# US 2012/0071657 A1 · Triazole compounds useful as protein kinase inhibitors

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- Number: US 2012/0071657 A1
- Document ID: US20120071657A1
- Status: Published application
- Kind: A1
- Application number: 13/094,183
- Filed: 2011-04-26
- Published: 2012-03-22
- Earliest claimed: 2000-09-15
- Assignees: Vertex Pharmaceuticals Incorporated
- Inventors: David Bebbington; Ronald Knegtel; Hayley Binch; Julian M.C. Golec; Pan Li; Jean-Damien Charrier
- Web page: https://patentgrep.com/patent/US20120071657A1

## CPC

- C07D 401/14: containing three or more hetero rings
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 3/08: for glucose homeostasis (pancreatic hormones A61P5/48)
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 3/14: for calcium homeostasis (vitamin D A61P3/02; parathyroid hormones A61P5/18; calcitonin A61P5/22; osteoporosis A61P19/10; bone metastasis A61P35/04)
- A61P 5/00: Drugs for disorders of the endocrine system
- A61P 5/48: of the pancreatic hormones
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 11/06: Antiasthmatics
- A61P 17/06: Antipsoriatics
- A61P 19/00: Drugs for skeletal disorders
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/10: for osteoporosis
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/12: Antivirals
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 231/12: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 233/56: with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
- C07D 249/08: 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 403/14: containing three or more hetero rings
- C07D 405/14: containing three or more hetero rings
- C07D 407/14: containing three or more hetero rings
- C07D 409/14: containing three or more hetero rings
- C07D 417/14: containing three or more hetero rings
- C07D 471/04: Ortho-condensed systems
- C07D 473/16: two nitrogen atoms
- C07D 487/04: Ortho-condensed systems
- C07D 491/04: Ortho-condensed systems
- C07D 493/04: Ortho-condensed systems
- C07D 495/04: Ortho-condensed systems
- C07D 513/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

This invention describes novel triazole compounds of formula IX: wherein Z1 is nitrogen or CR9 and Z2 is nitrogen or CH, provided that at least one of Z1 and Z2 is nitrogen; G is Ring C or Ring D; Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C has one or two ortho substituents independently selected from —R1; Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl; Rx and Ry are independently selected from T-R3, or Rx and Ry are taken together with their intervening atoms to form a fused ring; R1, R3, and T are as described in the specification. The compounds are useful as protein kinase inhibitors, especially as inhibitors of GSK-3 and Aurora, for treating diseases such as diabetes, cancer, and Alzheimer's disease.

## Claims

### Claim 1

A compound of formula IX:
or a pharmaceutically acceptable derivative or prodrug thereof, wherein:
Z1 is nitrogen or CR9 and Z2 is nitrogen or CH, provided that at least one of Z1 and Z2 is nitrogen;
G is Ring C or Ring D;
Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C has one or two ortho substituents independently selected from —R1, any substitutable non-ortho carbon position on Ring C is independently substituted by —R5, and two adjacent substituents on Ring C are optionally taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, said fused ring being optionally substituted by halo, oxo, or —R8;
Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein Ring D is substituted at any substitutable ring carbon by oxo or —R5, and at any substitutable ring nitrogen by —R4, provided that when Ring D is a six-membered aryl or heteroaryl ring, —R5 is hydrogen at each ortho carbon position of Ring D;
R1 is selected from -halo, —CN, —NO2, T-V—R6, phenyl, 5-6 membered heteroaryl ring, 5-6 membered heterocyclyl ring, or C1-6 aliphatic group, said phenyl, heteroaryl, and heterocyclyl rings each optionally substituted by up to three groups independently selected from halo, oxo, or —R8, said C1-6 aliphatic group optionally substituted with halo, cyano, nitro, or oxygen, or R1 and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C;
Rx and Ry are independently selected from T-R3, or Rx and Ry are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-8 membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, wherein any substitutable carbon on said fused ring formed by Rx and Ry is substituted by oxo or T-R3, and any substitutable nitrogen on said ring formed by Rx and Ry is substituted by R4;
T is a valence bond or a C1-4 alkylidene chain;
R2 is —R or -T-W—R6;
R3 is selected from —R, -halo, —OR, —C(═O)R, —CO2R, —COCOR, —COCH2COR, —NO2, —CN, —S(O)R, —S(O)2R, —SR, —N(R4)2, —CON(R7)2, —SO2N(R7)2, —OC(═O)R, —N(R7)COR, —N(R7)CO2 (optionally substituted C1-6 aliphatic), —N(R4)N(R4)2, —C═NN(R4)2, —C═N—OR, —N(R7)CON(R7)2, —N(R7)SO2N(R7)2, —N(R4)SO2R, or —OC(═O)N(R7)2;
each R is independently selected from hydrogen or an optionally substituted group selected from C1-6 aliphatic, C6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;
each R4 is independently selected from —R7, —COR7, —CO2(optionally substituted C1-6 aliphatic), —CON(R7)2, or —SO2R7, or two R4 on the same nitrogen are taken together to form a 5-8 membered heterocyclyl or heteroaryl ring;
each R5 is independently selected from —R, halo, —OR, —C(═O)R, —CO2R, —COCOR, —NO2, —CN, —S(O)R, —SO2R, —SR, —N(R4)2, —CON(R4)2, —SO2N(R4)2, —OC(═O)R, —N(R4)COR, —N(R4)CO2 (optionally substituted C1-6 aliphatic), —N(R4)N(R4)2, —C═NN(R4)2, —C═N—OR, —N(R4)CON(R4)2, —N(R4)SO2N(R4)2, —N(R4)SO2R, or —OC(═O)N(R4)2, or R5 and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C;
V is —O—, —S—, —SO—, —SO2—, —N(R6)SO2—, —SO2N(R6)—, —N(R6)—, —CO—, —CO2—, —N(R6)CO—, —N(R6)C(O)O—, —N(R6)CON(R6)—, —N(R6)SO2N(R6)—, —N(R6)N(R6)—, —C(O)N(R6)—, —OC(O)N(R6)—, —C(R6)2O—, —C(R6)2S—, —C(R6)2SO—, —C(R6)2SO2—, —C(R6)2SO2N(R6)—, —C(R6)2N(R6)—, —C(R6)2N(R6)C(O)—, —C(R6)2N(R6)C(O)O—, —C(R6)═NN(R6)—, —C(R6)═N—O—, —C(R6)2N(R6)N(R6)—, —C(R6)2N(R6)SO2N(R6)—, or —C(R6)2N(R6)CON(R6)—;
W is —C(R6)2O—, —C(R6)2S—, —C(R6)2SO—, —C(R6)2SO2—, —C(R6)2SO2N(R6)—, —C(R6)2N(R6)—, —CO—, —CO2—, —C(R6)OC(O)—, —C(R6)OC(O)N(R6)—, —C(R6)2N(R6)CO—, —C(R6)2N(R6)C(O)O—, —C(R6)═NN(R6)—, —C(R6)═N—O—, —C(R6)2N(R6)N(R6)—, —C(R6)2N(R6)SO2N(R6)—, —C(R6)2N(R6)CON(R6)—, or —CON(R6)—;
each R6 is independently selected from hydrogen, an optionally substituted C1-4 aliphatic group, or two R6 groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring;
each R7 is independently selected from hydrogen or an optionally substituted C1-6 aliphatic group, or two R7 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring;
each R8 is independently selected from an optionally substituted C1-4 aliphatic group, —OR6, —SR6, —COR6, —SO2R6, —N(R6)2, —N(R6)N(R6)2, —CN, —NO2, —CON(R6)2, or —CO2R6; and
R9 is selected from —R, halo, —OR, —C(═O)R, —CO2R, —COCOR, —NO2, —CN, —S(O)R, —SO2R, —SR, —N(R4)2, —CON(R4)2, —SO2N(R4)2, —OC(═O)R, —N(R4)COR, —N(R4)CO2 (optionally substituted C1-6 aliphatic), —N(R4)N(R4)2, —C═NN(R4)2, —C═N—OR, —N(R4)CON(R4)2, —N(R4)SO2N(R4)2, —N(R4)SO2R, or —OC(═O)N(R4)2.

### Claim at position 2

2-47. (canceled)