JP2007517904A - 置換された複素環化合物及び使用の方法 - Google Patents
置換された複素環化合物及び使用の方法 Download PDFInfo
- Publication number
- JP2007517904A JP2007517904A JP2006549571A JP2006549571A JP2007517904A JP 2007517904 A JP2007517904 A JP 2007517904A JP 2006549571 A JP2006549571 A JP 2006549571A JP 2006549571 A JP2006549571 A JP 2006549571A JP 2007517904 A JP2007517904 A JP 2007517904A
- Authority
- JP
- Japan
- Prior art keywords
- alkyl
- hept
- diazabicyclo
- phenyl
- pyrimidin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 238000000034 method Methods 0.000 title claims description 49
- 150000001420 substituted heterocyclic compounds Chemical class 0.000 title 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 52
- 210000001744 T-lymphocyte Anatomy 0.000 claims abstract description 45
- 201000010099 disease Diseases 0.000 claims abstract description 28
- 230000001404 mediated effect Effects 0.000 claims abstract description 17
- 230000001363 autoimmune Effects 0.000 claims abstract description 16
- 206010061218 Inflammation Diseases 0.000 claims abstract description 14
- 230000001154 acute effect Effects 0.000 claims abstract description 14
- 230000004054 inflammatory process Effects 0.000 claims abstract description 14
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims abstract description 14
- 238000002054 transplantation Methods 0.000 claims abstract description 13
- 201000004624 Dermatitis Diseases 0.000 claims abstract description 12
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 12
- 208000023275 Autoimmune disease Diseases 0.000 claims abstract description 11
- 102000042846 PKC family Human genes 0.000 claims abstract description 11
- 108091082203 PKC family Proteins 0.000 claims abstract description 11
- 208000010247 contact dermatitis Diseases 0.000 claims abstract description 11
- 208000026935 allergic disease Diseases 0.000 claims abstract description 10
- 208000023328 Basedow disease Diseases 0.000 claims abstract description 9
- 206010063837 Reperfusion injury Diseases 0.000 claims abstract description 9
- 208000006673 asthma Diseases 0.000 claims abstract description 9
- 201000005962 mycosis fungoides Diseases 0.000 claims abstract description 9
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims abstract description 8
- 206010025135 lupus erythematosus Diseases 0.000 claims abstract description 8
- 230000004083 survival effect Effects 0.000 claims abstract description 8
- 206010020751 Hypersensitivity Diseases 0.000 claims abstract description 7
- 201000004681 Psoriasis Diseases 0.000 claims abstract description 7
- 206010039085 Rhinitis allergic Diseases 0.000 claims abstract description 7
- 201000010105 allergic rhinitis Diseases 0.000 claims abstract description 7
- 206010003246 arthritis Diseases 0.000 claims abstract description 7
- 208000037906 ischaemic injury Diseases 0.000 claims abstract description 7
- 230000000302 ischemic effect Effects 0.000 claims abstract description 7
- 201000006417 multiple sclerosis Diseases 0.000 claims abstract description 7
- 206010039073 rheumatoid arthritis Diseases 0.000 claims abstract description 7
- 208000003950 B-cell lymphoma Diseases 0.000 claims abstract description 6
- 206010006187 Breast cancer Diseases 0.000 claims abstract description 6
- 208000026310 Breast neoplasm Diseases 0.000 claims abstract description 6
- 206010012442 Dermatitis contact Diseases 0.000 claims abstract description 6
- 208000009329 Graft vs Host Disease Diseases 0.000 claims abstract description 6
- 208000035895 Guillain-Barré syndrome Diseases 0.000 claims abstract description 6
- 208000030836 Hashimoto thyroiditis Diseases 0.000 claims abstract description 6
- 206010049567 Miller Fisher syndrome Diseases 0.000 claims abstract description 6
- 208000021386 Sjogren Syndrome Diseases 0.000 claims abstract description 6
- 206010042971 T-cell lymphoma Diseases 0.000 claims abstract description 6
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims abstract description 6
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 6
- 229940127089 cytotoxic agent Drugs 0.000 claims abstract description 6
- 208000024908 graft versus host disease Diseases 0.000 claims abstract description 6
- 230000009610 hypersensitivity Effects 0.000 claims abstract description 6
- 210000000056 organ Anatomy 0.000 claims abstract description 6
- 208000011580 syndromic disease Diseases 0.000 claims abstract description 6
- 208000026872 Addison Disease Diseases 0.000 claims abstract description 5
- 208000035285 Allergic Seasonal Rhinitis Diseases 0.000 claims abstract description 5
- 201000004384 Alopecia Diseases 0.000 claims abstract description 5
- 208000009137 Behcet syndrome Diseases 0.000 claims abstract description 5
- 206010009900 Colitis ulcerative Diseases 0.000 claims abstract description 5
- 206010009944 Colon cancer Diseases 0.000 claims abstract description 5
- 208000011231 Crohn disease Diseases 0.000 claims abstract description 5
- 206010018364 Glomerulonephritis Diseases 0.000 claims abstract description 5
- 108010068370 Glutens Proteins 0.000 claims abstract description 5
- 208000015023 Graves' disease Diseases 0.000 claims abstract description 5
- 206010021067 Hypopituitarism Diseases 0.000 claims abstract description 5
- 208000000185 Localized scleroderma Diseases 0.000 claims abstract description 5
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims abstract description 5
- 208000031845 Pernicious anaemia Diseases 0.000 claims abstract description 5
- 206010037575 Pustular psoriasis Diseases 0.000 claims abstract description 5
- 208000009359 Sezary Syndrome Diseases 0.000 claims abstract description 5
- 201000009594 Systemic Scleroderma Diseases 0.000 claims abstract description 5
- 206010042953 Systemic sclerosis Diseases 0.000 claims abstract description 5
- 206010053613 Type IV hypersensitivity reaction Diseases 0.000 claims abstract description 5
- 201000006704 Ulcerative Colitis Diseases 0.000 claims abstract description 5
- 208000024780 Urticaria Diseases 0.000 claims abstract description 5
- 206010047642 Vitiligo Diseases 0.000 claims abstract description 5
- 208000028004 allergic respiratory disease Diseases 0.000 claims abstract description 5
- 231100000360 alopecia Toxicity 0.000 claims abstract description 5
- 208000004631 alopecia areata Diseases 0.000 claims abstract description 5
- 208000010668 atopic eczema Diseases 0.000 claims abstract description 5
- 230000001684 chronic effect Effects 0.000 claims abstract description 5
- 208000025302 chronic primary adrenal insufficiency Diseases 0.000 claims abstract description 5
- 208000029742 colonic neoplasm Diseases 0.000 claims abstract description 5
- 201000001981 dermatomyositis Diseases 0.000 claims abstract description 5
- 235000021312 gluten Nutrition 0.000 claims abstract description 5
- 208000002551 irritable bowel syndrome Diseases 0.000 claims abstract description 5
- 201000005202 lung cancer Diseases 0.000 claims abstract description 5
- 208000020816 lung neoplasm Diseases 0.000 claims abstract description 5
- 201000008482 osteoarthritis Diseases 0.000 claims abstract description 5
- 201000010914 pustulosis of palm and sole Diseases 0.000 claims abstract description 5
- 208000011797 pustulosis palmaris et plantaris Diseases 0.000 claims abstract description 5
- 201000004335 respiratory allergy Diseases 0.000 claims abstract description 5
- 230000024664 tolerance induction Effects 0.000 claims abstract description 5
- 230000004614 tumor growth Effects 0.000 claims abstract description 5
- 230000005951 type IV hypersensitivity Effects 0.000 claims abstract description 5
- 208000027930 type IV hypersensitivity disease Diseases 0.000 claims abstract description 5
- 208000003807 Graves Disease Diseases 0.000 claims abstract description 4
- 201000001263 Psoriatic Arthritis Diseases 0.000 claims abstract description 4
- 208000036824 Psoriatic arthropathy Diseases 0.000 claims abstract description 4
- 208000021388 Sezary disease Diseases 0.000 claims abstract description 4
- 208000017983 photosensitivity disease Diseases 0.000 claims abstract description 4
- 208000005057 thyrotoxicosis Diseases 0.000 claims abstract description 4
- 210000004881 tumor cell Anatomy 0.000 claims abstract description 4
- 208000006311 Pyoderma Diseases 0.000 claims abstract description 3
- 206010040400 serum sickness Diseases 0.000 claims abstract description 3
- 238000002689 xenotransplantation Methods 0.000 claims abstract description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 485
- -1 tetrahydronaphthalenyl Chemical group 0.000 claims description 244
- 150000001875 compounds Chemical class 0.000 claims description 187
- 125000001424 substituent group Chemical group 0.000 claims description 104
- 229920006395 saturated elastomer Polymers 0.000 claims description 103
- 125000005843 halogen group Chemical group 0.000 claims description 98
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 88
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 78
- 229910052757 nitrogen Inorganic materials 0.000 claims description 74
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 70
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 69
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 63
- 229910052799 carbon Inorganic materials 0.000 claims description 61
- 125000004043 oxo group Chemical group O=* 0.000 claims description 51
- 125000004432 carbon atom Chemical group C* 0.000 claims description 49
- 229910052739 hydrogen Inorganic materials 0.000 claims description 40
- 229910052760 oxygen Inorganic materials 0.000 claims description 40
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 37
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N EtOH Substances CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 31
- 125000002883 imidazolyl group Chemical group 0.000 claims description 29
- 125000001544 thienyl group Chemical group 0.000 claims description 29
- 241000124008 Mammalia Species 0.000 claims description 28
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 28
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 28
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 28
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 28
- 125000000723 dihydrobenzofuranyl group Chemical group O1C(CC2=C1C=CC=C2)* 0.000 claims description 28
- 125000004852 dihydrofuranyl group Chemical group O1C(CC=C1)* 0.000 claims description 28
- 125000002541 furyl group Chemical group 0.000 claims description 28
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 claims description 28
- 125000001041 indolyl group Chemical group 0.000 claims description 28
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 28
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 28
- 125000002757 morpholinyl group Chemical group 0.000 claims description 28
- 125000002971 oxazolyl group Chemical group 0.000 claims description 28
- 125000004193 piperazinyl group Chemical group 0.000 claims description 28
- 125000003386 piperidinyl group Chemical group 0.000 claims description 28
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 claims description 28
- 125000004076 pyridyl group Chemical group 0.000 claims description 28
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 28
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 28
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 28
- 125000000335 thiazolyl group Chemical group 0.000 claims description 28
- 125000001425 triazolyl group Chemical group 0.000 claims description 28
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 27
- 125000001624 naphthyl group Chemical group 0.000 claims description 27
- 229910052717 sulfur Inorganic materials 0.000 claims description 26
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 25
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 claims description 25
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 23
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 23
- 125000004306 triazinyl group Chemical group 0.000 claims description 23
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 22
- 125000004429 atom Chemical group 0.000 claims description 20
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 20
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims description 20
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 20
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 claims description 20
- 125000004639 dihydroindenyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 19
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 claims description 17
- 125000006583 (C1-C3) haloalkyl group Chemical group 0.000 claims description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims description 16
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 15
- 125000004434 sulfur atom Chemical group 0.000 claims description 14
- 125000002619 bicyclic group Chemical group 0.000 claims description 13
- 208000035475 disorder Diseases 0.000 claims description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 12
- 230000006044 T cell activation Effects 0.000 claims description 11
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 11
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 11
- NKBWMBRPILTCRD-UHFFFAOYSA-N 2-Methylheptanoic acid Chemical compound CCCCCC(C)C(O)=O NKBWMBRPILTCRD-UHFFFAOYSA-N 0.000 claims description 9
- FQJRZOYTUCCBQR-UHFFFAOYSA-N tert-butyl 2-methylheptanoate Chemical compound CCCCCC(C)C(=O)OC(C)(C)C FQJRZOYTUCCBQR-UHFFFAOYSA-N 0.000 claims description 9
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 claims description 8
- 239000003937 drug carrier Substances 0.000 claims description 8
- 208000032839 leukemia Diseases 0.000 claims description 8
- 206010012689 Diabetic retinopathy Diseases 0.000 claims description 7
- 206010022489 Insulin Resistance Diseases 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- 229910052740 iodine Inorganic materials 0.000 claims description 7
- 206010012438 Dermatitis atopic Diseases 0.000 claims description 6
- 201000008937 atopic dermatitis Diseases 0.000 claims description 6
- 201000011510 cancer Diseases 0.000 claims description 6
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 5
- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical group O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 claims description 5
- 208000032131 Diabetic Neuropathies Diseases 0.000 claims description 5
- 125000003047 N-acetyl group Chemical group 0.000 claims description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- HUSCFUXDGASTLI-YDIPPGQESA-N 4-[5-[(1s,4s)-5-(2-phenoxypropyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]imidazo[1,2-c]pyrimidin-7-yl]-n-[(1s)-1-phenylethyl]pyridin-2-amine Chemical compound C1([C@H](C)NC=2N=CC=C(C=2)C=2N=C(N3C=CN=C3C=2)N2C[C@]3(N(C[C@]2([H])C3)CC(C)OC=2C=CC=CC=2)[H])=CC=CC=C1 HUSCFUXDGASTLI-YDIPPGQESA-N 0.000 claims description 4
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 claims description 4
- 208000008732 thymoma Diseases 0.000 claims description 4
- RQGMJYSQCBDCMZ-VJBMBRPKSA-N 4-[4-[(1s,4s)-5-ethyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]quinazolin-2-yl]-n-[(1s)-1-phenylethyl]pyridin-2-amine Chemical compound C1([C@H](C)NC=2N=CC=C(C=2)C=2N=C(C3=CC=CC=C3N=2)N2C[C@]3(N(C[C@]2([H])C3)CC)[H])=CC=CC=C1 RQGMJYSQCBDCMZ-VJBMBRPKSA-N 0.000 claims description 3
- 208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 claims description 3
- 206010012601 diabetes mellitus Diseases 0.000 claims description 3
- GKTBKKVWPNGMFG-NYVOZVTQSA-N n-[(1s)-1-phenylethyl]-4-[2-[(1s,4s)-2-propan-2-yl-2,5-diazabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyridin-2-amine Chemical compound C1([C@H](C)NC=2N=CC=C(C=2)C=2C=CN=C(N=2)N2C[C@]3(N(C[C@]2([H])C3)C(C)C)[H])=CC=CC=C1 GKTBKKVWPNGMFG-NYVOZVTQSA-N 0.000 claims description 3
- LWQDICDZDSPXPQ-OYDLWJJNSA-N n-[(1s)-1-phenylethyl]-4-[4-[(1s,4s)-2-propan-2-yl-2,5-diazabicyclo[2.2.1]heptan-5-yl]quinazolin-2-yl]pyridin-2-amine Chemical compound C1([C@H](C)NC=2N=CC=C(C=2)C=2N=C(C3=CC=CC=C3N=2)N2C[C@]3(N(C[C@]2([H])C3)C(C)C)[H])=CC=CC=C1 LWQDICDZDSPXPQ-OYDLWJJNSA-N 0.000 claims description 3
- SIIQBMIBASOKOD-ICSRJNTNSA-N n-benzyl-4-[3-[(1s,4s)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-6-fluoroindazol-1-yl]pyridin-2-amine Chemical compound C([C@]1(NC[C@]2([H])C1)[H])N2C(C1=CC=C(F)C=C11)=NN1C(C=1)=CC=NC=1NCC1=CC=CC=C1 SIIQBMIBASOKOD-ICSRJNTNSA-N 0.000 claims description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 3
- 208000023504 respiratory system disease Diseases 0.000 claims description 3
- OLFFOWYNQJKLDU-SNRMKQJTSA-N 2-[(1s,4s)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-3-methyl-6-[2-[[(1s)-1-phenylethyl]amino]pyridin-4-yl]pyrimidin-4-one Chemical compound C1([C@H](C)NC=2N=CC=C(C=2)C=2N=C(N(C(=O)C=2)C)N2C[C@]3(NC[C@]2([H])C3)[H])=CC=CC=C1 OLFFOWYNQJKLDU-SNRMKQJTSA-N 0.000 claims description 2
- MUSPLTOFMXRFOE-NDXORKPFSA-N 4-[2-[(1s,4s)-2,5-diazabicyclo[2.2.1]heptan-2-yl]pyridin-4-yl]-n-[(1s)-1-phenylethyl]pyridin-2-amine Chemical compound C1([C@H](C)NC=2N=CC=C(C=2)C=2C=C(N=CC=2)N2C[C@]3(NC[C@]2([H])C3)[H])=CC=CC=C1 MUSPLTOFMXRFOE-NDXORKPFSA-N 0.000 claims description 2
- BZLNQHVXJPCZCT-NYVOZVTQSA-N 4-[2-methylsulfanyl-6-[(1s,4s)-2-propan-2-yl-2,5-diazabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]-n-[(1s)-1-phenylethyl]pyridin-2-amine Chemical compound C1([C@H](C)NC=2N=CC=C(C=2)C=2C=C(N=C(SC)N=2)N2C[C@]3(N(C[C@]2([H])C3)C(C)C)[H])=CC=CC=C1 BZLNQHVXJPCZCT-NYVOZVTQSA-N 0.000 claims description 2
- PKWBFXMNHSZDTB-LNLFQRSKSA-N 4-[3-[(1s,4s)-2,5-diazabicyclo[2.2.1]heptan-2-yl]indazol-1-yl]-n-[(1s)-1-(2-fluorophenyl)ethyl]pyridin-2-amine Chemical compound C1([C@H](C)NC=2N=CC=C(C=2)N2N=C(C3=CC=CC=C32)N2C[C@]3(NC[C@]2([H])C3)[H])=CC=CC=C1F PKWBFXMNHSZDTB-LNLFQRSKSA-N 0.000 claims description 2
- TWYYQCKDAVLTKR-CUWPLCDZSA-N 4-[3-[(1s,4s)-2,5-diazabicyclo[2.2.1]heptan-2-yl]indazol-1-yl]-n-[(1s)-1-phenylethyl]pyridin-2-amine Chemical compound C1([C@H](C)NC=2N=CC=C(C=2)N2N=C(C3=CC=CC=C32)N2C[C@]3(NC[C@]2([H])C3)[H])=CC=CC=C1 TWYYQCKDAVLTKR-CUWPLCDZSA-N 0.000 claims description 2
- VZMQHTHDLXOOET-YYWHXJBOSA-N 4-[4-[(1s,4s)-2,5-diazabicyclo[2.2.1]heptan-2-yl]quinazolin-2-yl]-n-[(1s)-1-phenylethyl]pyridin-2-amine Chemical compound C1([C@H](C)NC=2N=CC=C(C=2)C=2N=C(C3=CC=CC=C3N=2)N2C[C@]3(NC[C@]2([H])C3)[H])=CC=CC=C1 VZMQHTHDLXOOET-YYWHXJBOSA-N 0.000 claims description 2
- UXAGYDYQHFDNBY-NYVOZVTQSA-N 4-[4-[(1s,4s)-2,5-diazabicyclo[2.2.1]heptan-2-yl]quinolin-2-yl]-n-[(1s)-1-phenylethyl]pyridin-2-amine Chemical compound C1([C@H](C)NC=2N=CC=C(C=2)C=2C=C(C3=CC=CC=C3N=2)N2C[C@]3(NC[C@]2([H])C3)[H])=CC=CC=C1 UXAGYDYQHFDNBY-NYVOZVTQSA-N 0.000 claims description 2
- ZABHCFAMEITAHK-OYDLWJJNSA-N 4-[4-[(1s,4s)-5-ethyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]quinolin-2-yl]-n-[(1s)-1-phenylethyl]pyridin-2-amine Chemical compound C1([C@H](C)NC=2N=CC=C(C=2)C=2C=C(C3=CC=CC=C3N=2)N2C[C@]3(N(C[C@]2([H])C3)CC)[H])=CC=CC=C1 ZABHCFAMEITAHK-OYDLWJJNSA-N 0.000 claims description 2
- FDAUXZFXTPDSRM-NYVOZVTQSA-N 4-[4-[(1s,4s)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]quinazolin-2-yl]-n-[(1s)-1-phenylethyl]pyridin-2-amine Chemical compound C1([C@H](C)NC=2N=CC=C(C=2)C=2N=C(C3=CC=CC=C3N=2)N2C[C@]3(N(C[C@]2([H])C3)C)[H])=CC=CC=C1 FDAUXZFXTPDSRM-NYVOZVTQSA-N 0.000 claims description 2
- RVQIRCOGFQIAJJ-VJBMBRPKSA-N 4-[4-[(1s,4s)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]quinolin-2-yl]-n-[(1s)-1-phenylethyl]pyridin-2-amine Chemical compound C1([C@H](C)NC=2N=CC=C(C=2)C=2C=C(C3=CC=CC=C3N=2)N2C[C@]3(N(C[C@]2([H])C3)C)[H])=CC=CC=C1 RVQIRCOGFQIAJJ-VJBMBRPKSA-N 0.000 claims description 2
- YMPJQANVEGWILT-YYWHXJBOSA-N 4-[5-[(1s,4s)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]-n-[(1s)-1-naphthalen-1-ylethyl]pyridin-2-amine Chemical compound C1=CC=C2C([C@H](C)NC=3N=CC=C(C=3)C=3N=C(N4N=CN=C4C=3)N3C[C@]4(NC[C@]3([H])C4)[H])=CC=CC2=C1 YMPJQANVEGWILT-YYWHXJBOSA-N 0.000 claims description 2
- JKVGSSMZDIFZSF-UXPWSPDFSA-N 4-[5-[(1s,4s)-2,5-diazabicyclo[2.2.1]heptan-2-yl]imidazo[1,2-c]pyrimidin-7-yl]-n-[(1r)-1-phenylethyl]pyridin-2-amine Chemical compound C1([C@@H](C)NC=2N=CC=C(C=2)C=2N=C(N3C=CN=C3C=2)N2C[C@]3(NC[C@]2([H])C3)[H])=CC=CC=C1 JKVGSSMZDIFZSF-UXPWSPDFSA-N 0.000 claims description 2
- XIXXFELFCFBDOU-OLKLTNODSA-N 4-[5-[(1s,4s)-2-butan-2-yl-2,5-diazabicyclo[2.2.1]heptan-5-yl]imidazo[1,2-c]pyrimidin-7-yl]-n-[(1s)-1-phenylethyl]pyridin-2-amine Chemical compound C1([C@H](C)NC=2N=CC=C(C=2)C=2N=C(N3C=CN=C3C=2)N2C[C@]3(N(C[C@]2([H])C3)C(C)CC)[H])=CC=CC=C1 XIXXFELFCFBDOU-OLKLTNODSA-N 0.000 claims description 2
- BRIYHAYUDAJLJV-VJBMBRPKSA-N 4-[5-[(1s,4s)-2-tert-butyl-2,5-diazabicyclo[2.2.1]heptan-5-yl]imidazo[1,2-c]pyrimidin-7-yl]-n-[(1s)-1-phenylethyl]pyridin-2-amine Chemical compound C1([C@H](C)NC=2N=CC=C(C=2)C=2N=C(N3C=CN=C3C=2)N2C[C@]3(N(C[C@@]2(C3)[H])C(C)(C)C)[H])=CC=CC=C1 BRIYHAYUDAJLJV-VJBMBRPKSA-N 0.000 claims description 2
- NBMSKMMNDPHSAZ-DKICCIFJSA-N 4-[5-[(1s,4s)-3-methyl-2-propan-2-yl-2,5-diazabicyclo[2.2.1]heptan-5-yl]imidazo[1,2-c]pyrimidin-7-yl]-n-[(1s)-1-phenylethyl]pyridin-2-amine Chemical compound C1([C@H](C)NC=2N=CC=C(C=2)C=2N=C(N3C=CN=C3C=2)N2C[C@@]3(C[C@@]2([H])C(C)N3C(C)C)[H])=CC=CC=C1 NBMSKMMNDPHSAZ-DKICCIFJSA-N 0.000 claims description 2
- XHQNKBJBTQDUFF-ZVJDSTMCSA-N 4-[5-[(1s,4s)-5-(2,2-difluoroethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]imidazo[1,2-c]pyrimidin-7-yl]-n-[(1s)-1-phenylethyl]-3h-pyridin-4-amine Chemical compound C([C@]1(N(C[C@]2([H])C1)CC(F)F)[H])N2C(N1C=CN=C1C=1)=NC=1C1(N[C@@H](C)C=2C=CC=CC=2)CC=NC=C1 XHQNKBJBTQDUFF-ZVJDSTMCSA-N 0.000 claims description 2
- GUHQBASITAZOSX-OYDLWJJNSA-N 4-[5-[(1s,4s)-5-(2-methylpropyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]imidazo[1,2-c]pyrimidin-7-yl]-n-[(1s)-1-phenylethyl]pyridin-2-amine Chemical compound C1([C@H](C)NC=2N=CC=C(C=2)C=2N=C(N3C=CN=C3C=2)N2C[C@]3(N(C[C@]2([H])C3)CC(C)C)[H])=CC=CC=C1 GUHQBASITAZOSX-OYDLWJJNSA-N 0.000 claims description 2
- BBLOJEWCGIQPDH-YGPDHOBYSA-N 4-[5-[(1s,4s)-5-(2-phenoxyethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]imidazo[1,2-c]pyrimidin-7-yl]-n-[(1s)-1-phenylethyl]pyridin-2-amine Chemical compound C1([C@H](C)NC=2N=CC=C(C=2)C=2N=C(N3C=CN=C3C=2)N2C[C@]3(N(C[C@]2([H])C3)CCOC=2C=CC=CC=2)[H])=CC=CC=C1 BBLOJEWCGIQPDH-YGPDHOBYSA-N 0.000 claims description 2
- QGKQXIRIUYZUDY-CAVYSCNFSA-N 4-[5-[(1s,4s)-5-benzyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]imidazo[1,2-c]pyrimidin-7-yl]-n-[(1s)-1-phenylethyl]pyridin-2-amine Chemical compound C1([C@H](C)NC=2N=CC=C(C=2)C=2N=C(N3C=CN=C3C=2)N2C[C@]3(N(C[C@]2([H])C3)CC=2C=CC=CC=2)[H])=CC=CC=C1 QGKQXIRIUYZUDY-CAVYSCNFSA-N 0.000 claims description 2
- XKSYHHVIDRYCNU-OYDLWJJNSA-N 4-[5-[(1s,4s)-5-butyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]imidazo[1,2-c]pyrimidin-7-yl]-n-[(1s)-1-phenylethyl]pyridin-2-amine Chemical compound C1([C@H](C)NC=2N=CC=C(C=2)C=2N=C(N3C=CN=C3C=2)N2C[C@]3(N(C[C@]2([H])C3)CCCC)[H])=CC=CC=C1 XKSYHHVIDRYCNU-OYDLWJJNSA-N 0.000 claims description 2
- UALKGXILIOUUGQ-OPXMRZJTSA-N 4-[5-[(1s,4s)-5-cyclopentyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]imidazo[1,2-c]pyrimidin-7-yl]-n-[(1s)-1-phenylethyl]pyridin-2-amine Chemical compound C1([C@H](C)NC=2N=CC=C(C=2)C=2N=C(N3C=CN=C3C=2)N2C[C@]3(N(C[C@]2([H])C3)C2CCCC2)[H])=CC=CC=C1 UALKGXILIOUUGQ-OPXMRZJTSA-N 0.000 claims description 2
- YWLVWOCNSRYDHO-YYWHXJBOSA-N 4-[5-[(1s,4s)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]imidazo[1,2-c]pyrimidin-7-yl]-n-[(1s)-1-phenylethyl]pyridin-2-amine Chemical compound C1([C@H](C)NC=2N=CC=C(C=2)C=2N=C(N3C=CN=C3C=2)N2C[C@]3(N(C[C@]2([H])C3)C)[H])=CC=CC=C1 YWLVWOCNSRYDHO-YYWHXJBOSA-N 0.000 claims description 2
- MTFKWAAUPVJALN-SNRMKQJTSA-N 4-[6-[(1s,4s)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-2-methylsulfanylpyrimidin-4-yl]-n-[(1s)-1-phenylethyl]pyridin-2-amine Chemical compound C1([C@H](C)NC=2N=CC=C(C=2)C=2C=C(N=C(SC)N=2)N2C[C@]3(NC[C@]2([H])C3)[H])=CC=CC=C1 MTFKWAAUPVJALN-SNRMKQJTSA-N 0.000 claims description 2
- 230000001413 cellular effect Effects 0.000 claims description 2
- CRZSXSCVAOQWRE-OYDLWJJNSA-N n-(2,2-dimethoxyethyl)-6-[2-[[(1s)-1-phenylethyl]amino]pyridin-4-yl]-2-[(1s,4s)-2-propan-2-yl-2,5-diazabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-amine Chemical compound C1([C@H](C)NC=2N=CC=C(C=2)C=2C=C(NCC(OC)OC)N=C(N=2)N2C[C@]3(N(C[C@]2([H])C3)C(C)C)[H])=CC=CC=C1 CRZSXSCVAOQWRE-OYDLWJJNSA-N 0.000 claims description 2
- ATQRNTSLYSZOSI-OIBXWCBGSA-N n-[(1r)-1-phenylethyl]-4-[5-[(1s,4s)-2-propan-2-yl-2,5-diazabicyclo[2.2.1]heptan-5-yl]imidazo[1,2-c]pyrimidin-7-yl]pyridin-2-amine Chemical compound C1([C@@H](C)NC=2N=CC=C(C=2)C=2N=C(N3C=CN=C3C=2)N2C[C@]3(N(C[C@]2([H])C3)C(C)C)[H])=CC=CC=C1 ATQRNTSLYSZOSI-OIBXWCBGSA-N 0.000 claims description 2
- AWAZGPBUVSVEEK-OYDLWJJNSA-N n-[(1s)-1-naphthalen-1-ylethyl]-4-[5-[(1s,4s)-2-propan-2-yl-2,5-diazabicyclo[2.2.1]heptan-5-yl]-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]pyridin-2-amine Chemical compound C1=CC=C2C([C@H](C)NC=3N=CC=C(C=3)C=3N=C(N4N=CN=C4C=3)N3C[C@]4(N(C[C@]3([H])C4)C(C)C)[H])=CC=CC2=C1 AWAZGPBUVSVEEK-OYDLWJJNSA-N 0.000 claims description 2
- PYLNCHYZWPUCNK-TUSQITKMSA-N n-[(1s)-1-phenylethyl]-4-[4-[(1s,4s)-2-propan-2-yl-2,5-diazabicyclo[2.2.1]heptan-5-yl]quinolin-2-yl]pyridin-2-amine Chemical compound C1([C@H](C)NC=2N=CC=C(C=2)C=2C=C(C3=CC=CC=C3N=2)N2C[C@]3(N(C[C@]2([H])C3)C(C)C)[H])=CC=CC=C1 PYLNCHYZWPUCNK-TUSQITKMSA-N 0.000 claims description 2
- FQVUVUVONWTCJN-VJBMBRPKSA-N n-[(1s)-1-phenylethyl]-4-[5-[(1s,4s)-5-propyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]imidazo[1,2-c]pyrimidin-7-yl]pyridin-2-amine Chemical compound C1([C@H](C)NC=2N=CC=C(C=2)C=2N=C(N3C=CN=C3C=2)N2C[C@]3(N(C[C@]2([H])C3)CCC)[H])=CC=CC=C1 FQVUVUVONWTCJN-VJBMBRPKSA-N 0.000 claims description 2
- 238000001959 radiotherapy Methods 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- VBRRTWCBLMRCLU-OYDLWJJNSA-N tert-butyl (1s,4s)-5-[1-[2-[[(1s)-1-phenylethyl]amino]pyridin-4-yl]indazol-3-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate Chemical compound C1([C@H](C)NC=2N=CC=C(C=2)N2N=C(C3=CC=CC=C32)N2C[C@]3(N(C[C@]2([H])C3)C(=O)OC(C)(C)C)[H])=CC=CC=C1 VBRRTWCBLMRCLU-OYDLWJJNSA-N 0.000 claims description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims 4
- LYLWBIPQXXROQN-UHFFFAOYSA-N CC(C)N(CC1C2)C2CN1C1=NC(C2=CC=CN=C2NCC2=CC=CC3=CC=CC=C23)=CC2=NC=CN12 Chemical compound CC(C)N(CC1C2)C2CN1C1=NC(C2=CC=CN=C2NCC2=CC=CC3=CC=CC=C23)=CC2=NC=CN12 LYLWBIPQXXROQN-UHFFFAOYSA-N 0.000 claims 1
- 206010030113 Oedema Diseases 0.000 claims 1
- 208000020424 Polyglandular disease Diseases 0.000 claims 1
- 230000003213 activating effect Effects 0.000 claims 1
- DTIGGPHKRSURDR-DQEYMECFSA-N n-(naphthalen-1-ylmethyl)-4-[5-[(1s,4s)-2-propan-2-yl-2,5-diazabicyclo[2.2.1]heptan-5-yl]imidazo[1,2-c]pyrimidin-7-yl]pyridin-2-amine Chemical compound C1=CC=C2C(CNC=3N=CC=C(C=3)C=3N=C(N4C=CN=C4C=3)N3C[C@]4(N(C[C@]3([H])C4)C(C)C)[H])=CC=CC2=C1 DTIGGPHKRSURDR-DQEYMECFSA-N 0.000 claims 1
- CHCSYRDEXKBZGG-YYWHXJBOSA-N n-[(1s)-1-phenylethyl]-4-[2-[(1s,4s)-2-propan-2-yl-2,5-diazabicyclo[2.2.1]heptan-5-yl]-1,3-thiazol-4-yl]pyridin-2-amine Chemical compound C1([C@H](C)NC=2N=CC=C(C=2)C=2N=C(SC=2)N2C[C@]3(N(C[C@]2([H])C3)C(C)C)[H])=CC=CC=C1 CHCSYRDEXKBZGG-YYWHXJBOSA-N 0.000 claims 1
- CZSYKLHLDRGUJW-OYDLWJJNSA-N n-[(1s)-1-phenylethyl]-4-[3-[(1s,4s)-2-propan-2-yl-2,5-diazabicyclo[2.2.1]heptan-5-yl]indazol-1-yl]pyridin-2-amine Chemical compound C1([C@H](C)NC=2N=CC=C(C=2)N2N=C(C3=CC=CC=C32)N2C[C@]3(N(C[C@]2([H])C3)C(C)C)[H])=CC=CC=C1 CZSYKLHLDRGUJW-OYDLWJJNSA-N 0.000 claims 1
- DMVHEESFRSZGIP-OCPXOFMESA-N n-[(1s)-1-phenylethyl]-4-[5-[(1s,4s)-2-(1,1,1-trifluoropropan-2-yl)-2,5-diazabicyclo[2.2.1]heptan-5-yl]imidazo[1,2-c]pyrimidin-7-yl]pyridin-2-amine Chemical compound C1([C@H](C)NC=2N=CC=C(C=2)C=2N=C(N3C=CN=C3C=2)N2C[C@]3(N(C[C@]2([H])C3)C(C)C(F)(F)F)[H])=CC=CC=C1 DMVHEESFRSZGIP-OCPXOFMESA-N 0.000 claims 1
- AIHQJENGTXVKMP-NYVOZVTQSA-N n-[(1s)-1-phenylethyl]-4-[5-[(1s,4s)-2-propan-2-yl-2,5-diazabicyclo[2.2.1]heptan-5-yl]-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]pyridin-2-amine Chemical compound C1([C@H](C)NC=2N=CC=C(C=2)C=2N=C(N3N=CN=C3C=2)N2C[C@]3(N(C[C@]2([H])C3)C(C)C)[H])=CC=CC=C1 AIHQJENGTXVKMP-NYVOZVTQSA-N 0.000 claims 1
- TZRHQHMCEFZZPQ-SFTDATJTSA-N n-[(2-fluorophenyl)methyl]-4-[5-[(1s,4s)-2-propan-2-yl-2,5-diazabicyclo[2.2.1]heptan-5-yl]imidazo[1,2-c]pyrimidin-7-yl]pyridin-2-amine Chemical compound C([C@]1(N(C[C@]2([H])C1)C(C)C)[H])N2C(N1C=CN=C1C=1)=NC=1C(C=1)=CC=NC=1NCC1=CC=CC=C1F TZRHQHMCEFZZPQ-SFTDATJTSA-N 0.000 claims 1
- RSWBCBOTSKKQOL-VXKWHMMOSA-N n-benzyl-4-[5-[(1s,4s)-2-propan-2-yl-2,5-diazabicyclo[2.2.1]heptan-5-yl]imidazo[1,2-c]pyrimidin-7-yl]pyridin-2-amine Chemical compound C([C@]1(N(C[C@]2([H])C1)C(C)C)[H])N2C(N1C=CN=C1C=1)=NC=1C(C=1)=CC=NC=1NCC1=CC=CC=C1 RSWBCBOTSKKQOL-VXKWHMMOSA-N 0.000 claims 1
- 125000000547 substituted alkyl group Chemical group 0.000 claims 1
- 238000011282 treatment Methods 0.000 abstract description 23
- 208000000389 T-cell leukemia Diseases 0.000 abstract description 5
- 208000028530 T-cell lymphoblastic leukemia/lymphoma Diseases 0.000 abstract description 4
- 230000001225 therapeutic effect Effects 0.000 abstract description 4
- 230000005784 autoimmunity Effects 0.000 abstract description 2
- 210000000481 breast Anatomy 0.000 abstract description 2
- 230000000241 respiratory effect Effects 0.000 abstract description 2
- 208000003200 Adenoma Diseases 0.000 abstract 1
- 206010003645 Atopy Diseases 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 198
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 170
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 129
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 120
- 239000007787 solid Substances 0.000 description 79
- 239000011734 sodium Substances 0.000 description 77
- 238000000746 purification Methods 0.000 description 71
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 60
- 238000003818 flash chromatography Methods 0.000 description 49
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 42
- 239000007858 starting material Substances 0.000 description 42
- 238000006243 chemical reaction Methods 0.000 description 39
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 36
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 36
- 239000011541 reaction mixture Substances 0.000 description 34
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 32
- 235000019439 ethyl acetate Nutrition 0.000 description 30
- 239000000243 solution Substances 0.000 description 30
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 27
- 210000004027 cell Anatomy 0.000 description 22
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 20
- 230000000694 effects Effects 0.000 description 20
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
- 239000003112 inhibitor Substances 0.000 description 18
- 239000012044 organic layer Substances 0.000 description 18
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 17
- 239000012267 brine Substances 0.000 description 17
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 17
- 238000004587 chromatography analysis Methods 0.000 description 16
- 239000012043 crude product Substances 0.000 description 16
- 239000003814 drug Substances 0.000 description 16
- 238000003556 assay Methods 0.000 description 15
- 238000004519 manufacturing process Methods 0.000 description 15
- 102000000588 Interleukin-2 Human genes 0.000 description 13
- 108010002350 Interleukin-2 Proteins 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 101001051777 Homo sapiens Protein kinase C alpha type Proteins 0.000 description 12
- 108090000315 Protein Kinase C Proteins 0.000 description 12
- 102000003923 Protein Kinase C Human genes 0.000 description 12
- 102100024924 Protein kinase C alpha type Human genes 0.000 description 12
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 11
- 235000019441 ethanol Nutrition 0.000 description 11
- 238000004128 high performance liquid chromatography Methods 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- RQEUFEKYXDPUSK-ZETCQYMHSA-N (1S)-1-phenylethanamine Chemical compound C[C@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-ZETCQYMHSA-N 0.000 description 10
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
- 102000009516 Protein Serine-Threonine Kinases Human genes 0.000 description 10
- 108010009341 Protein Serine-Threonine Kinases Proteins 0.000 description 10
- 108091008874 T cell receptors Proteins 0.000 description 10
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 10
- 150000001412 amines Chemical class 0.000 description 10
- 239000007788 liquid Substances 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 230000005587 bubbling Effects 0.000 description 9
- 239000010410 layer Substances 0.000 description 9
- UXAWXZDXVOYLII-UHFFFAOYSA-N tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate Chemical compound C1C2N(C(=O)OC(C)(C)C)CC1NC2 UXAWXZDXVOYLII-UHFFFAOYSA-N 0.000 description 9
- 108010044467 Isoenzymes Proteins 0.000 description 8
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- IGRLNCOFYMWKBU-UHFFFAOYSA-N ethyl 2-chloropyridine-4-carboxylate Chemical compound CCOC(=O)C1=CC=NC(Cl)=C1 IGRLNCOFYMWKBU-UHFFFAOYSA-N 0.000 description 8
- VQESHCXOMUBUOE-UHFFFAOYSA-N ethyl 3-(2-chloropyridin-4-yl)-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)C1=CC=NC(Cl)=C1 VQESHCXOMUBUOE-UHFFFAOYSA-N 0.000 description 8
- 210000005104 human peripheral blood lymphocyte Anatomy 0.000 description 8
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 8
- 229940002612 prodrug Drugs 0.000 description 8
- 239000000651 prodrug Substances 0.000 description 8
- 125000006239 protecting group Chemical group 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
- 230000004913 activation Effects 0.000 description 7
- 125000003710 aryl alkyl group Chemical group 0.000 description 7
- 210000003630 histaminocyte Anatomy 0.000 description 7
- WYAKPHAFBORCJU-UHFFFAOYSA-N 4-chloro-6-(2-chloropyridin-4-yl)-2-methylsulfanylpyrimidine Chemical compound CSC1=NC(Cl)=CC(C=2C=C(Cl)N=CC=2)=N1 WYAKPHAFBORCJU-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 102000004127 Cytokines Human genes 0.000 description 6
- 108090000695 Cytokines Proteins 0.000 description 6
- 108091000080 Phosphotransferase Proteins 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- 239000008280 blood Substances 0.000 description 6
- 229910002091 carbon monoxide Inorganic materials 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 6
- 102000020233 phosphotransferase Human genes 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 108090000623 proteins and genes Proteins 0.000 description 6
- 230000028327 secretion Effects 0.000 description 6
- QBVIAVCHWMDZEE-UHFFFAOYSA-N 6-(2-chloropyridin-4-yl)-n-(2,2-dimethoxyethyl)-2-methylsulfanylpyrimidin-4-amine Chemical compound CSC1=NC(NCC(OC)OC)=CC(C=2C=C(Cl)N=CC=2)=N1 QBVIAVCHWMDZEE-UHFFFAOYSA-N 0.000 description 5
- GRIOWTNZRKWBRR-UHFFFAOYSA-N 7-(2-chloropyridin-4-yl)-6h-imidazo[1,2-c]pyrimidin-5-one Chemical compound C=1C2=NC=CN2C(O)=NC=1C1=CC=NC(Cl)=C1 GRIOWTNZRKWBRR-UHFFFAOYSA-N 0.000 description 5
- 206010012688 Diabetic retinal oedema Diseases 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- 101001051767 Homo sapiens Protein kinase C beta type Proteins 0.000 description 5
- 102100024923 Protein kinase C beta type Human genes 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
- 239000002671 adjuvant Substances 0.000 description 5
- 229940024606 amino acid Drugs 0.000 description 5
- 125000003118 aryl group Chemical group 0.000 description 5
- 210000003719 b-lymphocyte Anatomy 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 201000011190 diabetic macular edema Diseases 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 230000006870 function Effects 0.000 description 5
- 238000002868 homogeneous time resolved fluorescence Methods 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 230000036457 multidrug resistance Effects 0.000 description 5
- 210000000440 neutrophil Anatomy 0.000 description 5
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- 230000035755 proliferation Effects 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- ZCBUQCWBWNUWSU-SFHVURJKSA-N ruboxistaurin Chemical compound O=C1NC(=O)C2=C1C(C1=CC=CC=C11)=CN1CCO[C@H](CN(C)C)CCN1C3=CC=CC=C3C2=C1 ZCBUQCWBWNUWSU-SFHVURJKSA-N 0.000 description 5
- 230000019491 signal transduction Effects 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 4
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 description 4
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
- XVXJVHGOGUUFCV-UHFFFAOYSA-N 5-chloro-7-(2-chloropyridin-4-yl)imidazo[1,2-c]pyrimidine Chemical compound C1=NC(Cl)=CC(C=2N=C(Cl)N3C=CN=C3C=2)=C1 XVXJVHGOGUUFCV-UHFFFAOYSA-N 0.000 description 4
- RHICYBDTZDMHOL-UHFFFAOYSA-N 6-(2-chloropyridin-4-yl)-2-methylsulfanyl-1h-pyrimidin-4-one Chemical compound O=C1NC(SC)=NC(C=2C=C(Cl)N=CC=2)=C1 RHICYBDTZDMHOL-UHFFFAOYSA-N 0.000 description 4
- 0 CC(N=C(C)N1*)=C(*)C1=O Chemical compound CC(N=C(C)N1*)=C(*)C1=O 0.000 description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 4
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 description 4
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
- 239000012895 dilution Substances 0.000 description 4
- 239000000975 dye Substances 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 230000014509 gene expression Effects 0.000 description 4
- 125000000623 heterocyclic group Chemical group 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 210000002540 macrophage Anatomy 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 230000003211 malignant effect Effects 0.000 description 4
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 4
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 4
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 4
- 239000006228 supernatant Substances 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- DRCWDHQXGIVRKV-UHFFFAOYSA-N tert-butyl 5-[7-(2-chloropyridin-4-yl)imidazo[1,2-c]pyrimidin-5-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC2CC1CN2C(N1C=CN=C1C=1)=NC=1C1=CC=NC(Cl)=C1 DRCWDHQXGIVRKV-UHFFFAOYSA-N 0.000 description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 4
- 229940124597 therapeutic agent Drugs 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- 229940104230 thymidine Drugs 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- QXCOHSRHFCHCHN-UHFFFAOYSA-N 2-chloropyridine-4-carboxylic acid Chemical compound OC(=O)C1=CC=NC(Cl)=C1 QXCOHSRHFCHCHN-UHFFFAOYSA-N 0.000 description 3
- WBUDEGTYTUJGIV-ROUUACIJSA-N 4-[5-[(1s,4s)-2,5-diazabicyclo[2.2.1]heptan-2-yl]imidazo[1,2-c]pyrimidin-7-yl]-n-[(2-fluorophenyl)methyl]pyridin-2-amine Chemical compound C([C@]1(NC[C@]2([H])C1)[H])N2C(N1C=CN=C1C=1)=NC=1C(C=1)=CC=NC=1NCC1=CC=CC=C1F WBUDEGTYTUJGIV-ROUUACIJSA-N 0.000 description 3
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N Butyraldehyde Chemical compound CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- BFPYWIDHMRZLRN-SLHNCBLASA-N Ethinyl estradiol Chemical group OC1=CC=C2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 BFPYWIDHMRZLRN-SLHNCBLASA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000002159 abnormal effect Effects 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 230000003110 anti-inflammatory effect Effects 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000007327 hydrogenolysis reaction Methods 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 238000010348 incorporation Methods 0.000 description 3
- 239000003701 inert diluent Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000006187 pill Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 230000009696 proliferative response Effects 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 235000018102 proteins Nutrition 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 238000012552 review Methods 0.000 description 3
- 229950000261 ruboxistaurin Drugs 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 210000002027 skeletal muscle Anatomy 0.000 description 3
- 150000003384 small molecules Chemical class 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 3
- UXAWXZDXVOYLII-JAMMHHFISA-N tert-butyl (4s)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate Chemical compound C1C2CN[C@]1([H])CN2C(=O)OC(C)(C)C UXAWXZDXVOYLII-JAMMHHFISA-N 0.000 description 3
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 3
- 125000003396 thiol group Chemical group [H]S* 0.000 description 3
- 239000000080 wetting agent Substances 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- QGPMEPLSFKEQBA-MTICXXPYSA-N (1s)-2-propan-2-yl-2,5-diazabicyclo[2.2.1]heptane;hydrochloride Chemical compound Cl.C1NC2CN(C(C)C)[C@@]1([H])C2 QGPMEPLSFKEQBA-MTICXXPYSA-N 0.000 description 2
- LRFWYBZWRQWZIM-UHFFFAOYSA-N (2-fluorophenyl)methanamine Chemical compound NCC1=CC=CC=C1F LRFWYBZWRQWZIM-UHFFFAOYSA-N 0.000 description 2
- ZJCGPQZERFBGSM-UHFFFAOYSA-N 1-(2-chloropyridin-4-yl)ethanone Chemical compound CC(=O)C1=CC=NC(Cl)=C1 ZJCGPQZERFBGSM-UHFFFAOYSA-N 0.000 description 2
- MNMDZSAWTQOEHX-BDAKNGLRSA-N 1-o-tert-butyl 2-o-ethyl (2s,4r)-4-hydroxypyrrolidine-1,2-dicarboxylate Chemical compound CCOC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C MNMDZSAWTQOEHX-BDAKNGLRSA-N 0.000 description 2
- OEGMTFRNUKJZNO-UHFFFAOYSA-N 2-(2-chloropyridin-4-yl)-1h-quinolin-4-one Chemical compound N=1C2=CC=CC=C2C(O)=CC=1C1=CC=NC(Cl)=C1 OEGMTFRNUKJZNO-UHFFFAOYSA-N 0.000 description 2
- PXBFMLJZNCDSMP-UHFFFAOYSA-N 2-Aminobenzamide Chemical compound NC(=O)C1=CC=CC=C1N PXBFMLJZNCDSMP-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- ACYHAAZAFBDUHT-UHFFFAOYSA-N 2-[[6-(2-chloropyridin-4-yl)-2-methylsulfanylpyrimidin-4-yl]amino]ethanol Chemical compound CSC1=NC(NCCO)=CC(C=2C=C(Cl)N=CC=2)=N1 ACYHAAZAFBDUHT-UHFFFAOYSA-N 0.000 description 2
- RRKPMLZRLKTDQV-UHFFFAOYSA-N 2-bromo-4-fluorobenzoic acid Chemical compound OC(=O)C1=CC=C(F)C=C1Br RRKPMLZRLKTDQV-UHFFFAOYSA-N 0.000 description 2
- XRXMNWGCKISMOH-UHFFFAOYSA-N 2-bromobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1Br XRXMNWGCKISMOH-UHFFFAOYSA-N 0.000 description 2
- GHISNTVCGGIMRA-UHFFFAOYSA-N 2-chloro-1-(2-chloropyridin-4-yl)ethanone Chemical compound ClCC(=O)C1=CC=NC(Cl)=C1 GHISNTVCGGIMRA-UHFFFAOYSA-N 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- INSOGOCJEZANTA-UHFFFAOYSA-N 4-(2-chloropyridin-4-yl)-6-methyl-2-methylsulfonylpyrimidine Chemical compound CS(=O)(=O)C1=NC(C)=CC(C=2C=C(Cl)N=CC=2)=N1 INSOGOCJEZANTA-UHFFFAOYSA-N 0.000 description 2
- WXCARTUZUBOCGO-UHFFFAOYSA-N 4-chloro-2-(2-chloropyridin-4-yl)quinazoline Chemical compound C1=NC(Cl)=CC(C=2N=C3C=CC=CC3=C(Cl)N=2)=C1 WXCARTUZUBOCGO-UHFFFAOYSA-N 0.000 description 2
- YWTFFBXMIBPNTH-GJZGRUSLSA-N 5-[(1s,4s)-2-tert-butyl-2,5-diazabicyclo[2.2.1]heptan-5-yl]-7-(2-chloropyridin-4-yl)imidazo[1,2-c]pyrimidine Chemical compound C([C@]1(N(C[C@@]2(C1)[H])C(C)(C)C)[H])N2C(N1C=CN=C1C=1)=NC=1C1=CC=NC(Cl)=C1 YWTFFBXMIBPNTH-GJZGRUSLSA-N 0.000 description 2
- CXSLWWNSXUZQBN-UHFFFAOYSA-N 6-(2-chloropyridin-4-yl)-3-methyl-2-methylsulfanylpyrimidin-4-one Chemical compound O=C1N(C)C(SC)=NC(C=2C=C(Cl)N=CC=2)=C1 CXSLWWNSXUZQBN-UHFFFAOYSA-N 0.000 description 2
- MDDHLLIVOCWBHU-UHFFFAOYSA-N 6-(2-chloropyridin-4-yl)-n-(2,2-dimethoxyethyl)-2-(2-propan-2-yl-2,5-diazabicyclo[2.2.1]heptan-5-yl)pyrimidin-4-amine Chemical compound N=1C(N2C3CC(N(C3)C(C)C)C2)=NC(NCC(OC)OC)=CC=1C1=CC=NC(Cl)=C1 MDDHLLIVOCWBHU-UHFFFAOYSA-N 0.000 description 2
- ARMTWGOJFFCUKB-UHFFFAOYSA-N 6-(2-chloropyridin-4-yl)-n-(2,2-dimethoxyethyl)-2-methylsulfinylpyrimidin-4-amine Chemical compound CS(=O)C1=NC(NCC(OC)OC)=CC(C=2C=C(Cl)N=CC=2)=N1 ARMTWGOJFFCUKB-UHFFFAOYSA-N 0.000 description 2
- 102100033350 ATP-dependent translocase ABCB1 Human genes 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- PMCOWOCKUQWYRL-UHFFFAOYSA-N Cc1nc(C)ncc1 Chemical compound Cc1nc(C)ncc1 PMCOWOCKUQWYRL-UHFFFAOYSA-N 0.000 description 2
- QMLVECGLEOSESV-RYUDHWBXSA-N Danofloxacin Chemical compound C([C@@H]1C[C@H]2CN1C)N2C(C(=CC=1C(=O)C(C(O)=O)=C2)F)=CC=1N2C1CC1 QMLVECGLEOSESV-RYUDHWBXSA-N 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 208000001204 Hashimoto Disease Diseases 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 102000000589 Interleukin-1 Human genes 0.000 description 2
- 108010002352 Interleukin-1 Proteins 0.000 description 2
- 102000004889 Interleukin-6 Human genes 0.000 description 2
- 108090001005 Interleukin-6 Proteins 0.000 description 2
- 102000004890 Interleukin-8 Human genes 0.000 description 2
- 108090001007 Interleukin-8 Proteins 0.000 description 2
- AMIMRNSIRUDHCM-UHFFFAOYSA-N Isopropylaldehyde Chemical compound CC(C)C=O AMIMRNSIRUDHCM-UHFFFAOYSA-N 0.000 description 2
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 2
- 229930182816 L-glutamine Natural products 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 108010047230 Member 1 Subfamily B ATP Binding Cassette Transporter Proteins 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 description 2
- 102000001253 Protein Kinase Human genes 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 230000006052 T cell proliferation Effects 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 2
- 235000011054 acetic acid Nutrition 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 2
- 230000000735 allogeneic effect Effects 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 210000003651 basophil Anatomy 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 125000005605 benzo group Chemical group 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000003560 cancer drug Substances 0.000 description 2
- 230000003915 cell function Effects 0.000 description 2
- 238000001516 cell proliferation assay Methods 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- SPWVRYZQLGQKGK-UHFFFAOYSA-N dichloromethane;hexane Chemical compound ClCCl.CCCCCC SPWVRYZQLGQKGK-UHFFFAOYSA-N 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000012897 dilution medium Substances 0.000 description 2
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 2
- 208000037765 diseases and disorders Diseases 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- HHXSZDXMSRXWJV-IBTYICNHSA-N ethyl (2s,4r)-4-hydroxypyrrolidine-2-carboxylate;hydrochloride Chemical compound Cl.CCOC(=O)[C@@H]1C[C@@H](O)CN1 HHXSZDXMSRXWJV-IBTYICNHSA-N 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 239000003365 glass fiber Substances 0.000 description 2
- 229940074045 glyceryl distearate Drugs 0.000 description 2
- 229940075507 glyceryl monostearate Drugs 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 125000001072 heteroaryl group Chemical group 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 210000002865 immune cell Anatomy 0.000 description 2
- 230000001900 immune effect Effects 0.000 description 2
- 230000028993 immune response Effects 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 2
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 2
- 208000027866 inflammatory disease Diseases 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 230000004073 interleukin-2 production Effects 0.000 description 2
- 229940100601 interleukin-6 Drugs 0.000 description 2
- XKTZWUACRZHVAN-VADRZIEHSA-N interleukin-8 Chemical compound C([C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@@H](NC(C)=O)CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CCSC)C(=O)N1[C@H](CCC1)C(=O)N1[C@H](CCC1)C(=O)N[C@@H](C)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC=1C=CC(O)=CC=1)C(=O)N[C@H](CO)C(=O)N1[C@H](CCC1)C(N)=O)C1=CC=CC=C1 XKTZWUACRZHVAN-VADRZIEHSA-N 0.000 description 2
- 229940096397 interleukin-8 Drugs 0.000 description 2
- 208000028867 ischemia Diseases 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 210000001616 monocyte Anatomy 0.000 description 2
- CZSYKLHLDRGUJW-BMTNDILFSA-N n-(1-phenylethyl)-4-[3-[(1s,4s)-2-propan-2-yl-2,5-diazabicyclo[2.2.1]heptan-5-yl]indazol-1-yl]pyridin-2-amine Chemical compound C([C@]1(N(C[C@]2([H])C1)C(C)C)[H])N2C(C1=CC=CC=C11)=NN1C(C=1)=CC=NC=1NC(C)C1=CC=CC=C1 CZSYKLHLDRGUJW-BMTNDILFSA-N 0.000 description 2
- PYLNCHYZWPUCNK-MHKYCTGGSA-N n-(1-phenylethyl)-4-[4-[(1s,4s)-2-propan-2-yl-2,5-diazabicyclo[2.2.1]heptan-5-yl]quinolin-2-yl]pyridin-2-amine Chemical compound C([C@]1(N(C[C@]2([H])C1)C(C)C)[H])N2C(C1=CC=CC=C1N=1)=CC=1C(C=1)=CC=NC=1NC(C)C1=CC=CC=C1 PYLNCHYZWPUCNK-MHKYCTGGSA-N 0.000 description 2
- XZSCQXCGJYANCB-UHFFFAOYSA-N n-[2-[tert-butyl(diphenyl)silyl]oxyethyl]-6-(2-chloropyridin-4-yl)-2-methylsulfinylpyrimidin-4-amine Chemical compound C=1C(C=2C=C(Cl)N=CC=2)=NC(S(=O)C)=NC=1NCCO[Si](C(C)(C)C)(C=1C=CC=CC=1)C1=CC=CC=C1 XZSCQXCGJYANCB-UHFFFAOYSA-N 0.000 description 2
- 239000000346 nonvolatile oil Substances 0.000 description 2
- 239000012038 nucleophile Substances 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 230000026731 phosphorylation Effects 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 230000000069 prophylactic effect Effects 0.000 description 2
- 238000011321 prophylaxis Methods 0.000 description 2
- 108060006633 protein kinase Proteins 0.000 description 2
- 208000009954 pyoderma gangrenosum Diseases 0.000 description 2
- 210000000664 rectum Anatomy 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 238000011808 rodent model Methods 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- 238000006884 silylation reaction Methods 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- JUJBNYBVVQSIOU-UHFFFAOYSA-M sodium;4-[2-(4-iodophenyl)-3-(4-nitrophenyl)tetrazol-2-ium-5-yl]benzene-1,3-disulfonate Chemical compound [Na+].C1=CC([N+](=O)[O-])=CC=C1N1[N+](C=2C=CC(I)=CC=2)=NC(C=2C(=CC(=CC=2)S([O-])(=O)=O)S([O-])(=O)=O)=N1 JUJBNYBVVQSIOU-UHFFFAOYSA-M 0.000 description 2
- 239000007909 solid dosage form Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 229960005322 streptomycin Drugs 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- LIZVWJJFLOXLII-ZUEZHPSSSA-N tert-butyl (1r)-5-[7-[2-(1-phenylethylamino)pyridin-4-yl]imidazo[1,2-c]pyrimidin-5-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate Chemical compound C([C@@](N(C1)C(=O)OC(C)(C)C)(C2)[H])C1N2C(N1C=CN=C1C=1)=NC=1C(C=1)=CC=NC=1NC(C)C1=CC=CC=C1 LIZVWJJFLOXLII-ZUEZHPSSSA-N 0.000 description 2
- UXAWXZDXVOYLII-YUMQZZPRSA-N tert-butyl (1s,4s)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate Chemical compound C1[C@@H]2N(C(=O)OC(C)(C)C)C[C@H]1NC2 UXAWXZDXVOYLII-YUMQZZPRSA-N 0.000 description 2
- NJBRZZCPRDXTKN-GJZUVCINSA-N tert-butyl (2S,4R)-4-[tert-butyl(diphenyl)silyl]-2-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate Chemical compound C(C)(C)(C)OC(=O)N1[C@](C[C@H](C1)[Si](C1=CC=CC=C1)(C1=CC=CC=C1)C(C)(C)C)(CO)O NJBRZZCPRDXTKN-GJZUVCINSA-N 0.000 description 2
- QUSBMWKWKFSNBI-UHFFFAOYSA-N tert-butyl 5-[2-(2-chloropyridin-4-yl)quinolin-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC2CC1CN2C(C1=CC=CC=C1N=1)=CC=1C1=CC=NC(Cl)=C1 QUSBMWKWKFSNBI-UHFFFAOYSA-N 0.000 description 2
- LOVMVLNCUDYXSP-UHFFFAOYSA-N tert-butyl 5-[2-methylsulfanyl-6-[2-(1-phenylethylamino)pyridin-4-yl]pyrimidin-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate Chemical compound N=1C(SC)=NC(N2C3CC(N(C3)C(=O)OC(C)(C)C)C2)=CC=1C(C=1)=CC=NC=1NC(C)C1=CC=CC=C1 LOVMVLNCUDYXSP-UHFFFAOYSA-N 0.000 description 2
- FYPVOSYRGWUIJH-UHFFFAOYSA-N tert-butyl 5-[4-(2-chloropyridin-4-yl)-6-methylpyrimidin-2-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate Chemical compound N=1C(N2C3CC(N(C3)C(=O)OC(C)(C)C)C2)=NC(C)=CC=1C1=CC=NC(Cl)=C1 FYPVOSYRGWUIJH-UHFFFAOYSA-N 0.000 description 2
- LHAGITCOMOVCCR-UHFFFAOYSA-N tert-butyl 5-[6-(2-chloropyridin-4-yl)-2-methylsulfanylpyrimidin-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate Chemical compound N=1C(SC)=NC(N2C3CC(N(C3)C(=O)OC(C)(C)C)C2)=CC=1C1=CC=NC(Cl)=C1 LHAGITCOMOVCCR-UHFFFAOYSA-N 0.000 description 2
- LIZVWJJFLOXLII-UHFFFAOYSA-N tert-butyl 5-[7-[2-(1-phenylethylamino)pyridin-4-yl]imidazo[1,2-c]pyrimidin-5-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate Chemical compound C=1C(C=2N=C(N3C=CN=C3C=2)N2C3CC(N(C3)C(=O)OC(C)(C)C)C2)=CC=NC=1NC(C)C1=CC=CC=C1 LIZVWJJFLOXLII-UHFFFAOYSA-N 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical group CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 238000011200 topical administration Methods 0.000 description 2
- PMMYEEVYMWASQN-IMJSIDKUSA-N trans-4-Hydroxy-L-proline Natural products O[C@@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-IMJSIDKUSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 102000003390 tumor necrosis factor Human genes 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 2
- RQEUFEKYXDPUSK-SSDOTTSWSA-N (1R)-1-phenylethanamine Chemical compound C[C@@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-SSDOTTSWSA-N 0.000 description 1
- KVTRUBZAMRIDHX-WHFBIAKZSA-N (1s,4s)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid Chemical compound C1N(C(O)=O)[C@]2([H])CN[C@@]1([H])C2 KVTRUBZAMRIDHX-WHFBIAKZSA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- LLNAMUJRIZIXHF-CLFYSBASSA-N (z)-2-methyl-3-phenylprop-2-en-1-ol Chemical compound OCC(/C)=C\C1=CC=CC=C1 LLNAMUJRIZIXHF-CLFYSBASSA-N 0.000 description 1
- FHUDAMLDXFJHJE-UHFFFAOYSA-N 1,1,1-trifluoropropan-2-one Chemical compound CC(=O)C(F)(F)F FHUDAMLDXFJHJE-UHFFFAOYSA-N 0.000 description 1
- 125000004901 1,2-dimethylpropylamino group Chemical group CC(C(C)C)N* 0.000 description 1
- DIWHJJUFVGEXGS-UHFFFAOYSA-N 1-(2-fluorophenyl)ethanamine Chemical compound CC(N)C1=CC=CC=C1F DIWHJJUFVGEXGS-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical group C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- MNMDZSAWTQOEHX-UHFFFAOYSA-N 1-o-tert-butyl 2-o-ethyl 4-hydroxypyrrolidine-1,2-dicarboxylate Chemical compound CCOC(=O)C1CC(O)CN1C(=O)OC(C)(C)C MNMDZSAWTQOEHX-UHFFFAOYSA-N 0.000 description 1
- RQEUFEKYXDPUSK-UHFFFAOYSA-N 1-phenylethylamine Chemical compound CC(N)C1=CC=CC=C1 RQEUFEKYXDPUSK-UHFFFAOYSA-N 0.000 description 1
- 150000007545 14-membered macrocycles Chemical class 0.000 description 1
- UTQNKKSJPHTPBS-UHFFFAOYSA-N 2,2,2-trichloroethanone Chemical group ClC(Cl)(Cl)[C]=O UTQNKKSJPHTPBS-UHFFFAOYSA-N 0.000 description 1
- XYPISWUKQGWYGX-UHFFFAOYSA-N 2,2,2-trifluoroethaneperoxoic acid Chemical compound OOC(=O)C(F)(F)F XYPISWUKQGWYGX-UHFFFAOYSA-N 0.000 description 1
- NKULBUOBGILEAR-UHFFFAOYSA-N 2,2-difluoroethyl trifluoromethanesulfonate Chemical compound FC(F)COS(=O)(=O)C(F)(F)F NKULBUOBGILEAR-UHFFFAOYSA-N 0.000 description 1
- QKWWDTYDYOFRJL-UHFFFAOYSA-N 2,2-dimethoxyethanamine Chemical compound COC(CN)OC QKWWDTYDYOFRJL-UHFFFAOYSA-N 0.000 description 1
- TUQSVSYUEBNNKQ-UHFFFAOYSA-N 2,4-dichloroquinazoline Chemical compound C1=CC=CC2=NC(Cl)=NC(Cl)=C21 TUQSVSYUEBNNKQ-UHFFFAOYSA-N 0.000 description 1
- UKHJNJFJCGBKSF-UHFFFAOYSA-N 2,5-diazabicyclo[2.2.1]heptane Chemical compound C1NC2CNC1C2 UKHJNJFJCGBKSF-UHFFFAOYSA-N 0.000 description 1
- OLFFOWYNQJKLDU-UHFFFAOYSA-N 2-(2,5-diazabicyclo[2.2.1]heptan-2-yl)-3-methyl-6-[2-(1-phenylethylamino)pyridin-4-yl]pyrimidin-4-one Chemical compound C=1C(C=2N=C(N(C)C(=O)C=2)N2C3CC(NC3)C2)=CC=NC=1NC(C)C1=CC=CC=C1 OLFFOWYNQJKLDU-UHFFFAOYSA-N 0.000 description 1
- WKRMNPJNOYZDEA-UHFFFAOYSA-N 2-(2-chloropyridin-4-yl)-1h-quinazolin-4-one Chemical compound C1=NC(Cl)=CC(C=2NC(=O)C3=CC=CC=C3N=2)=C1 WKRMNPJNOYZDEA-UHFFFAOYSA-N 0.000 description 1
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 1
- AXZRUTPBQMAWLP-UHFFFAOYSA-N 2-bromo-4-fluorobenzoyl chloride Chemical compound FC1=CC=C(C(Cl)=O)C(Br)=C1 AXZRUTPBQMAWLP-UHFFFAOYSA-N 0.000 description 1
- JJFOBACUIRKUPN-UHFFFAOYSA-N 2-bromoethoxybenzene Chemical compound BrCCOC1=CC=CC=C1 JJFOBACUIRKUPN-UHFFFAOYSA-N 0.000 description 1
- UUEQDBHKMOFLDP-UHFFFAOYSA-N 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=NC(Cl)=C1 UUEQDBHKMOFLDP-UHFFFAOYSA-N 0.000 description 1
- YZJSARUCMYJHNV-UHFFFAOYSA-N 2-dimethylsilylethyl(dimethyl)silane Chemical compound C[SiH](C)CC[SiH](C)C YZJSARUCMYJHNV-UHFFFAOYSA-N 0.000 description 1
- NSTREUWFTAOOKS-UHFFFAOYSA-N 2-fluorobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1F NSTREUWFTAOOKS-UHFFFAOYSA-N 0.000 description 1
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical compound C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 1
- FUMTXFNRSOTREL-UHFFFAOYSA-N 2-propan-2-yl-2,5-diazabicyclo[2.2.1]heptane Chemical compound C1C2N(C(C)C)CC1NC2 FUMTXFNRSOTREL-UHFFFAOYSA-N 0.000 description 1
- WJKMUGYQMMXILX-UHFFFAOYSA-N 2-trimethylsilylacetonitrile Chemical compound C[Si](C)(C)CC#N WJKMUGYQMMXILX-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- WIQRSJOCVVPMPS-UHFFFAOYSA-N 3-(1h-indol-2-yl)pyrrole-2,5-dione Chemical class O=C1NC(=O)C(C=2NC3=CC=CC=C3C=2)=C1 WIQRSJOCVVPMPS-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- NIDWUZTTXGJFNN-UHFFFAOYSA-N 3-bromopropoxybenzene Chemical compound BrCCCOC1=CC=CC=C1 NIDWUZTTXGJFNN-UHFFFAOYSA-N 0.000 description 1
- JFSOTTKKBLOHTK-UHFFFAOYSA-N 3-chloro-1-(2-chloropyridin-4-yl)indazole Chemical compound C12=CC=CC=C2C(Cl)=NN1C1=CC=NC(Cl)=C1 JFSOTTKKBLOHTK-UHFFFAOYSA-N 0.000 description 1
- QPHAGNNWDZSKJH-UHFFFAOYSA-N 3-chloro-2h-indazole Chemical compound C1=CC=CC2=C(Cl)NN=C21 QPHAGNNWDZSKJH-UHFFFAOYSA-N 0.000 description 1
- JOZZAIIGWFLONA-UHFFFAOYSA-N 3-methylbutan-2-amine Chemical compound CC(C)C(C)N JOZZAIIGWFLONA-UHFFFAOYSA-N 0.000 description 1
- 238000010600 3H thymidine incorporation assay Methods 0.000 description 1
- XIDCXQTZWYQGJQ-UHFFFAOYSA-N 4-(2-chloropyridin-4-yl)-2-(2,5-diazabicyclo[2.2.1]heptan-2-yl)-1,3-thiazole Chemical compound C1=NC(Cl)=CC(C=2N=C(SC=2)N2C3CC(NC3)C2)=C1 XIDCXQTZWYQGJQ-UHFFFAOYSA-N 0.000 description 1
- ATVUYSCEYHQUQX-UHFFFAOYSA-N 4-(2-chloropyridin-4-yl)-6-methyl-2-methylsulfanylpyrimidine Chemical compound CSC1=NC(C)=CC(C=2C=C(Cl)N=CC=2)=N1 ATVUYSCEYHQUQX-UHFFFAOYSA-N 0.000 description 1
- VLEGEAGQPWYQDQ-UHFFFAOYSA-N 4-(3-chloroindazol-1-yl)-n-(1-phenylethyl)pyridin-2-amine Chemical compound C=1C(N2C3=CC=CC=C3C(Cl)=N2)=CC=NC=1NC(C)C1=CC=CC=C1 VLEGEAGQPWYQDQ-UHFFFAOYSA-N 0.000 description 1
- VLEGEAGQPWYQDQ-AWEZNQCLSA-N 4-(3-chloroindazol-1-yl)-n-[(1s)-1-phenylethyl]pyridin-2-amine Chemical compound C1([C@@H](NC=2N=CC=C(C=2)N2C3=CC=CC=C3C(Cl)=N2)C)=CC=CC=C1 VLEGEAGQPWYQDQ-AWEZNQCLSA-N 0.000 description 1
- BPVKLTMPFYRYCP-DZIBYMRMSA-N 4-[2-(2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-methylpyrimidin-4-yl]-n-[(1s)-1-phenylethyl]pyridin-2-amine Chemical compound C1([C@@H](NC=2N=CC=C(C=2)C=2N=C(N=C(C)C=2)N2C3CC(NC3)C2)C)=CC=CC=C1 BPVKLTMPFYRYCP-DZIBYMRMSA-N 0.000 description 1
- KNKZWNBDGQAYTQ-WBAXXEDZSA-N 4-[2-[(1s,4s)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-1,3-thiazol-4-yl]-n-[(1s)-1-phenylethyl]pyridin-2-amine Chemical compound C1([C@H](C)NC=2N=CC=C(C=2)C=2N=C(SC=2)N2C[C@]3(NC[C@]2([H])C3)[H])=CC=CC=C1 KNKZWNBDGQAYTQ-WBAXXEDZSA-N 0.000 description 1
- TWYYQCKDAVLTKR-UHFFFAOYSA-N 4-[3-(2,5-diazabicyclo[2.2.1]heptan-2-yl)indazol-1-yl]-n-(1-phenylethyl)pyridin-2-amine Chemical compound C=1C(N2C3=CC=CC=C3C(N3C4CC(NC4)C3)=N2)=CC=NC=1NC(C)C1=CC=CC=C1 TWYYQCKDAVLTKR-UHFFFAOYSA-N 0.000 description 1
- TWYYQCKDAVLTKR-LMBAYHJBSA-N 4-[3-[(1s,4s)-2,5-diazabicyclo[2.2.1]heptan-2-yl]indazol-1-yl]-n-(1-phenylethyl)pyridin-2-amine Chemical compound C([C@]1(NC[C@]2([H])C1)[H])N2C(C1=CC=CC=C11)=NN1C(C=1)=CC=NC=1NC(C)C1=CC=CC=C1 TWYYQCKDAVLTKR-LMBAYHJBSA-N 0.000 description 1
- PKWBFXMNHSZDTB-SJQFFEKCSA-N 4-[3-[(1s,4s)-2,5-diazabicyclo[2.2.1]heptan-2-yl]indazol-1-yl]-n-[1-(2-fluorophenyl)ethyl]pyridin-2-amine Chemical compound C([C@]1(NC[C@]2([H])C1)[H])N2C(C1=CC=CC=C11)=NN1C(C=1)=CC=NC=1NC(C)C1=CC=CC=C1F PKWBFXMNHSZDTB-SJQFFEKCSA-N 0.000 description 1
- FDAUXZFXTPDSRM-XTWGIRIWSA-N 4-[4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)quinazolin-2-yl]-n-[(1s)-1-phenylethyl]pyridin-2-amine Chemical compound C1([C@@H](NC=2N=CC=C(C=2)C=2N=C3C=CC=CC3=C(N3C4CC(N(C4)C)C3)N=2)C)=CC=CC=C1 FDAUXZFXTPDSRM-XTWGIRIWSA-N 0.000 description 1
- UXAGYDYQHFDNBY-VRJTXETASA-N 4-[4-[(1s,4s)-2,5-diazabicyclo[2.2.1]heptan-2-yl]quinolin-2-yl]-n-(1-phenylethyl)pyridin-2-amine Chemical compound C([C@]1(NC[C@]2([H])C1)[H])N2C(C1=CC=CC=C1N=1)=CC=1C(C=1)=CC=NC=1NC(C)C1=CC=CC=C1 UXAGYDYQHFDNBY-VRJTXETASA-N 0.000 description 1
- CXOMHPRMHWPDIM-SNRMKQJTSA-N 4-[5-[(1s,4s)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]-n-[(1s)-1-phenylethyl]pyridin-2-amine Chemical compound C1([C@H](C)NC=2N=CC=C(C=2)C=2N=C(N3N=CN=C3C=2)N2C[C@]3(NC[C@]2([H])C3)[H])=CC=CC=C1 CXOMHPRMHWPDIM-SNRMKQJTSA-N 0.000 description 1
- JKVGSSMZDIFZSF-RFFXKOPCSA-N 4-[5-[(1s,4s)-2,5-diazabicyclo[2.2.1]heptan-2-yl]imidazo[1,2-c]pyrimidin-7-yl]-n-(1-phenylethyl)pyridin-2-amine Chemical compound C([C@]1(NC[C@]2([H])C1)[H])N2C(N1C=CN=C1C=1)=NC=1C(C=1)=CC=NC=1NC(C)C1=CC=CC=C1 JKVGSSMZDIFZSF-RFFXKOPCSA-N 0.000 description 1
- AXBBTYGYYOURMC-HGVHAKBWSA-N 4-[5-[(1s,4s)-2,5-diazabicyclo[2.2.1]heptan-2-yl]imidazo[1,2-c]pyrimidin-7-yl]-n-(3-methylbutan-2-yl)pyridin-2-amine Chemical compound C([C@]1(NC[C@]2([H])C1)[H])N2C(N1C=CN=C1C=1)=NC=1C1=CC=NC(NC(C)C(C)C)=C1 AXBBTYGYYOURMC-HGVHAKBWSA-N 0.000 description 1
- PBCNPJLVYGBQFI-VXKWHMMOSA-N 4-[5-[(1s,4s)-2,5-diazabicyclo[2.2.1]heptan-2-yl]imidazo[1,2-c]pyrimidin-7-yl]-n-(naphthalen-1-ylmethyl)pyridin-2-amine Chemical compound C1=CC=C2C(CNC=3N=CC=C(C=3)C=3N=C(N4C=CN=C4C=3)N3C[C@]4(NC[C@]3([H])C4)[H])=CC=CC2=C1 PBCNPJLVYGBQFI-VXKWHMMOSA-N 0.000 description 1
- JKVGSSMZDIFZSF-VDGAXYAQSA-N 4-[5-[(1s,4s)-2,5-diazabicyclo[2.2.1]heptan-2-yl]imidazo[1,2-c]pyrimidin-7-yl]-n-[(1s)-1-phenylethyl]pyridin-2-amine Chemical compound C1([C@H](C)NC=2N=CC=C(C=2)C=2N=C(N3C=CN=C3C=2)N2C[C@]3(NC[C@]2([H])C3)[H])=CC=CC=C1 JKVGSSMZDIFZSF-VDGAXYAQSA-N 0.000 description 1
- QVTDUABYWRUBET-VRJTXETASA-N 4-[5-[(1s,4s)-5-ethyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]imidazo[1,2-c]pyrimidin-7-yl]-n-(1-phenylethyl)pyridin-2-amine Chemical compound C([C@]1(N(C[C@]2([H])C1)CC)[H])N2C(N1C=CN=C1C=1)=NC=1C(C=1)=CC=NC=1NC(C)C1=CC=CC=C1 QVTDUABYWRUBET-VRJTXETASA-N 0.000 description 1
- QVTDUABYWRUBET-NYVOZVTQSA-N 4-[5-[(1s,4s)-5-ethyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]imidazo[1,2-c]pyrimidin-7-yl]-n-[(1s)-1-phenylethyl]pyridin-2-amine Chemical compound C1([C@H](C)NC=2N=CC=C(C=2)C=2N=C(N3C=CN=C3C=2)N2C[C@]3(N(C[C@]2([H])C3)CC)[H])=CC=CC=C1 QVTDUABYWRUBET-NYVOZVTQSA-N 0.000 description 1
- XHQNKBJBTQDUFF-UHFFFAOYSA-N 4-[5-[5-(2,2-difluoroethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]imidazo[1,2-c]pyrimidin-7-yl]-n-(1-phenylethyl)-3h-pyridin-4-amine Chemical compound C=1C=CC=CC=1C(C)NC1(C=2N=C(N3C=CN=C3C=2)N2C3CC(N(C3)CC(F)F)C2)CC=NC=C1 XHQNKBJBTQDUFF-UHFFFAOYSA-N 0.000 description 1
- KJOIOBIBHCDHSZ-BVVFMGSASA-N 4-[6-methyl-2-(2-propan-2-yl-2,5-diazabicyclo[2.2.1]heptan-5-yl)pyrimidin-4-yl]-n-[(1s)-1-phenylethyl]pyridin-2-amine Chemical compound C1([C@H](C)NC=2N=CC=C(C=2)C=2C=C(C)N=C(N=2)N2CC3CC2CN3C(C)C)=CC=CC=C1 KJOIOBIBHCDHSZ-BVVFMGSASA-N 0.000 description 1
- NQTVSPWQETZNLU-UHFFFAOYSA-N 4-chloro-2-(2-chloropyridin-4-yl)quinoline Chemical compound C1=NC(Cl)=CC(C=2N=C3C=CC=CC3=C(Cl)C=2)=C1 NQTVSPWQETZNLU-UHFFFAOYSA-N 0.000 description 1
- ICGLPKIVTVWCFT-UHFFFAOYSA-N 4-methylbenzenesulfonohydrazide Chemical compound CC1=CC=C(S(=O)(=O)NN)C=C1 ICGLPKIVTVWCFT-UHFFFAOYSA-N 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- DDFHBQSCUXNBSA-UHFFFAOYSA-N 5-(5-carboxythiophen-2-yl)thiophene-2-carboxylic acid Chemical compound S1C(C(=O)O)=CC=C1C1=CC=C(C(O)=O)S1 DDFHBQSCUXNBSA-UHFFFAOYSA-N 0.000 description 1
- ZNOOPTUPFYDTSW-UHFFFAOYSA-N 7-(2-chloropyridin-4-yl)-5-[5-(2,2-difluoroethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]imidazo[1,2-c]pyrimidine Chemical compound FC(F)CN1CC2CC1CN2C(N1C=CN=C1C=1)=NC=1C1=CC=NC(Cl)=C1 ZNOOPTUPFYDTSW-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 108091008875 B cell receptors Proteins 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- YCKUKVNHCSJVMB-UHFFFAOYSA-N C(c1ccccc1)Nc1nccc(-[n](c2c3cccc2)nc3N2C(C3)CNC3C2)c1 Chemical compound C(c1ccccc1)Nc1nccc(-[n](c2c3cccc2)nc3N2C(C3)CNC3C2)c1 YCKUKVNHCSJVMB-UHFFFAOYSA-N 0.000 description 1
- PUGFZQLLSBNMEZ-UHFFFAOYSA-N CC(C)(C)OC(N1C(CNc2nc(-c3cc(Cl)ncc3)nc3c2cccc3)C(C2)C2C1)=O Chemical compound CC(C)(C)OC(N1C(CNc2nc(-c3cc(Cl)ncc3)nc3c2cccc3)C(C2)C2C1)=O PUGFZQLLSBNMEZ-UHFFFAOYSA-N 0.000 description 1
- MDJGFQFXGRBWGL-UHFFFAOYSA-N CC(C)(C)OC(N1C(CNc2nc(Cl)nc3c2cccc3)C(C2)C2C1)=O Chemical compound CC(C)(C)OC(N1C(CNc2nc(Cl)nc3c2cccc3)C(C2)C2C1)=O MDJGFQFXGRBWGL-UHFFFAOYSA-N 0.000 description 1
- AWAZGPBUVSVEEK-XOYNAWAESA-N CC(C)N(CC1C2)C2CN1c1nc(-c2cc(N[C@@H](C)c3c(cccc4)c4ccc3)ncc2)cc2ncn[n]12 Chemical compound CC(C)N(CC1C2)C2CN1c1nc(-c2cc(N[C@@H](C)c3c(cccc4)c4ccc3)ncc2)cc2ncn[n]12 AWAZGPBUVSVEEK-XOYNAWAESA-N 0.000 description 1
- LWQDICDZDSPXPQ-XOYNAWAESA-N CC(C)N(CC1C2)C2CN1c1nc(-c2cc(N[C@@H](C)c3ccccc3)ncc2)nc2c1cccc2 Chemical compound CC(C)N(CC1C2)C2CN1c1nc(-c2cc(N[C@@H](C)c3ccccc3)ncc2)nc2c1cccc2 LWQDICDZDSPXPQ-XOYNAWAESA-N 0.000 description 1
- BYCQTSBDFUNCCD-HHYXZILKSA-N CCCCN(CC1C2)C2CN1C([n]1c(C2C)ncc1)=NC2c1cc(N[C@@H](C)c2ccccc2)ncc1 Chemical compound CCCCN(CC1C2)C2CN1C([n]1c(C2C)ncc1)=NC2c1cc(N[C@@H](C)c2ccccc2)ncc1 BYCQTSBDFUNCCD-HHYXZILKSA-N 0.000 description 1
- LRXQHKLZEBCTDL-RPCJCACASA-N C[C@@H](c1cccc2c1cccc2)Nc1nccc(-c2cc3ncn[n]3c([N-]3C(C4)CNC4C3)n2)c1 Chemical compound C[C@@H](c1cccc2c1cccc2)Nc1nccc(-c2cc3ncn[n]3c([N-]3C(C4)CNC4C3)n2)c1 LRXQHKLZEBCTDL-RPCJCACASA-N 0.000 description 1
- BBLOJEWCGIQPDH-IVINKASTSA-N C[C@@H](c1ccccc1)Nc1nccc(-c2cc3ncc[n]3c(N3C(C4)CN(CCOc5ccccc5)C4C3)n2)c1 Chemical compound C[C@@H](c1ccccc1)Nc1nccc(-c2cc3ncc[n]3c(N3C(C4)CN(CCOc5ccccc5)C4C3)n2)c1 BBLOJEWCGIQPDH-IVINKASTSA-N 0.000 description 1
- QGKQXIRIUYZUDY-CCGQDMKZSA-N C[C@@H](c1ccccc1)Nc1nccc(-c2cc3ncc[n]3c(N3C(C4)CN(Cc5ccccc5)C4C3)n2)c1 Chemical compound C[C@@H](c1ccccc1)Nc1nccc(-c2cc3ncc[n]3c(N3C(C4)CN(Cc5ccccc5)C4C3)n2)c1 QGKQXIRIUYZUDY-CCGQDMKZSA-N 0.000 description 1
- VZMQHTHDLXOOET-RPCJCACASA-N C[C@@H](c1ccccc1)Nc1nccc(-c2nc(cccc3)c3c(N3C(C4)CNC4C3)n2)c1 Chemical compound C[C@@H](c1ccccc1)Nc1nccc(-c2nc(cccc3)c3c(N3C(C4)CNC4C3)n2)c1 VZMQHTHDLXOOET-RPCJCACASA-N 0.000 description 1
- 102000004631 Calcineurin Human genes 0.000 description 1
- 108010042955 Calcineurin Proteins 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- JYYNAJVZFGKDEQ-UHFFFAOYSA-N Cc1ccnc(C)c1 Chemical compound Cc1ccnc(C)c1 JYYNAJVZFGKDEQ-UHFFFAOYSA-N 0.000 description 1
- 208000015943 Coeliac disease Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 102100030013 Endoribonuclease Human genes 0.000 description 1
- 101710199605 Endoribonuclease Proteins 0.000 description 1
- 108090000371 Esterases Proteins 0.000 description 1
- 206010017711 Gangrene Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 101001059454 Homo sapiens Serine/threonine-protein kinase MARK2 Proteins 0.000 description 1
- 102000008100 Human Serum Albumin Human genes 0.000 description 1
- 108091006905 Human Serum Albumin Proteins 0.000 description 1
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 1
- 206010020850 Hyperthyroidism Diseases 0.000 description 1
- 102000010789 Interleukin-2 Receptors Human genes 0.000 description 1
- 108010038453 Interleukin-2 Receptors Proteins 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 102100021339 Multidrug resistance-associated protein 1 Human genes 0.000 description 1
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical group ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 229940123866 Protein kinase C beta inhibitor Drugs 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 239000012979 RPMI medium Substances 0.000 description 1
- 208000017442 Retinal disease Diseases 0.000 description 1
- 206010038923 Retinopathy Diseases 0.000 description 1
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 101710113029 Serine/threonine-protein kinase Proteins 0.000 description 1
- 102100028904 Serine/threonine-protein kinase MARK2 Human genes 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical group [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 108010090804 Streptavidin Proteins 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 1
- 241000159243 Toxicodendron radicans Species 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 206010052779 Transplant rejections Diseases 0.000 description 1
- 102100040247 Tumor necrosis factor Human genes 0.000 description 1
- 102100031988 Tumor necrosis factor ligand superfamily member 6 Human genes 0.000 description 1
- 108050002568 Tumor necrosis factor ligand superfamily member 6 Proteins 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- MUUXBTFQEXVEEI-UHFFFAOYSA-N [2-(dimethyl-$l^{3}-silanyl)phenyl]-dimethylsilicon Chemical compound C[Si](C)C1=CC=CC=C1[Si](C)C MUUXBTFQEXVEEI-UHFFFAOYSA-N 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- IKHGUXGNUITLKF-XPULMUKRSA-N acetaldehyde Chemical compound [14CH]([14CH3])=O IKHGUXGNUITLKF-XPULMUKRSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000010398 acute inflammatory response Effects 0.000 description 1
- 125000004442 acylamino group Chemical group 0.000 description 1
- 230000001919 adrenal effect Effects 0.000 description 1
- 101150045355 akt1 gene Proteins 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000005197 alkyl carbonyloxy alkyl group Chemical group 0.000 description 1
- 201000009961 allergic asthma Diseases 0.000 description 1
- 238000011316 allogeneic transplantation Methods 0.000 description 1
- 108010004469 allophycocyanin Proteins 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 150000001414 amino alcohols Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000005911 anti-cytotoxic effect Effects 0.000 description 1
- 238000011861 anti-inflammatory therapy Methods 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000012131 assay buffer Substances 0.000 description 1
- 239000000305 astragalus gummifer gum Substances 0.000 description 1
- 230000003305 autocrine Effects 0.000 description 1
- 201000004995 autoimmune glomerulonephritis Diseases 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- FHCIILYMWWRNIZ-UHFFFAOYSA-N benzhydryl(chloro)silane Chemical compound C=1C=CC=CC=1C([SiH2]Cl)C1=CC=CC=C1 FHCIILYMWWRNIZ-UHFFFAOYSA-N 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 125000006267 biphenyl group Chemical group 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- BTWHOYYUFRKLCO-UHFFFAOYSA-N butyl-(2-tert-butylphenyl)-chloro-phenylsilane Chemical compound C(C)(C)(C)C1=C(C=CC=C1)[Si](Cl)(C1=CC=CC=C1)CCCC BTWHOYYUFRKLCO-UHFFFAOYSA-N 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- KWYZNESIGBQHJK-UHFFFAOYSA-N chloro-dimethyl-phenylsilane Chemical compound C[Si](C)(Cl)C1=CC=CC=C1 KWYZNESIGBQHJK-UHFFFAOYSA-N 0.000 description 1
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 230000000875 corresponding effect Effects 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 238000003568 cytokine secretion assay Methods 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000007872 degassing Methods 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical group [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 1
- 230000036267 drug metabolism Effects 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 238000011067 equilibration Methods 0.000 description 1
- 239000003797 essential amino acid Substances 0.000 description 1
- 235000020776 essential amino acid Nutrition 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- IIJNMGXVEGFXRQ-UHFFFAOYSA-N ethyl 3-(2-chloropyridin-4-yl)-3-oxopropanoate;lithium Chemical compound [Li].CCOC(=O)CC(=O)C1=CC=NC(Cl)=C1 IIJNMGXVEGFXRQ-UHFFFAOYSA-N 0.000 description 1
- VNSAFDGQUZWUFE-UHFFFAOYSA-N ethyl 3-chloropyridine-4-carboxylate Chemical compound CCOC(=O)C1=CC=NC=C1Cl VNSAFDGQUZWUFE-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000009650 gentamicin protection assay Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- ZRALSGWEFCBTJO-UHFFFAOYSA-N guanidine group Chemical group NC(=N)N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 1
- 150000004820 halides Chemical group 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 238000003306 harvesting Methods 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- USZLCYNVCCDPLQ-UHFFFAOYSA-N hydron;n-methoxymethanamine;chloride Chemical class Cl.CNOC USZLCYNVCCDPLQ-UHFFFAOYSA-N 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Chemical group O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 150000003949 imides Chemical group 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 238000002650 immunosuppressive therapy Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000010874 in vitro model Methods 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000031146 intracellular signal transduction Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 125000005929 isobutyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])OC(*)=O 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- XLTUPERVRFLGLJ-UHFFFAOYSA-N isothiocyanato(trimethyl)silane Chemical compound C[Si](C)(C)N=C=S XLTUPERVRFLGLJ-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 238000000021 kinase assay Methods 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 208000002780 macular degeneration Diseases 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical compound [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- 238000002826 magnetic-activated cell sorting Methods 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229940098895 maleic acid Drugs 0.000 description 1
- 125000005439 maleimidyl group Chemical group C1(C=CC(N1*)=O)=O 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910000000 metal hydroxide Inorganic materials 0.000 description 1
- 150000004692 metal hydroxides Chemical class 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- NNBBQNFHCVVQHZ-UHFFFAOYSA-N methyl carbamimidothioate;sulfuric acid Chemical compound CSC(N)=N.OS(O)(=O)=O NNBBQNFHCVVQHZ-UHFFFAOYSA-N 0.000 description 1
- 230000005787 mitochondrial ATP synthesis coupled electron transport Effects 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 238000007799 mixed lymphocyte reaction assay Methods 0.000 description 1
- 108010066052 multidrug resistance-associated protein 1 Proteins 0.000 description 1
- 206010028417 myasthenia gravis Diseases 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- ATQRNTSLYSZOSI-MXQSGTKOSA-N n-(1-phenylethyl)-4-[5-[(1s,4s)-2-propan-2-yl-2,5-diazabicyclo[2.2.1]heptan-5-yl]imidazo[1,2-c]pyrimidin-7-yl]pyridin-2-amine Chemical compound C([C@]1(N(C[C@]2([H])C1)C(C)C)[H])N2C(N1C=CN=C1C=1)=NC=1C(C=1)=CC=NC=1NC(C)C1=CC=CC=C1 ATQRNTSLYSZOSI-MXQSGTKOSA-N 0.000 description 1
- MQPYJDLLBABSOY-UHFFFAOYSA-N n-(2-carbamoylphenyl)-2-chloropyridine-4-carboxamide Chemical compound NC(=O)C1=CC=CC=C1NC(=O)C1=CC=NC(Cl)=C1 MQPYJDLLBABSOY-UHFFFAOYSA-N 0.000 description 1
- HHOLHUJDDAONTA-MFUMQWNRSA-N n-(3-methylbutan-2-yl)-4-[5-[(1s,4s)-2-propan-2-yl-2,5-diazabicyclo[2.2.1]heptan-5-yl]imidazo[1,2-c]pyrimidin-7-yl]pyridin-2-amine Chemical compound C([C@]1(N(C[C@]2([H])C1)C(C)C)[H])N2C(N1C=CN=C1C=1)=NC=1C1=CC=NC(NC(C)C(C)C)=C1 HHOLHUJDDAONTA-MFUMQWNRSA-N 0.000 description 1
- ATQRNTSLYSZOSI-VJBMBRPKSA-N n-[(1s)-1-phenylethyl]-4-[5-[(1s,4s)-2-propan-2-yl-2,5-diazabicyclo[2.2.1]heptan-5-yl]imidazo[1,2-c]pyrimidin-7-yl]pyridin-2-amine Chemical compound C1([C@H](C)NC=2N=CC=C(C=2)C=2N=C(N3C=CN=C3C=2)N2C[C@]3(N(C[C@]2([H])C3)C(C)C)[H])=CC=CC=C1 ATQRNTSLYSZOSI-VJBMBRPKSA-N 0.000 description 1
- REGNSKDFHUYCSB-UHFFFAOYSA-N n-[2-[tert-butyl(diphenyl)silyl]oxyethyl]-6-(2-chloropyridin-4-yl)-2-(2-propan-2-yl-2,5-diazabicyclo[2.2.1]heptan-5-yl)pyrimidin-4-amine Chemical compound CC(C)N1CC2CC1CN2C(N=C(C=1)C=2C=C(Cl)N=CC=2)=NC=1NCCO[Si](C(C)(C)C)(C=1C=CC=CC=1)C1=CC=CC=C1 REGNSKDFHUYCSB-UHFFFAOYSA-N 0.000 description 1
- HPBZIFNOQIRMFT-UHFFFAOYSA-N n-[2-[tert-butyl(diphenyl)silyl]oxyethyl]-6-(2-chloropyridin-4-yl)-2-methylsulfanylpyrimidin-4-amine Chemical compound C=1C(C=2C=C(Cl)N=CC=2)=NC(SC)=NC=1NCCO[Si](C(C)(C)C)(C=1C=CC=CC=1)C1=CC=CC=C1 HPBZIFNOQIRMFT-UHFFFAOYSA-N 0.000 description 1
- QSZPEWUJLWEIIW-UHFFFAOYSA-N n-[2-[tert-butyl(diphenyl)silyl]oxyethyl]-6-[2-(1-phenylethylamino)pyridin-4-yl]-2-(2-propan-2-yl-2,5-diazabicyclo[2.2.1]heptan-5-yl)pyrimidin-4-amine Chemical compound CC(C)N1CC2CC1CN2C(N=C(C=1)C=2C=C(NC(C)C=3C=CC=CC=3)N=CC=2)=NC=1NCCO[Si](C(C)(C)C)(C=1C=CC=CC=1)C1=CC=CC=C1 QSZPEWUJLWEIIW-UHFFFAOYSA-N 0.000 description 1
- YCKUKVNHCSJVMB-ICSRJNTNSA-N n-benzyl-4-[3-[(1s,4s)-2,5-diazabicyclo[2.2.1]heptan-2-yl]indazol-1-yl]pyridin-2-amine Chemical class C([C@]1(NC[C@]2([H])C1)[H])N2C(C1=CC=CC=C11)=NN1C(C=1)=CC=NC=1NCC1=CC=CC=C1 YCKUKVNHCSJVMB-ICSRJNTNSA-N 0.000 description 1
- VPWLVRVJXPFKLF-UHFFFAOYSA-N n-benzyl-4-[5-(2,5-diazabicyclo[2.2.1]heptan-2-yl)imidazo[1,2-c]pyrimidin-7-yl]pyridin-2-amine Chemical compound C=1C(C=2N=C(N3C=CN=C3C=2)N2C3CC(NC3)C2)=CC=NC=1NCC1=CC=CC=C1 VPWLVRVJXPFKLF-UHFFFAOYSA-N 0.000 description 1
- RIWRFSMVIUAEBX-UHFFFAOYSA-N n-methyl-1-phenylmethanamine Chemical compound CNCC1=CC=CC=C1 RIWRFSMVIUAEBX-UHFFFAOYSA-N 0.000 description 1
- 230000007896 negative regulation of T cell activation Effects 0.000 description 1
- 230000025020 negative regulation of T cell proliferation Effects 0.000 description 1
- 201000008383 nephritis Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- XURVRZSODRHRNK-UHFFFAOYSA-N o-quinodimethane Chemical compound C=C1C=CC=CC1=C XURVRZSODRHRNK-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- XYFCBTPGUUZFHI-UHFFFAOYSA-O phosphonium Chemical compound [PH4+] XYFCBTPGUUZFHI-UHFFFAOYSA-O 0.000 description 1
- 125000005545 phthalimidyl group Chemical group 0.000 description 1
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 230000010118 platelet activation Effects 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 230000001185 psoriatic effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical group OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- YAAWASYJIRZXSZ-UHFFFAOYSA-N pyrimidine-2,4-diamine Chemical class NC1=CC=NC(N)=N1 YAAWASYJIRZXSZ-UHFFFAOYSA-N 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- LDFKYHHSSGRMPD-UHFFFAOYSA-M sodium 2-(2-chloropyridin-4-yl)-3H-quinazolin-4-one hydroxide Chemical compound [OH-].[Na+].ClC1=NC=CC(=C1)C1=NC2=CC=CC=C2C(N1)=O LDFKYHHSSGRMPD-UHFFFAOYSA-M 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- ZVWLQTDCMAGVKX-RYUDHWBXSA-N tert-butyl (1s,4s)-5-(2-chloroquinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate Chemical compound C1=CC=C2C(N3C[C@]4(N(C[C@]3([H])C4)C(=O)OC(C)(C)C)[H])=NC(Cl)=NC2=C1 ZVWLQTDCMAGVKX-RYUDHWBXSA-N 0.000 description 1
- BGVCQJKTMDNEAB-HOTGVXAUSA-N tert-butyl (1s,4s)-5-[2-(2-chloropyridin-4-yl)quinazolin-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate Chemical compound C([C@]1(N(C[C@]2([H])C1)C(=O)OC(C)(C)C)[H])N2C(C1=CC=CC=C1N=1)=NC=1C1=CC=NC(Cl)=C1 BGVCQJKTMDNEAB-HOTGVXAUSA-N 0.000 description 1
- WVSJVAUBSKOKKB-XWDHDVEBSA-N tert-butyl (2S,4R)-4-[tert-butyl(diphenyl)silyl]-2-hydroxy-2-(1-hydroxyethyl)pyrrolidine-1-carboxylate Chemical compound C(C)(C)(C)OC(=O)N1[C@](C[C@H](C1)[Si](C1=CC=CC=C1)(C1=CC=CC=C1)C(C)(C)C)(C(C)O)O WVSJVAUBSKOKKB-XWDHDVEBSA-N 0.000 description 1
- UFJNFQNQLMGUTQ-JGVFFNPUSA-N tert-butyl (2s,4r)-4-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CO UFJNFQNQLMGUTQ-JGVFFNPUSA-N 0.000 description 1
- HHHWEVOSBOJPHE-UHFFFAOYSA-N tert-butyl 5-[4-(2-chloropyridin-4-yl)-1,3-thiazol-2-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC2CC1CN2C(SC=1)=NC=1C1=CC=NC(Cl)=C1 HHHWEVOSBOJPHE-UHFFFAOYSA-N 0.000 description 1
- MHZMQQLFQMCWPS-BVVFMGSASA-N tert-butyl 5-[4-methyl-6-[2-[[(1s)-1-phenylethyl]amino]pyridin-4-yl]pyrimidin-2-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate Chemical compound C1([C@@H](NC=2N=CC=C(C=2)C=2N=C(N=C(C)C=2)N2C3CC(N(C3)C(=O)OC(C)(C)C)C2)C)=CC=CC=C1 MHZMQQLFQMCWPS-BVVFMGSASA-N 0.000 description 1
- GJHFUWZBTZJSCZ-UHFFFAOYSA-N tert-butyl 5-[7-[2-(3-methylbutan-2-ylamino)pyridin-4-yl]imidazo[1,2-c]pyrimidin-5-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate Chemical compound C1=NC(NC(C)C(C)C)=CC(C=2N=C(N3C=CN=C3C=2)N2C3CC(N(C3)C(=O)OC(C)(C)C)C2)=C1 GJHFUWZBTZJSCZ-UHFFFAOYSA-N 0.000 description 1
- JEATYNJIXFUTEK-UHFFFAOYSA-N tert-butyl 5-[7-[2-(naphthalen-1-ylmethylamino)pyridin-4-yl]imidazo[1,2-c]pyrimidin-5-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate Chemical compound C1=CC=C2C(CNC=3N=CC=C(C=3)C=3N=C(N4C=CN=C4C=3)N3CC4CC3CN4C(=O)OC(C)(C)C)=CC=CC2=C1 JEATYNJIXFUTEK-UHFFFAOYSA-N 0.000 description 1
- PSZLQCYJFCYNPV-UHFFFAOYSA-N tert-butyl 5-carbamothioyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate Chemical compound C1C2N(C(=O)OC(C)(C)C)CC1N(C(N)=S)C2 PSZLQCYJFCYNPV-UHFFFAOYSA-N 0.000 description 1
- FQFILJKFZCVHNH-UHFFFAOYSA-N tert-butyl n-[3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCCNC1=NC(Cl)=NC=C1Br FQFILJKFZCVHNH-UHFFFAOYSA-N 0.000 description 1
- QFNFDHNZVTWZED-UHFFFAOYSA-N tert-butyl n-[[(2-methylpropan-2-yl)oxycarbonylamino]-pyrazol-1-ylmethylidene]carbamate Chemical compound CC(C)(C)OC(=O)NC(=NC(=O)OC(C)(C)C)N1C=CC=N1 QFNFDHNZVTWZED-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- QHOKENWFMZXSEU-UHFFFAOYSA-N tetrabutylazanium;nitrate Chemical compound [O-][N+]([O-])=O.CCCC[N+](CCCC)(CCCC)CCCC QHOKENWFMZXSEU-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 230000009424 thromboembolic effect Effects 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical group [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 1
- PQDJYEQOELDLCP-UHFFFAOYSA-N trimethylsilane Chemical compound C[SiH](C)C PQDJYEQOELDLCP-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- AQLJVWUFPCUVLO-UHFFFAOYSA-N urea hydrogen peroxide Chemical compound OO.NC(N)=O AQLJVWUFPCUVLO-UHFFFAOYSA-N 0.000 description 1
- HGBOYTHUEUWSSQ-UHFFFAOYSA-N valeric aldehyde Natural products CCCCC=O HGBOYTHUEUWSSQ-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/06—Peri-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/14—Decongestants or antiallergics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
- A61P5/16—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4 for decreasing, blocking or antagonising the activity of the thyroid hormones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
- A61P5/40—Mineralocorticosteroids, e.g. aldosterone; Drugs increasing or potentiating the activity of mineralocorticosteroids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/56—Amides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Diabetes (AREA)
- Immunology (AREA)
- Pulmonology (AREA)
- Endocrinology (AREA)
- Dermatology (AREA)
- Cardiology (AREA)
- Biomedical Technology (AREA)
- Urology & Nephrology (AREA)
- Hematology (AREA)
- Neurosurgery (AREA)
- Heart & Thoracic Surgery (AREA)
- Neurology (AREA)
- Rheumatology (AREA)
- Obesity (AREA)
- Ophthalmology & Optometry (AREA)
- Hospice & Palliative Care (AREA)
- Pain & Pain Management (AREA)
- Emergency Medicine (AREA)
- Psychiatry (AREA)
- Vascular Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US53661704P | 2004-01-14 | 2004-01-14 | |
| US11/034,042 US7582631B2 (en) | 2004-01-14 | 2005-01-11 | Substituted heterocyclic compounds and methods of use |
| PCT/US2005/000993 WO2005070934A1 (en) | 2004-01-14 | 2005-01-12 | Substituted diazabicycloheptanes and their use as protein kinase inhibitors |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2007517904A true JP2007517904A (ja) | 2007-07-05 |
| JP2007517904A5 JP2007517904A5 (https=) | 2008-02-28 |
Family
ID=34810481
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2006549571A Withdrawn JP2007517904A (ja) | 2004-01-14 | 2005-01-12 | 置換された複素環化合物及び使用の方法 |
Country Status (6)
| Country | Link |
|---|---|
| US (2) | US7582631B2 (https=) |
| EP (1) | EP1727821A1 (https=) |
| JP (1) | JP2007517904A (https=) |
| AU (1) | AU2005206524B2 (https=) |
| CA (1) | CA2553232A1 (https=) |
| WO (1) | WO2005070934A1 (https=) |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2011512340A (ja) * | 2008-02-15 | 2011-04-21 | エフ.ホフマン−ラ ロシュ アーゲー | 3−アルキルピペラジン誘導体及びその使用 |
| US8569294B2 (en) | 2006-03-15 | 2013-10-29 | Mitsubishi Tanabe Pharma Corporation | 2-(cyclic amino)-pyrimidone derivatives |
| JP2014141522A (ja) * | 2008-03-13 | 2014-08-07 | Guangzhou Institute Of Biomedicine And Health Chinese Academy Of Sciences | エストロゲン関連受容体モジュレータ化合物及びその使用 |
| JP2015503504A (ja) * | 2011-12-23 | 2015-02-02 | ミレニアム ファーマシューティカルズ, インコーポレイテッドMillennium Pharmaceuticals, Inc. | ヘテロアリールおよびその使用 |
| JP2015533822A (ja) * | 2012-09-28 | 2015-11-26 | イグニタ、インク. | 非定型プロテインキナーゼcのアザキナゾリン阻害薬 |
| JP2017509655A (ja) * | 2014-03-25 | 2017-04-06 | キャンサー・リサーチ・テクノロジー・リミテッド | 非定型プロテインキナーゼcのアザキナゾリン阻害薬 |
| JP2020516632A (ja) * | 2017-04-11 | 2020-06-11 | サンシャイン・レイク・ファーマ・カンパニー・リミテッドSunshine Lake Pharma Co.,Ltd. | フッ素置換されたインダゾール化合物及びその使用 |
| JP2021091703A (ja) * | 2016-01-07 | 2021-06-17 | シーエス ファーマテック リミテッド | Egfrチロシンキナーゼの臨床的に重要な変異体の選択的阻害薬 |
Families Citing this family (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070148628A1 (en) * | 2005-12-09 | 2007-06-28 | Philadelphia College Of Osteopathic Medicine | Organ preservation and/or perfusion |
| CA2637531A1 (en) * | 2006-02-17 | 2007-08-30 | Memory Pharmaceuticals Corporation | Compounds having 5-ht6 receptor affinity |
| US8288366B2 (en) | 2006-06-20 | 2012-10-16 | Chochinov Ronald H | Formulation for hair growth |
| JP2010522214A (ja) * | 2007-03-21 | 2010-07-01 | アルミラル, エセ.アー. | アデノシンレセプターアンタゴニストとしての置換ピリミジン |
| WO2009006267A2 (en) * | 2007-06-28 | 2009-01-08 | Wyeth | N'-(2-halobenzylidene)sulfonylhydrazides as intermediates in the manufacture of arylsulfonylindazoles |
| AU2008286760A1 (en) * | 2007-08-15 | 2009-02-19 | Memory Pharmaceuticals Corporation | 3' substituted compounds having 5-HT6 receptor affinity |
| US20100016297A1 (en) * | 2008-06-24 | 2010-01-21 | Memory Pharmaceuticals Corporation | Alkyl-substituted 3' compounds having 5-ht6 receptor affinity |
| US20100022581A1 (en) * | 2008-07-02 | 2010-01-28 | Memory Pharmaceuticals Corporation | Pyrrolidine-substituted azaindole compounds having 5-ht6 receptor affinity |
| US20100029629A1 (en) * | 2008-07-25 | 2010-02-04 | Memory Pharmaceuticals Corporation | Acyclic compounds having 5-ht6 receptor affinity |
| US20100056531A1 (en) * | 2008-08-22 | 2010-03-04 | Memory Pharmaceuticals Corporation | Alkyl-substituted 3' compounds having 5-ht6 receptor affinity |
| US20120316182A1 (en) | 2011-06-10 | 2012-12-13 | Calcimedica, Inc. | Compounds that modulate intracellular calcium |
| US9856240B2 (en) | 2011-10-19 | 2018-01-02 | Calcimedica, Inc. | Compounds that modulate intracellular calcium |
| WO2014093230A2 (en) * | 2012-12-10 | 2014-06-19 | Merck Patent Gmbh | Compositions and methods for the production of pyrimidine and pyridine compounds with btk inhibitory activity |
| EP3046560B1 (en) * | 2013-09-18 | 2021-01-06 | EpiAxis Therapeutics Pty Ltd | Stem cell modulation ii |
| WO2016036586A1 (en) * | 2014-09-03 | 2016-03-10 | Merck Sharp & Dohme Corp. | Compounds inhibiting leucine-rich repeat kinase enzyme activity |
| RU2020133727A (ru) * | 2018-03-21 | 2022-04-21 | Сучжоу Пухе Биофарма Ко., Лтд. | Ингибиторы shp2 и их применение |
| CN112881542B (zh) * | 2020-10-28 | 2022-11-18 | 上海安谱实验科技股份有限公司 | 一种稳定同位素氘标记的达氟沙星及其合成方法 |
| US11993580B1 (en) | 2022-12-02 | 2024-05-28 | Neumora Therapeutics, Inc. | Methods of treating neurological disorders |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PT72878B (en) | 1980-04-24 | 1983-03-29 | Merck & Co Inc | Process for preparing mannich-base hydroxamic acid pro-drugs for the improved delivery of non-steroidal anti-inflammatory agents |
| DE19610882A1 (de) * | 1996-03-20 | 1997-09-25 | Dresden Arzneimittel | Neue 1,3,5-trisubstituierte Indazol-Derivate mit antiasthmatischer, antiallergischer, entzündungshemmender und immunmodulierender Wirkung, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel |
| US6921762B2 (en) | 2001-11-16 | 2005-07-26 | Amgen Inc. | Substituted indolizine-like compounds and methods of use |
| PE20040079A1 (es) | 2002-04-03 | 2004-04-19 | Novartis Ag | Derivados de indolilmaleimida |
| DE60310548T2 (de) | 2002-05-07 | 2007-05-10 | Neurosearch A/S | Diazabicyclische biarylderivate |
| ATE440087T1 (de) | 2003-01-30 | 2009-09-15 | Boehringer Ingelheim Pharma | 2,4-diaminopyrimidinderivate, die sich als inhibitoren von pkc-theta eignen |
| EP1454908B1 (en) | 2003-03-07 | 2008-02-27 | Sanofi-Aventis | Substituted pyridinyl-2-(diaza-bicyclo-alkyl)-pyrimidinone derivatives |
| JP2007538011A (ja) * | 2004-05-07 | 2007-12-27 | メモリー・ファーマシューティカルズ・コーポレイション | 1h−インダゾール、ベンゾチアゾール、1,2−ベンゾイソキサゾール、1,2−ベンゾイソチアゾール、およびクロモン、ならびにそれらの調製および使用 |
-
2005
- 2005-01-11 US US11/034,042 patent/US7582631B2/en active Active
- 2005-01-12 WO PCT/US2005/000993 patent/WO2005070934A1/en not_active Ceased
- 2005-01-12 JP JP2006549571A patent/JP2007517904A/ja not_active Withdrawn
- 2005-01-12 AU AU2005206524A patent/AU2005206524B2/en not_active Expired - Fee Related
- 2005-01-12 EP EP05705583A patent/EP1727821A1/en not_active Withdrawn
- 2005-01-12 CA CA002553232A patent/CA2553232A1/en not_active Abandoned
-
2009
- 2009-02-04 US US12/322,671 patent/US20090149468A1/en not_active Abandoned
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8569294B2 (en) | 2006-03-15 | 2013-10-29 | Mitsubishi Tanabe Pharma Corporation | 2-(cyclic amino)-pyrimidone derivatives |
| JP2011512340A (ja) * | 2008-02-15 | 2011-04-21 | エフ.ホフマン−ラ ロシュ アーゲー | 3−アルキルピペラジン誘導体及びその使用 |
| JP2014141522A (ja) * | 2008-03-13 | 2014-08-07 | Guangzhou Institute Of Biomedicine And Health Chinese Academy Of Sciences | エストロゲン関連受容体モジュレータ化合物及びその使用 |
| JP2015503504A (ja) * | 2011-12-23 | 2015-02-02 | ミレニアム ファーマシューティカルズ, インコーポレイテッドMillennium Pharmaceuticals, Inc. | ヘテロアリールおよびその使用 |
| JP2015533822A (ja) * | 2012-09-28 | 2015-11-26 | イグニタ、インク. | 非定型プロテインキナーゼcのアザキナゾリン阻害薬 |
| JP2017509655A (ja) * | 2014-03-25 | 2017-04-06 | キャンサー・リサーチ・テクノロジー・リミテッド | 非定型プロテインキナーゼcのアザキナゾリン阻害薬 |
| JP2021091703A (ja) * | 2016-01-07 | 2021-06-17 | シーエス ファーマテック リミテッド | Egfrチロシンキナーゼの臨床的に重要な変異体の選択的阻害薬 |
| JP2020516632A (ja) * | 2017-04-11 | 2020-06-11 | サンシャイン・レイク・ファーマ・カンパニー・リミテッドSunshine Lake Pharma Co.,Ltd. | フッ素置換されたインダゾール化合物及びその使用 |
| JP7090639B2 (ja) | 2017-04-11 | 2022-06-24 | サンシャイン・レイク・ファーマ・カンパニー・リミテッド | フッ素置換されたインダゾール化合物及びその使用 |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2005206524B2 (en) | 2008-10-30 |
| WO2005070934A1 (en) | 2005-08-04 |
| AU2005206524A1 (en) | 2005-08-04 |
| US20050182072A1 (en) | 2005-08-18 |
| CA2553232A1 (en) | 2005-08-04 |
| EP1727821A1 (en) | 2006-12-06 |
| US7582631B2 (en) | 2009-09-01 |
| US20090149468A1 (en) | 2009-06-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US7582631B2 (en) | Substituted heterocyclic compounds and methods of use | |
| US10369153B2 (en) | Pyrrolopyrimidine compounds and uses thereof | |
| US8580802B2 (en) | Pyrrolo[2,3-D]pyrimidines as inhibitors of Janus kinases | |
| US20220387395A1 (en) | Urea, amide, and substituted heteroaryl compounds for cbl-b inhibition | |
| KR20230053661A (ko) | 비사이클 화합물과 비사이클 화합물을 포함하는 조성물 및 이들의 용도 | |
| US9550796B2 (en) | Pyrrolopyrrolone derivatives and their use as BET inhibitors | |
| CN115697980A (zh) | 作为dgkzeta抑制剂用于免疫活化的取代的氨基噻唑 | |
| US10611777B2 (en) | Imidazopyridazine compounds and their use | |
| KR102565546B1 (ko) | 신규 옥소이소퀴놀린 유도체 | |
| MX2008012860A (es) | Desazapurinas de utilidad como inhibidores de janus cinasas. | |
| KR102697255B1 (ko) | 벤즈이미다졸 유도체 및 이의 용도 | |
| US20150005277A1 (en) | Protein Kinase Inhibitors and Uses Thereof | |
| EA019941B1 (ru) | Соединения и композиции в качестве ингибиторов протеинкиназы | |
| KR102598246B1 (ko) | Jak 저해제로서 헤테로사이클릭 화합물, 및 이의 염 및 치료학적 용도 | |
| KR20140107421A (ko) | Pi3k의 활성 또는 기능의 억제제의 용도 | |
| CA3159835A1 (en) | 4-[[(7-aminopyrazolo[1,5-a]pyrimidin-5-yl)amino]methyl]piperidin-3-ol compounds and their therapeutic use | |
| US12590099B2 (en) | Inhibitors of histone deacetylase useful for the treatment or prevention of HIV infection | |
| KR20210100612A (ko) | 시클로알칸-1,3-디아민 유도체 | |
| MXPA06008025A (en) | Substituted diazabicycloheptanes and their use as protein kinase inhibitors | |
| CA3114259C (en) | Aminonorbornane derivative and manufacture method therefor and use thereof | |
| RU2772226C2 (ru) | Новые производные оксоизохинолина | |
| CA3114259A1 (en) | Aminonorbornane derivative and manufacture method therefor and use thereof | |
| EA049140B1 (ru) | Замещенные конденсированные гетероароматические бициклические соединения в качестве ингибиторов киназ и их применение | |
| HK40009542A (en) | Novel oxoisoquinoline derivative | |
| HK40015251B (en) | Novel oxoisoquinoline derivative |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20080110 |
|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20080110 |
|
| A761 | Written withdrawal of application |
Free format text: JAPANESE INTERMEDIATE CODE: A761 Effective date: 20080226 |