KINASE INHIBITORS

• US 20090291937A1
• Filed: 10/31/2008
• Published: 11/26/2009
• Est. Priority Date: 11/02/2007
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Twin, Heather, Keily, Shazia, Mak, Chau, Jimenez, Juan-Miguel, Young, Stephen, Davis, Chris, Miller, Andrew, Boyall, Dean, Mortimore, Michael, Settimo, Luca, Collier, Philip, Brenchley, Guy
• Granted Patent: US 8,173,635 B2
• Time in Patent Office: Days
• US Class Current: 514/210.21
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/04 for non-specific disorders of the connective tissue
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

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

1. A compound represented by structural formula I or IA:

or a pharmaceutically acceptable salt thereof wherein;

A and A′

are independently —

N—

or —

C(R⁺)—

;

ring B is five- or six-membered saturated carbocyclic or heterocyclic ring;

R₁ is halogen, —

CN, —

NO₂, or -T1-Q1;

T1 is absent or a C1-10 aliphatic wherein one or more methylene units of T1 are optionally and independently replaced by G wherein G is —

O—

, —

S(O)_p—

, —

N(R′

)—

, or —

C(O)—

; and

T1 is optionally and independently substituted with one or more J_T1;

Q1 is absent 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, or an 8-12 membered saturated, partially saturated, or fully unsaturated bicyclic ring having 0-5 heteroatoms independently selected from the group consisting of O, N, and S, wherein Q1 is optionally and independently substituted with one or more J_Q1;

wherein when R₁ is T1-Q1, then T1 and Q1 are not both absent;

R₂ is —

H, —

(CR⁺⁺₂)_nCN, —

(CR⁺⁺₂)_nN(R)₂, —

(CR⁺⁺₂)_nOR, —

(CR⁺⁺₂)_nC(O)N(R)₂, or C1-10 aliphatic optionally substituted with one or more halogen, phenyl, OR*, or N(R*)₂;

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)NR*, —

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 J_T1 is independently halogen, —

OR̂

, —

N(R̂

)₂, or —

CN;

each J_Q1 is independently halogen, C1-10 alkyl, C1-10 haloalkyl, —

OR″

, —

N(R″

)₂, —

CN, —

NO₂, —

S(O)_pR″

, —

S(O)_pNR″

, acyl, carbalkoxyalkyl, or acetoxyalkyl;

each R⁺ is independently —

H, halogen, or C1-10 alkyl optionally and independently substituted with up to five halogen groups;

each R⁺⁺ is independently —

H or halogen;

each R′

is independently —

H or C1-10 alkyl optionally and independently substituted with up to five halogen groups;

each R̂

is independently —

H, C1-10 alkyl, or aralkyl wherein each R̂

is 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 R is independently —

H or C1-10 alkyl 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 R** is independently —

H or C1-10 alkyl optionally and independently substituted with up to five halogen groups;

x is 0 or 1;

y is 0, 1 or 2;

each n is independently 0, 1, 2, or 3; and

each p is independently 0, 1, or 2.

2. The compound of claim 1, wherein:

R₂ is —

H, —

(CR⁺⁺₂)_nCN, —

(CR⁺⁺₂)_nN(R)₂, —

(CR⁺⁺₂)_nOR, —

(CR⁺⁺₂)_nC(O)N(R)₂, or C1-10 aliphatic optionally substituted with one or more halogen, OR*, or N(R*)₂.

3. The compound of claim 2, represented by structural formula I or IA:

or a pharmaceutically acceptable salt thereof wherein;

A and A′

are independently —

N—

or —

C(R⁻

)—

;

ring B is five- or six-membered saturated carbocyclic or heterocyclic ring;

R₁ is halogen, —

CN, —

NO₂, or -T1-Q1;

T1 is absent or a C1-10 aliphatic wherein up to three methylene units of T1 are optionally and independently replaced by G wherein G is —

O—

, —

S(O)_p—

, —

N(R′

)—

, or —

C(O)—

; and

T1 is optionally and independently substituted with one or more J_T1;

Q1 is absent 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, or an 8-12 membered saturated, partially saturated, or fully unsaturated bicyclic ring having 0-5 heteroatoms independently selected from the group consisting of O, N, and S, wherein Q1 is optionally and independently substituted with one or more J_Q1;

wherein when R₁ is T1-Q1, then T1 and Q1 are not both absent;

R₂ is —

H, C1-10 aliphatic, —

(CR⁺⁺₂)_nCN, —

(CR⁺⁺₂)_nN(R)₂, —

(CR⁺⁺₂)_nOR, or —

(CR⁺⁺₂)_nC(O)N(R)₂;

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 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 J_T1 is independently halogen, —

OR̂

, —

N(R̂

)₂, or —

CN;

each J_Q1 is independently halogen, C1-10 alkyl, C1-10 haloalkyl, —

OR″

, —

N(R″

)₂, —

CN, —

NO₂, —

S(O)_pR″

, —

S(O)_pNR″

, acyl, carbalkoxyalkyl, or acetoxyalkyl;

each R⁺ is independently —

H, halogen, or C1-10 alkyl optionally and independently substituted with up to five halogen groups;

each R⁺⁺ is independently —

H or halogen;

each R′

is independently —

H or C1-10 alkyl, optionally and independently substituted with up to five halogen groups;

each R̂

is independently —

H or C1-10 alkyl, 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 R is independently —

H or C1-10 alkyl, 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 R** is independently —

H or C1-10 alkyl, optionally and independently substituted with up to five halogen groups;

x is 0 or 1;

y is 0, 1 or 2;

each n is independently 0, 1, 2, or 3; and

each p is independently 0, 1, or 2.

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

5. The compound of claim 4 wherein:

A is —

N—

or —

C(R⁺)—

; and

A′

is —

C(R⁺)—

.

6. The compound of claim 5 wherein:

R⁺ is —

H.

7. The compound of claim 6 wherein:

R₁ is halogen, or -T1-Q1.

8. The compound of claim 7 wherein:

T1 is absent or a C1-10 aliphatic wherein up to three methylene units of T1 are optionally and independently replaced by G wherein G is —

O—

, —

N(R′

)—

, or —

C(O)—

; and

T1 is optionally and independently substituted with one or more J_T1.

9. The compound of claim 8 wherein:

Q1 is absent 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 Q1 is optionally and independently substituted with one or more J_Q1.

10. The compound of claim 9 wherein:

each J_T1 is independently —

OR̂

, —

N(R̂

)₂, or —

CN.

11. The compound of claim 10 wherein:

each J_Q1 is independently C1-10 alkyl, —

OR″

, —

N(R″

)₂, or acyl.

12. The compounds of claim 11 wherein:

R₂ is C1-10 aliphatic, —

(CR⁺⁺₂)_nCN, —

(CR⁺⁺₂)_nN(R)₂, —

(CR⁺⁺₂)_nOR, or —

(CR⁺⁺₂)_nC(O)N(R)₂.

13. The compound of claim 11 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*.

14. The compound of claim 11 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*.

15. The compound of claim 13 wherein:

A is —

C(R⁺)—

.

16. The compound of claim 15 wherein:

J_T1 is —

OR̂

.

17. The compound of claim 15 wherein:

R₂ is —

H, C1-10 aliphatic, —

(CR⁺⁺₂)_nCN, —

(CR⁺⁺₂)_nN(R)₂, or —

(CR⁺⁺₂)_nOR.

18. The compound of claim 17 wherein the compound is represented by structural formula IB:

or a pharmaceutically acceptable salt thereof.

19. The compound of claim 18 wherein:

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*.

20. The compound of claim 18 wherein:

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*.

21. The compound of claim 20 wherein:

R₂ is —

H, or C1-10 aliphatic; 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*.

22. The compound of claim 20 wherein:

R₂ is —

(CR⁺⁺₂)_nCN, —

(CR⁺⁺₂)_nN(R)₂, or —

(CR⁺⁺₂)_nOR.

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*.

23. The compound of claim 19 wherein:

R₂ is —

H, C1-10 aliphatic, —

(CR⁺⁺₂)_nCN, —

(CR⁺⁺₂)_nN(R)₂, —

(CR⁺⁺₂)_nOR, or —

(CR⁺⁺₂)_nC(O)N(R)₂; 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*.

24. The compound of claims 21-23 wherein

R₅ is —

H, C1, C1-4 haloalkyl, or C1-4 alkyl; and

R₆ is —

H or C1-4 alkyl.

25. The compound of claim 24 wherein

R₅ is —

H, Cl, trifluoromethyl, methyl, ethyl, or cyclopropyl; and

R₆ is —

H.

26. The compound of claim 25 wherein the compound is represented by structural formula IC:

or a pharmaceutically acceptable salt thereof.

27. The compound of any one of claims 1, 2 or 3 wherein the structural formula is represented by Formula IA.

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

43. A process for preparing a compound of claim 1 comprising:

a) boronation of a compound represented by a structural formula selected from the group consisting of;

in the presence of a boronation agent and a solvent, to give a compound represented by a structural formula selected from the group consisting of;

wherein;

each R^X is —

H or two R^Xs together form

b) cyclization of a compound represented by the following structural formula;

in the presence of hydrazine and a solvent to give a compound represented by the following structural formula;

c) suzuki coupling of the compound represented by formula ii or iia with a compound represented by formula iv in the presence of a solvent, a catalyst complex and a base to give a compound of claim 1.

56. A process for preparing a compound of claim 1, comprising:

a) cyclization of compound represented by represented by the following structural formula;

in the presence of hydrazine and a solvent to give a compound represented by the following structural formula;

b) protection of a compound represented by iv to give a compound represented by the following structural formula;

c) boronation of a compound represented by v in the presence of a boronation agent and a solvent to give a compound represented by represented by the following structural formula;

wherein;

each R^X is —

H or two R^Xs together form

d) suzuki coupling of the compound represented by formula vi with a compound represented a structural formula selected from the groups consisting of;

in the presence of solvent, a catalyst complex and a base to give a compound represented by a structural formula selected from the group consisting of;

e) deprotection of the compound represented by vii or viia in the presence of hydrazine to yield a compound of claim 1.

69. A method of treating or preventing a protein kinase-mediated condition in a subject in need thereof, comprising administering to the subject an effective amount of a compound or pharmaceutically acceptable salt thereof or composition of any one of claims 1 or 42.

70. The method of claim 69, wherein the protein kinase-mediated condition is a PKC mediated condition.

71. The method of claim 70, wherein the PKC-mediated condition is a PKCtheta mediated condition.

72. The method of claim 71, wherein the PKCtheta mediated condition is an autoimmune disease, an inflammatory disease or a proliferative or hyperproliferative disease.

73. The method of claim 72, wherein the PKCtheta mediated condition is selected from the group consisting of asthma, psoriasis, arthritis, rheumatoid arthritis, joint inflammation, multiple sclerosis, diabetes, inflammatory bowel disease, transplant rejection, T-cell leukaemias, lymphomas, and lupus.

74. The method of claim 71, wherein the PKCtheta mediated condition is an autoimmune disease.

75. The method of claim 74, wherein the autoimmune disease is selected from the group consisting of multiple sclerosis, rheumatoid arthritis, irritable bowel disease

76. The method of claim 75, wherein the autoimmune disease is multiple sclerosis.

77. The method of claim 75, wherein the autoimmune disease is rheumatoid arthritis.

78. The method of claim 75, wherein the autoimmune disease is irritable bowel disease.

79. The method of claim 72, wherein the PKCtheta mediated condition is selected from the group consisting of T-cell leukaemia and lymphoma.

28-40. -40. (canceled)

41. 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 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330

or a pharmaceutically acceptable salt thereof.

44-55. -55. (canceled)

57-68. -68. (canceled)