Bi-Aryl Meta-Pyrimidine Inhibitors of Kinases

• US 20090286789A1
• Filed: 10/14/2008
• Published: 11/19/2009
• Est. Priority Date: 11/01/2005
• Status: Active Grant

• Current Assignee: Impact Biomedicines, Inc. (Bristol-Myers Squibb Company)
• Original Assignee: TargeGen, Inc. (Sanofi )
• Inventors: Hood, John D., Noronha, Glenn
• Granted Patent: US 8,133,900 B2
• Time in Patent Office: Days
• US Class Current: 514/235.800
• CPC Class Codes: A61K 31/4545 containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• CPC Class Codes: A61K 31/505 Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: C07D 239/42 One nitrogen atom nitro radicals C07D239/30
• CPC Class Codes: C07D 239/48 Two nitrogen atoms
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links

Abstract

The invention provides methods of treating a disease selected from systemic sclerosis, rheumatoid arthritis, mastocytosis, and chronic eosinophilic leukemia comprising administering biaryl meta-pyrimidine compounds having the general structure (A) to a subject in need thereof. The pyrimidine compounds of the invention are capable of inhibiting kinases, such as members of the JAK kinase family, and various other specific receptor and non-receptor kinases.

Claims

1. A method for treating a disease selected from systemic sclerosis, rheumatoid arthritis, mastocytosis, chronic myelogenous leukemia, and chronic eosinophilic leukemia comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound represented by structure (A):

wherein;

X is selected from the group consisting of a bond, O, C═

O, SO₂, and CH₂;

Y is selected from the group consisting of a bond or NR⁹;

or X and Y taken together is a bond;

R⁹ is selected from H and C₁-C₆ alkyl;

each of R¹ and R² is independently selected from H and C₁-C₆ alkyl optionally substituted by halogen, amino or hydroxyl;

each of p, q, and n is independently selected from 0, 1, 2, 3, 4, 5, and 6;

G₀ is N, CH, or C,

wherein when G₀ is N;

each of R^J and R⁴, taken together with G₀, form a heterocyclic ring, wherein the formed heterocyclic ring is optionally substituted by one or two substitutents each independently selected from the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, hydroxyl, or carboxyl, and

wherein when G₀═

C, then R³ and R⁴, taken together with G₀, form an aromatic heterocyclic ring, and wherein when G₀═

CH, then R³ and R⁴, taken together with G₀, form a heterocyclic ring wherein the formed heterocyclic ring is optionally substituted by one or two substitutents each independently selected from the group consisting of halogen, C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, hydroxyl, or carboxyl;

G is N or CR^6′

where each R^6′

is independent of each other group R^6′

, and each G is independent of each other G, wherein not more than two groups G can be N;

R^6′

is selected from the group consisting of H, halogen, C(O)—

O-alkyl, alkyl, alkoxy, and haloalkyl or R^6′

is a bond when bonded to X;

A is selected from the group consisting of O, NR⁹, CH₂, S, SO, and SO₂;

R⁵ is methyl;

wherein each of R⁶, R⁷, R⁸ is independently selected for each occurrence from the group consisting of H, C₁-C₆ alkyl optionally substituted with halogen, amino, or hydroxyl, C₁-C₆ substituted or unsubstituted alkenyl, C₁-C₆ substituted or unsubstituted alkynyl, C₁-C₆ alkoxy optionally substituted by one, two, three or more halogens, SO₂H, SO₂(C₁-C₆ alkyl). SO₂-heterocycle, SO₂-cycloalkyl, SO₂NH₂, SO₂NH(C₁-C₆ alkyl), SO₂N(C₁-C₆ alkyl)(C₁-C₆ alkyl), SO₂NH(C₁-C₆ cycloalkyl), SO₂NH-heterocycle, SO₂NH(C₁-C₆ branched alkyl), NR⁹, NO₂, CN, OH, CONH₂, CO—

(C₁-C₆ alkyl), COOH, COO—

(C₁-C₆ alkyl), NHCO—

(C₁-C₆ alkyl), NHCONH-phenyl optionally substituted halogen, alkyl or haloalkyl, or heterocycle optionally substituted with halogen, alkyl, or hydroxyalkyl, or R⁶ and R⁷ taken together, or R⁷ and R⁸ taken together, or R⁶ and R⁸ taken together form a fused heterocylic ring, wherein the ring may be optionally substituted by halogen, alkyl, alkoxy, hydroxyl, or cyano;

G₁ is selected from the group consisting of CM, N, NH, S, and O;

G₂ is selected from the group consisting of CR⁷, N, NH, S, and O, with each group R⁷ being independent of every other group R⁷;

or pharmaceutically acceptable salts, or N-oxides, thereof.

2. The method of claim 1, wherein A is NH, and G, G₁ and G₂ are each CR^6′

.

3. The method of claim 2, wherein R₇ is SO₂NH(t-butyl).

4. The method of claim 2, wherein G₀ is N, and R³ and R⁴ are taken together with G₀ to form a heterocyclic ring.

5. The method of claim 4, wherein R₃ and R₄ form a non-aromatic heterocyclic ring.

6. The method of claim 4, wherein X and Y taken together is a bond, p, q, and n are each 0, and the heterocyclic ring is a piperazinyl substituted with methyl.

7. The method of claim 5, wherein the compound of structure (A) is

8. The method of claim 4, wherein X is O, Y is a bond, p is 0, q and n are each 1, and the heterocyclic ring is an unsubstituted pyrrolidinyl.

9. The method of claim 8, wherein the compound of structure (A) is

10. The method of claim 1, wherein R⁶, R⁷ and R⁸ are each independently selected from the group consisting of OH, methyl, ethyl, t-butyl, n-butyl, —

CF₃, —

OCF₃, —

OCH₃, —

S(O₂)—

NH−

/−

butyl, —

NH—

C(O)—

CH₃, or —

NH—

C(O)—

NH-phenyl.

12. The method of claim 1, wherein the at least one compound of structure (A) and/or its N-oxides, or pharmaceutically acceptable salts thereof, is in the form of a pharmaceutical composition which comprises a pharmaceutically acceptable carrier.

13. The method of claim 12, further comprising administration of an anti-inflammatory agent or an immunomodulatory agent.

14. The method of claim 1, wherein the disease is systemic scleroderma.

15. The method of claim 1, wherein the disease is rheumatoid arthritis.

16. The method of claim 1, wherein the disease is mastocytosis.

17. The method of claim 1, wherein the disease is drug resistant chronic myelogenous leukemia.

18. The method of claim 1, wherein the disease is chronic eosinophilic leukemia.

11. A method for treating a disease selected from systemic sclerosis, rheumatoid arthritis, mastocytosis, chronic myelogenous leukemia, and chronic eosinophilic leukemia comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound comprising a first moiety chemically connected to a second moiety, or pharmaceutically acceptable salts or N-oxides thereof, wherein the first moiety is selected from the group consisting of:

and wherein the second moiety is selected from the group consisting of;

19. A method of treating systemic sclerosis, comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by:

or its pharmaceutically acceptable salts or N-oxides.

20. A method of treating rheumatoid arthritis, comprising administering to a subject in need thereof a therapeutically effective amount of:

or its pharmaceutically acceptable salts or N-oxides.