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Details for Patent: 8,957,081

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Details for Patent: 8,957,081

Title:Compounds and compositions as protein kinase inhibitors
Abstract: The invention provides novel pyrimidine and pyridine derivatives and pharmaceutical compositions thereof, and methods for using such compounds. For example, the pyrimidine and pyridine derivatives of the invention may be used to treat, ameliorate or prevent a condition which responds to inhibition of anaplastic lymphoma kinase (ALK) activity, focal adhesion kinase (FAK), zeta-chain-associated protein kinase 70 (ZAP-70), insulin-like growth factor (IGF-1R), or a combination thereof.
Inventor(s): Michellys; Pierre-Yves (San Marcos, CA), Pei; Wei (San Diego, CA), Marsilje, III; Thomas H. (San Diego, CA), Chen; Bei (San Diego, CA), Uno; Tetsuo (San Diego, CA), Jin; Yunho (San Diego, CA), Jiang; Tao (San Diego, CA)
Assignee: IRM LLC (Hamilton, BM)
Filing Date:Sep 11, 2012
Application Number:13/610,422
Claims:1. A combination comprising a chemotherapeutic agent and a compound of Formula (1), ##STR00363## or a pharmaceutically acceptable salt thereof; wherein W is ##STR00364## A.sup.1 and A.sup.4 are independently C; each A.sup.2 and A.sup.3 is C; R.sup.1 and R.sup.2 together form an optionally substituted 5-6 membered aryl, or heteroaryl or heterocyclic ring comprising 1-3 nitrogen atoms; R.sup.3 is (CR.sub.2).sub.0-2SO.sub.2R.sup.12, (CR.sub.2).sub.0-2SO.sub.2NRR.sup.12, (CR.sub.2).sub.0-2C(O)O.sub.0-1R.sup.12, (CR.sub.2).sub.0-2CONRR.sup.12, CO.sub.2NH.sub.2, or cyano; R.sup.4, R.sup.7 and R.sup.10 are independently H; R, R.sup.5 and R.sup.5'are independently H or C.sub.1-6 alkyl; R.sup.6 is halo or O(C.sub.1-6 alkyl); R.sup.8 and R.sup.9 are independently C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, halo or X, or one of R.sup.8 and R.sup.9 is H; and provided one of R.sup.8 and R.sup.9 is X; X is (CR.sub.2).sub.qY, cyano, C(O)O.sub.0-1 R.sup.12, CONR(R.sup.12), CONR(CR.sub.2).sub.pNR(R.sup.12), CONR(CR.sub.2).sub.pOR.sup.12, CONR(CR.sub.2).sub.pSR.sup.12, CONR(CR.sub.2).sub.pS(O).sub.1-2R.sup.12 or (CR.sub.2).sub.1-.sub.6NR(CR.sub.2).sub.pOR.sup.12; Y is an optionally substituted 3-12 membered carbocyclic ring, a 5-12 membered aryl, or a 5-12 membered heteroaryl or heterocyclic ring comprising N, O and/or S and attached to A.sup.2 or A.sup.3 or both via a carbon atom of said heteroaryl or heterocyclic ring when q in (CR.sub.2).sub.qY is 0; R.sup.12 is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring, or a 5-7 membered heterocyclic ring comprising N, O and/or S; aryl or heteroaryl; or R.sup.12 is H, C.sub.1-6 alkyl; and n is 0; and p and q are independently 0-4.

2. The combination of claim 1, wherein R.sup.3 in said compound of Formula (1) is SO.sub.2R.sup.12, SO.sub.2NH.sub.2, SO.sub.2NRR.sup.12, CO.sub.2NH.sub.2, CONRR.sup.12, C(O)O.sub.0-1R.sup.12, or cyano; and R.sup.12 is C.sub.1-6 alkyl, an optionally substituted C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkenyl, pyrrolidinyl, piperazinyl, piperidinyl or morpholinyl.

3. The combination of claim 1, wherein said compound of Formula (1) is selected from the group consisting of TABLE-US-00005 203 ##STR00365## N2-(2-isopropoxy-5-methyl-4-(piperidin- 4-yl)phenyl)-N4-(2- (methylsulfonyl)phenyl)-7H-pyrrolo[2,3- d]pyrimidine-2,4-diamine; 204 ##STR00366## N2-(4-(1-ethylpiperidin-4-yl)-2- isopropoxy-5-methylphenyl)-N4-(2- (isopropylsulfonyl)phenyl)-7H- pyrrolo[2,3-d]pyrimidine-2,4-diamine; 205 ##STR00367## 2-(4-(5-isopropoxy-4-(4-(2- (isopropylsulfonyl) phenylamino)-7H- pyrrolo[2,3-d]pyrimidin-2-ylamino)-2- methylphenyl)piperidin-1-yl)propan-1-ol; 206 ##STR00368## N2-(2-isopropoxy-4-(1- isopropylpiperidin-4-yl)-5- methylphenyl)-N4-(2- (isopropylsulfonyl)phenylamino)-7H- pyrrolo[2,3-d]pyrimidine-2,4-diamine; 207 ##STR00369## 2-(4-(5-isopropoxy-4-(4-(2- (isopropylsulfonyl) phenylamino)-7H- pyrrolo[2,3-d]pyrimidin-2-ylamino)-2- methylphenyl)piperidin-1-yl)ethanol; 208 ##STR00370## N2-(2-isopropoxy-5-methyl-4-(1'- methyl-1,4'-bipiperidin-4-yl)phenyl)-N4- (2-(isopropylsulfonyl) phenyl)-7H- pyrrolo[2,3-d]pyrimidine-2,4-diamine; 215 ##STR00371## N2-(2-isopropoxy-4-methyl-5-(3- methylisoxazol-5-yl)phenyl)-N4-(2- pyrrolo[2,3-d]pyrimidine-2,4-diamine; 216 ##STR00372## N2-(2-isopropoxy-5-methyl-4-(piperidin- 2-yl)phenyl)-N4-(2-(isopropylsulfonyl) phenyl)-7H-pyrrolo[2,3-d]pyrimidine- 2,4-diamine; 217 ##STR00373## N2-(2-isopropoxy-4-(1-(2- methoxyethyl)piperidin-4-yl)-5- methylphenyl)-N4-(2-(isopropylsulfonyl) phenyl)-7H-pyrrolo[2,3-d]pyrimidine- 2,4-diamine; 218 ##STR00374## 3-(4-(5-isopropoxy-4-(4-(2- (isopropylsulfonyl) phenylamino)-7H- pyrrolo[2,3-d]pyrimidin-2-ylamino)-2- methylphenyl)piperidin-1-yppropan-1-ol; 219 ##STR00375## 2-(4-(5-isopropoxy-4-(4-(2- (isopropylsulfonyl) phenylamino)-7H- pyrrolo[2,3-d]pyrimidin-2-ylamino)-2- methylphenyl)piperidin-1-yl)acetic acid; 220 ##STR00376## 3-(4-(5-isopropoxy-4-(4-(2- (isopropylsulfonyl) phenylamino)-7H- pyrrolo[2,3-d]pyrimidin-2-ylamino)-2- methylphenyl)piperidin-1- yl)propanoic acid; 221 ##STR00377## 2-(4-(5-isopropoxy-4-(4-(2- (isopropylsulfonyl) phenylamino)-7H- pyrrolo[2,3-d]pyrimidin-2-ylamino)-2- methylphenyl)piperidin-1- yl)acetamide; 222 ##STR00378## 3-(4-(5-isopropoxy-4-(4-(2- (isopropylsulfonyl) phenylamino)-7H- pyrrolo[2,3-d]pyrimidin-2-ylamino)-2- methylphenyl)piperidin-1- yl)propanamide; 223 ##STR00379## 4-(5-isopropoxy-4-(4-(2- (isopropylsulfonyl) phenylamino)-7H- pyrrolo[2,3-d]pyrimidin-2-ylamino)-2- methylphenyl)-N,N- dimethylpiperidine-1-carboxamide; 224 ##STR00380## N2-(2-isopropoxy-5-methyl-4- (piperidin-3-yl)phenyl)-N4-(2- (isopropylsulfonyl)phenyl)-7H- pyrrolo[2,3-d]pyrimidine-2,4-diamine; 225 ##STR00381## N2-(2-isopropoxy-5-methyl-4-(1- methylpiperidin-3-yl)phenyl)-N4-(2- (isopropylsulfonyl)phenyl)-7H- pyrrolo[2,3-d]pyrimidine-2,4-diamine; 226 ##STR00382## 2-(3-(5-isopropoxy-4-(4-(2- (isopropylsulfonyl) phenylamino)-7H- pyrrolo[2,3-d]pyrimidin-2-ylamino)-2- methylphenyl)piperidin-1-yl)ethanol; 227 ##STR00383## N2-(2-isopropoxy-4-(1-(2- methoxyethyl)piperidin-3-yl)-5- methylphenyl)-N4-(2- (isopropylsulfonyl) phenyl)-7H- pyrrolo[2,3-d]pyrimidine-2,4-diamine; 228 ##STR00384## 5-(5-isopropoxy-4-(4-(2- (isopropylsulfonyl)phenylamino)-7H- pyrrolo[2,3-d]pyrimidin-2-ylamino)-2- methylphenyl)-N-methylpiperidine-2- carboxamide; and 244 ##STR00385## N2-(2-isopropoxy-4-(1- methylpiperidin-4-yl)phenyl)-N4-(2- (isopropylsulfonyl) phenyl)-7H pyrrolo[2,3-d]pyrimidine-2,4-diamine;

or a pharmaceutically acceptable salt thereof.

4. The combination of claim 1, wherein said compound TABLE-US-00006 229 ##STR00386## N6-(2-isopropoxy-5-methyl-4-(piperidin- 4-yl)phenyl)-N4-(2-(isopropylsulfonyl) phenyl)-1H-pyrazolo[3,4-d]pyrimidine- 4,6-diamine; 230 ##STR00387## N6-(4-(1-ethylpiperidin-4-yl)-2- isopropoxy-5-methylphenyl)-N4-(2- (isopropylsulfonyl)phenyl)-1H- pyrazolo[3,4-d]pyrimidine-4,6-diamine; 231 ##STR00388## N6-(2-isopropoxy-5-methyl-4-(1- methylpiperidin-4-yl)phenyl)-N4-(2- (isopropylsulfonyl)phenyl)-1H- pyrazolo[3,4-d]pyrimidine-4,6-diamine; 232 ##STR00389## 2-(4-(5-isopropoxy-4-(4-(2- (isopropylsulfonyl) phenylamino)-1H- pyrazolo[3,4-d]pyrimidin-6-ylamino)-2- methylphenyl)piperidin-1-yl)ethanol; 233 ##STR00390## N6-(2-isopropoxy-4-(1-(2-methoxyethyl) piperidin-4-yl)-5-methylphenyl)-N4-(2- (isopropylsulfonyl)phenyl)-1H- pyrazolo[3,4-d]pyrimidine-4,6-diamine; 234 ##STR00391## N6-(4-(4- (dimethylamino)cyclohexyl)-2- isopropoxy-5-methylphenyl)-N4-(2- (isopropylsulfonyl)phenyl)-1H- pyrazolo[3,4-d]pyrimidine-4,6- diamine; 235 ##STR00392## N6-(2-isopropoxy-5-methyl-4- (piperidin-2-yl)phenyl)-N4-(2- (isopropylsulfonyl) phenyl)-1H- pyrazolo[3,4-d]pyrimidine-4,6- diamine; 242 ##STR00393## N6-(2-isopropoxy-5-methyl-4- (piperidin-2-yl)phenyl)-N4-(2- (isopropylsulfonyl)-5-methylphenyl)- 1H-pyrazolo[3,4-d]pyrimidine-4,6- diamine; and 243 ##STR00394## N6-(2-isopropoxy-5-methyl-4- (piperidin-3-yl)phenyl)-N4-(2- (isopropylsulfonyl)-5-methylphenyl)- 1H-pyrazolo[3,4-d]pyrimidine-4,6- diamine;

or a pharmaceutically acceptable salt thereof.

5. The combination of claim 1, wherein said compound of Formula (1) is selected from the group consisting of TABLE-US-00007 209 ##STR00395## N2-(2-isopropoxy-5-methyl-4- methylpiperidin-4-yl)phenyl)-N6-(2- (isopropylsulfonyl)phenyl)-9H-purine- 2,6-diamine; 210 ##STR00396## N2-(2-isopropoxy-5-methyl-4-(1- methylpiperidin-4-yl)phenyl)-N4-(2- (isopropylsulfonyl)phenyl)quinazoline- 2,4-diamine; 211 ##STR00397## N2-(2-isopropoxy-5-methyl-4-(1- methylpiperidin-4-yl)phenyl)-N4-(2- (isopropylsulfonyl)phenyl)-6- methoxyquinazoline-2,4-diamine; 212 ##STR00398## N2-(2-isopropoxy-5-methyl-4-(1- methylpiperidin-4-yl)phenyl)-N4-(2- (isopropylsulfonyl)phenyl)-6,7- dimethoxyquinazoline-2,4-diamine; 214 ##STR00399## N2-(4-(4-(dimethylamino)cyclohexyl)-2- isopropoxy-5-methylphenyl)-N6-(2- (isopropylsulfonyl)phenyl)-9H-purine- 2,6-diamine; 237 ##STR00400## N2-(2-isopropoxy-5-methyl-4- (piperidin-4-yl)phenyl)-N4-(2- (isopropylsulfonyl) phenyl)-5,6,7,8- tetrahydropyrido[2,3-d]pyrimidine-2,4- diamine; 238 ##STR00401## N2-(2-isopropoxy-5-methyl-4- (piperidin-4-yl)phenyl)-N4-(2- (isopropylsulfonyl) phenyl)pyrido[2,3- d]pyrimidine-2,4-diamine; 245 ##STR00402## 2-(4-(3-isopropoxy-4-(6-(2- (isopropylsulfonyl) phenylamino)-9H- purin-2-ylamino)phenyl)piperidin-1- yl)ethanol; and 246 ##STR00403## N2-(2-isopropoxy-4-(1-methylpiperidin- 4-yl)phenyl)-N6-(2-(isopropylsulfonyl) phenyl)-9H-purine-2,6-diamine;

or a pharmaceutically acceptable salt thereof.

6. The combination of claim 1, wherein said compound of Formula (1) is N6-(4-(1-ethylpiperidin-4-yl)-2-isopropoxy-5-methylphenyl)-N4-(2-(isoprop- ylsulfonyl) phenyl)-1H-pyrazolol[3,4]-dlpyrimidine-4,6-diamine, or a pharmaceutically acceptable salt thereof.

7. The combination of claim 1, wherein said compound of Formula (1) is N6-(2-isopropoxy-5-methyl-4-(1-methylpiperidin-4-yl)phenyl)-N4-(2-(isopro- pylsulfonyl) phenyl)-1H-pyrazolo[3 ,4-d]pyrimidine-4,6-diamine, or a pharmaceutically acceptable salt thereof.
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