IP Library › Granted Patent US 8,633,210

Granted Patent B2

US 8,633,210 · App. 13/094,183 · Granted Jan 21, 2014

Triazole compounds useful as protein kinase inhibitors

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Quick Facts

Patent No.: US 8,633,210
App. No.: 13/094,183
Granted: Jan 21, 2014
Kind: B2

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Abstract

This invention describes novel triazole compounds of formula IX: wherein Z 1 is nitrogen or CR 9 and Z 2 is nitrogen or CH, provided that at least one of Z 1 and Z 2 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 —R 1 ; Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl; R x and R y are independently selected from T-R 3 , or R x and R y are taken together with their intervening atoms to form a fused ring; R 1 , R 3 , 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 (149)

1. A compound of formula IX:

wherein:

Z 1 is nitrogen and Z 2 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 —R 1 , any substitutable non-ortho carbon position on Ring C is independently substituted by —R 5 , 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 —R 8 ;

Ring D is a 6-7 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 —R 5 , and at any substitutable ring nitrogen by —R 4 , provided that when Ring D is a six-membered aryl or heteroaryl ring, —R 5 is hydrogen at each ortho carbon position of Ring D;

R 1 is selected from -halo, —CN, —NO 2 , T-V—R 6 , phenyl, 5-6 membered heteroaryl ring, 5-6 membered heterocyclyl ring, or C 1-6 aliphatic group, said phenyl, heteroaryl, and heterocyclyl rings each optionally substituted by up to three groups independently selected from halo, oxo, or —R 8 , said C 1-6 aliphatic group optionally substituted with halo, cyano, nitro, or oxygen, or R 1 and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C;

R x and R y are independently selected from T-R 3 , or R x and R y 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 R x and R y is substituted by oxo or T-R 3 , and any substitutable nitrogen on said ring formed by R x and R y is substituted by R 4 ;

T is a valence bond or a C 1-4 alkylidene chain;

R 2 is —R or -T-W—R 6 ;

R 3 is selected from —R, -halo, —OR, —C(═O)R, —CO 2 R, —COCOR, —COCH 2 COR, —NO 2 , —CN, —S(O)R, —S(O) 2 R, —SR, —N(R 4 ) 2 , —CON(R 7 ) 2 , —SO 2 N(R 7 ) 2 , —OC(═O)R, —N(R 7 )COR, —N(R 7 )CO 2 (optionally substituted C 1-6 aliphatic), —N(R 4 )N(R 4 ) 2 , —C═NN(R 4 ) 2 , —C═N—OR, —N(R 7 )CON(R 7 ) 2 , —N(R 7 )SO 2 N(R 7 ) 2 , —N(R 4 )SO 2 R, or —OC(═O)N(R 7 ) 2 ;

each R is independently selected from hydrogen or an optionally substituted group selected from C 1-6 aliphatic, C 6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;

each R 4 is independently selected from —R 7 , —COR 7 , —CO 2 (optionally substituted C 1-6 aliphatic), —CON(R 7 ) 2 , or —SO 2 R 7 , or two R 4 on the same nitrogen are taken together to form a 5-8 membered heterocyclyl or heteroaryl ring;

each R 5 is independently selected from —R, halo, —OR, —C(═O)R, —CO 2 R, —COCOR, —NO 2 , —CN, —S(O)R, —SO 2 R, —SR, —N(R 4 ) 2 , —CON(R 4 ) 2 , —SO 2 N(R 4 ) 2 , —OC(═O)R, —N(R 4 )COR, —N(R 4 )CO 2 (optionally substituted C 1-6 aliphatic), —N(R 4 )N(R 4 ) 2 , —C═NN(R 4 ) 2 , —C═N—OR, —N(R 4 )CON(R 4 ) 2 , —N(R 4 )SO 2 N(R 4 ) 2 , —N(R 4 )SO 2 R, or —OC(═O)N(R 4 ) 2 , or R 5 and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C;

V is —O—, —S—, —SO—, —SO 2 —, —N(R 6 )SO 2 —, —SO 2 N(R 6 )—, —N(R 6 )—, —CO—, —CO 2 —, —N(R 6 )CO—, —N(R 6 )C(O)O—, —N(R 6 )CON(R 6 )—, —N(R 6 )SO 2 N(R 6 )—, —N(R 6 )N(R 6 )—, —C(O)N(R 6 )—, —OC(O)N(R 6 )—, —C(R 6 ) 2 O—, —C(R 6 ) 2 S—, —C(R 6 ) 2 SO—, —C(R 6 ) 2 SO 2 —, —C(R 6 ) 2 SO 2 N(R 6 )—, —C(R 6 ) 2 N(R 6 )—, —C(R 6 ) 2 N(R 6 )C(O)—, —C(R 6 ) 2 N(R 6 )C(O)O—, —C(R 6 )═NN(R 6 )—, —C(R 6 )═N—O—, —C(R 6 ) 2 N(R 6 )N(R 6 )—, —C(R 6 ) 2 N(R 6 )SO 2 N(R 6 )—, or —C(R 6 ) 2 N(R 6 )CON(R 6 )—;

W is —C(R 6 ) 2 O—, —C(R 6 ) 2 S—, —C(R 6 ) 2 SO—, —C(R 6 ) 2 SO 2 —, —C(R 6 ) 2 SO 2 N(R 6 )—, —C(R 6 ) 2 N(R 6 )—, —CO—, —CO 2 —, —C(R 6 )OC(O)—, —C(R 6 )OC(O)N(R 6 )—, —C(R 6 ) 2 N(R 6 )CO—, —C(R 6 ) 2 N(R 6 )C(O)O—, —C(R 6 )═NN(R 6 )—, —C(R 6 )═N—O—, —C(R 6 ) 2 N(R 6 )N(R 6 )—, —C(R 6 ) 2 N(R 6 )SO 2 N(R 6 )—, —C(R 6 ) 2 N(R 6 )CON(R 6 )—, or —CON(R 6 )—;

each R 6 is independently selected from hydrogen, an optionally substituted C 1-4 aliphatic group, or two R 6 groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring;

each R 7 is independently selected from hydrogen or an optionally substituted C 1-6 aliphatic group, or two R 7 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; and

each R 8 is independently selected from an optionally substituted C 1-4 aliphatic group, —OR 6 , —SR 6 , —COR 6 , —SO 2 R 6 , —N(R 6 ) 2 , —N(R 6 )N(R 6 ) 2 , —CN, —NO 2 , —CON(R 6 ) 2 , or —CO 2 R 6 .

2. The compound according to claim 1 , wherein said compound is of formula X:

wherein;

T is a valence bond or a C 1-4 alkylidene chain;

R 2 is —R or -T-W—R 6 ;

R 3 is selected from —R, -halo, —OR, —C(═O)R, —CO 2 R, —COCOR, —COCH 2 COR, —NO 2 , —CN, —S(O)R, —S(O) 2 R, —SR, —N(R 4 ) 2 , —CON(R 7 ) 2 , —SO 2 N(R 7 ) 2 , —OC(═O)R, —N(R 7 )COR, —N(R 7 )CO 2 (optionally substituted C 1-6 aliphatic), —N(R 4 )N(R 4 ) 2 , —C═NN(R 4 ) 2 , —C═N—OR, —N(R 7 )CON(R 7 ) z , —N(R 7 )SO 2 N(R 7 ) 2 , —N(R 4 )SO 2 R, or —OC(═O)N(R 7 ) 2 ;

3. The compound according to claim 2 , wherein said compound has one or more features selected from the group consisting of:

(a) Ring C is a phenyl or pyridinyl ring, wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is selected from a naphthyl, quinolinyl or isoquinolinyl ring;

(b) R x is hydrogen or C 1-4 aliphatic and R y is T-R 3 , or R x and R y are taken together with their intervening atoms to form a 5-7 membered unsaturated or partially unsaturated ring having 0-2 ring nitrogens;

(c) R 1 is -halo, an optionally substituted C 1-6 aliphatic group, phenyl, —COR 6 , —OR 6 , —CN, —SO 2 R 6 , —SO 2 NH 2 , —N(R 6 ) 2 , —CO 2 R 6 , —CONH 2 , —NHCOR 6 , —OC(O)NH 2 , or —NHSO 2 R 6 ; and

(d) R 2 is hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C 1-6 aliphatic group.

4. The compound according to claim 3 , wherein:

(d) R 2 is hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C 1-6 aliphatic group.

5. The compound according to claim 3 , wherein said compound has one or more features selected from the group consisting of:

(a) Ring C is a phenyl or pyridinyl ring, wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring;

(b) R x is hydrogen or methyl and R y is —R, N(R 4 ) 2 , or —OR, or R x and R y are taken together with their intervening atoms to form a benzo ring or a 5-7 membered carbocyclo ring, wherein said ring formed by R x and R y is substituted with —R, halo, —OR, —C(═O)R, —CO 2 R, —COCOR, —NO 2 , —CN, —S(O)R, —SO 2 R, —SR, —N(R 4 ) 2 , —CON(R 4 ) 2 , —SO 2 N(R 4 ) 2 , —OC(═O)R, —N(R 4 )COR, —N(R 4 )CO 2 (optionally substituted C 1-6 aliphatic), —N(R 4 )N(R 4 ) 2 , —C═NN(R 4 ) 2 , —C═N—OR, —N(R 4 )CON(R 4 ) 2 , —N(R 4 )SO 2 N(R 4 ) 2 , —N(R 4 )SO 2 R, or —OC(═O)N(R 4 ) 2 ;

(d) R 2 is hydrogen or a substituted or unsubstituted group selected from aryl or a C 1-6 aliphatic group; and

(e) each R 5 is independently selected from H, -halo, —CN, —NO 2 , —N(R 4 ) 2 , optionally substituted C 1-6 aliphatic group, —OR, —C(O)R, —CO 2 R, —CONH(R 4 ), —N(R 4 )COR, —SO 2 N(R 4 ) 2 , or —N(R 4 )SO 2 R.

6. The compound according to claim 5 , wherein:

(a) Ring C is a phenyl or pyridinyl ring, wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring;

(d) R 2 is hydrogen or a substituted or unsubstituted group selected from aryl or a C 1-6 aliphatic group; and

7. The compound according to claim 5 , wherein said compound has one or more features selected from the group consisting of:

(a) Ring C is a phenyl or pyridinyl ring, wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring;

(b) R x is hydrogen or methyl and R y is methyl, methoxymethyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- or an optionally substituted group selected from 2-pyridyl, 4-pyridyl, piperidinyl, or phenyl, or R x and R y are taken together with their intervening atoms to form a benzo ring or a 6-membered carbocyclo ring;

(d) R 2 is hydrogen or a C 1-6 aliphatic group; and

(e) each R 5 is independently selected from H, —Cl, —F, —CN, —CF 3 , —NH 2 , —NH(C 1-4 aliphatic), —N(C 1-4 aliphatic) 2 , —O(C 1-4 aliphatic), C 1-4 aliphatic, and —CO 2 (C 1-4 aliphatic).

8. The compound according to claim 7 , wherein:

(a) Ring C is a phenyl or pyridinyl ring, wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring;

(d) R 2 is hydrogen or a C 1-6 aliphatic group; and

9. The compound according to claim 1 , wherein said compound is of formula XI:

wherein:

R x and R y are taken together with their intervening atoms to form a fused benzo ring or 5-8 membered carbocyclo ring, wherein any substitutable carbon on said fused ring formed by R x and R y is substituted by oxo or T-R 3 ;

T is a valence bond or a C 1-4 alkylidene chain;

R 2 is —R or -T-W—R 6 ;

R 3 is selected from —R, -halo, ═O, —OR, —C(═O)R, —CO 2 R, —COCOR, —COCH 2 COR, —NO 2 , —CN, —S(O)R, —S(O) 2 R, —SR, —N(R 4 ) 2 , —CON(R 4 ) 2 , —SO 2 N(R 4 ) 2 , —OC(═O)R, —N(R 4 )COR, —N(R 4 )CO 2 (optionally substituted C 1-6 aliphatic), —N(R 4 )N(R 4 ) 2 , —C═NN(R 4 ) 2 , —C═N—OR, —N(R 4 )CON(R 4 ) 2 , —N(R 4 )SO 2 N(R 4 ) 2 , —N(R 4 )SO 2 R, or —OC(═O)N(R 4 ) 2 ;

each R is independently selected from hydrogen, or an optionally substituted group selected from C 1-6 aliphatic, C 6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;

each R 6 is independently selected from hydrogen or an optionally substituted C 1-4 aliphatic group, or two R 6 groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; and

10. The compound according to claim 9 , wherein said compound has one or more features selected from the group consisting of:

(a) Ring D is selected from a phenyl, pyridinyl, piperidinyl, piperazinyl, azepanyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring;

(b) R x and R y are taken together with their intervening atoms to form a benzo ring or 5-7 membered carbocyclo ring; and

11. The compound according to claim 10 , wherein:

(a) Ring D is selected from a phenyl, pyridinyl, piperidinyl, piperazinyl, azepanyl, or morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring;

(b) R x and R y are taken together with their intervening atoms to form a benzo ring or 5-7 membered carbocyclo ring; and

12. The compound according to claim 10 , wherein said compound has one or more features selected from the group consisting of:

(a) Ring D is selected from phenyl, pyridinyl, piperidinyl, piperazinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl;

(b) R x and R y are taken together with their intervening atoms to form a benzo ring or 5-7 membered carbocyclo ring, wherein said ring formed by R x and R y is substituted with —R, oxo, halo, —OR, —C(═O)R, —CO 2 R, —COCOR, —NO 2 , —CN, —S(O)R, —SO 2 R, —SR, —N(R 4 ) 2 , —CON(R 4 ) 2 , —SO 2 N(R 4 ) 2 , —OC(═O)R, —N(R 4 )COR, —N(R 4 )CO 2 (optionally substituted C 1-6 aliphatic), —N(R 4 )N(R 4 ) 2 , —C═NN(R 4 ) 2 , —C═N—OR, —N(R 4 )CON(R 4 ) 2 , —N(R 4 )SO 2 N(R 4 ) 2 , —N(R 4 )SO 2 R, or —OC(═O)N(R 4 ) 2 ;

(d) each R 5 is independently selected from H, halo, oxo, CN, NO 2 , —N(R 4 ) 2 , —CO 2 R, —CONH(R 4 ), —N(R 4 )COR, —SO 2 N(R 4 ) 2 , —N(R 4 )SO 2 R, —SR, —OR, —C(O)R, or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl, C 6-10 aryl, or C 1-6 aliphatic.

13. The compound according to claim 12 , wherein:

14. The compound according to claim 12 , wherein said compound has one or more features selected from the group consisting of:

(a) R x and R y are taken together with their intervening atoms to form a benzo ring or 6-membered carbocyclo ring, wherein said ring formed by R x and R y is substituted with halo, CN, oxo, C 1-6 alkyl, C 1-6 alkoxy, (C 1-6 alkyl)carbonyl, (C 1-6 alkyl)sulfonyl, mono- or dialkylamino, mono- or dialkylaminocarbonyl, mono- or dialkylaminocarbonyloxy, or 5-6 membered heteroaryl;

(b) each R 5 is independently selected from H, -halo, —CN, -oxo, —SR, —OR, —N(R 4 ) 2 , —C(O)R, or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl, C 6-10 aryl, or C 1-6 aliphatic; and

15. The compound according to claim 14 , wherein:

16. The compound according to claim 1 , wherein said compound is of formula XII:

wherein:

R x and R y are independently selected from T-R 3 , or R x and R y are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-8 membered ring having 1-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, wherein any substitutable carbon on said fused ring is optionally and independently substituted by T-R 3 , and any substitutable nitrogen on said ring is substituted by R 4 ;

T is a valence bond or a C 1-4 alkylidene chain;

R 2 is —R or -T-W—R 6 ;

17. The compound according to claim 16 , wherein said compound has one or more features selected from the group consisting of:

18. The compound according to claim 17 , wherein:

(b) R x is hydrogen or C 1-4 aliphatic and R y is T-R 3 , or R x and R y are taken together with their intervening atoms to form an optionally substituted 5-7 membered unsaturated or partially unsaturated ring having 1-2 ring heteroatoms; and

19. The compound according to claim 17 , wherein said compound has one or more features selected from the group consisting of:

(b) R x is hydrogen or methyl and R y is —R, N(R 4 ) 2 , or —OR, or R x and R y are taken together with their intervening atoms to form a 5-7 membered unsaturated or partially unsaturated ring having 1-2 ring nitrogens, wherein said ring is optionally substituted with —R, halo, oxo, —OR, —C(═O)R, —CO 2 R, —COCOR, —NO 2 , —CN, —S(O)R, —SO 2 R, —SR, —N(R 4 ) 2 , —CON(R 4 ) 2 , —SO 2 N(R 4 ) 2 , —OC(═O)R, —N(R 4 )COR, —N(R 4 )CO 2 (optionally substituted C 1-6 aliphatic), —N(R 4 )N(R 4 ) 2 , —C═NN(R 4 ) 2 , —C═N—OR, —N(R 4 )CON(R 4 ) 2 , —N(R 4 )SO 2 N(R 4 ) 2 , —N(R 4 )SO 2 R, or —OC(═O)N(R 4 ) 2 ;

20. The compound according to claim 19 , wherein:

(b) R x is hydrogen or methyl and R y is —R, N(R 4 ) 2 , or —OR, or R x and R y are taken together with their intervening atoms to form a 5-7 membered unsaturated or partially unsaturated ring having 1-2 ring nitrogens, wherein said ring is substituted with —R, halo, oxo, —OR, —C(═O)R, —CO 2 R, —COCOR, —NO 2 , —CN, —S(O)R, —SO 2 R, —SR, —N(R 4 ) 2 , —CON(R 4 ) 2 , —SO 2 N(R 4 ) 2 , —OC(═O)R, —N(R 4 )COR, —N(R 4 )CO 2 (optionally substituted C 1-6 aliphatic), —N(R 4 )N(R 4 ) 2 , —C═NN(R 4 ) 2 , —C═N—OR, —N(R 4 )CON(R 4 ) 2 , —N(R 4 )SO 2 N(R 4 ) 2 , —N(R 4 )SO 2 R, or —OC(═O)N(R 4 ) 2 ;

21. The compound according to claim 19 , wherein said compound has one or more features selected from the group consisting of:

(a) R x and R y are taken together with their intervening atoms to form a 6-membered unsaturated or partially unsaturated ring having 1-2 ring nitrogens, substituted with halo, CN, oxo, C 1-6 alkyl, C 1-6 alkoxy, (C 1-6 alkyl)carbonyl, (C 1-6 alkyl)sulfonyl, mono- or dialkylamino, mono- or dialkylaminocarbonyl, mono- or dialkylaminocarbonyloxy, or 5-6 membered heteroaryl;

22. The compound according to claim 21 , wherein:

Assignments (3)

RELEASE OF SECURITY INTEREST Recorded Oct 14, 2016

From: MACQUARIE US TRADING LLC

To: VERTEX PHARMACEUTICALS INCORPORATED; VERTEX PHARMACEUTICALS (SAN DIEGO) LLC

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SECURITY INTEREST Recorded Jul 10, 2014

From: VERTEX PHARMACEUTICALS INCORPORATED; VERTEX PHARMACEUTICALS (SAN DIEGO) LLC

To: MACQUARIE US TRADING LLC

Reel/Frame 033292/0311 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 28, 2012

From: BEBBINGTON, DAVID; KNEGTEL, RONALD; BINCH, HAYLEY; GOLEC, JULIAN; LI, PAN; CHARRIER, JEAN-DAMIEN

To: VERTEX PHARMACEUTICALS INCORPORATED

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