WO2022162606A1 - Heterocyclic compounds as kinase inhibitor and uses thereof - Google Patents
Heterocyclic compounds as kinase inhibitor and uses thereof Download PDFInfo
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- WO2022162606A1 WO2022162606A1 PCT/IB2022/050756 IB2022050756W WO2022162606A1 WO 2022162606 A1 WO2022162606 A1 WO 2022162606A1 IB 2022050756 W IB2022050756 W IB 2022050756W WO 2022162606 A1 WO2022162606 A1 WO 2022162606A1
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- WIPO (PCT)
- Prior art keywords
- compound
- ylamino
- alkylene
- formula
- methyl
- Prior art date
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- 229940043355 kinase inhibitor Drugs 0.000 title description 5
- 239000003757 phosphotransferase inhibitor Substances 0.000 title description 5
- 150000002391 heterocyclic compounds Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 699
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 68
- 238000000034 method Methods 0.000 claims abstract description 62
- 206010064911 Pulmonary arterial hypertension Diseases 0.000 claims abstract description 50
- 201000011510 cancer Diseases 0.000 claims abstract description 43
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 claims abstract description 39
- 208000036971 interstitial lung disease 2 Diseases 0.000 claims abstract description 34
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 27
- 238000011282 treatment Methods 0.000 claims abstract description 23
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 9
- 125000002947 alkylene group Chemical group 0.000 claims description 234
- 150000003839 salts Chemical class 0.000 claims description 94
- 125000000623 heterocyclic group Chemical group 0.000 claims description 84
- 150000002367 halogens Chemical class 0.000 claims description 64
- 229910052736 halogen Inorganic materials 0.000 claims description 63
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 50
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 45
- 125000003118 aryl group Chemical group 0.000 claims description 41
- 108010019244 Checkpoint Kinase 1 Proteins 0.000 claims description 40
- 102000006459 Checkpoint Kinase 1 Human genes 0.000 claims description 40
- 201000010099 disease Diseases 0.000 claims description 37
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 30
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 30
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 29
- -1 octahydro- IH-indene Chemical compound 0.000 claims description 29
- 239000003814 drug Substances 0.000 claims description 26
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 25
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims description 24
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 24
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 24
- 229910052739 hydrogen Inorganic materials 0.000 claims description 24
- 239000001257 hydrogen Substances 0.000 claims description 24
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 23
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 21
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 18
- 125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 16
- 125000006714 (C3-C10) heterocyclyl group Chemical group 0.000 claims description 14
- 125000004429 atom Chemical group 0.000 claims description 14
- 150000002431 hydrogen Chemical group 0.000 claims description 14
- 125000002950 monocyclic group Chemical group 0.000 claims description 14
- 125000004043 oxo group Chemical group O=* 0.000 claims description 13
- 238000004519 manufacturing process Methods 0.000 claims description 12
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 10
- 125000003725 azepanyl group Chemical group 0.000 claims description 8
- 208000035475 disorder Diseases 0.000 claims description 8
- 239000003937 drug carrier Substances 0.000 claims description 8
- 229940124597 therapeutic agent Drugs 0.000 claims description 8
- 239000012453 solvate Substances 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- ADKDJHASTPQGEO-UHFFFAOYSA-N 1,2,3,3a,4,5,6,6a-octahydrocyclopenta[b]pyrrole Chemical compound C1CNC2CCCC21 ADKDJHASTPQGEO-UHFFFAOYSA-N 0.000 claims description 4
- CJNWCWVQGCSQRA-UHFFFAOYSA-N 2,3,4,4a,5,6,7,7a-octahydro-1h-cyclopenta[b]pyridine Chemical compound C1CCNC2CCCC21 CJNWCWVQGCSQRA-UHFFFAOYSA-N 0.000 claims description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- NNBZCPXTIHJBJL-UHFFFAOYSA-N decalin Chemical compound C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- KPXSPHQLZBMRLW-UHFFFAOYSA-N 2,3,4,4a,5,6,7,7a-octahydro-1h-cyclopenta[c]pyridine Chemical compound C1CNCC2CCCC21 KPXSPHQLZBMRLW-UHFFFAOYSA-N 0.000 claims description 3
- IQWUBPOREYWDLA-UHFFFAOYSA-N 5-[[6-(1-methylpyrazol-3-yl)-5-(piperidin-4-ylmethylamino)pyridazin-3-yl]amino]pyrazine-2-carbonitrile Chemical compound CN1N=C(C=C1)C1=C(C=C(N=N1)NC=1N=CC(=NC=1)C#N)NCC1CCNCC1 IQWUBPOREYWDLA-UHFFFAOYSA-N 0.000 claims description 3
- YSJDFGJHPCXCQR-UHFFFAOYSA-N 5-[[6-(1H-imidazol-2-yl)-5-(piperidin-4-ylmethylamino)pyridazin-3-yl]amino]pyrazine-2-carbonitrile Chemical compound C1CNCCC1CNC2=CC(=NN=C2C3=NC=CN3)NC4=NC=C(N=C4)C#N YSJDFGJHPCXCQR-UHFFFAOYSA-N 0.000 claims description 3
- FSJVLBOIJLAEDB-UHFFFAOYSA-N 5-[[6-(1H-imidazol-2-yl)-5-[(1-methylpiperidin-4-yl)methylamino]pyridazin-3-yl]amino]pyrazine-2-carbonitrile Chemical compound CN1CCC(CC1)CNC2=CC(=NN=C2C3=NC=CN3)NC4=NC=C(N=C4)C#N FSJVLBOIJLAEDB-UHFFFAOYSA-N 0.000 claims description 3
- UFBNNMJRANKXRF-UHFFFAOYSA-N 5-[[6-(azetidin-1-yl)-5-(piperidin-4-ylmethylamino)pyridazin-3-yl]amino]pyrazine-2-carbonitrile Chemical compound C1CN(C1)C2=NN=C(C=C2NCC3CCNCC3)NC4=NC=C(N=C4)C#N UFBNNMJRANKXRF-UHFFFAOYSA-N 0.000 claims description 3
- NTYDZLSCWANORQ-UHFFFAOYSA-N 6-[(5-cyanopyrazin-2-yl)amino]-4-(oxan-4-ylmethylamino)pyridazine-3-carboxamide Chemical compound C(#N)C=1N=CC(=NC=1)NC1=CC(=C(N=N1)C(=O)N)NCC1CCOCC1 NTYDZLSCWANORQ-UHFFFAOYSA-N 0.000 claims description 3
- RXACXSJIHKFIRL-UHFFFAOYSA-N 6-[(5-cyanopyrazin-2-yl)amino]-4-(piperidin-4-ylmethylamino)-N-(2,2,2-trifluoroethyl)pyridazine-3-carboxamide Chemical compound C1CNCCC1CNC2=CC(=NN=C2C(=O)NCC(F)(F)F)NC3=NC=C(N=C3)C#N RXACXSJIHKFIRL-UHFFFAOYSA-N 0.000 claims description 3
- ICQYLLBKJGBHKD-UHFFFAOYSA-N 6-[(5-cyanopyrazin-2-yl)amino]-4-(piperidin-4-ylmethylamino)-N-(trifluoromethyl)pyridazine-3-carboxamide Chemical compound C1CNCCC1CNC2=CC(=NN=C2C(=O)NC(F)(F)F)NC3=NC=C(N=C3)C#N ICQYLLBKJGBHKD-UHFFFAOYSA-N 0.000 claims description 3
- KDIKUSSIYWCOIQ-UHFFFAOYSA-N 6-[(5-cyanopyrazin-2-yl)amino]-4-[(2,6-dimethylpiperidin-3-yl)methylamino]-N-methylpyridazine-3-carboxamide Chemical compound CC1CCC(C(N1)C)CNC2=CC(=NN=C2C(=O)NC)NC3=NC=C(N=C3)C#N KDIKUSSIYWCOIQ-UHFFFAOYSA-N 0.000 claims description 3
- LQKRVSJABHLZDG-UHFFFAOYSA-N 6-[(5-cyanopyrazin-2-yl)amino]-N,N-dimethyl-4-[(4-methylmorpholin-2-yl)methylamino]pyridazine-3-carboxamide Chemical compound CN1CCOC(C1)CNC2=CC(=NN=C2C(=O)N(C)C)NC3=NC=C(N=C3)C#N LQKRVSJABHLZDG-UHFFFAOYSA-N 0.000 claims description 3
- FVJOPWOLQNJHSW-UHFFFAOYSA-N 6-[(5-cyanopyrazin-2-yl)amino]-N-methyl-4-(oxan-4-ylmethylamino)pyridazine-3-carboxamide Chemical compound C(#N)C=1N=CC(=NC=1)NC1=CC(=C(N=N1)C(=O)NC)NCC1CCOCC1 FVJOPWOLQNJHSW-UHFFFAOYSA-N 0.000 claims description 3
- LLEIAYWHJWXRQK-UHFFFAOYSA-N 6-[(5-cyanopyrazin-2-yl)amino]-N-methyl-4-(piperidin-3-ylmethylamino)pyridazine-3-carboxamide Chemical compound CNC(=O)C1=NN=C(C=C1NCC2CCCNC2)NC3=NC=C(N=C3)C#N LLEIAYWHJWXRQK-UHFFFAOYSA-N 0.000 claims description 3
- ITLCRAUSQKFZPZ-UHFFFAOYSA-N 6-[(5-cyanopyrazin-2-yl)amino]-N-methyl-4-(pyrrolidin-3-ylmethylamino)pyridazine-3-carboxamide Chemical compound CNC(=O)C1=NN=C(C=C1NCC2CCNC2)NC3=NC=C(N=C3)C#N ITLCRAUSQKFZPZ-UHFFFAOYSA-N 0.000 claims description 3
- LTGLZQUYUOCJHW-UHFFFAOYSA-N 6-[(5-cyanopyrazin-2-yl)amino]-N-methyl-4-[(1-methylpiperidin-4-yl)methylamino]pyridazine-3-carboxamide Chemical compound C(#N)C=1N=CC(=NC=1)NC1=CC(=C(N=N1)C(=O)NC)NCC1CCN(CC1)C LTGLZQUYUOCJHW-UHFFFAOYSA-N 0.000 claims description 3
- IKBOXLLHJRNWJU-UHFFFAOYSA-N 6-[(5-cyanopyrazin-2-yl)amino]-N-methyl-4-[(4-methylmorpholin-2-yl)methylamino]pyridazine-3-carboxamide Chemical compound CNC(=O)C1=NN=C(C=C1NCC2CN(CCO2)C)NC3=NC=C(N=C3)C#N IKBOXLLHJRNWJU-UHFFFAOYSA-N 0.000 claims description 3
- MESNAQDXLBLHDS-UHFFFAOYSA-N 6-[(5-cyanopyridin-2-yl)amino]-N-methyl-4-(morpholin-2-ylmethylamino)pyridazine-3-carboxamide Chemical compound CNC(=O)C1=NN=C(C=C1NCC2CNCCO2)NC3=NC=C(C=C3)C#N MESNAQDXLBLHDS-UHFFFAOYSA-N 0.000 claims description 3
- MQUFLSKQWASDME-UHFFFAOYSA-N 6-[(6-cyanopyridin-3-yl)amino]-N-methyl-4-(morpholin-2-ylmethylamino)pyridazine-3-carboxamide Chemical compound C(#N)C1=CC=C(C=N1)NC1=CC(=C(N=N1)C(=O)NC)NCC1CNCCO1 MQUFLSKQWASDME-UHFFFAOYSA-N 0.000 claims description 3
- MQUFLSKQWASDME-ZDUSSCGKSA-N 6-[(6-cyanopyridin-3-yl)amino]-N-methyl-4-[[(2S)-morpholin-2-yl]methylamino]pyridazine-3-carboxamide Chemical compound CNC(C(N=NC(NC1=CC=C(C#N)N=C1)=C1)=C1NC[C@H]1OCCNC1)=O MQUFLSKQWASDME-ZDUSSCGKSA-N 0.000 claims description 3
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 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 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
- 230000001404 mediated effect Effects 0.000 claims description 3
- UZHVXJZEHGSWQV-UHFFFAOYSA-N 1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole Chemical compound C1NCC2CCCC21 UZHVXJZEHGSWQV-UHFFFAOYSA-N 0.000 claims description 2
- AEBWATHAIVJLTA-UHFFFAOYSA-N 1,2,3,3a,4,5,6,6a-octahydropentalene Chemical compound C1CCC2CCCC21 AEBWATHAIVJLTA-UHFFFAOYSA-N 0.000 claims description 2
- NENLYAQPNATJSU-UHFFFAOYSA-N 1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline Chemical compound C1NCCC2CCCCC21 NENLYAQPNATJSU-UHFFFAOYSA-N 0.000 claims description 2
- POTIYWUALSJREP-UHFFFAOYSA-N 1,2,3,4,4a,5,6,7,8,8a-decahydroquinoline Chemical compound N1CCCC2CCCCC21 POTIYWUALSJREP-UHFFFAOYSA-N 0.000 claims description 2
- DFAKAYKNPJMQSX-UHFFFAOYSA-N 1-azaspiro[3.4]octane Chemical compound N1CCC11CCCC1 DFAKAYKNPJMQSX-UHFFFAOYSA-N 0.000 claims description 2
- QPEJAHMNOVMSOZ-UHFFFAOYSA-N 2-azaspiro[3.3]heptane Chemical compound C1CCC21CNC2 QPEJAHMNOVMSOZ-UHFFFAOYSA-N 0.000 claims description 2
- PSNDWZOXFDKLLH-UHFFFAOYSA-N 2-azaspiro[3.4]octane Chemical compound C1NCC11CCCC1 PSNDWZOXFDKLLH-UHFFFAOYSA-N 0.000 claims description 2
- IBODJKKYTBNWTD-UHFFFAOYSA-N 2-azaspiro[3.5]nonane Chemical compound C1NCC11CCCCC1 IBODJKKYTBNWTD-UHFFFAOYSA-N 0.000 claims description 2
- NINJAJLCZUYDGV-UHFFFAOYSA-N 2-azaspiro[4.4]nonane Chemical compound C1CCCC21CNCC2 NINJAJLCZUYDGV-UHFFFAOYSA-N 0.000 claims description 2
- SFCOKGCNIPSUQF-UHFFFAOYSA-N 2-azaspiro[4.5]decane Chemical compound C1NCCC21CCCCC2 SFCOKGCNIPSUQF-UHFFFAOYSA-N 0.000 claims description 2
- VZUJZECRVUMMJI-UHFFFAOYSA-N 2-azaspiro[5.5]undecane Chemical compound C1CCCCC21CNCCC2 VZUJZECRVUMMJI-UHFFFAOYSA-N 0.000 claims description 2
- LIZKZVQBLDHKCY-UHFFFAOYSA-N 3-azaspiro[5.5]undecane Chemical compound C1CCCCC21CCNCC2 LIZKZVQBLDHKCY-UHFFFAOYSA-N 0.000 claims description 2
- FIZARKJBNYKGJI-UHFFFAOYSA-N 4-azabicyclo[3.2.0]heptane Chemical compound N1CCC2CCC21 FIZARKJBNYKGJI-UHFFFAOYSA-N 0.000 claims description 2
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- FIEQFLLZBBTQHY-UHFFFAOYSA-N 6-azaspiro[4.5]decane Chemical compound C1CCCC21NCCCC2 FIEQFLLZBBTQHY-UHFFFAOYSA-N 0.000 claims description 2
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- JFNPSSKPSOKMJH-UHFFFAOYSA-N 7-azaspiro[4.5]decane Chemical compound C1CCCC21CNCCC2 JFNPSSKPSOKMJH-UHFFFAOYSA-N 0.000 claims description 2
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- DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 claims 2
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms 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
Definitions
- the present invention generally relates to compounds having Checkpoint kinase-1 (CHK-1) inhibitory activity, to the use of such compounds in the treatment of proliferative disorders, such as cancer; Pulmonary Arterial Hypertension (PAH) and Idiopathic Pulmonary Fibrosis (IPF).
- CHK-1 Checkpoint kinase-1
- the invention also provides method of synthesis of said compounds, method of using said compounds, pharmaceutical compositions comprising said compounds and method of using thereof.
- BACKGROUND OF THE INVENTION [3] A wide range of cancer chemotherapeutic agents act through DNA damaging pathway to induce DNA damage causing tumor growth inhibition. However, these chemotherapeutic agents lead to cell cycle arrest by induction of checkpoints at either S-phase or G2/M boundary. The G2 arrest allows the cell time to repair the damaged DNA before entering mitosis.
- Checkpoint kinase-1 (CHK-1) and an unrelated serine/threonine kinase, Checkpoint kinase-2 (CHK-2), play a central role in arresting the cell cycle at the G2-M boundary (O'Connell et al EMBO J (1997) vol. 16 p. 545-554).
- CHK-1 and/or CHK-2 induce this checkpoint by phosphorylating serine 216 of the CDC25 phosphatase, inhibiting the removal of two inactivating phosphates on cyclin dependent kinases (CDKs) (Zheng et al Nature (1998) vol.395 p.507-510).
- CDKs cyclin dependent kinases
- Another overlapping pathway mediated by p53 also elicits cycle arrest in response to DNA-damage.
- p53 is mutationally inactivated in many cancers, resulting in a partial deficiency in their ability to initiate a DNA-repair response.
- CHK-1 activity is also inhibited in p53-negative cancers, all ability to arrest and repair DNA in response to DNA-damage is removed resulting in mitotic catastrophe and enhancing the effect of the DNA damaging agents (Konarias et al. Oncogene (2001) vol. 20 p 7453-7463, Bunch and Eastman Clin. Can. Res. (1996) vol.2 p 791-797, Tenzer and Pruschy Curr. Med Chem (2003) vol 3 p 35-46).
- CHK-1 inhibition therefore, represents a novel therapeutic strategy to increase the lethality of DNA-damaging chemotherapeutic drugs in p53 pathway defective cancers. Abrogation of the remaining intact checkpoint should result in increased tumor cell death.
- CHK-1 inhibitors have demonstrated potentiation of a range of cytotoxic chemotherapy drugs both in vitro and in a range of pre-clinical models of human cancer including gemcitabine, irinotecan, cytarabine, and cisplatin. This “synthetic lethality” approach should increase the therapeutic activity of the chemotherapeutic drug without increasing the systemic toxicity as normal cells should remain protected by their functional p53 pathway.
- CHK-1 inhibitors have, therefore, the potential to be combined with a wide range of cytotoxic chemotherapeutic agents for the treatment of a diverse selection of human cancers.
- PAH Pulmonary Arterial Hypertension
- IPF Idiopathic Pulmonary Fibrosis
- PAH is a devastating disease accompanied with progressive vascular remodeling of distal pulmonary arteries leading to concomitant elevation of pulmonary artery pressure, perivascular inflammation, fibrotic changes, right ventricular hypertrophy, and death (Bourgeois et.al., Arterioscler Thromb Vasc Biol.
- CHK-1 and/or CHK-2 induce this checkpoint by phosphorylating serine 216 of the CDC25 phosphatase, inhibiting the removal of two inactivating phosphates on cyclin dependent kinases (CDKs) (Zheng et al Nature (1998) vol. 395 p. 507-510).
- CDKs cyclin dependent kinases
- PAH-IPF proliferating PAH-PASMCs show increased levels of ⁇ -H2AX and pRPA32, markers for DNA damage/replication stress and also display enhanced expression and activation of CHK1.
- pharmacological inhibition of CHK1 improves PAH in clinically relevant rat models suggesting that CHK1 inhibition could also be an attractive therapeutic option for PAH (Bourgeois et.al., Arterioscler Thromb Vasc Biol. 2019;39:1667–1681).
- another overlapping pathway mediated by p53 also elicits cycle arrest in response to DNA-damage.
- p53 is mutationally inactivated resulting in a partial deficiency in their ability to initiate a DNA-repair response. If CHK-1 activity is also inhibited in p53-negative cancers, all ability to arrest and repair DNA in response to DNA-damage is removed resulting in mitotic catastrophe and enhancing the effect of the DNA damaging agents (Konarias et al. Oncogene (2001) vol. 20 p 7453-7463, Bunch and Eastman Clin. Can. Res. (1996) vol. 2 p 791-797, Tenzer and Pruschy Curr. Med Chem (2003) vol 3 p 35-46). [6] Various attempts have been made to develop CHK-1 kinase inhibitors.
- US10000481B2 disclose 1H-pyrrolo[2,3-B] pyridine derivatives compounds as CHK-1 kinase inhibitors.
- US10010547B2 discloses pyrazol amino pyrazine derivatives as kinase inhibitors.
- WO/2018/086546A1 disclose 2-polysubstituted aromatic ring-pyrimidine derivatives as CHK-1 inhibitors.
- CHK-1 small molecule inhibitors of CHK-1 (Prexasertib/LY2606368, LY2603618 and SRA737) are currently in Phase I/II clinical evaluation in combination with gemcitabine, pemetrexed, fludarabine, cytarabine, and cisplatin.
- the main features of IPF-PH are excessive proliferation and resistance to apoptosis of fibroblasts and pulmonary arterial (PA) smooth muscle cells (PASMC) leading to aberrant accumulation of extracellular matrix in parenchyma and extensive vascular remodeling. It can be hypothesized that CHK1/2, which is upregulated and activated in IPF-PH contributes to fibrotic and vascular lesions in IPF-PH.
- DNA repair initiation enzyme ⁇ H2Ax which in turn correlates with PAH remodeling and fibrosis scores.
- the increase in DNA repair in IPF is associated with a significant upregulation of CHK1 and CHK2 in the lungs and distal PA of IPF patients and it was mainly localized within PASMC and fibrotic lesions.
- Some of the drugs which target proliferation could be protective against PAH and since CHK1 activation in PAH-PASMCs is known to be a decisive event in the initiation of pulmonary vascular remodeling in PAH, it could be a potential therapeutic target for PAH- IPF (Satoh et.al., Int J Mol Sci.
- the object of the present invention is to provide such pharmaceutical agents and treatments.
- the present invention provides a compound of formula (J): or a salt, thereof, wherein X 1 , X 2 , Q, A, L and R x are as detailed herein.
- the compound of formula (J) or a salt thereof is a compound of formula (I) or a salt thereof, as detailed herein.
- the compound of formula (J) or a salt thereof is a compound of formula (IA) or a salt thereof, as detailed herein.
- the compound of formula (IA) or a salt thereof is any of the compounds of formula (IA-1) to (IA-10) or a salt thereof, as detailed herein
- the compound of formula (J) or a salt thereof is a compound of formula (IB) or a salt thereof, as detailed herein.
- the compound of formula (IB) or a salt thereof is any of the compounds of formula (IB-1) to (IB-10) or a salt thereof, as detailed herein
- the compound of formula (J) or a salt thereof is a compound of formula (II) or a salt thereof, as detailed herein.
- the compound of formula (II) or a salt thereof is any of the compounds of formula (II-a) to (II-c) or a salt thereof, as detailed herein.
- the compound of formula (J) or a salt thereof is a compound of formula (III) or a salt thereof, as detailed herein.
- the compound of formula (III) or a salt thereof is any of the compounds of formula (III-a) to (III-c) or a salt thereof, as detailed herein.
- the compound of formula (J) or a salt thereof is a compound of formula (IV) or a salt thereof, as detailed herein.
- the compound of formula (IV) or a salt thereof is any of the compounds of formula (IV-a) to (IV-c) or a salt thereof, as detailed herein.
- the compound of formula (J) or a salt thereof is a compound of formula (V) or a salt thereof, as detailed herein.
- the compound of formula (V) or a salt thereof is any of the compounds of formula (V-a) to (V-f) or a salt thereof, as detailed herein.
- the compound of formula (J) or a salt thereof is a compound of formula (VI) or a salt thereof, as detailed herein.
- the compound of formula (VI) or a salt thereof is any of the compounds of formula (VI-a) to (VI-f) or a salt thereof, as detailed herein.
- the compound of formula (J) or a salt thereof is a compound of formula (VII) or a salt thereof, as detailed herein.
- the compound of formula (VII) or a salt thereof is any of the compounds of formula (VII-a) to (VII-f) or a salt thereof, as detailed herein.
- the compound of formula (J) or a salt thereof is a compound of formula (VIII) or a salt thereof, as detailed herein.
- the compound of formula (VIII) or a salt thereof is any of the compounds of formula (VIII-a) to (VIII-f) or a salt thereof, as detailed herein.
- the present invention provides method of treating a disease or disorder associated with this CHK kinase enzymes, more specifically CHK-1 kinase enzymes in an individual in need thereof, wherein the method comprises administering to the individual an effective amount of a compound of the present invention (collectively, a compound of formula (J), (I), (IA), (IA-1) to (IA-10), (IB) , (IB-1) to (IB-10), (II), (II-a) to (II-c), (III), (III-a) to (III-c), (IV), (IV-a) to (IV-c), (V), (V-a) to (V-f), (VI), (VI-a) to (VI-f)) (VII), (VII-a) to (VII-f), (VIII), (VIII-a) to (VIII-f) or a salt thereof.
- a compound of formula (J) a compound of formula (J), (I), (IA), (IA
- the present invention provides method of treating cancer in an individual in need thereof, wherein the method comprises administering to the individual an effective amount of a compound of the present invention (collectively, a compound of formula (J), (I), (IA), (IA-1) to (IA-10), (IB) , (IB-1) to (IB-10), (II), (II-a) to (II-c), (III), (III- a) to (III-c), (IV), (IV-a) to (IV-c), (V), (V-a) to (V-f), (VI), (VI-a) to (VI-f)) (VII), (VII-a) to (VII-f), (VIII), (VIII-a) to (VIII-f), or a salt thereof.
- a compound of formula (J) a compound of formula (J), (I), (IA), (IA-1) to (IA-10), (IB) , (IB-1) to (IB-10), (II
- the present invention provides method of treating Idiopathic Pulmonary Fibrosis (IPF) in an individual in need thereof, wherein the method comprises administering to the individual an effective amount of a compound of the present invention (collectively, a compound of formula (J), (I), (IA), (IA-1) to (IA-10), (IB) , (IB-1) to (IB-10), (II), (II-a) to (II-c), (III), (III-a) to (III-c), (IV), (IV-a) to (IV-c), (V), (V-a) to (V-f), (VI), (VI- a) to (VI-f)) (VII), (VII-a) to (VII-f), (VIII), (VIII-a) to (VIII-f)), or a salt thereof.
- a compound of the present invention collectively, a compound of formula (J), (I), (IA), (IA-1) to (IA-10), (IB
- the present invention provides method of treating I Pulmonary Arterial Hypertension (PAH) in an individual in need thereof, wherein the method comprises administering to the individual an effective amount of a compound of the present invention (collectively, a compound of formula (J), (I), (IA), (IA-1) to (IA-10), (IB) , (IB-1) to (IB-10), (II), (II-a) to (II-c), (III), (III-a) to (III-c), (IV), (IV-a) to (IV-c), (V), (V-a) to (V- f), (VI), (VI-a) to (VI-f)) (VII), (VII-a) to (VII-f), (VIII), (VIII-a) to (VIII-f)), or a salt thereof.
- a compound of formula (J) a compound of formula (J), (I), (IA), (IA-1) to (IA-10), (IB) , (
- the present invention provides method of treating a disease or disorder associated with this CHK kinase enzymes, more specifically CHK-1 kinase enzymes in an individual in need thereof, wherein the method comprises administering to the individual an effective amount of a compound of the present invention (collectively, a compound of formula (J), (I), (IA), (IA-1) to (IA-10), (IB) , (IB-1) to (IB-10), (II), (II-a) to (II-c), (III), (III-a) to (III-c), (IV), (IV-a) to (IV-c), (V), (V-a) to (V-f), (VI), (VI-a) to (VI-f)) (VII), (VII-a) to (VII-f), (VIII), (VIII-a) to (VIII-f)), or a salt thereof in combination with other therapeutic agents.
- a compound of the present invention collectively, a compound of formula (J), (
- the present invention provides pharmaceutical compositions, comprising a compound of the present invention (collectively, a compound of formula (J), (I), (IA), (IA-1) to (IA-10), (IB) , (IB-1) to (IB-10), (II), (II-a) to (II-c), (III), (III-a) to (III-c), (IV), (IV-a) to (IV-c), (V), (V-a) to (V-f), (VI), (VI-a) to (VI-f)) (VII), (VII-a) to (VII-f), (VIII), (VIII-a) to (VIII-f)), or a salt thereof.
- a compound of the present invention collectively, a compound of formula (J), (I), (IA), (IA-1) to (IA-10), (IB) , (IB-1) to (IB-10), (II), (II-a) to (II-c), (III),
- the present invention provides method of treating a disease or disorder associated with this CHK kinase enzymes, or more specifically CHK-1 kinase enzymes in an individual in need thereof, wherein the method comprises administering to the individual an effective amount of a pharmaceutical composition comprising a compound of the present invention (collectively, a compound of formula (J), (I), (IA), (IA-1) to (IA-10), (IB) , (IB-1) to (IB-10), (II), (II-a) to (II-c), (III), (III-a) to (III-c), (IV), (IV-a) to (IV-c), (V), (V-a) to (V-f), (VI), (VI-a) to (VI-f)) (VII), (VII-a) to (VII-f), (VIII), (VIII-a) to (VIII-f)), or a salt thereof.
- a pharmaceutical composition comprising a compound of the present invention (collectively,
- alkyl refers to and includes saturated linear and branched univalent hydrocarbon structures and combination thereof, having the number of carbon atoms designated (i.e., C 1 - C 10 means one to ten carbons). Particular alkyl groups are those having 1 to 20 carbon atoms (a “C 1 -C 20 alkyl”).
- alkyl groups are those having 1 to 8 carbon atoms (a “C 1 - C 8 alkyl”), 3 to 8 carbon atoms (a “C 3 -C 8 alkyl”), 1 to 6 carbon atoms (a “C 1 -C 6 alkyl”), 1 to 5 carbon atoms (a “C 1 -C 5 alkyl”), or 1 to 4 carbon atoms (a “C 1 -C 4 alkyl”).
- alkyl examples include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n- butyl, t-butyl, isobutyl, sec-butyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
- the alkenyl group may be in “cis” or “trans” configurations, or alternatively in “E” or “Z” configurations.
- Particular alkenyl groups are those having 2 to 20 carbon atoms (a “C 2 -C 20 alkenyl”), having 2 to 8 carbon atoms (a “C 2 -C 8 alkenyl”), having 2 to 6 carbon atoms (a “C 2 -C 6 alkenyl”), or having 2 to 4 carbon atoms (a “C 2 -C 4 alkenyl”).
- alkenyl examples include, but are not limited to, groups such as ethenyl (or vinyl), prop-1-enyl, prop-2-enyl (or allyl), 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-dienyl, homologs and isomers thereof, and the like.
- Alkylene as used herein refers to the same residues as alkyl, but having bivalency.
- alkylene groups are those having 1 to 6 carbon atoms (a “C 1 -C 6 alkylene”), 1 to 5 carbon atoms (a “C 1 -C 5 alkylene”), 1 to 4 carbon atoms (a “C 1 -C 4 alkylene”) or 1 to 3 carbon atoms (a “C 1 -C 3 alkylene”).
- alkylene include, but are not limited to, groups such as methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene (-CH 2 CH 2 CH 2 -), butylene (-CH 2 CH 2 CH 2 CH 2 -), and the like.
- Alkynyl refers to an unsaturated linear or branched univalent hydrocarbon chain or combination thereof, having at least one site of acetylenic unsaturation (i.e., having at least one moiety of the formula C ⁇ C) and having the number of carbon atoms designated (i.e., C 2 -C 10 means two to ten carbon atoms).
- Particular alkynyl groups are those having 2 to 20 carbon atoms (a “C 2 -C 20 alkynyl”), having 2 to 8 carbon atoms (a “C 2 -C 8 alkynyl”), having 2 to 6 carbon atoms (a “C 2 -C 6 alkynyl”), or having 2 to 4 carbon atoms (a “C 2 -C 4 alkynyl”).
- alkynyl examples include, but are not limited to, groups such as ethynyl (or acetylenyl), prop-1-ynyl, prop-2-ynyl (or propargyl), but-1-ynyl, but-2-ynyl, but-3-ynyl, homologs and isomers thereof, and the like.
- Aryl refers to and includes polyunsaturated aromatic hydrocarbon groups. Aryl may contain additional fused rings (e.g., from 1 to 3 rings), including additionally fused aryl, heteroaryl, cycloalkyl, and/or heterocyclyl rings. In one variation, the aryl group contains from 6 to 14 annular carbon atoms.
- aryl groups include, but are not limited to, phenyl, naphthyl, biphenyl, and the like.
- Cycloalkyl refers to and includes cyclic univalent hydrocarbon structures, which may be fully saturated, mono- or polyunsaturated, but which are non-aromatic, having the number of carbon atoms designated (e.g., C 1 -C 10 means one to ten carbons). Cycloalkyl can consist of one ring, such as cyclohexyl, or multiple rings, such as adamantly, but excludes aryl groups.
- a cycloalkyl comprising more than one ring may be fused, spiro or bridged, or combinations thereof.
- a preferred cycloalkyl is a cyclic hydrocarbon having from 3 to 13 annular carbon atoms.
- a more preferred cycloalkyl is a cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a "C 3 -C 8 cycloalkyl").
- Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, norbornyl, and the like.
- Halo or “halogen” refers to elements of the Group 17 series having atomic number 9 to 85. Preferred halo groups include fluoro, chloro, bromo and iodo. Where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached, e.g., dihaloaryl, dihaloalkyl, trihaloaryl etc. refer to aryl and alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be but are not necessarily the same halo; thus 4-chloro-3-fluorophenyl is within the scope of dihaloaryl.
- perhaloalkyl An alkyl group in which each hydrogen is replaced with a halo group is referred to as a “perhaloalkyl.”
- a preferred perhaloalkyl group is trifluoroalkyl (-CF 3 ).
- perhaloalkoxy refers to an alkoxy group in which a halogen takes the place of each H in the hydrocarbon making up the alkyl moiety of the alkoxy group.
- An example of a perhaloalkoxy group is trifluoromethoxy (-OCF 3 ).
- Heteroaryl refers to and includes unsaturated aromatic cyclic groups having from 1 to 10 annular carbon atoms and at least one annular heteroatom, including but not limited to heteroatoms such as nitrogen, oxygen and sulfur, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized.
- a heteroaryl group can be attached to the remainder of the molecule at an annular carbon or at an annular heteroatom.
- Heteroaryl may contain additional fused rings (e.g., from 1 to 3 rings), including additionally fused aryl, heteroaryl, cycloalkyl, and/or heterocyclyl rings.
- heteroaryl groups include, but are not limited to imidazolyl, pyrrolyl, pyrazolyl, 1,2,4- triazolyl, thiophenyl, furanyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridyl, pyrimidyl, pyridazinyl or pyrazinyl, and the like.
- Heterocycle or “heterocyclyl” refers to a saturated or an unsaturated non-aromatic group having from 1 to 10 annular carbon atoms and from 1 to 4 annular heteroatoms, such as nitrogen, sulfur or oxygen, and the like, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized.
- a heterocyclyl group may have a single ring or multiple condensed rings, but excludes heteroaryl groups.
- a heterocycle comprising more than one ring may be fused, spiro or bridged, or any combination thereof. In fused ring systems, one or more of the fused rings can be aryl or heteroaryl.
- heterocyclyl groups include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, morpholinyl, thiomorpholinyl, azepanyl tetrahydropyranyl, dihydropyranyl, piperidinyl, piperazinyl, pyrrolidinyl, thiazolinyl, thiazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, and the like.
- CHK refers to Checkpoint kinase, which includes CHK-1 and CHK-2.
- CHK refers herein specifically to CHK-1.
- “Optionally substituted” unless otherwise specified means that a group may be unsubstituted or substituted by one or more (e.g., 1, 2, 3, 4 or 5) of the substituents listed for that group in which the substituents may be the same of different.
- an optionally substituted group has one substituent.
- an optionally substituted group has two substituents.
- an optionally substituted group has three substituents.
- an optionally substituted group has four substituents.
- an optionally substituted group has 1 to 2, 2 to 5, 3 to 5, 2 to 3, 2 to 4, 3 to 4, 1 to 3, 1 to 4 or 1 to 5 substituents.
- a “pharmaceutically acceptable carrier” refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, which is nontoxic to a subject.
- a pharmaceutically acceptable carrier includes, but is not limited to, a buffer, excipient, stabilizer, or preservative.
- treatment or “treating” is an approach for obtaining beneficial or desired results including clinical results.
- beneficial or desired results include, but are not limited to, one or more of the following: decreasing symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, delaying the progression of the disease, and/or prolonging survival of individuals.
- beneficial or desired results include shrinking a tumor (reducing tumor size); decreasing the growth rate of the tumor (such as to suppress tumor growth); reducing the number of cancer cells; inhibiting, retarding or slowing to some extent and preferably stopping cancer cell infiltration into peripheral organs; inhibiting (slowing to some extent and preferably stopping) tumor metastasis; inhibiting tumor growth; preventing or delaying occurrence and/or recurrence of tumor; and/or relieving to some extent one or more of the symptoms associated with the cancer.
- shrinking a tumor reducing tumor size
- decreasing the growth rate of the tumor such as to suppress tumor growth
- reducing the number of cancer cells inhibiting, retarding or slowing to some extent and preferably stopping cancer cell infiltration into peripheral organs; inhibiting (slowing to some extent and preferably stopping) tumor metastasis; inhibiting tumor growth; preventing or delaying occurrence and/or recurrence of tumor; and/or relieving to some extent one or more of the symptoms associated with the cancer.
- beneficial or desired results include preventing or delaying occurrence and/or recurrence, such as of unwanted cell proliferation (idiopathic pulmonary fibrosis (IPF)).
- delaying development of a disease means to defer, hinder, slow, retard, stabilize, and/or postpone development of the disease (such as cancer, pulmonary arterial hypertension (PAH) and idiopathic pulmonary fibrosis (IPF)).
- PAH pulmonary arterial hypertension
- IPF idiopathic pulmonary fibrosis
- an “effective dosage” or “effective amount” of compound or salt thereof or pharmaceutical composition is an amount sufficient to effect beneficial or desired results.
- beneficial or desired results include results such as eliminating or reducing the risk, lessening the severity of, or delaying the onset of the disease, including biochemical, histological and/or behavioral symptoms of the disease, its complications and intermediate pathological phenotypes presenting during development of the disease.
- beneficial or desired results include ameliorating, palliating, lessening, delaying or decreasing one or more symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, enhancing effect of another medication such as via targeting, delaying the progression of the disease, and/or prolonging survival.
- an effective amount comprises an amount sufficient to cause a tumor to shrink and/or to decrease the growth rate of the tumor (such as to suppress tumor growth) or to prevent or delay other unwanted cell proliferation (idiopathic pulmonary fibrosis (IPF)).
- PAF pulmonary arterial hypertension
- an effective amount comprises an amount sufficient to prevent or delay the development of pulmonary arterial hypertension (PAH)).
- an effective amount is an amount sufficient to delay development. In some embodiments, an effective amount is an amount sufficient to prevent or delay occurrence and/or recurrence.
- An effective amount can be administered in one or more administrations, in the case of cancer, the effective amount of the drug or composition may: (i) reduce the number of cancer cells; (ii) reduce tumor size; (iii) inhibit, retard, slow to some extent and preferably stop cancer cell infiltration into peripheral organs; (iv) inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; (v) inhibit tumor growth; (vi) prevent or delay occurrence and/or recurrence of tumor; and/or (vii) relieve to some extent one or more of the symptoms associated with the cancer.
- an effective dosage can be administered in one or more administrations.
- an effective dosage of compound or a salt thereof, or pharmaceutical composition is an amount sufficient to accomplish prophylactic or therapeutic treatment either directly or indirectly. It is intended and understood that an effective dosage of a compound or salt thereof, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition. Thus, an “effective dosage” may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable result may be or is achieved. [55] As used herein, the term “individual” is a mammal, including humans.
- An individual includes, but is not limited to, human, bovine, horse, feline, canine, rodent, or primate.
- the individual is human.
- the individual (such as a human) may have advanced disease or lesser extent of disease, such as low tumor burden.
- the individual is at an early stage of a proliferative disease (such as cancer or idiopathic pulmonary fibrosis (IPF)).
- the individual is at an advanced stage of a proliferative disease (such as an advanced cancer).
- Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X”.
- the present invention provides a compound of Formula (J): wherein, X and X are independently N or C x 1 2 R ; provided that at least one of X 1 and X 2 is N; each Rx is independently hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 3- to 6- membered heterocyclyl, -CN, halogen, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 - C 6 haloalkyl, -OR7, -NR8R9, -C(O)R7, -NR7C(O)R8, -C(O)OR7 or -C(O)NR8R9, each of which is optionally substituted by oxo, halogen, CN, -OR10 or -NR
- C is 7- to 12-membered monocyclic or bicyclic heterocyclyl, C 3 -C 10 monocyclic or bicyclic cycloalkyl or -(C 1 -C 3 alkylene)C 7 -C 10 cycloalkyl, wherein each of C is optionally substituted by one or more R 4 ;
- D is -(C 1 -C 3 alkylene)3- to 6-membered heterocyclyl optionally substituted by one or more R 4 ;
- A is R 1 or R 1a ;
- R 1 is independently 5 -membered heteroaryl, 3- to 6-membered heterocyclyl or - 2 3
- R 1a is independently -C(O)NR 2 R 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, C 6 , aryl, 5- to 10-membered heteroaryl, -CN, halogen, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkyl, -OR 13 , -SR 13 , -S(O) 2 R 13 , -S(O) 2 NR 14 R 15 , -NR 13 S(O) 2 R 14 , -NR 14 R 15 ,
- R and R are independently hydrogen, -CD 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, C 6 , aryl, 5- to 6-membered heteroaryl, , C 1 -C 6 haloalkyl, -C(O)R 13 , -(C 1 -C 3 alkylene)OR 13 , -(C 1 -C 3 alkylene)SR 13 , -(C 1 - C 3 alkylene)S(O) 2 R 13 , -(C 1 -C 3 alkylene)S(O) 2 NR 14 R 15 , -(C 1 -C 3 alkylene)NR 13 S(O) 2 R 14 , -(C 1 -C 3 alkylene)NR 14 R 15 , -(C 1 -C 3 alkylene)NR 13 S(
- R 4 is oxo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -CN, halogen, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -OR 16 , -SR 16 , -S(O) 2 R 16 , -S(O) 2 NR 17 R 18 , -NR 16 S(O) 2 R 17 , -NR 17 R 18 , -C(O)R 16 , -NR 16 C(O)R 17 , -C(O)OR 16 , wherein each of R 4 is optionally substituted by oxo, - OH, halogen or -NH 2 ;
- R 5 is oxo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -CN, halogen, C 1 - C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -OR 16 , -SR 16 , -S(O) 2 R 16
- each R 13 , R 14 andR 15 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, C 6 , aryl, 5- to 6- membered heteroaryl, -(C 1 -C 3 alkylene) C 3 -C 6 cycloalkyl, -(C 1 -C 3 alkylene)3- to 6-membered heterocyclyl, or -(C 1 -C 3 alkylene)5- to 6-membered heteroaryl, wherein each of R 13 , R 14 and R 15 is independently optionally substituted by oxo, C 2 -C 6 alkenyl, C 2 -
- R 16 , R 17 and R 18 is independently hydrogen, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 aryl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocyclyl, C 3 -C 6 cyclo
- each R x is independently hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 3- to 6- membered heterocyclyl, -CN, halogen, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 - C 6 haloalkyl, -OR 7 , -NR 8 R 9 , -C(O)R 7 , -NR 7 C(O)R 8 , -C(O)OR 7 or -C(O)NR 8 R 9 , each of which is optionally substituted by oxo, halogen, CN, -OR 10 or -NR 11 R 12 ;
- D is -(C 1 -C 3 alkylene)3- to 6-membered heterocyclyl, optionally substituted by
- R 1 is independently 5 -membered heteroaryl, 3- to 6-membered heterocyclyl or -
- R 2 and R 3 are independently hydrogen, -CD 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, C 6 aryl, 5- to 6-membered heteroaryl, , C 1 -C 6 haloalkyl, -C(O)R 13 , -(C 1 -C 3 alkylene)OR 13 , -(C 1 -C 3 alkylene)SR 13 , -(C 1 - C 3 alkylene)S(O) 2 R 13 , -(C 1 -C 3 alkylene)S(O) 2 NR 14 R 15 , -(C 1 -C 3 alkylene)NR 13 S(O) 2 R 14 , -(C 1 -C 3 alkylene)NR 14 R 15 , -(C 1 -C 3 alkylene)NR 13 S(
- C 3 alkylene)C(O)ONR 14 R 15 , -(C 1 -C 3 alkylene)( C 3 -C 8 cycloalkyl) or -(C 1 -C 3 alkylene) (3 -10- membered heterocyclyl), -(C 1 -C 3 alkylene)C 6 aryl or -(C 1 -C 3 alkylene) 5- to 6-membered heteroaryl, wherein each of R and R are independently optionally substituted by R ;
- R and R are taken together with the atom to which they attached to form a 3- to 6- membered heterocyclyl optionally substituted by R 5 ;
- R 4 is oxo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -CN, halogen, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -OR 16 , -SR 16 , -S(O) 2 R 16 , -S(O) 2 NR 17 R 18 , -NR 16 S(O) 2 R 17 , -NR 17 R 18 , -C(O)R 16 , -NR 16 C(O)R 17 , -C(O)OR 16 , wherein each of R 4 is optionally substituted by oxo, - OH, halogen or -NH 2 ;
- R 5 is oxo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -CN, halogen, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -OR 16 , -SR 16 , -S(O) 2 R 16 , -S(O) 2 NR 17 R 18 , -NR 16 S(O) 2 R 17 , -NR 17 R 18 , -C(O)R 16 , -NR 16 C(O)R 17 , -C(O)OR 16 , C 3 -C 6 cycloalkyl, C 6 aryl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocyclyl, wherein each of R 5 is optionally substituted by oxo, -OH, halogen or -NH 2 ;
- each R , R andR is independently hydrogen or C 1 -C 6 alkyl optionally substituted by oxo, -OH, halogen or -NH 2 ; each R 10 , R 11 and R 12 is independently hydrogen, C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl;
- each R 13 , R 14 andR 15 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 , alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, C 6 , aryl, 5- to 6- membered heteroaryl, -(C 1 -C 3 alkylene) C 3 -C 6 cycloalkyl, -(C 1 -C 3 alkylene)3- to 6-membered heterocyclyl, or -(C 1 -C 3 alkylene)5- to 6-membered heteroaryl, wherein each of R 13 , R 14 and R 15 is independently optionally substituted by oxo, C 2 -C 6 alkenyl, C 2
- R 16 , R 17 and R 18 is independently hydrogen, C 2 -C 6 , alkenyl, C 2 -C 6 , alkynyl, Cr, aryl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocyclyl, C 3
- X 1 and X 2 are independently N or CR X ; provided that at least one of X 1 and X 2 is N. In some embodiments of a compound of formula (J), X 1 is N and X 2 is CR X . In some embodiments of a compound of formula (J), Xi is CR X and X 2 is N. In some embodiments X 1 and X 2 both are N.
- R x is independently selected from hydrogen, C 1 -C 6 alkyl, C 3 - Ce cycloalkyl, 3- to 6-membered heterocyclyl, -CN, halogen, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkyl, -OR 7 , -NR 8 R 9 , -C(O)R 7 , -NR 7 C(O)R 8 , -C(O)OR 7 or -C(O)NR 8 R 9 , each of which is optionally substituted by oxo, halogen, CN, -OR 10 or -NR n R 12 .
- R x is hydrogen.
- L is NH. In some embodiments of a compound of formula (J), L is O.
- C is 7- to 12-membered monocyclic or bicyclic heterocyclyl optionally substituted by one or more R 4 .
- 7- to 12-membered heterocyclyl is monocyclic heterocyclyl optionally substituted by one or more R 4 .
- 7- to 12-membered heterocyclyl is bicyclic heterocyclyl optionally substituted by one or more R 4 , which is fused, spiro or bridge bicyclic heterocyclyl.
- C is C 3 -C 10 monocyclic or bicyclic cycloalkyl, which is optionally substituted by one or more R 4 .
- C 3 -C 10 cycloalkyl ring is monocyclic cycloalkyl optionally substituted by one or more R4.
- C 3 -C 10 cycloalkyl ring is bicyclic cycloalkyl optionally substituted by one or more R4.
- C is azepanyl, decahydroquinoline, decahydroisoquinoline, octahydro-1H-indole, octahydrocyclopenta[b]pyrrole, octahydro-1H-cyclopenta[b]pyridine, octahydro-1H-cyclopenta[b]pyridine, octahydro-1H-cyclopenta[b]pyridine, octahydro-1H-cyclopenta[b]pyridine, octahydro-1H- cyclopenta[c]pyridine, octahydro-1H-cyclopenta[c]pyridine, octahydrocyclopenta[b]pyrrole, octahydrocyclopenta[c]pyrrole, 2-azabicyclo[3.2.0]heptane, 2-azabicyclo[4.2.0]octane, 3- azabicyclo[4.2.0]
- C is -(C 1 -C 3 alkylene)C 7 -C 10 cycloalkyl optionally substituted by one or more R4 , wherein cycloalkyl ring is monocylic or bicyclic.
- C 1 -C 3 alkylene as disclosed herein (in formula (J)) is substituted by one or more R4 or unsubstituted.
- C 1 -C 3 alkylene is a linear alkylene such as –CH 2 -.
- C 1 -C 3 alkylene is a branched alkylene, such as –CH(CH 3 )- and – C(CH 3 ) 2 -.
- C is –CH 2 - (bicyclo[3.1.1]heptane) and –CH 2 -((1R,5S)-bicyclo[3.2.1]octane).
- D is -(C 1 -C 3 alkylene)3- to 6- membered heterocyclyl optionally substituted by one or more R4.
- C 1 -C 3 alkylene as disclosed herein (in formula (J)) is substituted by one or more R4 or unsubstituted.
- C 1 -C 3 alkylene is a linear alkylene such as –CH 2 -, –CH 2 -–CH 2 -.
- C 1 -C 3 alkylene is a branched alkylene, such as –CH(CH 3 )- and –C(CH 3 ) 2 -.
- D is –CH 2 -(3- to 6-membered heterocyclyl) optionally substituted by one or more R4.
- D is –CH 2 -CH 2 -(3- to 6-membered heterocyclyl) optionally substituted by one or more R4.
- D is selected from – CH(CH 3 )-(3- to 6-membered heterocyclyl) or –C(CH 3 ) 2 -(3- to 6-membered heterocyclyl), each of which is optionally substituted by one or more R4.
- D is –CH 2 -(4-membered heterocyclyl) optionally substituted by one or more R4.
- D is –CH 2 -(5- membered heterocyclyl) optionally substituted by one or more R4.
- D is –CH 2 -(6-membered heterocyclyl) optionally substituted by one or more R4.
- R 4 is oxo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -CN, halogen, C 1 -C 6 alkoxy, C 1 - C 16 16 16 6 haloalkoxy, -OR , -SR , -S(O) 2 R , -S(O) 2 NR 17 R 18 , -NR16S(O) 2 R 17 , -NR 17 R 18 , -C(O)R16, -NR16C(O)R 17 , -C(O)OR16, wherein each of R4 is optionally substituted by oxo, - OH, halogen or -NH .
- R is C 1 -C 6 alkyl. In some embodiments of a compound of formula (J), R4 is methyl. In some embodiments of a compound of formula (J), R4 is -NH 2 , -F, -OH, -NH-CH 3 , and -N-(CH 3 ) 2 . In some embodiments of a compound of formula (J), R4 is -NH 2 . In some embodiments of a compound of formula (J), R4 is -F. In some embodiments of a compound of formula (J), R4 is -OH. In some embodiments of a compound of formula (J), R4 is -NHCH 3 .
- R4 is -N(CH 3 ) 2 .
- D is selected from the group of but not limited to , , , , , , , , , , , or wherein the wavy lines denote attachment points to rest of the molecule.
- D is .
- D is .
- D is .
- D is .
- D is .
- D is .
- D is .
- D is .
- D is . In some embodiments of a compound of formula (J), D is . In some embodiments of a compound of formula (J), D is . In some embodiments of a compound of formula (J), D is . In some embodiments of a compound of formula (J), D is . In some embodiments of a compound of formula (J), D is . In some embodiments of a compound of formula (J), D is . In some embodiments of a compound of formula (J), D is . In some embodiments of a compound of formula (J), D is . In some embodiments of a compound of formula (J), D is . In some embodiments of a compound of formula (J), D is . In some embodiments of a compound of formula (J), D is . In some embodiments of a compound of formula (J), D is . In some embodiments of a compound of formula (J), D is . In some embodiments of a compound of formula (J), D is . In some embodiments of a compound of formula (J
- C is selected from the group of but not limited to , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,
- C is .In some embodiments of a compound of formula (J), C is . In some embodiments of a compound of formula (J), C is . In some embodiments of a compound of formula (J), C is . In some embodiments of a compound of formula (J), C is In some embodiments of a compound of formula (J), C is . In some embodiments of a compound of formula (J), C is . In some embodiments of a compound of formula (J), C is . In some embodiments of a compound of formula (J), C is . In some embodiments of a compound of formula (J), C is . In some embodiments of a compound of formula (J), C is . In some embodiments of a compound of formula (J), C is . In some embodiments of a compound of formula (J), C is . In some embodiments of a compound of formula (J), C is . In some embodiments of a compound of formula (J), C is . In some embodiments of a compound of formula (J), C
- C is In some embodiments of a compound of formula (J), C is In some embodiments of a compound of formula (J), C is . In some embodiments of a compound of formula (J), C is . In some embodiments of a compound of formula (J), C is In some embodiments of a compound of formula (J), C is . In some embodiments of a compound of formula (J), C is In some embodiments of a compound of formula (J), C is . In some embodiments of a compound of formula (J), C is . In some embodiments of a compound of formula (J), C is . In some embodiments of a compound of formula (J), C is . In some embodiments of a compound of formula (J), C is . In some embodiments of a compound of formula (J), C is . In some embodiments of a compound of formula (J), C is . In some embodiments of a compound of formula (J), C is . In some embodiments of a compound of formula (J), C is . In some embodiment
- C is . In some embodiments of a compound of formula (J), C is . In some embodiments of a compound of formula (J), C is . In some embodiments of a compound of formula (J), C is . In some embodiments of a compound of formula (J), C is . In some embodiments of a compound of formula (J), C is . In some embodiments of a compound of formula (J), C is . In some embodiments of a compound of formula (J), C is .
- R 1 is selected from 5-membered 2 3 heteroaryl, 3- to 6-membered heterocyclyl or -C(O)NR R , wherein 5-membered heteroaryl and 3- to 6-membered heterocyclyl optionally substituted by R 5 .
- R 1a is -C(O)NR 2 R 3 .
- R 1a is C 1 -C 6 alkyl optionally substituted by R 5 .
- R 1a is C 2 -C 6 alkenyl optionally substituted by R 5 .
- R 1a is C 2 -C 6 alkynyl optionally substituted by R 5 .
- R 1a is C 3 - C 6 cycloalkyl optionally substituted by R 5 .
- R 1a is 3- to 6-membered heterocyclyl optionally substituted by R 5 . In some embodiments of a compound of formula (J), R 1a is C 6 aryl optionally substituted by R 5 . In some embodiments of a compound of formula (J), R 1a is 5- to 10-membered heteroaryl optionally substituted by R 5 . In some embodiments of a compound of formula (J), R 1a is -CN. In some embodiments of a compound of formula (J), R 1a is halogen. In some embodiments of a compound of formula (J), R 1a is C 1 -C 6 alkoxy.
- R 1a is C 1 -C 6 haloalkoxy. In some embodiments of a compound of formula (J), R 1a is C 1 -C 6 haloalkyl. In some embodiments of a compound of formula (J), R 1a is -OR 13 . In some embodiments of a compound of formula (J), R 1a is -SR 13 . In some embodiments of a compound of formula (J), R 1a is -S(O) 2 R 13 . In some embodiments of a compound of formula (J), R 1a is -S(O) 2 NR 14 R 15 .
- R 1a is -NR 13 S(O) 2 R 14 . In some embodiments of a compound of formula (J), R 1a is -NR 14 R 15 . In some embodiments of a compound of formula (J), R 1a is -C(O)R 13 . In some embodiments of a compound of formula (J), R 1a is -NR 13 C(O)R 14 . In some embodiments of a compound of formula (J), R 1a is -NR 13 C(O)NR 14 R 15 . In some embodiments of a compound of formula (J), R 1a is -C(O)OR 13 .
- R 1a is -C(O)ONR 14 R 15 .
- R 1a is -( C 1 - C 3 alkylene)OR 13
- R 1a is -(C 1 - C 3 alkylene)SR 13 .
- R 1a is -(C 1 - C 3 alkylene)S(O) 2 R 13 , -(C 1 -C 3 alkylene)S(O) 2 NR 14 R 15 .
- R 1a is -(C 1 -C 3 alkylene)NR 13 S(O) 2 R 14 . In some embodiments of a compound of formula (J), R 1a is -(C 1 -C 3 alkylene)NR 14 R 15 . In some embodiments of a compound of formula (J), R 1a is -(C 1 -C 3 alkylene)C(O)R 13 . In some embodiments of a compound of formula (J), R 1a is -(C 1 -C 3 alkylene)NR 13 C(O)R 14 .
- R 1a is -(C 1 -C 3 alkylene)NR 13 C(O)NR 14 R 15 . In some embodiments of a compound of formula (J), R 1a is -(C 1 -C 3 alkylene)C(O)OR 13 . In some embodiments of a compound of formula (J), R 1a is -(C 1 -C 3 alkylene)C(O)ONR 14 R 15 . In some embodiments of a compound of formula (J), R 1a is -(C 1 -C 3 alkylene) ( C 3 -C 8 cycloalkyl). In some embodiments of a compound of formula (J), R 1a is -(C 1 -C 3 alkylene)(3- 10-membered heterocyclyl).
- C 1 -C 3 alkylene of R 1a is substituted by R 5 or unsubstituted.
- C 1 - C3 alkylene of R 1a is linear or branched.
- R 5 is oxo, C 1 -C 6 alkyl, halogen, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -OR 16 , -SR 16 , -S(O) 2 R 16 , -S(O) 2 NR 17 R 18 , -NR 16 S(O) 2 R 17 , - NR 17 R 18 , -C(O)R 16 , -NR 16 C(O)R 17 , -C(O)OR 16 , C 3 -C 6 cycloalkyl, C 6 aryl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocyclyl, wherein each of R 5 is optionally substituted by oxo, -OH, halogen or -NH 2 .
- R 5 is oxo, C 1 -C 6 alkyl or halogen, wherein each of R 5 is optionally substituted by oxo, -OH, halogen or -NH 2 .
- R 5 is oxo, methyl, ethyl, cyclopentyl, cyclopentyl substituted by -OH, di-floro substituted phenyl, -NH 2 , -OH, Cl or F.
- R 1 is 5-membered heteroaryl , wherein the wavy lines denote attachment points to rest of the molecule.
- R 1 is 3- to 6-membered heterocyclyl optionally substituted by R 5 .
- R 1 is selected from , wherein the wavy lines denote attachment points to rest of the molecule.
- R 1 and R la are independently - C(O)NR 2 R 3 , wherein R 2 and R 3 are independently hydrogen, -CD 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, C 6 , aryl, 5- to 6- membered heteroaryl, , C 1 -C 6 haloalkyl, -C(O)R 13 , -(C 1 -C 3 alkylene)OR 13 , -(C 1 - C 3 alkylene)SR 13 , -(C 1 -C 3 alkylene)S(O) 2 R 13 , -(C 1 -C 3 alkylene)S(O) 2 NR 14 R 15 , -(C 1 - C 3 alkylene)NR 13 S(O) 2 R 14
- R 1 and R la are independently -
- R 1 is selected from , wherein the wavy lines denote attachment points to rest of the molecule.
- R 1a is selected from , wherein the wavy lines denote attachment points to rest of the molecule.
- X 1 1 and X 2 both are N and R is 5-membered heteroaryl, 3- to 6-membered heterocyclyl or –C(O)NR 2 R 3 , wherein 5- membered heteroaryl and 3- to 6-membered heterocyclyl optionally substituted by R5.
- X 1 1 and X 2 both are N and R is– C(O)NR2R3.
- X 1 and X 2 both are N and R1 is –C(O)NHCH 3 .
- X and 1 1 X 2 both are N and R is – C(O)NHCH 3 and D is -(C 1 -C 3 alkylene)3- to 6-membered heterocyclyl optionally substituted by R4.
- X 1 1 and X 2 both are N and R is – C(O)NHCH 3 and D is or [87]
- X x 1 1 is N and X 2 is CR ; and R is 5-membered heteroaryl, 3- to 6-membered heterocyclyl or –C(O)NR 2 R 3 , wherein 5- membered heteroaryl and 3- to 6-membered heterocyclyl optionally substituted by R5.
- X is N and X is CRx; an 1 1 2 d R is – C(O)NR 2 R 3 .
- X is N and x 1 X is CR ; and R1 is –C(O)NHCH 3 .
- X x 1 1 is N and X 2 is CR ; and R is –C(O)NHCH 3 and D is -(C 1 -C 3 alkylene)3- to 6-membered heterocyclyl optionally substituted by R4.
- X 1 is N and X 2 is CRx; and R1 is –C(O)NHCH 3 and D is , , o .
- X 1 is CRx and X 2 is N; and R1 is 5-membered heteroaryl, 3- to 6-membered heterocyclyl or –C(O)NR 2 R 3 , wherein 5- membered heteroaryl and 3- to 6-membered heterocyclyl optionally substituted by R5.
- X is CRx and X i 1 1 2 s N; and R is– C(O)NR2R3.
- X i x 1 s CR and X 2 is N; and R1 is –C(O)NHCH 3 .
- X 1 is CR x and X is N; and R 1 is –C(O)NHCH 3 and D is -(C 1 -C 3 alkylene)3- to 6-membered heterocyclyl optionally substituted by R4.
- X x 1 is CR and X 2 is N; and R1 is –C(O)NHCH 3 and D is [91]
- X 1 and X 2 both are N, L is NH and R 1a is -C(O)NR 2 R 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 6- membered heterocyclyl, C 6 aryl, 5- to 10-membered heteroaryl, -CN, halogen, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkyl, -OR 13 , -SR 13 , -S(O) 2 R 13 , -S(O) 2 NR 14 R 15 , -NR 13 S(O) 2
- X 1 and X 2 both are N; L is NH and R 1a is -C(O)NHCH 3 and C is azepanyl, C 3 -C 10 monocyclic or bicyclic cycloalkyl or -(C 1 - C 3 alkylene) C 7 -C 10 cycloalkyl, wherein each of C is optionally substituted by R 4 ;
- X 1 and X 2 both are N; L is NH and R 1a is -
- X 1 is N and X 2 is CR X ; L is NH and R 1a is -C(O)NR 2 R 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 6- membered heterocyclyl, C 6 , aryl, 5- to 10-membered heteroaryl, -CN, halogen, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkyl, -OR 13 , -SR 13 , -S(O) 2 R 13 , -S(O) 2 NR 14 R 15 , -NR 13 S(O) 2 R 14 , -NR 14 R 15 , -C(O)R 13 , -NR 13 C(O)R 14 , -NR
- X 1 is N and X 2 is CR X ; L is NH and R 1a is - C(O)NR 2 R 3 .
- X 1 is N and X 2 is CR X ; L is NH and R 1a is -C(O)NHCH 3 .
- X 1 is N and X 2 is CR X ;
- L is NH and R 1a is -C(O)NHCH 3 and C is azepanyl, C 3 -C 10 monocyclic or bicyclic cycloalkyl or -(C 1 - C 3 alkylene) C 7 -C 10 cycloalkyl, wherein each of C is optionally substituted by R 4 ;
- X 1 is N and X 2 is CR X ;
- L is NH and R 1a is -
- X 1 is CR X and X 2 is N; L is NH and R 1a is -C(O)NR 2 R 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 6- membered heterocyclyl, C 6 aryl, 5- to 10-membered heteroaryl, -CN, halogen, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkyl, -OR 13 , -SR 13 , -S(O) 2 R 13 , -S(O) 2 NR 14 R 15 , -NR 13 S(O) 2 R 14 , -NR 14 R 15 , -C(O)R 13 , -NR 13 C(O)R 14 , -NR 13 C(O)R 14 , -NR 13 C(O)R
- X 1 is CR X and X 2 is N; L is NH and R 1a is - C(O)NR 2 R 3 . In some embodiments of a compound of formula (J), X 1 is CR X and X 2 is N; L is
- R 1a is -C(O)NHCH 3 .
- X 1 is CR X and X2is N; L is NH and R 1a is -C(O)NHCH 3 and C is azepanyl, C 3 -C 10 monocyclic or bicyclic cycloalkyl or -(C 1 - C 3 alkylene)C 7 -C 10 cycloalkyl, wherein each of C is optionally substituted by R 4 ;
- X 1 is CR X and X 2 is N; L is NH and R 1a is -
- X 1 and X 2 both are N; L is O and R 1a is -C(O)NR 2 R 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 6- membered heterocyclyl, C 6 aryl, 5- to 10-membered heteroaryl, -CN, halogen, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkyl, -OR 13 , -SR 13 , -S(O) 2 R 13 , -S(O) 2 NR 14 R 15 , -NR 13 S(O) 2 R 14 , -NR 14 R 15 , -C(O)R 13 , -NR 13 C(O)R 14 , -NR 13 C(O)NR 14 R R
- Xi and X 2 both are N, L is O and R 1a is -C(O)NHCH 3 and C is azepanyl, C 3 -C 10 monocyclic or bicyclic cycloalkyl or -(C 1 - C 3 alkylene)C 7 -C 10 cycloalkyl, wherein each of C is optionally substituted by R 4 ;
- X 1 and X 2 both are N, L is O and R 1a is -
- X 1 is N and X 2 is CR X ; L is O and R 1a is -C(O)NR 2 R 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 6- membered heterocyclyl, C 6 aryl, 5- to 10-membered heteroaryl, -CN, halogen, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkyl, -OR 13 , -SR 13 , -S(O) 2 R 13 , -S(O) 2 NR 14 R 15 , -NR 13 S(O) 2 R 14 , -NR 14 R 15 , -C(O)R 13 , -NR 13 C(O)R 14 , -NR 13 C(O)R 14 , -NR 13 C(O)R
- X 1 is N and X 2 is CR X ; L is O and R 1a is -C(O)NHCH 3 .
- X 1 is N and X 2 is CR X ; L is O and R 1a is -C(O)NHCH 3 and C is azepanyl, C 3 -C 10 monocyclic or bicyclic cycloalkyl or -(C 1 - C 3 alkylene)C 7 -C 10 cycloalkyl, wherein each of C is optionally substituted by R 4 ;
- X 1 is N and X 2 is CR X ; L is O and R 1a is -
- X 1 is CR X and X 2 is N; L is O and R 1a is -C(O)NR 2 R 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 6- membered heterocyclyl, C 6 , aryl, 5- to 10-membered heteroaryl, -CN, halogen, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkyl, -OR 13 , -SR 13 , -S(O) 2 R 13 , -S(O) 2 NR 14 R 15 , -NR 13 S(O) 2 R 14 , -NR 14 R 15 , -C(O)R 13 , -NR 13 C(O)R 14 , -NR 13 C(O)R 14 , -NR 13 C
- X 1 is CR X and X 2 is N; L is O and R 1a is -C(O)NHCH 3 and C is azepanyl, C 3 -C 10 monocyclic or bicyclic cycloalkyl or -(C 1 - C 3 alkylene)C 7 -C 10 cycloalkyl, wherein each of C is optionally substituted by R 4 ;
- X 1 is CR X and X 2 is N; L is O and R 1a is -
- a compound of formula (J) is a compound of formula (IA): formula (IA), wherein X b X 2 , C, R 1a , L and R x as detailed herein.
- a compound of formula (J) is any of the compound of formula (IA-1 to IA-10): wherein C, R 1a , R 4 and R x as detailed herein.
- a compound of formula (J) is a compound of formula (IB): wherein X X 2 , C, L, R 2 , R 3 and R x as detailed herein.
- a compound of formula (J) is any of the compound of formula
- a compound of formula (J) is a compound of formula (II): wherein Xi, X2, R 1 , R 4 and R x as detailed herein.
- a compound of formula (J) is any of the compound of formula
- a compound of formula (J) is a compound of formula (III): wherein X b X 2 , R 1 , R 4 and R x as detailed herein.
- a compound of formula (J) is a compound of formula (Ill-a) to (III-c):
- a compound of formula (J) is a compound of formula (IV): wherein Xi, X2, D, R 2 , R 3 and R x as detailed herein.
- a compound of formula (J) is a compound of formula (IV-a) to (IV-c): wherein D, R 2 , R 3 and R x as detailed herein.
- a compound of formula (J) is a compound of formula (V): wherein X X 2 , R 2 , R 3 , R 4 and R x as detailed herein.
- a compound of formula (J) is a compound of formula (V-a) to
- a compound of formula (J) is a compound of formula (VI): wherein X X 2 , R 2 , R 3 , R 4 and R x as detailed herein.
- a compound of formula (J) is a compound of formula (Vl-a) to
- a compound of formula (J) is a compound of formula (VII):
- a compound of formula (J) is a compound of formula (Vll-a) to (Vll-f): wherein R 2 , R 3 , R 4 and R x are as detailed herein.
- a compound of formula (J) is a compound of formula (VIII): wherein X b X 2 , R 2 , R 3 , R 4 and R x as detailed herein.
- a compound of formula (J) is a compound of formula (Vlll-a) to (VUI-f):
- R 2 , R 3 , R 4 and R x are as detailed herein.
- salts of compounds referred to herein such as pharmaceutically acceptable salts.
- the invention also includes any or all of the stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomers or other forms of the compounds described.
- a compound as detailed herein may in one aspect be in a purified form and compositions comprising a compound in purified forms are detailed herein.
- Compositions comprising a compound as detailed herein or a salt thereof are provided, such as compositions of substantially pure compounds.
- a composition containing a compound as detailed herein or a salt thereof is in substantially pure form.
- substantially pure intends a composition that contains no more than 35 % impurity, wherein the impurity denotes a compound other than the compound comprising the majority of the composition or a salt thereof.
- a composition of substantially pure compound or a salt thereof is provided wherein the composition contains no more than 25 %, 20%, 15%, 10%, or 5% impurity.
- a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 3 %, 2%, 1% or 0.5% impurity.
- the compounds depicted herein may be present as salts even if salts are not depicted and it is understood that the present disclosure embraces all salts and solvates of the compounds depicted here, as well as the non-salt and non-solvate form of the compound, as is well understood by the skilled artisan.
- the salts of the compounds provided herein are pharmaceutically acceptable salts. Where one or more tertiary amine moiety is present in the compound, the N-oxides are also provided and described.
- tautomeric forms may be present for any of the compounds described herein, each and every tautomeric form is intended even though only one or some of the tautomeric forms may be explicitly depicted.
- the tautomeric forms specifically depicted may or may not be the predominant forms in solution or when used according to the methods described herein.
- the present disclosure also includes any or all of the stereochemical forms, including any enantiomeric or diastereomeric forms of the compounds described.
- the structure or name is intended to embrace all possible stereoisomers of a compound depicted, and each unique stereoisomer has a compound number bearing a suffix “a”, “b”, etc. All forms of the compounds are also embraced by the invention, such as crystalline or non-crystalline forms of the compounds.
- compositions comprising a compound of the invention are also intended, such as a composition of substantially pure compound, including a specific stereochemical form thereof, or a composition comprising mixtures of compounds of the invention in any ratio, including two or more stereochemical forms, such as in a racemic or non-racemic mixture.
- the invention also intends isotopically-labeled and/or isotopically-enriched forms of compounds described herein.
- the compounds herein may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
- the compound is isotopically-labeled, such as an isotopically-labeled compound of the formula (J) or variations thereof described herein, where a fraction of one or more atoms are replaced by an isotope of the same element.
- isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, chlorine, such as 2H, 3H, 11C, 13C, 14C 13N, 15O, 17O, 32P, 35S, 18F, 36Cl.
- Certain isotope labeled compounds are useful in compound or substrate tissue distribution studies.
- Isotopically-labeled compounds of the present invention can generally be prepared by standard methods and techniques known to those skilled in the art or by procedures similar to those described in the accompanying Examples substituting appropriate isotopically-labeled reagents in place of the corresponding non-labeled reagent.
- the invention also includes any or all metabolites of any of the compounds described.
- the metabolites may include any chemical species generated by a biotransformation of any of the compounds described, such as intermediates and products of metabolism of the compound, such as would be generated in vivo following administration to a human.
- Articles of manufacture comprising a compound described herein, or a salt or solvate thereof, in a suitable container are provided.
- the container may be a vial, jar, ampoule, preloaded syringe, i.v. bag, and the like.
- the compounds detailed herein are orally bioavailable.
- the compounds may also be formulated for parenteral (e.g., intravenous) administration.
- One or several compounds described herein can be used in the preparation of a medicament by combining the compound or compounds as an active ingredient with a pharmacologically acceptable carrier, which are known in the art. Depending on the therapeutic form of the medication, the carrier may be in various forms. In one variation, the manufacture of a medicament is for use in any of the methods disclosed herein, e.g., for the treatment of cancer.
- General synthetic schemes [138] The compounds of the invention may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter (such as the schemes provided in the Examples below). In the following process descriptions, the symbols when used in the formulae depicted are to be understood to represent those groups described above in relation to the formulae herein.
- a particular enantiomer of a compound may be accomplished from a corresponding mixture of enantiomers using any suitable conventional procedure for separating or resolving enantiomers.
- diastereomeric derivatives may be produced by reaction of a mixture of enantiomers, e.g., a racemate, and an appropriate chiral compound. The diastereomers may then be separated by any convenient means, for example by crystallization and the desired enantiomer recovered. In another resolution process, a racemate may be separated using chiral High Performance Liquid Chromatography. Alternatively, if desired a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described.
- Solvates and/or polymorphs of a compound provided herein or a pharmaceutically acceptable salt thereof are also contemplated. Solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are often formed during the process of crystallization. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound.
- Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and/or solubility. Various factors such as the recrystallization solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate.
- Scheme-1 wherein, X 1 x 1, X 2 , D, R and R are as defined in formula (J).
- Scheme-2 wherein, X 1 , X 2 , D, R1 and Rxare as defined in formula (J).
- Scheme-3 wherein, X, X, D, R2 , R3 a x 1 2 nd Rare as defined for formula (J).
- Scheme-4 wherein, X 1a x 1, X 2 , C, R and Rare as defined in formula (J).
- Scheme-5 wherein, X 1 , X 2 , C, R1a and Rxare as defined in formula (J).
- Scheme-6 wherein, X, X, C, R1a a x 1 2 nd Rare as defined in formula (J).
- Scheme-7 wherein, X 1a x 1, X 2 , C, R and Rare as defined in formula (J).
- compositions and Formulations [143] Pharmaceutical compositions of any of the compounds detailed herein are embraced by this disclosure.
- the present disclosure includes pharmaceutical compositions comprising a compound as detailed herein or a salt thereof and a pharmaceutically acceptable carrier or excipient.
- the pharmaceutically acceptable salt is an acid addition salt, such as a salt formed with an inorganic or organic acid.
- compositions may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration or a form suitable for administration by inhalation.
- a compound as detailed herein may in one aspect be in a purified form and compositions comprising a compound in purified forms are detailed herein.
- Compositions comprising a compound as detailed herein or a salt thereof are provided, such as compositions of substantially pure compounds.
- a composition containing a compound as detailed herein or a salt thereof is in substantially pure form.
- the compounds herein are synthetic compounds prepared for administration to an individual.
- compositions are provided containing a compound in substantially pure form.
- the present disclosure embraces pharmaceutical compositions comprising a compound detailed herein and a pharmaceutically acceptable carrier.
- methods of administering a compound are provided.
- the purified forms, pharmaceutical compositions and methods of administering the compounds are suitable for any compound or form thereof detailed herein.
- a compound detailed herein or salt thereof may be formulated for any available delivery route, including an oral, mucosal (e.g., nasal, sublingual, vaginal, buccal or rectal), parenteral (e.g., intramuscular, subcutaneous or intravenous), topical or transdermal delivery form.
- a compound or salt thereof may be formulated with suitable carriers to provide delivery forms that include, but are not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultices), pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal spray or inhalers), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water-in-oil liquid emulsions), solutions and elixirs.
- suitable carriers include, but are not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultic
- One or several compounds described herein or a salt thereof can be used in the preparation of a formulation, such as a pharmaceutical formulation, by combining the compound or compounds, or a salt thereof, as an active ingredient with a pharmaceutically acceptable carrier, such as those mentioned above.
- a pharmaceutically acceptable carrier such as those mentioned above.
- the carrier may be in various forms.
- pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re- wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants.
- Formulations comprising the compound may also contain other substances which have valuable therapeutic properties.
- compositions may be prepared by known pharmaceutical methods. Suitable formulations can be found, e.g., in Remington’s Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA, 20th ed. (2000), which is incorporated herein by reference.
- Compounds as described herein may be administered to individuals in a form of generally accepted oral compositions, such as tablets, coated tablets, and gel capsules in a hard or in soft shell, emulsions or suspensions.
- carriers which may be used for the preparation of such compositions, are lactose, corn starch or its derivatives, talc, stearate or its salts, etc.
- Acceptable carriers for gel capsules with soft shell are, for instance, plant oils, wax, fats, semisolid and liquid poly-ols, and so on.
- pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants.
- Any of the compounds described herein can be formulated in a tablet in any dosage form described, for example, a compound as described herein or a salt thereof can be incorporated in tablet in an amount ranging from about 1 mg to about 1000 mg.
- Compositions comprising a compound provided herein are also described.
- the composition comprises a compound or salt thereof and a pharmaceutically acceptable carrier or excipient.
- a composition of substantially pure compound is provided.
- Methods of Use Compounds and compositions detailed herein, such as a pharmaceutical composition containing a compound of any formula provided herein or a salt thereof and a pharmaceutically acceptable carrier or excipient, may be used in methods of administration and treatment as provided herein.
- the compounds and compositions may also be used in in vitro methods, such as in vitro methods of administering a compound or composition to cells for screening purposes and/or for conducting quality control assays.
- a method of treating a disease in an individual comprising administering an effective amount of a compound of the present invention (collectively, a compound of formula (J), (I), (IA), (IA-1) to (IA-10), (IB) , (IB-1) to (IB-10), (II), (II-a) to (II-c), (III), (III-a) to (III-c), (IV), (IV-a) to (IV-c), (V), (V-a) to (V-f), (VI), (VI-a) to (VI-f)) (VII), (VII-a) to (VII-f), (VIII), (VIII-a) to (VIII-f)) or any embodiment, variation or aspect thereof or the present compounds or the compounds detailed or described herein) or a pharmaceutically acceptable salt thereof, to the individual.
- a compound of the present invention collectively, a compound of formula (J), (I), (IA), (IA-1) to (IA-10),
- a method of treating a proliferative disease in an individual comprising administering an effective amount of the compound of the present invention (collectively, a compound of formula (J), (I), (IA), (IA-1) to (IA-10), (IB) , (IB-1) to (IB-10), (II), (II-a) to (II-c), (III), (III- a) to (III-c), (IV), (IV-a) to (IV-c), (V), (V-a) to (V-f), (VI), (VI-a) to (VI-f)) (VII), (VII-a) to (VII-f), (VIII), (VIII-a) to (VIII-f)) or a pharmaceutically acceptable salt thereof, to the individual.
- a compound of formula (J) comprising administering an effective amount of the compound of the present invention (collectively, a compound of formula (J), (I), (IA), (IA-1) to (IA-10), (
- Also provided herein is a method of treating cancer, pulmonary arterial hypertension (PAH) or idiopathic pulmonary fibrosis (IPF) in an individual comprising administering an effective amount of the compound of formula (J) or a pharmaceutically acceptable salt thereof, to the individual.
- the compound is administered to the individual according to a dosage and/or method of administration described herein.
- Another aspect of the invention relates to a method of treating a disease or disorder associated with Checkpoint kinase.
- the method involves administering to a patient in need of a treatment for diseases or disorders associated with Checkpoint kinase an effective amount of the compositions and compounds of the present invention (collectively, a compound of formula (J), (I), (IA), (IA-1) to (IA-10), (IB) , (IB-1) to (IB-10), (II), (II-a) to (II-c), (III), (III- a) to (III-c), (IV), (IV-a) to (IV-c), (V), (V-a) to (V-f), (VI), (VI-a) to (VI-f)) (VII), (VII-a) to (VII-f), (VIII), (VIII-a) to (VIII-f)).
- Another aspect of the invention is directed to a method inhibiting Checkpoint kinase.
- the method involves administering to a patient in need thereof an effective amount of the compositions or compounds of the present invention (collectively, a compound of formula (J), (I), (IA), (IA-1) to (IA-10), (IB) , (IB-1) to (IB-10), (II), (II-a) to (II-c), (III), (III-a) to (III-c), (IV), (IV-a) to (IV-c), (V), (V-a) to (V-f), (VI), (VI-a) to (VI-f)) (VII), (VII-a) to (VII- f), (VIII), (VIII-a) to (VIII-f)).
- a compound of the present invention (collectively, a compound of formula (J), (I), (IA), (IA-1) to (IA-10), (IB) , (IB-1) to (IB-10), (II), (II-a) to (II-c), (III), (III-a) to (III-c), (IV), (IV-a) to (IV-c), (V), (V-a) to (V-f), (VI), (VI-a) to (VI-f)) (VII), (VII-a) to (VII- f), (VIII), (VIII-a) to (VIII-f)) for the manufacture of a medicament for the treatment of a proliferative disease such as cancer, pulmonary arterial hypertension (PAH) and idiopathic pulmonary fibrosis (IPF).
- a proliferative disease such as cancer, pulmonary arterial hypertension (PAH) and idiopathic pulmonary fibrosis (IPF).
- a compound of the present invention (collectively, a compound of formula (J), (I), (IA), (IA-1) to (IA-10), (IB) , (IB-1) to (IB-10), (II), (II-a) to (II-c), (III), (III-a) to (III-c), (IV), (IV-a) to (IV-c), (V), (V-a) to (V-f), (VI), (VI-a) to (VI-f)) (VII), (VII-a) to (VII- f), (VIII), (VIII-a) to (VIII-f)) for the manufacture of a medicament for the treatment of cancer, wherein the cancer is selected from carcinomas, for example carcinomas of the bladder, breast, colon, kidney, epidermis, liver, lung, oesophagus, gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, gastrointestinal system, or skin,
- a compound of the present invention (collectively, a compound of formula (J), (I), (IA), (IA-1) to (IA-10), (IB) , (IB-1) to (IB-10), (II), (II-a) to (II-c), (III), (III-a) to (III-c), (IV), (IV-a) to (IV-c), (V), (V-a) to (V- f), (VI), (VI-a) to (VI-f)) (VII), (VII-a) to (VII-f), (VIII), (VIII-a) to (VIII-f)) for the manufacture of a medicament for the treatment of cancer, wherein the cancer is one which is characterized by a defective DNA repair mechanism or defective cell cycle.
- a compound of the present invention (collectively, a compound of formula (J), (I), (IA), (IA-1) to (IA-10), (IB) , (IB-1) to (IB-10), (II), (II-a) to (II-c), (III), (III-a) to (III-c), (IV), (IV-a) to (IV-c), (V), (V-a) to (V-f), (VI), (VI-a) to (VI-f)) (VII), (VII-a) to (VII- f), (VIII), (VIII-a) to (VIII-f)) for the manufacture of a medicament for the treatment of cancer, wherein the cancer is High grade serious ovarian cancer (HGSOC), Triple negative breast cancer (TNBC) and Small cell lung cancer (SCLC).
- HSSOC High grade serious ovarian cancer
- TNBC Triple negative breast cancer
- SCLC Small cell lung cancer
- CCNE1amplification occurs in approximately 20% of the HGSOC tumors.
- CCNE1amp is known to increase replication stress (RS) and genomic instability, leading to increased reliance on Checkpoint kinase 1 (CHK-1).
- CHK-1 inhibitors Lee et al Lancet Oncol. 201819(2), 207.
- Increased DNA repair and cell cycle checkpoint activation remain as the foremost reasons behind TNBC tumor resistance to chemotherapy and PARP inhibitor resistance. Synergy has been observed with CHK-1 inhibitors and PARP inhibitors in TNBC with elevated RAD51 expression (Mani et al. Breast Cancer Research (2019) 21:104).
- CHK-1 inhibition may be especially effective in SCLC with MYC amplification or MYC protein overexpression.
- CHK-1 inhibitors exhibited strong single-agent efficacy, augmented the effects of cisplatin or the PARP inhibitor olaparib, and improved the response of platinum-resistant models. (Cancer Res2017, 77(14), 3870 - 3884 – Sen et al).
- a compound of the present invention (collectively, a compound of formula (J), (I), (IA), (IA-1) to (IA-10), (IB) , (IB-1) to (IB-10), (II), (II-a) to (II-c), (III), (III-a) to (III-c), (IV), (IV-a) to (IV-c), (V), (V-a) to (V-f), (VI), (VI-a) to (VI-f)) (VII), (VII-a) to (VII- f), (VIII), (VIII-a) to (VIII-f)) for the manufacture of a medicament for the treatment of a idiopathic pulmonary fibrosis (IPF).
- IPF idiopathic pulmonary fibrosis
- IPF is a chronic scarring lung disease characterized by progressive and irreversible decline in lung function. It is closely associated with concomitantly occurring pulmonary arterial hypertension, wherein there is aberrant proliferation of arterial cells, vascular remodeling, inflammation and differentiation of fibroblasts into myofibroblasts.
- the goal of treatment in IPF is to manage the symptoms, retard disease progression, prevent acute exacerbations, and prolong survival. Certain medications like pirfenidone or nintedanib may slow the progression of the disease and lung transplantation is an option for patients who can undergo a major transplant surgery (Bargagli et.al., Pulmonol.2019;25(3):149).
- a compound of the present invention (collectively, a compound of formula (J), (I), (IA), (IA-1) to (IA-10), (IB) , (IB-1) to (IB-10), (II), (II-a) to (II-c), (III), (III-a) to (III-c), (IV), (IV-a) to (IV-c), (V), (V-a) to (V-f), (VI), (VI-a) to (VI-f)) (VII), (VII-a) to (VII- f), (VIII), (VIII-a) to (VIII-f)) for the manufacture of a medicament for the treatment of pulmonary arterial hypertension (PAH).
- PAH pulmonary arterial hypertension
- Pulmonary arterial hypertension is a debilitating disease associated with progressive vascular remodeling of distal pulmonary arteries leading to elevation of pulmonary artery pressure, right ventricular hypertrophy, and death.
- PAH pulmonary artery smooth muscle cells
- CHK1 expression is markedly increased in isolated PASMCs and distal PAs from patients with PAH.
- the disclosed compounds of the present invention can be administered in effective amounts to treat or prevent a disorder and/or prevent the development thereof in subjects.
- Combination Therapy [162]
- the compound of the present invention may be administered either simultaneously with, or before or after, one or more other therapeutic agents.
- the compound of the present invention may be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition as the other agents.
- Dysregulated DNA damage response genes are involved in pro-proliferative and apoptosis resistance characteristics of PAH-PASMCs. Genes involved in DNA repair pathway such as PARP-1, PIM-1, EYA3 and CHK1 are upregulated in PAH-PASMCs leading to increased DNA repair, proliferation and reduced apoptosis.
- PARP1 inhibitor PARP1 inhibitor
- SGI-1776 PIM1 inhibitor
- Benzarone EYA3 inhibitor
- MK-8776, CHK1 inhibitor
- the methods described herein comprise the additional step of co-administering to a subject in need thereof a second therapy e.g., an additional cancer therapeutic agent or an additional cancer treatment.
- the other active agent is selected from the group consisting of but not limited to antimetabolites, tubulin targeting agents, DNA binder and topoisomerase II inhibitors, alkylating agents, monoclonal antibodies, hormonal therapy, signal transduction inhibitors, proteasome inhibitors, DNA methyl transferases, cytokines and retinoids, hypoxia triggered DNA damaging agents, immunomodulaters (e.g. CTLA-4, LAG- 3, PD-1 antagonists etc. ) and monoclonal antibodies.
- the additional cancer therapeutic agent is a chemotherapy agent.
- chemotherapeutic agents used in cancer therapy include, for example, antimetabolites (e.g., folic acid, purine, and pyrimidine derivatives), alkylating agents (e.g., nitrogen mustards, nitrosoureas, platinum, alkyl sulfonates, hydrazines, triazenes, aziridines, spindle poison, cytotoxic agents, topoisomerase inhibitors and others), and hypomethylating agents (e.g.
- antimetabolites e.g., folic acid, purine, and pyrimidine derivatives
- alkylating agents e.g., nitrogen mustards, nitrosoureas, platinum, alkyl sulfonates, hydrazines, triazenes, aziridines, spindle poison, cytotoxic agents, topoisomerase inhibitors and others
- hypomethylating agents e.g.
- decitabine (5-aza-deoxycytidine), zebularine, isothiocyanates, azacitidine (5- azacytidine), 5-flouro-2'-deoxycytidine, 5,6-dihydro-5-azacytidine and others).
- agents include Aclarubicin, Actinomycin, Alitretinoin, Altretamine, Aminopterin, Aminolevulinic acid, Amrubicin, Amsacrine, Anagrelide, Arsenic trioxide, Asparaginase, Atrasentan, Belotecan, Bexarotene, bendamustine, Bleomycin, Bortezomib, Busulfan, Camptothecin, Capecitabine, Carboplatin, Carboquone, Carmofur, Carmustine, Celecoxib, Chlorambucil, Chlormethine, Cisplatin, Cladribine, Clofarabine, Crisantaspase, Cyclophosphamide, Cytarabine, dacarbazine, Dactinomycin, Daunorubicin, Decitabine, Demecolcine, Docetaxel, Doxorubicin, Efaproxiral, Elesclomol, Elsamitrucin, Eno
- any compound of the present invention can be combined with these targeted inhibitors.
- the compounds of the invention and combinations with chemotherapeutic agents or radiation therapies as described above may be administered over a prolonged term to maintain beneficial therapeutic effects or may be administered for a short period only. Alternatively they may be administered in a pulsatile or continuous manner.
- Other possible additional therapeutic modalities include gene therapy, peptide and dendritic cell vaccines, synthetic chlorotoxins, and radiolabeled drugs and antibodies.
- Dosing and Method of Administration [170] The dose of a compound administered to an individual (such as a human) may vary with the particular compound or salt thereof, the method of administration, and the particular disease, such as type and stage of cancer, being treated.
- the amount of the compound or salt thereof is a therapeutically effective amount.
- the effective amount of the compound may in one aspect be a dose of between about 0.01 and about 100 mg/kg.
- Effective amounts or doses of the compounds of the invention may be ascertained by routine methods, such as modeling, dose escalation, or clinical trials, taking into account routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the disease to be treated, the subject’s health status, condition, and weight.
- An exemplary dose is in the range of about from about 0.7 mg to 7 g daily, or about 7 mg to 350 mg daily, or about 350 mg to 1.75 g daily, or about 1.75 to 7 g daily.
- any of the methods provided herein may in one aspect comprise administering to an individual a pharmaceutical composition that contains an effective amount of a compound provided herein or a salt thereof and a pharmaceutically acceptable excipient.
- a compound or composition of the invention may be administered to an individual in accordance with an effective dosing regimen for a desired period of time or duration, such as at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer, which in some variations may be for the duration of the individual’s life.
- the compound is administered on a daily or intermittent schedule.
- the compound can be administered to an individual continuously (for example, at least once daily) over a period of time.
- the dosing frequency can also be less than once daily, e.g., about a once weekly dosing.
- the dosing frequency can be more than once daily, e.g., twice or three times daily.
- the dosing frequency can also be intermittent, including a ‘drug holiday’ (e.g., once daily dosing for 7 days followed by no doses for 7 days, repeated for any 14 day time period, such as about 2 months, about 4 months, about 6 months or more). Any of the dosing frequencies can employ any of the compounds described herein together with any of the dosages described herein.
- the compounds provided herein or a salt thereof may be administered to an individual via various routes, including, e.g., intravenous, intramuscular, subcutaneous, oral and transdermal.
- a compound provided herein can be administered frequently at low doses, known as 'metronomic therapy,' or as part of a maintenance therapy using compound alone or in combination with one or more additional drugs.
- Metronomic therapy or maintenance therapy can comprise administration of a compound provided herein in cycles.
- Metronomic therapy or maintenance therapy can comprise intra-tumoral administration of a compound provided herein.
- the invention provides a method of treating cancer in an individual by parenterally administering to the individual (e.g., a human) an effective amount of a compound or salt thereof.
- the route of administration is intravenous, intra-arterial, intramuscular, or subcutaneous.
- the route of administration is oral.
- the route of administration is transdermal.
- the invention also provides compositions (including pharmaceutical compositions) as described herein for the use in treating, preventing, and/or delaying the onset and/or development of cancer and other methods described herein.
- the composition comprises a pharmaceutical formulation which is present in a unit dosage form
- articles of manufacture comprising a compound of the disclosure or a salt thereof, composition, and unit dosages described herein in suitable packaging for use in the methods described herein. Suitable packaging is known in the art and includes, for example, vials, vessels, ampules, bottles, jars, flexible packaging and the like. An article of manufacture may further be sterilized and/or sealed.
- Kits The present disclosure further provides kits for carrying out the methods of the invention, which comprises one or more compounds described herein or a composition comprising a compound described herein.
- the kits may employ any of the compounds disclosed herein.
- the kit employs a compound described herein or a pharmaceutically acceptable salt thereof.
- the kits may be used for any one or more of the uses described herein, and, accordingly, may contain instructions for the treatment of cancer.
- Kits generally comprise suitable packaging.
- the kits may comprise one or more containers comprising any compound described herein. Each component (if there is more than one component) can be packaged in separate containers or some components can be combined in one container where cross-reactivity and shelf life permit.
- kits may be in unit dosage forms, bulk packages (e.g., multi-dose packages) or sub-unit doses.
- kits may be provided that contain sufficient dosages of a compound as disclosed herein and/or a second pharmaceutically active compound useful for a disease detailed herein to provide effective treatment of an individual for an extended period, such as any of a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more.
- Kits may also include multiple unit doses of the compounds and instructions for use and be packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies).
- kits may optionally include a set of instructions, generally written instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing instructions are also acceptable, relating to the use of component(s) of the methods of the present invention.
- the instructions included with the kit generally include information as to the components and their administration to an individual.
- Step-1 Synthesis of 6-(5-cyanopyrazin-2-ylamino)-N-(cyclopentylmethyl)-4-(morpholin- 2-ylmethylamino)pyridazine-3-carboxamide, (Compound No.1.1)
- Step-1 Synthesis of tert-butyl 2-((6-chloro-3-(methoxycarbonyl)pyridazin-4- ylamino)methyl)morpholine-4-carboxylate: To a solution of methyl 4, 6- dichloropyridazine-3-carboxylate (900 mg, 4.34 mmols, 1.0 eq) in THF (20 mL) was added TEA (1.5 mL, 10.85 mmols, 2.5 eq) followed by the addition of tert-butyl 2- (aminomethyl)morpholine-4-carboxylate (1030 mg, 4.77 mmols, 1.1 eq).
- reaction mixture was refluxed for 2 h.
- the progress of reaction was monitored by TLC and LCMS.
- the reaction mixture was quenched with ice water (10 mL) and extracted with ethyl acetate (3 ⁇ 100 mL). Combined organic phase was washed with water (3 ⁇ 20 mL) followed by brine wash (20 mL). Organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude. Crude was triturated with pentane and solid precipitate was filtered to obtain desired product (1.2 g) as white solid.
- Step-2 Synthesis of tert -butyl 2-((6-chloro-3- (cyclopentylmethylcarbamoyl)pyridazin-4-ylamino)methyl)morpholine-4-carboxylate: To a solution of tert -butyl 2-((6-chloro-3-(methoxycarbonyl)pyridazin-4- ylamino)methyl)morpholine-4-carboxylate (400 mg, 1.39 mmols, 1.0 eq) in THF (8 mL) was added cyclopentylmethanamine (207 mg, 2.09 mmols, 1.5 eq) followed by addition of trimethylaluminium (1.39 mL, 2.79 mmols, 2.0 eq) at 0 °C and the reaction mixture was stirred at RT for 4h.
- Step-3 Synthesis of tert -butyl 2-((6-(5-cyanopyrazin-2-ylamino)-3- (cyclopentylmethylcarbamoyl)pyridazin-4-ylamino)methyl)morpholine-4-carboxylate: A solution of tert -butyl 2-((6-chloro-3-(cyclopentylmethylcarbamoyl)pyridazin-4- ylamino)methyl)morpholine-4-carboxylate (200 mg, 0.44 mmols, 1.0 eq) and 5- aminopyrazine-2-carbonitrile (63.0 mg, 0.52 mmols, 1.2eq) in dioxane (6 mL) was purged with N 2 for 5 minutes and then Cs 2 CO 3 (430 mg, 1.32 mmols, 3.0 eq) was added and purged again for 5 minutes.
- Step-4 Synthesis of 6-(5-cyanopyrazin-2-ylamino)-N-(cyclopentylmethyl)-4- (morpholin-2-ylmethylamino)pyridazine-3-carboxamide: To a solution of tert -butyl 2- ((6-(5-cyanopyrazin-2-ylamino)-3-(cyclopentylmethylcarbamoyl)pyridazin-4- ylamino)methyl)morpholine-4-carboxylate (70 mg, 0.130 mmols, 1.0 eq) in DCM (5.0 mL), TFA (0.5 mL) was added at 0 °C and the resultant reaction mixture
- Example-2 Synthesis of 6-(5-cyanopyrazin-2-ylamino)-N-(2,2-difluoroethyl)-4-(morpholin- 2-ylmethylamino)pyridazine-3-carboxamide, (Compound No.1.2) [188]
- Step-1 Synthesis of tert-butyl 2-((6-chloro-3-(methoxycarbonyl)pyridazin-4- ylamino)methyl)morpholine-4-carboxylate: To a solution of methyl 4, 6- dichloropyridazine-3-carboxylate (900 mg, 4.34 mmols, 1.0 eq) in THF (20 mL) was added TEA (1.5 mL, 10.85 mmols, 2.5 eq) followed by the addition of tert-butyl 2- (aminomethyl)morpholine-4-carboxylate (1030 mg, 4.77 mmols, 1.1 eq).
- reaction mixture was refluxed for 2 h.
- the progress of reaction was monitored by TLC and LCMS.
- the reaction mixture was quenched with ice water (10 mL) and extracted with ethyl acetate (3 ⁇ 100 mL). Combined organic phase was washed with water (3 ⁇ 20 mL) followed by brine wash (20 mL). Organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude. Crude was triturated with pentane and solid precipitate was filtered to obtain desired product (1.2 g) as white solid.
- Step-2 Synthesis of tert-butyl 2-((6-chloro-3-(2,2- difluoroethylcarbamoyl)pyridazin-4-ylamino)methyl)morpholine-4-carboxylate: To a solution of tert-butyl 2-((6-chloro-3-(methoxycarbonyl)pyridazin-4- ylamino)methyl)morpholine-4-carboxylate (500 mg, 1.29 mmol, 1.0 eq) in ACN (10 mL) was added 2,2-difluoroethanamine (157.4 mg, 1.942 mmol, 1.5 eq) and then trimethylaluminium (373.3 mg, 2.59 mmol, 2.0 eq) was added and kept for stirring at RT for 8 h.
- Step-3 Synthesis of tert-butyl 2-((6-(5-cyanopyrazin-2-ylamino)-3-(2,2- difluoroethylcarbamoyl)pyridazin-4-ylamino)methyl)morpholine-4-carboxylate: A solution of tert-butyl 2-((6-chloro-3-(2,2-difluoroethylcarbamoyl)pyridazin-4- ylamino)methyl)morpholine-4-carboxylate (200 mg, 0.459 mmol, 1.0 eq) and 5- aminopyrazine-2-carbonitrile (66.2 mg, 0.551 mmol, 1.2 eq) in dioxane (5 mL) was purged with N 2 for 5 minutes.
- Step-4 Synthesis of 6-(5-cyanopyrazin-2-ylamino)-N-(2,2-difluoroethyl)-4- (morpholin-2-ylmethylamino)pyridazine-3-carboxamide : To a solution of tert-butyl 2- ((6-(5-cyanopyrazin-2-ylamino)-3-(2,2-difluoroethylcarbamoyl)pyridazin-4-ylamino)methyl) morpholine-4-carboxylate (100 mg, 0.192 mmol, 1 eq) in DCM (5.0 mL), TFA (0.5 mL) was added at 0 °C and the
- Step-1 Synthesis of tert-butyl 2-((6-chloro-3-(methoxycarbonyl)pyridazin-4- ylamino)methyl)morpholine-4-carboxylate: To a solution of methyl 4, 6- dichloropyridazine-3-carboxylate (900 mg, 4.34 mmols, 1.0 eq) in THF (20 mL) was added TEA (1.5 mL, 10.85 mmols, 2.5 eq) followed by the addition of tert-butyl 2- (aminomethyl)morpholine-4-carboxylate (1030 mg, 4.77 mmols, 1.1 eq).
- reaction mixture was refluxed for 2 h.
- the progress of reaction was monitored by TLC and LCMS.
- the reaction mixture was quenched with ice water (10 mL) and extracted with ethyl acetate (3 ⁇ 100 mL). Combined organic phase was washed with water (3 ⁇ 20 mL) followed by brine wash (20 mL). Organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude. Crude was triturated with pentane and solid precipitate was filtered to obtain desired product (1.2 g) as white solid.
- Step-2 Synthesis of tert-butyl 2-((6-chloro-3-(cyclopentylcarbomyl)pyridazin-4- ylamino)methyl)morpholine-4-carboxylate: To a solution of tert-butyl 2-((6-chloro-3- (methoxycarbonyl)pyridazin-4-ylamino)methyl)morpholine-4-carboxylate (600 mg, 1.55 mmols, 1.0 eq) in THF (20 mL) cyclopentylamine (264 mg, 3.10 mmols, 2.0 eq) was added followed by addition of trimethylaluminium (2M in toluene) (1.3 mL, 6.21 mmols, 4.0 eq) at 0 °C and the reaction mixture was stirred at RT for 5 h.
- 2M in toluene trimethylaluminium
- Step-3 Synthesis of tert-butyl 2-((6-(5-cyanopyrazin-2-ylamino)-3- (cyclopentylcarbamoyl)pyridazin-4-ylamino)methyl)morpholine-4-carboxylate: A solution of tert-butyl 2-((6-chloro-3-(cyclopentylcarbomyl)pyridazin-4- ylamino)methyl)morpholine-4-carboxylate (200 mg, 0.45 mmols, 1.0 eq) and 5- aminopyrazine-2-carbonitrile (65 mg, 0.54 mmols, 1.2 eq) in dioxane (8 mL) was purged under nitrogen for 10 minutes then Cs 2 CO 3 (445 mg, 1.36 mmols, 3.0 eq) was added and purged again for 5 minutes.
- Step-4 Synthesis of 6-(5-cyanopyrazin-2-ylamino)-N-(cyclopentylmethyl)-4- (morpholin-2-ylmethylamino)pyridazine-3-carboxamide: To a solution of tert-butyl 2-((6- (5-cyanopyrazin-2-ylamino)-3-(cyclopentylcarbamoyl)pyridazin-4- ylamino)methyl)morpholine-4-carboxylate (150 mg, 0.286 mmols, 1 eq) in DCM (6 mL) TFA (1.0mL) was added at 0 °C and stirred for 6h.
- Example-4 Synthesis of 6-(5-cyanopyrazin-2-ylamino)-N-phenyl-4-(piperidin- 4ylmethylamino)pyridazine-3-carboxamide, (Compound No.1.52) [196]
- Step-1 Synthesis of methyl 4-((1-(tert-butoxycarbonyl)piperidin-4- yl)methylamino)-6-chloropyridazine-3-carboxylate: To a solution of methyl 4, 6- dichloropyridazine-3-carboxylate (500 mg, 2.42 mmols, 1.0 eq) in THF (15 mL), TEA (1.5 mL, 3.62 mmols, 1.5 eq) was added dropwise to the reaction mixture followed by addition of tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (620 mg, 2.89 mmols, 1.2 eq) and the reaction mixture was refluxed for 2 h
- Step-2 Synthesis of tert-butyl 4-((6-chloro-3-(phenylcarbamoyl)pyridazin-4- ylamino)methyl)piperidine-1-carboxylate: To a solution of methyl 4-((1-(tert- butoxycarbonyl)piperidin-4-yl)methylamino)-6-chloropyridazine-3-carboxylate (500 mg, 1.30 mmols, 1.0 eq) in THF (10 mL), aniline (181 mg, 1.95 mmols, 1.5 eq) was added.
- Step-3 Synthesis of tert-butyl 4-((6-(5-cyanopyrazin-2-ylamino)-3- (phenylcarbamoyl)pyridazin-4-ylamino)methyl)piperidine-1-carboxylate: A solution of tert-butyl 4-((6-chloro-3-(phenylcarbamoyl)pyridazin-4-ylamino)methyl)piperidine-1- carboxylate (200 mg, 0.44 mmols, 1.0 eq) and 5-aminopyrazine-2-carbonitrile (60 mg, 0.528 mmols, 1.0 eq) in dioxane (5 mL) was purged with nitrogen for 5 minutes then Cs 2 CO 3 (428 mg, 1.32 mmols, 3.0 eq) was added and purged again for 5 minutes.
- xantphos (8 mg, 0.0076 mmols, 0.018 eq) and Pd 2 dba 3 (20 mg, 0.022 mmols, 0.05 eq) was added and the reaction mixture was heated at 180 °C for 16 h. Product formation was confirmed by TLC and LCMS. After the completion of reaction, the reaction mixture was quenched with ice water (20 mL) and extracted with ethyl acetate (3 ⁇ 15 mL). Collective organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to get the crude.
- Step-4 Synthesis of 6-(5-cyanopyrazin-2-ylamino)-N-phenyl-4-(piperidin-4- ylmethylamino)pyridazine-3-carboxamide: To a solution of tert-butyl 4-((6-(5- cyanopyrazin-2-ylamino)-3-(phenylcarbamoyl)pyridazin-4-ylamino)methyl)piperidine-1- carboxylate (60 mg, 0.1134 mmols, 1.0 eq) in DCM (5 mL), TFA (0.5 mL) was added at 0 °C and the reaction mixture was stirred for 2 h.
- Step-1 Synthesis of tert-butyl 4-((6-chloro-3-(ethylcarbamoyl)pyridazin-4- ylamino)methyl)piperidine-1-carboxylate: To a solution of methyl 4-((1-(tert- butoxycarbonyl)piperidin-4-yl)methylamino)-6-chloropyridazine-3-carboxylate (500 mg, 1.30 mmols, 1.0 eq) in ACN (15 mL) was added K 2 CO 3 (448 mg, 3.25 mmols, 2.5 eq) followed by addition of ethylamine (117 mg, 2.60 mmols, 2.0 eq).
- reaction mixture was refluxed for 3 h.
- Product formation was confirmed by TLC and LCMS.
- the reaction mixture was quenched with ice water (20 mL) and extracted with ethyl acetate (3 ⁇ 15 mL). Collective organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to get the crude.
- the crude was triturated with pentane to obtain the desired compound (500 mg).
- Step-2 Synthesis of tert-butyl 4-((6-(5-cyanopyrazin-2-ylamino)-3- (ethylcarbamoyl)pyridazin-4-ylamino)methyl)piperidine-1-carboxylate: A solution of tert-butyl 4-((6-chloro-3-(ethylcarbamoyl)pyridazin-4-ylamino)methyl)piperidine-1- carboxylate (250 mg, 0.629 mmols, 1.0 eq) and 5-aminopyrazine-2-carbonitrile (90 mg, 0.755 mmols, 1.2 eq) in dioxane (5 mL) was purged with nitrogen for 5 minutes followed by addition of Cs 2 CO 3 (614 mg, 1.89 mmols, 3.0 eq).
- reaction mixture was again purged for 5 minutes, then Xantphos (6.5 mg, 0.011 mmols, 0.018 eq) and Pd 2 dba 3 (30 mg, 0.031 mmols, 0.05 eq) was added and the reaction mixture was subjected to microwave for 45 minutes at 180 °C. Product formation was confirmed by TLC and LCMS. After the completion of reaction, the reaction mixture was quenched with ice water (20 mL) and extracted with ethyl acetate (3 ⁇ 15 mL). Collective organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to get the crude.
- Step-3 Synthesis of 6-(5-cyanopyrazin-2-ylamino)-N-ethyl-4-(piperidin-4- ylmethylamino)pyridazine-3-carboxamide: To a solution of tert-butyl 4-((6-(5- cyanopyrazin-2-ylamino)-3-(ethylcarbamoyl)pyridazin-4-ylamino)methyl)piperidine-1- carboxylate (90 mg, 0.187 mmols, 1 eq) in DCM (2 mL), TFA (0.03 mL, 0.467 mmols, 2.5 eq) was added at 0 °C and kept for stirring for
- Step-1 Synthesis of 6-(5-cyanopyrazin-2-ylamino)-N-ethyl-4-(piperidin-3- ylmethylamino)pyridazine-3-carboxamide, (Compound No.1.54)
- Step-1 Synthesis of methyl 4-((1-(tert-butoxycarbonyl)piperidin-3- yl)methylamino)-6-chloropyridazine-3-carboxylate: To a solution of methyl 4, 6- dichloropyridazine-3-carboxylate (300 mg, 1.50 mmols, 1.0 eq) in THF (15 mL), TEA (0.3 mL, 2.25 mmols, 1.5 eq) was added dropwise followed by addition of tert-butyl 3- (aminomethyl)piperidine-1-carboxylate (372 mg, 1.74 mmols, 1.2 eq) and the resultant reaction mixture was refluxed for 2 h.
- Step-2 Synthesis of tert-butyl 3-((6-chloro-3-(ethylcarbamoyl)pyridazin-4- ylamino)methyl)piperidine-1-carboxylate: To a solution of methyl 4-((1-(tert- butoxycarbonyl)piperidin-3-yl)methylamino)-6-chloropyridazine-3-carboxylate (300 mg, 0.781 mmols, 1.0 eq) in ACN (10 mL) was added K 2 CO 3 (269 mg, 1.95 mmols, 2.5 eq) followed by addition of ethylamine (70 mg, 1.56 mmols, 2.0 eq).
- reaction mixture was refluxed for 3 h. Progress of reaction was monitored by TLC and LCMS. The reaction mixture was quenched with ice water (20 mL) and extracted with ethyl acetate (3 ⁇ 15 mL). The organic layer was washed with brine (20 mL) and separated, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to get the crude. The crude was triturated with pentane to obtain the desired compound (400 mg) as light brown solid.
- Step-3 Synthesis of tert-butyl 3-((6-(5-cyanopyrazin-2-ylamino)-3 (ethylcarbamoyl)pyridazin-4-ylamino)methyl)piperidine-1-carboxylate: A solution of tert-butyl 3-((6-chloro-3-(ethylcarbamoyl)pyridazin-4-ylamino)methyl)piperidine-1- carboxylate (200 mg, 0.503 mmols, 1.0 eq) and 5-aminopyrazine-2-carbonitrile (72.5 mg, 0.604 mmols, 1.2 eq) in dioxane (5 mL) was purged with nitrogen for 5 minutes.
- the collective organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to get the crude.
- the crude was purified by flash chromatography by eluting in 60% ethyl acetate: hexane solvent system to obtain desired compound (120 mg) as yellow solid.
- Step-4 Synthesis of 6-(5-cyanopyrazin-2-ylamino)-N-ethyl-4-(piperidin-3- ylmethylamino)pyridazine-3-carboxamide: To a solution of tert-butyl 3-((6-(5- cyanopyrazin-2-ylamino)-3-(ethylcarbamoyl)pyridazin-4-ylamino)methyl)piperidine-1- carboxylate (120 mg, 0.249 mmols, 1.0 eq) in DCM (3 mL), TFA (85 mg , 0.748 mmols, 3.0 eq) was added at 0 °C and stirred for 6h.
- Step-1 Synthesis of 4-((1-(tert-butoxycarbonyl)piperidin-4-yl)methylamino)-6- chloropyridazine-3-carboxylic acid: To a solution of methyl 4-((1-(tert- butoxycarbonyl)piperidin-4-yl)methylamino)-6-chloropyridazine-3-carboxylate (200 mg, 0.520 mmols, 1.0 eq) in THF: water (3 mL: 3 mL) was added LiOH (38 mg, 1.56 mmols, 3.0 eq) and the reaction mixture was stirred at RT for 2 h.
- reaction mixture was acidified using 1N HCl (5 mL) and extracted with ethyl acetate (3 ⁇ 5 mL). Collective organic layer was washed with brine (10 mL) and dried over anhydrous sodium sulfate followed by concentration under reduced pressure to get the crude product. The crude was triturated with pentane to get desired compound (180 mg) as an off-white solid.
- Step-2 Synthesis of tert-butyl 4-((6-chloro-3-(pyridin-4-ylcarbamoyl)pyridazin- 4-ylamino)methyl)piperidine-1-carboxylate: To a solution of 4-((1-(tert- butoxycarbonyl)piperidin-4-yl)methylamino)-6-chloropyridazine-3-carboxylic acid (180 mg, 0.486 mmols, 1.0 eq) in DMF (3 mL), DIPEA (0.2 mL, 1.215 mmols, 2.5 eq) and HATU (277 mg, 0.729 mmols, 1.5 eq) was added at 0°C and the reaction mixture was stirred for 30 minutes.
- Step-3 Synthesis of tert-butyl 4-((6-(5-cyanopyrazin-2-ylamino)-3-(pyridin-4- ylcarbamoyl)pyridazin-4-ylamino)methyl)piperidine-1-carboxylate: To a solution of tert- butyl4-((6-chloro-3-(pyridin-4-ylcarbamoyl)pyridazin-4-ylamino)methyl)piperidine-1- carboxylate (150 mg, 0.336 mmols, 1.0 eq) in dioxane (3 mL), 5-aminopyrazine-2- carbonitrile (48 mg, 0.403 mmols, 1.2 eq) was added and the resultant reaction mixture was purged with nitrogen for 5 minutes followed by addition of Cs 2 CO 3 (328 mg, 1.001 mmols, 3.0 eq)
- Step-4 Synthesis of 6-(5-cyanopyrazin-2-ylamino)-4-(piperidin-4- ylmethylamino)-N-(pyridin-4-yl)pyridazine-3-carboxamide: To a solution of tert-butyl 4- ((6-(5-cyanopyrazin-2-ylamino)-3-(pyridin-4-ylcarbamoyl)pyridazin-4- ylamino)methyl)piperidine-1-carboxylate (70 mg, 0.132 mmols, 1.0 eq) in DCM (3 mL), TFA (45 mg , 0.396 mmols, 3.0 eq) was added at 0 °C and reaction mixture was stirred
- reaction mixture was concentrated under reduced pressure followed by addition of water (5 mL) and extraction with ether (3 ⁇ 10 mL). The aqueous layer was subjected to lyophilization, to yield crude. The crude was purified by reverse phase chromatography to yield desired compound as white solid (12 mg).
- Step-1 Synthesis of tert-butyl 4-((3-(benzylcarbamoyl)-6-chloropyridazin-4- ylamino)methyl)piperidine-1-carboxylate: To a solution of methyl 4-((1-(tert- butoxycarbonyl)piperidin-4-yl)methylamino)-6-chloropyridazine-3-carboxylate (0.5 g, 0.130 mols, 1.0 eq) and phenylmethanamine (0.2 g, 0.195 mols, 1.5 eq) in THF (10 mL), trimethylaluminium (2M in toluene) (1.87 mL, 0.260 mols, 2.0
- reaction mixture was stirred at RT for 4 h. The progress of reaction was monitored by TLC and LCMS. After the completion of reaction, ice cold water (20 mL) was added to the reaction mixture and filtered. Further, ethyl acetate (2 ⁇ 20 mL) was added and washed with water (2 ⁇ 30 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain desired compound (0.4 g) as white solid.
- Step-2 Synthesis of tert-butyl 4-((3-(benzylcarbamoyl)-6-(5-cyanopyrazin-2- ylamino)pyridazin-4-ylamino)methyl)piperidine-1-carboxylate: A solution of tert-butyl 4-((3-(benzylcarbamoyl)-6-chloropyridazin-4-ylamino)methyl)piperidine-1-carboxylate (330 mg, 0.718 mmols, 1.0 eq) and 5-aminopyrazine-2-carbonitrile (103.5 mg, 0.862 mmols, 1.2 eq) in dioxane (5 mL) was purged with nitrogen for 5 minutes then Cs 2 CO 3 (701 mg, 2.154 mmols, 3.0 eq) was added and purged again for 5 minutes, then Xantphos (7.47 mg,
- Step-3 Synthesis of N-benzyl-6-(5-cyanopyrazin-2-ylamino)-4-(piperidin-4- ylmethylamino)pyridazine-3-carboxamide: To a solution of tert-butyl 4-((3- (benzylcarbamoyl)-6-(5-cyanopyrazin-2-ylamino)pyridazin-4-ylamino)methyl)piperidine-1- carboxylate (180 mg, 0.331 mmols, 1 eq) in DCM (5 mL), TFA (0.63mL, 0.828 mmols, 2.5 eq) was added at 0 °C and the resulting reaction mixture was stirred for 2h.
- Step-1 Synthesis of tert-butyl 3-((3-(benzylcarbamoyl)-6-chloropyridazin-4- ylamino)methyl)piperidine-1-carboxylate: To solution of methyl 4-((1-(tert- butoxycarbonyl)piperidin-4-yl)methylamino)-6-chloropyridazine-3-carboxylate (0.5 g, 0.130 mols, 1.0 eq) and phenylmethanamine (0.20 g, 0.195 mols, 1.5 eq) in THF (10 mL), trimethylaluminium (2M in toluene) (1.87 mL, 0.260 mol, 2.0 e
- reaction mixture was stirred at RT for 4 h. The progress of reaction was monitored by TLC and LCMS. After the completion of reaction, ice cold water (20 mL) was added to the reaction mixture and filtered. Further, ethyl acetate (2 ⁇ 20 mL) was added and washed with water (2 ⁇ 30 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain desired compound (0.4 g) as white solid.
- Step-2 Synthesis of tert-butyl 3-((3-(benzylcarbamoyl)-6-(5-cyanopyrazin-2- ylamino)pyridazin-4-ylamino)methyl)piperidine-1-carboxylate: A solution of tert-butyl 3-((3-(benzylcarbamoyl)-6-chloropyridazin-4-ylamino)methyl)piperidine-1-carboxylate (400 mg, 0.871 mmols, 1.0 eq) and 5-aminopyrazine-2-carbonitrile (125.5 mg, 1.045 mmols, 1.2 eq) in dioxane (5 mL) was purged with nitrogen for 5 minutes then Cs 2 CO 3 (851.3 mg, 2.613 mmols, 3.0 eq) was added and purged again for 5 minutes, then Xantphos (9.07
- Step-3 Synthesis of N-benzyl-6-(5-cyanopyrazin-2-ylamino)-4-(piperidin-3- ylmethylamino)pyridazine-3-carboxamide : To a solution of tert-butyl 3-((3- (benzylcarbamoyl)-6-(5-cyanopyrazin-2-ylamino)pyridazin-4-ylamino)methyl)piperidine-1- carboxylate (180 mg, 0.331 mmols, 1.0 eq) in DCM (5 mL), TFA (0.63mL, 0.828 mmols, 2.5 eq) was added at 0 °C and reaction mixture was stirred for 6 h.
- Step-1 Synthesis of tert-butyl 4-((6-chloro-3-(methylcarbamoyl)pyridazin-4- ylamino)methyl)piperidine-1-carboxylate: To a solution of methyl 4-((1-(tert- butoxycarbonyl)piperidin-4-yl)methylamino)-6-chloropyridazine-3-carboxylate (500 mg, 1.30 mmols, 1.0 eq) in ACN (10 mL) was added K 2 CO 3 (530 mg, 3.89 mmols, 3.0 eq) followed by the addition of methylamine (0.36 mg, 3.89 mmols, 3.0 eq).
- reaction mixture was stirred at RT for 8 h.
- Product formation was confirmed by TLC and LCMS.
- the reaction mixture was quenched with ice water (20 mL) and extracted with ethyl acetate (3 ⁇ 15 mL). Collective organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to get the crude. Further, the crude was triturated with pentane to get obtain the desired compound (400 mg).
- Step-2 Synthesis of tert-butyl 4-((6-(5-cyanopyrazin-2-ylamino)-3- (methylcarbamoyl)pyridazin-4-ylamino)methyl)piperidine-1-carboxylate: A solution of tert-butyl 4-((6-chloro-3-(methylcarbamoyl)pyridazin-4-ylamino)methyl)piperidine-1- carboxylate (200 mg, 0.52 mmols, 1.0 eq) and 5-aminopyrazine-2-carbonitrile (60 mg, 0.52 mmols, 1.2 eq) in dioxane (5 mL) was purged with nitrogen for 5 minutes then Cs 2 CO 3 (508 mg, 1.56 mmols, 3 eq) was added and purged again for 5 minutes.
- Step-3 Synthesis of 6-(5-cyanopyrazin-2-ylamino)-N-methyl-4-(piperidin-4- ylmethylamino)pyridazine-3-carboxamide: To a solution of tert-butyl 4-((6-(5- cyanopyrazin-2-ylamino)-3-(methylcarbamoyl)pyridazin-4-ylamino)methyl)piperidine-1- carboxylate (100 mg, 0.213 mmols, 1.0 eq) in DCM (5 mL) TFA (0.5 mL) was added at 0 °C and kept for stirring for 2 h.
- Step-1 Synthesis of tert-butyl 3-((6-chloro-3-(2,2,2- trifluoroethylcarbamoyl)pyridazin-4-ylamino)methyl)piperidine-1-carboxylate: To a solution of methyl 4-((1-(tert-butoxycarbonyl)piperidin-3-yl)methylamino)-6- chloropyridazine-3-carboxylate (500 mg, 1.30 mmols, 1.0 eq) in THF (15 mL) was added 2,2,2-trifluoroethanamine hydrochloride (170 mg, 2.20 mmols, 1.5 eq) followed by addition of trifluoroethanamine hydrochloride (170 mg, 2.20 mmols, 1.5 eq) followed by addition of tri
- reaction mixture was stirred at RT for 4 h.
- Product formation was confirmed by TLC and LCMS.
- the reaction mixture was quenched with ice water (10 mL) and extracted with ethyl acetate (3 ⁇ 15 mL). Collective organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain the desired compound (370 mg).
- Step-2 Synthesis of tert-butyl 3-((6-(5-cyanopyrazin-2-ylamino)-3-(2,2,2- trifluoroethylcarbamoyl)pyridazin-4-ylamino)methyl)piperidine-1-carboxylate: A solution of crude tert-butyl 3-((6-chloro-3-(2,2,2-trifluoroethylcarbamoyl)pyridazin-4- ylamino)methyl)piperidine-1-carboxylate (200 mg, 0.44 mmols, 1.0 eq) and 5- aminopyrazine-2-carbonitrile (60 mg, 0.528 mmols, 1.2 eq) in dioxane (5 mL) was purged under nitrogen for 5 minutes then Cs 2 CO 3 (428 mg, 1.32 mmols, 3.0 eq) was added and purged again for
- Step-3 Synthesis of 6-(5-cyanopyrazin-2-ylamino)-4-(piperidin-3- ylmethylamino)-N-(2,2,2-trifluoroethyl)pyridazine-3-carboxamide: To a solution of tert- butyl 3-((6-(5-cyanopyrazin-2-ylamino)-3-(2,2,2-trifluoroethylcarbamoyl)pyridazin-4- ylamino)methyl)piperidine-1-carboxylate (120 mg, 0.223 mmols, 1.0 eq) in DCM (5 mL), TFA (0.5 mL) was added at 0 °C and resulting reaction mixture was stirred for
- Step-1 Synthesis of tert-butyl 4-((6-chloro-3-(cyclopentylcarbamoyl)pyridazin-4- ylamino)methyl)piperidine-1-carboxylate: To a solution of methyl 4-((1-(tert- butoxycarbonyl)piperidin-4-yl)methylamino)-6-chloropyridazine-3-carboxylate (200 mg, 0.520 mmols, 1.0 eq) in THF (10 mL) was added trimethylaluminium (2M in toluene) (0.65 mL, 1.30 mmols, 2.5 eq) followed by addition of cyclopentylamine
- the resulting reaction mixture was stirred at RT for 4 h. Product formation was confirmed by TLC and LCMS.
- the reaction mixture was quenched with ice water (20 mL) and extracted with ethyl acetate (3 ⁇ 15 mL). The organic layer was collected and washed with saturated solution sodium bicarbonate (20 mL). The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to get the crude.
- the crude was purified by flash chromatography using hexane: ethyl acetate as eluents to get desired compound (400 mg).
- Step-2 Synthesis of tert-butyl 4-((6-(5-cyanopyrazin-2-ylamino)-3- (cyclopentylcarbamoyl)pyridazin-4-ylamino)methyl)piperidine-1-carboxylate: A solution of tert-butyl 4-((6-chloro-3-(cyclopentylcarbamoyl)pyridazin-4- ylamino)methyl)piperidine-1-carboxylate (150 mg, 0.342 mmols, 1.0 eq) and 5- aminopyrazine-2-carbonitrile (45 mg, 0.376 mmols, 1.1 eq) in dioxane (4 mL) was purged with nitrogen for 5 minutes then Cs 2 CO 3 (334 mg, 1.02 mmols, 3.0 eq) was added and purged again for 5 minutes.
- Step-3 Synthesis of 6-(5-cyanopyrazin-2-ylamino)-N-cyclopentyl-4-(piperidin-4- ylmethylamino)pyridazine-3-carboxamide: To a solution of tert-butyl 4-((6-(5- cyanopyrazin-2-ylamino)-3-(cyclopentylcarbamoyl)pyridazin-4-ylamino)methyl)piperidine- 1-carboxylate (100 mg, 0.19 mmols, 1 eq) in DCM (5 mL), TFA (0.8 mL) was added at 0 °C and reaction mixture was stirred for 6h.
- Example-13 Synthesis of 6-(5-cyanopyrazin-2-ylamino)-N-cyclopentyl-4-(piperidin-3- ylmethylamino)pyridazine-3-carboxamide, (Compound No.1.61) [226]
- Step-1 Synthesis of tert-butyl 3-((6-chloro-3-(cyclopentylcarbamoyl)pyridazin-4- ylamino)methyl)piperidine-1-carboxylate: To a solution of methyl 4-((1-(tert- butoxycarbonyl)piperidin-4-yl)methylamino)-6-chloropyridazine-3-carboxylate (200 mg, 0.520 mmols, 1.0 eq) in THF (10 mL) was added trimethylaluminium (2M in toluene) (0.65 mL, 1.30 mmols, 2.5 eq) followed by addition of cyclopentylamine
- Step-2 Synthesis of tert-butyl 3-((6-(5-cyanopyrazin-2-ylamino)-3- (cyclopentylcarbamoyl)pyridazin-4-ylamino)methyl)piperidine-1-carboxylate: A solution of tert-butyl 3-((6-chloro-3-(cyclopentylcarbamoyl)pyridazin-4- ylamino)methyl)piperidine-1-carboxylate (150 mg, 0.342 mmols, 1.0 eq) and 5- aminopyrazine-2-carbonitrile (45 mg, 0.376 mmols, 1.1 eq) in dioxane (4 mL) was purged with nitrogen for 5 minutes then Cs 2 CO 3 (334 mg, 1.02 mmols, 3.0 eq) was added and the reaction mixture was purged again for 5 minutes.
- Step-3 Synthesis of 6-(5-cyanopyrazin-2-ylamino)-N-cyclopentyl-4-(piperidin-3- ylmethylamino)pyridazine-3-carboxamide: To a solution of tert-butyl 3-((6-(5- cyanopyrazin-2-ylamino)-3-(cyclopentylcarbamoyl)pyridazin-4-ylamino)methyl)piperidine- 1-carboxylate (100 mg, 0.19 mmols, 1 eq) in DCM (5 mL), TFA (0.8 mL) was added at 0 °C and reaction mixture was stirred for 6 h.
- Step-1 Synthesis of tert-butyl-3-(3-carbamoyl-6-chloropyridazin-4 ylamino)methyl)piperidine-1-carboxylate: A solution of methyl 4-((1-tert- butoxycarbonyl)piperidin-3-yl)methylamino)-6-chloropyridazine-3-carboxylate (200 mg, 0.520 mmols, 1.0 eq) in methanolic ammonia (5 mL) was stirred at RT for 20 h.
- Step-2 Synthesis of tert-butyl-3-((3-carbamoyl-6-(5-cyanopyrazin-2- ylamino)pyridazin-4-ylamino)methyl)piperidine-1-carboxylate: A solution of tert-butyl-3-(3- carbamoyl-6-chloropyridazin-4-ylamino)methyl)piperidine-1-carboxylate (100 mg, 0.270 mmols, 1.0 eq) and 5-aminopyrazine-2-carbonitrile (32 mg, 0.270 mmols, 1.0eq) in DMF (2 mL) was purged with nitrogen for 10 minutes then C
- Step-3 Synthesis of 6-(5-cyanopyrazin-2-ylamino)-4-(piperidin-3- ylmethylamino)pyridazine-3-carboxamide: To a solution of tert-butyl-3-((3-carbamoyl-6- (5-cyanopyrazin-2-ylamino)pyridazin-4-ylamino)methyl)piperidine-1-carboxylate (80mg, 0.153 mmols, 1 eq) in DCM (5 mL), TFA (0.8 mL) was added at 0 °C and reaction mixture was stirred for 2 h.
- Step-1 Synthesis of 6-(5-cyanopyrazin-2-ylamino)-4-(pyrrolidin-3- ylmethylamino)pyridazine-3-carboxamide, (Compound No.1.63)
- Step-1 Synthesis of methyl 4-((1-(tert-butoxycarbonyl)pyrrolidin-3- yl)methylamino)-6-chloropyridazine-3-carboxylate: To a solution of methyl 4, 6- dichloropyridazine-3-carboxylate (0.50 g, 0.241 mols, 1.0 eq) and tert-butyl 3- (aminomethyl)pyrrolidine-1-carboxylate (0.62 g, 0.289 mols, 1.2 eq) in THF (25 mL), TEA (0.52 mL, 0.362 mols, 1.5 eq) was added to the reaction mixture.
- reaction mixture was refluxed for 2 h.
- the product formation was confirmed by TLC and LCMS.
- reaction mixture was concentrated.
- the crude was diluted with water (3 ⁇ 50 mL) and extracted with ethyl acetate (2 ⁇ 40 mL). The organic layer was separated and washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the desired compound (0.95 g) as white solid).
- Step-2 Synthesis of tert-butyl 3-((3-(benzylcarbamoyl)-6-chloropyridazin-4- ylamino)methyl)pyrrolidine-1-carboxylate: To a solution of methyl 4-((1-(tert- butoxycarbonyl)pyrrolidin-3-yl)methylamino)-6-chloropyridazine-3-carboxylate (0.3 g, 0.81 mmols, 1.0 eq), methanolic ammonia (5 mL) was added. The reaction mixture was stirred at RT for 16h. The progress of reaction was monitored by TLC and LCMS.
- Step-3 Synthesis of tert-butyl 3-((3-carbamoyl-6-(5-cyanopyrazin-2- ylamino)pyridazin-4-ylamino)methyl)pyrrolidine-1-carboxylate: A solution of tert-butyl 3-((3-carbamoyl-6-chloropyridazin-4-ylamino)methyl)pyrrolidine-1-carboxylate (290 mg, 0.816 mmols, 1.0 eq) and 5-aminopyrazine-2-carbonitrile (117.6 mg, 0.980 mmols, 1.2 eq) in dioxane (5 mL) was purged with nitrogen for 5 minutes then
- Step-4 Synthesis of 6-(5-cyanopyrazin-2-ylamino)-4-(pyrrolidin-3- ylmethylamino)pyridazine-3-carboxamide: To a solution of tert-butyl 3-((3-carbamoyl-6- (5-cyanopyrazin-2-ylamino)pyridazin-4-ylamino)methyl)pyrrolidine-1-carboxylate (80 mg, 0.182 mmols, 1 eq) in DCM (3 mL), TFA (0.35 mL, 0.455 mmols, 2.5 eq) was added at 0 °C and stirred for 6 h.
- Step-1 Synthesis of 6-chloro-4-((1-methylpiperidin-4-yl) methyl amino) pyridazine-3-carboxylate: To a solution of methyl 4,6-dichloropyridazine-3-carboxylate (500 mg, 2.415 mmols, 1.0 eq) in THF (15 mL), TEA (0.513 mL, 3.622 mmols, 1.5 eq) was added dropwise to the reaction mixture followed by the addition of (1-methylpiperidin-4- yl)methanamine (309 mg, 2.415 mmols, 1.0 eq).
- the resulting reaction mixture was refluxed for 2 h. Product formation was confirmed by TLC and LCMS.
- the reaction mixture was quenched with ice water (10 mL) and extracted with ethyl acetate (3 ⁇ 15 mL). Collective organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure. Then the crude was triturated with pentane to obtain the desired compound (0.850g) as an off-white color solid.
- Step-2 Synthesis of 6-chloro-4-((1-methylpiperidin-4-yl)methylamino)-N-(2,2,2- trifluoroethyl)pyridazine-3-carboxamide: To a solution of methyl 6-chloro-4-((1- methylpiperidin-4-yl)methylamino)pyridazine-3-carboxylate (300 mg, 1.006 mmols, 1.0 eq) in THF (15 mL) was added 2,2,2-trifluoroethanamine hydrochloride (203 mg, 1.51 mmols, 1.5 eq) followed by the addition of trimethylaluminium (2M in toluene) (2.012 mL, 4.024 mmols, 2.0 eq) and stirred at RT for 4 h.
- 2,2,2-trifluoroethanamine hydrochloride 203 mg, 1.51 mmols, 1.5 eq
- 2M in toluene 2.012
- Step-3 Synthesis of 6-(5-cyanopyrazin-2-ylamino)-4-((1-methylpiperidin-4- yl)methyl amino)-N-(2, 2, 2-trifluoroethyl) pyridazine-3-carboxamide: A solution of 6- chloro-4-((1-methylpiperidin-4-yl)methyl amino)-N-(2, 2, 2-trifluoroethyl) pyridazine-3- carboxamide (250 mg, 0.683 mmols, 1.0 eq) and 5-aminopyrazine-2-carbonitrile (82 mg, 0.683 mmols, 1.0 eq) in dioxane (5 mL) was purged with nitrogen for 5 minutes then Cs 2 CO 3 (667 mg, 2.049 mmols, 3.0 eq) was added and purged again for 5 minutes.
- Step-1 Synthesis of tert-butyl 2-((6-chloro-3-(methoxycarbonyl)pyridazin-4- ylamino)methyl)morpholine-4-carboxylate: To a solution of methyl 4, 6- dichloropyridazine-3-carboxylate (900 mg, 4.34 mmols, 1.0 eq) in THF (20 mL) was added TEA (1.5 mL, 10.85 mmols, 2.5 eq) followed by the addition of tert-butyl 2- (aminomethyl)morpholine-4-carboxylate (1030 mg, 4.77 mmols, 1.1 eq).
- reaction mixture was refluxed for 2 h.
- the progress of reaction was monitored by TLC and LCMS.
- the reaction mixture was quenched with ice water (10 mL) and extracted with ethyl acetate (3 ⁇ 100 mL). Combined organic phase was washed with water (3 ⁇ 20 mL) followed by brine wash (20 mL). Organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude. Crude was triturated with pentane and solid precipitate was filtered to obtain desired product (1.2 g) as white solid.
- Step-2 Synthesis of tert-butyl 2-((6-chloro-3-(hydrazinecarbonyl)pyridazin-4- ylamino)methyl)morpholine-4-carboxylate: To a solution of tert-butyl 2-((6-chloro-3- (methoxycarbonyl)pyridazin-4-ylamino)methyl)morpholine-4-carboxylate (960 mg, 2.48 mmols, 1.0 eq) in methanol (20 m ) was added hydrazine hydrate (65% in water) (186.7 mg, 3.73 mmols, 1.5 eq) and the reaction mixture was stirred at RT for 16 h.
- reaction mixture was concentrated under reduced pressure. Further, ethyl acetate (100 mL) was added and organic phase was washed with water (3 ⁇ 20 mL) followed by brine wash (20 mL). Organic layer was separated and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude. Crude was triturated with pentane to obtain the desired compound (920 mg) as off white solid.
- Step-3 Synthesis of tert-butyl 2-((6-chloro-3-(5-methyl-1,3,4-oxadiazol-2- yl)pyridazin-4-ylamino)methyl)morpholine-4-carboxylate: To a solution of tert-butyl 2- ((6-chloro-3-(hydrazinecarbonyl)pyridazin-4-ylamino)methyl)morpholine-4-carboxylate (440 mg, 1.13 mmols, 1 eq) in xylene (10 mL) was added triethylorthoacetate (203.4 mg,1.25 mmols, 1.1 eq).
- reaction mixture was stirred at 180 °C for 16 h. Reaction was monitored by TLC and LCMS. After completion, reaction mixture was concentrated under reduced pressure. Then, ethyl acetate (100 mL) was added and organic phase was washed with water (3 ⁇ 20 mL) followed by brine wash (20 mL). Organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude. Crude was purified by flash chromatography using ethyl acetate: hexane (0-40%) as eluent to obtain desired compound (170mg) as viscous liquid.
- Step-4 Synthesis of tert-butyl 2-((6-(5-cyanopyrazin-2-ylamino)-3-(5-methyl- 1,3,4-oxadiazol-2-yl)pyridazin-4-ylamino)methyl)morpholine-4-carboxylate: A solution of tert-butyl 2-((6-chloro-3-(5-methyl-1,3,4-oxadiazol-2-yl)pyridazin-4- ylamino)methyl)morpholine-4-carboxylate (160 mg, 0.39 mmols, 1.0 eq) and 5- aminopyrazine-2-carbonitrile (42.1 mg, 0.35 mmols, 0.9 eq) in DMF (4 mL) was added Cs 2 CO 3 (381.4 mg, 1.17 mmols, 3 eq) at RT and reaction mixture was purged under nitrogen for 10 minutes.
- Step-5 Synthesis of 5-(6-(5-methyl-1,3,4-oxadiazol-2-yl)-5-(morpholin-2- ylmethylamino)pyridazin-3-ylamino)pyrazine-2-carbonitrile: To a solution of tert-butyl 2-((6-(5-cyanopyrazin-2-ylamino)-3-(5-methyl-1,3,4-oxadiazol-2-yl)pyridazin-4- ylamino)methyl) morpholine-4-carboxylate (48 mg, 0.
- Step-1 Synthesis of tert-butyl 2-((3-(benzylcarbamoyl)-6-chloropyridazin-4- ylamino)methyl)morpholine-4-carboxylate: To solution of tert-butyl 2-((6-chloro-3- (methoxycarbonyl)pyridazin-4-ylamino)methyl)morpholine-4-carboxylate (0.5 g, 0.129 mols, 1.0 eq) and phenylmethanamine (0.20 g, 0.195 mols, 1.5 eq) in THF (10 mL) followed by the addition of trimethylaluminium (2M in toluene) (1.87 mL, 0.260
- reaction mixture was stirred at RT for 4 h. The progress of reaction was monitored by TLC and LCMS. After the completion of reaction, ice cold water (20 mL) was added to the reaction mixture and filtered. Further, ethyl acetate (2 ⁇ 20 mL) was added and washed with water (2 ⁇ 30 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain desired product (0.4 g) as white solid.
- Step-2 Synthesis of tert-butyl 2-((3-(benzylcarbamoyl)-6-(5-cyanopyrazin-2- ylamino)pyridazin-4-ylamino)methyl)morpholine-4-carboxylate: A solution of tert-butyl 2-((3-(benzylcarbamoyl)-6-chloropyridazin-4-ylamino)methyl)morpholine-4-carboxylate (400 mg, 0.867 mmols, 1.0 eq) and 5-aminopyrazine-2-carbonitrile (124.9 mg, 1.040 mmols, 1.2 eq) in dioxane (5 mL) was purged with nitrogen for 5 minutes then Cs 2 CO 3 (847.4 mg, 2.601 mmols, 3.0 eq) was added and purged again for 5 minutes.
- Step-3 Synthesis of N-benzyl-6-(5-cyanopyrazin-2-ylamino)-4-(morpholin-2- ylmethylamino)pyridazine-3-carboxamide: To a solution of tert-butyl 2-((3- (benzylcarbamoyl)-6-(5-cyanopyrazin-2-ylamino)pyridazin-4-ylamino)methyl)morpholine-4- carboxylate (140 mg, 0.331 mmols, 1 eq) in DCM (5 mL), TFA (0.63 mL, 0.828 mmols, 2.5 eq) was added at 0 °C and kept for stirring for 6h.
- Step-1 Synthesis of 4-((1-(tert-butoxycarbonyl)piperidin-3-yl)methylamino)-6- chloropyridazine-3-carboxylic acid: To a solution of methyl 4-((1-(tert- butoxycarbonyl)piperidin-3-yl)methylamino)-6-chloropyridazine-3-carboxylate (200mg, 0.520 mmols, 1.0 eq) in THF: water (3mL: 3mL) was added LiOH (38 mg, 1.562 mmols, 3.0 eq) and the reaction mixture was stirred at RT for 2 h.
- reaction mixture was acidified by 1N HCl (5 mL) solution and extracted with ethyl acetate (3 ⁇ 5 mL). Collective organic layer was washed with brine (10 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to get the crude. The crude was triturated with pentane to get the desired compound (180 mg) as an off white color solid.
- Step-2 Synthesis of tert-butyl 3-((6-chloro-3-(pyridin-4-ylcarbamoyl)pyridazin- 4-ylamino)methyl)piperidine-1-carboxylate: To a solution of 4-((1-(tert- butoxycarbonyl)piperidin-3-yl)methylamino)-6-chloropyridazine-3-carboxylic acid (180 mg, 0.486 mmols, 1.0 eq) in DMF (3 mL), DIPEA (0.2 mL, 1.215 mmols, 2.5 eq) and HATU (277 mg, 0.729 mmols, 1.5 eq) was added at 0 °C and kept for stirring for 30 minutes.
- Step-3 Synthesis of tert-butyl 3-((6-(5-cyanopyrazin-2-ylamino)-3-(pyridin-4- ylcarbamoyl)pyridazin-4-ylamino)methyl)piperidine-1-carboxylate: A solution of tert- butyl 3-((6-chloro-3-(pyridin-4-ylcarbamoyl)pyridazin-4-ylamino)methyl)piperidine-1- carboxylate (150 mg, 0.336 mmols, 1.0 eq) and 5-aminopyrazine-2-carbonitrile (48 mg, 0.403 mmols, 1.2 eq) in dioxane (3 mL) was purged under nitrogen for 5 minutes then Cs 2 CO 3 (328 mg, 1.008 mmols, 3.0 eq) was added and purged again for 5 minutes.
- Step-4 Synthesis of 6-(5-cyanopyrazin-2-ylamino)-4-(piperidin-3- ylmethylamino)-N-(pyridin-4-yl)pyridazine-3-carboxamide: To a solution of tert-butyl 3- ((6-(5-cyanopyrazin-2-ylamino)-3-(pyridin-4-ylcarbamoyl)pyridazin-4- ylamino)methyl)piperidine-1-carboxylate (70 mg, 0.132 mmols, 1.0 eq) in DCM (3 mL), TFA (45 mg ,0.396 mmols, 3.0 eq) was added at 0 °C and kept for stirring
- reaction mixture was concentrated under reduced pressure. Then water (5 mL) was added to the reaction mixture and extracted with ether (3 ⁇ 10 mL). The aqueous layer was separated and lyophilized to provide crude product. The crude was purified by reverse phase chromatography to yield desired compound as formate salt and a white solid (4 mg).
- Step-1 Synthesis of tert-butyl 4-((6-chloro-3-(isopropylcarbamoyl) pyridazin-4- ylamino) methyl) piperidine-1-carboxylate: To a solution of methyl 4-((1-(tert- butoxycarbonyl) piperidin-4-yl)methylamino)-6-chloropyridazine-3-carboxylate (250 mg, 0.651 mmols, 1.0 eq) in ACN (10.0 mL) was added K 2 CO 3 (269 mg, 1.953 mmols, 3.0eq) and then propan-2-amine (0.117 mg, 1.953 mmols, 3.
- Step-2 Synthesis of tert-butyl 4-((6-(5-cyanopyrazin-2-ylamino)-3- (isopropylcarbamoyl) pyridazin-4-ylamino) methyl) piperidine-1-carboxylate: A solution of tert-butyl 4-((6-chloro-3-(isopropyl carbamoyl) pyridazin-4-ylamino) methyl) piperidine-1-carboxylate (200 mg, 0.485 mmols, 1.0 eq) and 5-aminopyrazine-2-carbonitrile (69 mg, 0.582 mmols, 1.2 eq) in dioxane (5 mL) was purged with N 2 for 5 minutes followed by addition of Cs 2 CO 3 (474 mg, 1.455 mmols, 3.0 eq) and purged again for 5 minutes.
- Step-3 Synthesis of 6-(5-cyanopyrazin-2-ylamino)-N-isopropyl-4-(piperidin-4- ylmethylamino) pyridazine-3-carboxamide: To a solution of tert -butyl 4-((6-(5- cyanopyrazin-2-ylamino)-3-(isopropyl carbamoyl) pyridazin-4-ylamino) methyl) piperidine- 1-carboxylate (100 mg, 0.201 mmols, 1 eq) in DCM (5.0 mL), TFA (0.5 mL) was added at 0°C and kept for stirring for 2h.
- Step-1 Synthesis of tert-butyl 4-((6-chloro-3-(hydrazinecarbonyl)pyridazin-4- ylamino)methyl)piperidine-1-carboxylate: To a solution of methyl 4-((1-(tert- butoxycarbonyl)piperidin-4-yl)methylamino)-6-chloropyridazine-3-carboxylate (510 mg, 1.29 mmols, 1.0 eq.) in methanol (20 mL) was added hydrazine hydrate (65%) (97.51 mg, 1.94 mmols, 1.5 eq) at ambient temperature.
- reaction mixture was stirred at RT for 16h. Reaction was monitored by TLC and LCMS. After completion, reaction mixture was concentrated under reduced pressure. Ethyl acetate (100 mL) was added and organic phase was washed with water (20 mL ⁇ 3) followed by brine wash (20 mL). Organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford crude. Crude was triturated with pentane and solid thus precipitated was filtered to afford the desired compound as an off white solid (510 mg).
- Step-2 Synthesis of tert-butyl 4-((6-chloro-3-(5-methyl-1,3,4-oxadiazol-2- yl)pyridazin-4-ylamino)methyl)piperidine-1-carboxylate: To a solution of tert-butyl 4-((6- chloro-3-(hydrazinecarbonyl)pyridazin-4-ylamino)methyl)piperidine-1-carboxylate (400 mg, 1.03 mmol, 1eq) in xylene (10 mL) was added triethylorthoacetate (185.4 mg, 1.14 mmol, 1.1 eq) at RT.
- reaction mixture was stirred at 180°C for 16h. Reaction was monitored by TLC and LCMS. After completion, reaction mixture was concentrated under reduced pressure. Ethyl acetate (100 mL) was added and organic phase was washed with water (20 mL ⁇ 3) followed by brine wash (20 mL). Organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford crude. Crude was purified by combi flash using ethyl acetate: hexane (0-40%) as eluent to afford the desired compound as viscous liquid (140 mg).
- Step-3 Synthesis of tert-butyl 4-((6-(5-cyanopyrazin-2-ylamino)-3-(5-methyl- 1,3,4-oxadiazol-2-yl)pyridazin-4-ylamino)methyl)piperidine-1-carboxylate: A solution of tert-butyl 4-((6-chloro-3-(5-methyl-1,3,4-oxadiazol-2-yl)pyridazin-4- ylamino)methyl)piperidine-1-carboxylate (270 mg, 0.66 mmols, 1.0 eq) and 5- aminopyrazine-2-carbonitrile (71.4 mg, 0.59 mmols, 0.9 eq) in DMF (4mL) was added Cs 2 CO 3 (646.7mg, 1.98 mmols, 3 eq) at RT and reaction mixture was purged under nitrogen for 10 minutes.
- Step-4 Synthesis of 5-(6-(5-methyl-1,3,4-oxadiazol-2-yl)-5-(piperidin-4- ylmethylamino)pyridazin-3-ylamino)pyrazine-2-carbonitrile: To a solution of tert-butyl 4-((6-(5-cyanopyrazin-2-ylamino)-3-(5-methyl-1,3,4-oxadiazol-2-yl)pyridazin-4- ylamino)methyl)piperidine-1-carboxylate (90 mg, 0.18 mmols, 1.0 eq) in DCM (1 mL) was added TFA (0.5 mL) and the reaction mixture was stirred at 0 °C for 6
- Step-1 Synthesis of 4-((4-(tert-butoxycarbonyl)morpholin-2-yl)methylamino)-6- chloropyridazine-3-carboxylic acid: To a solution of tert-butyl 2-((6-chloro-3- (methoxycarbonyl)pyridazin-4-ylamino)methyl)morpholine-4-carboxylate (910 mg, 2.35 mmols, 1.0 eq) in tetrahydrofuran : water (8:2) (30 mL) was added lithium hydroxide (296.4 mg, 2.05 mmols, 3 eq) at ambient temperature.
- reaction mixture was stirred at RT for 2h. Progress of reaction was monitored by TLC and LCMS. After completion, reaction mixture was concentrated under reduced pressure. Ethyl acetate (100 mL) was added and organic phase was washed with 1N hydrochloric acid (20 mL) followed by brine wash (20 mL). Organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford desired compound as a white solid (830 mg).
- Step-2 Synthesis of tert-butyl 2-((6-chloro-3-(pyridin-4-ylcarbamoyl)pyridazin- 4-ylamino)methyl)morpholine-4-carboxylate: To a solution of 4-((4-(tert- butoxycarbonyl)morpholin-2-yl)methylamino)-6-chloropyridazine-3-carboxylic acid (820 mg, 2.2 mmols, 1 eq) in DMF (10 mL) was added HATU (1.25 g, 3.3 mmols, 1.5 eq) at RT followed by addition of N-ethyl-N-isopropylpropan-2-amine (851.4 mg, 6.6 mmols, 3 eq) at same temperature.
- Step-3 Synthesis of tert-butyl 2-((6-(5-cyanopyrazin-2-ylamino)-3-(pyridin-4- ylcarbamoyl)pyridazin-4-ylamino)methyl)morpholine-4-carboxylate: To a solution of tert-butyl-2-((6-chloro-3-(pyridin-4-ylcarbamoyl)pyridazin-4-ylamino)methyl)morpholine-4- carboxylate (400 mg, 0.89 mmols, 1.0 eq) and 5-aminopyrazine-2-carbonitrile (96.42 mg, 0.80 mmols, 0.9 eq) in DMF (7 mL) was added Cs 2 CO 3 (872.3 mg, 2.67 mmols, 3 eq) at RT and reaction mixture was purged under nitrogen for 10 minutes.
- Step-4 Synthesis of 6-(5-cyanopyrazin-2-ylamino)-4-(morpholin-2- ylmethylamino)-N-(pyridin-4-yl)pyridazine-3-carboxamide: To a solution of tert-butyl 2- ((6-(5-cyanopyrazin-2-ylamino)-3-(pyridin-4-ylcarbamoyl)pyridazin-4- ylamino)methyl)morpholine-4-carboxylate (120 mg, 0.
- Example-23 Synthesis of 5-(6-(5-methyl-1,3,4-oxadiazol-2-yl)-5-(piperidin-3- ylmethylamino)pyridazin-3-ylamino)pyrazine-2-carbonitrile, (Compound No.1.71)
- Step-1 Synthesis of tert-butyl 3-((6-chloro-3-(hydrazinecarbonyl)pyridazin-4- ylamino)methyl)piperidine-1-carboxylate: To a solution of methyl 4-((1-(tert- butoxycarbonyl)piperidin-3-yl)methylamino)-6-chloropyridazine-3-carboxylate (800 mg, 2.07 mmols, 1.0 eq) in methanol (20 mL) was added hydrazine hydrate (65% solution) (156.03 mg, 3.11 mmols , 1.5 eq) at ambient temperature.
- reaction mixture was stirred at RT for 16h. Reaction was monitored by TLC and LCMS. After completion, reaction mixture was concentrated under reduced pressure. Ethyl acetate (250 mL) was added and organic phase was washed with water (20 mL ⁇ 3) followed by brine wash (20 mL). Organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude. Crude was triturated with pentane and the solid thus precipitated was filtered to afford the desired compound as an off white solid (780 mg).
- Step-2 Synthesis of tert-butyl 3-((6-chloro-3-(5-methyl-1,3,4-oxadiazol-2- yl)pyridazin-4-ylamino)methyl)piperidine-1-carboxylate: To a solution of tert-butyl 3-((6- chloro-3-(hydrazinecarbonyl)pyridazin-4-ylamino)methyl)piperidine-1-carboxylate (730 mg, 1.89 mmols, 1eq) in xylene (10 mL) was added triethylorthoacetate (398.5 mg, 2.45 mmols, 1.3 eq) at RT.
- reaction mixture was stirred at 180 °C for 16h. Reaction was monitored by TLC and LCMS. After completion, reaction mixture was concentrated under reduced pressure. Ethyl acetate (200 mL) was added and organic phase was washed with water (20 mL ⁇ 3) followed by brine wash (20 mL). Organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude. Crude was purified by combi flash using ethyl acetate: hexane (0-50%) as eluent to afford the desired compound as a viscous liquid (95 mg).
- Step-3 Synthesis of tert-butyl 3-((6-(5-cyanopyrazin-2-ylamino)-3-(5-methyl- 1,3,4-oxadiazol-2-yl)pyridazin-4-ylamino)methyl)piperidine-1-carboxylate: To a solution of tert -butyl 3-((6-chloro-3-(5-methyl-1,3,4-oxadiazol-2-yl)pyridazin-4- ylamino)methyl)piperidine-1-carboxylate (90 mg, 0.22 mmols , 1.0 eq) and 5-aminopyrazine- 2-carbonitrile (21.17 mg, 0.17 mmols , 0.8 eq) in DMF (4 mL) was added Cs 2 CO 3 (215.1 mg, 0.66 mmols, 3 eq) at RT and reaction mixture was purged under nitrogen for 10
- Step-4 Synthesis of 5-(6-(5-methyl-1,3,4-oxadiazol-2-yl)-5-(piperidin-3- ylmethylamino)pyridazin-3-ylamino)pyrazine-2-carbonitrile: To a solution of tert-butyl 3-((6-(5-cyanopyrazin-2-ylamino)-3-(5-methyl-1,3,4-oxadiazol-2-yl) pyridazin-4- ylamino)methyl)piperidine-1-carboxylate (50 mg, 0.
- Step-1 Synthesis of methyl 4-((1-(tert -butoxycarbonyl)pyrrolidin-3- yl)methylamino)-6-chloropyridazine-3-carboxylate: To a solution of methyl 4,6- dichloropyridazine-3-carboxylate (0.5 g, 0.241 mol, 1.0 eq) and tert -butyl 3- (aminomethyl)pyrrolidine-1-carboxylate (0.57 g, 0.289 mol, 1.2 eq) in THF (10 mL), triethylamine (0.52 mL, 0.362 mol, 1.5 eq) was added to the reaction mixture.
- THF 10 mL
- triethylamine 0.52 mL, 0.362 mol, 1.5 eq
- reaction mixture was heated and stirred at 90 °C for 4h.
- the product formation was confirmed by TLC and LCMS.
- reaction mixture was concentrated and crude was obtained.
- the crude was diluted with water (2 ⁇ 50 mL) and extracted with ethyl acetate (50 mL).
- the organic layer was separated and washed with brine (30 mL), dried over anhydrous anhydrous sodium sulfate and concentrated under reduced pressure to obtain methyl 4-((1-(tert -butoxycarbonyl)pyrrolidin-3-yl)methylamino)-6-chloropyridazine-3- carboxylate (0.90 g, white solid).
- Step-2 Synthesis of tert-butyl 3-((6-chloro-3-(phenylcarbamoyl)pyridazin-4- ylamino)methyl)pyrrolidine-1-carboxylate: To a solution of methyl 4-((1-(tert- butoxycarbonyl)pyrrolidin-3-yl)methylamino)-6-chloropyridazine-3-carboxylate (0.4 g, 0.108 mol, 1.0 eq) and aniline (0.15 g, 0.162 mol, 1.5 eq) in THF (7 mL), trimethylaluminium (2M in toluene) (0.15 mL, 0.108 mol, 2.0 eq) was added.
- reaction mixture was stirred at RT for 4h. The progress of reaction was monitored by TLC and LCMS. After the completion of reaction, ice cold water (10 mL) was added to the reaction mixture and the solid thus precipitated was filtered. Further, the solid was dissolved in ethyl acetate (40 mL) and washed with water (2 ⁇ 30 mL). The organic layer was separated, dried over anhydrous anhydrous sodium sulfate and concentrated under reduced pressure to obtain the desired compound as a white solid (0.4 g).
- Step-3 Synthesis of tert-butyl 3-((6-(5-cyanopyrazin-2-ylamino)-3- (phenylcarbamoyl)pyridazin-4-ylamino)methyl)pyrrolidine-1-carboxylate: A solution of tert -butyl 3-((6-chloro-3-(phenylcarbamoyl)pyridazin-4-ylamino)methyl)pyrrolidine-1- carboxylate (200 mg, 0.464 mmols, 1.0 eq) and 5-aminopyrazine-2-carbonitrile (66.8 mg, 0.556 mmols, 1.2 eq) in dioxane (3 mL) was purged with N 2 for 5 minutes followed by addition of Cs 2 CO 3 (453.5 mg, 1.392 mmols, 3.0 eq) and the reaction mixture was purged again for 5 minutes.
- Step-4 Synthesis of 6-(5-cyanopyrazin-2-ylamino)-N-phenyl-4-(pyrrolidin-3- ylmethylamino)pyridazine-3-carboxamide: To a solution of tert-butyl 3-((6-(5- cyanopyrazin-2-ylamino)-3-(phenylcarbamoyl)pyridazin-4-ylamino)methyl)pyrrolidine-1- carboxylate (100 mg, 0.240 mmols, 1 eq) in DCM (5 mL), TFA (0.46 mL, 0.601 mmols, 2.5 eq) was added at 0 °C
- Step-1 Synthesis of tert-butyl 3-((6-chloro-3-(2, 2, 2-trifluoroethylcarbamoyl) pyridazin-4-ylamino) methyl) pyrrolidine-1-carboxylate: To a solution of methyl 4-((1- (tert-butoxycarbonyl) pyrrolidin-3-yl) methyl amino)-6-chloropyridazine-3-carboxylate (250 mg, 0.673 mmols, 1.0 eq) in THF (15 mL) was added 2,2,2-trifluoroethanamine hydrochloride (136 mg, 1.010 mmols, 1.5 eq
- Step-2 Synthesis of tert-butyl 3-((6-(5-cyanopyrazin-2-ylamino)-3-(2, 2, 2- trifluoroethylcarbamoyl) pyridazin-4-ylamino) methyl) pyrrolidine-1-carboxylate: A solution of tert-butyl 3-((6-chloro-3-(2, 2, 2-trifluoroethylcarbamoyl) pyridazin-4-ylamino) methyl) pyrrolidine-1-carboxylate (200 mg, 0.456 mmols, 1.0 eq) and 5-aminopyrazine-2- carbonitrile (60 mg, 0.502 mmols, 1.0 eq) in dioxane (5 mL) was purged using N 2 for 5 minutes.
- Step-3 Synthesis of 6-(5-cyanopyrazin-2-ylamino)-4-(pyrrolidin-3- ylmethylamino)-N-(2,2,2-trifluoroethyl)pyridazine-3-carboxamide: To a solution of tert- butyl 3-((6-(5-cyanopyrazin-2-ylamino)-3-(2, 2, 2-trifluoroethylcarbamoyl) pyridazin-4- ylamino) methyl) pyrrolidine-1-carboxylate (100 mg, 0.191 mmols, 1.0 eq) in DCM (5.0 mL), TFA (0.5 mL) was added at 0°C and the reaction mixture was stirred for 2h.
- TFA 0.5 mL
- Step-1 Synthesis of tert-butyl 3-((6-chloro-3-(phenylcarbamoyl)pyridazin-4- ylamino)methyl)piperidine-1-carboxylate: To a solution of methyl 4-((1-(tert- butoxycarbonyl)piperidin-3-yl)methylamino)-6-chloropyridazine-3-carboxylate (500 mg, 1.55 mmols, 1.0 eq) in THF (10 mL) and aniline (2.88 mg, 3.0 mmols, 2.0 eq) was added trimethylaluminium (3.1 mL, 6.21 mmols, 4.0 eq) and the reaction mixture was
- Step-2 Synthesis of tert-butyl 3-((6-(5-cyanopyrazin-2-ylamino)-3- (phenylcarbamoyl)pyridazin-4-ylamino)methyl)piperidine-1-carboxylate: A solution of tert-butyl 3-((6-chloro-3-(phenylcarbamoyl)pyridazin-4-ylamino)methyl)piperidine-1- carboxylate (150 mg, 0.33 mmols, 1.0 eq) and 5-aminopyrazine-2-carbonitrile (48 mg, 0.40 mmols, 1.1 eq) in dioxane (8 mL) was purged with N 2 for 5 minutes followed by addition of Cs 2 CO 3 (241 mg, 0.74 mmols, 3.0 eq) and the reaction mixture was purged again for 5 minutes.
- Step-3 Synthesis of 6-(5-cyanopyrazin-2-ylamino)-N-phenyl-4-(piperidin-3- ylmethylamino)pyridazine-3-carboxamide: To a solution of tert-butyl 3-((6-(5- cyanopyrazin-2-ylamino)-3-(phenylcarbamoyl)pyridazin-4-ylamino)methyl)piperidine-1- carboxylate (200 mg, 0.37 mmols, 1 eq) in DCM (8.0 mL), TFA (1.2 mL) was added at 0°C and kept for stirring for 2h.
- Step-1 Synthesis of methyl 4-((1R,3R)-3-(tert- butoxycarbonylamino)cyclopentylamino)-6-chloropyridazine-3-carboxylate: To a solution of methyl 4,6-dichloropyridazine-3-carboxylate (250 mg, 1.21 mol, 1.0 eq) in THF (15 mL) was added tert-butyl (1R, 3R)-3-aminocyclopentylcarbamate (620 mg, 2.89 mmols, 1.2 eq), TEA (0.34 mL, 2.42 mol, 2.0 eq) and the reaction mixture was refluxed for 2h
- Step-2 Synthesis of tert-butyl (1R, 3R)-3-(6-chloro-3- (methylcarbamoyl)pyridazin-4-ylamino)cyclopentylcarbamate: A solution of methyl 4- ((1R,3R)-3-(tert-butoxycarbonylamino)cyclopentylamino)-6-chloropyridazine-3-carboxylate (400 mg, 1.08 mmols, 1.0 eq) in 8 mL MeNH 2 (2.0 M solution in MeOH) was stirred at RT for 1.5h. Product formation was confirmed by TLC and LCMS.
- Step-3 Synthesis of tert-butyl (1R, 3R)-3-(6-(5-cyanopyrazin-2-ylamino)-3- (methylcarbamoyl)pyridazin-4-ylamino)cyclopentylcarbamate: A solution of tert-butyl (1R, 3R)-3-(6-chloro-3-(methylcarbamoyl)pyridazin-4-ylamino)cyclopentylcarbamate (200 mg, 0.54 mmols, 1.0 eq) and 5-aminopyrazine-2-carbonitrile (77 mg, 0.65 mmols, 1.2 eq) in dioxane (8
- Step-4 Synthesis of 4-((1R, 3R)-3-aminocyclopentylamino)-6-(5-cyanopyrazin-2- ylamino)-N-methylpyridazine-3-carboxamide: To a solution of tert-butyl (1R, 3R)-3-(6-(5- cyanopyrazin-2-ylamino)-3-(methylcarbamoyl)pyridazin-4-ylamino)cyclopentylcarbamate (120 mg, 0.26 mmols, 1 eq) in DCM (6.0 mL), TFA (1.0 mL) was added at 0 °C and kept for stirring for 2h.
- Step-1 Synthesis of tert-butyl 2-((3,6-dichloropyridazin-4- ylamino)methyl)morpholine-4-carboxylate: To a solution of 3,4,6-trichloropyridazine (2.0 g, 10.92 mmols, 1.0 eq) in THF (40 mL) was added TEA (2.75 g, 27.3 mmols, 2.5 eq) followed by the addition of tert-butyl 2-(aminomethyl)morpholine-4-carboxylate (2.6 g, 12.12 mmols, 1.1eq) at ambient temperature.
- reaction mixture was stirred at 90 °C for 3h. Reaction was monitored by TLC and LCMS. After completion, reaction mixture was quenched with ice water (20 mL) and extracted with ethyl acetate (200 mL ⁇ 3). Combined organic phase was washed with water (30 mL ⁇ 3) followed by brine wash (20mL). Organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude. The crude was triturated with pentane and solid precipitated was filtered to afford the desired compound as a white solid (3.2g).
- Step-2 Synthesis of tert-butyl 2-((6-chloro-3-(1-methyl-1H-pyrazol-4-yl) pyridazin-4-ylamino) methyl) morpholine-4-carboxylate: To a solution of tert-butyl 2- ((3,6-dichloropyridazin-4-ylamino)methyl)morpholine-4-carboxylate (500 mg, 1.37 mmols, 1.0 eq) in dioxane : water (10 mL : 2.5 mL) was added 1-methyl-1H-pyrazol-4-ylboronic acid (173 mg, 1.37 mmols, 1.5 eq) followed by addition of K 2 CO 3 (300 mg, 2.74 mmols, 2.0 eq).
- Step-3 Synthesis of tert-butyl 2-((6-(6-cyanopyridin-3-ylamino)-3-(1-methyl-1H- pyrazol-4-yl) pyridazin-4-ylamino) methyl) morpholine-4-carboxylate: A solution of tert- butyl 2-((6-chloro-3-(1-methyl-1H-pyrazol-4-yl)pyridazin-4-ylamino)methyl)morpholine-4- carboxylate (200 mg, 0.488 mmols, 1.0 eq) and 5-aminopicolinonitrile (58 mg, 0.488 mmols, 1.0 eq) in dioxane (5 mL) was purged using nitrogen for 5 minutes then Cs 2 CO 3 (489 mg, 1.50 mmols, 3.0 eq) was added and purged again for 5 minutes.
- Step-4 Synthesis of 5-(6-(1-methyl-1H-pyrazol-4-yl)-5-(morpholin-2- ylmethylamino)pyridazin-3-ylamino)picolinonitrile: To a solution of tert-butyl 2-((6-(6- cyanopyridin-3-ylamino)-3-(1-methyl-1H-pyrazol-4-yl) pyridazin-4- ylamino)methyl)morpholine-4-carboxylate (100 mg, 0.203 mmols, 1 eq) in DCM (5 mL), TFA (0.5 mL) was added at 0 °C and resulting reaction mixture was stirred for 6 h.
- Step-1 Synthesis of tert-butyl 2-((6-chloro-3-(thiazol-2-yl)pyridazin-4- ylamino)methyl)morpholine-4-carboxylate: To a solution of tert -butyl 2-((3,6- dichloropyridazin-4-ylamino)methyl)morpholine-4-carboxylate (440 mg, 1.21 mmols, 1.0eq) and 2-(tributylstannyl)thiazole (906.6 mg, 2.42 mmols, 2.0 eq) in toluene (7mL) was added lithium chloride (52.11mg, 1.21mmols, 1.0eq) and copper i
- Tetrakis(triphenylphosphine)palladium(0) (280.09 mg, 0.24 mmols, 0.2 eq) was added and again nitrogen was purged for 5 minutes. Reaction mixture was stirred at 120 °C for 16h. Reaction was monitored by TLC and LCMS. After completion, reaction mixture was cooled to RT and ethyl acetate (100 mL) was added and organic phase was washed with water (20 mL ⁇ 3) followed by brine wash (20 mL). Organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude.
- Step-2 Synthesis of tert -butyl 2-((6-(5-cyanopyrazin-2-ylamino)-3-(thiazol-2- yl)pyridazin-4-ylamino)methyl)morpholine-4-carboxylate: To a solution of tert-butyl 2- ((6-chloro-3-(thiazol-2-yl)pyridazin-4-ylamino)methyl)morpholine-4-carboxylate (120 mg, 0.29 mmols, 1.0 eq) and 5-aminopyrazine-2-carbonitrile (28.02 mg, 0.23 mmols, 0.98 eq) in DMF (3mL) was added Cs 2 CO 3 (284.6 mg, 0.87
- Step-3 Synthesis of 5-(5-(morpholin-2-ylmethylamino)-6-(thiazol-2-yl)pyridazin- 3-ylamino)pyrazine-2-carbonitrile: To a solution of tert-butyl 2-((6-(5-cyanopyrazin-2- ylamino)-3-(thiazol-2-yl)pyridazin-4-ylamino)methyl)morpholine-4-carboxylate (80 mg, 0.
- Step-1 Synthesis of tert-butyl 2-((6-chloro-3-(oxazol-2-yl)pyridazin-4- ylamino)methyl)morpholine-4-carboxylate: To a solution of tert-butyl 2-((3,6- dichloropyridazin-4-ylamino)methyl)morpholine-4-carboxylate (0.5 g, 1.38 mmols, 1.0 eq) and 2-(tributylstannyl)oxazole (0.74 g, 2.07 mmols, 1.5 eq) in toluene (5 mL), CuI (0.13 g, 0.69 mmols, 0.5 eq), Li
- reaction mixture was purged under nitrogen atmosphere for 10 minutes.
- the reaction mixture was heated at 110 °C and stirred for 16 h.
- the progress of reaction was monitored by TLC and LCMS.
- the reaction mixture was passed through celite and ethyl acetate (2 ⁇ 20 mL) was added.
- the organic layer was washed with water (2 ⁇ 30 mL).
- the organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude reaction mixture.
- the crude reaction mixture was purified by flash chromatography using 70% ethyl acetate: hexane solvent system to obtain desired compound (0.25 g) as a white solid.
- Step-2 Synthesis of tert-butyl 2-((6-(5-cyanopyrazin-2-ylamino)-3-(oxazol-2- yl)pyridazin-4-ylamino)methyl)morpholine-4-carboxylate: A solution of tert-butyl 2-((6- chloro-3-(oxazol-2-yl)pyridazin-4-ylamino)methyl)morpholine-4-carboxylate (250 mg, 0.632 mmols, 1.0 eq) and 5-aminopyrazine-2-carbonitrile (91 mg, 0.759 mmols, 1.2 eq) in dioxane (3 mL) was purged with nitrogen for 5 minutes then Cs 2 CO 3 (617.7 mg, 1.896 mmols, 3.0 eq) was added and purged again for 5 minutes.
- Step-3 Synthesis of 5-(5-(morpholin-2-ylmethylamino)-6-(oxazol-2-yl)pyridazin- 3-ylamino)pyrazine-2-carbonitrile: To a solution of tert-butyl 2-((6-(5-cyanopyrazin-2- ylamino)-3-(oxazol-2-yl)pyridazin-4-ylamino)methyl)morpholine-4-carboxylate (80 mg, 0.167 mmols, 1 eq) in DCM (5 mL), TFA (0.32 mL, 0.417 mmols, 2.5 eq) was added at 0 °C.
- Step-1 Synthesis of tert-butyl 2-((6-chloro-3-(1-methyl-1H-pyrazol-4- yl)pyridazin-4-ylamino)methyl)morpholine-4-carboxylate: To a solution of tert-butyl 2- ((3,6-dichloropyridazin-4-ylamino)methyl)morpholine-4-carboxylate (1.0 g, 2.46 mmols, 1.0 eq) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.56 g, 2.46 mmols, 1.0 eq)
- reaction mixture was purged under nitrogen atmosphere for 10 minutes.
- the reaction mixture was heated at 90 °C for 16 h.
- the progress of reaction was monitored by TLC and LCMS.
- the reaction mixture was passed through celite and ethyl acetate (2 ⁇ 20 mL) was added.
- the organic layer was washed with water (2 ⁇ 30 mL).
- the organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude reaction mixture.
- the crude reaction mixture was purified by combi flash using 70% ethyl acetate: hexane solvent system to obtain desired compound (0.25 g) as yellow solid.
- Step-2 Synthesis of tert-butyl 2-((6-(5-cyanopyrazin-2-ylamino)-3-(1-methyl-1H- pyrazol-4-yl)pyridazin-4-ylamino)methyl)morpholine-4-carboxylate: A solution of tert- butyl 2-((6-chloro-3-(1-methyl-1H-pyrazol-4-yl)pyridazin-4-ylamino)methyl)morpholine-4- carboxylate (250 mg, 0.612 mmols, 1.0 eq) and 5-aminopyrazine-2-carbonitrile (88.2 mg, 0.735 mmols, 1.2 eq) in dioxane (4 mL) was purged with nitrogen for 5 minutes then Cs 2 CO 3 (598.1 mg, 1.836 mmols, 3.0 eq) was added and purged again for 5 minutes
- Step-3 Synthesis of 5-(6-(1-methyl-1H-pyrazol-4-yl)-5-(morpholin-2- ylmethylamino)pyridazin-3-ylamino)pyrazine-2-carbonitrile: To a solution of tert-butyl 2-((6-(5-cyanopyrazin-2-ylamino)-3-(1-methyl-1H-pyrazol-4-yl)pyridazin-4- ylamino)methyl)morpholine-4-carboxylate (70 mg, 0.142 mmols, 1 eq) in DCM (3 mL), TFA (0.3 mL, 0.355 mmols, 2.5 eq) was added at 0 °C.
- Step-1 Synthesis of methyl 4-((1r, 4r)-4-(tert- butoxycarbonylamino)cyclohexylamino)-6-chloropyridazine-3-carboxylate: To a solution of methyl 4,6-dichloropyridazine-3-carboxylate (450 mg, 2.18 mmols, 1.0 eq) and tert-butyl (1r, 4r)-4-aminocyclohexylcarbamate (0.56 g, 2.6 mmols, 1.2 eq) in THF (7 mL), was added triethylamine (1.5mL, 3.10 mmols, 1.5 methyl 4,6-dichloropyridazine-3-carboxylate (450 mg, 2.18 mmols, 1.0 eq) and tert-butyl (1r, 4r)-4-aminocyclohexylcarbamate (0.56 g, 2.6 mmols
- Step-2 Synthesis of tert-butyl (1r, 4r)-4-(6-chloro-3-(methylcarbamoyl)pyridazin- 4-ylamino)cyclohexylcarbamate: To a solution methyl 4-((1r, 4r)-4-(tert- butoxycarbonylamino)cyclohexylamino)-6-chloropyridazine-3-carboxylate (300 mg, 0.78 mmols, 1.0 eq) in methylamine solution in methanol (2.0 M) was stirred for 30 min at RT. Product formation was confirmed by TLC and LCMS.
- reaction mixture was quenched with ice water (10 mL) which resulted in precipitation of a solid which was filtered. This solid was triturated with pentane (20 mL ⁇ 2) to afford 270 mg of the desired compound as a white solid.
- Step-3 Synthesis of tert -butyl (1r, 4r)-4-(6-(5-cyanopyrazin-2-ylamino)-3- (methylcarbamoyl)pyridazin-4-ylamino)cyclohexylcarbamate: A solution of tert -butyl (1r, 4r)-4-(6-chloro-3-(methylcarbamoyl)pyridazin-4-ylamino)cyclohexylcarbamate (100 mg, 0.26 mmols, 1.0 eq) and 5-aminopyrazine-2-carbonitrile (37 mg, 0.31 mmols, 1.2eq) in dioxane (5 mL) was purged with N 2 for 5 minutes followed by addition of Cs 2 CO 3 (254 mg, 0.78mmols, 3.0 eq).the reaction mixture was purged again for 5 minutes.
- Step-4 Synthesis of: 4-((1r, 4r)-4-aminocyclohexylamino)-6-(5-cyanopyrazin-2- ylamino)-N-methylpyridazine-3-carboxamide: To a solution of tert-butyl (1r, 4r)-4-(6-(5- cyanopyrazin-2-ylamino)-3-(methylcarbamoyl)pyridazin-4-ylamino)cyclohexylcarbamate (70 mg, 0.150 mmols, 1.0 eq) in DCM (5.0 mL), TFA (0.5 mL) was added at 0°C and the reaction mixture was kept for
- Example-33 Synthesis of 4-(3-aminocyclobutylamino)-6-(5-cyanopyrazin-2-ylamino)-N- methylpyridazine-3-carboxamide, (Compound No.1.81) [297]
- Step-1 Synthesis of methyl 4-(3-(tert-butoxycarbonylamino)cyclobutylamino)-6- chloropyridazine-3-carboxylate: To a solution of methyl 4,6-dichloropyridazine-3- carboxylate (500 mg, 4.41 mmols, 1.0 eq) in THF (15 mL) was added TEA (609.8 mg, 6.03 mmols, 2.5 eq) followed by the addition of tert -butyl 3-aminocyclobutylcarbamate (494.8 mg, 2.65 mmols, 1.1 eq) at ambient temperature.
- TEA tert -butyl 3-aminocyclo
- reaction mixture was stirred at 90 °C for 3h. Progress of the reaction was monitored by TLC and LCMS. After completion, reaction mixture was quenched with ice water (10 mL) and extracted with ethyl acetate (100 mL ⁇ 3). The combined organic phase was washed with water (20 mL ⁇ 3) followed by brine wash (20 mL). Organic phase was separated and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude. The crude was triturated with pentane and the solid thus precipitated was filtered to afford 850 mg of the desired compound.
- Step-2 Synthesis of tert-butyl 3-(6-chloro-3-(methylcarbamoyl)pyridazin-4- ylamino)cyclobutylcarbamate: To a solution of methyl 4-(3-(tert- butoxycarbonylamino)cyclobutylamino)-6-chloropyridazine-3-carboxylate (600 mg, 1.68 mmols, 1.0 eq) was added methylamine (2M in methanol) (20 mL) at ambient temperature. Reaction mixture was stirred at RT for 30 minutes. Reaction was monitored by TLC and LCMS. After completion, reaction mixture was concentrated under reduced pressure.
- Step-3 Synthesis of tert-butyl 3-(6-(5-cyanopyrazin-2-ylamino)-3- (methylcarbamoyl)pyridazin-4-ylamino)cyclobutylcarbamate: To a solution of tert-butyl 3-(6-chloro-3-(methylcarbamoyl)pyridazin-4-ylamino)cyclobutylcarbamate (300 mg, 0.84 mmols, 1.0 eq) and 5-aminopyrazine-2-carbonitrile (80.9 mg, 0.67 mmols , 0.8 eq) in DMF (5 mL) was added Cs 2 CO 3 (821.5 mg, 2.52 mmols, 3.0 eq) at RT and the reaction mixture was purged using nitrogen for 10 minutes.
- Step-4 Synthesis of 4-(3-aminocyclobutylamino)-6-(5-cyanopyrazin-2-ylamino)- N-methylpyridazine-3-carboxamide: To a solution of tert -butyl 3-(6-(5-cyanopyrazin-2- ylamino)-3-(methylcarbamoyl)pyridazin-4-ylamino)cyclobutylcarbamate (150 mg, 0.34 mmols, 1.0 eq) in DCM (1 mL) was added TFA (0.8 mL) at 0 °C and the reaction mixture was stirred at RT for 2h.
- reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to afford crude. The crude was triturated with diethyl ether, filtered and purified by reverse phase chromatography to yield desired compound as a fomate salt; white solid (20 mg).
- Step-1 Synthesis of tert-butyl 2-((6-chloro-3-(thiophen-2-yl)pyridazin-4- ylamino)methyl)morpholine-4-carboxylate: To a solution of tert-butyl 2-((3,6- dichloropyridazin-4-ylamino)methyl)morpholine-4-carboxylate (500 mg, 1.377 mmols, 1.0 eq) and 4,4,5,5-tetramethyl-2-(thiophen-2-yl)-1,3,2-dioxaborolane (433 mg, 2.06 mmols, 1.5 eq) in dioxane : water (5 mL : 1.5 mL),
- reaction mixture was purged under nitrogen for 10 minutes.
- the reaction mixture was heated at 110 °C for 16 h.
- the progress of reaction was monitored by TLC and LCMS.
- the reaction mixture was passed through celite and ethyl acetate (2 ⁇ 20 mL) was added.
- the organic layer was washed with water (2 ⁇ 30 mL).
- the organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude.
- the crude reaction mixture was purified by combi flash using 70% ethyl acetate: hexane solvent system to obtain desired compound (220 mg) as a yellow solid.
- Step-2 Synthesis of tert-butyl 2-((6-(5-cyanopyrazin-2-ylamino)-3-(thiophen-2- yl)pyridazin-4-ylamino)methyl)morpholine-4-carboxylate: A solution of tert-butyl 2-((6- chloro-3-(thiophen-2-yl)pyridazin-4-ylamino)methyl)morpholine-4-carboxylate (220 mg, 0.536 mmols, 1.0 eq) and 5-aminopyrazine-2-carbonitrile (77 mg, 0.643 mmols, 1.2 eq) in DMF (4 mL) was purged with nitrogen for 5 minutes then Cs 2 CO 3 (522 mg, 1.608 mmols, 3.0 eq) was added and purged again for 5 minutes.
- Step-3 Synthesis of 5-(5-(morpholin-2-ylmethylamino)-6-(thiophen-2- yl)pyridazin-3-ylamino)pyrazine-2-carbonitrile: To a solution of tert-butyl 2-((6-(5- cyanopyrazin-2-ylamino)-3-(thiophen-2-yl)pyridazin-4-ylamino)methyl)morpholine-4- carboxylate (70 mg, 0.141 mmols, 1 eq) in DCM (3 mL), TFA (0.3 mL, 0.353 mmol, 2.5 eq) was added at 0 °C.
- Step-1 Synthesis of tert -butyl 2-((6-chloro-3-(thiazol-5-yl)pyridazin-4- ylamino)methyl)morpholine-4-carboxylate: To a solution of tert-butyl 2-((3,6- dichloropyridazin-4-ylamino)methyl)morpholine-4-carboxylate (500 mg, 1.37 mmols, 1.0 eq) and 5-(tributylstannyl)thiazole (618.2 mg, 1.65 mmols, 1.2 eq) in toluene (10mL) was added lithium chloride (58.0 mg, 1.37 mmols, 1.0 eq) and copper(
- Tetrakis(triphenylphosphine)palladium(0) (78.6 mg, 0.068 mmols, 0.05 eq) was added and the reaction mixture was again purged using nitrogen for 5 minutes. The resultant reaction mixture was stirred at 120 °C for 16h. Reaction was monitored by TLC and LCMS analyses. After completion, reaction mixture was cooled to RT. Ethyl acetate (100 mL) was added and organic phase was washed with water (20 mL ⁇ 3) followed by brine wash (20 mL). Organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude.
- Step-2 Synthesis of tert-butyl 2-((6-(5-cyanopyrazin-2-ylamino)-3-(thiazol-5- yl)pyridazin-4-ylamino)methyl)morpholine-4-carboxylate: To a solution of tert-butyl 2- ((6-chloro-3-(thiazol-5-yl)pyridazin-4-ylamino)methyl)morpholine-4-carboxylate (220 mg, 0.53 mmols, 1.0 eq) and 5-aminopyrazine-2-carbonitrile (51.38 mg, 0.42 mmols, 0.8 eq) in DMF (4 mL) was added Cs 2 CO 3 (518.4 mg, 1.59 mmol
- Step-3 Synthesis of 5-(5-(morpholin-2-ylmethylamino)-6-(thiazol-5-yl)pyridazin- 3-ylamino)pyrazine-2-carbonitrile: To a solution of tert -butyl 2-((6-(5-cyanopyrazin-2- ylamino)-3-(thiazol-5-yl)pyridazin-4-ylamino)methyl)morpholine-4-carboxylate (140 mg, 0.28 mmols, 1.0 eq) in DCM (2 mL) was added TFA (1 mL) at 0 °C and reaction was stirred at RT for 2h.
- Example-36 Synthesis of 4-(azetidin-3-ylmethylamino)-6-(5-cyanopyrazin-2-ylamino)-N- methylpyridazine-3-carboxamide, (Compound No.1.84)
- Step-1 Synthesis of methyl 4-((1-(tert-butoxycarbonyl)azetidin-3-yl)methyl amino)-6-chloropyridazine-3-carboxylate: To a solution of methyl 4,6-dichloropyridazine- 3-carboxylate (500 mg, 2.415 mmols, 1.0 eq) in THF (15 mL), diisopropylethylamine (1.5 mL, 3.622 mols, 1.5 eq) was added dropwise to the reaction mixture followed by addition of tert-butyl 3-(aminomethyl)azetidine-1-carboxylate (539 mg, 2.89 mmols, 1.2 eq).
- reaction mixture was refluxed for 2 h.
- Product formation was confirmed by TLC and LCMS.
- the reaction mixture was quenched with ice water (10 mL) and extracted with ethyl acetate (3 ⁇ 15 mL). Collective organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate and then concentrated under vacuo to get the crude. Then the crude was triturated with pentane to obtain desired compound (0.850 g) as an off white solid.
- Step-2 Synthesis of tert-butyl 3-((6-chloro-3-(methyl carbamoyl)pyridazin-4- ylamino) methyl)azetidine-1-carboxylate: To a solution of methyl 4-((1-(tert- butoxycarbonyl)azetidin-3-yl)methylamino)-6-chloropyridazine-3-carboxylate (250 mg, 0.696 mmols, 1.0 eq) in ACN (10 mL) was added K 2 CO 3 (289 mg, 2.096 mmols, 3.0 eq) followed by addition of methylamine (33% in water) (0.19 mL, 2.096 mmols, 3.0 eq).
- reaction mixture was stirred at RT for 8h. Product formation was confirmed by TLC and LCMS.
- the reaction mixture was quenched with ice water (20 mL) and extracted with ethyl acetate (3 ⁇ 15 mL). Collective organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to get the crude. Then the crude was triturated with pentane to obtain desired compound (250 mg).
- Step-3 Synthesis of tert-butyl 3-((6-(5-cyanopyrazin-2-ylamino)-3- (methylcarbamoyl) pyridazin-4-ylamino)methyl)azetidine-1-carboxylate: A solution of tert-butyl 3-((6-chloro-3-(methyl carbamoyl)pyridazin-4-ylamino)methyl) azetidine-1- carboxylate (200 mg, 0.56 mmols, 1 eq) and 5-aminopyrazine-2-carbonitrile (80 mg, 0.672 mmols, 1.2 eq) in dioxane (5 mL) was purged with nitrogen for 5 minutes then Cs 2 CO 3 (550 mg, 1.69 mmols, 3 eq) was added and purged again for 5 minutes.
- Step-4 Synthesis of 4-(azetidin-3-ylmethylamino)-6-(5-cyanopyrazin-2-ylamino)- N-methylpyridazine-3-carboxamide: To a solution of tert-butyl 3-((6-(5-cyanopyrazin-2- ylamino)-3-(methylcarbamoyl)pyridazin-4-ylamino)methyl)azetidine-1-carboxylate (100 mg, 0.227 mmols, 1 eq) in DCM (5 mL), TFA (0.5 mL) was added at 0 °C.
- Example-37 Synthesis of 4-(3-aminocyclohexylamino)-6-(5-cyanopyrazin-2-ylamino)-N- methylpyridazine-3-carboxamide, (Compound No.1.85)
- Step-1 Synthesis of tert-butyl 3-aminocyclohexylcarbamate: To a solution of cyclohexane-1,3-diamine (1.0 g, 8.75 mmols, 1eq) in 20 mL CHCl 3 at 0 °C was added di-tert- butyl dicarbonate (0.38 g, 1.75 mmols, 0.2 eq). The ice bath was removed and after 0.5 h, the reaction mixture was washed with saturated NaHCO 3 (3 ⁇ 20 mL) and washed with brine (2 ⁇ 20 mL).
- Step-2 Synthesis of methyl 4-(3-(tert-butoxycarbonylamino)cyclohexylamino)-6- chloropyridazine-3-carboxylate: To a solution of methyl 4,6-dichloropyridazine-3- carboxylate (310 mg, 1.49 mmols, 0.8 eq) in THF (10 mL) was added triethylamine (470 mg, 4.65 mmols, 2.5 eq) followed by the addition of tert-butyl 3-aminocyclohexylcarbamate (400 mg, 1.86 mmols, 1.0 eq) at ambient temperature.
- reaction mixture was stirred at 90 °C for 2h. Reaction was monitored by TLC and LCMS. After completion, reaction mixture was quenched with ice water (10 mL) and extracted with ethyl acetate (50 mL ⁇ 3). Combined organic phase was washed with water (20 mL ⁇ 3) followed by brine wash (20 mL). Organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford crude. Crude was triturated with pentane and the solid thus precipitated was filtered to afford the desired compound (315mg).
- Step-3 Synthesis of tert-butyl 3-(6-chloro-3-(methylcarbamoyl)pyridazin-4- ylamino)cyclohexylcarbamate: To methyl 4-(3-(tert- butoxycarbonylamino)cyclohexylamino)-6-chloropyridazine-3-carboxylate (310 mg, 0.8 mmols, 1.0 eq) was added methylamine (2M in methanol) (6 mL) at ambient temperature. Reaction mixture was stirred at RT for 30 minutes. Reaction was monitored by TLC and LCMS. After completion, reaction mixture was concentrated under reduced pressure.
- Step-4 Synthesis of tert-butyl 3-(6-(5-cyanopyrazin-2-ylamino)-3- (methylcarbamoyl)pyridazin-4-ylamino)cyclohexylcarbamate: A solution of tert-butyl 3- (6-chloro-3-(methylcarbamoyl)pyridazin-4-ylamino)cyclohexylcarbamate (270 mg, 0.70 mmols, 1.0 eq) and 5-aminopyrazine-2-carbonitrile (67.5 mg, 0.56 mmols, 0.8 eq) in DMF (5 mL) was added Cs 2 CO 3 (687.5 mg, 2.10mmols, 3 eq) at RT and reaction mixture was purged under nitrogen for 10 minutes.
- reaction mixture was again purged using nitrogen for 5 minutes. Reaction mixture was stirred at 180 °C for 16h. Reaction was monitored by TLC and LCMS. After completion, reaction mixture was cooled to RT. Ethyl acetate (100 mL) was added and organic phase was washed with water (20 mL ⁇ 3) followed by brine wash (20 mL). Organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford crude. Crude was triturated with pentane and filtered to afford the desired compound (220 mg).
- Step-5 Synthesis of 4-(3-aminocyclohexylamino)-6-(5-cyanopyrazin-2-ylamino)- N-methylpyridazine-3-carboxamide: To a solution of tert-butyl 3-(6-(5-cyanopyrazin-2- ylamino)-3-(methylcarbamoyl)pyridazin-4-ylamino)cyclohexylcarbamate (220 mg,0.49 mmol, 1.0 eq) in DCM (3 mL) was added TFA (1.5 mL) at 0°C and reaction was stirred at RT for 1h.
- Example-38 Synthesis of 4-(3-aminocyclohexylamino)-6-(5-cyanopyrazin-2-ylamino)-N- methylpyridazine-3-carboxamide, (Compound No.1.86)
- Step-1 Synthesis of methyl 4-(2-(1-(tert-butoxycarbonyl)piperidin-2- yl)ethylamino)-6-chloropyridazine-3-carboxylate: To a solution of methyl 4,6- dichloropyridazine-3-carboxylate (500 mg, 2.41 mmols, 1.0 eq) in THF (15 mL) was added triethyl amine (607.8 mg, 6.02 mmols, 2.5 eq) followed by the addition of tert-butyl 2-(2- aminoethyl)piperidine-1-carboxylate (606.6 mg, 2.65 mmols, 1.1 eq) at ambient temperature.
- reaction mixture was stirred at 90°C for 2h. Reaction was monitored by TLC and LCMS. After completion, reaction mixture was quenched with ice water (10 mL) and extracted with ethyl acetate (100 mL ⁇ 3). Combined organic phase was washed with water (20 mL ⁇ 3) followed by brine wash (20 mL). Organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford crude. Crude was triturated with pentane and the solid thus precipitated was filtered to afford the desired compound (1.1g).
- Step-2 Synthesis of tert-butyl 2-(2-(6-chloro-3-(methylcarbamoyl)pyridazin-4- ylamino)ethyl)piperidine-1-carboxylate: Methyl amine (2M in methanol) (20 mL) was added to a solution of methyl 4-(2-(1-(tert-butoxycarbonyl)piperidin-2-yl)ethylamino)-6- chloropyridazine-3-carboxylate (1.0 g, 2.51 mmols, 1.0 eq.) in methanol (10 mL) at ambient temperature.
- reaction mixture was stirred at RT for 30 minute. Reaction was monitored by TLC and LCMS. After completion, reaction mixture was concentrated under reduced pressure. Ethyl acetate (200 mL) was added and organic phase was washed with water (20 mL ⁇ 3) followed by brine wash (20 mL). Organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford crude. Crude was triturated with pentane and the solid thus precipitated was filtered to afford 800 mg of desired compound as an off white solid.
- Step-3 Synthesis of tert-butyl 2-(2-(6-(5-cyanopyrazin-2-ylamino)-3- (methylcarbamoyl)pyridazin-4-ylamino)ethyl)piperidine-1-carboxylate: A solution of tert-butyl 2-(2-(6-chloro-3-(methylcarbamoyl)pyridazin-4-ylamino)ethyl)piperidine-1- carboxylate (300 mg, 0.75 mmols , 1.0 eq) and 5-aminopyrazine-2-carbonitrile (72.54 mg, 0.60 mmols, 0.8 eq) in DMF (5 mL) was added Cs 2 CO 3 (738.4 mg, 2.26 mmols, 3 eq) at RT and the reaction mixture was purged under nitrogen for 10 minutes.
- Step-4 Synthesis of 4-(3-aminocyclohexylamino)-6-(5-cyanopyrazin-2-ylamino)- N-methylpyridazine-3-carboxamide: To a solution of tert-butyl 2-(2-(6-(5-cyanopyrazin-2- ylamino)-3-(methylcarbamoyl)pyridazin-4-ylamino)ethyl)piperidine-1-carboxylate (210 mg, 0.43 mmols, 1.0 eq) in DCM (2 mL) was added TFA (1.2 mL) at 0 °C and the reaction mixture was stirred at RT for 1h.
- Step-1 Synthesis of 6-(5-cyanopyrazin-2-ylamino)-N-methyl-4-(pyrrolidin-2- ylmethylamino)pyridazine-3-carboxamide, (Compound No.1.87)
- Step-1 Synthesis of methyl 4-((1-(tert-butoxycarbonyl)pyrrolidin-2- yl)methylamino)-6-chloropyridazine-3-carboxylate: To a solution of methyl 4,6- dichloropyridazine-3-carboxylate (800 mg, 8.86 mmols, 1.0 eq) in THF (30 mL) was added triethylamine (1.35 mL, 9.65 mmol, 2.5 eq) followed by the addition of tert-butyl 2- (aminomethyl)pyrrolidine-1-carboxylate (851.4 mg, 4.25 mmols, 1.1 eq) at ambient temperature.
- reaction mixture was stirred at 90 °C for 3h. Reaction was monitored by TLC and LCMS. After completion, reaction mixture was quenched with ice water (10 mL) and extracted with ethyl acetate (100 mL ⁇ 3). Combined organic phase was washed with water (20 mL ⁇ 3) followed by brine wash (20 mL). Organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford crude. Crude was triturated with pentane and the solid thus precipitated was filtered to afford the desired compound (1.7g).
- Step-2 Synthesis of tert-butyl 2-((6-chloro-3-(methylcarbamoyl)pyridazin-4- ylamino)methyl)pyrrolidine-1-carboxylate: To a solution of methyl 4-((1-(tert- butoxycarbonyl)pyrrolidin-2-yl)methylamino)-6-chloropyridazine-3-carboxylate (1.7g, 4.59 mmols, 1.0 eq) in methanol (10 mL) was added methyl amine (2M in methanol) (30 mL) at ambient temperature. Reaction mixture was stirred at RT for 30 minute.
- reaction was monitored by TLC and LCMS. After completion, reaction mixture was concentrated under reduced pressure. Ethyl acetate (300 mL) was added and organic phase was washed with water (20 mL ⁇ 3) followed by brine wash (20 mL). Organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford crude. Crude was triturated with pentane and the solid thus precipitated was filtered to afford the desired compound (1.2g).
- Step-3 Synthesis of tert-butyl 2-((6-(5-cyanopyrazin-2-ylamino)-3- (methylcarbamoyl)pyridazin-4-ylamino)methyl)pyrrolidine-1-carboxylate: A solution of tert-butyl 2-((6-chloro-3-(methylcarbamoyl)pyridazin-4-ylamino)methyl)pyrrolidine-1- carboxylate (200 mg, 0.54mmols, 1.0 eq) and 5-aminopyrazine-2-carbonitrile (52.03 mg, 0.43 mmols, 0.8 eq) in DMF (4 mL) was added Cs 2 CO 3 (530 mg, 1.62 mmols, 3 eq) at RT and the reaction mixture was purged under nitrogen for 10 minutes.
- Step-4 Synthesis of 6-(5-cyanopyrazin-2-ylamino)-N-methyl-4-(pyrrolidin-2- ylmethylamino)pyridazine-3-carboxamide: To a solution of tert-butyl 2-((6-(5- cyanopyrazin-2-ylamino)-3-(methylcarbamoyl)pyridazin-4-ylamino)methyl)pyrrolidine-1- carboxylate (180 mg, 0.39 mmols, 1.0 eq) in DCM (2 mL) was added TFA (1.0 mL) at 0 °C and reaction was stirred at RT for 1h.
- Step-1 Synthesis of methyl 4-(2-(1-(tert-butoxycarbonyl)azetidin-3- yl)ethylamino)-6-chloropyridazine-3-carboxylate: To a solution of methyl 4,6- dichloropyridazine-3-carboxylate (300 mg, 1.44 mmols, 1.0 eq) in THF (15 mL), DIPEA (0.378 mL, 2.17 mmols, 1.5 eq) was added dropwise to the reaction mixture followed by addition of tert-butyl 3-(2-aminoethyl)azetidine-1-carboxylate (345 mg, 1.72 mmols,
- reaction mixture was refluxed for 2 h.
- Product formation was confirmed by TLC and LCMS.
- the reaction mixture was quenched with ice water (10 mL) and extracted with ethyl acetate (3 ⁇ 15 mL). Collective organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to get the crude. Then the crude was triturated with pentane to obtain the desired compound (0.530 g) as an off-white solid.
- Step-2 Synthesis of tert-butyl 3-(2-(6-chloro-3-(methylcarbamoyl) pyridazin-4- ylamino) ethyl) azetidine-1-carboxylate: To a solution methyl 4-(2-(1-(tert- butoxycarbonyl)azetidin-3-yl)ethylamino)-6-chloropyridazine-3-carboxylate (300 mg, 0.810 mmols, 1.0 eq) in ACN (10 mL) was added K 2 CO 3 (335 mg, 2.43 mmol, 3.0eq) followed by addition of methylamine (0.225 mg, 2.43 mmols, 3.0 eq).
- reaction mixture was stirred at RT for 16h. Product formation was confirmed by TLC and LCMS.
- the reaction mixture was quenched with ice water (20 mL) and extracted with ethyl acetate (3 ⁇ 15 mL). Collective organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to get the crude. The crude was triturated with pentane to obtain desired compound (250 mg).
- Step-3 Synthesis of tert-butyl 3-(2-(6-(5-cyanopyrazin-2-ylamino)-3- (methylcarbamoyl) pyridazin-4-ylamino)ethyl)azetidine-1-carboxylate: A solution of tert-butyl 3-(2-(6-chloro-3-(methylcarbamoyl) pyridazin-4-ylamino) ethyl) azetidine-1- carboxylate (200 mg, 0.542 mmols, 1.0 eq) and 5-aminopyrazine-2-carbonitrile (78 mg, 0.650 mmols, 1.2 eq) in DMF (5 mL) was purged with nitrogen for 5 minutes then Cs 2 CO 3 (530 mg, 1.626 mmols, 3.0 eq) was added and purged again for 5 minutes.
- Step-4 Synthesis of 4-(2-(azetidin-3-yl)ethylamino)-6-(5-cyanopyrazin-2- ylamino)-N-methylpyridazine-3-carboxamide: To a solution of tert-butyl 3-(2-(6-(5- cyanopyrazin-2-ylamino)-3-(methylcarbamoyl)pyridazin-4-ylamino)ethyl)azetidine-1- carboxylate (100 mg, 0.220 mmols, 1 eq) in DCM (5 mL), TFA (0.5 mL) was added at 0 °C and the resulting reaction mixture was stirred for 6h.
- Step-1 Synthesis of 6-(5-cyanopyrazin-2-ylamino)-N-methyl-4-(2-(pyrrolidin-2-yl) ethylamino)pyridazine-3-carboxamide, (Compound No.1.89)
- Step-1 Synthesis of methyl 4-(2-(1-(tert-butoxycarbonyl)pyrrolidin-2- yl)ethylamino)-6-chloropyridazine-3-carboxylate: To a solution of methyl 4,6- dichloropyridazine-3-carboxylate (500 mg, 2.415 mmols, 1.0 eq) in THF (15 mL), diisopropylethylamine (0.631 mL, 3.62 mmols, 1.5 eq) was added dropwise to the reaction mixture.
- tert-butyl 2-(2-aminoethyl)pyrrolidine-1-carboxylate (621 mg, 2.89 mmols, 1.2 eq) was added and the resulting reaction mixture was refluxed for 2 h.
- Product formation was confirmed by TLC and LCMS.
- the reaction mixture was quenched with ice water (10 mL) and extracted with ethyl acetate (3 ⁇ 15 mL). Collective organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to get the crude. Then the crude was triturated with pentane to obtain the desired compound (0.850 g) as cream color solid.
- Step-2 Synthesis of tert-butyl 2-(2-(6-chloro-3-(methylcarbamoyl) pyridazin-4- ylamino) ethyl) pyrrolidine-1-carboxylate: To a solution methyl 4-(2-(1-(tert- butoxycarbonyl)pyrrolidin-2-yl)ethylamino)-6-chloropyridazine-3-carboxylate (200 mg, 0.519 mmols, 1.0 eq) in ACN (10 mL) was added K 2 CO 3 (215 mg, 1.55 mmols, 3.0 eq) followed by addition of methylamine (0.114 mg, 1.55 mmols, 3.0 eq) and the reaction mixture was kept for stirring at RT for 8 h.
- Step-3 Synthesis of tert-butyl 2-(2-(6-(5-cyanopyrazin-2-ylamino)-3- (methylcarbamoyl) pyridazin-4-ylamino)ethyl)pyrrolidine-1-carboxylate: A solution of tert-butyl 2-(2-(6-chloro-3-(methylcarbamoyl)pyridazin-4-ylamino)ethyl)pyrrolidine-1- carboxylate (200 mg, 0.52 mmols, 1.0 eq) and 5-aminopyrazine-2-carbonitrile(75 mg, 0.625 mmols, 1.2 eq) in DMF (5 mL) was purged with nitrogen for 5 minutes then Cs 2 CO 3 (508 mg, 1.56 mmols, 3.0 eq) was added and the reaction mixture was purged again for 5 minutes.
- Step-4 Synthesis of 6-(5-cyanopyrazin-2-ylamino)-N-methyl-4-(2-(pyrrolidin-2- yl)ethylamino) pyridazine-3-carboxamide: To a solution of tert-butyl 2-(2-(6-(5- cyanopyrazin-2-ylamino)-3-(methylcarbamoyl)pyridazin-4-ylamino) ethyl)pyrrolidine-1- carboxylate (100 mg, 0.213 mmols, 1 eq) in DCM (5 mL), TFA (0.5 mL) was added at 0 °C.
- Example-42 Synthesis of 4-(3-aminobicyclo [1.1.1] pentan-1-ylamino)-6-(5-cyanopyrazin-2- ylamino)-N-methylpyridazine-3-carboxamide, (Compound No.1.90) [332]
- Step-1 Synthesis of methyl 4-(3-(tert-butoxycarbonylamino) bicyclo [1.1.1] pentan-1-ylamino)-6-chloropyridazine-3-carboxylate: To a solution of methyl 4,6- dichloropyridazine-3-carboxylate (500 mg, 2.415 mmols, 1.0 eq) in THF (15 mL), trimethylamine (0.58 mL, 3.62 mmols, 1.5 eq) was added drop wise followed by addition of tert-butyl 3-aminobicyclo[1.1.1]pentan-1-ylcarbamate (574 mg, 2.89 mmols,
- reaction mixture was stirred at RT for 16 h. Product formation was confirmed by TLC and LCMS.
- the reaction mixture was quenched with ice water (10 mL) and extracted with ethyl acetate (3 ⁇ 50 mL). Collective organic layer was washed with brine (20 mL) and dried over sodium sulfate and then concentrated under reduced pressure to get the crude. The crude was triturated with pentane to get the desired compound as an off-white solid (0.968 g).
- Step-2 Synthesis of tert-butyl 3-(6-chloro-3-(methylcarbamoyl) pyridazin-4- ylamino) bicyclo [1.1.1] pentan-1-ylcarbamate: To a solution of methyl 4-(3-(tert- butoxycarbonylamino) bicyclo [1.1.1] pentan-1-ylamino)-6-chloropyridazine-3-carboxylate (800 mg, 2.173 mmols, 1.0 eq) in ACN (15 ml) was added methyl amine (33%) (0.60 mL, 6.519 mmols, 3.0 eq) and then Al(CH 3 ) 3 (0.312 mL, 4.36 mmols, 2.0 eq) was added and kept for stirring at RT for 8 h.
- Step-3 Synthesis of tert-butyl 3-(6-(5-cyanopyrazin-2-ylamino)-3- (methylcarbamoyl) pyridazin-4-ylamino) bicyclo [1.1.1]
- pentan-1-ylcarbamate A solution of tert-butyl 3-(6-chloro-3-(methylcarbamoyl) pyridazin-4-ylamino) bicyclo [1.1.1] pentan-1-ylcarbamate (500 mg, 1.367 mmols, 1.0 equi) and 5-aminopyrazine-2-carbonitrile (192 mg,1.634 mmols, 1.0 eq) in dioxane (5 mL) was purged with N 2 for 5 minutes then Cs 2 CO 3 (1.33 g, 4.101mmols, 3.0 eq) was added and purged again for 5 minutes.
- Step-4 Synthesis 4-(3-aminobicyclo [1.1.1] pentan-1-ylamino)-6-(5- cyanopyrazin-2-ylamino)-N-methylpyridazine-3-carboxamide: To a solution of tert-butyl 3-(6-(5-cyanopyrazin-2-ylamino)-3-(methylcarbamoyl) pyridazin-4-ylamino) bicyclo [1.1.1] pentan-1-ylcarbamate (110 mg, 0.243 mmols, 1 eq) in DCM (5.0 mL), TFA (0.5 mL) was added at 0°C and kept for stirring for 2h.
- Step-1 Synthesis of tert-butyl 3-(6-chloro-3-(methoxycarbonyl)pyridazin-4- ylamino)azepane-1-carboxylate: To a solution of methyl 4,6-dichloropyridazine-3- carboxylate (400 mg, 1.93 mmols, 1.0 eq) in THF (14 mL) was added triethylamine (487.3 mg, 4.82 mmols, 2.5 eq) followed by the addition of tert-butyl 3-aminoazepane-1- carboxylate (456 mg, 2.12 mmols, 1.1 eq) at ambient temperature.
- reaction mixture was stirred at 90 °C for 3h. Reaction was monitored by TLC and LCMS. After completion, reaction mixture was quenched with ice water (10 mL) and extracted with ethyl acetate (3 ⁇ 50 mL). Combined organic phase was washed with water (3 ⁇ 20 mL) followed by brine wash (20 mL). Organic phase was dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to afford crude.
- Step-2 Synthesis of tert-butyl 3-(6-chloro-3-(methylcarbamoyl)pyridazin-4- ylamino)azepane-1-carboxylate: To a solution of tert-butyl 3-(6-chloro-3- (methoxycarbonyl)pyridazin-4-ylamino)azepane-1-carboxylate (900 mg, 2.34 mmols, 1.0 eq) in methanol (10 mL) was added methylamine (2M in methanol) (18 mL) at ambient temperature.
- reaction mixture was stirred at RT for 30 minutes. Reaction was monitored by TLC and LCMS. After completion, reaction mixture was concentrated under reduced pressure. Ethyl acetate (100 mL) was added and organic phase was washed with water (3 ⁇ 20 mL) followed by brine wash (20 mL). Organic phase was dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to afford crude.
- Step-3 Synthesis of tert-butyl 3-(6-(5-cyanopyrazin-2-ylamino)-3- (methylcarbamoyl)pyridazin-4-ylamino)azepane-1-carboxylate: To a solution of tert- butyl 3-(6-chloro-3-(methylcarbamoyl)pyridazin-4-ylamino)azepane-1-carboxylate (300 mg, 0.78 mmols, 1.0 eq) and 5-aminopyrazine-2-carbonitrile (75 mg, 0.62 mmols , 0.8 eq) in DMF (5 mL) was added Cs 2 CO 3 (763.8 mg, 2.34 mmols, 3 eq) at RT and reaction mixture was purged under nitrogen
- Step-4 Synthesis of 4-(azepan-4-ylamino)-6-(5-cyanopyrazin-2-ylamino)-N- methylpyridazine-3-carboxamide: To a solution of tert-butyl 3-(6-(5-cyanopyrazin-2- ylamino)-3-(methylcarbamoyl)pyridazin-4-ylamino)azepane-1-carboxylate (180 mg, 0.48mmols, 1.0 eq) in DCM (3 mL) was added TFA (1.5 mL) at 0°C and the reaction was stirred at RT for 2h.
- reaction was monitored by TLC and LCMS. After completion, reaction mixture was concentrated under reduced pressure to afford crude. Then the reaction mixture was concentrated under reduced pressure to get the crude. The crude was purified by reverse phase chromatography to yield desired compound as a formate salt and a white solid (62 mg).
- Example-44 Synthesis of 4-(azepan-4-ylamino)-6-(5-cyanopyrazin-2-ylamino)-N- methylpyridazine-3-carboxamide (Compound No.1.92)
- Step-1 Synthesis of tert-butyl 4-(6-chloro-3-(methoxycarbonyl)pyridazin-4- ylamino)azepane-1-carboxylate: To a solution of methyl 4,6-dichloropyridazine-3- carboxylate (400mg, 1.93 mmols, 1.0 eq) in THF (14 ml) was added triethylamine (487.3 mg, 4.82 mmols, 2.5 eq) followed by the addition of tert-butyl 4-aminoazepane-1-carboxylate (456 mg, 2.12 mmols, 1.1 eq) at ambient temperature.
- reaction mixture was stirred at 90 °C for 3h. Reaction was monitored by TLC and LCMS. After completion, reaction mixture was quenched with ice water (10 mL) and extracted with Ethyl acetate (3 ⁇ 100 mL). Combined organic phase was washed with water (3 ⁇ 20 mL) followed by brine wash (2 mL). Organic phase was dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to afford crude. Crude was triturated with pentane and solid precipitated was filtered to afford 750 mg of desired compound.
- Step-2 Synthesis of tert-butyl 4-(6-chloro-3-(methylcarbamoyl)pyridazin-4- ylamino)azepane-1-carboxylate: To a solution of tert-butyl 4-(6-chloro-3- (methoxycarbonyl)pyridazin-4-ylamino)azepane-1-carboxylate (750 mg, 1.95 mmols, 1.0 eq.) in methanol (10 mL) was added methylamine (2M in methanol) (15 mL) at ambient temperature. Reaction mixture was stirred at RT for 30 minutes.
- reaction was monitored by TLC and LCMS. After completion, reaction mixture was concentrated under reduced pressure. Ethyl acetate (200 mL) was added and organic phase was washed with water (3 ⁇ 20 mL) followed by brine wash (20 mL). Organic phase was dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to afford crude. Crude was triturated with pentane and solid precipitated was filtered to afford 620 mg of desired compound.
- Step-3 Synthesis of tert-butyl 4-(6-(5-cyanopyrazin-2-ylamino)-3- (methylcarbamoyl)pyridazin-4-ylamino)azepane-1-carboxylate: To a solution of tert- butyl 4-(6-chloro-3-(methylcarbamoyl)pyridazin-4-ylamino)azepane-1-carboxylate (250 mg, 0.65mmols , 1.0 eq) and 5-aminopyrazine-2-carbonitrile (62.5 mg, 0.52mmols , 0.8 eq) in DMF (4 mL) was added Cs 2 CO 3 (636.6 mg, 1.95 mmols, 3 eq) at RT and the reaction mixture was purged under nitrogen for 10 minutes.
- Step-4 Synthesis of 4-(azepan-4-ylamino)-6-(5-cyanopyrazin-2-ylamino)-N- methylpyridazine-3-carboxamide: To a solution of tert-butyl 4-(6-(5-cyanopyrazin-2- ylamino)-3-(methylcarbamoyl)pyridazin-4-ylamino)azepane-1-carboxylate (150 mg, 0.32 mmols, 1.0 eq) in DCM (2 mL) was added TFA (0.9 mL) at 0°C and reaction was stirred at RT for 2h.
- Example-45 Synthesis of 5-(5-(3-aminocyclohexylamino)-6-(trifluoromethyl)pyridazin-3- ylamino)pyrazine-2-carbonitrile (Compound No.1.93)
- Step-1 Synthesis of 4-(3-(tert-butoxycarbonylamino)cyclohexylamino)-6- chloropyridazine-3-carboxylic acid: To the solution of methyl 4-(3-(tert- butoxycarbonylamino)cyclohexylamino)-6-chloropyridazine-3-carboxylate (1.2 g, 3.12 mmol, 1 eq) in THF (16 mL) was added lithium hydroxide (262.5 mg, 6.25 mmol, 2 eq) followed by water (4 mL) at ambient temperature.
- reaction mixture was stirred at RT for 2h. Reaction was monitored by TLC and LCMS. After completion, reaction mixture was concentrated and citric acid aqueous solution was added till pH ⁇ 4-5. Ethyl acetate (100 mL) was added and organic phase was washed with water (20 mL) followed by brine wash (20 mL). Organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude.
- Step-2 Synthesis of tert-butyl 3-(6-chloro-3-iodopyridazin-4- ylamino)cyclohexylcarbamate: To the solution of 4-(3-(tert- butoxycarbonylamino)cyclohexylamino)-6-chloropyridazine-3-carboxylic acid (1.1 g, 2.96mmol, 1eq) in ACN (20 mL) was added iodine (2.25 g, 8.89mmol, 3eq) followed by K PO (75 o 3 4 4mg, 3.
- reaction mixture was stirred at 90 C for 4h. Reaction was monitored by TLC and LCMS. After completion, reaction mixture was quenched with sodium thiosulphate aqueous solution (20 mL) and extracted with Ethyl acetate (3 ⁇ 100 mL). Combined organic phase was washed with water (3 ⁇ 20 mL) followed by brine wash (20 mL). Organic phase was dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to afford crude. Crude was purified by combiflash using ethyl acetate: hexane (0-50%) to afford 440 mg of the desired compound.
- Step-3 Synthesis of tert-butyl 3-(6-chloro-3-(trifluoromethyl)pyridazin-4- ylamino)cyclohexylcarbamate: To the solution of tert-butyl 3-(6-chloro-3-iodopyridazin-4- ylamino)cyclohexylcarbamate (420 mg, 0.92mmol, 1eq) in DMF (10 mL) was added 1,10- (Phenanthroline trifluoromethyl) copper (I) (349 mg, 1.1mmol, 1.2eq) at ambient temperature. Reaction mixture was stirred at 90 oC for 5h.
- Step-4 Synthesis of tert-butyl 3-(6-(5-cyanopyrazin-2-ylamino)-3- (trifluoromethyl)pyridazin-4-ylamino)cyclohexylcarbamate: A solution of tert-butyl 3-(6- chloro-3-(trifluoromethyl)pyridazin-4-ylamino)cyclohexylcarbamate (230 mg, 0.58mmol, 1.0 eq) and 5-aminopyrazine-2-carbonitrile (60 mg, 0.46mmol , 0.8 eq) in DMF (5 mL) was added Cs 2 CO 3 (570 mg, 1.74 mmol, 3 eq) at RT and the reaction mixture was purged under nitrogen for 10 minutes.
- Step-5 Synthesis of 5-(5-(3-aminocyclohexylamino)-6- (trifluoromethyl)pyridazin-3-ylamino)pyrazine-2-carbonitrile: To a solution of tert-butyl 3-(6-(5-cyanopyrazin-2-ylamino)-3-(trifluoromethyl)pyridazin-4- ylamino)cyclohexylcarbamate (200 mg, 0.41mmol, 1.0 eq) in DCM (3 mL) was added TFA (1.2 mL) at 0°C and reaction was stirred at RT for 1h.
- Step-1 Synthesis of 6-(5-cyanopyrazin-2-ylamino)-4-((4-fluoropiperidin-4-yl) methylamino)-N-methylpyridazine-3-carboxamide, (Compound No.1.94)
- Step-1 Synthesis of methyl 4-((1-(tert-butoxycarbonyl)-4-fluoropiperidin-4-yl) methyl amino)-6-chloropyridazine-3-carboxylate: To a solution of methyl 4, 6- dichloropyridazine-3-carboxylate (300 mg, 1.44 mmol, 1.0 eq) in THF (15 mL), triethylamine (0.304 mL, 2.17 mmol, 1.5 eq) was added drop wise followed by addition of tert-butyl 4-(amino methyl)-4-fluoropiperidine-1-carboxylate (400 mg, 1.72 mmol, 1.2 eq).
- the rection mixture was kept for stirring at RT for 16 h. Product formation was confirmed by TLC and LCMS.
- the reaction mixture was quenched with ice water (10 mL) and extracted with ethyl acetate (3 ⁇ 50 mL). Collective organic layer was washed with brine (20 mL) and dried over sodium sulfate and then concentrated under reduced pressure to get the crude. Then the crude was triturated with pentane to get the desired compound as an off-white solid (500 mg).
- Step-2 Synthesis of tert-butyl 4-((6-chloro-3-(methylcarbamoyl) pyridazin-4- ylamino) methyl)-4-fluoropiperidine-1-carboxylate: To a solution of methyl 4-((1-(tert- butoxycarbonyl)-4-fluoropiperidin-4-yl) methyl amino)-6-chloropyridazine-3-carboxylate (500 mg, 1.24 mmol, 1.0 eq) in ACN (15 ml) was added methyl amine (33% solution) (0.346 mL, 3.72 mmol, 3.0 eq) followed by addition of trimethylaluminium (0.357 mL, 2.48 mmol, 2.0eq) and the reaction mixture was kept for stirring at RT for 8 h.
- Step-3 Synthesis of tert-butyl 4-((6-(5-cyanopyrazin-2-ylamino)-3- (methylcarbamoyl) pyridazin-4-ylamino) methyl)-4-fluoropiperidine-1-carboxylate: A solution of tert-butyl 4-((6-chloro-3-(methylcarbamoyl) pyridazin-4-ylamino) methyl)-4- fluoropiperidine-1-carboxylate (250 mg, 0.621 mmol, 1.0 eq) and 5-aminopyrazine-2- carbonitrile (74 mg, 0.621 mmol, 1.0 eq) in dioxane (5 mL) was purged with N 2 for 5 minutes then Cs 2 CO 3 (606 mg, 1.86 mmol, 3.0eq) was added and purged again for 5 minutes.
- Step-4 Synthesis of 6-(5-cyanopyrazin-2-ylamino)-4-((4-fluoropiperidin-4-yl) methylamino)-N-methylpyridazine-3-carboxamide: To a solution of tert-butyl 4-((6-(5- cyanopyrazin-2-ylamino)-3-(methylcarbamoyl) pyridazin-4-ylamino) methyl)-4- fluoropiperidine-1-carboxylate (110 mg, 0.226 mmol, 1 eq) in DCM (5.0 mL), TFA (0.5 mL) was added at 0 °C and kept for stirring for 2h.
- Example-47 Synthesis of 4-(3-aminocyclohexylamino)-6-(5-cyanopyrazin-2-ylamino)-N- methylpyridazine-3-carboxamide (Compound No.1.95)
- Step-1 Synthesis of methyl 4-(4-(tert-butyldimethylsilyloxy)cyclohexylamino)-6- chloropyridazine-3-carboxylate: To a solution of methyl 4, 6-dichloropyridazine-3- carboxylate (350 mg, 1.690 mmol, 1.0 eq) in THF (15 mL), TEA (0.355 mL, 2.53 mmol, 1.5 eq) was added drop-wise to the reaction mixture then 4-(tert-butyl dimethylsilyloxy) cyclohexanamine (464 mg, 2.08 mmol, 1.2 eq) was added and kept for stirring at 900C for 6 h.
- Step-2 Synthesis of 4-(4-(tert-butyldimethylsilyloxy) cyclohexylamino)-6-chloro- N-methylpyridazine-3-carboxamide: To a solution of methyl 4-(4-(tert- butyldimethylsilyloxy) cyclohexylamino)-6-chloropyridazine-3-carboxylate (325 mg, 0.814 mmol, 1.0 eq) in THF (10 mL) was added methyl amine (33%) (0.1 mL, 0.98 mmol, 3.0 eq) followed by addition of trimethyl aluminium, 2M solution (0.407 mL,0.814 mmol,1.0equiv) and the reaction mixture was kept for stirring at RT for 8 h.
- Step-3 Synthesis of 4-(4-(tert-butyldimethylsilyloxy) cyclohexylamino)-6-(5- cyanopyrazin-2-ylamino)-N-methylpyridazine-3-carboxamide: A solution of 4-(4-(tert- butyldimethylsilyloxy) cyclohexylamino)-6-chloro-N-methylpyridazine-3-carboxamide (300 mg, 0.753 mmol, 1.0 eq) and 5-aminopyrazine-2-carbonitrile (108 mg, 0.904 mmol, 1.2 eq) in dioxane (5 mL) was purged with N 2 for 5 minutes then Cs 2 CO 3 (0.735 g, 2.59 mmol, 3.0eq) was added and purged again for 5 minutes.
- Step-4 Synthesis of 4-(3-aminocyclohexylamino)-6-(5-cyanopyrazin-2-ylamino)- N-methylpyridazine-3-carboxamide: To a solution of 4-(4-(tert-butyldimethylsilyloxy) cyclohexylamino)-6-(5-cyanopyrazin-2-ylamino)-N-methylpyridazine-3-carboxamide (110 mg, 0.227 mmol, 1.0 eq) in DCM (5.0 mL), TBAF (0.5 mL) was added at 0°C and kept for stirring for 6 h.
- CHK-1 kinase assay [357] IC 50 values of compounds for inhibition of CHK-1 kinase or percent inhibition at defined concentrations is determined by Z-LYTETM based TR-FRET assay. Kinase reactions are performed in a 10 ⁇ L volume in low-volume 384-well plates. The concentration of substrate (Ser Thr 19) is maintained at 2 ⁇ M in the assay, and the kinase reaction buffer consisted of 50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl2, 1 mM EGTA, 2 mM DTT.
- PASMC Cell Viability Assay [361] PASMC (PCS-100-023TM), Primary pulmonary artery smooth muscle cells, were seeded in the medium (Vascular cell basal medium, Cat # ATCC-PCS-100-030 with Vascular smooth muscle cell growth kit, Cat # ATCC-PCS-100-042) at a cell count of 3000 cells per 100 ⁇ l per well in a 96 well edge plate (167425; ThermoFisher).
- CHK-2 Kinase Assay [363] IC 50 values of compounds for inhibition of CHK-2 kinase or percent inhibition at defined concentrations is determined by Z-LYTETM based TR-FRET assay. Kinase reactions are performed in a 10 ⁇ L volume in low-volume 384-well plates. The concentration of substrate (Ser Thr 07) is maintained at 1 ⁇ M in the assay, and the kinase reaction buffer consisted of 50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl2, 1 mM EGTA.
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Abstract
The present disclosure relates generally to compounds useful in treatment of conditions associated with Checkpoint kinase (CHK), particularly CHK-1 enzymes. Specifically, the present invention discloses compound of formula (J), which exhibits inhibitory activity against CHK-1 enzymes. Methods of treating conditions associated with excessive activity of CHK-1 enzymes such as cancer, idiopathic pulmonary fibrosis (IPF) and pulmonary arterial hypertension (PAH) with such compounds is disclosed. Uses thereof, pharmaceutical compositions, kits and method of synthesis also disclosed. Formula (J)
Description
TITLE: HETEROCYCLIC COMPOUNDS AS KINASE INHIBITOR AND USES THEREOF CROSS REFERENCE TO RELATED APPLICATION [1] This application claims the priority benefits of IN Provisional Patent Applciation No. 202111004177, filed on January 30, 2021; disclosures of which are incorporated herein by reference in its entireties. FIELD OF THE INVENTION [2] The present invention generally relates to compounds having Checkpoint kinase-1 (CHK-1) inhibitory activity, to the use of such compounds in the treatment of proliferative disorders, such as cancer; Pulmonary Arterial Hypertension (PAH) and Idiopathic Pulmonary Fibrosis (IPF). The invention also provides method of synthesis of said compounds, method of using said compounds, pharmaceutical compositions comprising said compounds and method of using thereof. BACKGROUND OF THE INVENTION [3] A wide range of cancer chemotherapeutic agents act through DNA damaging pathway to induce DNA damage causing tumor growth inhibition. However, these chemotherapeutic agents lead to cell cycle arrest by induction of checkpoints at either S-phase or G2/M boundary. The G2 arrest allows the cell time to repair the damaged DNA before entering mitosis. Checkpoint kinase-1 (CHK-1) and an unrelated serine/threonine kinase, Checkpoint kinase-2 (CHK-2), play a central role in arresting the cell cycle at the G2-M boundary (O'Connell et al EMBO J (1997) vol. 16 p. 545-554). CHK-1 and/or CHK-2 induce this checkpoint by phosphorylating serine 216 of the CDC25 phosphatase, inhibiting the removal of two inactivating phosphates on cyclin dependent kinases (CDKs) (Zheng et al Nature (1998) vol.395 p.507-510). Another overlapping pathway mediated by p53 also elicits cycle arrest in response to DNA-damage. However, p53 is mutationally inactivated in many cancers, resulting in a partial deficiency in their ability to initiate a DNA-repair response. If CHK-1 activity is also inhibited in p53-negative cancers, all ability to arrest and repair DNA in response to DNA-damage is removed resulting in mitotic catastrophe and enhancing the effect of the DNA damaging agents (Konarias et al. Oncogene (2001) vol. 20 p 7453-7463,
Bunch and Eastman Clin. Can. Res. (1996) vol.2 p 791-797, Tenzer and Pruschy Curr. Med Chem (2003) vol 3 p 35-46). [4] CHK-1 inhibition, therefore, represents a novel therapeutic strategy to increase the lethality of DNA-damaging chemotherapeutic drugs in p53 pathway defective cancers. Abrogation of the remaining intact checkpoint should result in increased tumor cell death. CHK-1 inhibitors have demonstrated potentiation of a range of cytotoxic chemotherapy drugs both in vitro and in a range of pre-clinical models of human cancer including gemcitabine, irinotecan, cytarabine, and cisplatin. This “synthetic lethality” approach should increase the therapeutic activity of the chemotherapeutic drug without increasing the systemic toxicity as normal cells should remain protected by their functional p53 pathway. CHK-1 inhibitors have, therefore, the potential to be combined with a wide range of cytotoxic chemotherapeutic agents for the treatment of a diverse selection of human cancers. [5] Further, excessive and sustained proliferation, resistance to apoptosis by fine tuning of cell cycle and DNA repair machinery are few of the causative mechanisms of cancer, Pulmonary Arterial Hypertension (PAH) and Idiopathic Pulmonary Fibrosis (IPF). PAH is a devastating disease accompanied with progressive vascular remodeling of distal pulmonary arteries leading to concomitant elevation of pulmonary artery pressure, perivascular inflammation, fibrotic changes, right ventricular hypertrophy, and death (Bourgeois et.al., Arterioscler Thromb Vasc Biol. 2019;39:1667–1681). It is a concurrent complication of Idiopathic Pulmonary Fibrosis and affects its survival, functional status and progression, however no treatment other than lung transplantation are currently available (Wu et.al., Am J Respir Crit Care Med 2020;201:A2499). Besides genetic predisposition, a number of epigenetic factors such as oxidative stress and generation of reactive oxygen species cause DNA damage in pulmonary artery smooth muscle cells (PAH-PASMCs) and alter the cellular functions similar to cancer cells. Since DNA repair machinery has been targeted successfully to delineate the underlying molecular mechanisms of cancer and a wide range of chemotherapeutic agents are being explored, which act through DNA damaging pathway to induce DNA damage causing tumor growth inhibition, similar approach could be adopted for PAH-IPF. In cancer, these chemotherapeutic agents lead to cell cycle arrest by induction of checkpoints at either S-phase or G2/M boundary, wherein, the G2 arrest allows the cell time to repair the damaged DNA before entering mitosis. Checkpoint kinase-1 (CHK-1) and Checkpoint kinase-2 (CHK-2), serine/threonine kinases, are DNA damage sensors and
critical regulators of DNA repair and cell cycle progression. They are upregulated in cancer cells and play a central role in arresting the cell cycle at the G2-M boundary to facilitate DNA repair (O'Connell et al EMBO J (1997) vol. 16 p. 545-554). CHK-1 and/or CHK-2 induce this checkpoint by phosphorylating serine 216 of the CDC25 phosphatase, inhibiting the removal of two inactivating phosphates on cyclin dependent kinases (CDKs) (Zheng et al Nature (1998) vol. 395 p. 507-510). In PAH-IPF, proliferating PAH-PASMCs show increased levels of γ-H2AX and pRPA32, markers for DNA damage/replication stress and also display enhanced expression and activation of CHK1. Moreover, pharmacological inhibition of CHK1 improves PAH in clinically relevant rat models suggesting that CHK1 inhibition could also be an attractive therapeutic option for PAH (Bourgeois et.al., Arterioscler Thromb Vasc Biol. 2019;39:1667–1681). However, in cancer, another overlapping pathway mediated by p53 also elicits cycle arrest in response to DNA-damage. In many cancers, p53 is mutationally inactivated resulting in a partial deficiency in their ability to initiate a DNA-repair response. If CHK-1 activity is also inhibited in p53-negative cancers, all ability to arrest and repair DNA in response to DNA-damage is removed resulting in mitotic catastrophe and enhancing the effect of the DNA damaging agents (Konarias et al. Oncogene (2001) vol. 20 p 7453-7463, Bunch and Eastman Clin. Can. Res. (1996) vol. 2 p 791-797, Tenzer and Pruschy Curr. Med Chem (2003) vol 3 p 35-46). [6] Various attempts have been made to develop CHK-1 kinase inhibitors. For example, US10000481B2 (Vernalis) disclose 1H-pyrrolo[2,3-B] pyridine derivatives compounds as CHK-1 kinase inhibitors. US10010547B2 (Cascadian Therapeutics) discloses pyrazol amino pyrazine derivatives as kinase inhibitors. WO/2018/086546A1 (Zhejiang university) disclose 2-polysubstituted aromatic ring-pyrimidine derivatives as CHK-1 inhibitors. Some small molecule inhibitors of CHK-1 (Prexasertib/LY2606368, LY2603618 and SRA737) are currently in Phase I/II clinical evaluation in combination with gemcitabine, pemetrexed, fludarabine, cytarabine, and cisplatin. [7] The main features of IPF-PH are excessive proliferation and resistance to apoptosis of fibroblasts and pulmonary arterial (PA) smooth muscle cells (PASMC) leading to aberrant accumulation of extracellular matrix in parenchyma and extensive vascular remodeling. It can be hypothesized that CHK1/2, which is upregulated and activated in IPF-PH contributes to fibrotic and vascular lesions in IPF-PH. This is associated with DNA repair initiation enzyme γH2Ax which in turn correlates with PAH remodeling and fibrosis scores. The increase in
DNA repair in IPF is associated with a significant upregulation of CHK1 and CHK2 in the lungs and distal PA of IPF patients and it was mainly localized within PASMC and fibrotic lesions. Some of the drugs which target proliferation could be protective against PAH and since CHK1 activation in PAH-PASMCs is known to be a decisive event in the initiation of pulmonary vascular remodeling in PAH, it could be a potential therapeutic target for PAH- IPF (Satoh et.al., Int J Mol Sci. 2018;19, Bourgeois et.al., Arterioscler Thromb Vasc Biol. 2019;39:1667–1681). [8] Activation of the ATR-CHK1 signaling in PAH-PASMCs and significant therapeutic effects observed by the inhibition of this axis in animal models mimicking PAH reflects indicate that CHK1 may represent a new therapeutic avenue for patients with PAH. This would block or reversing pulmonary vascular remodeling, a key pathological feature of PAH for which current approved therapies have limited efficacy. Moreover, therapeutic effects observed for cancer by inhibition of CHK1 also highlight a continuing need for developing new CHK-1 inhibitors with pharmacokinetic and pharmacodynamic properties making them suitable for use as pharmaceutical agents. The object of the present invention is to provide such pharmaceutical agents and treatments. [9] Thus, there remains a continuing need for developing new CHK-1 inhibitors with pharmacokinetic and pharmacodynamic properties making them suitable for use as pharmaceutical agents. The object of the present invention is to provide such pharmaceutical agents and treatments. SUMMARY OF THE INVENTION [10] In one aspect, the present invention provides a compound of formula (J):
or a salt, thereof, wherein X1, X2, Q, A, L and Rx are as detailed herein.
[11] In one aspect, the compound of formula (J) or a salt thereof, is a compound of formula (I) or a salt thereof, as detailed herein. [12] In one aspect, the compound of formula (J) or a salt thereof, is a compound of formula (IA) or a salt thereof, as detailed herein. [13] In some aspects, the compound of formula (IA) or a salt thereof, is any of the compounds of formula (IA-1) to (IA-10) or a salt thereof, as detailed herein [14] In one aspect, the compound of formula (J) or a salt thereof, is a compound of formula (IB) or a salt thereof, as detailed herein. [15] In some aspects, the compound of formula (IB) or a salt thereof, is any of the compounds of formula (IB-1) to (IB-10) or a salt thereof, as detailed herein [16] In one aspect, the compound of formula (J) or a salt thereof, is a compound of formula (II) or a salt thereof, as detailed herein. [17] In some aspects, the compound of formula (II) or a salt thereof, is any of the compounds of formula (II-a) to (II-c) or a salt thereof, as detailed herein. [18] In one aspect, the compound of formula (J) or a salt thereof, is a compound of formula (III) or a salt thereof, as detailed herein. [19] In some aspects, the compound of formula (III) or a salt thereof, is any of the compounds of formula (III-a) to (III-c) or a salt thereof, as detailed herein. [20] In one aspect, the compound of formula (J) or a salt thereof, is a compound of formula (IV) or a salt thereof, as detailed herein. [21] In some aspects, the compound of formula (IV) or a salt thereof, is any of the compounds of formula (IV-a) to (IV-c) or a salt thereof, as detailed herein. [22] In one aspect, the compound of formula (J) or a salt thereof, is a compound of formula (V) or a salt thereof, as detailed herein. [23] In some aspects, the compound of formula (V) or a salt thereof, is any of the compounds of formula (V-a) to (V-f) or a salt thereof, as detailed herein.
[24] In one aspect, the compound of formula (J) or a salt thereof, is a compound of formula (VI) or a salt thereof, as detailed herein. [25] In some aspects, the compound of formula (VI) or a salt thereof, is any of the compounds of formula (VI-a) to (VI-f) or a salt thereof, as detailed herein. [26] In one aspect, the compound of formula (J) or a salt thereof, is a compound of formula (VII) or a salt thereof, as detailed herein. [27] In some aspects, the compound of formula (VII) or a salt thereof, is any of the compounds of formula (VII-a) to (VII-f) or a salt thereof, as detailed herein. [28] In one aspect, the compound of formula (J) or a salt thereof, is a compound of formula (VIII) or a salt thereof, as detailed herein. [29] In some aspects, the compound of formula (VIII) or a salt thereof, is any of the compounds of formula (VIII-a) to (VIII-f) or a salt thereof, as detailed herein. [30] In some another aspect, the present invention provides method of treating a disease or disorder associated with this CHK kinase enzymes, more specifically CHK-1 kinase enzymes in an individual in need thereof, wherein the method comprises administering to the individual an effective amount of a compound of the present invention (collectively, a compound of formula (J), (I), (IA), (IA-1) to (IA-10), (IB) , (IB-1) to (IB-10), (II), (II-a) to (II-c), (III), (III-a) to (III-c), (IV), (IV-a) to (IV-c), (V), (V-a) to (V-f), (VI), (VI-a) to (VI-f)) (VII), (VII-a) to (VII-f), (VIII), (VIII-a) to (VIII-f) or a salt thereof. [31] In some another aspect, the present invention provides method of treating cancer in an individual in need thereof, wherein the method comprises administering to the individual an effective amount of a compound of the present invention (collectively, a compound of formula (J), (I), (IA), (IA-1) to (IA-10), (IB) , (IB-1) to (IB-10), (II), (II-a) to (II-c), (III), (III- a) to (III-c), (IV), (IV-a) to (IV-c), (V), (V-a) to (V-f), (VI), (VI-a) to (VI-f)) (VII), (VII-a) to (VII-f), (VIII), (VIII-a) to (VIII-f), or a salt thereof. [32] In some another aspect, the present invention provides method of treating Idiopathic Pulmonary Fibrosis (IPF) in an individual in need thereof, wherein the method comprises administering to the individual an effective amount of a compound of the present invention (collectively, a compound of formula (J), (I), (IA), (IA-1) to (IA-10), (IB) , (IB-1) to (IB-10),
(II), (II-a) to (II-c), (III), (III-a) to (III-c), (IV), (IV-a) to (IV-c), (V), (V-a) to (V-f), (VI), (VI- a) to (VI-f)) (VII), (VII-a) to (VII-f), (VIII), (VIII-a) to (VIII-f)), or a salt thereof. [33] In some another aspect, the present invention provides method of treating I Pulmonary Arterial Hypertension (PAH) in an individual in need thereof, wherein the method comprises administering to the individual an effective amount of a compound of the present invention (collectively, a compound of formula (J), (I), (IA), (IA-1) to (IA-10), (IB) , (IB-1) to (IB-10), (II), (II-a) to (II-c), (III), (III-a) to (III-c), (IV), (IV-a) to (IV-c), (V), (V-a) to (V- f), (VI), (VI-a) to (VI-f)) (VII), (VII-a) to (VII-f), (VIII), (VIII-a) to (VIII-f)), or a salt thereof. [34] In some another aspect, the present invention provides method of treating a disease or disorder associated with this CHK kinase enzymes, more specifically CHK-1 kinase enzymes in an individual in need thereof, wherein the method comprises administering to the individual an effective amount of a compound of the present invention (collectively, a compound of formula (J), (I), (IA), (IA-1) to (IA-10), (IB) , (IB-1) to (IB-10), (II), (II-a) to (II-c), (III), (III-a) to (III-c), (IV), (IV-a) to (IV-c), (V), (V-a) to (V-f), (VI), (VI-a) to (VI-f)) (VII), (VII-a) to (VII-f), (VIII), (VIII-a) to (VIII-f)), or a salt thereof in combination with other therapeutic agents. [35] In some another aspect, the present invention provides pharmaceutical compositions, comprising a compound of the present invention (collectively, a compound of formula (J), (I), (IA), (IA-1) to (IA-10), (IB) , (IB-1) to (IB-10), (II), (II-a) to (II-c), (III), (III-a) to (III-c), (IV), (IV-a) to (IV-c), (V), (V-a) to (V-f), (VI), (VI-a) to (VI-f)) (VII), (VII-a) to (VII-f), (VIII), (VIII-a) to (VIII-f)), or a salt thereof. [36] In some another aspect, the present invention provides method of treating a disease or disorder associated with this CHK kinase enzymes, or more specifically CHK-1 kinase enzymes in an individual in need thereof, wherein the method comprises administering to the individual an effective amount of a pharmaceutical composition comprising a compound of the present invention (collectively, a compound of formula (J), (I), (IA), (IA-1) to (IA-10), (IB) , (IB-1) to (IB-10), (II), (II-a) to (II-c), (III), (III-a) to (III-c), (IV), (IV-a) to (IV-c), (V), (V-a) to (V-f), (VI), (VI-a) to (VI-f)) (VII), (VII-a) to (VII-f), (VIII), (VIII-a) to (VIII-f)), or a salt thereof.
[37] In some another aspect, the present invention provides processes for preparing compounds and intermediates thereof disclosed in the present invention. DETAIL DESCRIPTION OF THE INVENTION Definitions [38] “Alkyl” refers to and includes saturated linear and branched univalent hydrocarbon structures and combination thereof, having the number of carbon atoms designated (i.e., C1- C10 means one to ten carbons). Particular alkyl groups are those having 1 to 20 carbon atoms (a “C1-C20 alkyl”). More particular alkyl groups are those having 1 to 8 carbon atoms (a “C1- C8 alkyl”), 3 to 8 carbon atoms (a “C3-C8 alkyl”), 1 to 6 carbon atoms (a “C1-C6 alkyl”), 1 to 5 carbon atoms (a “C1-C5 alkyl”), or 1 to 4 carbon atoms (a “C1-C4 alkyl”). Examples of alkyl include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n- butyl, t-butyl, isobutyl, sec-butyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. [39] “Alkenyl” as used herein refers to an unsaturated linear or branched univalent hydrocarbon chain or combination thereof, having at least one site of olefinic unsaturation (i.e., having at least one moiety of the formula C=C) and having the number of carbon atoms designated (i.e., C2-C10 means two to ten carbon atoms). The alkenyl group may be in “cis” or “trans” configurations, or alternatively in “E” or “Z” configurations. Particular alkenyl groups are those having 2 to 20 carbon atoms (a “C2-C20 alkenyl”), having 2 to 8 carbon atoms (a “C2-C8 alkenyl”), having 2 to 6 carbon atoms (a “C2-C6 alkenyl”), or having 2 to 4 carbon atoms (a “C2-C4 alkenyl”). Examples of alkenyl include, but are not limited to, groups such as ethenyl (or vinyl), prop-1-enyl, prop-2-enyl (or allyl), 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-dienyl, homologs and isomers thereof, and the like. [40] “Alkylene” as used herein refers to the same residues as alkyl, but having bivalency. Particular alkylene groups are those having 1 to 6 carbon atoms (a “C1-C6 alkylene”), 1 to 5 carbon atoms (a “C1-C5 alkylene”), 1 to 4 carbon atoms (a “C1-C4 alkylene”) or 1 to 3 carbon atoms (a “C1-C3 alkylene”). Examples of alkylene include, but are not limited to, groups such as methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), and the like.
[41] “Alkynyl” as used herein refers to an unsaturated linear or branched univalent hydrocarbon chain or combination thereof, having at least one site of acetylenic unsaturation (i.e., having at least one moiety of the formula C≡C) and having the number of carbon atoms designated (i.e., C2-C10 means two to ten carbon atoms). Particular alkynyl groups are those having 2 to 20 carbon atoms (a “C2-C20 alkynyl”), having 2 to 8 carbon atoms (a “C2-C8 alkynyl”), having 2 to 6 carbon atoms (a “C2-C6 alkynyl”), or having 2 to 4 carbon atoms (a “C2-C4 alkynyl”). Examples of alkynyl include, but are not limited to, groups such as ethynyl (or acetylenyl), prop-1-ynyl, prop-2-ynyl (or propargyl), but-1-ynyl, but-2-ynyl, but-3-ynyl, homologs and isomers thereof, and the like. [42] “Aryl” refers to and includes polyunsaturated aromatic hydrocarbon groups. Aryl may contain additional fused rings (e.g., from 1 to 3 rings), including additionally fused aryl, heteroaryl, cycloalkyl, and/or heterocyclyl rings. In one variation, the aryl group contains from 6 to 14 annular carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, biphenyl, and the like. [43] “Carbonyl” refers to the group C=O. [44] “Cycloalkyl” refers to and includes cyclic univalent hydrocarbon structures, which may be fully saturated, mono- or polyunsaturated, but which are non-aromatic, having the number of carbon atoms designated (e.g., C1-C10 means one to ten carbons). Cycloalkyl can consist of one ring, such as cyclohexyl, or multiple rings, such as adamantly, but excludes aryl groups. A cycloalkyl comprising more than one ring may be fused, spiro or bridged, or combinations thereof. A preferred cycloalkyl is a cyclic hydrocarbon having from 3 to 13 annular carbon atoms. A more preferred cycloalkyl is a cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a "C3-C8 cycloalkyl"). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, norbornyl, and the like. [45] “Halo” or “halogen” refers to elements of the Group 17 series having atomic number 9 to 85. Preferred halo groups include fluoro, chloro, bromo and iodo. Where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached, e.g., dihaloaryl, dihaloalkyl, trihaloaryl etc. refer to aryl and alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be but are not necessarily the same halo; thus 4-chloro-3-fluorophenyl is within the scope of dihaloaryl.
An alkyl group in which each hydrogen is replaced with a halo group is referred to as a “perhaloalkyl.” A preferred perhaloalkyl group is trifluoroalkyl (-CF3). Similarly, “perhaloalkoxy” refers to an alkoxy group in which a halogen takes the place of each H in the hydrocarbon making up the alkyl moiety of the alkoxy group. An example of a perhaloalkoxy group is trifluoromethoxy (-OCF3). [46] “Heteroaryl” refers to and includes unsaturated aromatic cyclic groups having from 1 to 10 annular carbon atoms and at least one annular heteroatom, including but not limited to heteroatoms such as nitrogen, oxygen and sulfur, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule at an annular carbon or at an annular heteroatom. Heteroaryl may contain additional fused rings (e.g., from 1 to 3 rings), including additionally fused aryl, heteroaryl, cycloalkyl, and/or heterocyclyl rings. Examples of heteroaryl groups include, but are not limited to imidazolyl, pyrrolyl, pyrazolyl, 1,2,4- triazolyl, thiophenyl, furanyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridyl, pyrimidyl, pyridazinyl or pyrazinyl, and the like. [47] “Heterocycle” or “heterocyclyl” refers to a saturated or an unsaturated non-aromatic group having from 1 to 10 annular carbon atoms and from 1 to 4 annular heteroatoms, such as nitrogen, sulfur or oxygen, and the like, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. A heterocyclyl group may have a single ring or multiple condensed rings, but excludes heteroaryl groups. A heterocycle comprising more than one ring may be fused, spiro or bridged, or any combination thereof. In fused ring systems, one or more of the fused rings can be aryl or heteroaryl. Examples of heterocyclyl groups include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, morpholinyl, thiomorpholinyl, azepanyl tetrahydropyranyl, dihydropyranyl, piperidinyl, piperazinyl, pyrrolidinyl, thiazolinyl, thiazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, and the like. [48] “Oxo” refers to the moiety =O. [49] “CHK” refers to Checkpoint kinase, which includes CHK-1 and CHK-2. CHK refers herein specifically to CHK-1. [50] “Optionally substituted” unless otherwise specified means that a group may be unsubstituted or substituted by one or more (e.g., 1, 2, 3, 4 or 5) of the substituents listed for
that group in which the substituents may be the same of different. In one embodiment, an optionally substituted group has one substituent. In another embodiment, an optionally substituted group has two substituents. In another embodiment, an optionally substituted group has three substituents. In another embodiment, an optionally substituted group has four substituents. In some embodiments, an optionally substituted group has 1 to 2, 2 to 5, 3 to 5, 2 to 3, 2 to 4, 3 to 4, 1 to 3, 1 to 4 or 1 to 5 substituents. [51] A “pharmaceutically acceptable carrier” refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, which is nontoxic to a subject. A pharmaceutically acceptable carrier includes, but is not limited to, a buffer, excipient, stabilizer, or preservative. [52] As used herein, “treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. For example, beneficial or desired results include, but are not limited to, one or more of the following: decreasing symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, delaying the progression of the disease, and/or prolonging survival of individuals. In reference to cancers or other unwanted cell proliferation (idiopathic pulmonary fibrosis (IPF)), beneficial or desired results include shrinking a tumor (reducing tumor size); decreasing the growth rate of the tumor (such as to suppress tumor growth); reducing the number of cancer cells; inhibiting, retarding or slowing to some extent and preferably stopping cancer cell infiltration into peripheral organs; inhibiting (slowing to some extent and preferably stopping) tumor metastasis; inhibiting tumor growth; preventing or delaying occurrence and/or recurrence of tumor; and/or relieving to some extent one or more of the symptoms associated with the cancer. In some embodiments, beneficial or desired results include preventing or delaying occurrence and/or recurrence, such as of unwanted cell proliferation (idiopathic pulmonary fibrosis (IPF)). [53] As used herein, “delaying development of a disease” means to defer, hinder, slow, retard, stabilize, and/or postpone development of the disease (such as cancer, pulmonary arterial hypertension (PAH) and idiopathic pulmonary fibrosis (IPF)). This delay can be of varying lengths of time, depending on the history of the disease and/or individual being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease. For example, a late stage cancer, such as development of metastasis, may be delayed.
[54] As used herein, an “effective dosage” or “effective amount” of compound or salt thereof or pharmaceutical composition is an amount sufficient to effect beneficial or desired results. For prophylactic use, beneficial or desired results include results such as eliminating or reducing the risk, lessening the severity of, or delaying the onset of the disease, including biochemical, histological and/or behavioral symptoms of the disease, its complications and intermediate pathological phenotypes presenting during development of the disease. For therapeutic use, beneficial or desired results include ameliorating, palliating, lessening, delaying or decreasing one or more symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, enhancing effect of another medication such as via targeting, delaying the progression of the disease, and/or prolonging survival. In reference to cancers or other unwanted cell proliferation, an effective amount comprises an amount sufficient to cause a tumor to shrink and/or to decrease the growth rate of the tumor (such as to suppress tumor growth) or to prevent or delay other unwanted cell proliferation (idiopathic pulmonary fibrosis (IPF)). In reference to pulmonary arterial hypertension (PAH), an effective amount comprises an amount sufficient to prevent or delay the development of pulmonary arterial hypertension (PAH)). In some embodiments, an effective amount is an amount sufficient to delay development. In some embodiments, an effective amount is an amount sufficient to prevent or delay occurrence and/or recurrence. An effective amount can be administered in one or more administrations, in the case of cancer, the effective amount of the drug or composition may: (i) reduce the number of cancer cells; (ii) reduce tumor size; (iii) inhibit, retard, slow to some extent and preferably stop cancer cell infiltration into peripheral organs; (iv) inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; (v) inhibit tumor growth; (vi) prevent or delay occurrence and/or recurrence of tumor; and/or (vii) relieve to some extent one or more of the symptoms associated with the cancer. An effective dosage can be administered in one or more administrations. For purposes of this disclosure, an effective dosage of compound or a salt thereof, or pharmaceutical composition is an amount sufficient to accomplish prophylactic or therapeutic treatment either directly or indirectly. It is intended and understood that an effective dosage of a compound or salt thereof, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition. Thus, an “effective dosage” may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable result may be or is achieved.
[55] As used herein, the term “individual” is a mammal, including humans. An individual includes, but is not limited to, human, bovine, horse, feline, canine, rodent, or primate. In some embodiments, the individual is human. The individual (such as a human) may have advanced disease or lesser extent of disease, such as low tumor burden. In some embodiments, the individual is at an early stage of a proliferative disease (such as cancer or idiopathic pulmonary fibrosis (IPF)). In some embodiments, the individual is at an advanced stage of a proliferative disease (such as an advanced cancer). [56] Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X”. [57] It is understood that aspects and variations described herein also include “consisting” and/or “consisting essentially of” aspects and variations. Compounds [58] The present invention provides a compound of Formula (J):
wherein, X and X are independently N or C x 1 2 R ; provided that at least one of X1 and X2 is N; each Rx is independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6- membered heterocyclyl, -CN, halogen, C1-C6 alkoxy, C1-C6 haloalkoxy, C1- C6 haloalkyl, -OR7, -NR8R9, -C(O)R7, -NR7C(O)R8, -C(O)OR7 or -C(O)NR8R9, each of which is optionally substituted by oxo, halogen, CN, -OR10 or -NR11R12; L is NH or O;
Q is C or D;
C is 7- to 12-membered monocyclic or bicyclic heterocyclyl, C3-C10 monocyclic or bicyclic cycloalkyl or -(C1-C3 alkylene)C7-C10 cycloalkyl, wherein each of C is optionally substituted by one or more R4;
D is -(C1-C3 alkylene)3- to 6-membered heterocyclyl optionally substituted by one or more R4;
A is R1 or R1a;
R1 is independently 5 -membered heteroaryl, 3- to 6-membered heterocyclyl or - 2 3
C(O)NR R , wherein 5-membered heteroaryl and 3- to 6-membered heterocyclyl optionally substituted by R5; R1a is independently -C(O)NR2R3, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, C6, aryl, 5- to 10-membered heteroaryl, -CN, halogen, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6haloalkyl, -OR13, -SR13, -S(O)2R13 , -S(O)2NR14R15, -NR13S(O)2R14, -NR14R15,
-C(O)R13, -NR13C(O)R14, -NR13C(O)NR14R15, -C(O)OR13, -C(O)ONR14R15, -(C1- C3 alkylene)OR13, -(C1-C3 alkylene)SR13, -(C1-C3 alkylene)S(O)2R13, -(C1- C3 alkylene)S(O)2NR14R15, -(C1-C3 alkylene)NR13S(O)2R14, -(C1-C3 alkylene)NR14R15, -(C1- C3 alkylene)C(O)R13, -(C1-C3 alkylene)NR13C(O)R14, -(C1-
C3 alkylene)NR13C(O)NR14R15, -(C1-C3 alkylene)C(O)OR13, -(C1-
C3 alkylene)C(O)ONR14R15, -(C1-C3 alkylene)(C3-C8 cycloalkyl) or -(C1-C3 alkylene) (3 -10- membered heterocyclyl); wherein each of R1a is optionally substituted by R5;
R and R are independently hydrogen, -CD3, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, C6, aryl, 5- to 6-membered heteroaryl, , C1-C6haloalkyl, -C(O)R13, -(C1-C3 alkylene)OR13, -(C1-C3 alkylene)SR13, -(C1- C3 alkylene)S(O)2R13, -(C1-C3 alkylene)S(O)2NR14R15, -(C1-C3 alkylene)NR13S(O)2R14, -(C1- C3 alkylene)NR14R15, -(C1-C3 alkylene)C(O)R13, -(C1-C3 alkylene)NR13C(O)R14, -(C1- C3 alkylene)NR13C(O)NR14R15, -(C1-C3 alkylene)C(O)OR13, -(C1-
C3 alkylene)C(O)ONR14R15, -(C1-C3 alkylene)(C3-C8 cycloalkyl), -(C1-C3 alkylene) (3 -10- membered heterocyclyl), -(C1-C3 alkylene)C6 aryl or -(C1-C3 alkylene) 5- to 6-membered heteroaryl, wherein each of R and R are independently optionally substituted by R ;
or R2 and R3 are taken together with the atom to which they attached to form a 3- to 6- membered heterocyclyl optionally substituted by R5;
R4 is oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -CN, halogen, C1-C6 alkoxy, C1-C6 haloalkoxy, -OR16, -SR16, -S(O)2R16 , -S(O)2NR17R18, -NR16S(O)2R17, -NR17R18, -C(O)R16, -NR16C(O)R17, -C(O)OR16, wherein each of R4 is optionally substituted by oxo, - OH, halogen or -NH2;
R5 is oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -CN, halogen, C1- C6haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OR16, -SR16, -S(O)2R16
, -S(O)2NR17R18, -NR16S(O)2R17, -NR17R18, -C(O)R16, -NR16C(O)R17, -C(O)OR16, C3-C6 cycloalkyl, C6, aryl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocyclyl, wherein each of R5 is optionally substituted by oxo, -OH, halogen or -NH2; each R , R andR is independently hydrogen or C1-C6 alkyl optionally substituted by oxo, -OH, halogen or -NH2; each R10, R11 and R12 is independently hydrogen, C1-C6 alkyl or C3-C8 cycloalkyl;
11 12 or R and R1' ' are taken together with the atom to which they attached to form a 3- to 6- membered heterocyclyl; each R13, R14andR15 is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, C6, aryl, 5- to 6- membered heteroaryl, -(C1-C3 alkylene) C3-C6 cycloalkyl, -(C1-C3 alkylene)3- to 6-membered heterocyclyl, or -(C1-C3 alkylene)5- to 6-membered heteroaryl, wherein each of R13, R14 and R15 is independently optionally substituted by oxo, C2-C6 alkenyl, C2-C6 alkynyl, -CN, halogen, C1-C6 alkoxy, C1-C6 haloalkoxy, -OR16, -SR16, -S(O)2R16
, -S(O)2NR17R18, -NR16S(O)2R17, -NR17R18, -C(O)R16, -NR16C(O)R17, -C(O)0R16 or C1-C6 alkyl optionally substituted by oxo, -OH, halogen or -NH2; or R14 andR15 are taken together with the atom to which they attached to form a 3- to 6- membered heterocyclyl optionally substituted by oxo, OH or halogen, or C1-C6 alkyl optionally substituted by oxo, -OH, halogen or -NH2;
each R16, R17 and R18 is independently hydrogen, C2-C6 alkenyl, C2-C6 alkynyl, C6 aryl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocyclyl, C3-C6 cycloalkyl or C1-C6 alkyl optionally substituted by oxo, -OH, halogen or -NH2; and or R17 and R18 are taken together with the atom to which they attached to form a 3- to 6- membered heterocyclyl optionally substituted by oxo, -OH, halogen or -NH2, or C1-C6 alkyl optionally substituted by oxo, -OH, halogen or -NH2; provided that: [59] when Q is C then L is –O- or –NH- and A is R1a; [60] when Q is D then L is –NH- and A is R1; [61] when Q is D, L is –NH- and A is R1 then: (i) when D is 1
; and X1 and X2 both are N; then R is other than
,
(ii) the compound is not selected from: 6-(5-cyanopyrazin-2-ylamino)-4-(piperidin-4-ylmethylamino)pyridazine-3- carboxamide; 6-(5-cyanopyrazin-2-ylamino)-N-methyl-4-((1-methylpiperidin-4- yl)methylamino)pyridazine-3-carboxamide; 6-(5-cyanopyrazin-2-ylamino)-4-((tetrahydro-2H-pyran-4-
yl)methylamino)pyridazine-3-carboxamide; 6-(5-cyanopyrazin-2-ylamino)-N-methyl-4-((tetrahydro-2H-pyran-4- yl)methylamino)pyridazine-3-carboxamide; 6-(5-cyanopyrazin-2-ylamino)-N,N-dimethyl-4-(piperidin-4- ylmethylamino)pyridazine-3-carboxamide; 6-(6-cyanopyridin-3-ylamino)-N-methyl-4-(morpholin-2-ylmethylamino)pyridazine- 3-carboxamide; 6-(5-cyanopyrazin-2-ylamino)-N-(3,3-difluorocyclobutyl)-4-(piperidin-4- ylmethylamino)pyridazine-3-carboxamide; 6-(5-cyanopyrazin-2-ylamino)-4-(piperidin-4-ylmethylamino)-N- (trifluoromethyl)pyridazine-3-carboxamide; 6-(5-cyanopyrazin-2-ylamino)-4-(piperidin-4-ylmethylamino)-N-(2,2,2- trifluoroethyl)pyridazine-3-carboxamide; 6-(5-cyanopyrazin-2-ylamino)-N-methyl-4-((4-methylmorpholin-2- yl)methylamino)pyridazine-3-carboxamide; 6-(5-cyanopyrazin-2-ylamino)-N,N-dimethyl-4-((4-methylmorpholin-2- yl)methylamino)pyridazine-3-carboxamide; 6-(5-cyanopyridin-2-ylamino)-N-methyl-4-(morpholin-2-ylmethylamino)pyridazine- 3-carboxamide; (R)-6-(6-cyanopyridin-3-ylamino)-N-methyl-4-(morpholin-2- ylmethylamino)pyridazine-3-carboxamide; (S)-6-(6-cyanopyridin-3-ylamino)-N-methyl-4-(morpholin-2- ylmethylamino)pyridazine-3-carboxamide; (R)-6-(5-cyanopyridin-2-ylamino)-N-methyl-4-(morpholin-2- ylmethylamino)pyridazine-3-carboxamide; (S)-6-(5-cyanopyridin-2-ylamino)-N-methyl-4-(morpholin-2-
ylmethylamino)pyridazine-3-carboxamide; 6-(5-cyanopyrazin-2-ylamino)-N-methyl-4-(piperidin-3-ylmethylamino)pyridazine-3- carboxamide; (R)-6-(5-cyanopyrazin-2-ylamino)-N-methyl-4-(piperidin-3- ylmethylamino)pyridazine-3-carboxamide; (S)-6-(5-cyanopyrazin-2-ylamino)-N-methyl-4-(piperidin-3- ylmethylamino)pyridazine-3-carboxamide; 6-(5-cyanopyrazin-2-ylamino)-4-((2,6-dimethylpiperidin-3-yl)methylamino)-N- methylpyridazine-3-carboxamide; 6-(5-cyanopyrazin-2-ylamino)-N-methyl-4-(pyrrolidin-3-ylmethylamino)pyridazine- 3-carboxamide; 5-(6-(1-methyl-1H-pyrazol-3-yl)-5-(piperidin-4-ylmethylamino)pyridazin-3- ylamino)pyrazine-2-carbonitrile; 5-(6-(1H-imidazol-2-yl)-5-(piperidin-4-ylmethylamino)pyridazin-3- ylamino)pyrazine-2-carbonitrile; 5-(6-(1H-imidazol-2-yl)-5-((1-methylpiperidin-4-yl)methylamino)pyridazin-3- ylamino)pyrazine-2-carbonitrile; or 5-(6-(azetidin-1-yl)-5-(piperidin-4-ylmethylamino)pyridazin-3-ylamino)pyrazine-2- carbonitrile. [62] In some embodiments, a compound of formula (J) is a compound of formula (I):
wherein,
X1 and X2 are independently N or CRX; provided that at least one of X1 and X2 is
N; each Rx is independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6- membered heterocyclyl, -CN, halogen, C1-C6 alkoxy, C1-C6 haloalkoxy, C1- C6haloalkyl, -OR7, -NR8R9, -C(O)R7, -NR7C(O)R8, -C(O)OR7 or -C(O)NR8R9, each of which is optionally substituted by oxo, halogen, CN, -OR10 or -NR11R12;
D is -(C1-C3 alkylene)3- to 6-membered heterocyclyl, optionally substituted by
R4;
R1 is independently 5 -membered heteroaryl, 3- to 6-membered heterocyclyl or -
C(O)NR2R3 , wherein 5-membered heteroaryl and 3- to 6-membered heterocyclyl optionally substituted by R5;
R2 and R3 are independently hydrogen, -CD3, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, C6 aryl, 5- to 6-membered heteroaryl, , C1-C6haloalkyl, -C(O)R13, -(C1-C3 alkylene)OR13, -(C1-C3 alkylene)SR13, -(C1- C3 alkylene)S(O)2R13, -(C1-C3 alkylene)S(O)2NR14R15, -(C1-C3 alkylene)NR13S(O)2R14, -(C1- C3 alkylene)NR14R15, -(C1-C3 alkylene)C(O)R13, -(C1-C3 alkylene)NR13C(O)R14, -(C1- C3 alkylene)NR13C(O)NR14R15, -(C1-C3 alkylene)C(O)OR13, -(C1-
C3 alkylene)C(O)ONR14R15, -(C1-C3 alkylene)( C3-C8 cycloalkyl) or -(C1-C3 alkylene) (3 -10- membered heterocyclyl), -(C1-C3 alkylene)C6 aryl or -(C1-C3 alkylene) 5- to 6-membered heteroaryl, wherein each of R and R are independently optionally substituted by R ;
2 3 or R and R are taken together with the atom to which they attached to form a 3- to 6- membered heterocyclyl optionally substituted by R5;
R4is oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -CN, halogen, C1-C6 alkoxy, C1-C6 haloalkoxy, -OR16, -SR16, -S(O)2R16 , -S(O)2NR17R18, -NR16S(O)2R17, -NR17R18, -C(O)R16, -NR16C(O)R17, -C(O)OR16, wherein each of R4 is optionally substituted by oxo, - OH, halogen or -NH2;
R5 is oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -CN, halogen, C1-C6 alkoxy, C1-C6 haloalkoxy, -OR16, -SR16, -S(O)2R16 , -S(O)2NR17R18, -NR16S(O)2R17, -NR17R18, -C(O)R16, -NR16C(O)R17, -C(O)OR16, C3-C6 cycloalkyl, C6 aryl, 5- to 6-membered
heteroaryl, 3- to 6-membered heterocyclyl, wherein each of R5 is optionally substituted by oxo, -OH, halogen or -NH2;
7 8 9 each R , R andR is independently hydrogen or C1-C6 alkyl optionally substituted by oxo, -OH, halogen or -NH2; each R10, R11and R12 is independently hydrogen, C1-C6 alkyl or C3-C8 cycloalkyl;
11 12 or R and R1' ' are taken together with the atom to which they attached to form a 3- to 6- membered heterocyclyl; each R13, R14andR15 is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6, alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, C6, aryl, 5- to 6- membered heteroaryl, -(C1-C3 alkylene) C3-C6 cycloalkyl, -(C1-C3 alkylene)3- to 6-membered heterocyclyl, or -(C1-C3 alkylene)5- to 6-membered heteroaryl, wherein each of R13, R14 and R15 is independently optionally substituted by oxo, C2-C6 alkenyl, C2-C6 alkynyl, -CN, halogen, C1-C6 alkoxy, C1-C6 haloalkoxy, -OR16, -SR16, -S(O)2R16
, -S(O)2NR17R18, -NR16S(O)2R17, -NR17R18, -C(O)R16, -NR16C(O)R17, -C(O)0R16 or C1-C6 alkyl optionally substituted by oxo, -OH, halogen or -NH2; or R14 andR15 are taken together with the atom to which they attached to form a 3- to 6- membered heterocyclyl optionally substituted by oxo, OH or halogen, or C1-C6 alkyl optionally substituted by oxo, -OH, halogen or -NH2; each R16, R17 and R18 is independently hydrogen, C2-C6, alkenyl, C2-C6, alkynyl, Cr, aryl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocyclyl, C3-C6 cycloalkyl or C1-C6 alkyl optionally substituted by oxo, -OH, halogen or -NH2; and or R17 and R18 are taken together with the atom to which they attached to form a 3- to 6- membered heterocyclyl optionally substituted by oxo, -OH, halogen or -NH2, or C1-C6 alkyl optionally substituted by oxo, -OH, halogen or -NH2; provided that:
(i) when D is
; and X and X both 1 1 2 are N; then R is other than
(ii) the compound is not selected from: 6-(5-cyanopyrazin-2-ylamino)-4-(piperidin-4-ylmethylamino)pyridazine-3- carboxamide; 6-(5-cyanopyrazin-2-ylamino)-N-methyl-4-((1-methylpiperidin-4- yl)methylamino)pyridazine-3-carboxamide; 6-(5-cyanopyrazin-2-ylamino)-4-((tetrahydro-2H-pyran-4- yl)methylamino)pyridazine-3-carboxamide; 6-(5-cyanopyrazin-2-ylamino)-N-methyl-4-((tetrahydro-2H-pyran-4- yl)methylamino)pyridazine-3-carboxamide; 6-(5-cyanopyrazin-2-ylamino)-N,N-dimethyl-4-(piperidin-4- ylmethylamino)pyridazine-3-carboxamide; 6-(6-cyanopyridin-3-ylamino)-N-methyl-4-(morpholin-2-ylmethylamino)pyridazine- 3-carboxamide; 6-(5-cyanopyrazin-2-ylamino)-N-(3,3-difluorocyclobutyl)-4-(piperidin-4- ylmethylamino)pyridazine-3-carboxamide; 6-(5-cyanopyrazin-2-ylamino)-4-(piperidin-4-ylmethylamino)-N-
(trifluoromethyl)pyridazine-3-carboxamide; 6-(5-cyanopyrazin-2-ylamino)-4-(piperidin-4-ylmethylamino)-N-(2,2,2- trifluoroethyl)pyridazine-3-carboxamide; 6-(5-cyanopyrazin-2-ylamino)-N-methyl-4-((4-methylmorpholin-2- yl)methylamino)pyridazine-3-carboxamide; 6-(5-cyanopyrazin-2-ylamino)-N,N-dimethyl-4-((4-methylmorpholin-2- yl)methylamino)pyridazine-3-carboxamide; 6-(5-cyanopyridin-2-ylamino)-N-methyl-4-(morpholin-2-ylmethylamino)pyridazine- 3-carboxamide; (R)-6-(6-cyanopyridin-3-ylamino)-N-methyl-4-(morpholin-2- ylmethylamino)pyridazine-3-carboxamide; (S)-6-(6-cyanopyridin-3-ylamino)-N-methyl-4-(morpholin-2- ylmethylamino)pyridazine-3-carboxamide; (R)-6-(5-cyanopyridin-2-ylamino)-N-methyl-4-(morpholin-2- ylmethylamino)pyridazine-3-carboxamide; (S)-6-(5-cyanopyridin-2-ylamino)-N-methyl-4-(morpholin-2- ylmethylamino)pyridazine-3-carboxamide; 6-(5-cyanopyrazin-2-ylamino)-N-methyl-4-(piperidin-3-ylmethylamino)pyridazine-3- carboxamide; (R)-6-(5-cyanopyrazin-2-ylamino)-N-methyl-4-(piperidin-3- ylmethylamino)pyridazine-3-carboxamide; (S)-6-(5-cyanopyrazin-2-ylamino)-N-methyl-4-(piperidin-3- ylmethylamino)pyridazine-3-carboxamide; 6-(5-cyanopyrazin-2-ylamino)-4-((2,6-dimethylpiperidin-3-yl)methylamino)-N- methylpyridazine-3-carboxamide; 6-(5-cyanopyrazin-2-ylamino)-N-methyl-4-(pyrrolidin-3-ylmethylamino)pyridazine-
3 -carboxamide;
5-(6-(l-methyl-lH-pyrazol-3-yl)-5-(piperidin-4-ylmethylamino)pyridazin-3- ylamino)pyrazine-2-carbonitrile;
5-(6-(lH-imidazol-2-yl)-5-(piperidin-4-ylmethylamino)pyridazin-3- ylamino)pyrazine-2-carbonitrile;
5-(6-( 1 H-imidazol-2-yl) -5 -((1 -methylpiperidin-4-yl)methylamino)pyridazin-3 - ylamino)pyrazine-2-carbonitrile; or
5-(6-(azetidin-l-yl)-5-(piperidin-4-ylmethylamino)pyridazin-3-ylamino)pyrazine-2- carbonitrile.
[63] In some embodiments of a compound of formula (J), X1 and X2 are independently N or CRX; provided that at least one of X1 and X2 is N. In some embodiments of a compound of formula (J), X1 is N and X2 is CRX. In some embodiments of a compound of formula (J), Xi is CRX and X2 is N. In some embodiments X1 and X2 both are N.
[64] In some embodiments, Rx is independently selected from hydrogen, C1-C6 alkyl, C3- Ce cycloalkyl, 3- to 6-membered heterocyclyl, -CN, halogen, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6haloalkyl, -OR7, -NR8R9, -C(O)R7, -NR7C(O)R8, -C(O)OR7 or -C(O)NR8R9, each of which is optionally substituted by oxo, halogen, CN, -OR10 or -NRnR12. In some embodiments, Rxis hydrogen.
[65] In some embodiments of a compound of formula (J), L is NH. In some embodiments of a compound of formula (J), L is O.
[66] In some embodiments of a compound of formula (J), C is 7- to 12-membered monocyclic or bicyclic heterocyclyl optionally substituted by one or more R4. In some embodiments of a compound of formula (J), 7- to 12-membered heterocyclyl is monocyclic heterocyclyl optionally substituted by one or more R4. In some embodiments of a compound of formula (J), 7- to 12-membered heterocyclyl is bicyclic heterocyclyl optionally substituted by one or more R4, which is fused, spiro or bridge bicyclic heterocyclyl. In some embodiments of a compound of formula (J), C is C3-C10 monocyclic or bicyclic cycloalkyl, which is optionally substituted by one or more R4. In some embodiments of a compound of formula (J), C3-C10 cycloalkyl ring is monocyclic cycloalkyl optionally substituted by one or
more R4. In some embodiments of a compound of formula (J), C3-C10 cycloalkyl ring is bicyclic cycloalkyl optionally substituted by one or more R4. In some embodiments of a compound of formula (J), C is azepanyl, decahydroquinoline, decahydroisoquinoline, octahydro-1H-indole, octahydrocyclopenta[b]pyrrole, octahydro-1H-cyclopenta[b]pyridine, octahydro-1H-cyclopenta[b]pyridine, octahydro-1H-cyclopenta[b]pyridine, octahydro-1H- cyclopenta[c]pyridine, octahydro-1H-cyclopenta[c]pyridine, octahydrocyclopenta[b]pyrrole, octahydrocyclopenta[c]pyrrole, 2-azabicyclo[3.2.0]heptane, 2-azabicyclo[4.2.0]octane, 3- azabicyclo[4.2.0]octane, 2-azaspiro[3.3]heptane, 1-azaspiro[3.3]heptane, 5- azaspiro[3.4]octane, 6-azaspiro[3.4]octane, 5-azaspiro[3.5]nonane, 6-azaspiro[3.5]nonane, 7- azaspiro[3.5]nonane, 2-azaspiro[3.4]octane, 1-azaspiro[3.4]octane, 1-azaspiro[4.4]nonane, 2- azaspiro[4.4]nonane, 6-azaspiro[4.5]decane, 7-azaspiro[4.5]decane, 8-azaspiro[4.5]decane, 2- azaspiro[3.5]nonane, 1-azaspiro[3.5]nonane, 1-azaspiro[4.5]decane, 2-azaspiro[4.5]decane, 1-azaspiro[5.5]undecane, 2-azaspiro[5.5]undecane, 3-azaspiro[5.5]undecane, cyclopropyl, cyclobutyl, cyclopentyl cyclohexyl, bicyclo[1.1.1]pentyl, decahydronaphthalene, octahydro- 1H-indene or octahydropentalene, wherein each of C is optionally substituted by one or more R4. [67] In some embodiments of a compound of formula (J), C is -(C1-C3 alkylene)C7-C10 cycloalkyl optionally substituted by one or more R4 , wherein cycloalkyl ring is monocylic or bicyclic. In one variation, C1-C3 alkylene as disclosed herein (in formula (J)) is substituted by one or more R4 or unsubstituted. In other variation, C1-C3 alkylene is a linear alkylene such as –CH2-. In another variation, C1-C3 alkylene is a branched alkylene, such as –CH(CH3)- and – C(CH3)2-. In some embodiments of a compound of formula (J), C is –CH2- (bicyclo[3.1.1]heptane) and –CH2-((1R,5S)-bicyclo[3.2.1]octane). [68] In some embodiments of a compound of formula (J), D is -(C1-C3 alkylene)3- to 6- membered heterocyclyl optionally substituted by one or more R4. In one variation, C1-C3 alkylene as disclosed herein (in formula (J)) is substituted by one or more R4 or unsubstituted. In other variation, C1-C3 alkylene is a linear alkylene such as –CH2-, –CH2-–CH2-. In another variation, C1-C3 alkylene is a branched alkylene, such as –CH(CH3)- and –C(CH3)2-. [69] In some embodiments of a compound of formula (J), D is –CH2-(3- to 6-membered heterocyclyl) optionally substituted by one or more R4. In some embodiments of a compound of formula (J), D is –CH2-CH2-(3- to 6-membered heterocyclyl) optionally substituted by one or more R4. In some embodiments of a compound of formula (J), D is selected from –
CH(CH3)-(3- to 6-membered heterocyclyl) or –C(CH3)2-(3- to 6-membered heterocyclyl), each of which is optionally substituted by one or more R4. In some embodiments of a compound of formula (J), D is –CH2-(4-membered heterocyclyl) optionally substituted by one or more R4. In some embodiments of a compound of formula (J), D is –CH2-(5- membered heterocyclyl) optionally substituted by one or more R4. In some embodiments of a compound of formula (J), D is –CH2-(6-membered heterocyclyl) optionally substituted by one or more R4. [70] In some embodiments of a compound of formula (J), R4 is oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -CN, halogen, C1-C6 alkoxy, C1- C 16 16 16 6 haloalkoxy, -OR , -SR , -S(O)2R , -S(O)2NR17R18, -NR16S(O)2R17, -NR17R18, -C(O)R16, -NR16C(O)R17, -C(O)OR16, wherein each of R4 is optionally substituted by oxo, - OH, halogen or -NH . In some embodiments o 4 2 f a compound of formula (J), R is C1-C6 alkyl. In some embodiments of a compound of formula (J), R4 is methyl. In some embodiments of a compound of formula (J), R4 is -NH2, -F, -OH, -NH-CH3, and -N-(CH3)2. In some embodiments of a compound of formula (J), R4 is -NH2. In some embodiments of a compound of formula (J), R4 is -F. In some embodiments of a compound of formula (J), R4 is -OH. In some embodiments of a compound of formula (J), R4 is -NHCH3. In some embodiments of a compound of formula (J), R4 is -N(CH3)2. [71] In some embodiments of a compound of formula (J), D is selected from the group of but not limited to , , , , , , , , , , , , , , or wherein the wavy lines denote attachment points to rest of the molecule.
[72] In some embodiments of a compound of formula (J), D is . In some embodiments of a compound of formula (J), D is . In some embodiments of a compound of formula (J), D is . In some embodiments of a compound of formula (J), D is . In some embodiments of a compound of formula (J), D is . In some embodiments of a compound of formula (J), D is . In some embodiments of a compound of formula (J), D is . In some embodiments of a compound of formula (J), D is . In some embodiments of a compound of formula (J), D is . In some embodiments of a compound of formula (J), D is . In some embodiments of a compound of formula (J), D is . In some embodiments of a
compound of formula (J), D is . In some embodiments of a compound of formula (J), D is . In some embodiments of a compound of formula (J), D is . [73] In some embodiments of a compound of formula (J), C is selected from the group of but not limited to , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,
,wherein the wavy lines denote attachment points to rest of the molecule. [74] In some embodiments of a compound of formula (J), C is
.In some embodiments of a compound of formula (J), C is
. In some embodiments of a compound of formula (J), C is
. In some embodiments of a compound of formula (J), C is
In some embodiments of a compound of formula (J), C is
In some embodiments of a compound of formula (J), C is
. In
some embodiments of a compound of formula (J), C is
. In some embodiments of a compound of formula (J), C is
. In some embodiments of a compound of formula (J), C is
. In some embodiments of a compound of formula (J), C is In some embodiments of a compound of formula (J), C is
.
In some embodiments of a compound of formula (J), C is
. In some embodiments of a compound of formula (J), C is
In some embodiments of a compound of formula (J), C is In some embodiments of a compound of formula
(J), C is . In some embodiments of a compound of formula (J), C is In
some embodiments of a compound of formula (J), C is . In some embodiments of a compound of formula (J), C is . In some embodiments of a compound of formula (J), C is . In some embodiments of a compound of formula (J), C is . In some embodiments of a compound of formula (J), C is . In some embodiments of a compound of formula (J), C is . In some embodiments of a compound of formula (J), C is . In some embodiments of a compound of formula (J), C is . In some embodiments of a compound of formula (J), C is . In some embodiments of a compound of formula (J), C is . In some embodiments of a compound of formula (J), C is .
[75] In some embodiments of a compound of formula (J), R1 is selected from 5-membered 2 3 heteroaryl, 3- to 6-membered heterocyclyl or -C(O)NR R , wherein 5-membered heteroaryl and 3- to 6-membered heterocyclyl optionally substituted by R5.
[76] In some embodiments of a compound of formula (J), R1a is -C(O)NR2R3. In some embodiments of a compound of formula (J), R1a is C1-C6 alkyl optionally substituted by R5. In some embodiments of a compound of formula (J), R1a is C2-C6 alkenyl optionally substituted by R5. In some embodiments of a compound of formula (J), R1a is C2-C6 alkynyl optionally substituted by R5. In some embodiments of a compound of formula (J), R1a is C3- C6 cycloalkyl optionally substituted by R5. In some embodiments of a compound of formula (J), R1a is 3- to 6-membered heterocyclyl optionally substituted by R5. In some embodiments of a compound of formula (J), R1a is C6 aryl optionally substituted by R5. In some embodiments of a compound of formula (J), R1a is 5- to 10-membered heteroaryl optionally substituted by R5. In some embodiments of a compound of formula (J), R1a is -CN. In some embodiments of a compound of formula (J), R1a is halogen. In some embodiments of a compound of formula (J), R1a is C1-C6 alkoxy. In some embodiments of a compound of formula (J), R1a is C1-C6 haloalkoxy. In some embodiments of a compound of formula (J), R1a is C1-C6haloalkyl. In some embodiments of a compound of formula (J), R1a is -OR13. In some embodiments of a compound of formula (J), R1a is -SR13. In some embodiments of a compound of formula (J), R1a is -S(O)2R13. In some embodiments of a compound of formula (J), R1a is -S(O)2NR14R15. In some embodiments of a compound of formula (J), R1a is -NR13S(O)2R14. In some embodiments of a compound of formula (J), R1a is -NR14R15. In some embodiments of a compound of formula (J), R1a is -C(O)R13. In some embodiments of a compound of formula (J), R1a is -NR13C(O)R14. In some embodiments of a compound of formula (J), R1a is -NR13C(O)NR14R15. In some embodiments of a compound of formula (J), R1a is -C(O)OR13. In some embodiments of a compound of formula (J), R1a is -C(O)ONR14R15. In some embodiments of a compound of formula (J), R1a is -( C1- C3 alkylene)OR13, In some embodiments of a compound of formula (J), R1a is -(C1- C3 alkylene)SR13. In some embodiments of a compound of formula (J), R1a is -(C1- C3 alkylene)S(O)2R13, -(C1-C3 alkylene)S(O)2NR14R15. In some embodiments of a compound of formula (J), R1a is -(C1-C3 alkylene)NR13S(O)2R14. In some embodiments of a compound of formula (J), R1a is -(C1-C3 alkylene)NR14R15. In some embodiments of a compound of formula (J), R1a is -(C1-C3 alkylene)C(O)R13. In some embodiments of a compound of formula (J), R1a is -(C1-C3 alkylene)NR13C(O)R14. In some embodiments of a compound of
formula (J), R1a is -(C1-C3 alkylene)NR13C(O)NR14R15. In some embodiments of a compound of formula (J), R1a is -(C1-C3 alkylene)C(O)OR13. In some embodiments of a compound of formula (J), R1a is -(C1-C3 alkylene)C(O)ONR14R15. In some embodiments of a compound of formula (J), R1a is -(C1-C3 alkylene) ( C3-C8 cycloalkyl). In some embodiments of a compound of formula (J), R1a is -(C1-C3 alkylene)(3- 10-membered heterocyclyl).
[77] In some embodiments of a compound of formula (J), C1-C3 alkylene of R1a is substituted by R5 or unsubstituted. In some embodiments of a compound of formula (J), C1- C3 alkylene of R1a is linear or branched.
[78] In some embodiments of a compound of formula (J), R5 is oxo, C1-C6 alkyl, halogen, C1-C6 alkoxy, C1-C6 haloalkoxy, -OR16, -SR16, -S(O)2R16 , -S(O)2NR17R18, -NR16S(O)2R17, - NR17R18, -C(O)R16, -NR16C(O)R17, -C(O)OR16, C3-C6 cycloalkyl, C6 aryl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocyclyl, wherein each of R5 is optionally substituted by oxo, -OH, halogen or -NH2. In some embodiments of a compound of formula (J), R5 is oxo, C1-C6 alkyl or halogen, wherein each of R5 is optionally substituted by oxo, -OH, halogen or -NH2. In some embodiments of a compound of formula (J), R5 is oxo, methyl, ethyl, cyclopentyl, cyclopentyl substituted by -OH, di-floro substituted phenyl, -NH2, -OH, Cl or F.
[79] In some embodiments of a compound of formula (J), R1 is 5-membered heteroaryl
, wherein the wavy lines denote attachment points to rest of the molecule.
[80] In some embodiments of a compound of formula (J), R1 is 3- to 6-membered heterocyclyl optionally substituted by R5. In some embodiments, R1 is selected from
, wherein the wavy lines denote attachment points to rest of the molecule.
[81] In some embodiments of a compound of formula (J), R1 and Rla are independently - C(O)NR2R3, wherein R2 and R3 are independently hydrogen, -CD3, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, C6, aryl, 5- to 6- membered heteroaryl, , C1-C6haloalkyl, -C(O)R13, -(C1-C3 alkylene)OR13, -(C1- C3 alkylene)SR13, -(C1-C3 alkylene)S(O)2R13, -(C1-C3 alkylene)S(O)2NR14R15, -(C1- C3 alkylene)NR13S(O)2R14, -(C1-C3 alkylene)NR14R15, -(C1-C3 alkylene)C(O)R13, -(C1- C3 alkylene)NR13C(O)R14, -(C1-C3 alkylene)NR13C(O)NR14R15, -(C1- C3 alkylene)C(O)OR13, -(C1-C3 alkylene)C(O)ONR14R15, -(C1-C3 alkylene)(C3-C8 cycloalkyl), -(C1-C3 alkylene) (3 -10-membered heterocyclyl), -(C1-C3 alkylene) C6 aryl or -(C1-C3 alkylene) 5- to 6-membered heteroaryl, wherein each of R and R are independently optionally substituted by R5.
or
, wherein the wavy lines denote attachment points to rest of the molecule. [83] In some embodiments of a compound of formula (J), R1 is selected from
,
wherein the wavy lines denote attachment points to rest of the molecule.
[84] In some embodiments of a compound of formula (J), R1a is selected from ,
, wherein the wavy lines denote attachment points to rest of the
molecule. [85] In some embodiments of a compound of formula (J), X 1 1 and X2 both are N and R is 5-membered heteroaryl, 3- to 6-membered heterocyclyl or –C(O)NR2R3, wherein 5- membered heteroaryl and 3- to 6-membered heterocyclyl optionally substituted by R5. In some embodiments of a compound of formula (J), X 1 1 and X2 both are N and R is– C(O)NR2R3. In some embodiments of a compound of formula (J), X1 and X2 both are N and R1 is –C(O)NHCH3. [86] In some embodiments of a compound of formula (J), X and 1 1 X2 both are N and R is – C(O)NHCH3 and D is -(C1-C3 alkylene)3- to 6-membered heterocyclyl optionally substituted by R4. In some embodiments of a compound of formula (J), X 1 1 and X2 both are N and R is – C(O)NHCH3 and D is
or
[87] In some embodiments of a compound of formula (J), X x 1 1 is N and X2 is CR ; and R is 5-membered heteroaryl, 3- to 6-membered heterocyclyl or –C(O)NR2R3, wherein 5-
membered heteroaryl and 3- to 6-membered heterocyclyl optionally substituted by R5. In some embodiments of a compound of formula (J), X is N and X is CRx; an 1 1 2 d R is – C(O)NR2R3. In some embodiments of a compound of formula (J), X is N and x 1 X is CR ; and R1 is –C(O)NHCH3. [88] In some embodiments of a compound of formula (J), X x 1 1 is N and X2 is CR ; and R is –C(O)NHCH3 and D is -(C1-C3 alkylene)3- to 6-membered heterocyclyl optionally substituted by R4. In some embodiments of a compound of formula (J), X1 is N and X2 is CRx; and R1 is –C(O)NHCH3 and D is
, , o . [89] In some embodiments of a compound of formula (J), X1 is CRx and X2 is N; and R1 is 5-membered heteroaryl, 3- to 6-membered heterocyclyl or –C(O)NR2R3, wherein 5- membered heteroaryl and 3- to 6-membered heterocyclyl optionally substituted by R5. In some embodiments of a compound of formula (J), X is CRx and X i 1 1 2 s N; and R is– C(O)NR2R3. In some embodiments of a compound of formula (J), X i x 1 s CR and X2 is N; and R1 is –C(O)NHCH3. [90] In some embodiments of a compound of formula (J), X1 is CRx and X is N; and R1 is –C(O)NHCH3 and D is -(C1-C3 alkylene)3- to 6-membered heterocyclyl optionally substituted by R4. In some embodiments of a compound of formula (J), X x 1 is CR and X2 is N; and R1 is –C(O)NHCH3 and D is
[91] In some embodiments of a compound of formula (J), X1 and X2 both are N, L is NH and R1a is -C(O)NR2R3, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 6- membered heterocyclyl, C6 aryl, 5- to 10-membered heteroaryl, -CN, halogen, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6haloalkyl, -OR13, -SR13, -S(O)2R13 , -S(O)2NR14R15, -NR13S(O)2R14, -NR14R15, -C(O)R13, -NR13C(O)R14, -NR13C(O)NR14R15, -C(O)OR13, -C(O)ONR14R15, -(C1- C3 alkylene)OR13, -(C1-C3 alkylene)SR13, -(C1-C3 alkylene)S(O)2R13, -(C1- C3 alkylene)S(O)2NR14R15, -(C1-C3 alkylene)NR13S(O)2R14, -(C1-C3 alkylene)NR14R15, -(C1- C3 alkylene)C(O)R13, -(C1-C3 alkylene)NR13C(O)R14, -(C1-
C3 alkylene)NR13C(O)NR14R15, -(C1-C3 alkylene)C(O)OR13, -(C1- C3 alkylene)C(O)ONR14R15, -(C1-C3 alkylene)(C3-C8 cycloalkyl) or -(C1-C3 alkylene) (3 -10- membered heterocyclyl); wherein each of R1a is optionally substituted by R5. In some embodiments of a compound of formula (J), X1 and X2 both are N; L is NH and R1a is - C(O)NR R . In some embodiments of a compound of formula (J), X1 and X2both are N; L is NH and R1a is -C(O)NHCH3.
[92] In some embodiments of a compound of formula (J), X1 and X2 both are N; L is NH and R1a is -C(O)NHCH3 and C is azepanyl, C3-C10 monocyclic or bicyclic cycloalkyl or -(C1- C3 alkylene) C7-C10 cycloalkyl, wherein each of C is optionally substituted by R4; In some embodiments of a compound of formula (J), X1 and X2 both are N; L is NH and R1a is -
[93] In some embodiments of a compound of formula (J), X1 is N and X2 is CRX; L is NH and R1a is -C(O)NR2R3, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 6- membered heterocyclyl, C6, aryl, 5- to 10-membered heteroaryl, -CN, halogen, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6haloalkyl, -OR13, -SR13, -S(O)2R13 , -S(O)2NR14R15, -NR13S(O)2R14,
-NR14R15, -C(O)R13, -NR13C(O)R14, -NR13C(O)NR14R15, -C(O)OR13, -C(O)ONR14R15, -( C1- C3 alkylene)OR13, -(C1-C3 alkylene)SR13, -(C1-C3 alkylene)S(O)2R13, -(C1- C3 alkylene)S(O)2NR14R15, -(C1-C3 alkylene)NR13S(O)2R14, -(C1-C3 alkylene)NR14R15, -(C1- C3 alkylene)C(O)R13, -(C1-C3 alkylene)NR13C(O)R14, -(C1- C3 alkylene)NR13C(O)NR14R15, -(C1-C3 alkylene)C(O)OR13, -(C1- C3 alkylene)C(O)ONR14R15, -(C1-C3 alkylene)(C3-C8 cycloalkyl) or -(C1-C3 alkylene) (3 -10- membered heterocyclyl); wherein each of R1a is optionally substituted by R5. In some embodiments of a compound of formula (J), X1 is N and X2 is CRX; L is NH and R1a is - C(O)NR2R3. In some embodiments of a compound of formula (J), X1 is N and X2 is CRX; L is NH and R1a is -C(O)NHCH3.
[94] In some embodiments of a compound of formula (J), X1 is N and X2 is CRX; L is NH and R1a is -C(O)NHCH3 and C is azepanyl, C3-C10 monocyclic or bicyclic cycloalkyl or -(C1- C3 alkylene) C7-C10 cycloalkyl, wherein each of C is optionally substituted by R4; In some embodiments of a compound of formula (J), X1 is N and X2 is CRX; L is NH and R1a is -
[95] In some embodiments of a compound of formula (J), X1 is CRX and X2 is N; L is NH and R1a is -C(O)NR2R3, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 6- membered heterocyclyl, C6 aryl, 5- to 10-membered heteroaryl, -CN, halogen, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6haloalkyl, -OR13, -SR13, -S(O)2R13 , -S(O)2NR14R15, -NR13S(O)2R14, -NR14R15, -C(O)R13, -NR13C(O)R14, -NR13C(O)NR14R15, -C(O)OR13, -C(O)ONR14R15, -(C1- C3 alkylene)OR13, -(C1-C3 alkylene)SR13, -(C1-C3 alkylene)S(O)2R13, -(C1- C3 alkylene)S(O)2NR14R15, -(C1-C3 alkylene)NR13S(O)2R14, -(C1-C3 alkylene)NR14R15, -(C1- C3 alkylene)C(O)R13, -(C1-C3 alkylene)NR13C(O)R14, -(C1-
C3 alkylene)NR13C(O)NR14R15, -(C1-C3 alkylene)C(O)OR13, -(C1- C3 alkylene)C(O)ONR14R15, -(C1-C3 alkylene)(C3-C8 cycloalkyl) or -(C1-C3 alkylene) (3 -10- membered heterocyclyl); wherein each of R1a is optionally substituted by R5. In some embodiments of a compound of formula (J), X1 is CRX and X2 is N; L is NH and R1a is - C(O)NR2R3. In some embodiments of a compound of formula (J), X1 is CRX and X2 is N; L is
NH and R1a is -C(O)NHCH3.
[96] In some embodiments of a compound of formula (J), X1 is CRX and X2is N; L is NH and R1a is -C(O)NHCH3 and C is azepanyl, C3-C10 monocyclic or bicyclic cycloalkyl or -(C1- C3 alkylene)C7-C10 cycloalkyl, wherein each of C is optionally substituted by R4; In some embodiments of a compound of formula (J), X1 is CRX and X2 is N; L is NH and R1a is -
[97] In some embodiments of a compound of formula (J), X1 and X2both are N; L is O and R1a is -C(O)NR2R3, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 6- membered heterocyclyl, C6 aryl, 5- to 10-membered heteroaryl, -CN, halogen, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6haloalkyl, -OR13, -SR13, -S(O)2R13 , -S(O)2NR14R15, -NR13S(O)2R14, -NR14R15, -C(O)R13, -NR13C(O)R14, -NR13C(O)NR14R15, -C(O)OR13, -C(O)ONR14R15, -(C1- C3 alkylene)OR13, -(C1-C3 alkylene)SR13, -(C1-C3 alkylene)S(O)2R13, -(C1- C3 alkylene)S(O)2NR14R15, -(C1-C3 alkylene)NR13S(O)2R14, -(C1-C3 alkylene)NR14R15, -(C1- C3 alkylene)C(O)R13, -(C1-C3 alkylene)NR13C(O)R14, -(C1- C3 alkylene)NR13C(O)NR14R15, -(C1-C3 alkylene)C(O)OR13, -(C1-
C3 alkylene)C(O)ONR14R15, -(C1-C3 alkylene)(C3-C8 cycloalkyl) or -(C1-C3 alkylene) (3 -10- membered heterocyclyl); wherein each of R1a is optionally substituted by R5. In some embodiments of a compound of formula (J), X1 and X2 both are N, L is O and R1a is -
C(O)NR2R3 . In some embodiments of a compound of formula (J), X1 and X2 both are N, L is O and R1a is -C(O)NHCH3.
[98] In some embodiments of a compound of formula (J), Xi and X2 both are N, L is O and R1a is -C(O)NHCH3 and C is azepanyl, C3-C10 monocyclic or bicyclic cycloalkyl or -(C1- C3 alkylene)C7-C10 cycloalkyl, wherein each of C is optionally substituted by R4; In some embodiments of a compound of formula (J), X1 and X2 both are N, L is O and R1a is -
[99] In some embodiments of a compound of formula (J), X1 is N and X2 is CRX; L is O and R1a is -C(O)NR2R3, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 6- membered heterocyclyl, C6 aryl, 5- to 10-membered heteroaryl, -CN, halogen, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6haloalkyl, -OR13, -SR13, -S(O)2R13 , -S(O)2NR14R15, -NR13S(O)2R14, -NR14R15, -C(O)R13, -NR13C(O)R14, -NR13C(O)NR14R15, -C(O)OR13, -C(O)ONR14R15, -(C1- C3 alkylene)OR13, -(C1-C3 alkylene)SR13, -(C1-C3 alkylene)S(O)2R13, -(C1- C3 alkylene)S(O)2NR14R15, -(C1-C3 alkylene)NR13S(O)2R14, -(C1-C3 alkylene)NR14R15, -(C1- C3 alkylene)C(O)R13, -(C1-C3 alkylene)NR13C(O)R14, -(C1-
C3 alkylene)NR13C(O)NR14R15, -(C1-C3 alkylene)C(O)OR13, -(C1- C3 alkylene)C(O)ONR14R15, -(C1-C3 alkylene)(C3-C8 cycloalkyl) or -(C1-C3 alkylene) (3 -10- membered heterocyclyl); wherein each of R1a is optionally substituted by R5. In some embodiments of a compound of formula (J), X1 is N and X2 is CRX; L is O and R1a is - C(O)NR2R3. In some embodiments of a compound of formula (J), X1 is N and X2 is CRX; L is O and R1a is -C(O)NHCH3.
[100] In some embodiments of a compound of formula (J), X1 is N and X2 is CRX; L is O and R1a is -C(O)NHCH3 and C is azepanyl, C3-C10 monocyclic or bicyclic cycloalkyl or -(C1- C3 alkylene)C7-C10 cycloalkyl, wherein each of C is optionally substituted by R4; In some embodiments of a compound of formula (J), X1 is N and X2 is CRX; L is O and R1a is -
[101] In some embodiments of a compound of formula (J), X1 is CRX and X2 is N; L is O and R1a is -C(O)NR2R3, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 6- membered heterocyclyl, C6, aryl, 5- to 10-membered heteroaryl, -CN, halogen, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6haloalkyl, -OR13, -SR13, -S(O)2R13 , -S(O)2NR14R15, -NR13S(O)2R14, -NR14R15, -C(O)R13, -NR13C(O)R14, -NR13C(O)NR14R15, -C(O)OR13, -C(O)ONR14R15, -(C1- C3 alkylene)OR13, -(C1-C3 alkylene)SR13, -(C1-C3 alkylene)S(O)2R13, -(C1- C3 alkylene)S(O)2NR14R15, -(C1-C3 alkylene)NR13S(O)2R14, -(C1-C3 alkylene)NR14R15, -(C1- C3 alkylene)C(O)R13, -(C1-C3 alkylene)NR13C(O)R14, -(C1-
C3 alkylene)NR13C(O)NR14R15, -(C1-C3 alkylene)C(O)OR13, -(C1- C3 alkylene)C(O)ONR14R15, -(C1-C3 alkylene)(C3-C8 cycloalkyl) or -(C1-C3 alkylene) (3 -10- membered heterocyclyl); wherein each of R1a is optionally substituted by R5. In some embodiments of a compound of formula (J), X1 is CRX and X2 is N; L is O and R1a is - C(O)NR2R3. In some embodiments of a compound of formula (J), X1 is CRX and X2 is N; L is O and R1a is -C(O)NHCH3.
[102] In some embodiments of a compound of formula (J), X1 is CRX and X2 is N; L is O and R1a is -C(O)NHCH3 and C is azepanyl, C3-C10 monocyclic or bicyclic cycloalkyl or -(C1- C3 alkylene)C7-C10 cycloalkyl, wherein each of C is optionally substituted by R4; In some embodiments of a compound of formula (J), X1 is CRX and X2 is N; L is O and R1a is -
[103] It is understood that each description of Xb X2, D, Rx and R1 may be independently combined with each description of Xi, X2, D, Rx and R1 the same as if each and every combination were specifically and individually listed. Similarly it is also understood that each description of Xb X2, C, Rxand R1a may be independently combined with each description of Xi, X2, C, Rx and R1a the same as if each and every combination were specifically and individually listed. [104] In some embodiments, a compound of formula (J) is a compound of formula (IA):
formula (IA), wherein Xb X2, C, R1a, L and Rx as detailed herein.
[105] In some embodiments, a compound of formula (J) is any of the compound of formula (IA-1 to IA-10):
wherein C, R1a, R4 and Rx as detailed herein.
[106] In some embodiments, a compound of formula (J) is a compound of formula (IB):
wherein X X2, C, L, R2, R3 and Rx as detailed herein.
[107] In some embodiments, a compound of formula (J) is any of the compound of formula
[108] In some embodiments, a compound of formula (J) is a compound of formula (II):
wherein Xi, X2, R1, R4 and Rx as detailed herein.
[109] In some embodiments, a compound of formula (J) is any of the compound of formula
(Il-a) to (II-c):
[110] In some embodiments, a compound of formula (J) is a compound of formula (III):
wherein Xb X2, R1, R4 and Rx as detailed herein.
[ 111] In some embodiments, a compound of formula (J) is a compound of formula (Ill-a) to (III-c):
[112] In some embodiments, a compound of formula (J) is a compound of formula (IV):
wherein Xi, X2, D, R2, R3 and Rx as detailed herein.
[113] In some embodiments, a compound of formula (J) is a compound of formula (IV-a) to (IV-c):
wherein D, R2, R3 and Rx as detailed herein.
[114] In some embodiments, a compound of formula (J) is a compound of formula (V):
wherein X X2, R2, R3, R4 and Rx as detailed herein.
[115] In some embodiments, a compound of formula (J) is a compound of formula (V-a) to
[116] In some embodiments, a compound of formula (J) is a compound of formula (VI):
wherein X X2, R2, R3, R4 and Rx as detailed herein.
[117] In some embodiments, a compound of formula (J) is a compound of formula (Vl-a) to
(VI-f):
[118] In some embodiments, a compound of formula (J) is a compound of formula (VII):
[119] In some embodiments, a compound of formula (J) is a compound of formula (Vll-a) to (Vll-f):
wherein R2, R3, R4 and Rx are as detailed herein.
[120] In some embodiments, a compound of formula (J) is a compound of formula (VIII):
wherein Xb X2, R2, R3, R4 and Rx as detailed herein.
wherein R2 , R3, R4 and Rx are as detailed herein. [122] Also provided are salts of compounds referred to herein, such as pharmaceutically acceptable salts. The invention also includes any or all of the stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomers or other forms of the compounds described. [123] A compound as detailed herein may in one aspect be in a purified form and compositions comprising a compound in purified forms are detailed herein. Compositions comprising a compound as detailed herein or a salt thereof are provided, such as compositions of substantially pure compounds. In some embodiments, a composition containing a compound as detailed herein or a salt thereof is in substantially pure form. Unless otherwise stated, “substantially pure” intends a composition that contains no more than 35 % impurity, wherein the impurity denotes a compound other than the compound comprising the majority of the composition or a salt thereof. In some embodiments, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains no more than 25 %, 20%, 15%, 10%, or 5% impurity. In some embodiments, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 3 %, 2%, 1% or 0.5% impurity. [124] Representative compounds of formula (J) are listed in table 1. It is understood that individual enantiomers and diastereomers are included in the generic compound structures shown in table 1. Specific synthetic methods for preparing compounds No. 1.1, 1.2, 1.36, 1.52 to 1.95 of table 1 are provided example herein. [125] The compounds No. 1.3 to 1.35, 1.37 to 1.51 and 1.96 to 1.354 in table 1 can be prepared in a manner analogous to the techniques used in connection with the preparation of the compounds No. 1.1, 1.2, 1.36, 1.52 to 1.95 given in the table 1 and in accordance, using
appropriate, analogous starting materials and by utilizing the general synthetic schemes 1 to 9 illustrated below. Table-1: Compounds
[126] In some embodiments, provided herein are compounds described in table 1, or a salt, polymorph, solvate, enantiomer, stereoisomer or tautomer thereof, and uses thereof. [127] The embodiments and variations described herein are suitable for compounds of any formulae detailed herein, where applicable. [128] Representative examples of compounds detailed herein, including intermediates and final compounds according to the present disclosure are depicted herein. It is understood that in one aspect, any of the compounds may be used in the methods detailed herein, including, where applicable, intermediate compounds that may be isolated and administered to an individual. [129] The compounds depicted herein may be present as salts even if salts are not depicted and it is understood that the present disclosure embraces all salts and solvates of the compounds depicted here, as well as the non-salt and non-solvate form of the compound, as is well understood by the skilled artisan. In some embodiments, the salts of the compounds provided herein are pharmaceutically acceptable salts. Where one or more tertiary amine moiety is present in the compound, the N-oxides are also provided and described.
[130] Where tautomeric forms may be present for any of the compounds described herein, each and every tautomeric form is intended even though only one or some of the tautomeric forms may be explicitly depicted. The tautomeric forms specifically depicted may or may not be the predominant forms in solution or when used according to the methods described herein. [131] The present disclosure also includes any or all of the stereochemical forms, including any enantiomeric or diastereomeric forms of the compounds described. The structure or name is intended to embrace all possible stereoisomers of a compound depicted, and each unique stereoisomer has a compound number bearing a suffix “a”, “b”, etc. All forms of the compounds are also embraced by the invention, such as crystalline or non-crystalline forms of the compounds. Compositions comprising a compound of the invention are also intended, such as a composition of substantially pure compound, including a specific stereochemical form thereof, or a composition comprising mixtures of compounds of the invention in any ratio, including two or more stereochemical forms, such as in a racemic or non-racemic mixture. [132] The invention also intends isotopically-labeled and/or isotopically-enriched forms of compounds described herein. The compounds herein may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. In some embodiments, the compound is isotopically-labeled, such as an isotopically-labeled compound of the formula (J) or variations thereof described herein, where a fraction of one or more atoms are replaced by an isotope of the same element. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, chlorine, such as 2H, 3H, 11C, 13C, 14C 13N, 15O, 17O, 32P, 35S, 18F, 36Cl. Certain isotope labeled compounds (e.g. 3H and 14C) are useful in compound or substrate tissue distribution studies. Incorporation of heavier isotopes such as deuterium (2H) can afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life, or reduced dosage requirements and, hence may be preferred in some instances. [133] Isotopically-labeled compounds of the present invention can generally be prepared by standard methods and techniques known to those skilled in the art or by procedures similar to those described in the accompanying Examples substituting appropriate isotopically-labeled reagents in place of the corresponding non-labeled reagent.
[134] The invention also includes any or all metabolites of any of the compounds described. The metabolites may include any chemical species generated by a biotransformation of any of the compounds described, such as intermediates and products of metabolism of the compound, such as would be generated in vivo following administration to a human. [135] Articles of manufacture comprising a compound described herein, or a salt or solvate thereof, in a suitable container are provided. The container may be a vial, jar, ampoule, preloaded syringe, i.v. bag, and the like. [136] Preferably, the compounds detailed herein are orally bioavailable. However, the compounds may also be formulated for parenteral (e.g., intravenous) administration. [137] One or several compounds described herein can be used in the preparation of a medicament by combining the compound or compounds as an active ingredient with a pharmacologically acceptable carrier, which are known in the art. Depending on the therapeutic form of the medication, the carrier may be in various forms. In one variation, the manufacture of a medicament is for use in any of the methods disclosed herein, e.g., for the treatment of cancer. General synthetic schemes [138] The compounds of the invention may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter (such as the schemes provided in the Examples below). In the following process descriptions, the symbols when used in the formulae depicted are to be understood to represent those groups described above in relation to the formulae herein. [139] Where it is desired to obtain a particular enantiomer of a compound, this may be accomplished from a corresponding mixture of enantiomers using any suitable conventional procedure for separating or resolving enantiomers. Thus, for example, diastereomeric derivatives may be produced by reaction of a mixture of enantiomers, e.g., a racemate, and an appropriate chiral compound. The diastereomers may then be separated by any convenient means, for example by crystallization and the desired enantiomer recovered. In another resolution process, a racemate may be separated using chiral High Performance Liquid Chromatography. Alternatively, if desired a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described.
[140] Chromatography, recrystallization and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular isomer of a compound or to otherwise purify a product of a reaction. [141] Solvates and/or polymorphs of a compound provided herein or a pharmaceutically acceptable salt thereof are also contemplated. Solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are often formed during the process of crystallization. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and/or solubility. Various factors such as the recrystallization solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate. [142] In some embodiments, compounds of the present invention (collectively, a compound of formula (J), (I), (IA), (IA-1) to (IA-10), (IB) , (IB-1) to (IB-10), (II), (II-a) to (II-c), (III), (III-a) to (III-c), (IV), (IV-a) to (IV-c), (V), (V-a) to (V-f), (VI), (VI-a) to (VI-f)) (VII), (VII- a) to (VII-f), (VIII), (VIII-a) to (VIII-f)) may be synthesized according to Scheme-1 to Scheme-9. Scheme-1:
wherein, X 1 x 1, X2, D, R and R are as defined in formula (J).
Scheme-2:
wherein, X1, X2, D, R1 and Rxare as defined in formula (J). Scheme-3:
wherein, X, X, D, R2 , R3 a x 1 2 nd Rare as defined for formula (J). Scheme-4:
wherein, X 1a x 1, X2, C, R and Rare as defined in formula (J).
Scheme-5:
wherein, X1, X2, C, R1a and Rxare as defined in formula (J). Scheme-6:
wherein, X, X, C, R1a a x 1 2 nd Rare as defined in formula (J). Scheme-7:
wherein, X 1a x 1, X2, C, R and Rare as defined in formula (J).
Scheme-8:
wherein, X1, X2, C, R2 , R3 and Rxare as defined for formula (J). Scheme-9:
wherein, X 2 3 x 1, X2, C, R , R and R are as defined for formula (J). Pharmaceutical Compositions and Formulations [143] Pharmaceutical compositions of any of the compounds detailed herein are embraced by this disclosure. Thus, the present disclosure includes pharmaceutical compositions comprising a compound as detailed herein or a salt thereof and a pharmaceutically acceptable carrier or excipient. In one aspect, the pharmaceutically acceptable salt is an acid addition salt, such as a salt formed with an inorganic or organic acid. Pharmaceutical compositions may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration or a form suitable for administration by inhalation.
[144] A compound as detailed herein may in one aspect be in a purified form and compositions comprising a compound in purified forms are detailed herein. Compositions comprising a compound as detailed herein or a salt thereof are provided, such as compositions of substantially pure compounds. In some embodiments, a composition containing a compound as detailed herein or a salt thereof is in substantially pure form. [145] In one variation, the compounds herein are synthetic compounds prepared for administration to an individual. In another variation, compositions are provided containing a compound in substantially pure form. In another variation, the present disclosure embraces pharmaceutical compositions comprising a compound detailed herein and a pharmaceutically acceptable carrier. In another variation, methods of administering a compound are provided. The purified forms, pharmaceutical compositions and methods of administering the compounds are suitable for any compound or form thereof detailed herein. [146] A compound detailed herein or salt thereof may be formulated for any available delivery route, including an oral, mucosal (e.g., nasal, sublingual, vaginal, buccal or rectal), parenteral (e.g., intramuscular, subcutaneous or intravenous), topical or transdermal delivery form. A compound or salt thereof may be formulated with suitable carriers to provide delivery forms that include, but are not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultices), pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal spray or inhalers), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water-in-oil liquid emulsions), solutions and elixirs. [147] One or several compounds described herein or a salt thereof can be used in the preparation of a formulation, such as a pharmaceutical formulation, by combining the compound or compounds, or a salt thereof, as an active ingredient with a pharmaceutically acceptable carrier, such as those mentioned above. Depending on the therapeutic form of the system (e.g., transdermal patch vs. oral tablet), the carrier may be in various forms. In addition, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re- wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants. Formulations comprising the compound may also contain other substances which have valuable therapeutic properties. Pharmaceutical formulations may be prepared by known pharmaceutical methods. Suitable
formulations can be found, e.g., in Remington’s Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA, 20th ed. (2000), which is incorporated herein by reference. [148] Compounds as described herein may be administered to individuals in a form of generally accepted oral compositions, such as tablets, coated tablets, and gel capsules in a hard or in soft shell, emulsions or suspensions. Examples of carriers, which may be used for the preparation of such compositions, are lactose, corn starch or its derivatives, talc, stearate or its salts, etc. Acceptable carriers for gel capsules with soft shell are, for instance, plant oils, wax, fats, semisolid and liquid poly-ols, and so on. In addition, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants. [149] Any of the compounds described herein can be formulated in a tablet in any dosage form described, for example, a compound as described herein or a salt thereof can be incorporated in tablet in an amount ranging from about 1 mg to about 1000 mg. [150] Compositions comprising a compound provided herein are also described. In one variation, the composition comprises a compound or salt thereof and a pharmaceutically acceptable carrier or excipient. In another variation, a composition of substantially pure compound is provided. Methods of Use [151] Compounds and compositions detailed herein, such as a pharmaceutical composition containing a compound of any formula provided herein or a salt thereof and a pharmaceutically acceptable carrier or excipient, may be used in methods of administration and treatment as provided herein. The compounds and compositions may also be used in in vitro methods, such as in vitro methods of administering a compound or composition to cells for screening purposes and/or for conducting quality control assays. [152] Provided herein is a method of treating a disease in an individual comprising administering an effective amount of a compound of the present invention (collectively, a compound of formula (J), (I), (IA), (IA-1) to (IA-10), (IB) , (IB-1) to (IB-10), (II), (II-a) to (II-c), (III), (III-a) to (III-c), (IV), (IV-a) to (IV-c), (V), (V-a) to (V-f), (VI), (VI-a) to (VI-f)) (VII), (VII-a) to (VII-f), (VIII), (VIII-a) to (VIII-f)) or any embodiment, variation or aspect
thereof or the present compounds or the compounds detailed or described herein) or a pharmaceutically acceptable salt thereof, to the individual. Further provided herein is a method of treating a proliferative disease in an individual, comprising administering an effective amount of the compound of the present invention (collectively, a compound of formula (J), (I), (IA), (IA-1) to (IA-10), (IB) , (IB-1) to (IB-10), (II), (II-a) to (II-c), (III), (III- a) to (III-c), (IV), (IV-a) to (IV-c), (V), (V-a) to (V-f), (VI), (VI-a) to (VI-f)) (VII), (VII-a) to (VII-f), (VIII), (VIII-a) to (VIII-f)) or a pharmaceutically acceptable salt thereof, to the individual. Also provided herein is a method of treating cancer, pulmonary arterial hypertension (PAH) or idiopathic pulmonary fibrosis (IPF) in an individual comprising administering an effective amount of the compound of formula (J) or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the compound is administered to the individual according to a dosage and/or method of administration described herein. [153] Another aspect of the invention relates to a method of treating a disease or disorder associated with Checkpoint kinase. The method involves administering to a patient in need of a treatment for diseases or disorders associated with Checkpoint kinase an effective amount of the compositions and compounds of the present invention (collectively, a compound of formula (J), (I), (IA), (IA-1) to (IA-10), (IB) , (IB-1) to (IB-10), (II), (II-a) to (II-c), (III), (III- a) to (III-c), (IV), (IV-a) to (IV-c), (V), (V-a) to (V-f), (VI), (VI-a) to (VI-f)) (VII), (VII-a) to (VII-f), (VIII), (VIII-a) to (VIII-f)). [154] Another aspect of the invention is directed to a method inhibiting Checkpoint kinase. The method involves administering to a patient in need thereof an effective amount of the compositions or compounds of the present invention (collectively, a compound of formula (J), (I), (IA), (IA-1) to (IA-10), (IB) , (IB-1) to (IB-10), (II), (II-a) to (II-c), (III), (III-a) to (III-c), (IV), (IV-a) to (IV-c), (V), (V-a) to (V-f), (VI), (VI-a) to (VI-f)) (VII), (VII-a) to (VII- f), (VIII), (VIII-a) to (VIII-f)). [155] The use of a compound of the present invention (collectively, a compound of formula (J), (I), (IA), (IA-1) to (IA-10), (IB) , (IB-1) to (IB-10), (II), (II-a) to (II-c), (III), (III-a) to (III-c), (IV), (IV-a) to (IV-c), (V), (V-a) to (V-f), (VI), (VI-a) to (VI-f)) (VII), (VII-a) to (VII- f), (VIII), (VIII-a) to (VIII-f)) for the manufacture of a medicament for the treatment of a proliferative disease such as cancer, pulmonary arterial hypertension (PAH) and idiopathic pulmonary fibrosis (IPF).
[156] The use of a compound of the present invention (collectively, a compound of formula (J), (I), (IA), (IA-1) to (IA-10), (IB) , (IB-1) to (IB-10), (II), (II-a) to (II-c), (III), (III-a) to (III-c), (IV), (IV-a) to (IV-c), (V), (V-a) to (V-f), (VI), (VI-a) to (VI-f)) (VII), (VII-a) to (VII- f), (VIII), (VIII-a) to (VIII-f)) for the manufacture of a medicament for the treatment of cancer, wherein the cancer is selected from carcinomas, for example carcinomas of the bladder, breast, colon, kidney, epidermis, liver, lung, oesophagus, gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, gastrointestinal system, or skin, hematopoieitic tumours such as leukaemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non- Hodgkin's lymphoma, hairy cell lymphoma, or Burkett's lymphoma; hematopoieitic tumours of myeloid lineage, for example acute and chronic myelogenous leukaemias, myelodysplastic syndrome, or promyelocytic leukaemia; p53 negative or mutated tumours; MYC oncogene- driven cancer such as B-cell lymphoma, leukemia, neuroblastoma, breast cancer or lung cancer; thyroid follicular cancer; tumours of mesenchymal origin, for example fibrosarcoma or habdomyosarcoma; tumours of the central or peripheral nervous system, for example astrocytoma, neuroblastoma, glioma or schwannoma; melanoma; seminoma; teratocarcinoma; osteosarcoma; xeroderma pigmentosum; keratoctanthoma; thyroid follicular cancer; Ewing's sarcoma or Kaposi's sarcoma. The use of a compound of the present invention (collectively, a compound of formula (J), (I), (IA), (IA-1) to (IA-10), (IB) , (IB-1) to (IB-10), (II), (II-a) to (II-c), (III), (III-a) to (III-c), (IV), (IV-a) to (IV-c), (V), (V-a) to (V- f), (VI), (VI-a) to (VI-f)) (VII), (VII-a) to (VII-f), (VIII), (VIII-a) to (VIII-f)) for the manufacture of a medicament for the treatment of cancer, wherein the cancer is one which is characterized by a defective DNA repair mechanism or defective cell cycle. [157] The use of a compound of the present invention (collectively, a compound of formula (J), (I), (IA), (IA-1) to (IA-10), (IB) , (IB-1) to (IB-10), (II), (II-a) to (II-c), (III), (III-a) to (III-c), (IV), (IV-a) to (IV-c), (V), (V-a) to (V-f), (VI), (VI-a) to (VI-f)) (VII), (VII-a) to (VII- f), (VIII), (VIII-a) to (VIII-f)) for the manufacture of a medicament for the treatment of cancer, wherein the cancer is High grade serious ovarian cancer (HGSOC), Triple negative breast cancer (TNBC) and Small cell lung cancer (SCLC). CCNE1amplification occurs in approximately 20% of the HGSOC tumors. CCNE1amp is known to increase replication stress (RS) and genomic instability, leading to increased reliance on Checkpoint kinase 1 (CHK-1). Hence, CCNE1 amplification correlates to clinical response to CHK-1 inhibitors (Lee et al Lancet Oncol. 201819(2), 207). Increased DNA repair and cell cycle checkpoint activation remain as the foremost reasons behind TNBC tumor resistance to chemotherapy and PARP
inhibitor resistance. Synergy has been observed with CHK-1 inhibitors and PARP inhibitors in TNBC with elevated RAD51 expression (Mani et al. Breast Cancer Research (2019) 21:104). CHK-1 inhibition may be especially effective in SCLC with MYC amplification or MYC protein overexpression. CHK-1 inhibitors exhibited strong single-agent efficacy, augmented the effects of cisplatin or the PARP inhibitor olaparib, and improved the response of platinum-resistant models. (Cancer Res2017, 77(14), 3870 - 3884 – Sen et al). [158] The use of a compound of the present invention (collectively, a compound of formula (J), (I), (IA), (IA-1) to (IA-10), (IB) , (IB-1) to (IB-10), (II), (II-a) to (II-c), (III), (III-a) to (III-c), (IV), (IV-a) to (IV-c), (V), (V-a) to (V-f), (VI), (VI-a) to (VI-f)) (VII), (VII-a) to (VII- f), (VIII), (VIII-a) to (VIII-f)) for the manufacture of a medicament for the treatment of a idiopathic pulmonary fibrosis (IPF). IPF is a chronic scarring lung disease characterized by progressive and irreversible decline in lung function. It is closely associated with concomitantly occurring pulmonary arterial hypertension, wherein there is aberrant proliferation of arterial cells, vascular remodeling, inflammation and differentiation of fibroblasts into myofibroblasts. The goal of treatment in IPF is to manage the symptoms, retard disease progression, prevent acute exacerbations, and prolong survival. Certain medications like pirfenidone or nintedanib may slow the progression of the disease and lung transplantation is an option for patients who can undergo a major transplant surgery (Bargagli et.al., Pulmonol.2019;25(3):149). A number of agents are currently being investigated in Phase II clinical trials for IPF, including the monoclonal antibodies simtuzumab, tralokinumab, lebrikizumab and FG-3019, a lysophosphatidic acid receptor antagonist (BMS- 986020). These molecules are directed against several growth factors and cytokines that are known to play a role in the proliferation, activation, differentiation or inappropriate survival of fibroblasts (Sgalla et.al., Expert Opin Biol Ther.2020 Jul;20(7):779-786). [159] The use of a compound of the present invention (collectively, a compound of formula (J), (I), (IA), (IA-1) to (IA-10), (IB) , (IB-1) to (IB-10), (II), (II-a) to (II-c), (III), (III-a) to (III-c), (IV), (IV-a) to (IV-c), (V), (V-a) to (V-f), (VI), (VI-a) to (VI-f)) (VII), (VII-a) to (VII- f), (VIII), (VIII-a) to (VIII-f)) for the manufacture of a medicament for the treatment of pulmonary arterial hypertension (PAH). Pulmonary arterial hypertension (PAH) is a debilitating disease associated with progressive vascular remodeling of distal pulmonary arteries leading to elevation of pulmonary artery pressure, right ventricular hypertrophy, and death. Although presenting high levels of DNA damage that normally jeopardize their
viability, pulmonary artery smooth muscle cells (PASMCs) from patients with PAH exhibit a cancer-like proproliferative and apoptosis-resistant phenotype accounting for vascular lumen obliteration. CHK1 expression is markedly increased in isolated PASMCs and distal PAs from patients with PAH. Moreover, multiple complementary animal models recapitulating the disease, including monocrotaline rats and the simian immunodeficiency virus–infected macaques show better effects with CHK1 inhibition (Bourgeois et.al., Arterioscler Thromb Vasc Biol.2019;39:1667–1681). [160] Using a pharmacological and molecular loss of function approach, it has been depicted that CHK1 promotes PAH-PASMCs proliferation and resistance to apoptosis. In- vivo, pharmacological inhibition of CHK1 significantly reduces vascular remodeling and improves hemodynamic parameters in experimental rat models of PAH (Bourgeois et.al., Arterioscler Thromb Vasc Biol.2019;39:1667–1681). [161] The disclosed compounds of the present invention can be administered in effective amounts to treat or prevent a disorder and/or prevent the development thereof in subjects. Combination Therapy [162] The compound of the present invention may be administered either simultaneously with, or before or after, one or more other therapeutic agents. The compound of the present invention may be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition as the other agents. [163] Dysregulated DNA damage response genes are involved in pro-proliferative and apoptosis resistance characteristics of PAH-PASMCs. Genes involved in DNA repair pathway such as PARP-1, PIM-1, EYA3 and CHK1 are upregulated in PAH-PASMCs leading to increased DNA repair, proliferation and reduced apoptosis. Studies have shown specific pharmacological inhibitors like ABT-888 (PARP1 inhibitor), SGI-1776 (PIM1 inhibitor), Benzarone (EYA3 inhibitor), and MK-8776, (CHK1 inhibitor) which downregulate their target genes, leading to reduced proliferation and increased apoptosis, suggesting their therapeutic potential as standalone or in combination (Sharma et.al., Genes 2020, 11, 1224; doi:10.3390/genes11101224). Inhibition of PARP-1, HDACs, and BRD4 has also been reported to improve vascular remodeling in PAH animal models (Meloche et.al., Circulation. 2014;129:786–797). Also, combining CHK1 inhibitor along with DNA damaging agents such as etoposide and 5-hydroxy uracil has been speculated to reduce
proliferation and increase apoptosis. Combination of Nintedanib and CHK1 inhibitor has been studied in different models for PAH. [164] In some embodiments, the methods described herein comprise the additional step of co-administering to a subject in need thereof a second therapy e.g., an additional cancer therapeutic agent or an additional cancer treatment. Exemplary additional cancer therapeutic agents include for example, In one embodiment, the other active agent is selected from the group consisting of but not limited to antimetabolites, tubulin targeting agents, DNA binder and topoisomerase II inhibitors, alkylating agents, monoclonal antibodies, hormonal therapy, signal transduction inhibitors, proteasome inhibitors, DNA methyl transferases, cytokines and retinoids, hypoxia triggered DNA damaging agents, immunomodulaters (e.g. CTLA-4, LAG- 3, PD-1 antagonists etc. ) and monoclonal antibodies. [165] In some embodiments, the additional cancer therapeutic agent is a chemotherapy agent. Examples of chemotherapeutic agents used in cancer therapy include, for example, antimetabolites (e.g., folic acid, purine, and pyrimidine derivatives), alkylating agents (e.g., nitrogen mustards, nitrosoureas, platinum, alkyl sulfonates, hydrazines, triazenes, aziridines, spindle poison, cytotoxic agents, topoisomerase inhibitors and others), and hypomethylating agents (e.g. , decitabine (5-aza-deoxycytidine), zebularine, isothiocyanates, azacitidine (5- azacytidine), 5-flouro-2'-deoxycytidine, 5,6-dihydro-5-azacytidine and others). Exemplary agents include Aclarubicin, Actinomycin, Alitretinoin, Altretamine, Aminopterin, Aminolevulinic acid, Amrubicin, Amsacrine, Anagrelide, Arsenic trioxide, Asparaginase, Atrasentan, Belotecan, Bexarotene, bendamustine, Bleomycin, Bortezomib, Busulfan, Camptothecin, Capecitabine, Carboplatin, Carboquone, Carmofur, Carmustine, Celecoxib, Chlorambucil, Chlormethine, Cisplatin, Cladribine, Clofarabine, Crisantaspase, Cyclophosphamide, Cytarabine, Dacarbazine, Dactinomycin, Daunorubicin, Decitabine, Demecolcine, Docetaxel, Doxorubicin, Efaproxiral, Elesclomol, Elsamitrucin, Enocitabine, Epirubicin, Estramustine, Etoglucid, Etoposide, Floxuridine, Fludarabine, Fluorouracil (5FU), Fotemustine, Gemcitabine, Gliadel implants, Hydroxycarbamide, Hydroxyurea, Idarubicin, Ifosfamide, Irinotecan, Irofulven, Ixabepilone, Larotaxel, Leucovorin, Liposomal doxorubicin, Liposomal daunorubicin, Lonidamine, Lomustine, Lucanthone, Mannosulfan, Masoprocol, Melphalan, Mercaptopurine, Mesna, Methotrexate, Methyl aminolevulinate, Mitobronitol, Mitoguazone, Mitotane, Mitomycin, Mitoxantrone, Nedaplatin, Nimustine, Oblimersen, Omacetaxine, Ortataxel, Oxaliplatin, Paclitaxel, Pegaspargase, Pemetrexed,
Pentostatin, Pirarubicin, Pixantrone, Plicamycin, Porfimer sodium, Prednimustine, Procarbazine, Raltitrexed, Ranimustine, Rubitecan, Sapacitabine, Semustine, Sitimagene ceradenovec, Strataplatin, Streptozocin, Talaporfin, Tegafur-uracil, Temoporfin, Temozolomide, Teniposide, Tesetaxel, Testolactone, Tetranitrate, Thiotepa, Tiazofurine, Tioguanine, Tipifarnib, Topotecan, Trabectedin, Triaziquone, Triethylenemelamine, Triplatin, Tretinoin, Treosulfan, Trofosfamide, Uramustine, Valrubicin, Verteporfin, Vinblastine, Vincristine, Vindesine, Vinflunine, Vinorelbine, Vorinostat, Zorubicin, and other cytostatic or cytotoxic agents described herein [166] In some embodiments, the additional cancer therapeutic agents are tyrosine kinase inhibitors, PI3K/mTOR inhibitors, PARP inhibitors such as Olaparib, Rucaparib, Niraparib, Talazoparib, Wee1 inhibitors, CDK4/6 inhibitors such as Palbociclib, Ribociclib, Abemaciclib, DNA-PK inhibitors, ATM inhibitors and ATR inhibitors etc. Any compound of the present invention can be combined with these targeted inhibitors. [167] The compounds of the invention and combinations with chemotherapeutic agents or radiation therapies as described above may be administered over a prolonged term to maintain beneficial therapeutic effects or may be administered for a short period only. Alternatively they may be administered in a pulsatile or continuous manner. [168] Other possible additional therapeutic modalities include gene therapy, peptide and dendritic cell vaccines, synthetic chlorotoxins, and radiolabeled drugs and antibodies. [169] Dosing and Method of Administration [170] The dose of a compound administered to an individual (such as a human) may vary with the particular compound or salt thereof, the method of administration, and the particular disease, such as type and stage of cancer, being treated. In some embodiments, the amount of the compound or salt thereof is a therapeutically effective amount. [171] The effective amount of the compound may in one aspect be a dose of between about 0.01 and about 100 mg/kg. Effective amounts or doses of the compounds of the invention may be ascertained by routine methods, such as modeling, dose escalation, or clinical trials, taking into account routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the disease to be treated, the subject’s health status, condition, and weight. An exemplary dose is in the range of about
from about 0.7 mg to 7 g daily, or about 7 mg to 350 mg daily, or about 350 mg to 1.75 g daily, or about 1.75 to 7 g daily. [172] Any of the methods provided herein may in one aspect comprise administering to an individual a pharmaceutical composition that contains an effective amount of a compound provided herein or a salt thereof and a pharmaceutically acceptable excipient. [173] A compound or composition of the invention may be administered to an individual in accordance with an effective dosing regimen for a desired period of time or duration, such as at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer, which in some variations may be for the duration of the individual’s life. In one variation, the compound is administered on a daily or intermittent schedule. The compound can be administered to an individual continuously (for example, at least once daily) over a period of time. The dosing frequency can also be less than once daily, e.g., about a once weekly dosing. The dosing frequency can be more than once daily, e.g., twice or three times daily. The dosing frequency can also be intermittent, including a ‘drug holiday’ (e.g., once daily dosing for 7 days followed by no doses for 7 days, repeated for any 14 day time period, such as about 2 months, about 4 months, about 6 months or more). Any of the dosing frequencies can employ any of the compounds described herein together with any of the dosages described herein. [174] The compounds provided herein or a salt thereof may be administered to an individual via various routes, including, e.g., intravenous, intramuscular, subcutaneous, oral and transdermal. A compound provided herein can be administered frequently at low doses, known as 'metronomic therapy,' or as part of a maintenance therapy using compound alone or in combination with one or more additional drugs. Metronomic therapy or maintenance therapy can comprise administration of a compound provided herein in cycles. Metronomic therapy or maintenance therapy can comprise intra-tumoral administration of a compound provided herein. [175] In one aspect, the invention provides a method of treating cancer in an individual by parenterally administering to the individual (e.g., a human) an effective amount of a compound or salt thereof. In some embodiments, the route of administration is intravenous, intra-arterial, intramuscular, or subcutaneous. In some embodiments, the route of administration is oral. In still other embodiments, the route of administration is transdermal.
[176] The invention also provides compositions (including pharmaceutical compositions) as described herein for the use in treating, preventing, and/or delaying the onset and/or development of cancer and other methods described herein. In certain embodiments, the composition comprises a pharmaceutical formulation which is present in a unit dosage form [177] Also provided are articles of manufacture comprising a compound of the disclosure or a salt thereof, composition, and unit dosages described herein in suitable packaging for use in the methods described herein. Suitable packaging is known in the art and includes, for example, vials, vessels, ampules, bottles, jars, flexible packaging and the like. An article of manufacture may further be sterilized and/or sealed. [178] Kits [179] The present disclosure further provides kits for carrying out the methods of the invention, which comprises one or more compounds described herein or a composition comprising a compound described herein. The kits may employ any of the compounds disclosed herein. In one variation, the kit employs a compound described herein or a pharmaceutically acceptable salt thereof. The kits may be used for any one or more of the uses described herein, and, accordingly, may contain instructions for the treatment of cancer. [180] Kits generally comprise suitable packaging. The kits may comprise one or more containers comprising any compound described herein. Each component (if there is more than one component) can be packaged in separate containers or some components can be combined in one container where cross-reactivity and shelf life permit. [181] The kits may be in unit dosage forms, bulk packages (e.g., multi-dose packages) or sub-unit doses. For example, kits may be provided that contain sufficient dosages of a compound as disclosed herein and/or a second pharmaceutically active compound useful for a disease detailed herein to provide effective treatment of an individual for an extended period, such as any of a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more. Kits may also include multiple unit doses of the compounds and instructions for use and be packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies). [182] The kits may optionally include a set of instructions, generally written instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing
instructions are also acceptable, relating to the use of component(s) of the methods of the present invention. The instructions included with the kit generally include information as to the components and their administration to an individual. [183] The invention can be further understood by reference to the following examples, which are provided by way of illustration and are not meant to be limiting. EXAMPLES Example-1: Synthesis of 6-(5-cyanopyrazin-2-ylamino)-N-(cyclopentylmethyl)-4-(morpholin- 2-ylmethylamino)pyridazine-3-carboxamide, (Compound No.1.1)
[184] Step-1: Synthesis of tert-butyl 2-((6-chloro-3-(methoxycarbonyl)pyridazin-4- ylamino)methyl)morpholine-4-carboxylate: To a solution of methyl 4, 6- dichloropyridazine-3-carboxylate (900 mg, 4.34 mmols, 1.0 eq) in THF (20 mL) was added TEA (1.5 mL, 10.85 mmols, 2.5 eq) followed by the addition of tert-butyl 2- (aminomethyl)morpholine-4-carboxylate (1030 mg, 4.77 mmols, 1.1 eq). The resulting reaction mixture was refluxed for 2 h. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was quenched with ice water (10 mL) and extracted with ethyl acetate (3 × 100 mL). Combined organic phase was washed with water (3 × 20 mL) followed by brine wash (20 mL). Organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude. Crude was triturated with pentane and solid precipitate was filtered to obtain desired product (1.2 g) as white solid. LCMS: 387.1 [M+1] + [185] Step-2: Synthesis of tert -butyl 2-((6-chloro-3- (cyclopentylmethylcarbamoyl)pyridazin-4-ylamino)methyl)morpholine-4-carboxylate: To a solution of tert -butyl 2-((6-chloro-3-(methoxycarbonyl)pyridazin-4- ylamino)methyl)morpholine-4-carboxylate (400 mg, 1.39 mmols, 1.0 eq) in THF (8 mL) was added cyclopentylmethanamine (207 mg, 2.09 mmols, 1.5 eq) followed by addition of trimethylaluminium (1.39 mL, 2.79 mmols, 2.0 eq) at 0 °C and the reaction mixture was stirred at RT for 4h. Product formation was confirmed by TLC and LCMS analyses. The reaction mixture was quenched with sodium bicarbonate (50 mL) and extracted with ethyl
acetate (15 mL 3). The collective organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to get the crude. Crude was washed with n-pentane (20 mL x 2) to afford the desired compound as an off- white solid. LCMS: 454.2 [M+1]+ [186] Step-3: Synthesis of tert -butyl 2-((6-(5-cyanopyrazin-2-ylamino)-3- (cyclopentylmethylcarbamoyl)pyridazin-4-ylamino)methyl)morpholine-4-carboxylate: A solution of tert -butyl 2-((6-chloro-3-(cyclopentylmethylcarbamoyl)pyridazin-4- ylamino)methyl)morpholine-4-carboxylate (200 mg, 0.44 mmols, 1.0 eq) and 5- aminopyrazine-2-carbonitrile (63.0 mg, 0.52 mmols, 1.2eq) in dioxane (6 mL) was purged with N2 for 5 minutes and then Cs2CO3 (430 mg, 1.32 mmols, 3.0 eq) was added and purged again for 5 minutes. Xantphos (15 mg, 0.016 mmols, 0.06 eq) and Pd2dba3 (32 mg, 0.035 mmols, 0.08 eq) was added and then the reaction mixture was heated for 16h at 180 °C. Product formation was confirmed by TLC and LCMS analyses. The reaction mixture was quenched with ice water (20 mL) and extracted with ethyl acetate (15 × 3) mL. The collective organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to get the crude. The crude was purified by combiflash chromatography by using 12g redi sap column and by eluting in 90% ethyl acetate: hexane solvent system to get the desired compound as a light yellow solid (70 mg). LCMS: 538.3 [M+1]+ [187] Step-4: Synthesis of 6-(5-cyanopyrazin-2-ylamino)-N-(cyclopentylmethyl)-4- (morpholin-2-ylmethylamino)pyridazine-3-carboxamide: To a solution of tert -butyl 2- ((6-(5-cyanopyrazin-2-ylamino)-3-(cyclopentylmethylcarbamoyl)pyridazin-4- ylamino)methyl)morpholine-4-carboxylate (70 mg, 0.130 mmols, 1.0 eq) in DCM (5.0 mL), TFA (0.5 mL) was added at 0 °C and the resultant reaction mixture was kept for stirring for 2h. Product formation was confirmed by TLC and LCMS analyses. The reaction mixture was concentrated under reduced pressure to get the crude. The crude was purified by reverse phase chromatography to yield desired compound as a formate salt and a yellow solid (20 mg). LCMS: 438.7 [M+1]+; 1H NMR (400 MHz, DMSO-d6; after D2O addition): δ 8.93 (s, 1H), 8.76 (s, 1H), 7.36 (s, 1H), 3.83 (dd, J = 11.1, 2.9 Hz, 1H), 3.59-3.47 (m, 1H), 3.28 (dd, J = 13.7, 4.0 Hz, 1H), 3.18 (t, J = 6.4 Hz, 3H), 2.94 (d, J = 12.3 Hz, 1H), 2.79 (d, J = 12.6 Hz, 1H), 2.72 (dd, J = 11.9, 3.5 Hz, 1H), 2.56 (d, J = 11.2 Hz, 2H), 2.14 (h, J = 7.4 Hz, 1H), 1.64
(td, J = 11.5, 6.2 Hz, 2H), 1.55 (q, J = 11.0, 8.7 Hz, 2H), 1.47 (t, J = 7.4 Hz, 2H), 1.22 (dq, J = 13.1, 7.0 Hz, 2H). Example-2: Synthesis of 6-(5-cyanopyrazin-2-ylamino)-N-(2,2-difluoroethyl)-4-(morpholin- 2-ylmethylamino)pyridazine-3-carboxamide, (Compound No.1.2)
[188] Step-1: Synthesis of tert-butyl 2-((6-chloro-3-(methoxycarbonyl)pyridazin-4- ylamino)methyl)morpholine-4-carboxylate: To a solution of methyl 4, 6- dichloropyridazine-3-carboxylate (900 mg, 4.34 mmols, 1.0 eq) in THF (20 mL) was added TEA (1.5 mL, 10.85 mmols, 2.5 eq) followed by the addition of tert-butyl 2- (aminomethyl)morpholine-4-carboxylate (1030 mg, 4.77 mmols, 1.1 eq). The resulting reaction mixture was refluxed for 2 h. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was quenched with ice water (10 mL) and extracted with ethyl acetate (3 × 100 mL). Combined organic phase was washed with water (3 × 20 mL) followed by brine wash (20 mL). Organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude. Crude was triturated with pentane and solid precipitate was filtered to obtain desired product (1.2 g) as white solid. LCMS: 387.1 [M+1] + [189] Step-2: Synthesis of tert-butyl 2-((6-chloro-3-(2,2- difluoroethylcarbamoyl)pyridazin-4-ylamino)methyl)morpholine-4-carboxylate: To a solution of tert-butyl 2-((6-chloro-3-(methoxycarbonyl)pyridazin-4- ylamino)methyl)morpholine-4-carboxylate (500 mg, 1.29 mmol, 1.0 eq) in ACN (10 mL) was added 2,2-difluoroethanamine (157.4 mg, 1.942 mmol, 1.5 eq) and then trimethylaluminium (373.3 mg, 2.59 mmol, 2.0 eq) was added and kept for stirring at RT for 8 h. Product formation was confirmed by TLC and LCMS. The reaction mixture was quenched with ice water (10 mL) and extracted with ethyl acetate (3 × 50 mL). Collective organic layer was washed with brine (20 mL), dried over sodium sulfate and then concentrated under reduced pressure to get the crude. Then the crude was triturated with pentane to get the desired compound (0.200 g). LCMS: 436.2 [M+1] + + ; 438.2 [M+3]
[190] Step-3: Synthesis of tert-butyl 2-((6-(5-cyanopyrazin-2-ylamino)-3-(2,2- difluoroethylcarbamoyl)pyridazin-4-ylamino)methyl)morpholine-4-carboxylate: A solution of tert-butyl 2-((6-chloro-3-(2,2-difluoroethylcarbamoyl)pyridazin-4- ylamino)methyl)morpholine-4-carboxylate (200 mg, 0.459 mmol, 1.0 eq) and 5- aminopyrazine-2-carbonitrile (66.2 mg, 0.551 mmol, 1.2 eq) in dioxane (5 mL) was purged with N2 for 5 minutes. Cs2CO3 (448 mg, 1.377 mmol, 3.0 eq) was added and purged again for 5 minutes, then Xantphos (4.7 mg, 0.008 mmol, 0.018 eq) and Pd2dba3 (21 mg, 0.02 mmol, 0.05eq) was added and the vial was closed and kept for heating in microwave for 45 minutes at 180 °C. Product formation was confirmed by TLC and LCMS. The reaction mixture was quenched with ice water (20 mL) and extracted with ethyl acetate (3 × 15 mL). Collective organic layer was washed with brine (20 mL) and dried over Na2SO4 and then concentrated under reduced pressure to get the crude. The crude was purified by combi flash chromatography by using 12g redi sap column and by eluting in 50% ethyl acetate: hexane solvent system to obtain the desired compound (100 mg, light brown solid). LCMS: 520.6 [M+1] + [191] Step-4: Synthesis of 6-(5-cyanopyrazin-2-ylamino)-N-(2,2-difluoroethyl)-4- (morpholin-2-ylmethylamino)pyridazine-3-carboxamide : To a solution of tert-butyl 2- ((6-(5-cyanopyrazin-2-ylamino)-3-(2,2-difluoroethylcarbamoyl)pyridazin-4-ylamino)methyl) morpholine-4-carboxylate (100 mg, 0.192 mmol, 1 eq) in DCM (5.0 mL), TFA (0.5 mL) was added at 0 °C and the reaction mixture was stirred for 2h. Product formation was confirmed by TLC and LCMS. Then the RM was concentrated under reduced pressure to get the crude. The crude was purified by reverse phase chromatography to yield desired compound as a trifluoroacetate salt and a white solid (10 mg). LCMS: 420.2 [M+1]+; 1H NMR (400 MHz, DMSO-d6; after D2O addition) δ 8.82 (s, 1H), 8.73 (s, 1H), 7.49 (s, 1H), 4.02 (dd, J = 12.9, 3.8 Hz, 3H), 3.77-3.61 (m, 3H), 3.43 (dd, J = 14.2, 3.8 Hz, 1H), 3.30 (dd, J = 13.8, 6.9 Hz, 2H), 3.21- 3.14 (m, 1H), 3.00 (dd, J = 13.8, 9.9 Hz, 1H), 2.87 (t, J = 12.0 Hz, 1H). Example-3: Synthesis of 6-(5-cyanopyrazin-2-ylamino)-N-(cyclopentylmethyl)-4-(morpholin- 2-ylmethylamino)pyridazine-3-carboxamide, (Compound No.1.36)
[192] Step-1: Synthesis of tert-butyl 2-((6-chloro-3-(methoxycarbonyl)pyridazin-4- ylamino)methyl)morpholine-4-carboxylate: To a solution of methyl 4, 6- dichloropyridazine-3-carboxylate (900 mg, 4.34 mmols, 1.0 eq) in THF (20 mL) was added TEA (1.5 mL, 10.85 mmols, 2.5 eq) followed by the addition of tert-butyl 2- (aminomethyl)morpholine-4-carboxylate (1030 mg, 4.77 mmols, 1.1 eq). The resulting reaction mixture was refluxed for 2 h. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was quenched with ice water (10 mL) and extracted with ethyl acetate (3 × 100 mL). Combined organic phase was washed with water (3 × 20 mL) followed by brine wash (20 mL). Organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude. Crude was triturated with pentane and solid precipitate was filtered to obtain desired product (1.2 g) as white solid. LCMS: 387.1 [M+1] + [193] Step-2: Synthesis of tert-butyl 2-((6-chloro-3-(cyclopentylcarbomyl)pyridazin-4- ylamino)methyl)morpholine-4-carboxylate: To a solution of tert-butyl 2-((6-chloro-3- (methoxycarbonyl)pyridazin-4-ylamino)methyl)morpholine-4-carboxylate (600 mg, 1.55 mmols, 1.0 eq) in THF (20 mL) cyclopentylamine (264 mg, 3.10 mmols, 2.0 eq) was added followed by addition of trimethylaluminium (2M in toluene) (1.3 mL, 6.21 mmols, 4.0 eq) at 0 °C and the reaction mixture was stirred at RT for 5 h. Product formation was confirmed by TLC and LCMS. The reaction mixture was quenched with ice water (2 × 20 mL) and extracted with ethyl acetate (3 × 30 mL). Collective organic layer was washed with sodium bicarbonate solution (20 mL) and dried over anhydrous sodium sulfate hexane and then concentrated under reduced pressure to get the crude. Then the crude was purified by flash chromatography: ethyl acetate to obtain the desired compound (0.350 g) as an off-white solid. LCMS: 440.1 [M+1] + [194] Step-3: Synthesis of tert-butyl 2-((6-(5-cyanopyrazin-2-ylamino)-3- (cyclopentylcarbamoyl)pyridazin-4-ylamino)methyl)morpholine-4-carboxylate: A solution of tert-butyl 2-((6-chloro-3-(cyclopentylcarbomyl)pyridazin-4- ylamino)methyl)morpholine-4-carboxylate (200 mg, 0.45 mmols, 1.0 eq) and 5- aminopyrazine-2-carbonitrile (65 mg, 0.54 mmols, 1.2 eq) in dioxane (8 mL) was purged under nitrogen for 10 minutes then Cs2CO3 (445 mg, 1.36 mmols, 3.0 eq) was added and purged again for 5 minutes. Further, Xantphos (16 mg, 0.036 mmols, 0.06 eq) and Pd2dba3 (33 mg, 0.036 mmols, 0.08 eq) was added. The reaction mixture was heated for 16 h at 180
°C. Product formation was confirmed by TLC and LCMS. The reaction mixture was quenched with water (20 mL) and extracted with Ethyl acetate (3 × 15 mL). Collective organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to get the crude. Then the crude was purified by flash chromatography by eluting in 60% ethyl acetate: hexane solvent system to get the desired compound (150 mg). LCMS: 524.5 [M+1] + [195] Step-4: Synthesis of 6-(5-cyanopyrazin-2-ylamino)-N-(cyclopentylmethyl)-4- (morpholin-2-ylmethylamino)pyridazine-3-carboxamide: To a solution of tert-butyl 2-((6- (5-cyanopyrazin-2-ylamino)-3-(cyclopentylcarbamoyl)pyridazin-4- ylamino)methyl)morpholine-4-carboxylate (150 mg, 0.286 mmols, 1 eq) in DCM (6 mL) TFA (1.0mL) was added at 0 °C and stirred for 6h. Product formation was confirmed by TLC and LCMS. Then the reaction mixture was concentrated under reduced pressure to get the crude. The crude was purified by reverse phase chromatography to yield desired compound as formate salt and a white solid (35 mg). LCMS: 424.5 [M+1] +; 1H NMR (400 MHz, DMSO-d6, after D2O addition) δ 8.88 (s, 1H), 8.74 (s, 1H), 8.63 (d, J = 7.8 Hz, 1H), 8.24 (s, 1H), 7.40 (s, 1H), 4.19 (p, J = 7.4 Hz, 1H), 4.01-3.90 (m, 1H), 3.71-3.58 (m, 2H), 3.36 (dd, J = 13.7, 4.1 Hz, 1H), 3.24 (dd, J = 14.0, 7.1 Hz, 1H), 3.17 (d, J = 12.6 Hz, 1H), 3.04 (d, J = 12.7 Hz, 1H), 2.96-2.82 (m, 1H), 2.76 (t, J = 11.8 Hz, 1H), 1.87 (h, J = 7.3 Hz, 2H), 1.66 (d, J = 11.8 Hz, 2H), 1.55 (d, J = 15.0 Hz, 4H). Example-4: Synthesis of 6-(5-cyanopyrazin-2-ylamino)-N-phenyl-4-(piperidin- 4ylmethylamino)pyridazine-3-carboxamide, (Compound No.1.52)
[196] Step-1: Synthesis of methyl 4-((1-(tert-butoxycarbonyl)piperidin-4- yl)methylamino)-6-chloropyridazine-3-carboxylate: To a solution of methyl 4, 6- dichloropyridazine-3-carboxylate (500 mg, 2.42 mmols, 1.0 eq) in THF (15 mL), TEA (1.5 mL, 3.62 mmols, 1.5 eq) was added dropwise to the reaction mixture followed by addition of tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (620 mg, 2.89 mmols, 1.2 eq) and the reaction mixture was refluxed for 2 h. Product formation was confirmed by TLC and LCMS.
After the completion of reaction, the reaction mixture was quenched with ice water (10 mL) and extracted with ethyl acetate (3 × 15 mL). Collective organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to get the crude. The crude was then triturated with pentane to obtain the desired compound (0.820 g) as an off white solid. LCMS: 385.3 [M+1] + [197] Step-2: Synthesis of tert-butyl 4-((6-chloro-3-(phenylcarbamoyl)pyridazin-4- ylamino)methyl)piperidine-1-carboxylate: To a solution of methyl 4-((1-(tert- butoxycarbonyl)piperidin-4-yl)methylamino)-6-chloropyridazine-3-carboxylate (500 mg, 1.30 mmols, 1.0 eq) in THF (10 mL), aniline (181 mg, 1.95 mmols, 1.5 eq) was added. Further, trimethyl aluminium (0.9 mL, 2.60 mmols, 2.0 eq) was added and the reaction mixture was stirred at RT for 5 h. Product formation was confirmed by TLC and LCMS. After completion of reaction, the reaction mixture was quenched with ice water (10 mL) and extracted with ethyl acetate (3 × 15 mL). Collective organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain the crude compound (370 mg). LCMS: 446.3 [M+1] + [198] Step-3: Synthesis of tert-butyl 4-((6-(5-cyanopyrazin-2-ylamino)-3- (phenylcarbamoyl)pyridazin-4-ylamino)methyl)piperidine-1-carboxylate: A solution of tert-butyl 4-((6-chloro-3-(phenylcarbamoyl)pyridazin-4-ylamino)methyl)piperidine-1- carboxylate (200 mg, 0.44 mmols, 1.0 eq) and 5-aminopyrazine-2-carbonitrile (60 mg, 0.528 mmols, 1.0 eq) in dioxane (5 mL) was purged with nitrogen for 5 minutes then Cs2CO3 (428 mg, 1.32 mmols, 3.0 eq) was added and purged again for 5 minutes. Further, xantphos (8 mg, 0.0076 mmols, 0.018 eq) and Pd2dba3 (20 mg, 0.022 mmols, 0.05 eq) was added and the reaction mixture was heated at 180 °C for 16 h. Product formation was confirmed by TLC and LCMS. After the completion of reaction, the reaction mixture was quenched with ice water (20 mL) and extracted with ethyl acetate (3 × 15 mL). Collective organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to get the crude. The crude was then purified by flash chromatography using 12g redi sap column and ethyl acetate: hexane (0-60%) as eluent to obtain the desired compound (60 mg) as a light brown solid. LCMS: 530.3 [M+1] + [199] Step-4: Synthesis of 6-(5-cyanopyrazin-2-ylamino)-N-phenyl-4-(piperidin-4- ylmethylamino)pyridazine-3-carboxamide: To a solution of tert-butyl 4-((6-(5- cyanopyrazin-2-ylamino)-3-(phenylcarbamoyl)pyridazin-4-ylamino)methyl)piperidine-1-
carboxylate (60 mg, 0.1134 mmols, 1.0 eq) in DCM (5 mL), TFA (0.5 mL) was added at 0 °C and the reaction mixture was stirred for 2 h. Product formation was confirmed by TLC and LCMS. The reaction mixture was concentrated under reduced pressure to get the crude. The crude was purified by reverse phase chromatography to yield desired compound as a white solid (5.2 mg). LCMS: 430.5 [M+1]+; 1H NMR (400 MHz, DMSO-d6 after D2O addition) : δ 8.93 (s, 1H), 8.79 (s, 1H), 7.77 (d, J = 8.0 Hz, 2H), 7.50 (s, 1H), 7.36 (t, J = 7.8 Hz, 2H), 7.13 (t, J = 7.4 Hz, 1H), 3.17 (t, J = 8.4 Hz, 3H), 2.72 (t, J = 12.1 Hz, 2H), 1.90-1.77 (m, 2H), 1.41-1.28 (m, 2H), 1.22- 1.06 (m, 2H). Example-5: Synthesis of 6-(5-cyanopyrazin-2-ylamino)-N-ethyl-4-(piperidin-4- ylmethylamino)pyridazine-3-carboxamide, (Compound No.1.53)
[200] Step-1: Synthesis of tert-butyl 4-((6-chloro-3-(ethylcarbamoyl)pyridazin-4- ylamino)methyl)piperidine-1-carboxylate: To a solution of methyl 4-((1-(tert- butoxycarbonyl)piperidin-4-yl)methylamino)-6-chloropyridazine-3-carboxylate (500 mg, 1.30 mmols, 1.0 eq) in ACN (15 mL) was added K2CO3 (448 mg, 3.25 mmols, 2.5 eq) followed by addition of ethylamine (117 mg, 2.60 mmols, 2.0 eq). The resultant reaction mixture was refluxed for 3 h. Product formation was confirmed by TLC and LCMS. After the completion of reaction, the reaction mixture was quenched with ice water (20 mL) and extracted with ethyl acetate (3 × 15 mL). Collective organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to get the crude. The crude was triturated with pentane to obtain the desired compound (500 mg). LCMS: 398.4 [M+1] + [201] Step-2: Synthesis of tert-butyl 4-((6-(5-cyanopyrazin-2-ylamino)-3- (ethylcarbamoyl)pyridazin-4-ylamino)methyl)piperidine-1-carboxylate: A solution of tert-butyl 4-((6-chloro-3-(ethylcarbamoyl)pyridazin-4-ylamino)methyl)piperidine-1- carboxylate (250 mg, 0.629 mmols, 1.0 eq) and 5-aminopyrazine-2-carbonitrile (90 mg, 0.755 mmols, 1.2 eq) in dioxane (5 mL) was purged with nitrogen for 5 minutes followed by
addition of Cs2CO3 (614 mg, 1.89 mmols, 3.0 eq). The resultant reaction mixture was again purged for 5 minutes, then Xantphos (6.5 mg, 0.011 mmols, 0.018 eq) and Pd2dba3 (30 mg, 0.031 mmols, 0.05 eq) was added and the reaction mixture was subjected to microwave for 45 minutes at 180 °C. Product formation was confirmed by TLC and LCMS. After the completion of reaction, the reaction mixture was quenched with ice water (20 mL) and extracted with ethyl acetate (3 × 15 mL). Collective organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to get the crude. The crude was purified by flash chromatography by using 12g redi sap column and by eluting in 60% ethyl acetate: hexane solvent system to obtain the desired product (90 mg) as light brown solid. LCMS: 482.4 [M+1] + [202] Step-3: Synthesis of 6-(5-cyanopyrazin-2-ylamino)-N-ethyl-4-(piperidin-4- ylmethylamino)pyridazine-3-carboxamide: To a solution of tert-butyl 4-((6-(5- cyanopyrazin-2-ylamino)-3-(ethylcarbamoyl)pyridazin-4-ylamino)methyl)piperidine-1- carboxylate (90 mg, 0.187 mmols, 1 eq) in DCM (2 mL), TFA (0.03 mL, 0.467 mmols, 2.5 eq) was added at 0 °C and kept for stirring for 6 h. Then the reaction mixture was concentrated under reduced pressure to get the crude. The crude was purified by reverse phase chromatography to yield desired compound as as a white solid (6 mg). LCMS: 382.4 [M+1] +; 1H NMR (400 MHz, DMSO-d6) δ 9.06 (t, J = 6.0 Hz, 1H), 8.97 (d, J = 7.7 Hz, 1H), 8.82 (s, 1H), 7.40 (s, 1H), 3.35-3.18 (m, 8H), 3.07 (t, J = 6.0 Hz, 2H), 2.98 (d, J = 12.1 Hz, 2H), 1.88 (s, 1H), 1.73 (dt, J = 11.0, 4.0 Hz, 1H), 1.65 (d, J = 13.1 Hz, 1H), 1.24- 1.07 (m, 4H). Example-6: Synthesis of 6-(5-cyanopyrazin-2-ylamino)-N-ethyl-4-(piperidin-3- ylmethylamino)pyridazine-3-carboxamide, (Compound No.1.54)
[203] Step-1: Synthesis of methyl 4-((1-(tert-butoxycarbonyl)piperidin-3- yl)methylamino)-6-chloropyridazine-3-carboxylate: To a solution of methyl 4, 6- dichloropyridazine-3-carboxylate (300 mg, 1.50 mmols, 1.0 eq) in THF (15 mL), TEA (0.3 mL, 2.25 mmols, 1.5 eq) was added dropwise followed by addition of tert-butyl 3-
(aminomethyl)piperidine-1-carboxylate (372 mg, 1.74 mmols, 1.2 eq) and the resultant reaction mixture was refluxed for 2 h. Product formation was confirmed by TLC and LCMS. After the completion of reaction, the reaction mixture was quenched with ice water (20 mL) and extracted with ethyl acetate (3 × 15 mL). Collective organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to get the crude. The crude was triturated with pentane to get the desired compound (560 mg) as off-white solid. LCMS: 385.3 [M+1]+ [204] Step-2: Synthesis of tert-butyl 3-((6-chloro-3-(ethylcarbamoyl)pyridazin-4- ylamino)methyl)piperidine-1-carboxylate: To a solution of methyl 4-((1-(tert- butoxycarbonyl)piperidin-3-yl)methylamino)-6-chloropyridazine-3-carboxylate (300 mg, 0.781 mmols, 1.0 eq) in ACN (10 mL) was added K2CO3 (269 mg, 1.95 mmols, 2.5 eq) followed by addition of ethylamine (70 mg, 1.56 mmols, 2.0 eq). The reaction mixture was refluxed for 3 h. Progress of reaction was monitored by TLC and LCMS. The reaction mixture was quenched with ice water (20 mL) and extracted with ethyl acetate (3 × 15 mL). The organic layer was washed with brine (20 mL) and separated, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to get the crude. The crude was triturated with pentane to obtain the desired compound (400 mg) as light brown solid. LCMS: 398.4 [M+1] + [205] Step-3: Synthesis of tert-butyl 3-((6-(5-cyanopyrazin-2-ylamino)-3 (ethylcarbamoyl)pyridazin-4-ylamino)methyl)piperidine-1-carboxylate: A solution of tert-butyl 3-((6-chloro-3-(ethylcarbamoyl)pyridazin-4-ylamino)methyl)piperidine-1- carboxylate (200 mg, 0.503 mmols, 1.0 eq) and 5-aminopyrazine-2-carbonitrile (72.5 mg, 0.604 mmols, 1.2 eq) in dioxane (5 mL) was purged with nitrogen for 5 minutes. After that Cs2CO3 (491.6 mg, 1.51 mmols, 3.0 eq) was added and the reaction mixture was purged again for 5 minutes with nitrogen, followed by addition of xantphos (5.2 mg, 0.009 mmols, 0.018 eq) and Pd2dba3 (23 mg, 0.025 mmols, 0.05 eq). The resultant reaction mixture was subjected to microwave irradiation for 45 minutes at 180 °C. The product formation was confirmed by TLC and LCMS. The reaction mixture was quenched with ice water (20 mL) and extracted with ethyl acetate (3 × 15 mL). The collective organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to get the crude. The crude was purified by flash chromatography by eluting in 60%
ethyl acetate: hexane solvent system to obtain desired compound (120 mg) as yellow solid. LCMS: 482.5 [M+1] + [206] Step-4: Synthesis of 6-(5-cyanopyrazin-2-ylamino)-N-ethyl-4-(piperidin-3- ylmethylamino)pyridazine-3-carboxamide: To a solution of tert-butyl 3-((6-(5- cyanopyrazin-2-ylamino)-3-(ethylcarbamoyl)pyridazin-4-ylamino)methyl)piperidine-1- carboxylate (120 mg, 0.249 mmols, 1.0 eq) in DCM (3 mL), TFA (85 mg , 0.748 mmols, 3.0 eq) was added at 0 °C and stirred for 6h. The progress of reaction was monitored by TLC and LCMS. After the completion of reaction, the reaction mixture was concentrated under reduced pressure to get the crude. The crude was purified by reverse phase chromatography to yield desired compound as white solid (25mg). LCMS: 382.5 [M+1] +; 1H NMR (400 MHz, DMSO-d6 after D2O addition) δ 8.91 (s, 1H), 8.76 (s, 1H), 7.37 (s, 1H), 3.28 (q, J = 7.1 Hz, 2H), 3.07 (dq, J = 18.7, 11.5, 9.0 Hz, 3H), 2.95 (d, J = 12.0 Hz, 1H), 2.40 (t, J = 11.3 Hz, 2H), 1.92-1.76 (m, 2H), 1.68 (d, J = 19.1 Hz, 2H), 1.44 (q, J = 12.3 Hz, 1H), 1.25-1.02 (m, 3H). Example-7: Synthesis of 6-(5-cyanopyrazin-2-ylamino)-4-(piperidin-4-ylmethylamino)-N- (pyridin-4-yl)pyridazine-3-carboxamide, (Compound No.1.55)
[207] Step-1: Synthesis of 4-((1-(tert-butoxycarbonyl)piperidin-4-yl)methylamino)-6- chloropyridazine-3-carboxylic acid: To a solution of methyl 4-((1-(tert- butoxycarbonyl)piperidin-4-yl)methylamino)-6-chloropyridazine-3-carboxylate (200 mg, 0.520 mmols, 1.0 eq) in THF: water (3 mL: 3 mL) was added LiOH (38 mg, 1.56 mmols, 3.0 eq) and the reaction mixture was stirred at RT for 2 h. Product formation was confirmed by TLC and LCMS. After the completion of reaction, reaction mixture was acidified using 1N HCl (5 mL) and extracted with ethyl acetate (3 × 5 mL). Collective organic layer was washed with brine (10 mL) and dried over anhydrous sodium sulfate followed by concentration under reduced pressure to get the crude product. The crude was triturated with pentane to get desired compound (180 mg) as an off-white solid. LCMS: 315.3 [M-56+H] +
[208] Step-2: Synthesis of tert-butyl 4-((6-chloro-3-(pyridin-4-ylcarbamoyl)pyridazin- 4-ylamino)methyl)piperidine-1-carboxylate: To a solution of 4-((1-(tert- butoxycarbonyl)piperidin-4-yl)methylamino)-6-chloropyridazine-3-carboxylic acid (180 mg, 0.486 mmols, 1.0 eq) in DMF (3 mL), DIPEA (0.2 mL, 1.215 mmols, 2.5 eq) and HATU (277 mg, 0.729 mmols, 1.5 eq) was added at 0°C and the reaction mixture was stirred for 30 minutes. Pyridin-4-amine (116 mg, 0.972 mmols, 2.0 eq) was added and the resultant reaction mixture was stirred at RT for 16h. Product formation was confirmed by TLC and LCMS. After the completion of reaction, the reaction mixture was quenched with ice water (20 mL) and extracted with ethyl acetate (3 × 15 mL). The collective organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to get the desired compound (150 mg) as pale yellow solid. LCMS: 447.4 [M+1] + [209] Step-3: Synthesis of tert-butyl 4-((6-(5-cyanopyrazin-2-ylamino)-3-(pyridin-4- ylcarbamoyl)pyridazin-4-ylamino)methyl)piperidine-1-carboxylate: To a solution of tert- butyl4-((6-chloro-3-(pyridin-4-ylcarbamoyl)pyridazin-4-ylamino)methyl)piperidine-1- carboxylate (150 mg, 0.336 mmols, 1.0 eq) in dioxane (3 mL), 5-aminopyrazine-2- carbonitrile (48 mg, 0.403 mmols, 1.2 eq) was added and the resultant reaction mixture was purged with nitrogen for 5 minutes followed by addition of Cs2CO3 (328 mg, 1.001 mmols, 3.0 eq) and the reaction mixture was purged again for 5 minutes. Xantphos (3.4 mg, 0.006 mmols, 0.018 eq) and Pd2dba3 (15 mg, 0.016 mmols, 0.05 eq) was added and the reaction mixture was subjected to microwave irradiation for 45 minutes at 180 °C. Product formation was confirmed by TLC and LCMS. The reaction mixture was quenched with ice water (20 mL) and extracted with ethyl acetate (3 × 15 mL). Collective organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to get the crude product. The crude was purified by flash chromatography by eluting in 60% ethyl acetate: hexane solvent system to obtain the desired compound (70 mg) as yellow solid. LCMS: 531.5 [M+1] + [210] Step-4: Synthesis of 6-(5-cyanopyrazin-2-ylamino)-4-(piperidin-4- ylmethylamino)-N-(pyridin-4-yl)pyridazine-3-carboxamide: To a solution of tert-butyl 4- ((6-(5-cyanopyrazin-2-ylamino)-3-(pyridin-4-ylcarbamoyl)pyridazin-4- ylamino)methyl)piperidine-1-carboxylate (70 mg, 0.132 mmols, 1.0 eq) in DCM (3 mL), TFA (45 mg , 0.396 mmols, 3.0 eq) was added at 0 °C and reaction mixture was stirred for 6h. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was
concentrated under reduced pressure followed by addition of water (5 mL) and extraction with ether (3 × 10 mL). The aqueous layer was subjected to lyophilization, to yield crude. The crude was purified by reverse phase chromatography to yield desired compound as white solid (12 mg). LCMS: 431.5 [M+1] +; 1H NMR (400 MHz, DMSO-d6) after D2O addition: δ 8.96 (s, 1H), 8.81 (s, 1H), 8.46 (d, J = 5.6 Hz, 2H), 7.88 (d, J = 5.6 Hz, 2H), 7.51 (s, 1H), 3.15 (d, J = 6.5 Hz, 2H), 3.04 (d, J = 12.2 Hz, 2H), 2.57 (d, J = 11.9 Hz, 2H), 1.80 (d, J = 9.8 Hz, 1H), 1.72 (d, J = 15.0 Hz, 2H), 1.32 – 1.17 (m, 2H). Example-8: Synthesis of N-benzyl-6-(5-cyanopyrazin-2-ylamino)-4-(piperidin-4- ylmethylamino)pyridazine-3-carboxamide, (Compound No.1.56)
[211] Step-1: Synthesis of tert-butyl 4-((3-(benzylcarbamoyl)-6-chloropyridazin-4- ylamino)methyl)piperidine-1-carboxylate: To a solution of methyl 4-((1-(tert- butoxycarbonyl)piperidin-4-yl)methylamino)-6-chloropyridazine-3-carboxylate (0.5 g, 0.130 mols, 1.0 eq) and phenylmethanamine (0.2 g, 0.195 mols, 1.5 eq) in THF (10 mL), trimethylaluminium (2M in toluene) (1.87 mL, 0.260 mols, 2.0 eq) was added. The reaction mixture was stirred at RT for 4 h. The progress of reaction was monitored by TLC and LCMS. After the completion of reaction, ice cold water (20 mL) was added to the reaction mixture and filtered. Further, ethyl acetate (2 × 20 mL) was added and washed with water (2 × 30 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain desired compound (0.4 g) as white solid. LCMS: 460.4 [M+1] + [212] Step-2: Synthesis of tert-butyl 4-((3-(benzylcarbamoyl)-6-(5-cyanopyrazin-2- ylamino)pyridazin-4-ylamino)methyl)piperidine-1-carboxylate: A solution of tert-butyl 4-((3-(benzylcarbamoyl)-6-chloropyridazin-4-ylamino)methyl)piperidine-1-carboxylate (330 mg, 0.718 mmols, 1.0 eq) and 5-aminopyrazine-2-carbonitrile (103.5 mg, 0.862 mmols, 1.2 eq) in dioxane (5 mL) was purged with nitrogen for 5 minutes then Cs2CO3 (701 mg, 2.154 mmols, 3.0 eq) was added and purged again for 5 minutes, then Xantphos (7.47 mg, 0.012 mmols, 0.018 eq) and Pd2dba3 (32.8 mg, 0.035 mmols, 0.05 eq) was added and the vial was
subjected to microwave irradiation at 180 °C for 45 minutes. Product formation was confirmed by TLC and LCMS. The reaction mixture was quenched with ice water (30 mL) and extracted with ethyl acetate (2 × 30 mL). Collective organic layer was washed with brine (25 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to get the crude. Then the crude was purified by flash chromatography by eluting in 60% ethyl acetate: hexane solvent system to get desired compound (180 mg) as light brown solid. LCMS: 544.4 [M+1] + [213] Step-3: Synthesis of N-benzyl-6-(5-cyanopyrazin-2-ylamino)-4-(piperidin-4- ylmethylamino)pyridazine-3-carboxamide: To a solution of tert-butyl 4-((3- (benzylcarbamoyl)-6-(5-cyanopyrazin-2-ylamino)pyridazin-4-ylamino)methyl)piperidine-1- carboxylate (180 mg, 0.331 mmols, 1 eq) in DCM (5 mL), TFA (0.63mL, 0.828 mmols, 2.5 eq) was added at 0 °C and the resulting reaction mixture was stirred for 2h. Then the reaction mixture was concentrated under reduced pressure to get the crude. The crude was purified by reverse phase chromatography to yield desired compound as white solid (25 mg). LCMS: 444.6 [M+1] + ; 1H NMR (400 MHz, DMSO-d6, after D2O addition) δ 9.61 (t, J = 6.4 Hz, 1H), 8.98 (s, 1H), 8.89 (t, J = 5.7 Hz, 1H), 8.82 (s, 1H), 7.42 (s, 1H), 7.33 (d, J = 6.7 Hz, 2H), 7.28- 7.18 (m, 1H), 4.47 (d, J = 6.4 Hz, 2H), 3.06 (t, J = 6.0 Hz, 1H), 2.95 (d, J = 12.3 Hz, 1H), 2.48- 2.35 (m, 4H), 1.66 (dd, J = 26.9, 12.0 Hz, 2H), 1.12 (qd, J = 11.7, 3.9 Hz, 2H). Example-9: Synthesis of N-benzyl-6-(5-cyanopyrazin-2-ylamino)-4-(piperidin-3- ylmethylamino)pyridazine-3-carboxamide, (Compound No.1.57)
[214] Step-1: Synthesis of tert-butyl 3-((3-(benzylcarbamoyl)-6-chloropyridazin-4- ylamino)methyl)piperidine-1-carboxylate: To solution of methyl 4-((1-(tert- butoxycarbonyl)piperidin-4-yl)methylamino)-6-chloropyridazine-3-carboxylate (0.5 g, 0.130 mols, 1.0 eq) and phenylmethanamine (0.20 g, 0.195 mols, 1.5 eq) in THF (10 mL), trimethylaluminium (2M in toluene) (1.87 mL, 0.260 mol, 2.0 eq) was added. The reaction mixture was stirred at RT for 4 h. The progress of reaction was monitored by TLC and LCMS. After the completion of reaction, ice cold water (20 mL) was added to the reaction
mixture and filtered. Further, ethyl acetate (2 × 20 mL) was added and washed with water (2 × 30 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain desired compound (0.4 g) as white solid. LCMS: 460.4 [M+1]+ [215] Step-2: Synthesis of tert-butyl 3-((3-(benzylcarbamoyl)-6-(5-cyanopyrazin-2- ylamino)pyridazin-4-ylamino)methyl)piperidine-1-carboxylate: A solution of tert-butyl 3-((3-(benzylcarbamoyl)-6-chloropyridazin-4-ylamino)methyl)piperidine-1-carboxylate (400 mg, 0.871 mmols, 1.0 eq) and 5-aminopyrazine-2-carbonitrile (125.5 mg, 1.045 mmols, 1.2 eq) in dioxane (5 mL) was purged with nitrogen for 5 minutes then Cs2CO3 (851.3 mg, 2.613 mmols, 3.0 eq) was added and purged again for 5 minutes, then Xantphos (9.07 mg, 0.015 mmols, 0.018 eq) and Pd2dba3 (39.8 mg, 0.043 mmols, 0.05 eq) was added and the vial was subjected to microwave irradiation for 45 minutes at 180 °C. Product formation was confirmed by TLC and LCMS. The reaction mixture was quenched with ice water (30 mL) and extracted with ethyl acetate (2 × 40 mL). Collective organic layer was washed with brine (25 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to get the crude. Then the crude was purified by flash chromatography by eluting in 60% ethyl acetate: hexane solvent system to get desired compound (180 mg) as light brown solid. LCMS: 544.5 [M+1] + [216] Step-3: Synthesis of N-benzyl-6-(5-cyanopyrazin-2-ylamino)-4-(piperidin-3- ylmethylamino)pyridazine-3-carboxamide : To a solution of tert-butyl 3-((3- (benzylcarbamoyl)-6-(5-cyanopyrazin-2-ylamino)pyridazin-4-ylamino)methyl)piperidine-1- carboxylate (180 mg, 0.331 mmols, 1.0 eq) in DCM (5 mL), TFA (0.63mL, 0.828 mmols, 2.5 eq) was added at 0 °C and reaction mixture was stirred for 6 h. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was concentrated under reduced pressure to get the crude. The crude was purified by reverse phase chromatography to yield desired compound as white solid (17 mg). LCMS: 444.6 [M+1] +; 1H NMR (400 MHz, DMSO-d6, after D2O addition) δ 8.97 (s, 1H), 8.80 (d, J = 1.4 Hz, 1H), 7.40 (s, 1H), 7.39- 7.28 (m, 3H), 7.23 (td, J = 6.1, 2.5 Hz, 2H), 4.46 (s, 2H), 3.06 (qd, J = 13.4, 6.5 Hz, 1H), 2.99- 2.90 (m, 1H), 2.85 (d, J = 12.3 Hz, 1H), 2.35-2.23 (m, 2H), 1.80-1.71 (m, 1H), 1.59 (dd, J = 10.7, 6.5 Hz, 1H), 1.37 (q, J = 13.9, 13.1 Hz, 2H), 1.23-1.07 (m, 2H). Example-10: Synthesis of 6-(5-cyanopyrazin-2-ylamino)-N-methyl-4-(piperidin-4- ylmethylamino)pyridazine-3-carboxamide, (Compound No.1.58)
[217] Step-1: Synthesis of tert-butyl 4-((6-chloro-3-(methylcarbamoyl)pyridazin-4- ylamino)methyl)piperidine-1-carboxylate: To a solution of methyl 4-((1-(tert- butoxycarbonyl)piperidin-4-yl)methylamino)-6-chloropyridazine-3-carboxylate (500 mg, 1.30 mmols, 1.0 eq) in ACN (10 mL) was added K2CO3 (530 mg, 3.89 mmols, 3.0 eq) followed by the addition of methylamine (0.36 mg, 3.89 mmols, 3.0 eq). The resulting reaction mixture was stirred at RT for 8 h. Product formation was confirmed by TLC and LCMS. The reaction mixture was quenched with ice water (20 mL) and extracted with ethyl acetate (3 × 15 mL). Collective organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to get the crude. Further, the crude was triturated with pentane to get obtain the desired compound (400 mg). LCMS: 384.4 [M+1] + [218] Step-2: Synthesis of tert-butyl 4-((6-(5-cyanopyrazin-2-ylamino)-3- (methylcarbamoyl)pyridazin-4-ylamino)methyl)piperidine-1-carboxylate: A solution of tert-butyl 4-((6-chloro-3-(methylcarbamoyl)pyridazin-4-ylamino)methyl)piperidine-1- carboxylate (200 mg, 0.52 mmols, 1.0 eq) and 5-aminopyrazine-2-carbonitrile (60 mg, 0.52 mmols, 1.2 eq) in dioxane (5 mL) was purged with nitrogen for 5 minutes then Cs2CO3 (508 mg, 1.56 mmols, 3 eq) was added and purged again for 5 minutes. Further, Xantphos (8.0 mg, 0.009 mmols, 0.018 eq) and Pd2dba3 (24 mg, 0.026 mmols, 0.05 eq) was added and then the vial was subjected to microwave irradiation for 45 minutes at 180 °C. Product formation was confirmed by TLC and LCMS. The reaction mixture was quenched with ice water (20 mL) and extracted with ethyl acetate (3 × 15 mL). Collective organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to get the crude. Then the crude was purified by flash chromatography by eluting in 60% ethyl acetate: hexane solvent system to get the desired compound (120 mg) as light brown solid. LCMS: 468.4 [M+1] + [219] Step-3: Synthesis of 6-(5-cyanopyrazin-2-ylamino)-N-methyl-4-(piperidin-4- ylmethylamino)pyridazine-3-carboxamide: To a solution of tert-butyl 4-((6-(5- cyanopyrazin-2-ylamino)-3-(methylcarbamoyl)pyridazin-4-ylamino)methyl)piperidine-1-
carboxylate (100 mg, 0.213 mmols, 1.0 eq) in DCM (5 mL) TFA (0.5 mL) was added at 0 °C and kept for stirring for 2 h. Product formation was confirmed by TLC and LCMS. Then the reaction mixture was concentrated under reduced pressure to get the crude. The crude was purified by reverse phase chromatography to yield desired compound as a white solid (30 mg). LCMS: 368.5 [M+1] +; 1H NMR (400 MHz, DMSO-d6, after D2O addition) δ 8.90 (s, 1H), 8.81 (s, 1H), 7.47 (s, 1H), 3.29 (d, J = 12.6 Hz, 2H), 3.17 (d, J = 6.3 Hz, 2H), 2.83 (d, J = 28.8 Hz, 4H), 1.89 (dd, J = 28.1, 9.7 Hz, 3H), 1.41 (q, J = 9.0, 6.9 Hz, 3H). Example-11: Synthesis of 6-(5-cyanopyrazin-2-ylamino)-4-(piperidin-3-ylmethylamino)-N- (2,2,2-trifluoroethyl)pyridazine-3-carboxamide, (Compound No.1.59)
[220] Step-1: Synthesis of tert-butyl 3-((6-chloro-3-(2,2,2- trifluoroethylcarbamoyl)pyridazin-4-ylamino)methyl)piperidine-1-carboxylate: To a solution of methyl 4-((1-(tert-butoxycarbonyl)piperidin-3-yl)methylamino)-6- chloropyridazine-3-carboxylate (500 mg, 1.30 mmols, 1.0 eq) in THF (15 mL) was added 2,2,2-trifluoroethanamine hydrochloride (170 mg, 2.20 mmols, 1.5 eq) followed by addition of trimethylaluminium (2M in toluene) (1.2 mL, 2.58 mmols, 2.0 eq). The resulting reaction mixture was stirred at RT for 4 h. Product formation was confirmed by TLC and LCMS. The reaction mixture was quenched with ice water (10 mL) and extracted with ethyl acetate (3 × 15 mL). Collective organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain the desired compound (370 mg). LCMS: 452.2 [M+1] + [221] Step-2: Synthesis of tert-butyl 3-((6-(5-cyanopyrazin-2-ylamino)-3-(2,2,2- trifluoroethylcarbamoyl)pyridazin-4-ylamino)methyl)piperidine-1-carboxylate: A solution of crude tert-butyl 3-((6-chloro-3-(2,2,2-trifluoroethylcarbamoyl)pyridazin-4- ylamino)methyl)piperidine-1-carboxylate (200 mg, 0.44 mmols, 1.0 eq) and 5- aminopyrazine-2-carbonitrile (60 mg, 0.528 mmols, 1.2 eq) in dioxane (5 mL) was purged under nitrogen for 5 minutes then Cs2CO3 (428 mg, 1.32 mmols, 3.0 eq) was added and purged again for 5 minutes. Further, Xantphos (8.0 mg, 0.0076 mmols, 0.018 eq) and
Pd2dba3 (20 mg, 0.022 mmols, 0.05 eq) was added and reaction mixture was subjected to microwave irradiation for 45 minutes at 180°C. Product formation was confirmed by TLC and LCMS. The reaction mixture was quenched with ice water (20 mL) and extracted with ethyl acetate (3 × 15 mL). Collective organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to get the crude. The crude was purified by flash chromatography by eluting in 60% ethyl acetate: hexane solvent system to obtain the desired compound (120 mg) as light brown solid. LCMS: 536.4 [M+1] + [222] Step-3: Synthesis of 6-(5-cyanopyrazin-2-ylamino)-4-(piperidin-3- ylmethylamino)-N-(2,2,2-trifluoroethyl)pyridazine-3-carboxamide: To a solution of tert- butyl 3-((6-(5-cyanopyrazin-2-ylamino)-3-(2,2,2-trifluoroethylcarbamoyl)pyridazin-4- ylamino)methyl)piperidine-1-carboxylate (120 mg, 0.223 mmols, 1.0 eq) in DCM (5 mL), TFA (0.5 mL) was added at 0 °C and resulting reaction mixture was stirred for 2 h. Product formation was confirmed by TLC and LCMS. Further, the reaction mixture was concentrated under reduced pressure to get the crude. The crude was purified by reverse phase chromatography to yield desired compound as a white solid (18 mg). LCMS: 436.5 [M+1]+; 1H NMR (400 MHz, Deuterium Oxide) δ 8.62 (d, J = 1.3 Hz, 1H), 8.52 (s, 1H), 7.41 (s, 1H), 4.15 (q, J = 9.3 Hz, 2H), 3.52-3.38 (m, 2H), 3.29 (d, J = 6.6 Hz, 3H), 2.95 (td, J = 12.9, 12.5, 2.7 Hz, 1H), 2.83 (t, J = 12.3 Hz, 1H), 2.25- 2.12 (m, 1H), 2.06-1.97 (m, 2H), 1.75 (q, J = 13.6 Hz, 1H), 1.40 (dt, J = 12.5, 9.5 Hz, 1H). Example-12: Synthesis of 6-(5-cyanopyrazin-2-ylamino)-N-cyclopentyl-4-(piperidin-4- ylmethylamino)pyridazine-3-carboxamide, (Compound No.1.60)
[223] Step-1: Synthesis of tert-butyl 4-((6-chloro-3-(cyclopentylcarbamoyl)pyridazin-4- ylamino)methyl)piperidine-1-carboxylate: To a solution of methyl 4-((1-(tert- butoxycarbonyl)piperidin-4-yl)methylamino)-6-chloropyridazine-3-carboxylate (200 mg, 0.520 mmols, 1.0 eq) in THF (10 mL) was added trimethylaluminium (2M in toluene) (0.65 mL, 1.30 mmols, 2.5 eq) followed by addition of cyclopentylamine (88 mg, 1.04 mmols, 2.0
eq). The resulting reaction mixture was stirred at RT for 4 h. Product formation was confirmed by TLC and LCMS. The reaction mixture was quenched with ice water (20 mL) and extracted with ethyl acetate (3 × 15 mL). The organic layer was collected and washed with saturated solution sodium bicarbonate (20 mL). The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to get the crude. The crude was purified by flash chromatography using hexane: ethyl acetate as eluents to get desired compound (400 mg). LCMS: 438.2 [M+1]+ [224] Step-2: Synthesis of tert-butyl 4-((6-(5-cyanopyrazin-2-ylamino)-3- (cyclopentylcarbamoyl)pyridazin-4-ylamino)methyl)piperidine-1-carboxylate: A solution of tert-butyl 4-((6-chloro-3-(cyclopentylcarbamoyl)pyridazin-4- ylamino)methyl)piperidine-1-carboxylate (150 mg, 0.342 mmols, 1.0 eq) and 5- aminopyrazine-2-carbonitrile (45 mg, 0.376 mmols, 1.1 eq) in dioxane (4 mL) was purged with nitrogen for 5 minutes then Cs2CO3 (334 mg, 1.02 mmols, 3.0 eq) was added and purged again for 5 minutes. Further, Xantphos (19 mg, 0.034 mmols, 0.1 eq) and Pd2dba3 (15 mg, 0.017 mmols, 0.05 eq) was added and then the vial was subjected to microwave irradiation for 45 minutes at 180 °C. Product formation was confirmed by TLC and LCMS. The reaction mixture was quenched with ice water (20 mL) and extracted with ethyl acetate (3 × 15 mL). Collective organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to get the crude. Then the crude was purified by flash chromatography by eluting in 60% ethyl acetate: hexane solvent system to get the desired compound (100 mg) as light brown solid. LCMS: 522.4 [M+1] + [225] Step-3: Synthesis of 6-(5-cyanopyrazin-2-ylamino)-N-cyclopentyl-4-(piperidin-4- ylmethylamino)pyridazine-3-carboxamide: To a solution of tert-butyl 4-((6-(5- cyanopyrazin-2-ylamino)-3-(cyclopentylcarbamoyl)pyridazin-4-ylamino)methyl)piperidine- 1-carboxylate (100 mg, 0.19 mmols, 1 eq) in DCM (5 mL), TFA (0.8 mL) was added at 0 °C and reaction mixture was stirred for 6h. Product formation was confirmed by TLC and LCMS. The reaction mixture was concentrated under reduced pressure to get the crude. The crude was purified by reverse phase chromatography to yield desired compound as a formate salt; white solid (3.5 mg). LCMS: 422.2 [M+1]+; 1H NMR (400 MHz, DMSO-d6; after D2O addition) δ 8.92 (d, J = 11.6 Hz, 1H), 8.79 (s, 1H), 7.43 (s, 1H), 4.27-4.16 (m, 1H), 3.23 (d, J = 13.0 Hz, 2H), 3.14 (d, J = 6.3 Hz, 2H), 2.78 (t, J = 12.7 Hz, 2H), 2.07 (s, 1H), 1.85 (d, J =
14.5 Hz, 3H), 1.80 (d, J = 4.1 Hz, 1H), 1.69 (s, 2H), 1.63-1.46 (m, 3H), 1.36 (q, J = 12.2, 11.4 Hz, 2H), 1.21 (s, 1H). Example-13: Synthesis of 6-(5-cyanopyrazin-2-ylamino)-N-cyclopentyl-4-(piperidin-3- ylmethylamino)pyridazine-3-carboxamide, (Compound No.1.61)
[226] Step-1: Synthesis of tert-butyl 3-((6-chloro-3-(cyclopentylcarbamoyl)pyridazin-4- ylamino)methyl)piperidine-1-carboxylate: To a solution of methyl 4-((1-(tert- butoxycarbonyl)piperidin-4-yl)methylamino)-6-chloropyridazine-3-carboxylate (200 mg, 0.520 mmols, 1.0 eq) in THF (10 mL) was added trimethylaluminium (2M in toluene) (0.65 mL, 1.30 mmols, 2.5 eq) followed by addition of cyclopentylamine (88 mg, 1.04 mmols, 2 eq). The resulting reaction mixture was stirred at RT for 4 h. Product formation was confirmed by TLC and LCMS. The reaction mixture was quenched with ice water (20 mL) and extracted with ethyl acetate (3 × 15 mL). Collective organic layer was washed with saturated solution sodium bicarbonate (20 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to get the crude. The crude was purified by combi flash chromatography using hexane: ethyl acetate as eluents to obtain the desired compound (400mg). LCMS: 438.2 [M+1]+ [227] Step-2: Synthesis of tert-butyl 3-((6-(5-cyanopyrazin-2-ylamino)-3- (cyclopentylcarbamoyl)pyridazin-4-ylamino)methyl)piperidine-1-carboxylate: A solution of tert-butyl 3-((6-chloro-3-(cyclopentylcarbamoyl)pyridazin-4- ylamino)methyl)piperidine-1-carboxylate (150 mg, 0.342 mmols, 1.0 eq) and 5- aminopyrazine-2-carbonitrile (45 mg, 0.376 mmols, 1.1 eq) in dioxane (4 mL) was purged with nitrogen for 5 minutes then Cs2CO3 (334 mg, 1.02 mmols, 3.0 eq) was added and the reaction mixture was purged again for 5 minutes. Further, Xantphos (19 mg, 0.034 mmols, 0.1 eq) and Pd2dba3 (15 mg, 0.017 mmols, 0.05 eq) was added and then the reaction mixture was subjected to microwave irradiation for 45 minutes at 180 °C. Product formation was confirmed by TLC and LCMS. The reaction mixture was quenched with ice water (20 mL) and extracted with ethyl acetate (3 × 15 mL). Collective organic layer was washed with brine
(20 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to get the crude. The crude was purified by flash chromatography by eluting in 60% ethyl acetate: hexane solvent system to get the desired compound as a light brown solid (100 mg). LCMS: 522.3 [M+1] + [228] Step-3: Synthesis of 6-(5-cyanopyrazin-2-ylamino)-N-cyclopentyl-4-(piperidin-3- ylmethylamino)pyridazine-3-carboxamide: To a solution of tert-butyl 3-((6-(5- cyanopyrazin-2-ylamino)-3-(cyclopentylcarbamoyl)pyridazin-4-ylamino)methyl)piperidine- 1-carboxylate (100 mg, 0.19 mmols, 1 eq) in DCM (5 mL), TFA (0.8 mL) was added at 0 °C and reaction mixture was stirred for 6 h. Product formation was confirmed by TLC and LCMS. The reaction mixture was concentrated under reduced pressure to get the crude. The crude was purified by reverse phase chromatography to yield desired compound as a formate salt; white solid (3.5 mg). LCMS: 422.2 [M+1]+; 1H NMR (400 MHz, DMSO-d6; after D2O addition) δ 8.91 (s, 1H), 8.76 (s, 1H), 7.39 (s, 1H), 4.19 (q, J = 6.9 Hz, 2H), 3.21-2.99 (m, 3H), 2.63 (d, J = 11.1 Hz, 2H), 1.91 (dd, J = 24.9, 12.9 Hz, 3H), 1.82-1.63 (m, 4H), 1.63-1.40 (m, 4H), 1.21 (d, J = 12.1 Hz, 2H). Example-14: Synthesis of 6-(5-cyanopyrazin-2-ylamino)-4-(piperidin-3- ylmethylamino)pyridazine-3-carboxamide, (Compound No.1.62)
[229] Step-1: Synthesis of tert-butyl-3-(3-carbamoyl-6-chloropyridazin-4 ylamino)methyl)piperidine-1-carboxylate: A solution of methyl 4-((1-tert- butoxycarbonyl)piperidin-3-yl)methylamino)-6-chloropyridazine-3-carboxylate (200 mg, 0.520 mmols, 1.0 eq) in methanolic ammonia (5 mL) was stirred at RT for 20 h. Product formation was confirmed by TLC and LCMS. The reaction mixture was concentrated under reduced pressure to get the crude. Then the crude was purified by flash chromatography hexane: ethyl acetate to get the desired compound (150 mg). LCMS: 370.1 [M+1]+ [230] Step-2: Synthesis of tert-butyl-3-((3-carbamoyl-6-(5-cyanopyrazin-2- ylamino)pyridazin-4-ylamino)methyl)piperidine-1-carboxylate: A solution of tert-butyl-3-(3-
carbamoyl-6-chloropyridazin-4-ylamino)methyl)piperidine-1-carboxylate (100 mg, 0.270 mmols, 1.0 eq) and 5-aminopyrazine-2-carbonitrile (32 mg, 0.270 mmols, 1.0eq) in DMF (2 mL) was purged with nitrogen for 10 minutes then Cs2CO3 (264 mg, 0.81 mmols, 3.0eq) was added and purged again for 5 minutes. Further, Xantphos (15 mg, 0.027 mmols, 0.1eq) and Pd2dba3 (12 mg, 0.013 mmols, 0.05 eq) was added and resulting reaction mixture was subjected to microwave irradiation for 45 minutes at 180 °C. Product formation was confirmed by TLC and LCMS. The reaction mixture was quenched with ice water (20 mL) and extracted with ethyl acetate (3 × 15 mL). Collective organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to get the crude. Then the crude was purified by combi flash chromatography by eluting in 60% ethyl acetate: hexane solvent system to get the desired compound (70 mg) as light brown solid. LCMS: 454.0 [M+1] + [231] Step-3: Synthesis of 6-(5-cyanopyrazin-2-ylamino)-4-(piperidin-3- ylmethylamino)pyridazine-3-carboxamide: To a solution of tert-butyl-3-((3-carbamoyl-6- (5-cyanopyrazin-2-ylamino)pyridazin-4-ylamino)methyl)piperidine-1-carboxylate (80mg, 0.153 mmols, 1 eq) in DCM (5 mL), TFA (0.8 mL) was added at 0 °C and reaction mixture was stirred for 2 h. Product formation was confirmed by TLC and LCMS. Then the reaction mixture was concentrated under reduced pressure to get the crude. The crude was purified by reverse phase chromatography to yield desired compound as a white solid (32 mg). LCMS: 354.5 [M+1] +; 1H NMR (400 MHz, DMSO-d6, after D2O addition) δ 8.95 (s, 1H), 8.80 (s, 1H), 7.40 (s, 1H), 3.19 – 3.07 (m, 1H), 3.07 – 2.99 (m, 1H), 2.95 (d, J = 12.2 Hz, 1H), 2.39 (t, J = 11.2 Hz, 2H), 1.79 (d, J = 15.6 Hz, 3H), 1.72 – 1.59 (m, 1H), 1.44 (q, J = 12.6 Hz, 1H), 1.28 – 1.10 (m, 1H). Example-15: Synthesis of 6-(5-cyanopyrazin-2-ylamino)-4-(pyrrolidin-3- ylmethylamino)pyridazine-3-carboxamide, (Compound No.1.63)
[232] Step-1: Synthesis of methyl 4-((1-(tert-butoxycarbonyl)pyrrolidin-3- yl)methylamino)-6-chloropyridazine-3-carboxylate: To a solution of methyl 4, 6-
dichloropyridazine-3-carboxylate (0.50 g, 0.241 mols, 1.0 eq) and tert-butyl 3- (aminomethyl)pyrrolidine-1-carboxylate (0.62 g, 0.289 mols, 1.2 eq) in THF (25 mL), TEA (0.52 mL, 0.362 mols, 1.5 eq) was added to the reaction mixture. The resultant reaction mixture was refluxed for 2 h. The product formation was confirmed by TLC and LCMS. After the completion of reaction, reaction mixture was concentrated. The crude was diluted with water (3 × 50 mL) and extracted with ethyl acetate (2 × 40 mL). The organic layer was separated and washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the desired compound (0.95 g) as white solid). LCMS: 371.3 [M+1] + [233] Step-2: Synthesis of tert-butyl 3-((3-(benzylcarbamoyl)-6-chloropyridazin-4- ylamino)methyl)pyrrolidine-1-carboxylate: To a solution of methyl 4-((1-(tert- butoxycarbonyl)pyrrolidin-3-yl)methylamino)-6-chloropyridazine-3-carboxylate (0.3 g, 0.81 mmols, 1.0 eq), methanolic ammonia (5 mL) was added. The reaction mixture was stirred at RT for 16h. The progress of reaction was monitored by TLC and LCMS. After, the completion of reaction, the methanolic ammonia was evaporated and solid residue was obtained. Further, obtained solid was washed with pentane to obtain the desired compound (0.29 g) as white solid. LCMS: 356.3 [M+1] + [234] Step-3: Synthesis of tert-butyl 3-((3-carbamoyl-6-(5-cyanopyrazin-2- ylamino)pyridazin-4-ylamino)methyl)pyrrolidine-1-carboxylate: A solution of tert-butyl 3-((3-carbamoyl-6-chloropyridazin-4-ylamino)methyl)pyrrolidine-1-carboxylate (290 mg, 0.816 mmols, 1.0 eq) and 5-aminopyrazine-2-carbonitrile (117.6 mg, 0.980 mmols, 1.2 eq) in dioxane (5 mL) was purged with nitrogen for 5 minutes then Cs2CO3 (797.5 mg, 2.448 mmols, 3.0 eq) was added and purged again for 5 minutes. Further, Xantphos (8.49 mg, 0.014 mmols, 0.018 eq) and Pd2dba3 (36.6 mg, 0.040 mmols, 0.05 eq) was added and the vial was subjected under microwave irradiation for 45 minutes at 180 °C. Product formation was confirmed by TLC and LCMS. The reaction mixture was quenched with ice water (30 mL) and extracted with ethyl acetate (2 × 30 mL). The collective organic layer was washed with brine (25 mL) and dried over anhydrous sodium sulfate and concentrated under reduced pressure to get the crude. The crude was purified by combi flash chromatography by eluting in 60% ethyl acetate: hexane solvent system to obtain desired compound (80 mg) as light brown solid. LCMS: 440.4 [M+1] +
[235] Step-4: Synthesis of 6-(5-cyanopyrazin-2-ylamino)-4-(pyrrolidin-3- ylmethylamino)pyridazine-3-carboxamide: To a solution of tert-butyl 3-((3-carbamoyl-6- (5-cyanopyrazin-2-ylamino)pyridazin-4-ylamino)methyl)pyrrolidine-1-carboxylate (80 mg, 0.182 mmols, 1 eq) in DCM (3 mL), TFA (0.35 mL, 0.455 mmols, 2.5 eq) was added at 0 °C and stirred for 6 h. Then the reaction mixture was concentrated under reduced pressure to get the crude. Then the reaction mixture was concentrated under reduced pressure to get the crude. The crude was purified by reverse phase chromatography to yield desired compound as formate salt and an off white solid (12 mg). LCMS: 340.4 [M+1] +; 1H NMR (400 MHz, DMSO-d6, after D2O addition) δ 8.91 (s, 1H), 8.78 (s, 1H), 8.40 (s, 1H), 7.45 (s, 1H), 3.30- 3.11 (m, 3H), 3.02 (q, J = 9.8, 9.1 Hz, 2H), 2.79 (dd, J = 11.3, 7.2 Hz, 2H), 2.02 (dt, J = 15.0, 7.5 Hz, 1H), 1.59 (p, J = 8.8, 7.9 Hz, 1H). Example-16: Synthesis of 6-(5-cyanopyrazin-2-ylamino)-4-((1-methylpiperidin-4-yl) methyl amino)-N-(2, 2, 2-trifluoroethyl) pyridazine-3-carboxamide, (Compound No.1.64)
[236] Step-1: Synthesis of methyl 6-chloro-4-((1-methylpiperidin-4-yl) methyl amino) pyridazine-3-carboxylate: To a solution of methyl 4,6-dichloropyridazine-3-carboxylate (500 mg, 2.415 mmols, 1.0 eq) in THF (15 mL), TEA (0.513 mL, 3.622 mmols, 1.5 eq) was added dropwise to the reaction mixture followed by the addition of (1-methylpiperidin-4- yl)methanamine (309 mg, 2.415 mmols, 1.0 eq). The resulting reaction mixture was refluxed for 2 h. Product formation was confirmed by TLC and LCMS. The reaction mixture was quenched with ice water (10 mL) and extracted with ethyl acetate (3 × 15 mL). Collective organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure. Then the crude was triturated with pentane to obtain the desired compound (0.850g) as an off-white color solid. LCMS: 298.12 [M+1] + [237] Step-2: Synthesis of 6-chloro-4-((1-methylpiperidin-4-yl)methylamino)-N-(2,2,2- trifluoroethyl)pyridazine-3-carboxamide: To a solution of methyl 6-chloro-4-((1- methylpiperidin-4-yl)methylamino)pyridazine-3-carboxylate (300 mg, 1.006 mmols, 1.0 eq)
in THF (15 mL) was added 2,2,2-trifluoroethanamine hydrochloride (203 mg, 1.51 mmols, 1.5 eq) followed by the addition of trimethylaluminium (2M in toluene) (2.012 mL, 4.024 mmols, 2.0 eq) and stirred at RT for 4 h. Product formation was confirmed by TLC and LCMS. The reaction mixture was quenched with ice water (10 mL) and extracted with ethyl acetate (3 × 15 mL). Collective organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to get the crude (0.250 g). The crude was used as such in the next step. LCMS: 366.3 [M+1] + [238] Step-3: Synthesis of 6-(5-cyanopyrazin-2-ylamino)-4-((1-methylpiperidin-4- yl)methyl amino)-N-(2, 2, 2-trifluoroethyl) pyridazine-3-carboxamide: A solution of 6- chloro-4-((1-methylpiperidin-4-yl)methyl amino)-N-(2, 2, 2-trifluoroethyl) pyridazine-3- carboxamide (250 mg, 0.683 mmols, 1.0 eq) and 5-aminopyrazine-2-carbonitrile (82 mg, 0.683 mmols, 1.0 eq) in dioxane (5 mL) was purged with nitrogen for 5 minutes then Cs2CO3 (667 mg, 2.049 mmols, 3.0 eq) was added and purged again for 5 minutes. Further, Xantphos (19 mg, 0.034 mmols, 0.05 eq) and Pd2dba3 (11 mg, 0.0122 mmols, 0.018 eq) was added and then the vial subjected under microwave irradiation for 45 minutes at 180 °C. Product formation was confirmed by TLC and LCMS. The reaction mixture was quenched with ice water (20 mL) and extracted with ethyl acetate (3 × 15 mL). Collective organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to get the crude. The crude was purified by reverse phase chromatography to yield desired compound as formate salt and a white solid (30 mg). LCMS: 450.5 [M+1] +; 1H NMR (400 MHz, DMSO-d6, after D2O addition) δ 8.92 (s, 1H), 8.80 (s, 1H), 8.30 (s, 1H), 7.49 (s, 1H), 4.05 (q, J = 9.4 Hz, 2H), 3.13 (d, J = 6.6 Hz, 2H), 2.95 (d, J = 11.3 Hz, 2H), 2.30 (s, 3H), 2.16 (t, J = 11.5 Hz, 1H), 2.07 (s, 2H), 1.69 (dd, J = 23.4, 10.8 Hz, 2H), 1.32 (q, J = 10.2, 7.2 Hz, 2H). Example-17: Synthesis of 5-(6-(5-methyl-1,3,4-oxadiazol-2-yl)-5-(morpholin-2- ylmethylamino)pyridazin-3-ylamino)pyrazine-2-carbonitrile, (Compound No.1.65)
[239] Step-1: Synthesis of tert-butyl 2-((6-chloro-3-(methoxycarbonyl)pyridazin-4- ylamino)methyl)morpholine-4-carboxylate: To a solution of methyl 4, 6- dichloropyridazine-3-carboxylate (900 mg, 4.34 mmols, 1.0 eq) in THF (20 mL) was added TEA (1.5 mL, 10.85 mmols, 2.5 eq) followed by the addition of tert-butyl 2- (aminomethyl)morpholine-4-carboxylate (1030 mg, 4.77 mmols, 1.1 eq). The resulting reaction mixture was refluxed for 2 h. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was quenched with ice water (10 mL) and extracted with ethyl acetate (3 × 100 mL). Combined organic phase was washed with water (3 × 20 mL) followed by brine wash (20 mL). Organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude. Crude was triturated with pentane and solid precipitate was filtered to obtain desired product (1.2 g) as white solid. LCMS: 387.1 [M+1] + [240] Step-2: Synthesis of tert-butyl 2-((6-chloro-3-(hydrazinecarbonyl)pyridazin-4- ylamino)methyl)morpholine-4-carboxylate: To a solution of tert-butyl 2-((6-chloro-3- (methoxycarbonyl)pyridazin-4-ylamino)methyl)morpholine-4-carboxylate (960 mg, 2.48 mmols, 1.0 eq) in methanol (20 m ) was added hydrazine hydrate (65% in water) (186.7 mg, 3.73 mmols, 1.5 eq) and the reaction mixture was stirred at RT for 16 h. The progress of reaction was monitored by TLC and LCMS. After completion, reaction mixture was concentrated under reduced pressure. Further, ethyl acetate (100 mL) was added and organic phase was washed with water (3 × 20 mL) followed by brine wash (20 mL). Organic layer was separated and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude. Crude was triturated with pentane to obtain the desired compound (920 mg) as off white solid. LCMS: 387.1 [M+1] + [241] Step-3: Synthesis of tert-butyl 2-((6-chloro-3-(5-methyl-1,3,4-oxadiazol-2- yl)pyridazin-4-ylamino)methyl)morpholine-4-carboxylate: To a solution of tert-butyl 2- ((6-chloro-3-(hydrazinecarbonyl)pyridazin-4-ylamino)methyl)morpholine-4-carboxylate (440 mg, 1.13 mmols, 1 eq) in xylene (10 mL) was added triethylorthoacetate (203.4 mg,1.25 mmols, 1.1 eq). The resulting reaction mixture was stirred at 180 °C for 16 h. Reaction was monitored by TLC and LCMS. After completion, reaction mixture was concentrated under reduced pressure. Then, ethyl acetate (100 mL) was added and organic phase was washed with water (3 × 20 mL) followed by brine wash (20 mL). Organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford
crude. Crude was purified by flash chromatography using ethyl acetate: hexane (0-40%) as eluent to obtain desired compound (170mg) as viscous liquid. LCMS: 411.1 [M+1] + [242] Step-4: Synthesis of tert-butyl 2-((6-(5-cyanopyrazin-2-ylamino)-3-(5-methyl- 1,3,4-oxadiazol-2-yl)pyridazin-4-ylamino)methyl)morpholine-4-carboxylate: A solution of tert-butyl 2-((6-chloro-3-(5-methyl-1,3,4-oxadiazol-2-yl)pyridazin-4- ylamino)methyl)morpholine-4-carboxylate (160 mg, 0.39 mmols, 1.0 eq) and 5- aminopyrazine-2-carbonitrile (42.1 mg, 0.35 mmols, 0.9 eq) in DMF (4 mL) was added Cs2CO3 (381.4 mg, 1.17 mmols, 3 eq) at RT and reaction mixture was purged under nitrogen for 10 minutes. Further, Xantphos (22.5 mg, 0.039 mmols, 0.1 eq) and Pd2dba3 (35.7 mg, 0.039 mmols, 0.1 eq) was added and again nitrogen was purged for 5 minutes. Reaction mixture was stirred at 180 °C for 16 h. The progress of reaction was monitored by TLC and LCMS. After completion, ethyl acetate (100 mL) was added and organic phase was washed with water (3 × 20 mL) followed by brine wash (20 mL). Organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude. Crude was purified by flash using ethyl acetate: hexane (0-80%) as eluent to afford desired compound (52mg) as off white solid. LCMS: 495.2 [M+1] + [243] Step-5: Synthesis of 5-(6-(5-methyl-1,3,4-oxadiazol-2-yl)-5-(morpholin-2- ylmethylamino)pyridazin-3-ylamino)pyrazine-2-carbonitrile: To a solution of tert-butyl 2-((6-(5-cyanopyrazin-2-ylamino)-3-(5-methyl-1,3,4-oxadiazol-2-yl)pyridazin-4- ylamino)methyl) morpholine-4-carboxylate (48 mg, 0. 09 mmols, 1.0 eq) in DCM (1 mL) was added TFA (0.3 mL) at 0 °C and reaction was stirred at RT for 6h. Reaction was monitored by TLC and LCMS. After completion, reaction mixture was concentrated under reduced pressure to afford crude. The crude was purified by reverse phase chromatography to yield desired compound as trifluoroacetate salt and a white solid (17 mg). LCMS: 395.2 [M+1] +; 1H NMR (400 MHz, DMSO-d6, after D2O addition) δ 8.78 (d, J = 10.4 Hz, 2H), 7.73 (s, 1H), 4.09-3.88 (m, 2H), 3.57 (dd, J = 14.5, 3.7 Hz, 1H), 3.44 (dd, J = 14.2, 6.9 Hz, 1H), 3.30 (d, J = 12.8 Hz, 1H), 3.14 (d, J = 12.6 Hz, 1H), 2.98 (dd, J = 13.1, 9.1 Hz, 1H), 2.87 (t, J = 12.0 Hz, 1H), 2.62 (s, 3H). Example-18: Synthesis of N-benzyl-6-(5-cyanopyrazin-2-ylamino)-4-(morpholin-2- ylmethylamino)pyridazine-3-carboxamide, (Compound No.1.66)
[244] Step-1: Synthesis of tert-butyl 2-((3-(benzylcarbamoyl)-6-chloropyridazin-4- ylamino)methyl)morpholine-4-carboxylate: To solution of tert-butyl 2-((6-chloro-3- (methoxycarbonyl)pyridazin-4-ylamino)methyl)morpholine-4-carboxylate (0.5 g, 0.129 mols, 1.0 eq) and phenylmethanamine (0.20 g, 0.195 mols, 1.5 eq) in THF (10 mL) followed by the addition of trimethylaluminium (2M in toluene) (1.87 mL, 0.260 mols, 2.0 eq). The reaction mixture was stirred at RT for 4 h. The progress of reaction was monitored by TLC and LCMS. After the completion of reaction, ice cold water (20 mL) was added to the reaction mixture and filtered. Further, ethyl acetate (2 × 20 mL) was added and washed with water (2 × 30 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain desired product (0.4 g) as white solid. LCMS: 462.4 [M+1] + [245] Step-2: Synthesis of tert-butyl 2-((3-(benzylcarbamoyl)-6-(5-cyanopyrazin-2- ylamino)pyridazin-4-ylamino)methyl)morpholine-4-carboxylate: A solution of tert-butyl 2-((3-(benzylcarbamoyl)-6-chloropyridazin-4-ylamino)methyl)morpholine-4-carboxylate (400 mg, 0.867 mmols, 1.0 eq) and 5-aminopyrazine-2-carbonitrile (124.9 mg, 1.040 mmols, 1.2 eq) in dioxane (5 mL) was purged with nitrogen for 5 minutes then Cs2CO3 (847.4 mg, 2.601 mmols, 3.0 eq) was added and purged again for 5 minutes. Further, Xantphos (9.02 mg, 0.015 mmols, 0.018 eq) and Pd2dba3 (39.6 mg, 0.043 mmols, 0.05 eq) was added and the vial was subjected to microwave irradiation for 45 minutes at 180 °C. Product formation was confirmed by TLC and LCMS. The reaction mixture was quenched with ice water (30 mL) and extracted with ethyl acetate (2 × 30 mL). Collective organic layer was washed with brine (25 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to get the crude. Then the crude was purified by combi flash chromatography by eluting in 45% ethyl acetate: hexane solvent system to get desired product (145 mg) as light brown solid. LCMS: 546.6 [M+1] + [246] Step-3: Synthesis of N-benzyl-6-(5-cyanopyrazin-2-ylamino)-4-(morpholin-2- ylmethylamino)pyridazine-3-carboxamide: To a solution of tert-butyl 2-((3- (benzylcarbamoyl)-6-(5-cyanopyrazin-2-ylamino)pyridazin-4-ylamino)methyl)morpholine-4-
carboxylate (140 mg, 0.331 mmols, 1 eq) in DCM (5 mL), TFA (0.63 mL, 0.828 mmols, 2.5 eq) was added at 0 °C and kept for stirring for 6h. Then the reaction mixture was concentrated under reduced pressure to get the crude. The crude was purified by reverse phase chromatography to yield desired compound as formate salt and an off white solid (40 mg). LCMS: 446.5 [M+1] +; 1H NMR (400 MHz, DMSO-d6, after D2O addition) δ 9.55 (t, J = 6.3 Hz, 1H), 8.94 (s, 1H), 8.87 (t, J = 5.5 Hz, 1H), 8.79 (s, 1H), 8.28 (s, 1H), 7.41 (s, 1H), 7.32 (d, J = 4.8 Hz, 2H), 7.24 (d, J = 5.9 Hz, 1H), 4.46 (d, J = 5.6 Hz, 2H), 3.81 (d, J = 11.4 Hz, 1H), 3.67 (t, J = 7.0 Hz, 1H), 3.50 (d, J = 12.1 Hz, 1H), 3.28 (dt, J = 9.8, 5.1 Hz, 1H), 3.17 (dt, J = 13.3, 5.7 Hz, 1H), 2.93 (d, J = 12.3 Hz, 1H), 2.82- 2.57 (m, 3H). Example-19: Synthesis of 6-(5-cyanopyrazin-2-ylamino)-4-(piperidin-3-ylmethylamino)-N- (pyridin-4-yl)pyridazine-3-carboxamide, (Compound No.1.67)
[247] Step-1: Synthesis of 4-((1-(tert-butoxycarbonyl)piperidin-3-yl)methylamino)-6- chloropyridazine-3-carboxylic acid: To a solution of methyl 4-((1-(tert- butoxycarbonyl)piperidin-3-yl)methylamino)-6-chloropyridazine-3-carboxylate (200mg, 0.520 mmols, 1.0 eq) in THF: water (3mL: 3mL) was added LiOH (38 mg, 1.562 mmols, 3.0 eq) and the reaction mixture was stirred at RT for 2 h. Product formation was confirmed by TLC and LCMS. After the completion of reaction, the reaction mixture was acidified by 1N HCl (5 mL) solution and extracted with ethyl acetate (3 × 5 mL). Collective organic layer was washed with brine (10 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to get the crude. The crude was triturated with pentane to get the desired compound (180 mg) as an off white color solid. LCMS: 315.2 [M-Boc+1] + [248] Step-2: Synthesis of tert-butyl 3-((6-chloro-3-(pyridin-4-ylcarbamoyl)pyridazin- 4-ylamino)methyl)piperidine-1-carboxylate: To a solution of 4-((1-(tert- butoxycarbonyl)piperidin-3-yl)methylamino)-6-chloropyridazine-3-carboxylic acid (180 mg, 0.486 mmols, 1.0 eq) in DMF (3 mL), DIPEA (0.2 mL, 1.215 mmols, 2.5 eq) and HATU (277 mg, 0.729 mmols, 1.5 eq) was added at 0 °C and kept for stirring for 30 minutes. Then,
pyridin-4-amine (116 mg, 0.972 mmols, 2.0 eq) was added and the resulting reaction mixture was stirred at RT for 16h. Product formation was confirmed by TLC and LCMS. The reaction mixture was quenched with ice water (20 mL) and extracted with ethyl acetate (3 × 15 mL). Collective organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to get the desired compound (150 mg) as pale yellow solid. LCMS: 447.4 [M+1] + [249] Step-3: Synthesis of tert-butyl 3-((6-(5-cyanopyrazin-2-ylamino)-3-(pyridin-4- ylcarbamoyl)pyridazin-4-ylamino)methyl)piperidine-1-carboxylate: A solution of tert- butyl 3-((6-chloro-3-(pyridin-4-ylcarbamoyl)pyridazin-4-ylamino)methyl)piperidine-1- carboxylate (150 mg, 0.336 mmols, 1.0 eq) and 5-aminopyrazine-2-carbonitrile (48 mg, 0.403 mmols, 1.2 eq) in dioxane (3 mL) was purged under nitrogen for 5 minutes then Cs2CO3 (328 mg, 1.008 mmols, 3.0 eq) was added and purged again for 5 minutes. Further, Xantphos (3.4 mg, 0.006 mmols, 0.018 eq) and Pd2dba3 (15 mg, 0.016 mmols, 0.05 eq) was added and then the vial was subjected to microwave irradiation for 45 minutes at 180 °C. Product formation was confirmed by TLC and LCMS. The reaction mixture was quenched with ice water (20 mL) and extracted with ethyl acetate (3 × 15 mL). Collective organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to get the crude. Then the crude was purified by flash chromatography by eluting in 60% ethyl acetate: hexane solvent system to get the desired compound (70mg) as yellow solid. LCMS: 531.5 [M+1]+ [250] Step-4: Synthesis of 6-(5-cyanopyrazin-2-ylamino)-4-(piperidin-3- ylmethylamino)-N-(pyridin-4-yl)pyridazine-3-carboxamide: To a solution of tert-butyl 3- ((6-(5-cyanopyrazin-2-ylamino)-3-(pyridin-4-ylcarbamoyl)pyridazin-4- ylamino)methyl)piperidine-1-carboxylate (70 mg, 0.132 mmols, 1.0 eq) in DCM (3 mL), TFA (45 mg ,0.396 mmols, 3.0 eq) was added at 0 °C and kept for stirring for 6h. After the completion of reaction as monitored by TLC and LCMS, the reaction mixture was concentrated under reduced pressure. Then water (5 mL) was added to the reaction mixture and extracted with ether (3 × 10 mL). The aqueous layer was separated and lyophilized to provide crude product. The crude was purified by reverse phase chromatography to yield desired compound as formate salt and a white solid (4 mg). LCMS: 431.5 [M+1] +; 1H NMR (400 MHz, DMSO-d6, after D2O addition) δ 8.95 (s, 1H), 8.82 (s, 1H), 8.47 (d, J = 5.6 Hz, 2H), 8.38 (s, 1H), 7.88 (d, J = 5.3 Hz, 2H), 7.53 (s, 1H), 3.32 – 3.17 (m, 2H), 3.13 (d, J = 10.9
Hz, 1H), 2.73 (t, J = 11.8 Hz, 2H), 2.03 (q, J = 11.2, 8.2 Hz, 1H), 1.89 – 1.69 (m, 2H), 1.55 (d, J = 11.5 Hz, 1H), 1.26 (dd, J = 26.2, 15.3 Hz, 2H). Example-20: Synthesis of 6-(5-cyanopyrazin-2-ylamino)-N-isopropyl-4-(piperidin-4- ylmethylamino)pyridazine-3-carboxamide, (Compound No.1.68)
[251] Step-1: Synthesis of tert-butyl 4-((6-chloro-3-(isopropylcarbamoyl) pyridazin-4- ylamino) methyl) piperidine-1-carboxylate: To a solution of methyl 4-((1-(tert- butoxycarbonyl) piperidin-4-yl)methylamino)-6-chloropyridazine-3-carboxylate (250 mg, 0.651 mmols, 1.0 eq) in ACN (10.0 mL) was added K2CO3 (269 mg, 1.953 mmols, 3.0eq) and then propan-2-amine (0.117 mg, 1.953 mmols, 3.0 eq) was added and kept for stirring at RT for 8h. Product formation was confirmed by TLC and LCMS. The reaction mixture was quenched with ice water (20 mL) and extracted with ethyl acetate (15 × 3 mL). Collective organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to get the crude. The crude was triturated with pentane to get the desired compound as a white solid (270 mg, crude). LCMS: 412.4 [M+1] + [252] Step-2: Synthesis of tert-butyl 4-((6-(5-cyanopyrazin-2-ylamino)-3- (isopropylcarbamoyl) pyridazin-4-ylamino) methyl) piperidine-1-carboxylate: A solution of tert-butyl 4-((6-chloro-3-(isopropyl carbamoyl) pyridazin-4-ylamino) methyl) piperidine-1-carboxylate (200 mg, 0.485 mmols, 1.0 eq) and 5-aminopyrazine-2-carbonitrile (69 mg, 0.582 mmols, 1.2 eq) in dioxane (5 mL) was purged with N2 for 5 minutes followed by addition of Cs2CO3 (474 mg, 1.455 mmols, 3.0 eq) and purged again for 5 minutes. Xantphos (5.0 mg, 0.008 mmols, 0.018eq) and Pd2dba3 (22 mg, 0.024mmols, 0.05 eq) was added and then the vial was subjected to microwave irradiation for 45 minutes at 180 °C. Product formation was confirmed by TLC and LCMS. The reaction mixture was quenched with ice water (20 mL) and extracted with ethyl acetate (15 × 3 mL). Collective organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to get the crude. The crude was purified by combi flash chromatography by using 12g redi sap column and by eluting in 60% ethyl acetate: hexane
solvent system to get the desired compound as light brown solid (120 mg). LCMS: 496.5 [M+1] + [253] Step-3: Synthesis of 6-(5-cyanopyrazin-2-ylamino)-N-isopropyl-4-(piperidin-4- ylmethylamino) pyridazine-3-carboxamide: To a solution of tert -butyl 4-((6-(5- cyanopyrazin-2-ylamino)-3-(isopropyl carbamoyl) pyridazin-4-ylamino) methyl) piperidine- 1-carboxylate (100 mg, 0.201 mmols, 1 eq) in DCM (5.0 mL), TFA (0.5 mL) was added at 0°C and kept for stirring for 2h. Product formation was confirmed by TLC and LCMS analyses. The reaction mixture was concentrated under reduced pressure to get the crude. The crude was purified by reverse phase chromatography to yield desired compound as a formate salt; white solid (30 mg). LCMS: 396.6 [M+1] +; 1H NMR (400 MHz, DMSO-d6, after D2O addition δ 8.86 (s, 1H), 8.74 (s, 1H), 8.37 (s, 1H), 7.41 (s, 1H), 4.07 (p, J = 6.6 Hz, 1H), 3.26 (d, J = 12.5 Hz, 2H), 3.14 (d, J = 6.0 Hz, 2H), 2.88- 2.77 (m, 2H), 1.86 (t, J = 16.0 Hz, 3H), 1.47-1.31 (m, 2H), 1.17 (d, J = 6.6 Hz, 6H). Example-21: Synthesis of 5-(6-(5-methyl-1,3,4-oxadiazol-2-yl)-5-(piperidin-4- ylmethylamino)pyridazin-3-ylamino)pyrazine-2-carbonitrile, (Compound No.1.69)
[254] Step-1: Synthesis of tert-butyl 4-((6-chloro-3-(hydrazinecarbonyl)pyridazin-4- ylamino)methyl)piperidine-1-carboxylate: To a solution of methyl 4-((1-(tert- butoxycarbonyl)piperidin-4-yl)methylamino)-6-chloropyridazine-3-carboxylate (510 mg, 1.29 mmols, 1.0 eq.) in methanol (20 mL) was added hydrazine hydrate (65%) (97.51 mg, 1.94 mmols, 1.5 eq) at ambient temperature. Reaction mixture was stirred at RT for 16h. Reaction was monitored by TLC and LCMS. After completion, reaction mixture was concentrated under reduced pressure. Ethyl acetate (100 mL) was added and organic phase was washed with water (20 mL × 3) followed by brine wash (20 mL). Organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford crude. Crude was triturated with pentane and solid thus precipitated was filtered to afford the desired compound as an off white solid (510 mg). LCMS: 385.1 [M+1]+
[255] Step-2: Synthesis of tert-butyl 4-((6-chloro-3-(5-methyl-1,3,4-oxadiazol-2- yl)pyridazin-4-ylamino)methyl)piperidine-1-carboxylate: To a solution of tert-butyl 4-((6- chloro-3-(hydrazinecarbonyl)pyridazin-4-ylamino)methyl)piperidine-1-carboxylate (400 mg, 1.03 mmol, 1eq) in xylene (10 mL) was added triethylorthoacetate (185.4 mg, 1.14 mmol, 1.1 eq) at RT. Reaction mixture was stirred at 180°C for 16h. Reaction was monitored by TLC and LCMS. After completion, reaction mixture was concentrated under reduced pressure. Ethyl acetate (100 mL) was added and organic phase was washed with water (20 mL × 3) followed by brine wash (20 mL). Organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford crude. Crude was purified by combi flash using ethyl acetate: hexane (0-40%) as eluent to afford the desired compound as viscous liquid (140 mg). LCMS: 409.1 [M+1]+ [256] Step-3: Synthesis of tert-butyl 4-((6-(5-cyanopyrazin-2-ylamino)-3-(5-methyl- 1,3,4-oxadiazol-2-yl)pyridazin-4-ylamino)methyl)piperidine-1-carboxylate: A solution of tert-butyl 4-((6-chloro-3-(5-methyl-1,3,4-oxadiazol-2-yl)pyridazin-4- ylamino)methyl)piperidine-1-carboxylate (270 mg, 0.66 mmols, 1.0 eq) and 5- aminopyrazine-2-carbonitrile (71.4 mg, 0.59 mmols, 0.9 eq) in DMF (4mL) was added Cs2CO3 (646.7mg, 1.98 mmols, 3 eq) at RT and reaction mixture was purged under nitrogen for 10 minutes. Xantphos (38.2 mg, 0.066 mmols, 0.1eq) and Pd2dba3 (60.48 mg, 0.066mmols, 0.1 eq) was added and again nitrogen was purged for 5 minutes. Reaction mixture was subjected to microwave irradiation at 180 °C for 45 minutes. Reaction was monitored by TLC and LCMS. After completion, reaction mixture was cooled to RT. Ethyl acetate (100 mL) was added and organic phase was washed with water (20 mL × 3) followed by brine wash (20 mL). Organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford crude. Crude was purified by combi flash using ethyl acetate: hexane (0-80%) as eluent to afford the desired compound as an off white solid (93mg). LCMS: 493.1[M+1] + [257] Step-4: Synthesis of 5-(6-(5-methyl-1,3,4-oxadiazol-2-yl)-5-(piperidin-4- ylmethylamino)pyridazin-3-ylamino)pyrazine-2-carbonitrile: To a solution of tert-butyl 4-((6-(5-cyanopyrazin-2-ylamino)-3-(5-methyl-1,3,4-oxadiazol-2-yl)pyridazin-4- ylamino)methyl)piperidine-1-carboxylate (90 mg, 0.18 mmols, 1.0 eq) in DCM (1 mL) was added TFA (0.5 mL) and the reaction mixture was stirred at 0 °C for 6h. Reaction was monitored by TLC and LCMS. After completion, reaction mixture was concentrated under
reduced pressure to afford crude. The crude was purified by reverse phase chromatography to yield desired compound as formate salt and a white solid (33 mg). LCMS: 393.2 [M+1] +; 1H NMR (400 MHz, DMSO-d6, after D2O addition) δ 8.75 (d, J = 14.1 Hz, 2H), 8.33 (s, 1H), 7.66 (s, 1H), 3.37-3.16 (m, 4H), 2.91-2.76 (m, 2H), 2.60 (s, 3H), 1.96 (s, 1H), 1.88 (d, J = 13.9 Hz, 2H), 1.42 (q, J = 12.4, 11.7 Hz, 2H). Example-22: Synthesis of 6-(5-cyanopyrazin-2-ylamino)-4-(morpholin-2-ylmethylamino)-N- (pyridin-4-yl)pyridazine-3-carboxamide, (Compound No.1.70)
[258] Step-1: Synthesis of 4-((4-(tert-butoxycarbonyl)morpholin-2-yl)methylamino)-6- chloropyridazine-3-carboxylic acid: To a solution of tert-butyl 2-((6-chloro-3- (methoxycarbonyl)pyridazin-4-ylamino)methyl)morpholine-4-carboxylate (910 mg, 2.35 mmols, 1.0 eq) in tetrahydrofuran : water (8:2) (30 mL) was added lithium hydroxide (296.4 mg, 2.05 mmols, 3 eq) at ambient temperature. Reaction mixture was stirred at RT for 2h. Progress of reaction was monitored by TLC and LCMS. After completion, reaction mixture was concentrated under reduced pressure. Ethyl acetate (100 mL) was added and organic phase was washed with 1N hydrochloric acid (20 mL) followed by brine wash (20 mL). Organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford desired compound as a white solid (830 mg). LCMS: 373.2 [M+1] + [259] Step-2: Synthesis of tert-butyl 2-((6-chloro-3-(pyridin-4-ylcarbamoyl)pyridazin- 4-ylamino)methyl)morpholine-4-carboxylate: To a solution of 4-((4-(tert- butoxycarbonyl)morpholin-2-yl)methylamino)-6-chloropyridazine-3-carboxylic acid (820 mg, 2.2 mmols, 1 eq) in DMF (10 mL) was added HATU (1.25 g, 3.3 mmols, 1.5 eq) at RT followed by addition of N-ethyl-N-isopropylpropan-2-amine (851.4 mg, 6.6 mmols, 3 eq) at same temperature. Pyridin-4-amine (228.2 mg, 2.42 mmols, 1.1 eq) was added and the reaction mixture was stirred at RT for 16h. Reaction was monitored by TLC and LCMS. After completion, ethyl acetate (100 mL) was added and organic phase was washed with
water (20 mL × 3) followed by brine wash (20 mL). Organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude. The crude product was purified by combi flash using ethyl acetate: hexane (0-50%) as eluent to afford the desired compound as a white solid (610 mg). LCMS: 449.1 [M+1] + [260] Step-3: Synthesis of tert-butyl 2-((6-(5-cyanopyrazin-2-ylamino)-3-(pyridin-4- ylcarbamoyl)pyridazin-4-ylamino)methyl)morpholine-4-carboxylate: To a solution of tert-butyl-2-((6-chloro-3-(pyridin-4-ylcarbamoyl)pyridazin-4-ylamino)methyl)morpholine-4- carboxylate (400 mg, 0.89 mmols, 1.0 eq) and 5-aminopyrazine-2-carbonitrile (96.42 mg, 0.80 mmols, 0.9 eq) in DMF (7 mL) was added Cs2CO3 (872.3 mg, 2.67 mmols, 3 eq) at RT and reaction mixture was purged under nitrogen for 10 minutes. Xantphos (51.5 mg, 0.089 mmols, 0.1 eq) and Pd2dba3 (81.6 mg, 0.089 mmols, 0.1 eq) were added and again nitrogen was purged for 5 minutes. Reaction mixture was subjected to microwave irradiation at 180 °C for 45 minutes. Reaction progress was monitored by TLC and LCMS. After completion, reaction mixture was cooled to RT. Ethyl acetate (100 mL) was added and organic phase was washed with water (20 mL × 3) followed by brine wash (20 mL). Organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude. Crude was purified by combi flash using ethyl acetate: hexane (0-90%) as eluent to afford the desired compound as an off-white solid (120 mg). LCMS: 533.2 [M+1] + [261] Step-4: Synthesis of 6-(5-cyanopyrazin-2-ylamino)-4-(morpholin-2- ylmethylamino)-N-(pyridin-4-yl)pyridazine-3-carboxamide: To a solution of tert-butyl 2- ((6-(5-cyanopyrazin-2-ylamino)-3-(pyridin-4-ylcarbamoyl)pyridazin-4- ylamino)methyl)morpholine-4-carboxylate (120 mg, 0. 22 mmols, 1.0 eq) in DCM (1 mL) was added TFA (0.6 mL) at 0 °C and reaction was stirred at RT for 6h. Reaction was monitored by TLC and LCMS. The reaction mixture was concentrated under reduced pressure to get the crude. The crude was purified by reverse phase chromatography to yield desired compound as a formate salt; white solid (30 mg). LCMS: 433.1 [M+1] +; 1H NMR (400 MHz, DMSO-d6, after D2O addition δ 8.94 (d, J = 1.4 Hz, 1H), 8.78 (d, J = 1.5 Hz, 1H), 8.51- 8.40 (m, 2H), 7.93- 7.77 (m, 2H), 7.51 (s, 1H), 3.93-3.85 (m, 1H), 3.63- 3.53 (m, 1H), 3.38 (dd, J = 13.7, 3.9 Hz, 1H), 3.26 (dd, J = 13.9, 7.2 Hz, 1H), 3.09-2.99 (m, 1H), 2.88 (d, J = 12.4 Hz, 1H), 2.78 (td, J = 12.2, 3.4 Hz, 1H), 2.62 (d, J = 11.6 Hz, 2H). Example-23: Synthesis of 5-(6-(5-methyl-1,3,4-oxadiazol-2-yl)-5-(piperidin-3- ylmethylamino)pyridazin-3-ylamino)pyrazine-2-carbonitrile, (Compound No.1.71)
[262] Step-1: Synthesis of tert-butyl 3-((6-chloro-3-(hydrazinecarbonyl)pyridazin-4- ylamino)methyl)piperidine-1-carboxylate: To a solution of methyl 4-((1-(tert- butoxycarbonyl)piperidin-3-yl)methylamino)-6-chloropyridazine-3-carboxylate (800 mg, 2.07 mmols, 1.0 eq) in methanol (20 mL) was added hydrazine hydrate (65% solution) (156.03 mg, 3.11 mmols , 1.5 eq) at ambient temperature. Reaction mixture was stirred at RT for 16h. Reaction was monitored by TLC and LCMS. After completion, reaction mixture was concentrated under reduced pressure. Ethyl acetate (250 mL) was added and organic phase was washed with water (20 mL × 3) followed by brine wash (20 mL). Organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude. Crude was triturated with pentane and the solid thus precipitated was filtered to afford the desired compound as an off white solid (780 mg). LCMS: 385.1 [M+1] + [263] Step-2: Synthesis of tert-butyl 3-((6-chloro-3-(5-methyl-1,3,4-oxadiazol-2- yl)pyridazin-4-ylamino)methyl)piperidine-1-carboxylate: To a solution of tert-butyl 3-((6- chloro-3-(hydrazinecarbonyl)pyridazin-4-ylamino)methyl)piperidine-1-carboxylate (730 mg, 1.89 mmols, 1eq) in xylene (10 mL) was added triethylorthoacetate (398.5 mg, 2.45 mmols, 1.3 eq) at RT. Reaction mixture was stirred at 180 °C for 16h. Reaction was monitored by TLC and LCMS. After completion, reaction mixture was concentrated under reduced pressure. Ethyl acetate (200 mL) was added and organic phase was washed with water (20 mL × 3) followed by brine wash (20 mL). Organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude. Crude was purified by combi flash using ethyl acetate: hexane (0-50%) as eluent to afford the desired compound as a viscous liquid (95 mg). LCMS: 409.1 [M+1]+ [264] Step-3: Synthesis of tert-butyl 3-((6-(5-cyanopyrazin-2-ylamino)-3-(5-methyl- 1,3,4-oxadiazol-2-yl)pyridazin-4-ylamino)methyl)piperidine-1-carboxylate: To a solution of tert -butyl 3-((6-chloro-3-(5-methyl-1,3,4-oxadiazol-2-yl)pyridazin-4- ylamino)methyl)piperidine-1-carboxylate (90 mg, 0.22 mmols , 1.0 eq) and 5-aminopyrazine-
2-carbonitrile (21.17 mg, 0.17 mmols , 0.8 eq) in DMF (4 mL) was added Cs2CO3 (215.1 mg, 0.66 mmols, 3 eq) at RT and reaction mixture was purged under nitrogen for 10 minutes. Xantphos (12.71 mg, 0.02 mmols, 0.1eq) and Pd2dba3 (20.13 mg, 0.02mmols, 0.1 eq) were added and again nitrogen was purged for 5 minutes. Reaction mixture was subjected to microwave irradiation at 180 °C for 45 minutes. Reaction was monitored by TLC and LCMS. After completion, reaction mixture was cooled to RT. Ethyl acetate (100 mL) was added and organic phase was washed with water (20 mL × 3) followed by brine wash (20 mL). Organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude. Crude was purified by combi flash using ethyl acetate: hexane (0-80%) as eluent to afford the desired compound as an off white solid (50 mg). LCMS: 493.0 [M+1] + [265] Step-4: Synthesis of 5-(6-(5-methyl-1,3,4-oxadiazol-2-yl)-5-(piperidin-3- ylmethylamino)pyridazin-3-ylamino)pyrazine-2-carbonitrile: To a solution of tert-butyl 3-((6-(5-cyanopyrazin-2-ylamino)-3-(5-methyl-1,3,4-oxadiazol-2-yl) pyridazin-4- ylamino)methyl)piperidine-1-carboxylate (50 mg, 0. 10 mmols, 1.0 eq) in DCM (1 mL) was added TFA (0.3 mL) at 0°C and reaction was stirred at RT for 6h. Reaction was monitored by TLC and LCMS. After completion, reaction mixture was concentrated under reduced pressure to afford crude. The crude was purified by reverse phase chromatography to yield desired compound as a formate salt; white solid (27 mg). LCMS: 393.0 [M+1]+; 1H NMR (400 MHz, DMSO-d6; after D2O addition) δ 8.82 (d, J = 8.8 Hz, 2H), 8.38 (s, 1H), 7.68 (s, 1H), 3.34 (h, J = 7.4 Hz, 2H), 3.22 (dd, J = 12.7, 3.3 Hz, 1H), 3.13 (d, J = 12.4 Hz, 1H), 2.63 (s, 5H), 2.06 (h, J = 8.2, 7.0 Hz, 1H), 1.82 (dd, J = 21.1, 14.6 Hz, 2H), 1.56 (q, J = 13.3, 12.1 Hz, 1H), 1.35-1.20 (m, 1H). Example-24: Synthesis 6-(5-cyanopyrazin-2-ylamino)-N-phenyl-4-(pyrrolidin-3- ylmethylamino)pyridazine-3-carboxamide, (Compound No.1.72)
[266] Step-1: Synthesis of methyl 4-((1-(tert -butoxycarbonyl)pyrrolidin-3- yl)methylamino)-6-chloropyridazine-3-carboxylate: To a solution of methyl 4,6- dichloropyridazine-3-carboxylate (0.5 g, 0.241 mol, 1.0 eq) and tert -butyl 3-
(aminomethyl)pyrrolidine-1-carboxylate (0.57 g, 0.289 mol, 1.2 eq) in THF (10 mL), triethylamine (0.52 mL, 0.362 mol, 1.5 eq) was added to the reaction mixture. The resultant reaction mixture was heated and stirred at 90 °C for 4h. The product formation was confirmed by TLC and LCMS. After the completion of reaction, reaction mixture was concentrated and crude was obtained. The crude was diluted with water (2 × 50 mL) and extracted with ethyl acetate (50 mL). The organic layer was separated and washed with brine (30 mL), dried over anhydrous anhydrous sodium sulfate and concentrated under reduced pressure to obtain methyl 4-((1-(tert -butoxycarbonyl)pyrrolidin-3-yl)methylamino)-6-chloropyridazine-3- carboxylate (0.90 g, white solid). LCMS: 371.3 [M+1] + [267] Step-2: Synthesis of tert-butyl 3-((6-chloro-3-(phenylcarbamoyl)pyridazin-4- ylamino)methyl)pyrrolidine-1-carboxylate: To a solution of methyl 4-((1-(tert- butoxycarbonyl)pyrrolidin-3-yl)methylamino)-6-chloropyridazine-3-carboxylate (0.4 g, 0.108 mol, 1.0 eq) and aniline (0.15 g, 0.162 mol, 1.5 eq) in THF (7 mL), trimethylaluminium (2M in toluene) (0.15 mL, 0.108 mol, 2.0 eq) was added. The reaction mixture was stirred at RT for 4h. The progress of reaction was monitored by TLC and LCMS. After the completion of reaction, ice cold water (10 mL) was added to the reaction mixture and the solid thus precipitated was filtered. Further, the solid was dissolved in ethyl acetate (40 mL) and washed with water (2 × 30 mL). The organic layer was separated, dried over anhydrous anhydrous sodium sulfate and concentrated under reduced pressure to obtain the desired compound as a white solid (0.4 g). LCMS: 432.3 [M+1] + [268] Step-3: Synthesis of tert-butyl 3-((6-(5-cyanopyrazin-2-ylamino)-3- (phenylcarbamoyl)pyridazin-4-ylamino)methyl)pyrrolidine-1-carboxylate: A solution of tert -butyl 3-((6-chloro-3-(phenylcarbamoyl)pyridazin-4-ylamino)methyl)pyrrolidine-1- carboxylate (200 mg, 0.464 mmols, 1.0 eq) and 5-aminopyrazine-2-carbonitrile (66.8 mg, 0.556 mmols, 1.2 eq) in dioxane (3 mL) was purged with N2 for 5 minutes followed by addition of Cs2CO3 (453.5 mg, 1.392 mmols, 3.0 eq) and the reaction mixture was purged again for 5 minutes. Xantphos (4.83 mg, 0.008 mmols, 0.018 eq) and Pd2dba3 (21.2 mg, 0.023 mmols, 0.05 eq) was then added to the reaction mixture and it was subjected to microwave irradiation for 45 minutes at 180 °C. Product formation was confirmed by TLC and LCMS. The reaction mixture was quenched with ice water (10 mL) and extracted with ethyl acetate (2 × 20 mL). The organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to get the crude. Further, the
crude was purified by combi flash chromatography by using 12g redi sap column and by eluting in 55% ethyl acetate : hexane solvent system to get the desired compound as a yellow solid (100 mg). LCMS: 516.5 [M+1] + [269] Step-4: Synthesis of 6-(5-cyanopyrazin-2-ylamino)-N-phenyl-4-(pyrrolidin-3- ylmethylamino)pyridazine-3-carboxamide: To a solution of tert-butyl 3-((6-(5- cyanopyrazin-2-ylamino)-3-(phenylcarbamoyl)pyridazin-4-ylamino)methyl)pyrrolidine-1- carboxylate (100 mg, 0.240 mmols, 1 eq) in DCM (5 mL), TFA (0.46 mL, 0.601 mmols, 2.5 eq) was added at 0 °C and kept for stirring for 6h. Then the reaction mixture was concentrated under reduced pressure to get the crude. The crude was purified by reverse phase chromatography to yield desired compound as a formate salt; white solid (15 mg). LCMS: 416.6 [M+1]+; 1H NMR (400 MHz, DMSO-d6; after D2O addition) δ 8.97 (s, 1H), 8.82 (s, 1H), 8.40 (s, 1H, formate), 7.81 (d, J = 8.0 Hz, 2H), 7.52 (s, 1H), 7.36 (t, J = 7.8 Hz, 2H), 7.13 (t, J = 7.4 Hz, 1H), 3.31 (t, J = 9.1 Hz, 2H), 3.28-3.16 (m, 2H), 3.09 (dt, J = 11.3, 7.8 Hz, 1H), 2.88 (dd, J = 11.4, 7.4 Hz, 1H), 2.60 (q, J = 7.5 Hz, 1H), 2.06 (dq, J = 12.9, 7.0 Hz, 1H), 1.66 (dt, J = 12.8, 7.8 Hz, 1H). Example-25: Synthesis 6-(5-cyanopyrazin-2-ylamino)-4-(pyrrolidin-3-ylmethylamino)-N- (2,2,2-trifluoroethyl)pyridazine-3-carboxamide, (Compound No.1.73)
[270] Step-1: Synthesis of tert-butyl 3-((6-chloro-3-(2, 2, 2-trifluoroethylcarbamoyl) pyridazin-4-ylamino) methyl) pyrrolidine-1-carboxylate: To a solution of methyl 4-((1- (tert-butoxycarbonyl) pyrrolidin-3-yl) methyl amino)-6-chloropyridazine-3-carboxylate (250 mg, 0.673 mmols, 1.0 eq) in THF (15 mL) was added 2,2,2-trifluoroethanamine hydrochloride (136 mg, 1.010 mmols, 1.5 eq) followed by addition of trimethylaluminium (0.673 mL, 1.34 mmols, 2.0 eq) and the reaction mixture was stirred at RT for 4h. Product formation was confirmed by TLC and LCMS. The reaction mixture was quenched with ice water (10 mL) and extracted with ethyl acetate (15 × 3 mL). The collective organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate and then concentrated
under reduced pressure to get the crude which was taken as such to the next step (200 mg, crude). LCMS: 438.3 [M+1] + [271] Step-2: Synthesis of tert-butyl 3-((6-(5-cyanopyrazin-2-ylamino)-3-(2, 2, 2- trifluoroethylcarbamoyl) pyridazin-4-ylamino) methyl) pyrrolidine-1-carboxylate: A solution of tert-butyl 3-((6-chloro-3-(2, 2, 2-trifluoroethylcarbamoyl) pyridazin-4-ylamino) methyl) pyrrolidine-1-carboxylate (200 mg, 0.456 mmols, 1.0 eq) and 5-aminopyrazine-2- carbonitrile (60 mg, 0.502 mmols, 1.0 eq) in dioxane (5 mL) was purged using N2 for 5 minutes. Cs2CO3 (445 mg, 1.37 mmols, 3.0 eq) was added and the reaction mixture was purged again for 5 minutes. Xantphos (20.0 mg, 0.023 mmols, 0.05 eq) and Pd2dba3 (7.0 mg, 0.094 mmols, 0.018 eq) was added and then the vial was subjected to microwave irradiation for 45 minutes at 180 °C. Product formation was confirmed by TLC and LCMS. The reaction mixture was quenched with ice water (20 mL) and extracted with ethyl acetate (15 × 3 mL). The collective organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to get the crude. Then the crude was purified by combi flash chromatography using 12g redi sap column and by eluting in 60% ethyl acetate: hexane solvent system to get the desired compound as a light brown solid (110 mg). LCMS: 522.4 [M+1] + [272] Step-3: Synthesis of 6-(5-cyanopyrazin-2-ylamino)-4-(pyrrolidin-3- ylmethylamino)-N-(2,2,2-trifluoroethyl)pyridazine-3-carboxamide: To a solution of tert- butyl 3-((6-(5-cyanopyrazin-2-ylamino)-3-(2, 2, 2-trifluoroethylcarbamoyl) pyridazin-4- ylamino) methyl) pyrrolidine-1-carboxylate (100 mg, 0.191 mmols, 1.0 eq) in DCM (5.0 mL), TFA (0.5 mL) was added at 0°C and the reaction mixture was stirred for 2h. Product formation was confirmed by TLC and LCMS analyses. The reaction mixture was concentrated under reduced pressure to get the crude. The crude was purified by reverse phase chromatography to yield desired compound as a formate salt; white solid (30 mg). LCMS: 422.5 [M+1]+; 1H NMR (400 MHz, DMSO-d6; after D2O addition) 1H NMR (400 MHz, DMSO-d6; after D2O addition) δ 8.91 (s, 1H), 8.81 (s, 1H), 8.39 (s, 1H, formate H), 7.53 (s, 1H), 4.06 (q, J = 9.5 Hz, 2H), 3.32- 3.16 (m, 3H), 3.07 (dt, J = 11.4, 7.8 Hz, 1H), 2.86 (dd, J = 11.4, 7.4 Hz, 1H), 2.58 (h, J = 7.6 Hz, 2H), 2.04 (dq, J = 13.4, 7.1 Hz, 1H), 1.63 (dq, J = 12.7, 7.9 Hz, 1H). Example-26: Synthesis 6-(5-cyanopyrazin-2-ylamino)-N-phenyl-4-(piperidin-3- ylmethylamino)pyridazine-3-carboxamide, (Compound No.1.74)
[273] Step-1: Synthesis of tert-butyl 3-((6-chloro-3-(phenylcarbamoyl)pyridazin-4- ylamino)methyl)piperidine-1-carboxylate: To a solution of methyl 4-((1-(tert- butoxycarbonyl)piperidin-3-yl)methylamino)-6-chloropyridazine-3-carboxylate (500 mg, 1.55 mmols, 1.0 eq) in THF (10 mL) and aniline (2.88 mg, 3.0 mmols, 2.0 eq) was added trimethylaluminium (3.1 mL, 6.21 mmols, 4.0 eq) and the reaction mixture was stirred at RT for 5h. Product formation was confirmed by TLC and LCMS. The reaction mixture was quenched with ice water (20 mL) and extracted with ethyl acetate (15 × 3 mL). The collective organic layer was washed with saturated sodium bicarbonate solution (20 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to get the crude. The crude was purified by combi flash chromatography using ethyl acetate: hexane solvent system to obtain the desired compound (300 mg). LCMS: 446.1 [M+1] + [274] Step-2: Synthesis of tert-butyl 3-((6-(5-cyanopyrazin-2-ylamino)-3- (phenylcarbamoyl)pyridazin-4-ylamino)methyl)piperidine-1-carboxylate: A solution of tert-butyl 3-((6-chloro-3-(phenylcarbamoyl)pyridazin-4-ylamino)methyl)piperidine-1- carboxylate (150 mg, 0.33 mmols, 1.0 eq) and 5-aminopyrazine-2-carbonitrile (48 mg, 0.40 mmols, 1.1 eq) in dioxane (8 mL) was purged with N2 for 5 minutes followed by addition of Cs2CO3 (241 mg, 0.74 mmols, 3.0 eq) and the reaction mixture was purged again for 5 minutes. Xantphos (11 mg, 0.020 mmols, 0.06 eq) and Pd2dba3 (24 mg, 0.026 mmols, 0.08 eq) was added and then the vial was heated at 180 °C for 16h. Product formation was confirmed by TLC and LCMS. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (15 × 3 mL). The collective organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to get the crude. The crude was purified by combi flash chromatography by using 12g redi sap column and by eluting using 60% ethyl acetate: hexane solvent system to get the desired compound (100 mg).LCMS: 530.0 [M+1] + [275] Step-3: Synthesis of 6-(5-cyanopyrazin-2-ylamino)-N-phenyl-4-(piperidin-3- ylmethylamino)pyridazine-3-carboxamide: To a solution of tert-butyl 3-((6-(5- cyanopyrazin-2-ylamino)-3-(phenylcarbamoyl)pyridazin-4-ylamino)methyl)piperidine-1-
carboxylate (200 mg, 0.37 mmols, 1 eq) in DCM (8.0 mL), TFA (1.2 mL) was added at 0°C and kept for stirring for 2h. Product formation was confirmed by TLC and LCMS analyses. The reaction mixture was concentrated under reduced pressure to get the crude. The crude was purified by reverse phase chromatography to yield desired compound as a TFA salt; white solid (25 mg). LCMS: 430.0 [M+1]+; 1H NMR (400 MHz, DMSO-d6; after D2O addition) δ 8.88-8.83 (m, 1H), 8.77 (d, J = 1.5 Hz, 1H), 7.74 (d, J = 8.0 Hz, 2H), 7.44 (s, 1H), 7.36 (t, J = 7.8 Hz, 2H), 7.14 (t, J = 7.4 Hz, 1H), 3.26 (dd, J = 12.6, 3.4 Hz, 2H), 3.24-3.16 (m, 2H), 2.83-2.73 (m, 1H), 2.68 (t, J = 12.1 Hz, 1H), 2.08 (d, J = 10.0 Hz, 1H), 1.84 (d, J = 12.5 Hz, 2H), 1.58 (q, J = 13.5 Hz, 1H), 1.34-1.21 (m, 1H). Example-27: Synthesis 4-((1R, 3R)-3-aminocyclopentylamino)-6-(5-cyanopyrazin-2- ylamino)-N-methylpyridazine-3-carboxamide, (Compound No.1.75)
[276] Step-1: Synthesis of methyl 4-((1R,3R)-3-(tert- butoxycarbonylamino)cyclopentylamino)-6-chloropyridazine-3-carboxylate: To a solution of methyl 4,6-dichloropyridazine-3-carboxylate (250 mg, 1.21 mol, 1.0 eq) in THF (15 mL) was added tert-butyl (1R, 3R)-3-aminocyclopentylcarbamate (620 mg, 2.89 mmols, 1.2 eq), TEA (0.34 mL, 2.42 mol, 2.0 eq) and the reaction mixture was refluxed for 2h. Product formation was confirmed by TLC and LCMS. The reaction mixture was quenched with ice water (2 × 50 mL) and extracted with ethyl acetate (60 × 3mL). Collective organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to get the crude. The crude was purified by combi flash chromatography by eluting in (0-50%) ethyl acetate: hexane solvent system to get desired compound as on off white solid (0.450 g). LCMS: 371.1[M+1] + [277] Step-2: Synthesis of tert-butyl (1R, 3R)-3-(6-chloro-3- (methylcarbamoyl)pyridazin-4-ylamino)cyclopentylcarbamate: A solution of methyl 4- ((1R,3R)-3-(tert-butoxycarbonylamino)cyclopentylamino)-6-chloropyridazine-3-carboxylate (400 mg, 1.08 mmols, 1.0 eq) in 8 mL MeNH2 (2.0 M solution in MeOH) was stirred at RT for 1.5h. Product formation was confirmed by TLC and LCMS. The reaction mixture was
quenched with ice water (20 mL) resulting in precipitation of a solid which was filtered and dried. This crude product was purified by combi flash chromatography to yield the desired compound as a white solid (300mg). LCMS: 370.1 [M+1] + [278] Step-3: Synthesis of tert-butyl (1R, 3R)-3-(6-(5-cyanopyrazin-2-ylamino)-3- (methylcarbamoyl)pyridazin-4-ylamino)cyclopentylcarbamate: A solution of tert-butyl (1R, 3R)-3-(6-chloro-3-(methylcarbamoyl)pyridazin-4-ylamino)cyclopentylcarbamate (200 mg, 0.54 mmols, 1.0 eq) and 5-aminopyrazine-2-carbonitrile (77 mg, 0.65 mmols, 1.2 eq) in dioxane (8 mL) was purged with N2 for 5 minutes and then Cs2CO3 (530 mg, 1.62 mmols, 3.0eq) was added and purged again for 5 minutes. Xantphos (18 mg, 0.032 mmols, 0.06eq) and Pd2dba3 (39 mg, 0.043 mmols, 0.08 eq) was added and then the reaction mixture was heated at 180 °C for 16h. Product formation was confirmed by TLC and LCMS. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (15 × 3 mL). The collective organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to get the crude. The crude was purified by combi flash chromatography by using 12g redi sap column and by eluting in 60% Ethyl acetate: Hexane solvent system to get the desired compound as a light brown solid (120 mg). LCMS: 454.0 [M+1] + [279] Step-4: Synthesis of 4-((1R, 3R)-3-aminocyclopentylamino)-6-(5-cyanopyrazin-2- ylamino)-N-methylpyridazine-3-carboxamide: To a solution of tert-butyl (1R, 3R)-3-(6-(5- cyanopyrazin-2-ylamino)-3-(methylcarbamoyl)pyridazin-4-ylamino)cyclopentylcarbamate (120 mg, 0.26 mmols, 1 eq) in DCM (6.0 mL), TFA (1.0 mL) was added at 0 °C and kept for stirring for 2h. Product formation was confirmed by TLC and LCMS analyses. The crude was purified by reverse phase chromatography to yield desired compound as a TFA salt; white solid (50 mg). LCMS: 354.0 [M+1]+; 1H NMR (400 MHz, DMSO-d6; after D2O addition) δ 8.82 (d, J = 1.5 Hz, 1H), 8.76 (d, J = 1.4 Hz, 1H), 7.39 (s, 1H), 4.01 (p, J = 6.4 Hz, 1H), 3.67 (p, J = 7.0 Hz, 1H), 2.78 (s, 3H), 2.26 (dd, J = 12.4, 7.0 Hz, 1H), 2.13 (ddt, J = 27.6, 13.6, 7.2 Hz, 2H), 1.95 (ddd, J = 14.0, 8.3, 5.6 Hz, 1H), 1.62 (ddd, J = 19.0, 14.8, 7.4 Hz, 2H). Example-28: Synthesis of 5-(6-(1-methyl-1H-pyrazol-4-yl)-5-(morpholin-2- ylmethylamino)pyridazin-3-ylamino)picolinonitrile, (Compound No.1.76)
[280] Step-1: Synthesis of tert-butyl 2-((3,6-dichloropyridazin-4- ylamino)methyl)morpholine-4-carboxylate: To a solution of 3,4,6-trichloropyridazine (2.0 g, 10.92 mmols, 1.0 eq) in THF (40 mL) was added TEA (2.75 g, 27.3 mmols, 2.5 eq) followed by the addition of tert-butyl 2-(aminomethyl)morpholine-4-carboxylate (2.6 g, 12.12 mmols, 1.1eq) at ambient temperature. Reaction mixture was stirred at 90 °C for 3h. Reaction was monitored by TLC and LCMS. After completion, reaction mixture was quenched with ice water (20 mL) and extracted with ethyl acetate (200 mL × 3). Combined organic phase was washed with water (30 mL × 3) followed by brine wash (20mL). Organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude. The crude was triturated with pentane and solid precipitated was filtered to afford the desired compound as a white solid (3.2g). LCMS: 363.1[M+1] + [281] Step-2: Synthesis of tert-butyl 2-((6-chloro-3-(1-methyl-1H-pyrazol-4-yl) pyridazin-4-ylamino) methyl) morpholine-4-carboxylate: To a solution of tert-butyl 2- ((3,6-dichloropyridazin-4-ylamino)methyl)morpholine-4-carboxylate (500 mg, 1.37 mmols, 1.0 eq) in dioxane : water (10 mL : 2.5 mL) was added 1-methyl-1H-pyrazol-4-ylboronic acid (173 mg, 1.37 mmols, 1.5 eq) followed by addition of K2CO3 (300 mg, 2.74 mmols, 2.0 eq). Further, PdCl2(dppf).DCM complex (111 mg, 0.137 mmols, 0.1 eq) was added and reaction mixture was purged using nitrogen for 10 minutes. Reaction mixture was heated at 90 °C for 16 h. Product formation was confirmed by TLC and LCMS. The reaction mixture was quenched with ice water (10 mL) and extracted with ethyl acetate (3 × 15 mL). Collective organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to get the crude. The crude was triturated with pentane to get the desired compound (0.250 g) as an off white solid. LCMS: 409.3 [M+1] + [282] Step-3: Synthesis of tert-butyl 2-((6-(6-cyanopyridin-3-ylamino)-3-(1-methyl-1H- pyrazol-4-yl) pyridazin-4-ylamino) methyl) morpholine-4-carboxylate: A solution of tert- butyl 2-((6-chloro-3-(1-methyl-1H-pyrazol-4-yl)pyridazin-4-ylamino)methyl)morpholine-4- carboxylate (200 mg, 0.488 mmols, 1.0 eq) and 5-aminopicolinonitrile (58 mg, 0.488 mmols, 1.0 eq) in dioxane (5 mL) was purged using nitrogen for 5 minutes then Cs2CO3 (489 mg,
1.50 mmols, 3.0 eq) was added and purged again for 5 minutes. Further, Xantphos (14 mg, 0.0251 mmols, 0.05 eq) and Pd2dba3 (8 mg, 0.0936 mmols, 0.018 eq) was added and then the vial was closed and kept for heating in microwave for 45 minutes at 180 °C. Product formation was confirmed by TLC and LCMS. The reaction mixture was quenched with ice water (20 mL) and extracted with ethyl acetate (3 × 15 mL). Collective organic layer was washed with brine (20 mL) and dried over sodium sulfate and then concentrated under reduced pressure to get the crude. The crude was purified by flash chromatography by eluting in 60% ethyl acetate: hexane solvent system to get the desired compound (110 mg) as a light brown solid. LCMS: 492.3 [M+1] + [283] Step-4: Synthesis of 5-(6-(1-methyl-1H-pyrazol-4-yl)-5-(morpholin-2- ylmethylamino)pyridazin-3-ylamino)picolinonitrile: To a solution of tert-butyl 2-((6-(6- cyanopyridin-3-ylamino)-3-(1-methyl-1H-pyrazol-4-yl) pyridazin-4- ylamino)methyl)morpholine-4-carboxylate (100 mg, 0.203 mmols, 1 eq) in DCM (5 mL), TFA (0.5 mL) was added at 0 °C and resulting reaction mixture was stirred for 6 h. Product formation was confirmed by TLC and LCMS. Then the reaction mixture was concentrated under reduced pressure to get the crude. The crude was purified by reverse phase chromatography to yield desired compound as a trifluoroacetate salt; white solid (30 mg). LCMS: 392.6 [M+1]+; 1H NMR (400 MHz, DMSO-d6; after D2O addition) δ 1H NMR (400 MHz, DMSO-d6) δ 8.86 (d, J = 2.6 Hz, 1H), 8.47 (dd, J = 8.8, 2.6 Hz, 1H), 8.06 (s, 1H), 7.86 (d, J = 8.7 Hz, 1H), 7.79 (s, 1H), 6.31 (s, 1H), 3.90 (s, 3H), 3.86 (d, J = 3.3 Hz, 1H), 3.81- 3.74 (m, 1H), 3.58 (td, J = 11.8, 2.5 Hz, 1H), 3.22 (q, J = 8.0, 6.8 Hz, 2H), 3.10-3.02 (m, 1H), 2.93 (d, J = 12.6 Hz, 1H), 2.80 (td, J = 12.2, 3.5 Hz, 1H), 2.63 (d, J = 11.6 Hz, 1H). Example-29: Synthesis of 5-(5-(morpholin-2-ylmethylamino)-6-(thiazol-2-yl)pyridazin-3- ylamino)pyrazine-2-carbonitrile, (Compound No.1.77)
[284] Step-1: Synthesis of tert-butyl 2-((6-chloro-3-(thiazol-2-yl)pyridazin-4- ylamino)methyl)morpholine-4-carboxylate: To a solution of tert -butyl 2-((3,6- dichloropyridazin-4-ylamino)methyl)morpholine-4-carboxylate (440 mg, 1.21 mmols, 1.0eq)
and 2-(tributylstannyl)thiazole (906.6 mg, 2.42 mmols, 2.0 eq) in toluene (7mL) was added lithium chloride (52.11mg, 1.21mmols, 1.0eq) and copper iodide (115.74 mg, 0.60 mmols, 0.5 eq) at RT and the reaction mixture was purged under nitrogen for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (280.09 mg, 0.24 mmols, 0.2 eq) was added and again nitrogen was purged for 5 minutes. Reaction mixture was stirred at 120 °C for 16h. Reaction was monitored by TLC and LCMS. After completion, reaction mixture was cooled to RT and ethyl acetate (100 mL) was added and organic phase was washed with water (20 mL × 3) followed by brine wash (20 mL). Organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude. The crude was purified by combi flash chromatography by eluting in (0-50%) ethyl acetate: hexane solvent system to get desired compound (130 mg). LCMS: 412.1 [M+1] + [285] Step-2: Synthesis of tert -butyl 2-((6-(5-cyanopyrazin-2-ylamino)-3-(thiazol-2- yl)pyridazin-4-ylamino)methyl)morpholine-4-carboxylate: To a solution of tert-butyl 2- ((6-chloro-3-(thiazol-2-yl)pyridazin-4-ylamino)methyl)morpholine-4-carboxylate (120 mg, 0.29 mmols, 1.0 eq) and 5-aminopyrazine-2-carbonitrile (28.02 mg, 0.23 mmols, 0.98 eq) in DMF (3mL) was added Cs2CO3 (284.6 mg, 0.87 mmols, 3 eq) at RT and reaction mixture was purged under nitrogen for 10 minutes. Xantphos (16.81 mg, 0.029 mmols, 0.1eq) and Pd2dba3 (26.6 mg, 0.029 mmols, 0.1 eq) were added and the reaction mixture was again purged for 5 minutes. Reaction mixture was stirred at 180 °C for 16h. Reaction was monitored by TLC and LCMS. After completion, reaction mixture was cooled to RT. Ethyl acetate (100 mL) was added and organic phase was washed with water (20 mL × 3) followed by brine wash (20 mL). Organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude. The crude was triturated with pentane and the solid thus precipitated was filtered to afford the desired compound (80 mg). LCMS: 496.1 [M+1] + [286] Step-3: Synthesis of 5-(5-(morpholin-2-ylmethylamino)-6-(thiazol-2-yl)pyridazin- 3-ylamino)pyrazine-2-carbonitrile: To a solution of tert-butyl 2-((6-(5-cyanopyrazin-2- ylamino)-3-(thiazol-2-yl)pyridazin-4-ylamino)methyl)morpholine-4-carboxylate (80 mg, 0. 16 mmols, 1.0 eq) in DCM (1 mL) was added TFA (0.6 mL) at 0°C and the reaction was stirred at RT for 2h. Reaction was monitored by TLC and LCMS. After completion, reaction mixture was concentrated under reduced pressure to afford crude. The crude was purified by reverse phase chromatography to yield desired compound as a formate salt; white solid (5
mg). LCMS: 396.1 [M+1]+; 1H NMR (400 MHz, DMSO-d6; after D2O addition) δ 8.86 (s, 1H), 8.73 (s, 1H), 8.32 (s, 1H), 7.99 (d, J = 3.3 Hz, 1H), 7.76 (d, J = 3.4 Hz, 1H), 7.50 (s, 1H), 3.79 (s, 1H), 3.64-3.51 (m, 1H), 3.51-3.40 (m, 1H), 3.33 (dd, J = 14.1, 7.1 Hz, 1H), 3.05 (d, J = 12.5 Hz, 1H), 2.88 (d, J = 12.7 Hz, 1H), 2.84-2.72 (m, 1H), 2.63 (s, 1H), 1.88 (s, 1H). Example-30: Synthesis of 5-(5-(morpholin-2-ylmethylamino)-6-(oxazol-2-yl)pyridazin-3- ylamino)pyrazine-2-carbonitrile, (Compound No.1.78)
[287] Step-1: Synthesis of tert-butyl 2-((6-chloro-3-(oxazol-2-yl)pyridazin-4- ylamino)methyl)morpholine-4-carboxylate: To a solution of tert-butyl 2-((3,6- dichloropyridazin-4-ylamino)methyl)morpholine-4-carboxylate (0.5 g, 1.38 mmols, 1.0 eq) and 2-(tributylstannyl)oxazole (0.74 g, 2.07 mmols, 1.5 eq) in toluene (5 mL), CuI (0.13 g, 0.69 mmols, 0.5 eq), LiCl (0.05 g, 1.38 mmols, 1.0 eq) and PdCl2(dppf).DCM complex (0.56 g, 0.69 mmol, 0.5 eq) was added. The reaction mixture was purged under nitrogen atmosphere for 10 minutes. The reaction mixture was heated at 110 °C and stirred for 16 h. The progress of reaction was monitored by TLC and LCMS. After, the completion of reaction, the reaction mixture was passed through celite and ethyl acetate (2 × 20 mL) was added. The organic layer was washed with water (2 × 30 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude reaction mixture. The crude reaction mixture was purified by flash chromatography using 70% ethyl acetate: hexane solvent system to obtain desired compound (0.25 g) as a white solid. LCMS: 396.3 [M+1] + [288] Step-2: Synthesis of tert-butyl 2-((6-(5-cyanopyrazin-2-ylamino)-3-(oxazol-2- yl)pyridazin-4-ylamino)methyl)morpholine-4-carboxylate: A solution of tert-butyl 2-((6- chloro-3-(oxazol-2-yl)pyridazin-4-ylamino)methyl)morpholine-4-carboxylate (250 mg, 0.632 mmols, 1.0 eq) and 5-aminopyrazine-2-carbonitrile (91 mg, 0.759 mmols, 1.2 eq) in dioxane (3 mL) was purged with nitrogen for 5 minutes then Cs2CO3 (617.7 mg, 1.896 mmols, 3.0 eq) was added and purged again for 5 minutes. Further, Xantphos (6.58 mg, 0.011 mmols, 0.018 eq) and Pd2dba3 (28.9 mg, 0.031 mmols, 0.05 eq) was added and the vial was subjected to
microwave irradiation for 45 minutes at 180 °C. Product formation was confirmed by TLC and LCMS. The reaction mixture was quenched with ice water (10 mL) and extracted with ethyl acetate (2 × 20 mL). The organic layer was washed with brine (20 mL) and dried over sodium sulfate and then concentrated under reduced pressure to get the crude. Further, the crude was purified by flash chromatography by eluting in 90% ethyl acetate: hexane solvent system to obtain desired compound (80 mg) as yellow solid. LCMS: 480.3 [M+1] + [289] Step-3: Synthesis of 5-(5-(morpholin-2-ylmethylamino)-6-(oxazol-2-yl)pyridazin- 3-ylamino)pyrazine-2-carbonitrile: To a solution of tert-butyl 2-((6-(5-cyanopyrazin-2- ylamino)-3-(oxazol-2-yl)pyridazin-4-ylamino)methyl)morpholine-4-carboxylate (80 mg, 0.167 mmols, 1 eq) in DCM (5 mL), TFA (0.32 mL, 0.417 mmols, 2.5 eq) was added at 0 °C. The resulting reaction mixture was stirred for 2h. Then the reaction mixture was concentrated under reduced pressure to get the crude. The crude was purified by reverse phase chromatography to yield desired compound as a trifluoroacetate salt; white solid (15 mg). LCMS: 380.5 [M+1]+; 1H NMR (400 MHz, DMSO-d6; after D2O addition) δ 8.83 (s, 1H), 8.78 (s, 1H), 8.31 (s, 1H), 7.66 (s, 1H), 7.54 (s, 1H), 4.04 (dd, J = 12.6, 3.6 Hz, 1H), 4.00- 3.91 (m, 1H), 3.73 (d, J = 11.4 Hz, 1H), 3.58-3.52 (m, 1H), 3.44 (dd, J = 14.4, 6.8 Hz, 1H), 3.34 (d, J = 12.6 Hz, 1H), 3.17 (t, J = 11.3 Hz, 1H), 3.01 (td, J = 12.6, 3.8 Hz, 1H), 2.90 (t, J = 11.9 Hz, 1H). Example-31: Synthesis of 5-(6-(1-methyl-1H-pyrazol-4-yl)-5-(morpholin-2- ylmethylamino)pyridazin-3-ylamino)pyrazine-2-carbonitrile, (Compound No.1.79)
[290] Step-1: Synthesis of tert-butyl 2-((6-chloro-3-(1-methyl-1H-pyrazol-4- yl)pyridazin-4-ylamino)methyl)morpholine-4-carboxylate: To a solution of tert-butyl 2- ((3,6-dichloropyridazin-4-ylamino)methyl)morpholine-4-carboxylate (1.0 g, 2.46 mmols, 1.0 eq) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.56 g, 2.46 mmols, 1.0 eq) in dioxane : water (10 mL: 2.5 mL), Pd(PPh3)4 (0.31 g, 0.24 mmols, 0.1 eq) and K2CO3 (0.76 g, 5.52 mmols, 2.0 eq) was added. The reaction mixture was purged under nitrogen atmosphere for 10 minutes. The reaction mixture was heated at 90 °C for 16 h. The
progress of reaction was monitored by TLC and LCMS. After, the completion of reaction, the reaction mixture was passed through celite and ethyl acetate (2 × 20 mL) was added. The organic layer was washed with water (2 × 30 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude reaction mixture. The crude reaction mixture was purified by combi flash using 70% ethyl acetate: hexane solvent system to obtain desired compound (0.25 g) as yellow solid. LCMS: 409.3 [M+1] + [291] Step-2: Synthesis of tert-butyl 2-((6-(5-cyanopyrazin-2-ylamino)-3-(1-methyl-1H- pyrazol-4-yl)pyridazin-4-ylamino)methyl)morpholine-4-carboxylate: A solution of tert- butyl 2-((6-chloro-3-(1-methyl-1H-pyrazol-4-yl)pyridazin-4-ylamino)methyl)morpholine-4- carboxylate (250 mg, 0.612 mmols, 1.0 eq) and 5-aminopyrazine-2-carbonitrile (88.2 mg, 0.735 mmols, 1.2 eq) in dioxane (4 mL) was purged with nitrogen for 5 minutes then Cs2CO3 (598.1 mg, 1.836 mmols, 3.0 eq) was added and purged again for 5 minutes. Further, Xantphos (6.37 mg, 0.011 mmols, 0.018 eq) and Pd2dba3 (28 mg, 0.030 mmols, 0.05 eq) was added and the vial was subjected to microwave irradiation for 45 minutes at 180 °C. Product formation was confirmed by TLC and LCMS. The reaction mixture was quenched with ice water (10 mL) and extracted with ethyl acetate (2 × 20 mL). The organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to get the crude. Further, the crude was purified by flash chromatography by eluting in 90% ethyl acetate: hexane solvent system to get desired compound (70 mg) as yellow solid. LCMS: 493.3 [M+1] + [292] Step-3: Synthesis of 5-(6-(1-methyl-1H-pyrazol-4-yl)-5-(morpholin-2- ylmethylamino)pyridazin-3-ylamino)pyrazine-2-carbonitrile: To a solution of tert-butyl 2-((6-(5-cyanopyrazin-2-ylamino)-3-(1-methyl-1H-pyrazol-4-yl)pyridazin-4- ylamino)methyl)morpholine-4-carboxylate (70 mg, 0.142 mmols, 1 eq) in DCM (3 mL), TFA (0.3 mL, 0.355 mmols, 2.5 eq) was added at 0 °C. The resulting reaction mixture was stirred for 6 h. Then the reaction mixture was concentrated under reduced pressure to get the crude. The crude was purified by reverse phase chromatography to yield desired compound as a formate salt; white solid (7 mg). LCMS: 393.5 [M+1]+; 1H NMR (400 MHz, DMSO-d6; after D2O addition) δ 8.96 (s, 1H), 8.72 (s, 1H), 8.28 (s, 1H, formate), 8.11 (s, 1H), 7.81 (s, 1H), 7.24 (s, 1H), 3.91 (s, 3H), 3.85-3.77 (m, 1H), 3.70 (t, J = 8.3 Hz, 1H), 3.53-3.46 (m, 1H),
3.22 (t, J = 5.8 Hz, 1H), 2.98 (d, J = 12.3 Hz, 1H), 2.82 (d, J = 12.3 Hz, 1H), 2.73 (dd, J = 12.7, 9.4 Hz, 1H), 2.57 (d, J = 11.3 Hz, 2H). Example-32: Synthesis of: 4-((1r,4r)-4-aminocyclohexylamino)-6-(5-cyanopyrazin-2- ylamino)-N-methylpyridazine-3-carboxamide, (Compound No.1.80)
[293] Step-1: Synthesis of methyl 4-((1r, 4r)-4-(tert- butoxycarbonylamino)cyclohexylamino)-6-chloropyridazine-3-carboxylate: To a solution of methyl 4,6-dichloropyridazine-3-carboxylate (450 mg, 2.18 mmols, 1.0 eq) and tert-butyl (1r, 4r)-4-aminocyclohexylcarbamate (0.56 g, 2.6 mmols, 1.2 eq) in THF (7 mL), was added triethylamine (1.5mL, 3.10 mmols, 1.5 eq) drop wise to the reaction mixture and it was kept for stirring at 90°C for 4h. Product formation was confirmed by TLC and LCMS. The reaction mixture was quenched with ice water (10 mL) and extracted with ethyl acetate (15 × 3) mL, Collective organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to get the crude. The crude was triturated with pentane and the solid thus precipitated was filtered to afford 650 mg of the desired compound as an off white solid. LCMS: 385.3[M+1] + [294] Step-2: Synthesis of tert-butyl (1r, 4r)-4-(6-chloro-3-(methylcarbamoyl)pyridazin- 4-ylamino)cyclohexylcarbamate: To a solution methyl 4-((1r, 4r)-4-(tert- butoxycarbonylamino)cyclohexylamino)-6-chloropyridazine-3-carboxylate (300 mg, 0.78 mmols, 1.0 eq) in methylamine solution in methanol (2.0 M) was stirred for 30 min at RT. Product formation was confirmed by TLC and LCMS. After completion, reaction mixture was quenched with ice water (10 mL) which resulted in precipitation of a solid which was filtered. This solid was triturated with pentane (20 mL × 2) to afford 270 mg of the desired compound as a white solid. LCMS: 384.1 [M+1] + [295] Step-3: Synthesis of tert -butyl (1r, 4r)-4-(6-(5-cyanopyrazin-2-ylamino)-3- (methylcarbamoyl)pyridazin-4-ylamino)cyclohexylcarbamate: A solution of tert -butyl (1r, 4r)-4-(6-chloro-3-(methylcarbamoyl)pyridazin-4-ylamino)cyclohexylcarbamate (100 mg, 0.26 mmols, 1.0 eq) and 5-aminopyrazine-2-carbonitrile (37 mg, 0.31 mmols, 1.2eq) in
dioxane (5 mL) was purged with N2 for 5 minutes followed by addition of Cs2CO3(254 mg, 0.78mmols, 3.0 eq).the reaction mixture was purged again for 5 minutes. Xantphos (9.0 mg, 0.0156 mmols, 0.06 eq) and pd2dba3(19 mg, 0.0208 mmols, 0.08 eq) was added and then the vial was subjected to microwave irradiation for 45 minutes at 180 °C. Product formation was confirmed by TLC and LCMS. The reaction mixture was quenched with ice water (20 mL) and extracted with ethyl acetate (15 × 3 mL). The collective organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to get the crude. The crude was purified by combi flash chromatography by using 12g redi sap column and by eluting in 90% ethyl acetate: hexane solvent system to get desired compound (70 mg, light brown solid). LCMS: 468.3 [M+1] + [296] Step-4: Synthesis of: 4-((1r, 4r)-4-aminocyclohexylamino)-6-(5-cyanopyrazin-2- ylamino)-N-methylpyridazine-3-carboxamide: To a solution of tert-butyl (1r, 4r)-4-(6-(5- cyanopyrazin-2-ylamino)-3-(methylcarbamoyl)pyridazin-4-ylamino)cyclohexylcarbamate (70 mg, 0.150 mmols, 1.0 eq) in DCM (5.0 mL), TFA (0.5 mL) was added at 0°C and the reaction mixture was kept for stirring for 2h. Product formation was confirmed by TLC and LCMS analyses. The reaction mixture was concentrated under reduced pressure to get the crude. The crude was purified by reverse phase chromatography to yield desired compound as a formate salt; white solid (5 mg). LCMS: 368.6 [M+1]+; 1H NMR (400 MHz, DMSO-d6; after D2O addition) δ 8.98 (s, 1H), 8.73 (s, 1H), 8.40 (s, 1H), 7.34 (s, 1H), 3.27 (d, J = 10.3 Hz, 1H), 2.98 (t, J = 10.6 Hz, 1H), 2.77 (s, 3H), 2.08 – 2.01 (m, 1H), 1.96 (t, J = 7.6 Hz, 1H), 1.77 (d, J = 6.5 Hz, 1H), 1.43 (q, J = 12.7 Hz, 1H), 1.32 (q, J = 12.4, 11.8 Hz, 1H), 1.24-1.10 (m, 2H), 0.81 (dt, J = 9.8, 6.2 Hz, 1H). Example-33: Synthesis of 4-(3-aminocyclobutylamino)-6-(5-cyanopyrazin-2-ylamino)-N- methylpyridazine-3-carboxamide, (Compound No.1.81)
[297] Step-1: Synthesis of methyl 4-(3-(tert-butoxycarbonylamino)cyclobutylamino)-6- chloropyridazine-3-carboxylate: To a solution of methyl 4,6-dichloropyridazine-3- carboxylate (500 mg, 4.41 mmols, 1.0 eq) in THF (15 mL) was added TEA (609.8 mg, 6.03 mmols, 2.5 eq) followed by the addition of tert -butyl 3-aminocyclobutylcarbamate (494.8
mg, 2.65 mmols, 1.1 eq) at ambient temperature. Reaction mixture was stirred at 90 °C for 3h. Progress of the reaction was monitored by TLC and LCMS. After completion, reaction mixture was quenched with ice water (10 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic phase was washed with water (20 mL × 3) followed by brine wash (20 mL). Organic phase was separated and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude. The crude was triturated with pentane and the solid thus precipitated was filtered to afford 850 mg of the desired compound. LCMS: 357.2 [M+1] + [298] Step-2: Synthesis of tert-butyl 3-(6-chloro-3-(methylcarbamoyl)pyridazin-4- ylamino)cyclobutylcarbamate: To a solution of methyl 4-(3-(tert- butoxycarbonylamino)cyclobutylamino)-6-chloropyridazine-3-carboxylate (600 mg, 1.68 mmols, 1.0 eq) was added methylamine (2M in methanol) (20 mL) at ambient temperature. Reaction mixture was stirred at RT for 30 minutes. Reaction was monitored by TLC and LCMS. After completion, reaction mixture was concentrated under reduced pressure. Ethyl acetate (200 mL) was added and organic phase was washed with water (20 mL × 3) followed by brine wash (20 mL). Organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude. The crude was triturated with pentane and the solid thus precipitated was filtered to afford the desired compound as an off white solid (590 mg). LCMS: 356.1 [M+1] + [299] Step-3: Synthesis of tert-butyl 3-(6-(5-cyanopyrazin-2-ylamino)-3- (methylcarbamoyl)pyridazin-4-ylamino)cyclobutylcarbamate: To a solution of tert-butyl 3-(6-chloro-3-(methylcarbamoyl)pyridazin-4-ylamino)cyclobutylcarbamate (300 mg, 0.84 mmols, 1.0 eq) and 5-aminopyrazine-2-carbonitrile (80.9 mg, 0.67 mmols , 0.8 eq) in DMF (5 mL) was added Cs2CO3 (821.5 mg, 2.52 mmols, 3.0 eq) at RT and the reaction mixture was purged using nitrogen for 10 minutes. Xantphos (48.5 mg, 0.08 mmols, 0.1eq) and Pd2dba3 (76.86 mg, 0.08 mmols, 0.1 eq) were added and the reaction mixture was purged again for 5 minutes. Reaction mixture was stirred at 180 °C for 16h. Reaction was monitored by TLC and LCMS. After completion, reaction mixture was cooled to RT. Ethyl acetate (100 mL) was added and organic phase was washed with water (20 mL × 3) followed by brine wash (20 mL). Organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude. The crude was triturated with pentane and filtered to afford the desired compound (150 mg). LCMS: 440.1 [M+1] +
[300] Step-4: Synthesis of 4-(3-aminocyclobutylamino)-6-(5-cyanopyrazin-2-ylamino)- N-methylpyridazine-3-carboxamide: To a solution of tert -butyl 3-(6-(5-cyanopyrazin-2- ylamino)-3-(methylcarbamoyl)pyridazin-4-ylamino)cyclobutylcarbamate (150 mg, 0.34 mmols, 1.0 eq) in DCM (1 mL) was added TFA (0.8 mL) at 0 °C and the reaction mixture was stirred at RT for 2h. Reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to afford crude. The crude was triturated with diethyl ether, filtered and purified by reverse phase chromatography to yield desired compound as a fomate salt; white solid (20 mg). LCMS: 340.1 [M+1]+; 1H NMR (400 MHz, DMSO-d6; after D2O addition) δ 8.92 (d, J = 6.7 Hz, 1H), 8.75 (d, J = 8.5 Hz, 1H), 8.39 (s, 1H, FORMATE), 7.29 (s, 0.4H), 7.20 (s, 0.6H), 4.10 (s, 1H), 3.39 (t, J = 8.0 Hz, 1H), 2.79 (s, 3H), 2.42 (dt, J = 8.2, 4.3 Hz, 1H), 2.28 (q, J = 12.3, 11.1 Hz, 2H), 2.01-1.80 (m, 1H). Example-34: Synthesis of 5-(5-(morpholin-2-ylmethylamino)-6-(thiophen-2-yl)pyridazin-3- ylamino)pyrazine-2-carbonitrile, (Compound No 1.82.)
[301] Step-1: Synthesis of tert-butyl 2-((6-chloro-3-(thiophen-2-yl)pyridazin-4- ylamino)methyl)morpholine-4-carboxylate: To a solution of tert-butyl 2-((3,6- dichloropyridazin-4-ylamino)methyl)morpholine-4-carboxylate (500 mg, 1.377 mmols, 1.0 eq) and 4,4,5,5-tetramethyl-2-(thiophen-2-yl)-1,3,2-dioxaborolane (433 mg, 2.06 mmols, 1.5 eq) in dioxane : water (5 mL : 1.5 mL), PdCl2(dppf)DCM (102 mg, 0.137 mmols, 0.1 eq) and Na2CO3 (291 mg, 2.754 mmols, 2.0 eq) was added. The reaction mixture was purged under nitrogen for 10 minutes. The reaction mixture was heated at 110 °C for 16 h. The progress of reaction was monitored by TLC and LCMS. After the completion of reaction, the reaction mixture was passed through celite and ethyl acetate (2 × 20 mL) was added. The organic layer was washed with water (2 × 30 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude. The crude reaction mixture was purified by combi flash using 70% ethyl acetate: hexane solvent system to obtain desired compound (220 mg) as a yellow solid. LCMS: 411.2 [M+1] +
[302] Step-2: Synthesis of tert-butyl 2-((6-(5-cyanopyrazin-2-ylamino)-3-(thiophen-2- yl)pyridazin-4-ylamino)methyl)morpholine-4-carboxylate: A solution of tert-butyl 2-((6- chloro-3-(thiophen-2-yl)pyridazin-4-ylamino)methyl)morpholine-4-carboxylate (220 mg, 0.536 mmols, 1.0 eq) and 5-aminopyrazine-2-carbonitrile (77 mg, 0.643 mmols, 1.2 eq) in DMF (4 mL) was purged with nitrogen for 5 minutes then Cs2CO3 (522 mg, 1.608 mmols, 3.0 eq) was added and purged again for 5 minutes. Xantphos (6.0 mg, 0.0010 mmols, 0.02 eq) and Pd2dba3 (24 mg, 0.026 mmols, 0.05 eq) were added and the vial was heated for 16h at 180 °C. Product formation was confirmed by TLC and LCMS. The reaction mixture was quenched with ice water (10 mL) and extracted with ethyl acetate (2 × 20 mL). The organic layer was washed with brine (20 mL) and dried over sodium sulfate and then concentrated under reduced pressure to get the crude. Further, the crude was purified by flash chromatography by eluting in 5% MeOH: DCM solvent system to obtain desired compound (70 mg) as yellow solid. LCMS: 495.4 [M+1] + [303] Step-3: Synthesis of 5-(5-(morpholin-2-ylmethylamino)-6-(thiophen-2- yl)pyridazin-3-ylamino)pyrazine-2-carbonitrile: To a solution of tert-butyl 2-((6-(5- cyanopyrazin-2-ylamino)-3-(thiophen-2-yl)pyridazin-4-ylamino)methyl)morpholine-4- carboxylate (70 mg, 0.141 mmols, 1 eq) in DCM (3 mL), TFA (0.3 mL, 0.353 mmol, 2.5 eq) was added at 0 °C. The reaction mixture was stirred for 2h. Then the reaction mixture was concentrated under reduced pressure to get the crude. Crude was purified by reverse phase chromatography to yield desired compound as an off white solid (8 mg). LCMS: 395.5 [M+1]+; 1H NMR (400 MHz, DMSO-d6; after D2O addition) δ 8.93 (s, 1H), 8.72 (s, 1H), 8.33 (s, 1H), 7.67 (d, J = 5.1 Hz, 1H), 7.52 (d, J = 3.7 Hz, 1H), 7.35 (s, 1H), 7.22 (t, J = 4.3 Hz, 1H), 3.58-3.47 (m, 1H), 3.26 (qd, J = 14.1, 5.5 Hz, 2H), 2.99 (d, J = 12.9 Hz, 1H), 2.82 (d, J = 12.4 Hz, 1H), 2.73 (t, J = 11.8 Hz, 1H), 2.60 (d, J = 11.5 Hz, 2H), 2.08 (d, J = 11.6 Hz, 1H). Example-35: Synthesis of 5-(5-(morpholin-2-ylmethylamino)-6-(thiazol-5-yl)pyridazin-3- ylamino)pyrazine-2-carbonitrile, (Compound No.1.83)
[304] Step-1: Synthesis of tert -butyl 2-((6-chloro-3-(thiazol-5-yl)pyridazin-4- ylamino)methyl)morpholine-4-carboxylate: To a solution of tert-butyl 2-((3,6- dichloropyridazin-4-ylamino)methyl)morpholine-4-carboxylate (500 mg, 1.37 mmols, 1.0 eq) and 5-(tributylstannyl)thiazole (618.2 mg, 1.65 mmols, 1.2 eq) in toluene (10mL) was added lithium chloride (58.0 mg, 1.37 mmols, 1.0 eq) and copper(I) iodide (130.0 mg, 0.68 mmols, 0.5 eq) at RT and the reaction mixture was purged using nitrogen for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (78.6 mg, 0.068 mmols, 0.05 eq) was added and the reaction mixture was again purged using nitrogen for 5 minutes. The resultant reaction mixture was stirred at 120 °C for 16h. Reaction was monitored by TLC and LCMS analyses. After completion, reaction mixture was cooled to RT. Ethyl acetate (100 mL) was added and organic phase was washed with water (20 mL × 3) followed by brine wash (20 mL). Organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude. Crude was purified by combiflash using ethyl acetate:hexane (0- 50%) as eluent to afford the desired compound (230 mg). LCMS: 412.1 [M+1] + [305] Step-2: Synthesis of tert-butyl 2-((6-(5-cyanopyrazin-2-ylamino)-3-(thiazol-5- yl)pyridazin-4-ylamino)methyl)morpholine-4-carboxylate: To a solution of tert-butyl 2- ((6-chloro-3-(thiazol-5-yl)pyridazin-4-ylamino)methyl)morpholine-4-carboxylate (220 mg, 0.53 mmols, 1.0 eq) and 5-aminopyrazine-2-carbonitrile (51.38 mg, 0.42 mmols, 0.8 eq) in DMF (4 mL) was added Cs2CO3 (518.4 mg, 1.59 mmols, 3.0 eq) at RT and reaction mixture was purged under nitrogen for 10 minutes. Xantphos (30.6 mg, 0.053 mmols, 0.1 eq) and Pd2dba3 (48.5 mg, 0.053 mmols, 0.1eq) were added to the reaction mixture and it was again purged using nitrogen for 5 minutes. Reaction mixture was stirred at 180°C for 16h. Reaction was monitored by TLC and LCMS. After completion, reaction mixture was cooled to RT. Ethyl acetate (100 mL) was added to the reaction mixture and organic phase was washed with water (20 mL × 3) followed by brine wash (20 mL). Organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude. Crude was washed with n-pentane (20 mL × 2) to afford the desired compound as an off-white solid (140 mg). LCMS: 496.1 [M+1] + [306] Step-3: Synthesis of 5-(5-(morpholin-2-ylmethylamino)-6-(thiazol-5-yl)pyridazin- 3-ylamino)pyrazine-2-carbonitrile: To a solution of tert -butyl 2-((6-(5-cyanopyrazin-2- ylamino)-3-(thiazol-5-yl)pyridazin-4-ylamino)methyl)morpholine-4-carboxylate (140 mg, 0.28 mmols, 1.0 eq) in DCM (2 mL) was added TFA (1 mL) at 0 °C and reaction was stirred
at RT for 2h. Reaction was monitored by TLC and LCMS. After completion, reaction mixture was concentrated under reduced pressure to afford crude. Crude was purified by reverse phase chromatography to yield desired compound as a pale yellow solid (20 mg). LCMS: 396.1 [M+1]+; 1H NMR (400 MHz, DMSO-d6; after D2O addition) δ 9.16 (s, 1H), 8.93 (s, 1H), 8.72 (s, 1H), 8.29 (s, 1H), 7.38 (s, 1H), 3.74 (d, J = 11.2 Hz, 1H), 3.64 (q, J = 7.2, 6.5 Hz, 1H), 3.49 – 3.37 (m, 1H), 3.22 (t, J = 5.4 Hz, 2H), 2.83 (d, J = 12.3 Hz, 1H), 2.61 (d, J = 13.8 Hz, 2H), 2.44 – 2.37 (m, 1H). Example-36: Synthesis of 4-(azetidin-3-ylmethylamino)-6-(5-cyanopyrazin-2-ylamino)-N- methylpyridazine-3-carboxamide, (Compound No.1.84)
[307] Step-1: Synthesis of methyl 4-((1-(tert-butoxycarbonyl)azetidin-3-yl)methyl amino)-6-chloropyridazine-3-carboxylate: To a solution of methyl 4,6-dichloropyridazine- 3-carboxylate (500 mg, 2.415 mmols, 1.0 eq) in THF (15 mL), diisopropylethylamine (1.5 mL, 3.622 mols, 1.5 eq) was added dropwise to the reaction mixture followed by addition of tert-butyl 3-(aminomethyl)azetidine-1-carboxylate (539 mg, 2.89 mmols, 1.2 eq). The resulting reaction mixture was refluxed for 2 h. Product formation was confirmed by TLC and LCMS. The reaction mixture was quenched with ice water (10 mL) and extracted with ethyl acetate (3 × 15 mL). Collective organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate and then concentrated under vacuo to get the crude. Then the crude was triturated with pentane to obtain desired compound (0.850 g) as an off white solid. LCMS: 356.3[M+1] + [308] Step-2: Synthesis of tert-butyl 3-((6-chloro-3-(methyl carbamoyl)pyridazin-4- ylamino) methyl)azetidine-1-carboxylate: To a solution of methyl 4-((1-(tert- butoxycarbonyl)azetidin-3-yl)methylamino)-6-chloropyridazine-3-carboxylate (250 mg, 0.696 mmols, 1.0 eq) in ACN (10 mL) was added K2CO3 (289 mg, 2.096 mmols, 3.0 eq) followed by addition of methylamine (33% in water) (0.19 mL, 2.096 mmols, 3.0 eq). The resulting reaction mixture was stirred at RT for 8h. Product formation was confirmed by TLC and LCMS. The reaction mixture was quenched with ice water (20 mL) and extracted with
ethyl acetate (3 × 15 mL). Collective organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to get the crude. Then the crude was triturated with pentane to obtain desired compound (250 mg). LCMS: 355.2 [M+1] + [309] Step-3: Synthesis of tert-butyl 3-((6-(5-cyanopyrazin-2-ylamino)-3- (methylcarbamoyl) pyridazin-4-ylamino)methyl)azetidine-1-carboxylate: A solution of tert-butyl 3-((6-chloro-3-(methyl carbamoyl)pyridazin-4-ylamino)methyl) azetidine-1- carboxylate (200 mg, 0.56 mmols, 1 eq) and 5-aminopyrazine-2-carbonitrile (80 mg, 0.672 mmols, 1.2 eq) in dioxane (5 mL) was purged with nitrogen for 5 minutes then Cs2CO3 (550 mg, 1.69 mmols, 3 eq) was added and purged again for 5 minutes. Further, Xantphos (16 mg, 0.0281 mmols, 0.05 eq) and Pd2dba3 (9 mg, 0.010 mmols, 0.018 eq) was added and the vial was subjected to microwave irradiation for 45 minutes at 180 °C. Product formation was confirmed by TLC and LCMS. The reaction mixture was quenched with ice water (20 mL) and extracted with ethyl acetate (3 × 15 mL). Collective organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to get the crude. Then the crude was purified by flash chromatography by eluting in 60% ethyl acetate: hexane solvent system to get desired compound (120 mg) as a light brown solid. LCMS: 440.3 [M+1] + [310] Step-4: Synthesis of 4-(azetidin-3-ylmethylamino)-6-(5-cyanopyrazin-2-ylamino)- N-methylpyridazine-3-carboxamide: To a solution of tert-butyl 3-((6-(5-cyanopyrazin-2- ylamino)-3-(methylcarbamoyl)pyridazin-4-ylamino)methyl)azetidine-1-carboxylate (100 mg, 0.227 mmols, 1 eq) in DCM (5 mL), TFA (0.5 mL) was added at 0 °C. The resulting reaction mixture was stirred for 6 h. Product formation was confirmed by TLC and LCMS. The reaction mixture was concentrated under reduced pressure to get the crude. Crude was purified by reverse phase chromatography to yield desired compound as a white solid (25 mg). LCMS: 340.5 [M+1]+; 1H NMR (400 MHz, DMSO-d6; after D2O addition) δ 8.84 (s, 1H), 8.74 (s, 1H), 7.39 (s, 1H), 3.85 (s, 1H), 3.63 (dd, J = 9.9, 6.9 Hz, 2H), 3.44 (d, J = 7.0 Hz, 2H), 3.05 (dq, J = 15.2, 7.6 Hz, 2H), 2.78 (s, 3H). Example-37: Synthesis of 4-(3-aminocyclohexylamino)-6-(5-cyanopyrazin-2-ylamino)-N- methylpyridazine-3-carboxamide, (Compound No.1.85)
[311] Step-1: Synthesis of tert-butyl 3-aminocyclohexylcarbamate: To a solution of cyclohexane-1,3-diamine (1.0 g, 8.75 mmols, 1eq) in 20 mL CHCl3 at 0 °C was added di-tert- butyl dicarbonate (0.38 g, 1.75 mmols, 0.2 eq). The ice bath was removed and after 0.5 h, the reaction mixture was washed with saturated NaHCO3 (3 × 20 mL) and washed with brine (2 × 20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to afford the desired compound which was used without purification in next step (410 mg). LCMS: 215.1 [M+1] + [312] Step-2: Synthesis of methyl 4-(3-(tert-butoxycarbonylamino)cyclohexylamino)-6- chloropyridazine-3-carboxylate: To a solution of methyl 4,6-dichloropyridazine-3- carboxylate (310 mg, 1.49 mmols, 0.8 eq) in THF (10 mL) was added triethylamine (470 mg, 4.65 mmols, 2.5 eq) followed by the addition of tert-butyl 3-aminocyclohexylcarbamate (400 mg, 1.86 mmols, 1.0 eq) at ambient temperature. Then the reaction mixture was stirred at 90 °C for 2h. Reaction was monitored by TLC and LCMS. After completion, reaction mixture was quenched with ice water (10 mL) and extracted with ethyl acetate (50 mL × 3). Combined organic phase was washed with water (20 mL × 3) followed by brine wash (20 mL). Organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford crude. Crude was triturated with pentane and the solid thus precipitated was filtered to afford the desired compound (315mg). LCMS: 385.2 [M+1] + [313] Step-3: Synthesis of tert-butyl 3-(6-chloro-3-(methylcarbamoyl)pyridazin-4- ylamino)cyclohexylcarbamate: To methyl 4-(3-(tert- butoxycarbonylamino)cyclohexylamino)-6-chloropyridazine-3-carboxylate (310 mg, 0.8 mmols, 1.0 eq) was added methylamine (2M in methanol) (6 mL) at ambient temperature.
Reaction mixture was stirred at RT for 30 minutes. Reaction was monitored by TLC and LCMS. After completion, reaction mixture was concentrated under reduced pressure. Ethyl acetate (100 mL) was added and organic phase was washed with water (20 mL × 3) followed by brine wash (20 mL). Organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford crude. Crude was triturated with pentane and solid thus precipitated was filtered to afford the desired compound as a viscous liquid (280 mg). LCMS: 384.2 [M+1] + [314] Step-4: Synthesis of tert-butyl 3-(6-(5-cyanopyrazin-2-ylamino)-3- (methylcarbamoyl)pyridazin-4-ylamino)cyclohexylcarbamate: A solution of tert-butyl 3- (6-chloro-3-(methylcarbamoyl)pyridazin-4-ylamino)cyclohexylcarbamate (270 mg, 0.70 mmols, 1.0 eq) and 5-aminopyrazine-2-carbonitrile (67.5 mg, 0.56 mmols, 0.8 eq) in DMF (5 mL) was added Cs2CO3 (687.5 mg, 2.10mmols, 3 eq) at RT and reaction mixture was purged under nitrogen for 10 minutes. Xantphos (40.5 mg, 0.07 mmols, 0.1eq) and Pd2dba3 (64.3 mg, 0.07 mmols, 0.1 eq) were added and the reaction mixture was again purged using nitrogen for 5 minutes. Reaction mixture was stirred at 180 °C for 16h. Reaction was monitored by TLC and LCMS. After completion, reaction mixture was cooled to RT. Ethyl acetate (100 mL) was added and organic phase was washed with water (20 mL × 3) followed by brine wash (20 mL). Organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford crude. Crude was triturated with pentane and filtered to afford the desired compound (220 mg). LCMS: 468.2 [M+1] + [315] Step-5: Synthesis of 4-(3-aminocyclohexylamino)-6-(5-cyanopyrazin-2-ylamino)- N-methylpyridazine-3-carboxamide: To a solution of tert-butyl 3-(6-(5-cyanopyrazin-2- ylamino)-3-(methylcarbamoyl)pyridazin-4-ylamino)cyclohexylcarbamate (220 mg,0.49 mmol, 1.0 eq) in DCM (3 mL) was added TFA (1.5 mL) at 0°C and reaction was stirred at RT for 1h. Reaction was monitored by TLC and LCMS. After completion, reaction mixture was concentrated under reduced pressure to afford crude. The crude was purified by reverse phase chromatography to yield desired compound as a formate salt and a white solid (55 mg). LCMS: 368.2 [M+1]+; 1H NMR (400 MHz, DMSO-d6; after D2O addition): δ 8.88 (d, J = 6.3 Hz, 1H), 8.74 (d, J = 12.0 Hz, 1H), 8.37 (s, 1H), 7.42 (d, J = 24.1 Hz, 1H), 3.97-3.87 (m, 1H), 3.43 (t, J = 11.7 Hz, 1H), 3.20-3.04 (m, 1H), 2.78 (d, J = 6.4 Hz, 3H), 2.30-2.20 (m, 1H), 2.03- 1.87 (m, 2H), 1.82 (d, J = 13.3 Hz, 1H), 1.69-1.59 (m, 1H), 1.41 (t, J = 12.9 Hz, 1H), 1.32-1.21 (m, 1H), 1.11 (td, J = 13.2, 4.2 Hz, 1H).
Example-38: Synthesis of 4-(3-aminocyclohexylamino)-6-(5-cyanopyrazin-2-ylamino)-N- methylpyridazine-3-carboxamide, (Compound No.1.86)
[316] Step-1: Synthesis of methyl 4-(2-(1-(tert-butoxycarbonyl)piperidin-2- yl)ethylamino)-6-chloropyridazine-3-carboxylate: To a solution of methyl 4,6- dichloropyridazine-3-carboxylate (500 mg, 2.41 mmols, 1.0 eq) in THF (15 mL) was added triethyl amine (607.8 mg, 6.02 mmols, 2.5 eq) followed by the addition of tert-butyl 2-(2- aminoethyl)piperidine-1-carboxylate (606.6 mg, 2.65 mmols, 1.1 eq) at ambient temperature. Reaction mixture was stirred at 90°C for 2h. Reaction was monitored by TLC and LCMS. After completion, reaction mixture was quenched with ice water (10 mL) and extracted with ethyl acetate (100 mL × 3). Combined organic phase was washed with water (20 mL × 3) followed by brine wash (20 mL). Organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford crude. Crude was triturated with pentane and the solid thus precipitated was filtered to afford the desired compound (1.1g). LCMS: 399.1 [M+1] + [317] Step-2: Synthesis of tert-butyl 2-(2-(6-chloro-3-(methylcarbamoyl)pyridazin-4- ylamino)ethyl)piperidine-1-carboxylate: Methyl amine (2M in methanol) (20 mL) was added to a solution of methyl 4-(2-(1-(tert-butoxycarbonyl)piperidin-2-yl)ethylamino)-6- chloropyridazine-3-carboxylate (1.0 g, 2.51 mmols, 1.0 eq.) in methanol (10 mL) at ambient temperature. Reaction mixture was stirred at RT for 30 minute. Reaction was monitored by TLC and LCMS. After completion, reaction mixture was concentrated under reduced pressure. Ethyl acetate (200 mL) was added and organic phase was washed with water (20 mL × 3) followed by brine wash (20 mL). Organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford crude. Crude was triturated with pentane and the solid thus precipitated was filtered to afford 800 mg of desired compound as an off white solid. LCMS: 398.1 [M+1] + [318] Step-3: Synthesis of tert-butyl 2-(2-(6-(5-cyanopyrazin-2-ylamino)-3- (methylcarbamoyl)pyridazin-4-ylamino)ethyl)piperidine-1-carboxylate: A solution of tert-butyl 2-(2-(6-chloro-3-(methylcarbamoyl)pyridazin-4-ylamino)ethyl)piperidine-1-
carboxylate (300 mg, 0.75 mmols , 1.0 eq) and 5-aminopyrazine-2-carbonitrile (72.54 mg, 0.60 mmols, 0.8 eq) in DMF (5 mL) was added Cs2CO3 (738.4 mg, 2.26 mmols, 3 eq) at RT and the reaction mixture was purged under nitrogen for 10 minutes. Xantphos (43.35 mg, 0.07 mmols, 0.1eq) and Pd2dba3 (69 mg, 0.07 mmols, 0.1 eq) were added and again nitrogen was purged for 5 minutes. Reaction mixture was stirred at 180 °C for 16h. Reaction was monitored by TLC and LCMS. After completion, reaction mixture was cooled to RT. Ethyl acetate (100 mL) was added and organic phase was washed with water (20 mL × 3) followed by brine wash (20 mL). Organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford crude. Crude was triturated with pentane and filtered to afford the desired compound (210 mg). LCMS: 482.2 [M+1] + [319] Step-4: Synthesis of 4-(3-aminocyclohexylamino)-6-(5-cyanopyrazin-2-ylamino)- N-methylpyridazine-3-carboxamide: To a solution of tert-butyl 2-(2-(6-(5-cyanopyrazin-2- ylamino)-3-(methylcarbamoyl)pyridazin-4-ylamino)ethyl)piperidine-1-carboxylate (210 mg, 0.43 mmols, 1.0 eq) in DCM (2 mL) was added TFA (1.2 mL) at 0 °C and the reaction mixture was stirred at RT for 1h. Reaction was monitored by TLC and LCMS. After completion, reaction mixture was concentrated under reduced pressure to afford crude. The crude was purified by reverse phase chromatography to yield desired compound as a formate salt and a white solid (40 mg). LCMS: 382.2 [M+1]+; 1H NMR (400 MHz, DMSO-d6; after D2O addition): δ 8.92 (s, 1H), 8.75 (d, J = 1.4 Hz, 1H), 8.36 (s, 1H), 7.40 (s, 1H), 3.31 (t, J = 7.1 Hz, 2H), 3.19 (d, J = 12.7 Hz, 1H), 3.04-2.93 (m, 1H), 2.82 (d, J = 10.6 Hz, 1H), 2.79 (s, 3H), 1.95-1.80 (m, 2H), 1.80-1.66 (m, 2H), 1.49 (dt, J = 25.7, 12.1 Hz, 2H), 1.37 (dd, J = 15.9, 9.2 Hz, 2H). Example-39: Synthesis of 6-(5-cyanopyrazin-2-ylamino)-N-methyl-4-(pyrrolidin-2- ylmethylamino)pyridazine-3-carboxamide, (Compound No.1.87)
[320] Step-1: Synthesis of methyl 4-((1-(tert-butoxycarbonyl)pyrrolidin-2- yl)methylamino)-6-chloropyridazine-3-carboxylate: To a solution of methyl 4,6- dichloropyridazine-3-carboxylate (800 mg, 8.86 mmols, 1.0 eq) in THF (30 mL) was added triethylamine (1.35 mL, 9.65 mmol, 2.5 eq) followed by the addition of tert-butyl 2- (aminomethyl)pyrrolidine-1-carboxylate (851.4 mg, 4.25 mmols, 1.1 eq) at ambient
temperature. Reaction mixture was stirred at 90 °C for 3h. Reaction was monitored by TLC and LCMS. After completion, reaction mixture was quenched with ice water (10 mL) and extracted with ethyl acetate (100 mL × 3). Combined organic phase was washed with water (20 mL × 3) followed by brine wash (20 mL). Organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford crude. Crude was triturated with pentane and the solid thus precipitated was filtered to afford the desired compound (1.7g). LCMS: 371.2[M+1] + [321] Step-2: Synthesis of tert-butyl 2-((6-chloro-3-(methylcarbamoyl)pyridazin-4- ylamino)methyl)pyrrolidine-1-carboxylate: To a solution of methyl 4-((1-(tert- butoxycarbonyl)pyrrolidin-2-yl)methylamino)-6-chloropyridazine-3-carboxylate (1.7g, 4.59 mmols, 1.0 eq) in methanol (10 mL) was added methyl amine (2M in methanol) (30 mL) at ambient temperature. Reaction mixture was stirred at RT for 30 minute. Reaction was monitored by TLC and LCMS. After completion, reaction mixture was concentrated under reduced pressure. Ethyl acetate (300 mL) was added and organic phase was washed with water (20 mL × 3) followed by brine wash (20 mL). Organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford crude. Crude was triturated with pentane and the solid thus precipitated was filtered to afford the desired compound (1.2g). LCMS: 370.2 [M+1] +; 372.2 [M+3] + [322] Step-3: Synthesis of tert-butyl 2-((6-(5-cyanopyrazin-2-ylamino)-3- (methylcarbamoyl)pyridazin-4-ylamino)methyl)pyrrolidine-1-carboxylate: A solution of tert-butyl 2-((6-chloro-3-(methylcarbamoyl)pyridazin-4-ylamino)methyl)pyrrolidine-1- carboxylate (200 mg, 0.54mmols, 1.0 eq) and 5-aminopyrazine-2-carbonitrile (52.03 mg, 0.43 mmols, 0.8 eq) in DMF (4 mL) was added Cs2CO3 (530 mg, 1.62 mmols, 3 eq) at RT and the reaction mixture was purged under nitrogen for 10 minutes. Xantphos (31.2 mg, 0.05 mmols, 0.1eq) and Pd2dba3 (49.6 mg, 0.05 mmols, 0.1 eq) were added and again nitrogen was purged for 5 minutes. Reaction mixture was stirred at 180 °C for 16h. Reaction was monitored by TLC and LCMS. After completion, reaction mixture was cooled to RT. Ethyl acetate (100 mL) was added and organic phase was washed with water (20 mL × 3) followed by brine wash (20 mL). Organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford crude. Crude was triturated with pentane and filtered to afford the desired compound (180 mg). LCMS: 454.2 [M+1] +
[323] Step-4: Synthesis of 6-(5-cyanopyrazin-2-ylamino)-N-methyl-4-(pyrrolidin-2- ylmethylamino)pyridazine-3-carboxamide: To a solution of tert-butyl 2-((6-(5- cyanopyrazin-2-ylamino)-3-(methylcarbamoyl)pyridazin-4-ylamino)methyl)pyrrolidine-1- carboxylate (180 mg, 0.39 mmols, 1.0 eq) in DCM (2 mL) was added TFA (1.0 mL) at 0 °C and reaction was stirred at RT for 1h. Reaction was monitored by TLC and LCMS. After completion, reaction mixture was concentrated under reduced pressure to afford crude. The crude was purified by reverse phase chromatography to yield desired compound as a formate salt and a white solid (56 mg). LCMS: 354.2 [M+1]+; 1H NMR (400 MHz, DMSO-d6; after D2O addition): δ 8.88 (s, 1H), 8.74 (s, 1H), 8.33 (s, 1H), 7.41 (s, 1H), 3.67 (p, J = 7.9 Hz, 2H), 3.52 – 3.40 (m, 2H), 3.11 (h, J = 5.0, 4.5 Hz, 2H), 2.79 (s, 3H), 2.11 (dd, J = 12.9, 7.2 Hz, 1H), 1.89 (ddq, J = 28.7, 13.1, 7.0, 6.4 Hz, 3H), 1.61 (dq, J = 16.0, 8.2 Hz, 2H). Example-40: Synthesis of 4-(2-(azetidin-3-yl)ethylamino)-6-(5-cyanopyrazin-2-ylamino)-N- methylpyridazine-3-carboxamide, (Compound No.1.88)
[324] Step-1: Synthesis of methyl 4-(2-(1-(tert-butoxycarbonyl)azetidin-3- yl)ethylamino)-6-chloropyridazine-3-carboxylate: To a solution of methyl 4,6- dichloropyridazine-3-carboxylate (300 mg, 1.44 mmols, 1.0 eq) in THF (15 mL), DIPEA (0.378 mL, 2.17 mmols, 1.5 eq) was added dropwise to the reaction mixture followed by addition of tert-butyl 3-(2-aminoethyl)azetidine-1-carboxylate (345 mg, 1.72 mmols, 1.2 eq). The reaction mixture was refluxed for 2 h. Product formation was confirmed by TLC and LCMS. The reaction mixture was quenched with ice water (10 mL) and extracted with ethyl acetate (3 × 15 mL). Collective organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to get the crude. Then the crude was triturated with pentane to obtain the desired compound (0.530 g) as an off-white solid. LCMS: 371.4 [M+1]+ [325] Step-2: Synthesis of tert-butyl 3-(2-(6-chloro-3-(methylcarbamoyl) pyridazin-4- ylamino) ethyl) azetidine-1-carboxylate: To a solution methyl 4-(2-(1-(tert- butoxycarbonyl)azetidin-3-yl)ethylamino)-6-chloropyridazine-3-carboxylate (300 mg, 0.810 mmols, 1.0 eq) in ACN (10 mL) was added K2CO3 (335 mg, 2.43 mmol, 3.0eq) followed by
addition of methylamine (0.225 mg, 2.43 mmols, 3.0 eq). The resulting reaction mixture was stirred at RT for 16h. Product formation was confirmed by TLC and LCMS. The reaction mixture was quenched with ice water (20 mL) and extracted with ethyl acetate (3 × 15 mL). Collective organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to get the crude. The crude was triturated with pentane to obtain desired compound (250 mg). LCMS: 370.3 [M+1] + [326] Step-3: Synthesis of tert-butyl 3-(2-(6-(5-cyanopyrazin-2-ylamino)-3- (methylcarbamoyl) pyridazin-4-ylamino)ethyl)azetidine-1-carboxylate: A solution of tert-butyl 3-(2-(6-chloro-3-(methylcarbamoyl) pyridazin-4-ylamino) ethyl) azetidine-1- carboxylate (200 mg, 0.542 mmols, 1.0 eq) and 5-aminopyrazine-2-carbonitrile (78 mg, 0.650 mmols, 1.2 eq) in DMF (5 mL) was purged with nitrogen for 5 minutes then Cs2CO3 (530 mg, 1.626 mmols, 3.0 eq) was added and purged again for 5 minutes. Further, Xantphos (15 mg, 0.0271 mmols, 0.05 eq) and Pd2dba3 (10 mg, 0.0098 mmols, 0.018 eq) was added and the sealed tube was closed and kept for heating for 16 h at 180 °C. Product formation was confirmed by TLC and LCMS. The reaction mixture was quenched with ice water (20 mL) and extracted with ethyl acetate (3 × 15 mL). Collective organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate and concentrated under reduced pressure to get the crude. The crude was purified by flash chromatography by eluting in 60% ethyl acetate: hexane solvent system to obtain the desired compound (120 mg) as a light brown solid. LCMS: 454.3 [M+1] + [327] Step-4: Synthesis of 4-(2-(azetidin-3-yl)ethylamino)-6-(5-cyanopyrazin-2- ylamino)-N-methylpyridazine-3-carboxamide: To a solution of tert-butyl 3-(2-(6-(5- cyanopyrazin-2-ylamino)-3-(methylcarbamoyl)pyridazin-4-ylamino)ethyl)azetidine-1- carboxylate (100 mg, 0.220 mmols, 1 eq) in DCM (5 mL), TFA (0.5 mL) was added at 0 °C and the resulting reaction mixture was stirred for 6h. Product formation was confirmed by TLC and LCMS. Then the reaction mixture was concentrated under reduced pressure to get the crude. The crude was purified by reverse phase chromatography to yield desired compound as a formate salt and a white solid (40 mg). LCMS: 354.5 [M+1]+; 1H NMR (400 MHz, DMSO-d6; after D2O addition): δ 1H NMR (400 MHz, DMSO-d6) δ 8.88 (s, 1H), 8.75 (s, 1H), 7.39 (s, 1H), 3.87 (t, J = 9.1 Hz, 2H), 3.58 (t, J = 8.6 Hz, 2H), 3.15 (t, J = 7.0 Hz, 2H), 2.85-2.80 (m, 1H), 2.78 (s, 3H), 1.88 (q, J = 7.2 Hz, 2H).
Example-41: Synthesis of 6-(5-cyanopyrazin-2-ylamino)-N-methyl-4-(2-(pyrrolidin-2-yl) ethylamino)pyridazine-3-carboxamide, (Compound No.1.89)
[328] Step-1: Synthesis of methyl 4-(2-(1-(tert-butoxycarbonyl)pyrrolidin-2- yl)ethylamino)-6-chloropyridazine-3-carboxylate: To a solution of methyl 4,6- dichloropyridazine-3-carboxylate (500 mg, 2.415 mmols, 1.0 eq) in THF (15 mL), diisopropylethylamine (0.631 mL, 3.62 mmols, 1.5 eq) was added dropwise to the reaction mixture. Then tert-butyl 2-(2-aminoethyl)pyrrolidine-1-carboxylate (621 mg, 2.89 mmols, 1.2 eq) was added and the resulting reaction mixture was refluxed for 2 h. Product formation was confirmed by TLC and LCMS. The reaction mixture was quenched with ice water (10 mL) and extracted with ethyl acetate (3 × 15 mL). Collective organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to get the crude. Then the crude was triturated with pentane to obtain the desired compound (0.850 g) as cream color solid. LCMS: 385.3[M+1]+ [329] Step-2: Synthesis of tert-butyl 2-(2-(6-chloro-3-(methylcarbamoyl) pyridazin-4- ylamino) ethyl) pyrrolidine-1-carboxylate: To a solution methyl 4-(2-(1-(tert- butoxycarbonyl)pyrrolidin-2-yl)ethylamino)-6-chloropyridazine-3-carboxylate (200 mg, 0.519 mmols, 1.0 eq) in ACN (10 mL) was added K2CO3 (215 mg, 1.55 mmols, 3.0 eq) followed by addition of methylamine (0.114 mg, 1.55 mmols, 3.0 eq) and the reaction mixture was kept for stirring at RT for 8 h. Product formation was confirmed by TLC and LCMS. The reaction mixture was quenched with ice water (20 mL) and extracted with ethyl acetate (3 × 15 mL). Collective organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to get the crude. Then the crude was triturated with pentane to obtain desired compound (200 mg). LCMS: 384.3 [M+1] + [330] Step-3: Synthesis of tert-butyl 2-(2-(6-(5-cyanopyrazin-2-ylamino)-3- (methylcarbamoyl) pyridazin-4-ylamino)ethyl)pyrrolidine-1-carboxylate: A solution of tert-butyl 2-(2-(6-chloro-3-(methylcarbamoyl)pyridazin-4-ylamino)ethyl)pyrrolidine-1-
carboxylate (200 mg, 0.52 mmols, 1.0 eq) and 5-aminopyrazine-2-carbonitrile(75 mg, 0.625 mmols, 1.2 eq) in DMF (5 mL) was purged with nitrogen for 5 minutes then Cs2CO3 (508 mg, 1.56 mmols, 3.0 eq) was added and the reaction mixture was purged again for 5 minutes. Further, Xantphos (6.0 mg, 0.0094 mmols, 0.018 eq) and Pd2dba3 (24 mg, 0.026 mmols, 0.05 eq) was added and the resultant vial was subjected to microwave irradiation for 45 minutes at 180 °C. Product formation was confirmed by TLC and LCMS. The reaction mixture was quenched with ice water (20 mL) and extracted with ethyl acetate (3 × 15 mL). Collective organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to get the crude. Then the crude was purified by flash chromatography by eluting in 60% ethyl acetate: hexane solvent system to obtain desired compound (120 mg) as a light brown solid. LCMS: 468.3 [M+1]+ [331] Step-4: Synthesis of 6-(5-cyanopyrazin-2-ylamino)-N-methyl-4-(2-(pyrrolidin-2- yl)ethylamino) pyridazine-3-carboxamide: To a solution of tert-butyl 2-(2-(6-(5- cyanopyrazin-2-ylamino)-3-(methylcarbamoyl)pyridazin-4-ylamino) ethyl)pyrrolidine-1- carboxylate (100 mg, 0.213 mmols, 1 eq) in DCM (5 mL), TFA (0.5 mL) was added at 0 °C. The resulting reaction mixture was stirred for 6 h. Product formation was confirmed by TLC and LCMS. Then the reaction mixture was concentrated under reduced pressure to get the crude. The crude was purified by reverse phase chromatography to yield desired compound as a formate salt and a white solid (30 mg). LCMS: 368.5 [M+1]+; 1H NMR (400 MHz, DMSO-d6; after D2O addition): δ 8.92 (s, 1H), 8.75 (s, 1H), 8.38 (s, 1H), 7.41 (s, 1H), 3.40 (q, J = 7.5 Hz, 1H), 3.29 (d, J = 7.9 Hz, 2H), 3.18-3.06 (m, 2H), 2.79 (s, 3H), 2.12 (tt, J = 11.8, 4.9 Hz, 1H), 2.01-1.77 (m, 4H), 1.55 (dt, J = 12.7, 8.8 Hz, 1H). Example-42: Synthesis of 4-(3-aminobicyclo [1.1.1] pentan-1-ylamino)-6-(5-cyanopyrazin-2- ylamino)-N-methylpyridazine-3-carboxamide, (Compound No.1.90)
[332] Step-1: Synthesis of methyl 4-(3-(tert-butoxycarbonylamino) bicyclo [1.1.1] pentan-1-ylamino)-6-chloropyridazine-3-carboxylate: To a solution of methyl 4,6- dichloropyridazine-3-carboxylate (500 mg, 2.415 mmols, 1.0 eq) in THF (15 mL),
trimethylamine (0.58 mL, 3.62 mmols, 1.5 eq) was added drop wise followed by addition of tert-butyl 3-aminobicyclo[1.1.1]pentan-1-ylcarbamate (574 mg, 2.89 mmols, 1.2 eq). The reaction mixture was stirred at RT for 16 h. Product formation was confirmed by TLC and LCMS. The reaction mixture was quenched with ice water (10 mL) and extracted with ethyl acetate (3 × 50 mL). Collective organic layer was washed with brine (20 mL) and dried over sodium sulfate and then concentrated under reduced pressure to get the crude. The crude was triturated with pentane to get the desired compound as an off-white solid (0.968 g). LCMS: 369.3 [M+1] + [333] Step-2: Synthesis of tert-butyl 3-(6-chloro-3-(methylcarbamoyl) pyridazin-4- ylamino) bicyclo [1.1.1] pentan-1-ylcarbamate: To a solution of methyl 4-(3-(tert- butoxycarbonylamino) bicyclo [1.1.1] pentan-1-ylamino)-6-chloropyridazine-3-carboxylate (800 mg, 2.173 mmols, 1.0 eq) in ACN (15 ml) was added methyl amine (33%) (0.60 mL, 6.519 mmols, 3.0 eq) and then Al(CH3)3 (0.312 mL, 4.36 mmols, 2.0 eq) was added and kept for stirring at RT for 8 h. Product formation was confirmed by TLC and LCMS. The reaction mixture was quenched with ice water (10 mL) and extracted with ethyl acetate (3 × 50 mL). Collective organic layer was washed with brine (20 mL) and dried over sodium sulfate and then concentrated under reduced pressure to get the crude. The crude was triturated using pentane to get the desired compound (0.53 g). LCMS: 368.3 [M+1]+ [334] Step-3: Synthesis of tert-butyl 3-(6-(5-cyanopyrazin-2-ylamino)-3- (methylcarbamoyl) pyridazin-4-ylamino) bicyclo [1.1.1] pentan-1-ylcarbamate: A solution of tert-butyl 3-(6-chloro-3-(methylcarbamoyl) pyridazin-4-ylamino) bicyclo [1.1.1] pentan-1-ylcarbamate (500 mg, 1.367 mmols, 1.0 equi) and 5-aminopyrazine-2-carbonitrile (192 mg,1.634 mmols, 1.0 eq) in dioxane (5 mL) was purged with N2 for 5 minutes then Cs2CO3 (1.33 g, 4.101mmols, 3.0 eq) was added and purged again for 5 minutes. Xantphos (28.0 mg, 0.068 mmols,0.05eq) and Pd2dba3 (23 mg, 0.024 mmols, 0.018 eq) was added and then the vial was closed and kept for heating in microwave for 45 minutes at 180 °C. Product formation was confirmed by TLC and LCMS. The reaction mixture was quenched with ice water (20 mL) and extracted with ethylacetate (3× 15 mL). Collective organic layer was washed with brine (20 mL) and dried over Na2SO4 and then concentrated under reduced pressure to get the crude. The crude was purified by combi flash chromatography by using 12g redi sap column and by eluting in 60% ethyl acetate: hexane solvent system to get the desired compound (110 mg, light brown solid). LCMS: 452.3 [M+1] +
[335] Step-4: Synthesis 4-(3-aminobicyclo [1.1.1] pentan-1-ylamino)-6-(5- cyanopyrazin-2-ylamino)-N-methylpyridazine-3-carboxamide: To a solution of tert-butyl 3-(6-(5-cyanopyrazin-2-ylamino)-3-(methylcarbamoyl) pyridazin-4-ylamino) bicyclo [1.1.1] pentan-1-ylcarbamate (110 mg, 0.243 mmols, 1 eq) in DCM (5.0 mL), TFA (0.5 mL) was added at 0°C and kept for stirring for 2h. Product formation was confirmed by TLC and LCMS. Then the RM was concentrated under reduced pressure to get the crude. The crude was purified by reverse phase chromatography to yield desired compound as a trifluoroacetate salt and a white solid (10 mg). LCMS: 352.5 [M+1]+; 1H NMR (400 MHz, DMSO-d6; after D2O addition): δ 11.27 (s, 1H), 9.23 (s, 1H), 9.14-9.00 (m, 1H), 8.94 (s, 1H), 8.82 (d, J = 7.2 Hz, 3H), 7.92 (s, 1H), 2.79 (d, J = 4.9 Hz, 3H), 2.44 (s, 6H). Example-43: Synthesis of 4-(azepan-3-ylamino)-6-(5-cyanopyrazin-2-ylamino)-N- methylpyridazine-3-carboxamide, (Compound No.1.91)
[336] Step-1: Synthesis of tert-butyl 3-(6-chloro-3-(methoxycarbonyl)pyridazin-4- ylamino)azepane-1-carboxylate: To a solution of methyl 4,6-dichloropyridazine-3- carboxylate (400 mg, 1.93 mmols, 1.0 eq) in THF (14 mL) was added triethylamine (487.3 mg, 4.82 mmols, 2.5 eq) followed by the addition of tert-butyl 3-aminoazepane-1- carboxylate (456 mg, 2.12 mmols, 1.1 eq) at ambient temperature. Reaction mixture was stirred at 90 °C for 3h. Reaction was monitored by TLC and LCMS. After completion, reaction mixture was quenched with ice water (10 mL) and extracted with ethyl acetate (3 × 50 mL). Combined organic phase was washed with water (3 × 20 mL) followed by brine wash (20 mL). Organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude. Crude was triturated with pentane and solid precipitated was filtered to afford 900 mg of desired compound LCMS: 385.1 [M+1] + [337] Step-2: Synthesis of tert-butyl 3-(6-chloro-3-(methylcarbamoyl)pyridazin-4- ylamino)azepane-1-carboxylate: To a solution of tert-butyl 3-(6-chloro-3- (methoxycarbonyl)pyridazin-4-ylamino)azepane-1-carboxylate (900 mg, 2.34 mmols, 1.0 eq) in methanol (10 mL) was added methylamine (2M in methanol) (18 mL) at ambient
temperature. The reaction mixture was stirred at RT for 30 minutes. Reaction was monitored by TLC and LCMS. After completion, reaction mixture was concentrated under reduced pressure. Ethyl acetate (100 mL) was added and organic phase was washed with water (3 × 20 mL) followed by brine wash (20 mL). Organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude. Crude was triturated with pentane and the solid thus precipitated was filtered to afford the desired compound (720 mg) LCMS: 384.0 [M+1] + [338] Step-3: Synthesis of tert-butyl 3-(6-(5-cyanopyrazin-2-ylamino)-3- (methylcarbamoyl)pyridazin-4-ylamino)azepane-1-carboxylate: To a solution of tert- butyl 3-(6-chloro-3-(methylcarbamoyl)pyridazin-4-ylamino)azepane-1-carboxylate (300 mg, 0.78 mmols, 1.0 eq) and 5-aminopyrazine-2-carbonitrile (75 mg, 0.62 mmols , 0.8 eq) in DMF (5 mL) was added Cs2CO3 (763.8 mg, 2.34 mmols, 3 eq) at RT and reaction mixture was purged under nitrogen for 10 minutes. Xantphos (45 mg, 0.07 mmols, 0.1eq) and Pd2dba3 (71.4 mg, 0.07 mmols, 0.1 eq) were added and again nitrogen was purged for 5 minutes. Reaction mixture was stirred at 180 °C for 16h. Reaction was monitored by TLC and LCMS. After completion, reaction mixture was cooled to RT. Ethyl acetate (100 mL) was added and organic phase was washed with water (3 × 20 mL) followed by brine wash (20 mL). Organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude. Crude was triturated with pentane and filtered to afford 180 mg of desired compound. LCMS: 468.2 [M+1] + [339] Step-4: Synthesis of 4-(azepan-4-ylamino)-6-(5-cyanopyrazin-2-ylamino)-N- methylpyridazine-3-carboxamide: To a solution of tert-butyl 3-(6-(5-cyanopyrazin-2- ylamino)-3-(methylcarbamoyl)pyridazin-4-ylamino)azepane-1-carboxylate (180 mg, 0.48mmols, 1.0 eq) in DCM (3 mL) was added TFA (1.5 mL) at 0°C and the reaction was stirred at RT for 2h. Reaction was monitored by TLC and LCMS. After completion, reaction mixture was concentrated under reduced pressure to afford crude. Then the reaction mixture was concentrated under reduced pressure to get the crude. The crude was purified by reverse phase chromatography to yield desired compound as a formate salt and a white solid (62 mg). LCMS: 368.4 [M+1]+; 1H NMR (400 MHz, DMSO-d6; after D2O addition): δ 8.89 (s, 1H), 8.75 (s, 1H), 8.29 (s, 1H), 7.38 (s, 1H), 3.15 (dd, J = 13.8, 3.8 Hz, 1H), 2.98 (ddd, J = 21.5, 13.1, 7.7 Hz, 3H), 2.78 (s, 3H), 1.95 (d, J = 11.9 Hz, 1H), 1.71 (dd, J = 20.8, 10.1 Hz, 5H), 1.58 (d, J = 11.2 Hz, 1H).
Example-44: Synthesis of 4-(azepan-4-ylamino)-6-(5-cyanopyrazin-2-ylamino)-N- methylpyridazine-3-carboxamide (Compound No.1.92)
[340] Step-1: Synthesis of tert-butyl 4-(6-chloro-3-(methoxycarbonyl)pyridazin-4- ylamino)azepane-1-carboxylate: To a solution of methyl 4,6-dichloropyridazine-3- carboxylate (400mg, 1.93 mmols, 1.0 eq) in THF (14 ml) was added triethylamine (487.3 mg, 4.82 mmols, 2.5 eq) followed by the addition of tert-butyl 4-aminoazepane-1-carboxylate (456 mg, 2.12 mmols, 1.1 eq) at ambient temperature. Reaction mixture was stirred at 90 °C for 3h. Reaction was monitored by TLC and LCMS. After completion, reaction mixture was quenched with ice water (10 mL) and extracted with Ethyl acetate (3 × 100 mL). Combined organic phase was washed with water (3 × 20 mL) followed by brine wash (2 mL). Organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude. Crude was triturated with pentane and solid precipitated was filtered to afford 750 mg of desired compound. LCMS: 385.0 [M+1]+ [341] Step-2: Synthesis of tert-butyl 4-(6-chloro-3-(methylcarbamoyl)pyridazin-4- ylamino)azepane-1-carboxylate: To a solution of tert-butyl 4-(6-chloro-3- (methoxycarbonyl)pyridazin-4-ylamino)azepane-1-carboxylate (750 mg, 1.95 mmols, 1.0 eq.) in methanol (10 mL) was added methylamine (2M in methanol) (15 mL) at ambient temperature. Reaction mixture was stirred at RT for 30 minutes. Reaction was monitored by TLC and LCMS. After completion, reaction mixture was concentrated under reduced pressure. Ethyl acetate (200 mL) was added and organic phase was washed with water (3 × 20 mL) followed by brine wash (20 mL). Organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude. Crude was triturated with pentane and solid precipitated was filtered to afford 620 mg of desired compound. LCMS: 384.2 [M+H] + [342] Step-3: Synthesis of tert-butyl 4-(6-(5-cyanopyrazin-2-ylamino)-3- (methylcarbamoyl)pyridazin-4-ylamino)azepane-1-carboxylate: To a solution of tert- butyl 4-(6-chloro-3-(methylcarbamoyl)pyridazin-4-ylamino)azepane-1-carboxylate (250 mg, 0.65mmols , 1.0 eq) and 5-aminopyrazine-2-carbonitrile (62.5 mg, 0.52mmols , 0.8 eq) in
DMF (4 mL) was added Cs2CO3 (636.6 mg, 1.95 mmols, 3 eq) at RT and the reaction mixture was purged under nitrogen for 10 minutes. Xantphos (37.6 mg, 0.06 mmols, 0.1eq) and Pd2dba3 (59.6 mg, 0.06 mmols, 0.1 eq) were added and again nitrogen was purged for 5 minutes. Reaction mixture was stirred at 180 °C for 16h. Reaction was monitored by TLC and LCMS. After completion, reaction mixture was cooled to RT. Ethyl acetate (100 mL) was added and organic phase was washed with water (3 × 20 mL) followed by brine wash (20 mL). Organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude. Crude was triturated with pentane and filtered to afford 150 mg of desired compound. LCMS: 468.2 [M+1] + [343] Step-4: Synthesis of 4-(azepan-4-ylamino)-6-(5-cyanopyrazin-2-ylamino)-N- methylpyridazine-3-carboxamide: To a solution of tert-butyl 4-(6-(5-cyanopyrazin-2- ylamino)-3-(methylcarbamoyl)pyridazin-4-ylamino)azepane-1-carboxylate (150 mg, 0.32 mmols, 1.0 eq) in DCM (2 mL) was added TFA (0.9 mL) at 0°C and reaction was stirred at RT for 2h. Reaction was monitored by TLC and LCMS. After completion, reaction mixture was concentrated under reduced pressure to afford crude. The crude was purified by reverse phase chromatography to yield desired compound as a formate salt and a white solid (41 mg). LCMS: 368.4 [M+1]+; 1H NMR (400 MHz, DMSO-d6; after D2O addition): δ 8.74 (d, J = 5.9 Hz, 2H), 7.22 (s, 1H), 3.71 (dd, J = 8.5, 4.5 Hz, 1H), 3.24 (dd, J = 13.7, 6.9 Hz, 1H), 3.19-3.04 (m, 3H), 2.78 (s, 3H), 2.21-2.01 (m, 2H), 1.90 (d, J = 11.9 Hz, 2H), 1.81 (d, J = 12.2 Hz, 1H), 1.72-1.58 (m, 1H). Example-45: Synthesis of 5-(5-(3-aminocyclohexylamino)-6-(trifluoromethyl)pyridazin-3- ylamino)pyrazine-2-carbonitrile (Compound No.1.93)
[344] Step-1: Synthesis of 4-(3-(tert-butoxycarbonylamino)cyclohexylamino)-6- chloropyridazine-3-carboxylic acid: To the solution of methyl 4-(3-(tert-
butoxycarbonylamino)cyclohexylamino)-6-chloropyridazine-3-carboxylate (1.2 g, 3.12 mmol, 1 eq) in THF (16 mL) was added lithium hydroxide (262.5 mg, 6.25 mmol, 2 eq) followed by water (4 mL) at ambient temperature. Reaction mixture was stirred at RT for 2h. Reaction was monitored by TLC and LCMS. After completion, reaction mixture was concentrated and citric acid aqueous solution was added till pH ~ 4-5. Ethyl acetate (100 mL) was added and organic phase was washed with water (20 mL) followed by brine wash (20 mL). Organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude. Crude was triturated with pentane and the solid thus precipitated was filtered to afford 980 mg of the desired compound LCMS: 371.1 [M+1]+ [345] Step-2: Synthesis of tert-butyl 3-(6-chloro-3-iodopyridazin-4- ylamino)cyclohexylcarbamate: To the solution of 4-(3-(tert- butoxycarbonylamino)cyclohexylamino)-6-chloropyridazine-3-carboxylic acid (1.1 g, 2.96mmol, 1eq) in ACN (20 mL) was added iodine (2.25 g, 8.89mmol, 3eq) followed by K PO (75 o 3 4 4mg, 3. mmol,1.2eq) at ambient temperature. Reaction mixture was stirred at 90 C for 4h. Reaction was monitored by TLC and LCMS. After completion, reaction mixture was quenched with sodium thiosulphate aqueous solution (20 mL) and extracted with Ethyl acetate (3 × 100 mL). Combined organic phase was washed with water (3 × 20 mL) followed by brine wash (20 mL). Organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude. Crude was purified by combiflash using ethyl acetate: hexane (0-50%) to afford 440 mg of the desired compound. LCMS: 453.1 [M+1]+ [346] Step-3: Synthesis of tert-butyl 3-(6-chloro-3-(trifluoromethyl)pyridazin-4- ylamino)cyclohexylcarbamate: To the solution of tert-butyl 3-(6-chloro-3-iodopyridazin-4- ylamino)cyclohexylcarbamate (420 mg, 0.92mmol, 1eq) in DMF (10 mL) was added 1,10- (Phenanthroline trifluoromethyl) copper (I) (349 mg, 1.1mmol, 1.2eq) at ambient temperature. Reaction mixture was stirred at 90 oC for 5h. Reaction was monitored by TLC and LCMS. After completion Ethyl acetate (200 mL) was added and organic phase was washed with water (3 × 20 mL) followed by brine wash (20 mL). Organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude. Crude was purified by combiflash using ethyl acetate: hexane (0-30%) to afford 260 mg of desired compound. LCMS: 395.2 [M+1]+ [347] Step-4: Synthesis of tert-butyl 3-(6-(5-cyanopyrazin-2-ylamino)-3- (trifluoromethyl)pyridazin-4-ylamino)cyclohexylcarbamate: A solution of tert-butyl 3-(6-
chloro-3-(trifluoromethyl)pyridazin-4-ylamino)cyclohexylcarbamate (230 mg, 0.58mmol, 1.0 eq) and 5-aminopyrazine-2-carbonitrile (60 mg, 0.46mmol , 0.8 eq) in DMF (5 mL) was added Cs2CO3 (570 mg, 1.74 mmol, 3 eq) at RT and the reaction mixture was purged under nitrogen for 10 minutes. Xantphos (33.5mg, 0.05 mmol, 0.1eq) and Pd2dba3 (53.3 mg, 0.05 mmol, 0.1 eq) were added and again nitrogen was purged for 5 minutes. Reaction mixture was stirred at 180 °C for 16h. Reaction was monitored by TLC and LCMS. After completion, reaction mixture was cooled to RT. Ethyl acetate (200 mL) was added and organic phase was washed with water (3 × 20 mL) followed by brine wash (20 mL). Organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude. Crude was triturated with pentane and filtered to afford 210 mg of the desired compound. LCMS: 479.1 [M+1]+ [348] Step-5: Synthesis of 5-(5-(3-aminocyclohexylamino)-6- (trifluoromethyl)pyridazin-3-ylamino)pyrazine-2-carbonitrile: To a solution of tert-butyl 3-(6-(5-cyanopyrazin-2-ylamino)-3-(trifluoromethyl)pyridazin-4- ylamino)cyclohexylcarbamate (200 mg, 0.41mmol, 1.0 eq) in DCM (3 mL) was added TFA (1.2 mL) at 0°C and reaction was stirred at RT for 1h. Reaction was monitored by TLC and LCMS. After completion, reaction mixture was concentrated under reduced pressure to afford crude. The crude was purified by reverse phase chromatography to yield desired compound as a formate salt and a white solid (70 mg). LCMS: 379.2 [M+1]+; 1H NMR (400 MHz, DMSO-d6; after D2O addition): δ 8.88 (d, J = 14.8 Hz, 1H), 8.78 (s, 1H), 8.39 (s, 1H, formate), 7.62 (d, J = 8.4 Hz, 1H), 3.46 (d, J = 10.5 Hz, 1H), 3.20-3.04 (m, 1H), 2.14 (d, J = 11.5 Hz, 1H), 1.89 (d, J = 14.8 Hz, 1H), 1.81 (d, J = 13.2 Hz, 1H), 1.67 (s, 1H), 1.51 (dt, J = 23.0, 10.8 Hz, 2H), 1.39 (q, J = 10.7 Hz, 1H), 1.24 (t, J = 12.5 Hz, 1H). Example-46: Synthesis of 6-(5-cyanopyrazin-2-ylamino)-4-((4-fluoropiperidin-4-yl) methylamino)-N-methylpyridazine-3-carboxamide, (Compound No.1.94)
[349] Step-1: Synthesis of methyl 4-((1-(tert-butoxycarbonyl)-4-fluoropiperidin-4-yl) methyl amino)-6-chloropyridazine-3-carboxylate: To a solution of methyl 4, 6- dichloropyridazine-3-carboxylate (300 mg, 1.44 mmol, 1.0 eq) in THF (15 mL), triethylamine (0.304 mL, 2.17 mmol, 1.5 eq) was added drop wise followed by addition of tert-butyl 4-(amino methyl)-4-fluoropiperidine-1-carboxylate (400 mg, 1.72 mmol, 1.2 eq). The rection mixture was kept for stirring at RT for 16 h. Product formation was confirmed by TLC and LCMS. The reaction mixture was quenched with ice water (10 mL) and extracted with ethyl acetate (3 × 50 mL). Collective organic layer was washed with brine (20 mL) and dried over sodium sulfate and then concentrated under reduced pressure to get the crude. Then the crude was triturated with pentane to get the desired compound as an off-white solid (500 mg). LCMS: 403.5 [M+1]+ [350] Step-2: Synthesis of tert-butyl 4-((6-chloro-3-(methylcarbamoyl) pyridazin-4- ylamino) methyl)-4-fluoropiperidine-1-carboxylate: To a solution of methyl 4-((1-(tert- butoxycarbonyl)-4-fluoropiperidin-4-yl) methyl amino)-6-chloropyridazine-3-carboxylate (500 mg, 1.24 mmol, 1.0 eq) in ACN (15 ml) was added methyl amine (33% solution) (0.346 mL, 3.72 mmol, 3.0 eq) followed by addition of trimethylaluminium (0.357 mL, 2.48 mmol, 2.0eq) and the reaction mixture was kept for stirring at RT for 8 h. Product formation was confirmed by TLC and LCMS. The reaction mixture was quenched with ice water (10 mL) and extracted with ethyl acetate (3 × 50 mL). Collective organic layer was washed with brine (20 mL) and dried over sodium sulfate and then concentrated under reduced pressure to get the crude. Then the crude was triturated with pentane to get the desired compound (270 mg). LCMS: 402.3 [M+1]+ [351] Step-3: Synthesis of tert-butyl 4-((6-(5-cyanopyrazin-2-ylamino)-3- (methylcarbamoyl) pyridazin-4-ylamino) methyl)-4-fluoropiperidine-1-carboxylate: A solution of tert-butyl 4-((6-chloro-3-(methylcarbamoyl) pyridazin-4-ylamino) methyl)-4- fluoropiperidine-1-carboxylate (250 mg, 0.621 mmol, 1.0 eq) and 5-aminopyrazine-2- carbonitrile (74 mg, 0.621 mmol, 1.0 eq) in dioxane (5 mL) was purged with N2 for 5 minutes then Cs2CO3(606 mg, 1.86 mmol, 3.0eq) was added and purged again for 5 minutes. Xantphos (18.0 mg, 0.031mmol, 0.05eq) and Pd2dba3 (10 mg, 0.011 mmol, 0.018 eq) was added and then the vial was closed and kept for heating at 180°C for 16 h. Product formation was confirmed by TLC and LCMS. The reaction mixture was quenched with ice water (20 mL) and extracted with ethyl acetate (3 × 15 mL). Collective organic layer was washed with
brine (20 mL) and dried over sodium sulfate and then concentrated under reduced pressure to get the crude. The crude was purified by combi flash chromatography by using 12g redi sap column and by eluting in 60% EtOAc: Hexane solvent system to get the desired compound (110 mg, light brown solid).LCMS: 486.2 [M+1] + [352] Step-4: Synthesis of 6-(5-cyanopyrazin-2-ylamino)-4-((4-fluoropiperidin-4-yl) methylamino)-N-methylpyridazine-3-carboxamide: To a solution of tert-butyl 4-((6-(5- cyanopyrazin-2-ylamino)-3-(methylcarbamoyl) pyridazin-4-ylamino) methyl)-4- fluoropiperidine-1-carboxylate (110 mg, 0.226 mmol, 1 eq) in DCM (5.0 mL), TFA (0.5 mL) was added at 0 °C and kept for stirring for 2h. Product formation was confirmed by TLC and LCMS. Then the RM was concentrated under reduced pressure to get the crude. The crude was purified by reverse phase chromatography to yield desired compound as a formate salt and a white solid (30 mg). LCMS: 386.5 [M+1]+; 1H NMR (400 MHz, DMSO-d6; after D2O addition) δ 8.88 (s, 1H), 8.79 (s, 1H), 8.35 (s, 1H), 7.54 (s, 1H), 3.50 (d, J = 20.5 Hz, 3H), 3.08 (d, J = 12.5 Hz, 2H), 2.88 (t, J = 12.0 Hz, 2H), 2.79 (s, 3H), 1.98-1.83 (m, 2H), 1.76 (t, J = 13.4 Hz, 1H). Example-47: Synthesis of 4-(3-aminocyclohexylamino)-6-(5-cyanopyrazin-2-ylamino)-N- methylpyridazine-3-carboxamide (Compound No.1.95)
[353] Step-1: Synthesis of methyl 4-(4-(tert-butyldimethylsilyloxy)cyclohexylamino)-6- chloropyridazine-3-carboxylate: To a solution of methyl 4, 6-dichloropyridazine-3- carboxylate (350 mg, 1.690 mmol, 1.0 eq) in THF (15 mL), TEA (0.355 mL, 2.53 mmol, 1.5 eq) was added drop-wise to the reaction mixture then 4-(tert-butyl dimethylsilyloxy) cyclohexanamine (464 mg, 2.08 mmol, 1.2 eq) was added and kept for stirring at 900C for 6 h. Product formation was confirmed by TLC and LCMS. The reaction mixture was quenched with ice water (10 mL) and extracted with ethyl acetate (3 × 50 mL). Collective organic layer was washed with brine (20 mL) and dried over Na2SO4 and then concentrated under reduced pressure to get the crude. Then the crude was triturated with pentane to get the desired compound as an off-white solid (0.325 g). LCMS: 402.3 [M+1]+
[354] Step-2: Synthesis of 4-(4-(tert-butyldimethylsilyloxy) cyclohexylamino)-6-chloro- N-methylpyridazine-3-carboxamide: To a solution of methyl 4-(4-(tert- butyldimethylsilyloxy) cyclohexylamino)-6-chloropyridazine-3-carboxylate (325 mg, 0.814 mmol, 1.0 eq) in THF (10 mL) was added methyl amine (33%) (0.1 mL, 0.98 mmol, 3.0 eq) followed by addition of trimethyl aluminium, 2M solution (0.407 mL,0.814 mmol,1.0equiv) and the reaction mixture was kept for stirring at RT for 8 h. Product formation was confirmed by TLC and LCMS. The reaction mixture was quenched with ice water (10 mL) and extracted with ethyl acetate (3 × 50 mL). Collective organic layer was washed with brine (20 mL) and dried over Na2SO4 and then concentrated under reduced pressure to get the crude. The crude was triturated with pentane to obtain the desired compound (0.300 g). LCMS: 399.3 [M+1]+ [355] Step-3: Synthesis of 4-(4-(tert-butyldimethylsilyloxy) cyclohexylamino)-6-(5- cyanopyrazin-2-ylamino)-N-methylpyridazine-3-carboxamide: A solution of 4-(4-(tert- butyldimethylsilyloxy) cyclohexylamino)-6-chloro-N-methylpyridazine-3-carboxamide (300 mg, 0.753 mmol, 1.0 eq) and 5-aminopyrazine-2-carbonitrile (108 mg, 0.904 mmol, 1.2 eq) in dioxane (5 mL) was purged with N 2 for 5 minutes then Cs 2 CO 3 (0.735 g, 2.59 mmol, 3.0eq) was added and purged again for 5 minutes. Xantphos (21.0 mg, 0.0367 mmol, 0.05eq) and Pd2dba3 (12 mg, 0.0135 mmol, 0.018 eq) was added and then the vial was closed and subjected to microwave irradiation for 45 minutes at 180 °C. Product formation was confirmed by TLC and LCMS. The reaction mixture was quenched with ice water (20 mL) and extracted with ethyl acetate (3 × 15 mL). Collective organic layer was washed with brine (20 mL) and dried over sodium sulfate and then concentrated under reduced pressure to get the crude. The crude was purified by combi flash chromatography by using 12g redi sap column and by eluting in 60% ethyl acetate: hexane solvent system to get the desired compound (110 mg, light brown solid). LCMS: 483.3 [M+1] + [356] Step-4: Synthesis of 4-(3-aminocyclohexylamino)-6-(5-cyanopyrazin-2-ylamino)- N-methylpyridazine-3-carboxamide: To a solution of 4-(4-(tert-butyldimethylsilyloxy) cyclohexylamino)-6-(5-cyanopyrazin-2-ylamino)-N-methylpyridazine-3-carboxamide (110 mg, 0.227 mmol, 1.0 eq) in DCM (5.0 mL), TBAF (0.5 mL) was added at 0°C and kept for stirring for 6 h. Product formation was confirmed by TLC and LCMS. The reaction mixture was concentrated under reduced pressure to get the crude. The crude was purified by reverse phase chromatography to yield desired compound as a formate salt and a white solid (30 mg).
LCMS: 369.4 [M+1]+; 1H NMR (400 MHz, DMSO-d6; after D2O addition) δ 8.96 (s, 1H), 8.77 (s, 1H), 7.34 (s, 1H), 3.50 (s, 1H), 3.28 (s, 1H), 2.76 (s, 3H), 1.97 (d, J = 11.7 Hz, 2H), 1.84 (d, J = 11.6 Hz, 2H), 1.29 (dt, J = 22.9, 11.5 Hz, 4H). BIOLOGICAL EXAMPLES Example-B1: CHK-1 kinase assay [357] IC50 values of compounds for inhibition of CHK-1 kinase or percent inhibition at defined concentrations is determined by Z-LYTETM based TR-FRET assay. Kinase reactions are performed in a 10 μL volume in low-volume 384-well plates. The concentration of substrate (Ser Thr 19) is maintained at 2 μM in the assay, and the kinase reaction buffer consisted of 50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl2, 1 mM EGTA, 2 mM DTT. Incubate the serially diluted compounds (3-fold) in DMSO (0.5 % in final reaction) with cocktail of CHK-1 kinase (5 ng/ml; Cat # P3040, ThermoFisher), substrate Ser Thr 19, (2 µM; Cat # PV4529, ThermoFisher), ATP (53 μM; Cat # PV3227, ThermoFisher) and buffer. Allow the Kinase reactions to proceed for 1 hour at room temperature after which5 μL of a 1:256 dilution of Development Reagent A is added. Incubate the plate at room temperature for 60 minutes and read on a BMG Pherastar plate reader using the Z-LYTE™ filter block for Z-LYTE™ TR-FRET. [358] The resulting TR-FRET emission ratio is used to calculate percent inhibition by normalizing with the control using the following formula:- [% Inhibition = 1-{(% Phosphorylation sample / % Phosphorylation control (0% Inhibition)} * 100] [359] For calculation of IC50, the percent inhibition obtained is plotted against the concentration of inhibitor, and the data is fit to a sigmoidal dose-response curve with a variable slope. The IC50 is calculated from the curve. [360] The results of % inhibition of CHK1 enzyme at 30 nM and 300nM and the IC50 of CHK1 are given in the table-B1
Table-B1
*NA=Not Available Example-B2: PASMC Cell Viability Assay [361] PASMC (PCS-100-023™), Primary pulmonary artery smooth muscle cells, were seeded in the medium (Vascular cell basal medium, Cat # ATCC-PCS-100-030 with Vascular smooth muscle cell growth kit, Cat # ATCC-PCS-100-042) at a cell count of 3000 cells per 100 μl per well in a 96 well edge plate (167425; ThermoFisher). Cells were allowed to grow at 37°C for 24 hr in 5% CO2 (culture conditions) in a Nuaire incubator (humidified). Serially diluted compounds (100 μl) were added to the culture plate 24 hr later and the cultures (PASMC) were further incubated in culture conditions for 72 hr. Experiment was terminated at the completion of 72 hr exposure to the drug by replacing the medium with 100 μl of 1 mM of resazurin (R7017; Sigma) prepared in culture medium and the plates were further incubated in culture conditions for 4 hr. Fluorescence was then measured using a multimodal plate reader (Biotek Synergy Neo) at an excitation wavelength of 535 nm and emission wavelength of 590 nm to obtain relative fluorescence units. Data analysis was done by subtracting the background fluorescence (only medium blank) value from each reading and then normalizing with the vehicle control (DMSO treated cells) to obtain percent survival/proliferation. Percent survival at different doses was used to calculate IC50 by fitting the curve to the “four-parameter variable slope logistic model” using Prism Graph Pad. [362] The results of PASMC cell viability assay are provided in the table-B2. Table-B2
Example-B3: CHK-2 Kinase Assay [363] IC50 values of compounds for inhibition of CHK-2 kinase or percent inhibition at defined concentrations is determined by Z-LYTETM based TR-FRET assay. Kinase reactions are performed in a 10 μL volume in low-volume 384-well plates. The concentration of substrate (Ser Thr 07) is maintained at 1 μM in the assay, and the kinase reaction buffer consisted of 50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl2, 1 mM EGTA. Incubate the serially diluted compounds (3-fold) in DMSO (0.5 % in final reaction) with cocktail of CHK2 kinase (5 ng/ml; Cat # PV3367, ThermoFisher), substrate Ser Thr 07, (1 µM; Cat # PV3208, ThermoFisher), ATP (84 μM; Cat # PV3227, ThermoFisher) and buffer. Allow the Kinase reactions to proceed for 1 hour at room temperature after which 5 μL of a 1:45000 dilution of Development Reagent A is added. Incubate the plate at room temperature for 60 minutes and read on a BMG Pherastar plate reader using the Z-LYTE™ filter block for Z- LYTE™ TR-FRET. [364] The resulting TR-FRET emission ratio is used to calculate percent inhibition by normalizing with the control using the following formula:- [% Inhibition = 1-{(% Phosphorylation sample / % Phosphorylation control (0% Inhibition)} * 100]
[365] For calculation of IC50, the percent inhibition obtained is plotted against the concentration of inhibitor, and the data was fit to a sigmoidal dose-response curve with a variable slope. The IC50 is calculated from the curve. [366] It is understood that the foregoing examples and embodiments described above are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and the scope of the appended claims.
Claims
I/We Claim:
1. A compound of formula (J):
wherein, X1 and X2 are independently N or CRX; provided that at least one of X1 and X2 is N; each Rx is independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, -CN, halogen, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6haloalkyl, -OR7 , - NR8R9, -C(O)R7, -NR7C(O)R8, -C(O)OR7 or -C(O)NR8R9, each of which is optionally substituted by oxo, halogen, CN, -OR10 or -NRnR12;
L is NH or O;
Q is C or D;
C is 7- to 12-membered monocyclic or bicyclic heterocyclyl, C3-C10 monocyclic or bicyclic cycloalkyl or -(C1-C3 alkylene)C7-C10 cycloalkyl, wherein each of C is optionally substituted by one or more R4;
D is -(C1-C3 alkylene)3- to 6-membered heterocyclyl optionally substituted by one or more R4 ;
A is R1 or R1a;
R1 is independently 5 -membered heteroaryl, 3- to 6-membered heterocyclyl or - 2 3
C(O)NR R , wherein 5-membered heteroaryl and 3- to 6-membered heterocyclyl optionally substituted by R5;
R1a is independently -C(O)NR2R3, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, C6, aryl, 5- to 10-membered heteroaryl, -CN, halogen, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6haloalkyl, -OR13, -SR13, -S(O)2R13 , -S(O)2NR14R15, -NR13S(O)2R14, -NR14R15,
-C(O)R13, -NR13C(O)R14, -NR13C(O)NR14R15, -C(O)OR13, -C(O)ONR14R15, -(C1- C3 alkylene)OR13, -(C1-C3 alkylene)SR13, -(C1-C3 alkylene)S(O)2R13, -(C1- C3 alkylene)S(O)2NR14R15, -(C1-C3 alkylene)NR13S(O)2R14, -(C1-C3 alkylene)NR14R15, -(C1- C3 alkylene)C(O)R13, -(C1-C3 alkylene)NR13C(O)R14, -(C1-
C3 alkylene)NR13C(O)NR14R15, -(C1-C3 alkylene)C(O)OR13, -(C1- C3 alkylene)C(O)ONR14R15, -(C1-C3 alkylene)(C3-C8 cycloalkyl) or -(C1-C3 alkylene) (3 -10- membered heterocyclyl); wherein each of R1a is optionally substituted by R5;
R and R are independently hydrogen, -CD3, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, C6, aryl, 5- to 6-membered heteroaryl, , C1-C6haloalkyl, -C(O)R13, -(C1-C3 alkylene)OR13, -(C1-C3 alkylene)SR13, -(C1- C3 alkylene)S(O)2R13, -(C1-C3 alkylene)S(O)2NR14R15, -(C1-C3 alkylene)NR13S(O)2R14, -(C1- C3 alkylene)NR14R15, -(C1-C3 alkylene)C(O)R13, -(C1-C3 alkylene)NR13C(O)R14, -(C1- C3 alkylene)NR13C(O)NR14R15, -(C1-C3 alkylene)C(O)OR13, -(C1- C3 alkylene)C(O)ONR14R15, -(C1-C3 alkylene)(C3-C8 cycloalkyl), -(C1-C3 alkylene) (3 -10- membered heterocyclyl), -(C1-C3 alkylene)C6 aryl or -(C1-C3 alkylene) 5- to 6-membered heteroaryl, wherein each of R2 and R3 are independently optionally substituted by R ; or R2 and R3 are taken together with the atom to which they attached to form a 3- to 6- membered heterocyclyl optionally substituted by R5;
R4 is oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -CN, halogen, C1-C6 alkoxy, C1-C6 haloalkoxy, -OR16, -SR16, -S(O)2R16 , -S(O)2NR17R18, -NR16S(O)2R17, -NR17R18, -C(O)R16, -NR16C(O)R17, -C(O)OR16, wherein each of R4 is optionally substituted by oxo, - OH, halogen or -NH2;
R5 is oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -CN, halogen, C1- C6haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OR16, -SR16, -S(O)2R16
, -S(O)2NR17R18, -NR16S(O)2R17, -NR17R18, -C(O)R16, -NR16C(O)R17, -C(O)OR16, C3-C6 cycloalkyl, C6, aryl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocyclyl, wherein each of R5 is optionally substituted by oxo, -OH, halogen or -NH2;
7 8 9 each R , R andR is independently hydrogen or C1-C6 alkyl optionally substituted by oxo, -OH, halogen or -NH2; each R10, R11 and R1' ’ is independently hydrogen, C1-C6 alkyl or C3-C8 cycloalkyl; or R11 and R12 ' are taken together with the atom to which they attached to form a 3- to 6- membered heterocyclyl; each R13, R14andR15 is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, C6 aryl, 5- to 6- membered heteroaryl, -(C1-C3 alkylene)C3-C6 cycloalkyl, -(C1-C3 alkylene)3- to 6-membered heterocyclyl, or -(C1-C3 alkylene)5- to 6-membered heteroaryl, wherein each of R13, R14 and R15 is independently optionally substituted by oxo, C2-C6 alkenyl, C2-C6 alkynyl, -CN, halogen, C1-C6 alkoxy, C1-C6 haloalkoxy, -OR16, -SR16, -S(O)2R16
, -S(O)2NR17R18, -NR16S(O)2R17, -NR17R18, -C(0)R16, -NR16C(O)R17, -C(0)0R16 or C1-C6 alkyl optionally substituted by oxo, -OH, halogen or -NH2; or R14 and R15 are taken together with the atom to which they attached to form a 3- to 6- membered heterocyclyl optionally substituted by oxo, OH or halogen, or C1-C6 alkyl optionally substituted by oxo, -OH, halogen or -NH2; each R16, R17 and R18 ’ is independently hydrogen, C2-C6 alkenyl, C2-C6 alkynyl, C6 aryl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocyclyl, C3-C6 cycloalkyl or C1-C6 alkyl optionally substituted by oxo, -OH, halogen or -NH2; and or R17 and R18 are taken together with the atom to which they attached to form a 3- to 6- membered heterocyclyl optionally substituted by oxo, -OH, halogen or -NH2, or C1-C6 alkyl optionally substituted by oxo, -OH, halogen or -NH2; provided that:
[367] when Q is C then L is -O- or -NH- and A is R1a; or
[368] when Q is D then L is -NH- and A is R1;
[369] when Q is D, L is -NH- and A is R1 then:
(ii) the compound is not selected from:
6-(5-cyanopyrazin-2-ylamino)-4-(piperidin-4-ylmethylamino)pyridazine-3- c arboxamide;
6-(5-cyanopyrazin-2-ylamino)-N-methyl-4-((l-methylpiperidin-4- yl)methylamino)pyridazine-3-carboxamide;
6-(5-cyanopyrazin-2-ylamino)-4-((tetrahydro-2H-pyran-4- yl)methylamino)pyridazine-3-carboxamide;
6-(5-cyanopyrazin-2-ylamino)-N-methyl-4-((tetrahydro-2H-pyran-4- yl)methylamino)pyridazine-3-carboxamide;
6-(5-cyanopyrazin-2-ylamino)-N,N-dimethyl-4-(piperidin-4- ylmethylamino)pyridazine -3 -c arboxamide ;
6-(6-cyanopyridin-3-ylamino)-N-methyl-4-(morpholin-2-ylmethylamino)pyridazine- 3 -carboxamide;
6-(5-cyanopyrazin-2-ylamino)-N-(3,3-difluorocyclobutyl)-4-(piperidin-4- ylmethylamino)pyridazine -3 -c arboxamide ;
6-(5-cyanopyrazin-2-ylamino)-4-(piperidin-4-ylmethylamino)-N- (trifluoromethyl)pyridazine-3-carboxamide;
6-(5-cyanopyrazin-2-ylamino)-4-(piperidin-4-ylmethylamino)-N-(2,2,2- trifluoroethyl)pyridazine-3 -carboxamide ;
6-(5-cyanopyrazin-2-ylamino)-N-methyl-4-((4-methylmorpholin-2- yl)methylamino)pyridazine-3-carboxamide;
6-(5-cyanopyrazin-2-ylamino)-N,N-dimethyl-4-((4-methylmorpholin-2- yl)methylamino)pyridazine-3-carboxamide;
6-(5-cyanopyridin-2-ylamino)-N-methyl-4-(morpholin-2-ylmethylamino)pyridazine- 3 -carboxamide;
(R)-6-(6-cyanopyridin-3-ylamino)-N-methyl-4-(morpholin-2- ylmethylamino)pyridazine -3 -c arboxamide ;
(S)-6-(6-cyanopyridin-3-ylamino)-N-methyl-4-(morpholin-2- ylmethylamino)pyridazine-3-carboxamide;
(R)-6-(5-cyanopyridin-2-ylamino)-N-methyl-4-(morpholin-2- ylmethylamino)pyridazine -3 -c arboxamide ;
(S)-6-(5-cyanopyridin-2-ylamino)-N-methyl-4-(morpholin-2- ylmethylamino)pyridazine -3 -c arboxamide ;
6-(5-cyanopyrazin-2-ylamino)-N-methyl-4-(piperidin-3-ylmethylamino)pyridazine-3- carboxamide;
(R)-6-(5-cyanopyrazin-2-ylamino)-N-methyl-4-(piperidin-3- ylmethylamino)pyridazine -3 -c arboxamide ;
(S)-6-(5-cyanopyrazin-2-ylamino)-N-methyl-4-(piperidin-3- ylmethylamino)pyridazine -3 -c arboxamide ;
6-(5-cyanopyrazin-2-ylamino)-4-((2,6-dimethylpiperidin-3-yl)methylamino)-N- methylpyridazine-3-carboxamide;
6-(5-cyanopyrazin-2-ylamino)-N-methyl-4-(pyrrolidin-3-ylmethylamino)pyridazine- 3 -carboxamide;
5-(6-(l-methyl-lH-pyrazol-3-yl)-5-(piperidin-4-ylmethylamino)pyridazin-3- ylamino)pyrazine-2-carbonitrile;
5-(6-(lH-imidazol-2-yl)-5-(piperidin-4-ylmethylamino)pyridazin-3- ylamino)pyrazine-2-carbonitrile;
5-(6-( 1 H-imidazol-2-yl) -5 -((1 -methylpiperidin-4-yl)methylamino)pyridazin-3 - ylamino)pyrazine-2-carbonitrile; or
5-(6-(azetidin-l-yl)-5-(piperidin-4-ylmethylamino)pyridazin-3-ylamino)pyrazine-2- carbonitrile.
2. The compound of claim 1, wherein X1 and X1 are selected from:
(a) X1 is N and X2 is CRX;
(b) X1 is CRX and X2 is N; and
(c) X1 and X2 both are N.
3. The compound of claim 1, wherein Rx is hydrogen.
4. The compound of claim 1, wherein L is selected from the group consisting of NH and O.
5. The compound of claim 1, wherein C is 7- to 12-membered monocyclic or bicyclic heterocyclyl, C3-C10 monocyclic or bicyclic cycloalkyl or -(C1-C3 alkylene)C7-C10 cycloalkyl, wherein each of C is optionally substituted by one or more R4.
6. The compound of claim 5, wherein C is selected from the group consisting of azepanyl, decahydroquinoline, decahydroisoquinoline, octahydro -IH-indole, octahydrocyclopenta[b]pyrrole, octahydro-lH-cyclopenta[b]pyridine, octahydro- 1H- cyclopenta[b]pyridine, octahydro- lH-cyclopenta[b]pyridine, octahydro- 1H- cyclopenta[c]pyridine, octahydro- lH-cyclopenta[c]pyridine, octahydrocyclopenta[b]pyrrole, octahydrocyclopenta[c]pyrrole, 2-azabicyclo[3.2.0]heptane, 2-azabicyclo[4.2.0]octane, 3- azabicyclo[4.2.0]octane, 2-azaspiro[3.3]heptane, l-azaspiro[3.3]heptane, 5- azaspiro[3.4]octane, 6-azaspiro[3.4]octane, 5-azaspiro[3.5]nonane, 6-azaspiro[3.5]nonane, 7- azaspiro[3.5]nonane, 2-azaspiro[3.4]octane, 1 -azaspiro [3.4] octane, l-azaspiro[4.4]nonane, 2- azaspiro[4.4]nonane, 6-azaspiro[4.5]decane, 7-azaspiro[4.5]decane, 8-azaspiro[4.5]decane, 2- azaspiro[3.5]nonane, l-azaspiro[3.5]nonane, l-azaspiro[4.5]decane, 2-azaspiro[4.5]decane, l-azaspiro[5.5]undecane, 2-azaspiro[5.5]undecane, 3-azaspiro[5.5]undecane, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[l.l.l]pentyl, decahydronaphthalene, octahydro- IH-indene, octahydropentalene, -CH2-(bicyclo[3.1.1]heptane) and -CH2-((1R,5S)- bicyclo [3.2.1] octane), wherein each of C is optionally substituted by one or more R4..
8. The compound of claim 1, wherein D is -(C1-C3 alkylene)3- to 6-membered heterocyclyl optionally substituted by one or more R4. 9. The compound of claim 8, wherein D is selected from the group consisting of
10. The compound of claim 1, wherein R1 is independently 5-membered heteroaryl, 3- to 6-membered heterocyclyl or -C(O)NR2R3 , wherein 5-membered heteroaryl and 3- to 6- membered heterocyclyl optionally substituted by R5.
12. The compound of claim 1, wherein R1a is independently -C(O)NR2R3, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, C6, aryl, 5- to 10-membered heteroaryl, -CN, halogen, C1-C6 alkoxy, C1-C6 haloalkoxy, C1- C6haloalkyl, -OR13, -SR13, -S(O)2R13 , -S(O)2NR14R15, -NR13S(O)2R14, -NR14R15, -C(O)R13, -NR13C(O)R14, -NR13C(O)NR14R15, -C(O)OR13, -C(O)ONR14R15, -(C1- C3 alkylene)OR13, -(C1-C3 alkylene)SR13, -(C1-C3 alkylene)S(O)2R13, -(C1- C3 alkylene)S(O)2NR14R15, -(C1-C3 alkylene)NR13S(O)2R14, -(C1-C3 alkylene)NR14R15, -(C1- C3 alkylene)C(O)R13, -(C1-C3 alkylene)NR13C(O)R14, -(C1-
C3 alkylene)NR13C(O)NR14R15, -(C1-C3 alkylene)C(O)OR13, -(C1- C3 alkylene)C(O)ONR14R15, -(C1-C3 alkylene)(C3-C8 cycloalkyl) or -(C1-C3 alkylene) (3 -10- membered heterocyclyl); wherein each of R1a is optionally substituted by R5.
10 15. The compound of claim 1, wherein the compound is a compound of formula (IA):
16. The compound of claim 1, wherein the compound is any of the compound of formula (IA-1 to IA-10):
17. The compound of claim 1, wherein the compound is a compound of formula (IB):
wherein X X2, C, L, R2, R3 and Rx are as defined in claim 1.
18. The compound of claim 1, wherein the compound is any of the compound of formula (IA-1 to IA-10):
199
19. The compound of claim 1, wherein the compound is a compound of formula (II):
wherein Xb X2R1, R4 and Rx are as defined in claim 1.
20. The compound of claim 1, wherein the compound is any of the compound of formula (Il-a) to (II-c):
wherein R1, R4 and Rx are as defined in claim 1.
21. The compound of claim 1, wherein the compound is a compound of formula (III):
wherein Xi, X2, D, R1, R4 and Rx are as defined in claim 1. 22. The compound of claim 1, wherein the compound is any of the compound of formula (Ill-a) to (III-c):
wherein R1, R4 and Rx are as defined in claim 1.
23. The compound of claim 1, wherein the compound is a compound of formula (IV):
wherein X X2, D, R2, R3 and Rx are as defined in claim 1.
24. The compound of claim 1, wherein the compound is any of the compound of formula (IV-a) to (IV-c):
wherein D, R2, R3 and Rx are as defined in claim 1.
25. The compound of claim 1, wherein the compound is a compound of formula (V):
wherein Xi, X2, R2, R3, R4 and Rx are as defined in claim 1.
26. The compound of claim 1, wherein the compound is any of the compound of formula of formula (V-a) to (V-f):
wherein R2, R3, R4 and Rx are as defined in claim 1.
27. The compound of claim 1, wherein the compound is a compound of formula (VI):
28. The compound of claim 1, wherein the compound is any of the compound of formula of formula (Vl-a) to (Vl-f):
29. The The compound of claim 1, wherein the compound is a compound of formula
30. The compound of claim 1, wherein the compound is any of the compound of formula of formula (Vll-a) to (Vll-f):
31. The compound of claim 1, wherein the compound is a compound of formula
32. The compound of claim 1, wherein the compound is any of the compound of formula of formula (Vlll-a) to (Vlll-f):
wherein R2, R3, R4 and Rx are as defined in claim 1.
33. The compound of claim 1, wherein the compound is selected from Compound
Nos. 1.1 to 1.354 in table- 1 or a salt thereof.
34. The compound of any one of claims 1 to 33, being used for manufacture of a medicament for treatment of a disorder characterized by excessive level of Checkpoint kinase-1 (CHK-1).
35. A method of treating disease associated with Checkpoint kinase-1 (CHK-1) in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a compound of any one of claims 1 to 33.
36. A method of treating cancer in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a compound of any one of claims Ito 33.
37. A method of inhibiting Checkpoint kinase- 1 (CHK-1) in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a compound of any one of claims 1 to 33.
38. A method of treating Idiopathic Pulmonary Fibrosis (IPF) in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a compound of any one of claims 1 to 33.
39. A method of treating Pulmonary Arterial Hypertension (PAH) in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a compound of any one of claims 1 to 33.
40. A method of treating cancer, IPF or PAH in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a compound of any one of claims 1 to 33 in combination with another therapeutic agent.
41. A pharmaceutical composition comprising a compound of any one of claims 1 to 33 and a pharmaceutically acceptable carrier.
42. A method of treating disease associated with Checkpoint kinase-1 (CHK-1) in an individual in need thereof comprising administering to the individual the pharmaceutical composition of claim 39.
43. Use of a compound of any one of claims 1 to 33, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for treatment of a disease mediated by Checkpoint kinase-1 (CHK-1).
44. A kit comprising a compound of any one of claims 1 to 33.
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Citations (2)
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WO2018086546A1 (en) * | 2016-11-10 | 2018-05-17 | 浙江大学 | 2-polysubstituted aromatic ring-pyrimidine derivative and preparation and medical use |
CN111253370A (en) * | 2020-03-24 | 2020-06-09 | 浙江大学 | N-polysubstituted pyridine-2-aminopyrimidine derivatives and application thereof |
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2022
- 2022-01-28 WO PCT/IB2022/050756 patent/WO2022162606A1/en active Application Filing
- 2022-01-28 EP EP22745480.8A patent/EP4298095A1/en active Pending
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WO2018086546A1 (en) * | 2016-11-10 | 2018-05-17 | 浙江大学 | 2-polysubstituted aromatic ring-pyrimidine derivative and preparation and medical use |
CN111253370A (en) * | 2020-03-24 | 2020-06-09 | 浙江大学 | N-polysubstituted pyridine-2-aminopyrimidine derivatives and application thereof |
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