# US 8,541,445 B2 · Pyrazolopyridines

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- Number: US 8,541,445 B2
- Document ID: US8541445B2
- Status: Granted
- Kind: B2
- Application number: 13/289,320
- Filed: 2011-11-04
- Published: 2012-07-12
- Granted: 2013-09-24
- Earliest claimed: 2009-05-06
- Assignees: Vertex Pharmaceuticals Incorporated
- Applicants: Juan-Miguel Jimenez; Philip Collier
- Inventors: Juan-Miguel Jimenez; Philip Collier
- Web page: https://patentgrep.com/patent/US8541445B2

## CPC

- C07D 471/04: Ortho-condensed systems
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 11/06: Antiasthmatics
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to compounds useful as inhibitors of protein kinase. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders. The invention also provides processes for preparing compounds of the inventions.

## Claims

### Claim 1

A compound represented by structural formula I or IA:
or a pharmaceutically acceptable salt thereof wherein:
each ring A is independently a five membered heteroaromatic ring,
ring B is five- or six-membered saturated carbocyclic or heterocyclic ring;
R2 is —H, —(CR++2)nCN, —(CR++2)nC(O)N(R*)2, —(CR++2)nOR*, —(CR++2)nN(R*)2, —(CR++2)nN(R*)C(O)R*, or C1-10 aliphatic optionally substituted with one or more halogen, or phenyl;
each R3 and R4 independently are —H, halogen, C1-10 aliphatic, heterocyclyl, heterocyclylalkyl, aryl, or aralkyl, wherein R3 and R4 are optionally and independently substituted with one or more selected from the group consisting of C1-10 alkyl, halogen, —CN, —NO2, —N(R*)2, —S(O)pR*, —S(O)pNR*, —C(O)N(R*)2, —NR*C(O), —OC(O)N(R*)2, —N(R*)C(O)OR*, —N(R*)C(O)N(R*)2 and —OR*; or
R3 and R4 taken together with the carbon to which they are attached form C═O, or a 3-8 membered saturated, partially saturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from the groups consisting of O, N, and S, wherein the ring is optionally and independently substituted with one or more selected from the group consisting of ═O, ═S, ═N—R*, C1-10 aliphatic, C1-10 haloaliphatic, halogen, —CN, —NO2, —N(R*)2, —S(O)pR*, —S(O)pNR*, —C(O)N(R*)2, —NR*C(O), —OC(O)N(R*)2, —N(R*)C(O)OR*, —N(R*)C(O)N(R*)2 and —OR*;
each R5 and R6 are independently —H, halogen, C1-10 haloaliphatic, or C1-10 aliphatic;
each R7 is independently C1-10 haloaliphatic, C1-10 aliphatic, halogen, —NO2, —(CR++2)nCN, —(CR++2)nN(R**)2, —(CR++2)nOR**, or —(CR++2)nC(O)N(R**)2, or two R7 groups together with the carbon to which they are attached form C═O;
each R++ is independently —H or halogen;
each R* is independently —H or C1-10 alkyl or aralkyl optionally and independently substituted with up to five halogen groups;
each R** is independently —H or C1-10 alkyl optionally and independently substituted with up to five halogen groups;
each n is independently 0, or 1-10; and
each p is independently 0, 1, or 2.

### Claim 2 (depends on 1)

The compound of claim 1 wherein the structural formula is represented by Formula I.

### Claim 3 (depends on 1)

The compounds of claim 1 wherein:
R2 is —H, —(CR++2)nCN, —(CR++2)nC(O)N(R*)2, —(CR++2)nOR*, —(CR++2)nN(R*)2, or C1-3 aliphatic optionally substituted with one or more halogen.

### Claim 4 (depends on 3)

The compound of claim 3 wherein:
each R3 and R4 independently is —H, C1-10 aliphatic, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, or aralkyl wherein R3 and R4 are optionally and independently substituted with one or more selected from the group consisting of halogen, —CN, —NO2, —N(R*)2, and —OR*; or
R3 and R4 taken together with the carbon to which they are attached form C═O, or a 3-8 membered saturated, partially saturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from the groups consisting of O, N, and S, wherein the ring is optionally and independently substituted with one or more selected from the group consisting of ═O, ═S, C1-10 aliphatic, C1-10 haloaliphatic, halogen, —CN, —N(R*)2, and —OR*.

### Claim 5 (depends on 4)

The compound of claim 4 wherein:
each R3 and R4 independently is —H, C1-10 aliphatic, cycloalkylalkyl, wherein R3 and R4 are optionally and independently substituted with one or more selected from the group consisting of halogen, —CN, —NO2, —N(R*)2, and —OR*; or
R3 and R4 taken together with the carbon to which they are attached form C═O, or a 3-8 membered saturated, partially saturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from the groups consisting of O, N, and S, wherein the ring is optionally and independently substituted with one or more selected from the group consisting of C1-10 aliphatic, C1-10 haloaliphatic, halogen, —CN, —N(R*)2, and —OR*.

### Claim 6 (depends on 2)

The compounds of claim 2 wherein:
R2 is —H, —(CR++2)nCN, —(CR++2)nOR*, —(CR++2)nN(R*)2, or C1-3 aliphatic optionally substituted with one or more halogen.

### Claim 7 (depends on 6)

The compound of claim 6 wherein:
R2 is —H, —(CR++2)nCN, —(CR++2)nOR*, —(CR++2)nN(R*)2, or C1-3 aliphatic optionally substituted with one or more halogen; and
R3 and R4 taken together with the carbon to which they are attached form a 3-8 membered saturated, or partially saturated monocyclic ring having 0-3 heteroatoms independently selected from the groups consisting of O, N, and S, wherein the ring is optionally and independently substituted with one or more selected from the group consisting of ═O, ═S, C1-10 aliphatic, C1-10 haloaliphatic, halogen, —CN, —N(R*)2, and —OR*.

### Claim 8 (depends on 7)

The compound of claim 7 wherein:
R2 is —H, —(CR++2)nCN, —(CR++2)nOR*, —(CR++2)nN(R*)2, or C1-3 aliphatic optionally substituted with one or more halogen; and
R3 and R4 taken together with the carbon to which they are attached form a monocyclic ring selected from the group consisting of cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, diazepanyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, imidazolinyl, thiazolidinyl, or oxazolidinyl, wherein the ring is optionally and independently substituted with one or more selected from the group consisting of ═O, ═S, C1-10 aliphatic, C1-10 haloaliphatic, halogen, —CN, —N(R*)2, and —OR*.

### Claim 9 (depends on 8)

The compound of claim 8 wherein:
R2 is —H, —(CR++2)nCN, —(CR++2)nOR*, —(CR++2)nN(R*)2, or C1-3 aliphatic optionally substituted with one or more halogen; and
R3 and R4 taken together with the carbon to which they are attached form a monocyclic ring selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, diazepanyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, imidazolinyl, thiazolidinyl, or oxazolidinyl, wherein the ring is optionally and independently substituted with one or more selected from the group consisting of ═O, ═S, C1-10 aliphatic, C1-10 haloaliphatic, halogen, —CN, —N(R*)2, and —OR*.

### Claim 10 (depends on 8)

The compound of claim 8 wherein:
R2 is —H, —(CR++2)nCN, —(CR++2)nOR*, —(CR++2)nN(R*)2, or C1-3 aliphatic optionally substituted with one or more halogen; and
R3 and R4 taken together with the carbon to which they are attached form a monocyclic ring selected from the group consisting of cyclopropyl, cyclobutyl, cyclohexyl, or cyclopentyl, wherein the ring is optionally and independently substituted with one or more selected from the group consisting of ═O, ═S, C1-10 aliphatic, C1-10 haloaliphatic, halogen, —CN, —N(R*)2, and —OR*.

### Claim 11 (depends on 8)

The compounds of claim 8 wherein:
R2 is —H, —(CR++2)nCN, —(CR++2)nOR*, —(CR++2)nN(R*)2, or C1-3 aliphatic optionally substituted with one or more halogen; and
each R3 and R4 independently is —H, C1-10 aliphatic, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, or aralkyl wherein R3 and R4 are optionally and independently substituted with one or more selected from the group consisting of halogen, —CN, —NO2, —N(R*)2, and —OR*.

### Claim 12 (depends on 1)

The compounds of claim 1 wherein
R5 is —H, Cl, C1-4 haloalkyl, or C1-4 alkyl; and
R6 is —H or C1-4 alkyl.

### Claim 13 (depends on 12)

The compounds of claim 12 wherein
R5 is —H, Cl, trifluoromethyl, methyl, ethyl, or cyclopropyl; and
R6 is —H.

### Claim 14 (depends on 13)

The compounds of claim 13 wherein
R5 is trifluoromethyl; and
R6 is —H.

### Claim 15 (depends on 14)

The compound of claim 14 wherein:
each R7 is independently C1-10 aliphatic, C1-10 haloaliphatic, halogen, —CN, —N(R**)2, or —OR**; or two R7 groups together with the carbon to which they are attached form C═O.

### Claim 16

A compound represented by a structural formula selected from the group consisting of:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
or a pharmaceutically acceptable salt thereof.

### Claim 17 (depends on 1)

A composition comprising a compound or pharmaceutically acceptable salt thereof according to claim 1, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.