# US 8,785,444 B2 · Thiazoles and pyrazoles useful as kinase inhibitors

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- Number: US 8,785,444 B2
- Document ID: US8785444B2
- Status: Granted
- Kind: B2
- Application number: 13/564,838
- Filed: 2012-08-02
- Published: 2013-05-09
- Granted: 2014-07-22
- Earliest claimed: 2007-05-02
- Assignees: Vertex Pharmaceuticals Incorporated
- Applicants: Michael Mortimore; Julian Golec; Christopher Davis; Daniel Robinson; John Studley
- Inventors: Michael Mortimore; Julian Golec; Christopher Davis; Daniel Robinson; John Studley
- Web page: https://patentgrep.com/patent/US8785444B2

## CPC

- C07D 417/14: containing three or more hetero rings
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 401/14: containing three or more hetero rings
- 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 Aurora protein kinases. The invention also provides pharmaceutically acceptable compositions comprising those compounds and methods of using the compounds and compositions in the treatment of various disease, conditions, and disorders. The invention also provides processes for preparing compounds of the invention.

## Claims

### Claim 1

A compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
X1 is N or CH;
X2 is N or CH;
X3 is N;
provided that at least one of X1 and X2 is nitrogen;
Ht is thiazole or pyrazole, wherein each ring is optionally and independently substituted with R2 and R2′;
Q is —O—, —NR′—, —S—, —C(═O)—, or —C(R′)2—;
RX is H or F;
RY is —Z—R10;
R1 is T-(Ring D);
Ring D is a 5-7 membered monocyclic aryl or heteroaryl ring, wherein said heteroaryl has 1-4 ring heteroatoms selected from O, N, and S; Ring D can optionally be fused with Ring D′;
Ring D′ is a 5-8 aromatic, partially saturated, or fully unsaturated ring containing 0-4 ring heteroatoms selected from nitrogen, oxygen or sulfur;
Ring D and Ring D′ are each independently and optionally substituted with 0-4 occurrences of oxo or —W—R5;
each T is independently a C1-4 alkylidene chain or is absent;
R2 is H, C1-3 alkyl, or cyclopropyl;
R2′ is H;
each Z and W is independently a bond or a C1-10 alkylidene chain wherein up to six methylene units of the alkylidene chain are optionally replaced by V;
each V is selected from —O—, —C(═O)—, —S(O)—, —S(O)2—, —S—, or —N(R4)—;
each R5 is independently —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(R)COR, —N(R7)CO2(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 hydrogen, a C1-6 aliphatic group, a C6-10 aryl ring, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 4-10 ring atoms; wherein said heteroaryl or heterocyclyl ring has 1-4 ring heteroatoms selected from nitrogen, oxygen, or sulfur; R is optionally substituted with 0-6 R9;
each R4 is —R7, —COR7, —CO2R7, —CON(R7)2, or —SO2R7;
each R6 is independently hydrogen or C1-6 alkyl;
each R7 is independently hydrogen or an optionally substituted C1-6 aliphatic group; or two R7 on the same nitrogen are taken together with the nitrogen to form an optionally substituted 4-8 membered heterocyclyl or heteroaryl ring containing 1-4 heteroatoms selected from nitrogen, oxygen, or sulfur;
each R9 is —R′, -halo, —OR′, —C(═O)R′, —CO2R′, —COCOR′, COCH2COR′, —NO2, —CN, —S(O)R′, —S(O)2R′, —SR′, —N(R′)2, —CON(R′)2, —SO2N(R′)2, —OC(═O)R′, —N(R′)COR′, —N(R′)CO2(C1-6 aliphatic), —N(R′)N(R′)2, —N(R′)CON(R′)2, —N(R′)SO2N(R′)2, —N(R′)SO2R′, —OC(═O)N(R′)2, ═NN(R′)2, ═N—OR′, or ═O;
each R10 is a 4-membered heterocyclic ring containing 1 heteroatom selected from O, N, and S; each R10 is optionally substituted with 0-6 occurrences of J;
each J is independently R, -halo, —OR, oxo, —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(C1-6 aliphatic), —N(R4)N(R4)2, ═NN(R4)2, ═N—OR, —N(R7)CON(R7)2, —N(R7)SO2N(R7)2, —N(R4)SO2R, —OC(═O)N(R7)2, or —OP(═O)(OR″)2; or
2 J groups, on the same atom or on different atoms, together with the atom(s) to which they are bound, form a 3-8 membered saturated, partially saturated, or unsaturated ring having 0-2 heteroatoms selected from O, N, or S; wherein 1-4 hydrogen atoms on the ring formed by the 2 J groups is optionally replaced with halo, C1-3alkyl, or —O(C1-3alkyl); or two hydrogen atoms on the ring are optionally replaced with oxo or a spiro-attached C3-4 cycloalkyl; wherein said C1-3alkyl is optionally substituted with 1-3 fluorine;
each R′ is independently hydrogen or a C1-6 aliphatic group; or two R′, together with atom(s) to which they are bound, form a 3-6 membered carbocyclyl or a 3-6 membered heterocyclyl containing 0-1 heteroatoms selected from O, N, and S; and
each R″ is independently H or C1-2alkyl.

### Claim 2 (depends on 1)

The compound of claim 1, wherein X1 is N.

### Claim 3 (depends on 1)

The compound of claim 1, wherein X1 is CH.

### Claim 4 (depends on 1)

The compound of claim 1, wherein X2 is N.

### Claim 5 (depends on 1)

The compound of claim 1, wherein X2 is CH.

### Claim 6 (depends on 1)

The compound of claim 1 selected from a compound of formula I-a, I-d, or I-e:

### Claim 7 (depends on 6)

The compound of claim 6 selected from a compound of formula I-a.

### Claim 8 (depends on 1)

The compound of claim 1, wherein Ht is

### Claim 9 (depends on 8)

The compound of claim 8, wherein Q is —S—.

### Claim 10 (depends on 8)

The compound of claim 8, wherein Q is —O—.

### Claim 11 (depends on 9, 10)

The compound of any one of claim 9 or 10, wherein R2 is H or C1-3 alkyl.

### Claim 12 (depends on 9, 10)

The compound of any one of claim 9 or 10, wherein RX is H.

### Claim 13 (depends on 1)

The compound of claim 1, wherein Ring D is a 5-6 membered monocyclic aryl or heteroaryl ring; and Ring D is fused with Ring D′.

### Claim 14 (depends on 1)

The compound of claim 1, wherein Ring D-D′ is an 8-12 membered bicyclic aryl or heteroaryl containing 1-5 heteroatoms selected from nitrogen, oxygen, or sulfur.

### Claim 15 (depends on 1)

The compound of claim 1, wherein Ring D is a 5-6 membered monocyclic aryl or heteroaryl ring; and wherein D is not fused with D′.

### Claim 16 (depends on 15)

The compound of claim 15, wherein Ring D is a 6-membered monocyclic aryl or heteroaryl ring.

### Claim 17 (depends on 16)

The compound of claim 16, wherein Ring D is phenyl or pyridyl.

### Claim 18 (depends on 17)

The compound of claim 17, wherein Ring D is phenyl.

### Claim 19 (depends on 1)

The compound of claim 1, wherein RY is —Z—R10.

### Claim 20 (depends on 19)

The compound of claim 19, wherein Z is absent.

### Claim 21 (depends on 19)

The compound of claim 19, wherein Z is a C1-6 alkylidene chain wherein 1-2 methylene units of Z is optionally replaced by O, —N(R6)—, or S.

### Claim 22 (depends on 19, 20, 21)

The compound of any one of claims 19-21, wherein R10 is an optionally substituted azetidine.

### Claim 23 (depends on 1)

A composition comprising a compound of formula I:
or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein the variables are defined according to claim 1.