-3-azido-cyclobutyl) -1H-imidazol-4-yl] -2-naphthalene-1- 340 mg (79% yield) of mono-acetamide were obtained. [267] [268] Example 6 [269] N- [1- (cis-3-amino-cyclobutyl) -1H-imidazol-4-yl] -2-naphthalen-1-yl-acetamide [270] N- [l- (cis-3-azido-cyclobutyl) -1H-imidazol-4-yl] -2-naphthalen-1-yl-acetamide (Preparation 4, step 4; 330 mg , 0.95 mmol) was treated with triphenylphosphine (301 mg, 1.15 mmol) in tetrahydrofuran (10 mL) and water (1 mL). The solution was stirred for 18 hours at room temperature. The solvent was removed in vacuo and the resulting residue was purified by silica gel chromatography (20: 1: 0.5 chloroform-methanol-ammonium hydroxide) to give N- [1- (cis-3-amino-cyclobutyl)- 289 mg (95% yield) of 1H-imidazol-4-yl] -2-naphthalen-1-yl-acetamide were obtained. [271] [272] Example 7a [273] 6-Methyl-pyridine-2-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide [274] A solution of 6-methylpicolinic acid (9.4 mg, 0.07 mmol) in methylene chloride at 23 ° C. was dissolved in 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (84 mg) and DMAP (2 mg) Treated with. 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 then stirred for 3 hours. Water was added and the solution was neutralized with aqueous NaOH and extracted with ethyl acetate. The organic layer was dried (MgSO 4 ), filtered and concentrated in vacuo. Purification by silica gel chromatography (20: 1 CHCl 3 -MeOH) gave 6-methyl-pyridine-2-carboxylic acid {3- [4- (2-naphthalen-1-yl-acetylamino) -imidazole 26 mg (95% yield) of 1-yl] -cyclobutyl} -amide were prepared. [275] [276] Example 7b [277] 1H-imidazole-4-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide [278] The title compound was prepared similar to Example 7a. [279] [280] Example 7c [281] 6-hydroxy-pyridine-2-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide [282] The title compound was prepared similar to Example 7a. [283] [284] Example 7d [285] 3-Methyl-pyridine-2-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide [286] The title compound was prepared similar to Example 7a. [287] [288] Example 7e [289] 2-Pyridin-3-yl-thiazole-4-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide [290] The title compound was prepared similar to Example 7a. [291] [292] Example 7f [293] 6- {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutylcarbamoyl} -nicotinic acid methyl ester [294] The title compound was prepared similar to Example 7a. [295] [296] Example 7 g [297] Pyrazine-2-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide [298] The title compound was prepared similar to Example 7a. [299] [300] Example 7h [301] N- {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -benzamide [302] The title compound was prepared similar to Example 7a. [303] [304] Example 7i [305] 5-Methyl-pyrazine-2-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide [306] The title compound was prepared similar to Example 7a. [307] [308] Example 7j [309] N- {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -isobutyramide [310] The title compound was prepared similar to Example 7a. [311] [312] Example 7k [313] 6-Chloro-pyridine-2-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide [314] The title compound was prepared similar to Example 7a. [315] [316] Example 8 [317] N- [1- (cis-3-amino-cyclobutyl) -1H-imidazol-4-yl] -2-naphthalen-1-yl-acetamide using various carboxylic acids according to the following procedure (Example 6) was acylated and then purified: carboxylic acid (RCO 2 H, 1 equiv, 0.075 mmol) in 1 dram screw cap vial in N- [1- (cis-3-amino) in methylene chloride (1 mL) Solution of -cyclobutyl) -1H-imidazol-4-yl] -2-naphthalen-1-yl-acetamide (0.33 equiv, 8 mg, 0.025 mmol) was added. PS-carbodiimide (Argonaut Technologies, 0.5 equiv, 39 mg, 0.038 mmol, 1 mmol / g) was then added. The mixture was shaken at 23 ° C for 24 h. Note: If the acid is insoluble in methylene chloride, N, N-dimethylformamide (0.5 mL) was added. Each reaction mixture was transferred to methylene chloride (0.5 mL) with a 3 mL SPE cartridge (20 micron frit) with 2 dram vials to collect solvent. The solvent was passed 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 was concentrated under a stream of nitrogen and the crude product was purified by LCMS (column: 3.9 x 150 mm Waters Symmetry C 18 , 5 μΜ; flow rate = 1.0 ml / min; solvent system: A = 0.1% aqueous TFA; B = Acetonitrile; linear gradient from 10 to 100% B over 10 minutes). When the desired parent ions (M + H) were observed, the crude reaction mixture was purified by HPLC (column: 30 x 150 mm Waters Simmetry C 18 , 5 μΜ; flow rate = 20 mL / min; solvent system: A = 0.1% aqueous TFA B = acetonitrile; linear gradient from 0 to 100% B over 15 minutes) and the appropriate fractions were measured by in-line mass spectrometry. Analytical HPLC using 254 nM UV and diode array to detect purity of the chromatographed compound (Column: 2.1 x 150 mm Waters Symmetry C 18 , 5 μM; Flow: 0.5 mL / min; Solvent System: A = 0.1% Aqueous TFA; B = acetonitrile; linear gradient from 0 to 100% B over 10 minutes). [318] The following compounds were prepared by the method described above. Their mass spectral data and chromatographic retention times are listed in Table 1. [319] Example 8a [320] Quinoline-2-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide [321] Example 8b [322] 1H-Pyrrole-2-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide [323] Example 8c [324] N- {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -2-m-tolyl-acetamide [325] Example 8d [326] Pyridine-2-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide [327] Example 8e [328] 2- (3-hydroxy-phenyl) -N- {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -acetamide [329] [330] Preparation Example 5 [331] 4- {3- [4- (2-Naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutylcarbamoyl} -piperidine-1-carboxylic acid 9H-fluorene- 9-ylmethyl ester [332] Step 1 [333] 4-piperidine carboxylic acid (129 mg, 1 mmol) was treated with sodium hydroxide (80 mg, 2 mmol) in water / dioxane (1: 1, 10 mL). After 30 min stirring at room temperature, 9-fluorenylmethyl chloroformate (259 mg, 1 mmol) in dioxane (2 mL) was added dropwise and the reaction solution was stirred for 4 h. The solvent was removed in vacuo and diluted with water. The pH was adjusted to 1 with HCl (1 N) and the aqueous solution was extracted with ethyl acetate. The organic layer was dried (MgSO 4 ), filtered and concentrated in vacuo. Purification by silica gel chromatography (50: 1: 0.5 chloroform-methanol-acetic acid), 340 mg (97% yield) of N-1- (fluorenylmethyloxycarbonyl) -4-piperidinylcarboxylic acid Obtained. [334] [335] Step 2 [336] A solution of N-1- (fluorenylmethyloxycarbonyl) -4-piperidinylcarboxylic acid (Preparation 5, step 1; 77 mg) in methylene chloride was added to 1- (3-dimethylaminopropyl) -3 Treated with ethylcarbodiimide 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) is added It was. The resulting mixture was then stirred for 4 hours. Water was added, the solution was neutralized and extracted with ethyl acetate. The organic layer was dried (MgSO 4 ), filtered and concentrated in vacuo. Purification by silica gel chromatography (20: 1 chloroform-methanol), 4- {3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutylcarba 101 mg (77% yield) of moyl} -piperidine-1-carboxylic acid 9H-fluorene-9-ylmethyl ester were obtained. [337] [338] Example 9 [339] Piperidine-4-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide hydrochloride [340] 4- {3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutylcarbamoyl} -piperidine-1-carboxyl in DMF (5 mL) Acid 9H-fluorene-9-ylmethyl ester (Preparation 5, 100 mg, 0.15 mmol) was treated with piperidine (0.5 mL) and stirred at room temperature for 2 hours. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (4: 1: 0.08 chloroform-methanol-ammonium hydroxide) to give a free base. The free base is dissolved in diethyl ether and treated with 1N HCl in methanol to give piperidine-4-carboxylic acid {cis-3- [4- (2-naphthalene) which is an HCl salt (64 mg, 91% yield). -1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide hydrochloride was obtained. [341] [342] Preparation Example 6 [343] Isoquinolin-5-yl-acetic acid [344] Step 1 [345] 5-aminoisoquinoline (5.0 g, 34.7 mmol) was mixed with 48% aqueous HBr (65 mL) at -78 ° C for 15 minutes. Then sodium nitrite (3.1 g, 45 mmol) in water (6 mL) was 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 foaming. After the addition was complete, the reaction vessel was equipped with a reflux condenser and the mixture was heated to 100 ° C for 4 hours. The mixture was poured onto ice (about 200 g) and made basic (pH = 10) with KOH. The aqueous mixture was extracted with ethyl acetate and the combined organic layers were washed with brine, dried (MgSO 4 ), filtered and concentrated in vacuo. Purification by silica gel chromatography (10: 1 hexane-ethyl acetate) afforded 3.8 g (53% yield) of 5-bromoisoquinoline. [346] [347] Step 2 [348] 5-bromoisoquinoline (Preparation Example 6, step 1, 1.04 g, 5.0 mmol) was dissolved in toluene (20 mL) under allyltributyltin (1.7 mL, 5.5 mmol) and dichloropalladium bis (triphenylphosphine). ) (176 mg, 0.25 mmol). The mixture was heated to reflux for 16 h. After cooling to room temperature, a saturated aqueous solution of potassium fluoride (20 mL) was added with stirring, and a precipitate formed. After stirring for 15 minutes, the mixture is filtered, the organic layer is separated from the aqueous layer, concentrated in vacuo and purified by silica gel chromatography (6: 1 hexane-ethyl acetate) to give 778 mg of 5-allylisoquinoline ( 92% yield). [349] [350] Step 3 [351] 5-allylisoquinoline (Preparation 6, step 2; 169 mg, 1.0 mmol) in methylene chloride (2 mL), acetic acid (0.5 mL) and water (0.5 mL) at 23 ° C. was diluted with dimethyl in methylene chloride (1 mL). Treated with polyethylene glycol (Mn about 500, 95 μl, 100 mg, 0.2 mmol). The mixture was cooled to 0 ° C., powdered KMnO 4 (521 mg, 3.3 mmol) was added in portions and the temperature kept below 30 ° C. After vigorous stirring for 18 hours, the solvent was removed in vacuo, methanolic hydrogen chloride (10 mL, 1N) was added and the mixture was refluxed for 4 hours. Methanol was removed in vacuo, the residue was diluted with water and the mixture was made basic (pH = 9) with Na 2 CO 3 . The mixture is extracted with ethyl acetate and the resulting organic layer 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 methyl ester was obtained. [352] [353] Note: After silica gel chromatography, 5-isoquinolylcarboxaldehyde impurities were present (about 20%). [354] Step 4 [355] Isoquinolin-5-yl-acetic acid methyl ester (Preparation 6, step 3; 90 mg, 0.448 mmol) was treated with aqueous sodium hydroxide (4N, 3 mL) and the solution was heated at 50 ° C. for 4 h. The solution was cooled to 0 ° C., acetic acid (2 mL) was added dropwise and a precipitate formed. 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 dried in air to yield 35 mg (47% yield) of isoquinolin-5-yl-acetic acid. [356] [357] Preparation Example 7 [358] N- [cis-3- (4-nitro-imidazol-1H-yl) cyclobutyl] acetamide [359] Step 1 [360] Trans-toluene-4-sulfonic acid 3- (4-nitro-imidazol-1-yl) -cyclobutyl ester in ethanol (100 mL), water (35 mL) and chloroform (20 mL) (Preparation 1, step 2 ; 3.6 g, 10.7 mmol) was mixed with sodium azide (7 g, 107 mmol). The mixture was heated to 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 layer was washed with brine, dried (MgSO 4 ), filtered and concentrated in vacuo. Purified by silica gel chromatography (1: 1 to 3: 1 ethyl acetate-hexane), 2.2 g (99%) of 1- (3-cis-azido-cyclobutyl) -4-nitro-1H-imidazole Obtained. [361] [362] Step 2 [363] 1- (3-cis-azido-cyclobutyl) -4-nitro-1H-imidazole (Preparation 7, Step 1; 2.2 g, 10.7 mmol) in THF (100 mL) was added triphenylphosphine (3.36 g , 12.8 mmol) and water (10 mL). The solution was stirred at rt for 18 h. The solvent is removed in vacuo and the residue is purified by silica gel chromatography (20: 1: 0.4 chloroform-methanol-ammonium hydroxide) to give 1- (3-cis-amino-cyclobutyl) -4-nitro-1H 1.95 g (100% yield) of imidazole were obtained. [364] [365] Step 3 [366] 1- (3-cis-amino-cyclobutyl) -4-nitro-1H-imidazole (Preparation 7, Step 2; 500 mg, 2.75 mmol) as in Example 7 was coupled with acetic acid and purified, 594 mg (96% yield) of N- [cis-3- (4-nitro-imidazol-1H-yl) -cyclobutyl] acetamide were obtained. [367] [368] Preparation Example 8 [369] N- [cis-3- (4-nitro-imidazol-1-yl) -cyclobutyl] -benzamide [370] N- [cis-3- (4-nitro-imidazol-1-yl) -cyclobutyl] -benzamide was prepared similar to the product of Preparation 7. [371] [372] Preparation Example 9 [373] Pyridine-2-carboxylic acid [cis-3- (4-nitro-imidazol-1-yl) -cyclobutyl] -amide [374] Pyridine-2-carboxylic acid [cis-3- (4-nitro-imidazol-1-yl) -cyclobutyl] -amide was prepared similar to the product of Preparation 7. [375] [376] Example 9a [377] N- [1- (cis-3-acetylamino-cyclobutyl) -1H-imidazol-4-yl] -2-naphthalen-2-yl-acetamide [378] N- [cis-3- (4-nitro-imidazol-1H-yl) -cyclobutyl] acetamide (Preparation 7; 50 mg, 0.22 mmol) as in Example 1 was hydrogenated and 2-nap Acylated with methyl acetic acid, 35 mg (44% yield) of N- [1- (cis-3-acetylamino-cyclobutyl) -1H-imidazol-4-yl] -2-naphthalen-2-yl-acetamide ) Was obtained. [379] [380] Example 9b [381] N- {cis-3- [4- (2-isoquinolin-5-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -benzamide [382] The title compound was prepared similar to Example 9a using Preparation Example 8 and isoquinolin-5-yl acetic acid (Preparation Example 6). [383] [384] Example 9c [385] Pyridine-2-carboxylic acid {cis-3- [4- (2-isoquinolin-5-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide [386] The title compound was prepared in analogy to Example 9a using Preparation Example 9 and isoquinolin-5-yl acetic acid (Preparation Example 6). [387] [388] Example 10 [389] N- {cis-3- [4- (3-naphthalen-1-yl-ureido) -imidazol-1-yl] -cyclobutyl} -acetamide [390] 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 an inseparable mixture of mono- and bis-phenyl carbamate products which were then subjected to silica gel chromatography (20: 1: 0.2 chloroform-methanol-ammonium hydroxide) to give 1: 1 DMF / dioxane (500 [Mu] l). 1-naphthylamine (31 mg, 0.22 mmol) was added and the mixture was heated at 70 ° C. for 16 h. Purified twice by silica gel chromatography (20: 1: 0.02 chloroform-methanol-ammonium hydroxide) to give N- {cis-3- [4- (3-naphthalen-1-yl-ureido) -imidazole- 4.4 mg (5% yield) of 1-yl] -cyclobutyl} -acetamide were obtained. [391]
权利要求:
Claims (13) [1" claim-type="Currently amended] A compound of formula 1 or a pharmaceutically acceptable salt thereof. <Formula 1> Where R 1 is straight or branched chain (C 1 -C 8 ) alkyl, straight or branched chain (C 2 -C 8 ) alkenyl, straight or branched chain (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 To 11-membered) heterobicycloalkyl, (C 6 -C 14 ) aryl or (5- to 14-membered) heteroaryl, wherein R 1 is F, Cl, Br, I, nitro, cyano, -CF 3 ,- NR 7 R 8 , -NR 7 C (= 0) R 8 , -NR 7 C (= 0) OR 8 , -NR 7 C (= 0) NR 8 R 9 , -NR 7 S (= 0) 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 , 1 to 6 substituents R 5 independently selected from -S (= 0) 2 R 7 , -S (= 0) 2 NR 7 R 8 , -OS (= 0) 2 R 7 , -N 3 and R 7 Optionally substituted; R 2 is H, F, —CH 3 , —CN or —C (═O) OR 7 ; R 3 is —C (═O) NR 9 —, —C (═O) O—, —C (═O) (CR 10 R 11 ) n -or-(CR 10 R 11 ) n- ; R 4 is straight or branched chain (C 1 -C 8 ) alkyl, straight or branched chain (C 2 -C 8 ) alkenyl, straight or branched chain (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 To 11-membered) heterobicycloalkyl, (C 6 -C 14 ) aryl or (5- to 14-membered) heteroaryl, wherein R 4 is F, Cl, Br, I, nitro, cyano, -CF 3 ,- NR 7 R 8 , -NR 7 C (= 0) R 8 , -NR 7 C (= 0) OR 8 , -NR 7 C (= 0) NR 8 R 9 , -NR 7 S (= 0) 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 to 3 substituents R 6 independently selected from -S (= 0) 2 R 7 , -S (= 0) 2 NR 7 R 8 or R 7 ; Each R 7 , R 8 and R 9 is independently H, straight or branched chain (C 1 -C 8 ) alkyl, straight or branched chain (C 2 -C 8 ) alkenyl, straight or branched chain (C 2 -C 8 ) alkynyl, (C 3 -C 8 ) cycloalkyl, (C 4 -C 8 ) cycloalkenyl, (3 to 8 membered) heterocycloalkyl, (C 5 -C 11 ) bicycloalkyl, (C 7 -C 11 ) bicycloalkenyl, (5- to 11-membered) heterobicycloalkyl, (C 6 -C 14 ) aryl and (5- to 14-membered) heteroaryl, wherein R 7 , R 8 and R 9 Are each independently 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 (= 0) NR 11 R 12 , -NR 10 S (= 0) 2 R 11 , -NR 10 S (= 0) 2 NR 11 R 12 , -OR 10 , -OC (= 0) 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 (= 0) 2 NR 10 R 11 , -C (= 0) R 10 , -C (= 0) OR 10 , -C (= 0) NR 10 R 11 and R 10 independently Optionally substituted with 1 to 6 substituents selected; If R 7 and R 8 are present as NR 7 R 8 , they are instead 3 to 3 containing one or two additional heteroatoms independently selected from N, O and S together with the nitrogen of NR 7 R 8 to which they are attached; Optionally form a heterocycloalkyl moiety of a seven membered ring; Each R 10 , R 11 and R 12 is independently H, straight or branched chain (C 1 -C 8 ) alkyl, straight or branched chain (C 2 -C 8 ) alkenyl, straight or branched chain (C 2 -C 8 ) alkynyl, (C 3 -C 8 ) cycloalkyl, (C 4 -C 8 ) cycloalkenyl, (3 to 8 membered) heterocycloalkyl, (C 5 -C 11 ) bicycloalkyl, (C 7 -C 11 ) bicycloalkenyl, (5- to 11-membered) heterobicycloalkyl, (C 6 -C 14 ) aryl and (5- to 14-membered) heteroaryl, wherein R 10 , R 11 and R 12 Are each independently F, Cl, Br, I, -NO 2 , -CN, -CF 3 , -NR 13 R 14 , -NR 13 C (= 0) R 14 , -NR 13 C (= 0) 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) OR 13 , -C (= O) NR 13 Independent from R 14 and R 13 Optionally substituted with 1 to 6 substituents selected from; Each R 13 , R 14 and R 15 is independently H, straight or branched chain (C 1 -C 8 ) alkyl, straight or branched chain (C 2 -C 8 ) alkenyl, straight or branched chain (C 2 -C 8 ) alkynyl, (C 3 -C 8 ) cycloalkyl, (C 4 -C 8 ) cycloalkenyl, (3 to 8 membered) heterocycloalkyl, (C 5 -C 11 ) bicycloalkyl, (C 7 -C 11 ) bicycloalkenyl, (5- to 11-membered) heterobicycloalkyl, (C 6 -C 14 ) aryl and (5- to 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 (= 0) R 17 , -NR 16 C (= 0) OR 17 , -NR 16 C (= 0) NR 17 R 18 , -NR 16 S (= 0) 2 R 17 , -NR 16 S (= 0) 2 NR 17 R 18 , -OR 16 , -OC (= 0) 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 (= O) OR 16 , -C (= O) NR 16 Independent of R 17 and R 16 Optionally substituted with 1 to 6 substituents selected from; Each R 16 , R 17 and R 18 is independently H, straight or branched chain (C 1 -C 8 ) alkyl, straight or branched chain (C 2 -C 8 ) alkenyl, straight or branched chain (C 2 -C 8 ) alkynyl, (C 3 -C 8 ) cycloalkyl, (C 4 -C 8 ) cycloalkenyl, (3 to 8 membered) heterocycloalkyl, (C 5 -C 11 ) bicycloalkyl, (C 7 -C 11 ) bicycloalkenyl, (5- to 11-membered) heterobicycloalkyl, (C 6 -C 13 ) aryl and (5- to 12-membered) heteroaryl; n is 0, 1, 2 or 3; Wherein R 10 and R 11 in —C (═O) (CR 10 R 11 ) n − and — (CR 10 R 11 ) n − are independently defined as above for each repeated n. [2" claim-type="Currently amended] The compound of claim 1, wherein R 3 is —C (═O) NH or —C (═O) (CR 10 R 11 ) n −. [3" claim-type="Currently amended] The compound of claim 1, wherein R 1 is optionally substituted (C 3 -C 8 ) cycloalkyl or optionally substituted (C 5 -C 11 ) bicycloalkyl. [4" claim-type="Currently amended] 4. A compound according to claim 3, wherein R 1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl or bicyclo- [3.1.0] -hexyl, each of which is optionally substituted. [5" claim-type="Currently amended] The compound of claim 1, wherein R 1 is optionally substituted straight or branched chain (C 1 -C 8 ) alkyl or optionally substituted straight or branched chain (C 2 -C 8 ) alkenyl. [6" claim-type="Currently amended] The compound of claim 1, wherein R 4 is (C 6 -C 14 ) aryl or (5- to 14-membered) heteroaryl, each of which is optionally substituted. [7" claim-type="Currently amended] The compound of claim 6, wherein R 4 is phenyl, pyridyl, naphthyl, quinolyl or isoquinolyl, each of which is optionally substituted. [8" claim-type="Currently amended] 8. The compound of claim 1, wherein R 2 is hydrogen. [9" claim-type="Currently amended] The method of claim 1, 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, (1-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-pyridine-2-carboxylic acid {cis-3- [4- (2-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide, 1 H-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) -imidazol-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} -amide, 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-naphthalen-1-yl-acetylamino) -imidazol-1-yl] -cyclobutyl} -amide, 1H-pyrrole-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} -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-acetylamino-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 Compounds selected from the group consisting of and pharmaceutically acceptable salts of the compounds. [10" claim-type="Currently amended] A pharmaceutical composition for the treatment of a disease or disorder comprising a therapeutically effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier in a mammal comprising a disease or condition comprising abnormal cell growth or neurodegenerative disease or disorder. [11" claim-type="Currently amended] Pharmaceuticals for treating such diseases or disorders in a mammal, wherein the treatment comprises a therapeutically effective amount of a disease or disorder that can be achieved or promoted by modifying dopamine mediated neurotransmission or an inhibitory effective amount of a cdk5 inhibitor and a pharmaceutically acceptable carrier. Composition. [12" claim-type="Currently amended] Male fertility and sperm movement; diabetes; Impaired glucose tolerance; Metabolic syndrome or syndrome X; Polycystic ovary syndrome; Lipogenesis and obesity; Muscle development and weakness, eg, age-related poor physical performance; Acute myopathy, eg muscular dystrophy and / or cachexia associated with burns, bedside care, limb fixation, or chest, abdomen, and / or orthopedic major surgery; blood poisoning; Hair loss, hair softening and baldness; And a therapeutically effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier for a disease or disorder selected from immunodeficiency. [13" claim-type="Currently amended] cdk5 inhibitors, and SSRIs, NK-1 receptor antagonists, 5HT 1D antagonists, ziprasidone, olanzapine, risperidone, L-745870, sonepyprazole, RP 62203, NGD 941, Valaperidone, Plesinoxane, Gepyron, Acetylcholine A pharmaceutical composition comprising an effective amount of a second component selected from the group consisting of esterase inhibitors, TPA, NIF, potassium channel modulators such as BMS-204352, and NMDA receptor antagonists and a pharmaceutically acceptable carrier.
类似技术:
公开号 | 公开日 | 专利标题 US9682083B2|2017-06-20|Pyrrolo[2,3-D]pyrimidine derivatives, process for their preparation and their use as kinase inhibitors US10478423B2|2019-11-19|Substituted indazole derivatives active as kinase inhibitiors EP2797927B1|2019-09-25|THIENO[3,2-d]PYRIMIDINE DERIVATIVES HAVING INHIBITORY ACTIVITY FOR PROTEIN KINASES KR20190018558A|2019-02-22|Heterocyclic amides as kinase inhibitors RU2675857C2|2018-12-25|Inhibiting jak compounds based on pyrazolopyrimidine and methods RU2523544C2|2014-07-20|SUBSTITUTED PYRAZOLO[1,5-a]PYRIMIDINE COMPOUNDS AS TROPOMYOSIN-RELATED KINASE INHIBITORS EP2393360B1|2015-11-04|Pyridazinone compounds ES2398843T3|2013-03-22|Imidazotriazines and imidazopyrimidines as kinase inhibitors EP2086979B1|2015-06-03|Imidazo[1,2-b]pyridazine and pyrazolo[1,5-a]pyrimidine derivatives and their use as protein kinase inhibitors EP2507227B1|2014-10-08|Tetrazolones as protein kinase c inhibitors and uses thereof RU2274639C2|2006-04-20|Derivatives of substituted triazoldiamine, pharmaceutical composition based on thereof and method for its preparing AU2006279794B2|2011-04-07|Pyrazole compounds that modulate HSP90 activity KR100711538B1|2007-04-27|Aminopyrazole derivatives US6710209B2|2004-03-23|Heteroaryl-substituted quinolin-2-one derivatives useful as anticancer agents RU2264403C2|2005-11-20|Substituted 2-aryl-3-|imidazo[1,2-a]-pyrimidines, pharmaceutical compositions comprising thereof and associated methods US7208499B2|2007-04-24|Pyrimidine derivatives for the treatment of abnormal cell growth EP1235825B1|2006-01-25|Novel benzoimidazole derivatives useful as antiproliferative agents KR101527232B1|2015-06-09|Cyclopenta〔d〕pyrimidines as akt protein kinase inhibitors EP1678166B1|2009-07-29|Protein kinase inhibitors EP2736514B1|2017-10-18|Alkynyl substituted pyrimidinyl-pyrroles active as kinases inhibitors EP1625121B1|2010-02-24|Pyrimidine derivatives for the treatment of abnormal cell growth EP1322650B1|2008-09-24|Farnesyl transferase inhibiting 6-heterocyclylmethyl quinoline and quinazoline derivatives JP4027406B2|2007-12-26|Phthalazinone derivatives KR101099161B1|2011-12-27|Triazolopyrazine derivatives useful as anti-cancer agents KR100738862B1|2007-07-13|Pyrimidine derivatives
同族专利:
公开号 | 公开日 JP2008255123A|2008-10-23| NO20030472L|2003-03-27| MA26932A1|2004-12-20| NO20030472D0|2003-01-30| MXPA03000939A|2003-06-24| PE20020337A1|2002-05-08| IL153787D0|2003-07-31| JP2004505111A|2004-02-19| IS6662A|2002-12-19| EP1305295A1|2003-05-02| BG107469A|2003-09-30| HU0303069A2|2004-03-01| CZ2003225A3|2004-02-18| EE200300049A|2004-10-15| CN1444567A|2003-09-24| AU7094401A|2002-02-13| HU0303069A3|2004-04-28| DOP2001000220A|2002-05-15| UY26862A1|2002-02-28| NZ523272A|2004-08-27| WO2002010141A1|2002-02-07| GT200100147A|2002-06-25| CR6861A|2004-03-11| BR0112862A|2003-07-01| EA200300097A1|2003-06-26| SV2002000571A|2002-10-24| PA8523701A1|2002-04-25| CA2418115A1|2002-02-07| TNSN01114A1|2005-11-10| PL365134A1|2004-12-27| ECSP034445A|2003-03-10| SK1042003A3|2004-05-04| OA12345A|2004-04-13| ZA200300819B|2004-04-20| HRP20030048A2|2003-04-30| JP4166084B2|2008-10-15| AR032629A1|2003-11-19|
引用文献:
公开号 | 申请日 | 公开日 | 申请人 | 专利标题
法律状态:
2000-07-31|Priority to US22172400P 2000-07-31|Priority to US60/221,724 2001-07-25|Application filed by 화이자 프로덕츠 인크. 2001-07-25|Priority to PCT/IB2001/001335 2003-03-06|Publication of KR20030019644A
优先权:
[返回顶部]
申请号 | 申请日 | 专利标题 US22172400P| true| 2000-07-31|2000-07-31| US60/221,724|2000-07-31| PCT/IB2001/001335|WO2002010141A1|2000-07-31|2001-07-25|Imidazole derivatives| 相关专利
Sulfonates, polymers, resist compositions and patterning process
Washing machine
Washing machine
Device for fixture finishing and tension adjusting of membrane
Structure for Equipping Band in a Plane Cathode Ray Tube
Process for preparation of 7 alpha-carboxyl 9, 11-epoxy steroids and intermediates useful therein an
国家/地区
|