IP Library › Patent Application 14774208

Patent Application

App. No. 14/774,208

HETEROARYL COMPOUNDS AND USES THEREOF

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Patent No.: US None
App. No.: 14/774,208

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Abstract

The present invention provides compounds, pharmaceutically acceptable compositions thereof, and methods of using the same. Compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful for treating a variety of diseases, disorders or conditions, associated with abnormal cellular responses triggered by protein kinase-mediated events. Compounds provided by this invention are also useful for the study of kinases in biological and pathological phenoma, the study of intracellular signal transduction pathways mediated by such kinases and the comparative evaluation of new kinase inhibitors.

Claims (3591)

1 . A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

each R 1 , R 2 , R 3 , R 3′ , R 4 , R 4′ , R 5 , R 5′ , R 6 , R 6′ , R 6″ , R xa , R xb , R xb′ , R xc , R ya , R ya′ , R yb and R yb′ is independently selected from hydrogen or deuterium;

provided that at least one of R 1 , R 2 , R 3 , R 3′ , R 4 , R 4′ , R 5 , R 5′ , R 6 , R 6′ , R 6″ , R xa , R xb , R xb′ , R xc , R ya , R ya′ , R yb and R yb′ is deuterium.

2 . The compound according to claim 1 , wherein each of R 2 , R 3 and R 3′ is hydrogen.

3 . The compound according to claim 1 or claim 2 , wherein R 4 and R 4′ are the same.

4 . The compound according to any of claims 1 - 3 , wherein R 5 and R 5′ are the same.

5 . The compound according to any of claims 1 - 4 , wherein R 6 , R 6′ and R 6″ are the same.

6 . The compound according to any of claims 1 - 5 , wherein each of R 4 and R 4′ is deuterium.

7 . The compound according to any of claims 1 - 6 , wherein each of R 5 and R 5′ is deuterium.

8 . The compound according to any of claims 1 - 7 , wherein each of R 6 , R 6′ and R 6″ is deuterium.

9 . The compound according to any of claims 1 - 5 , wherein each of R 4 and R 4′ is hydrogen.

10 . The compound according to any of claims 1 - 6 , wherein each of R 5 and R 5′ is hydrogen.

11 . The compound according to any of claims 1 - 7 , wherein each of R 6 , R 6′ and R 6″ is hydrogen.

12 . The compound according to any of claims 1 - 11 , wherein R 1 is deuterium.

13 . The compound according to any of claims 1 - 11 , wherein R 1 is hydrogen.

14 . The compound according to any of claims 1 - 13 , wherein R xa is deuterium.

15 . The compound according to any of claims 1 - 14 , wherein each of R xb and R xb′ is deuterium.

16 . The compound according to any of claims 1 - 15 , wherein R xc is deuterium.

17 . The compound according to any of claims 1 - 13 , wherein R xa is hydrogen.

18 . The compound according to any of claims 1 - 14 , wherein each of R xb and R xb′ is hydrogen.

19 . The compound according to any of claims 1 - 15 , wherein R xc is hydrogen.

20 . The compound according to any of claims 1 - 19 , wherein each of R ya and R ya′ is deuterium.

21 . The compound according to any of claims 1 - 20 , wherein each of R yb and R yb′ is deuterium.

22 . The compound according to any of claims 1 - 19 , wherein each of R ya and R ya′ is hydrogen.

23 . The compound according to any of claims 1 - 20 , wherein each of R yb and R yb′ is hydrogen.

24 . The compound according to claim 2 , wherein each of R 1 , R xa , R xb , R xb′ , R xc , R ya , R ya′ , R yb and R yb′ is hydrogen, and the compound is selected from any of the compounds in the following table:

Compound #

R 4 /R 4′

R 5 /R 5′

R 6 /R 6′ /R 6″

II-1

II-2

II-3

II-4

II-5

II-6

II-7

25 . The compound according to claim 2 , wherein R 1 is deuterium, each of R xa , R xb , R xb′ , R xc , R ya , R ya′ , R yb and R yb′ is hydrogen, and the compound is selected from any of the compounds in the following table:

Compound #

R 4 /R 4′

R 5 /R 5′

R 6 /R 6′ /R 6″

II-8

II-9

II-10

II-11

II-12

II-13

II-14

II-15

26 . The compound according to claim 2 , wherein each of R 1 , R 4 , R 4′ , R 5 , R 5′ , R 6 , R 6′ , R 6″ , R ya , R ya′ , R yb and R yb′ is hydrogen, and the compound is selected from any of the compounds in the following table:

Compound #

R xa

R xb /R xb′

R xc

III-1

III-2

III-3

III-4

III-5

III-6

III-7

27 . The compound according to claim 2 , wherein each of R 1 , R 4 , R 4′ , R 5 , R 5′ , R 6 , R 6′ , R 6″ , R xa , R xb , R xb′ and R xc is hydrogen, and the compound is selected from any of the compounds in the following table:

Compound #

R ya /R ya′

R yb /R yb′

IV-1

IV-2

IV-3

28 . The compound according to claim 2 , wherein each of R 4 , R 4′ , R 5 , R 5′ , R 6 , R 6′ , R 6″ , R ya , R ya′ , R yb and R yb′ is hydrogen, and the compound is selected from any of the compounds in the following table:

Compound #

R 1

R xa

R xb /R xb′

R xc

V-1

V-2

V-3

V-4

V-5

V-6

V-7

29 . The compound according to claim 2 , wherein each of R 1 , R ya , R ya′ , R yb and R yb′ is hydrogen, and the compound is selected from any of the compounds in the following table:

Compound #

R 4 /R 4′

R 5 /R 5′

R 6 /R 6′ /R 6″

R xa

R xb /R xb′

R xc

V-8

V-9

V-10

V-11

V-12

V-13

V-14

V-15

V-16

V-17

V-18

V-19

V-20

V-21

V-22

V-23

V-24

V-25

V-26

V-27

V-28

V-29

V-30

V-31

V-32

V-33

V-34

V-35

V-36

V-37

V-38

V-39

V-40

V-41

V-42

V-43

V-44

V-45

V-46

V-47

V-48

V-49

V-50

V-51

V-52

V-53

V-54

V-55

V-56

30 . The compound according to claim 2 , wherein R 1 is deuterium, each of R ya , R ya′ , R yb and R yb′ is hydrogen, and the compound is selected from any of the compounds in the following table:

Compound #

R 4 /R 4′

R 5 /R 5′

R 6 /R 6′ /R 6″

R xa

R xb /R xb′

R xc

V-57

V-58

V-59

V-60

V-61

V-62

V-63

V-64

V-65

V-66

V-67

V-68

V-69

V-70

V-71

V-72

V-73

V-74

V-75

V-76

V-77

V-78

V-79

V-80

V-81

V-82

V-83

V-84

V-85

V-86

V-87

V-88

V-89

V-90

V-91

V-92

V-93

V-94

V-95

V-96

V-97

V-98

V-99

V-100

V-101

V-102

V-103

V-104

V-105

31 . The compound according to claim 2 , wherein each of R 4 , R 4′ , R 5 , R 5′ , R 6 , R 6′ , R 6″ , R xa , R xb , R xb′ and R xc is hydrogen, and the compound is selected from any of the compounds in the following table:

Compound #

R 1

R ya /R ya′

R yb /R yb′

VI-1

VI-2

VI-3

VI-4

VI-5

VI-6

32 . The compound according to claim 2 , wherein each of R 1 , R xa , R xb , R xb′ and R xc is hydrogen, and the compound is selected from any of the compounds in the following table:

Compound #

R 4 /R 4′

R 5 /R 5′

R 6 /R 6′ /R 6″

R ya /R ya′

R yb /R yb′

VI-7

VI-8

VI-9

VI-10

VI-11

VI-12

VI-13

VI-14

VI-15

VI-16

VI-17

VI-18

VI-19

VI-20

VI-21

VI-22

VI-23

VI-24

VI-25

VI-26

VI-27

33 . The compound according to claim 2 , wherein R 1 is deuterium, each of R xa , R xb , R xb′ and R xc is hydrogen, and the compound is selected from any of the compounds in the following table:

Compound #

R 4 /R 4′

R 5 /R 5′

R 6 /R 6′ /R 6″

R ya /R ya′

R yb /R yb′

VI-28

VI-29

VI-30

VI-31

VI-32

VI-33

VI-34

VI-35

VI-36

VI-37

VI-38

VI-39

VI-40

VI-41

VI-42

VI-43

VI-44

VI-45

VI-46

VI-47

VI-48

34 . The compound according to claim 2 , wherein each of R 1 , R 4 , R 4′ , R 5 , R 5′ , R 6 , R 6′ and R 6′ is hydrogen, and the compound is selected from any of the compounds in the following table:

Compound #

R xa

R xb /R xb′

R xc

R ya /R ya′

R yb /R yb′

VII-1

VII-2

VII-3

VII-4

VII-5

VII-6

VII-7

VII-8

VII-9

VII-10

VII-11

VII-12

VII-13

VII-14

VII-15

VII-16

VII-17

VII-18

VII-19

VII-20

VII-21

35 . The compound according to claim 2 , wherein each of R 4 , R 4′ , R 5 , R 5′ , R 6 , R 6′ and R 6″ is hydrogen, and the compound is selected from any of the compounds in the following table:

Compound #

R 1

R xa

R xb /R xb′

R xc

R ya /R ya′

R yb /R yb′

VII-22

VII-23

VII-24

VII-25

VII-26

VII-27

VII-28

VII-29

VII-30

VII-31

VII-32

VII-33

VII-34

VII-35

VII-36

VII-37

VII-38

VII-39

VII-40

VII-41

VII-42

36 . The compound according to claim 2 , wherein R 4 and R 4′ are deuterium, each of R 5 , R 5′ , R 6 , R 6′ and R 6″ is hydrogen, and the compound is selected from any of the compounds in the following table:

Compound #

R 1

R xa

R xb /R xb′

R xc

R ya /R ya′

R yb /R yb′

VII-43

VII-44

VII-45

VII-46

VII-47

VII-48

VII-49

VII-50

VII-51

VII-52

VII-53

VII-54

VII-55

VII-56

VII-57

VII-58

VII-59

VII-60

VII-61

VII-62

VII-63

VII-64

VII-65

VII-66

VII-67

VII-68

VII-69

VII-70

VII-71

VII-72

VII-73

VII-74

VII-75

VII-76

VII-77

VII-78

VII-79

VII-80

VII-81

VII-82

VII-83

VII-84

37 . The compound according to claim 2 , wherein R 5 and R 5′ are deuterium, each of R 4 , R 4′ R 6 , R 6′ and R 6″ is hydrogen, and the compound is selected from any of the compounds in the following table:

Compound #

R 1

R xa

R xb /R xb′

R xc

R ya /R ya′

R yb /R yb′

VII-85

VII-86

VII-87

VII-88

VII-89

VII-90

VII-91

VII-92

VII-93

VII-94

VII-95

VII-96

VII-97

VII-98

VII-99

VII-100

VII-101

VII-102

VII-103

VII-104

VII-105

VII-106

VII-107

VII-108

VII-109

VII-110

VII-111

VII-112

VII-113

VII-114

VII-115

VII-116

VII-117

VII-118

VII-119

VII-120

VII-121

VII-122

VII-123

VII-124

VII-125

VII-126

38 . The compound according to claim 2 , wherein each of R 6 , R 6′ and R 6″ is deuterium, each of R 4 , R 4′ , R 5 and R 5′ is hydrogen, and the compound is selected from any of the compounds in the following table:

Compound #

R 1

R xa

R xb /R xb′

R xc

R ya /R ya′

R yb /R yb′

VII-127

VII-128

VII-129

VII-130

VII-131

VII-132

VII-133

VII-134

VII-135

VII-136

VII-137

VII-138

VII-139

VII-140

VII-141

VII-142

VII-143

VII-144

VII-145

VII-146

VII-147

VII-148

VII-149

VII-150

VII-151

VII-152

VII-153

VII-154

VII-155

VII-156

VII-157

VII-158

VII-159

VII-160

VII-161

VII-162

VII-163

VII-164

VII-165

VII-166

VII-167

VII-168

39 . The compound according to claim 2 , wherein each of R 4 , R 4′ , R 5 and R 5′ is deuterium, each of R 6 , R 6′ and R 6″ is hydrogen, and the compound is selected from any of the compounds in the following table:

Compound #

R 1

R xa

R xb /R xb′

R xc

R ya /R ya′

R yb /R yb′

VII-169

VII-170

VII-171

VII-172

VII-173

VII-174

VII-175

VII-176

VII-177

VII-178

VII-179

VII-180

VII-181

VII-182

VII-183

VII-184

VII-185

VII-186

VII-187

VII-188

VII-189

VII-190

VII-191

VII-192

VII-193

VII-194

VII-195

VII-196

VII-197

VII-198

VII-199

VII-200

VII-201

VII-202

VII-203

VII-204

VII-205

VII-206

VII-207

VII-208

VII-209

VII-210

40 . The compound according to claim 2 , wherein each of R 4 , R 4′ , R 6 , R 6′ , and R 6″ is deuterium, each of R 5 and R 5′ is hydrogen, and the compound is selected from any of the compounds in the following table:

Compound #

R 1

R xa

R xb /R xb′

R xc

R ya /R ya′

R yb /R yb′

VII-211

VII-212

VII-213

VII-214

VII-215

VII-216

VII-217

VII-218

VII-219

VII-220

VII-221

VII-222

VII-223

VII-224

VII-225

VII-226

VII-227

VII-228

VII-229

VII-230

VII-231

VII-232

VII-233

VII-234

VII-235

VII-236

VII-237

VII-238

VII-239

VII-240

VII-241

VII-242

VII-243

VII-244

VII-245

VII-246

VII-247

VII-248

VII-249

VII-250

VII-251

VII-252

41 . The compound according to claim 2 , wherein each of R 5 , R 5′ , R 6 , R 6′ and R 6″ is deuterium, each of R 4 and R 4′ is hydrogen, and the compound is selected from any of the compounds in the following table:

Compound #

R 1

R xa

R xb /R xb′

R xc

R ya /R ya′

R yb /R yb′

VII-253

VII-254

VII-255

VII-256

VII-257

VII-258

VII-259

VII-260

VII-261

VII-262

VII-263

VII-264

VII-265

VII-266

VII-267

VII-268

VII-269

VII-270

VII-271

VII-272

VII-273

VII-274

VII-275

VII-276

VII-277

VII-278

VII-279

VII-280

VII-281

VII-282

VII-283

VII-284

VII-285

VII-286

VII-287

VII-288

VII-289

VII-290

VII-291

VII-292

VII-293

VII-294

42 . The compound according to claim 2 , wherein each of R 4 , R 4′ , R 5 , R 5′ , R 6 , R 6′ and R 6″ is deuterium, and the compound is selected from any of the compounds in the following table:

Compound #

R 1

R xa

R xb /R xb′

R xc

R ya /R ya′

R yb /R yb′

VII-295

VII-296

VII-297

VII-298

VII-299

VII-300

VII-301

VII-302

VII-303

VII-304

VII-305

VII-306

VII-307

VII-308

VII-309

VII-310

VII-311

VII-312

VII-313

VII-314

VII-315

VII-316

VII-317

VII-318

VII-319

VII-320

VII-321

VII-322

VII-323

VII-324

VII-325

VII-326

VII-327

VII-328

VII-329

VII-330

VII-331

VII-332

VII-333

VII-334

VII-335

VII-336

43 . A composition comprising a compound according to any one of claims 1 - 42 and a pharmaceutically acceptable adjuvant, carrier, or vehicle.

44 . The composition according to claim 43 , in combination with an additional therapeutic agent.

45 . The composition according to claim 44 , wherein the additional therapeutic agent is a chemotherapeutic agent.

46 . A method for inhibiting BTK, or a mutant thereof, activity in a patient or in a biological sample comprising the step of administering to said patient or contacting said biological sample with a compound according to any one of claims 1 - 42 .

47 . The method according to claim 46 , wherein the BTK, or a mutant thereof, activity is inhibited irreversibly.

48 . The method according to claim 47 , wherein the BTK, or a mutant thereof, activity is inhibited irreversibly by covalently modifying Cys 481 of BTK.

49 . A method for treating a BTK-mediated disorder in a patient in need thereof, comprising the step of administering to said patient a compound according to any one of claims 1 - 42 or a composition according to claim 43 .

50 . The method according to claim 49 , wherein the disorder is an autoimmune disease, a heteroimmune disease, an inflammatory disease, a cancer, a disease of the bone and joints, or a thromboembolic disorder.

51 . The method according to claim 50 , wherein the disorder is selected from rheumatoid arthritis, multiple sclerosis, B-cell chronic lymphocytic leukemia, acute lymphocytic leukemia, hairy cell leukemia, non-Hodgkin's lymphoma, Hodgkin's lymphoma, multiple myeloma, bone cancer, bone metastasis, osteoporosis, irritable bowel syndrome, Crohn's disease, lupus, or disorders associated with renal transplant.

Assignments (2)

MERGER AND CHANGE OF NAME Recorded Feb 16, 2017

From: CELGENE AVILOMICS RESEARCH, INC.; CELGENE CAR LLC

To: CELGENE CAR LLC

Reel/Frame 041738/0041 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 10, 2015

From: TESTER, RICHLAND WAYNE; CHATURVEDI, PRASOON

To: CELGENE AVILOMICS RESEARCH, INC.

Reel/Frame 036530/0692 →