Compounds and compositions as protein kinase inhibitors

1. A combination comprising a chemotherapeutic agent and a compound of Formula (1),

or a pharmaceutically acceptable salt thereof; wherein

W is

A 1 and A 4 are independently C;

each A 2 and A 3 is C;

R 1 and R 2 together form an optionally substituted 5-6 membered aryl, or heteroaryl or heterocyclic ring comprising 1-3 nitrogen atoms;

R 3 is (CR 2 ) 0-2 SO 2 R 12 , (CR 2 ) 0-2 SO 2 NRR 12 , (CR 2 ) 0-2 C(O)O 0-1 R 12 , (CR 2 ) 0-2 CONRR 12 , CO 2 NH 2 , or cyano;

R 4 , R 7 and R 10 are independently H;

R, R 5 and R 5′ are independently H or C 1-6 alkyl;

R 6 is halo or O(C 1-6 alkyl);

R 8 and R 9 are independently C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo or X, or one of R 8 and R 9 is H; and provided one of R 8 and R 9 is X;

X is (CR 2 ) q Y, cyano, C(O)O 0-1 R 12 , CONR(R 12 ), CONR(CR 2 ) p NR(R 12 ), CONR(CR 2 ) p OR 12 , CONR(CR 2 ) p SR 12 , CONR(CR 2 ) p S(O) 1-2 R 12 or (CR 2 ) 1- 6 NR(CR 2 ) p OR 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 2 or A 3 or both via a carbon atom of said heteroaryl or heterocyclic ring when q in (CR 2 ) q Y is 0;

R 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 12 is H, C 1-6 alkyl; and

n is 0; and

p and q are independently 0-4.

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

203

N2-(2-isopropoxy-5-methyl-4-(piperidin-

4-yl)phenyl)-N4-(2-

(methylsulfonyl)phenyl)-7H-pyrrolo[2,3-

d]pyrimidine-2,4-diamine;

204

N2-(4-(1-ethylpiperidin-4-yl)-2-

isopropoxy-5-methylphenyl)-N4-(2-

(isopropylsulfonyl)phenyl)-7H-

pyrrolo[2,3-d]pyrimidine-2,4-diamine;

205

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

N2-(2-isopropoxy-4-(1-

isopropylpiperidin-4-yl)-5-

methylphenyl)-N4-(2-

(isopropylsulfonyl)phenylamino)-7H-

pyrrolo[2,3-d]pyrimidine-2,4-diamine;

207

2-(4-(5-isopropoxy-4-(4-(2-

(isopropylsulfonyl) phenylamino)-7H-

pyrrolo[2,3-d]pyrimidin-2-ylamino)-2-

methylphenyl)piperidin-1-yl)ethanol;

208

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

N2-(2-isopropoxy-4-methyl-5-(3-

methylisoxazol-5-yl)phenyl)-N4-(2-

pyrrolo[2,3-d]pyrimidine-2,4-diamine;

216

N2-(2-isopropoxy-5-methyl-4-(piperidin-

2-yl)phenyl)-N4-(2-(isopropylsulfonyl)

phenyl)-7H-pyrrolo[2,3-d]pyrimidine-

2,4-diamine;

217

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

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

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

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

2-(4-(5-isopropoxy-4-(4-(2-

(isopropylsulfonyl) phenylamino)-7H-

pyrrolo[2,3-d]pyrimidin-2-ylamino)-2-

methylphenyl)piperidin-1-

yl)acetamide;

222

3-(4-(5-isopropoxy-4-(4-(2-

(isopropylsulfonyl) phenylamino)-7H-

pyrrolo[2,3-d]pyrimidin-2-ylamino)-2-

methylphenyl)piperidin-1-

yl)propanamide;

223

4-(5-isopropoxy-4-(4-(2-

(isopropylsulfonyl) phenylamino)-7H-

pyrrolo[2,3-d]pyrimidin-2-ylamino)-2-

methylphenyl)-N,N-

dimethylpiperidine-1-carboxamide;

224

N2-(2-isopropoxy-5-methyl-4-

(piperidin-3-yl)phenyl)-N4-(2-

(isopropylsulfonyl)phenyl)-7H-

pyrrolo[2,3-d]pyrimidine-2,4-diamine;

225

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

2-(3-(5-isopropoxy-4-(4-(2-

(isopropylsulfonyl) phenylamino)-7H-

pyrrolo[2,3-d]pyrimidin-2-ylamino)-2-

methylphenyl)piperidin-1-yl)ethanol;

227

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

5-(5-isopropoxy-4-(4-(2-

(isopropylsulfonyl)phenylamino)-7H-

pyrrolo[2,3-d]pyrimidin-2-ylamino)-2-

methylphenyl)-N-methylpiperidine-2-

carboxamide; and

244

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

229

N6-(2-isopropoxy-5-methyl-4-(piperidin-

4-yl)phenyl)-N4-(2-(isopropylsulfonyl)

phenyl)-1H-pyrazolo[3,4-d]pyrimidine-

4,6-diamine;

230

N6-(4-(1-ethylpiperidin-4-yl)-2-

isopropoxy-5-methylphenyl)-N4-(2-

(isopropylsulfonyl)phenyl)-1H-

pyrazolo[3,4-d]pyrimidine-4,6-diamine;

231

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

2-(4-(5-isopropoxy-4-(4-(2-

(isopropylsulfonyl) phenylamino)-1H-

pyrazolo[3,4-d]pyrimidin-6-ylamino)-2-

methylphenyl)piperidin-1-yl)ethanol;

233

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

N6-(4-(4-

(dimethylamino)cyclohexyl)-2-

isopropoxy-5-methylphenyl)-N4-(2-

(isopropylsulfonyl)phenyl)-1H-

pyrazolo[3,4-d]pyrimidine-4,6-

diamine;

235

N6-(2-isopropoxy-5-methyl-4-

(piperidin-2-yl)phenyl)-N4-(2-

(isopropylsulfonyl) phenyl)-1H-

pyrazolo[3,4-d]pyrimidine-4,6-

diamine;

242

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

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

209

N2-(2-isopropoxy-5-methyl-4-

methylpiperidin-4-yl)phenyl)-N6-(2-

(isopropylsulfonyl)phenyl)-9H-purine-

2,6-diamine;

210

N2-(2-isopropoxy-5-methyl-4-(1-

methylpiperidin-4-yl)phenyl)-N4-(2-

(isopropylsulfonyl)phenyl)quinazoline-

2,4-diamine;

211

N2-(2-isopropoxy-5-methyl-4-(1-

methylpiperidin-4-yl)phenyl)-N4-(2-

(isopropylsulfonyl)phenyl)-6-

methoxyquinazoline-2,4-diamine;

212

N2-(2-isopropoxy-5-methyl-4-(1-

methylpiperidin-4-yl)phenyl)-N4-(2-

(isopropylsulfonyl)phenyl)-6,7-

dimethoxyquinazoline-2,4-diamine;

214

N2-(4-(4-(dimethylamino)cyclohexyl)-2-

isopropoxy-5-methylphenyl)-N6-(2-

(isopropylsulfonyl)phenyl)-9H-purine-

2,6-diamine;

237

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

N2-(2-isopropoxy-5-methyl-4-

(piperidin-4-yl)phenyl)-N4-(2-

(isopropylsulfonyl) phenyl)pyrido[2,3-

d]pyrimidine-2,4-diamine;

245

2-(4-(3-isopropoxy-4-(6-(2-

(isopropylsulfonyl) phenylamino)-9H-

purin-2-ylamino)phenyl)piperidin-1-

yl)ethanol; and

246

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-(isopropylsulfonyl) 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-(isopropylsulfonyl) phenyl)-1H-pyrazolo[3 ,4-d]pyrimidine-4,6-diamine, or a pharmaceutically acceptable salt thereof.