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NZ761374B2 - Heterocyclic inhibitors of atr kinase - Google Patents
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NZ761374B2 - Heterocyclic inhibitors of atr kinase - Google Patents

Heterocyclic inhibitors of atr kinase

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Publication number
NZ761374B2
NZ761374B2 NZ761374A NZ76137418A NZ761374B2 NZ 761374 B2 NZ761374 B2 NZ 761374B2 NZ 761374 A NZ761374 A NZ 761374A NZ 76137418 A NZ76137418 A NZ 76137418A NZ 761374 B2 NZ761374 B2 NZ 761374B2
Authority
NZ
New Zealand
Prior art keywords
recited
chosen
compound
salt
alkyl
Prior art date
Application number
NZ761374A
Other versions
NZ761374A (en
Inventor
Christopher Lawrence Carroll
Jason Bryant Cross
Francesco Maria Emilia Di
Michael Garrett Johnson
Philip Jones
David Lapointe
Sarah Lively
Suyambu Kesava Vijayan Ramaswamy
Original Assignee
Board Of Regents The University Of Texas System
Chempartner Corporation
Filing date
Publication date
Application filed by Board Of Regents The University Of Texas System, Chempartner Corporation filed Critical Board Of Regents The University Of Texas System
Priority claimed from PCT/US2018/042128 external-priority patent/WO2019014618A1/en
Publication of NZ761374A publication Critical patent/NZ761374A/en
Publication of NZ761374B2 publication Critical patent/NZ761374B2/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D411/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D411/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Abstract

The present disclosure relates to heterocyclic compounds and methods which may be useful as inhibitors of ATR kinase for the treatment or prevention of cancer. Ataxia-telangiectasia and Rad3-related kinase (ATR) is a member of the phosphatidylinositol 3-kinas-related protein kinase (PIKK) family, which also includes ataxia telangiectasia mutated (ATM) kinase, DNA-dependent protein kinase (DNA-PK), suppressor of morphogenesis in genitalia-1 (SMG-1), mammalian target of rapamycin (mTOR) and transformation / transcription associated protein (TRAPP). ATR and ATM are key regulators of the cellular DNA damage response (DDR) pathways, and are involved in maintaining the genome integrity in response to DNA-damage. Several distinct types of DNA lesions can occur as a consequence of diverse damaging events, including errors in normal replication processing, exposure to ionizing radiations (IR) and genotoxic agents, and different mechanisms of DNA repair have evolved to resolve specific kinds of DNA damage. The present invention provides compounds which have been found to inhibit ATR kinase, together with methods of synthesizing and using the compounds, including pharmaceutical compositions comprising the compounds and methods for the treatment of ATR kinase-mediated diseases, including cancers, in a patient by administering the compounds.

Claims (97)

1. A compound of structural Formula (II): or a salt thereof, wherein: R and R are independently chosen from C alkyl, C haloalkyl, C cycloalkyl, C 1-4 1-4 3-6 3-6 heterocycloalkyl, C aryl, and 5-10 membered heteroaryl, any of which is optionally 5 1 2 substituted with one or more R groups, or R and R , together with the sulfur to which they are both attached, form a 4, 5, 6, or 7-membered heterocycloalkyl ring which is optionally substituted with one or more R groups; R is chosen from C alkyl, and C haloalkyl; 1-6 1-6 R is chosen from C aryl or 5-10 membered heteroaryl, either of which is optionally substituted with one or more R groups; 5 8 9 each R is independently chosen from NR R , halogen, cyano, hydroxy, oxo, alkyl, haloalkyl, C cycloalkyl, 3-6 membered heterocycloalkyl, hydroxyalkyl, OR , 7 8 7 8 7 8 9 8 8 8 9 NR C(O)R , NR C(O)OR , NR C(O)NR R , C(O)R , C(O)OR , and C(O)NR R ; 6 11 12 each R is independently chosen from NR R , halogen, cyano, hydroxy, oxo, alkyl, haloalkyl, C cycloalkyl, 3-6 membered heterocycloalkyl, hydroxyalkyl, OR , 10 11 10 11 10 11 12 11 11 NR C(O)R , NR C(O)OR , NR C(O)NR R , C(O)R , C(O)OR , and 11 12 C(O)NR R ; 7 8 9 each R , R and R is independently chosen from hydrogen, C1-4alkyl, C3-6cycloalkyl, and 3-6 membered heterocycloalkyl, any of which is optionally substituted with halo, 7 8 9 hydroxy, C1-3alkyl, C1-3haloalkyl and C1-3alkoxy; or any two of R , R and R , together with the atom to which they are both attached can form a 3-7 membered cycloalkyl or heterocycloalkyl ring; and 10 11 12 each R , R and R is independently chosen from hydrogen, C alkyl, C 1-4 3- cycloalkyl, 3-6 membered heterocycloalkyl, any of which is optionally substituted with 10 11 one or more groups chosen from halo, hydroxy and alkoxy; or any two of R , R and R , together with the atom to which they are both attached, can form a 3-7 membered cycloalkyl or heterocycloalkyl ring.
2. The compound as recited in claim 1, or a salt thereof, wherein R is C1-6alkyl.
3. The compound as recited in claim 1, or a salt thereof, wherein R is chosen from methyl, fluoromethyl, difluoromethyl, and trifluoromethyl.
4. The compound as recited in any one of claims 1-3, or a salt thereof, wherein R is 5-10 membered heteroaryl and is optionally substituted with one or more R groups.
5. The compound as recited in claim 4, or a salt thereof, wherein R is chosen from indole, pyrrolopyridine, pyrazolopyridine, imidazopyridine, pyrrolopyrazine, pyrazolopyrazine, pyrrolopyrimidine, pyrazolopyrimidine, imidazolopyrimidine, pyrrolopyridazine, pyrazolopyridazine, and imidazolopyridazine, any of which is optionally substituted with one or more R groups.
6. The compound as recited in claim 4, or a salt thereof, wherein R is chosen from 1H- pyrazolyl, 1H-pyrazolyl, 1H-pyrazolyl, 1H-imidazolyl, 1H-imidazolyl, 1H- imidazolyl, pyridinyl, pyridinyl, pyrimidinyl, 1H-indolyl, 1H-indol yl,1H-indazolyl,1H-indazolyl, 1H-benzo[d]imidazolyl, 1H-benzo[d]imidazol yl,1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, pyrazolo[1,5-a]pyridin- 3-yl, imidazo[1,2-a]pyridinyl, imidazo[1,2-a]pyridinyl, 1H-imidazo[4,5-c]pyridin- 1-yl, 7H-pyrrolo[2,3-d]pyrimidinyl,1H-pyrazolo[3,4-b]pyridinyl, 3H-imidazo[4,5- b]pyridinyl, and 1H-benzo[d][1,2,3]triazolyl, any of which is optionally substituted with one or two R groups.
7. The compound as recited in claim 4, or a salt thereof, wherein R is pyridinyl and is optionally substituted with one or more R groups.
8. The compound as recited in claim 7, or a salt thereof, wherein R is unsubstituted pyridinyl.
9. The compound as recited in claim 7, or a salt thereof, wherein R is pyridinyl and is substituted with one R group.
10. The compound as recited in claim 7, or a salt thereof, wherein R is pyridinyl and is substituted with two R groups.
11. The compound as recited in any one of claims 7-10, or a salt thereof, wherein said pyridinyl is pyridinyl,.
12. The compound as recited in any one of claims 1-6, wherein each R is independently 11 12 11 10 11 chosen from NR R , halogen, cyano, hydroxy, oxo, OR , NR C(O)R , 10 11 10 11 12 11 11 11 12 NR C(O)OR , NR C(O)NR R , C(O)R , C(O)OR , and C(O)NR R .
13. The compound as recited in any one of claims 1-12, or a salt thereof, wherein each R is 8 8 8 9 independently chosen from C(O)R , C(O)OR , and C(O)NR R .
14. The compound as recited in any one of claims 1-13, or a salt thereof, wherein R and R are, independently, optionally substituted with one or two R groups.
15. The compound as recited in claim 14, or a salt thereof, wherein R and R are independently chosen from C alkyl, C haloalkyl, C cycloalkyl, and 3-6 membered 1-4 1-4 3-6 heterocycloalkyl and are optionally substituted with one or two R groups.
16. The compound as recited in claim 15, or a salt thereof, wherein R and R are independently chosen from C alkyl, C cycloalkyl, and 3-6 membered heterocycloalkyl. 1-4 3-6
17. The compound as recited in claim 16, or a salt thereof, wherein R is chosen from pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-c]pyridinyl, 1H-benzo[d]imidazolyl, any of which is optionally substituted with one or two R groups.
18. The compound as recited in claim 17, or a salt thereof, wherein R is chosen from 1H- benzo[d]imidazolyl and 1H-pyrrolo[2,3-b]pyridinyl, either of which is optionally substituted with one or two R groups.
19. The compound as recited in any one of claims 1-18, or a salt thereof, wherein R is methyl.
20. The compound as recited in any one of claims 1-19, or a salt thereof, wherein R and R are independently chosen from methyl, cyclopropyl, and oxetanyl.
21. The compound as recited in any one of claims 1-19, or a salt thereof, wherein R and R , together with the sulfur to which they are both attached, form a thiomorpholine ring 5 8 8 which is optionally substituted with one or two R groups chosen from C(O)R , C(O)OR , and C(O)NR R .
22. The compound as recited in claim 21, or a salt thereof, wherein R and R , together with the sulfur to which they are both attached, form a thiomorpholine ring which is 5 8 8 substituted on the nitrogen with an R group chosen from C(O)R and C(O)OR .
23. A compound of structural Formula (IV): or a salt thereof, wherein: X is chosen from N and CR ; Y is chosen from N and CR ; R and R are independently chosen from C alkyl, C haloalkyl, C cycloalkyl, C 1-4 1-4 3-6 3-6 heterocycloalkyl, C aryl,and heteroaryl, any of which is optionally substituted with one 5 1 2 or more R groups, or R and R , together with the sulfur to which they are both attached, form a 4, 5, 6, or 7-membered heterocycloalkyl ring which is optionally substituted with one or more R groups; R is chosen from C alkyl, and C haloalkyl; 1-6 1-6 5 8 9 each R is independently chosen from NR R , halogen, cyano, hydroxy, oxo, alkyl, haloalkyl, C cycloalkyl, 3-6 membered heterocycloalkyl, hydroxyalkyl, OR , 7 8 7 8 7 8 9 8 8 8 9 NR C(O)R , NR C(O)OR , NR C(O)NR R , C(O)R , C(O)OR , and C(O)NR R ; 6a 6b 11 12 R and R are independently chosen from H, NR R , halogen, cyano, hydroxy, oxo, alkyl, haloalkyl, C cycloalkyl, 3-6 membered heterocycloalkyl, hydroxyalkyl, 11 10 11 10 11 10 11 12 11 11 OR , NR C(O)R , NR C(O)OR , NR C(O)NR R , C(O)R , C(O)OR , and 11 12 C(O)NR R , 6a 6b or R and R , together with the intervening atoms, combine to form a heteroaryl ring, which is optionally substituted with one or more R groups; 6c 6d 11 12 each R and R is independently chosen from H, NR R , halogen, cyano, hydroxy, oxo, alkyl, haloalkyl, C cycloalkyl, 3-6 membered heterocycloalkyl, hydroxyalkyl, 11 10 11 10 11 10 11 12 11 11 OR , NR C(O)R , NR C(O)OR , NR C(O)NR R , C(O)R , C(O)OR , and 11 12 C(O)NR R ; 6 11 12 R is chosen from NR R , halogen, cyano, hydroxy, oxo, alkyl, haloalkyl, C3- 11 10 11 cycloalkyl, 3-6 membered heterocycloalkyl, hydroxyalkyl, OR , NR C(O)R , 10 11 10 11 12 11 11 11 12 NR C(O)OR , NR C(O)NR R , C(O)R , C(O)OR , and C(O)NR R ; 7 8 9 each R , R and R is independently chosen from hydrogen, C alkyl, C cycloalkyl, 1-4 3-6 and 3-6 membered heterocycloalkyl, any of which is optionally substituted with halo, 7 8 9 hydroxy, C alkyl, C haloalkyl, and C alkoxy; or any two of R , R and R , together 1-3 1-3 1-3 with the atom to which they are both attached can form a 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl ring; and 10 11 12 each R , R and R is independently chosen from hydrogen, C alkyl, C 1-4 3- 6cycloalkyl, and 3-6 membered heterocycloalkyl, any of which is optionally substituted 10 11 with one or more groups chosen from halo, hydroxy and alkoxy; or any two of R , R and R , together with the atom to which they are both attached, can form a 3-7 membered cycloalkyl or heterocycloalkyl ring.
24. A compound of structural Formula (IVa): (IVa) or a salt thereof, wherein: X is chosen from N and CR ; Y is chosen from N and CR ; R and R are independently chosen from C alkyl, C haloalkyl, C cycloalkyl, C 1-4 1-4 3-6 3-6 heterocycloalkyl, C aryl,and heteroaryl, any of which is optionally substituted with one 5 1 2 or more R groups, or R and R , together with the sulfur to which they are both attached, form a 4, 5, 6, or 7-membered heterocycloalkyl ring which is optionally substituted with one or more R groups; R is chosen from C alkyl, and C haloalkyl; 1-6 1-6 5 8 9 each R is independently chosen from NR R , halogen, cyano, hydroxy, oxo, alkyl, haloalkyl, C cycloalkyl, 3-6 membered heterocycloalkyl, hydroxyalkyl, OR , 7 8 7 8 7 8 9 8 8 8 9 NR C(O)R , NR C(O)OR , NR C(O)NR R , C(O)R , C(O)OR , and C(O)NR R ; 6a 6b 11 12 R and R are independently chosen from H, NR R , halogen, cyano, hydroxy, oxo, alkyl, haloalkyl, C cycloalkyl, 3-6 membered heterocycloalkyl, hydroxyalkyl, 11 10 11 10 11 10 11 12 11 11 OR , NR C(O)R , NR C(O)OR , NR C(O)NR R , C(O)R , C(O)OR , and 11 12 C(O)NR R , 6a 6b or R and R , together with the intervening atoms, combine to form a heteroaryl ring, which is optionally substituted with one or more R groups; 6c 6d 11 12 each R and R is independently chosen from H, NR R , halogen, cyano, hydroxy, oxo, alkyl, haloalkyl, C cycloalkyl, 3-6 membered heterocycloalkyl, hydroxyalkyl, 11 10 11 10 11 10 11 12 11 11 OR , NR C(O)R , NR C(O)OR , NR C(O)NR R , C(O)R , C(O)OR , and 11 12 C(O)NR R ; 6 11 12 R is chosen from NR R , halogen, cyano, hydroxy, oxo, alkyl, haloalkyl, C3- 11 10 11 cycloalkyl, 3-6 membered heterocycloalkyl, hydroxyalkyl, OR , NR C(O)R , 10 11 10 11 12 11 11 11 12 NR C(O)OR , NR C(O)NR R , C(O)R , C(O)OR , and C(O)NR R ; 7 8 9 each R , R and R is independently chosen from hydrogen, C alkyl, C cycloalkyl, 1-4 3-6 and 3-6 membered heterocycloalkyl, any of which is optionally substituted with halo, 7 8 9 hydroxy, C alkyl, C haloalkyl, and C alkoxy; or any two of R , R and R , together 1-3 1-3 1-3 with the atom to which they are both attached can form a 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl ring; and 10 11 12 each R , R and R is independently chosen from hydrogen, C alkyl, C 1-4 3- 6cycloalkyl, and 3-6 membered heterocycloalkyl, any of which is optionally substituted 10 11 with one or more groups chosen from halo, hydroxy and alkoxy; or any two of R , R and R , together with the atom to which they are both attached, can form a 3-7 membered cycloalkyl or heterocycloalkyl ring.
25. The compound as recited in claim 23, or salt thereof, wherein R is C alkyl. 3 1-6
26. The compound as recited in claim 23, or salt thereof, wherein R is chosen from methyl, fluoromethyl, difluoromethyl, and trifluoromethyl.
27. The compound as recited in claim 23, or salt thereof, wherein R is methyl.
28. The compound as recited in any one of claims 23-26, or salt thereof, wherein: R is chosen from H, alkyl, haloalkyl, C cycloalkyl, 3-6 membered heterocycloalkyl, and OR ; and R is H.
29. The compound as recited in any one of claims 23-28, or salt thereof, wherein X is CR ; and Y is N.
30. The compound as recited in claim 29, or salt thereof, wherein R is NH2.
31. The compound as recited in claim 30, or a salt thereof, wherein: 6a 11 R is chosen from H and OR ; and R is C alkyl.
32. The compound as recited in any one of claims 23-31, or a salt thereof, wherein R and R are independently chosen from cyclopropyl, oxetanyl, and methyl.
33. The compound as recited in claim 32, or a salt thereof, wherein R and R are methyl.
34. The compound as recited in claim 32, or a salt thereof, wherein R is methyl and R is cyclopropyl.
35. The compound as recited in claim 32, or a salt thereof, wherein R is cyclopropyl and R is methyl.
36. The compound as recited in claim 1, chosen from: O N N , , , S OCH O N N S OCH O N N 3 O N N , , , , , , .0. .0. .0. N ^ N N ^ A A fT^N A-X4! a o^s"n^n^v^ci NH2 nh2 , , , .0. .0. .0. N ^ N N N A ^ fj^N c, °A-A .W 0^SiN^N^ ¦Cl o^s"n^n^ NH2 nh2 nh2 , , , .0. .0. ‘Dvxb: nh2 nh2 0CH3 , , , .0. .0. oas,jrb 'D^xb: NH nh2 0CH3 och3 0^S^N 0;S$N nh2 ^ z.N ^ ¦*¦ 2 o' NH O N N , , , O N N , , , O N N , , , S NH S NH O N N O N N Cl Cl , , , 0 N N 0CH3 OH 0^S^N^N ^ N N (' N N (' N N g N N N N XI s A i r ^ N N '/ N N , , , , , , , , , , '/ Vo o Z— r-t Jr O Z—(/ z o zV z f~( F zV z O Z—(Z V,2 z \-/2 \= (° \-,z 7 O 7 o ll ^ NN // \\ z z / S' '/ V5 Z ^ J O Z—(l \—/ \= _F S' O Z—<7 z o z—<7 z \^2 V,2 z z X ll V z r-( _F z- S' o z—<7 z r^( 2 O Z—<7 \__ / S' o Z—(7 z z—<7 z o z—<7 z z \__/ ^^C/2 "CO. o <^0 CO , , , , O N N , , , , , , , , , , , , UT\ X z .o. LM r-\ J--( LT^ o z—(' z o ) Z— ) z— r~{ _J~L O z— y—z c/5 \___/ \___/ CO O '----' O CO CO / *0 d'b x o 7 o z Lr\ /-(?-( O z—(Z z o ) z—<7 z /-( Jr \__/ \ N__/ A O z—<7 z // o 7 z o ) z z O z—(/ z \___/ cov CO ' \\ o \ / Vv r^'7- o '—7 o xz CO /'b T^o Z~J/ \' LM r~( F\ ) z—<7 z o z—(/ z ^ Jr \__ / o o ) z z O z—(/ z o z—(7 z \___/ z ; co Q \ / \x : co ¦z ,OT* N—7 O /'b —O , , , , , , , , , , , , , , , , , , O N N , , , , and , or a salt thereof.
37. The compound as recited in claim 1, chosen from: O N N , , , S OCH O N N S OCH O N N 3 O N N , , , Cx Cx Cx oas,j6 o^s"n^n^ ^N ^N NH2 nh2 , , , .0. .0. .0. N ^ N N ^ A'-s-A ^S-'A ^vj(S ^ Cl O^'N^N'Sr^l 0^S"N^N^ o^s"n^n^V^ NH2 nh2 nh2 , , , .0. .0. .0. N ^ N N N A fj^N N^YV01 ^SiNAN^ 01 o^s"n^n^ 0^S"'n nh2 nh2 nh2 , , , Cx Cx oas,xb; ‘Ovxb: o"s"n^n^ nh2 nh2 OCH3 , , , .0. .0. “A,,/; °a-s-xC: NH NH2 OCH3 och3 O N N , , , O N N , , , O N N , , , S NH S NH O N N O N N Cl Cl , , , , , , , , , and , or a salt thereof.
38. The compound as recited in claim 1, chosen from: S OCH O N N , , , , , , O N N , , and , or a salt thereof.
39. The compound as recited in claim 1, chosen from: S OCH O N N , , , , , , O N N , and , or a salt thereof.
40. The compound as recited in claim 24, chosen from: O N N , , , O N N , , , , , , , , , O N N , , , N O N N O N N NH CH , , , , , , , , , and , or a salt thereof.
41. A compound of structural Formula (Va): or a salt thereof, wherein: X is chosen from N and CR ; Y is chosen from N and CR ; R and R are independently chosen from C alkyl, C haloalkyl, C cycloalkyl, C 1-4 1-4 3-6 3-6 heterocycloalkyl, C aryl, and 5-10 membered heteroaryl, any of which is optionally 5 1 2 substituted with one or more R groups, or R and R , together with the sulfur to which they are both attached, form a 4, 5, 6, or 7-membered heterocycloalkyl ring which is optionally substituted with one or more R groups; R is chosen from C1-6alkyl, and C1-6haloalkyl; 5 8 9 each R is independently chosen from NR R , halogen, cyano, hydroxy, oxo, alkyl, haloalkyl, C cycloalkyl, 3-6 membered heterocycloalkyl, hydroxyalkyl, OR , 7 8 7 8 7 8 9 8 8 8 9 NR C(O)R , NR C(O)OR , NR C(O)NR R , C(O)R , C(O)OR , and C(O)NR R ; 6a 6b 11 12 R and R are independently chosen from H, NR R , halogen, cyano, hydroxy, oxo, alkyl, haloalkyl, C cycloalkyl, 3-6 membered heterocycloalkyl, hydroxyalkyl, 11 10 11 10 11 10 11 12 11 11 OR , NR C(O)R , NR C(O)OR , NR C(O)NR R , C(O)R , C(O)OR , and 11 12 C(O)NR R , 6a 6b or R and R , together with the intervening atoms, combine to form a heteroaryl ring, which is optionally substituted with one or more R groups; 6c 6d 11 12 each R and R is independently chosen from H, NR R , halogen, cyano, hydroxy, oxo, alkyl, haloalkyl, C cycloalkyl, 3-6 membered heterocycloalkyl, hydroxyalkyl, 11 10 11 10 11 10 11 12 11 11 OR , NR C(O)R , NR C(O)OR , NR C(O)NR R , C(O)R , C(O)OR , and 11 12 C(O)NR R ; 6 11 12 R is chosen from NR R , halogen, cyano, hydroxy, oxo, alkyl, haloalkyl, C 11 10 11 cycloalkyl, 3-6 membered heterocycloalkyl, hydroxyalkyl, OR , NR C(O)R , 10 11 10 11 12 11 11 11 12 NR C(O)OR , NR C(O)NR R , C(O)R , C(O)OR , and C(O)NR R ; 7 8 9 each R , R and R is independently chosen from hydrogen, C alkyl, C cycloalkyl, 1-4 3-6 and 3-6 membered heterocycloalkyl, any of which is optionally substituted with halo, 7 8 9 hydroxy, C1-3alkyl, C1-3haloalkyl, and C1-3alkoxy; or any two of R , R and R , together with the atom to which they are both attached can form a 3-7 membered cycloalkyl or heterocycloalkyl ring; and 10 11 12 each R , R and R is independently chosen from hydrogen, C alkyl, C 1-4 3- cycloalkyl, and 3-6 membered heterocycloalkyl, any of which is optionally substituted 10 11 with one or more groups chosen from halo, hydroxy and alkoxy; or any two of R , R and R , together with the atom to which they are both attached, can form a 3-7 membered cycloalkyl or heterocycloalkyl ring. 6a 6b
42. The compound as recited in claim 30, or a salt thereof, wherein R and R , together with the intervening atoms, combine to form a pyridyl ring.
43. The compound as recited in claim 29, or a salt thereof, wherein 6a 6b R and R are independently chosen from H, alkyl, haloalkyl, C cycloalkyl, 3-6 membered heterocycloalkyl, hydroxyalkyl; and 6c 6d each R and R is independently chosen from H, alkyl, haloalkyl, C cycloalkyl, 3-6 membered heterocycloalkyl, and hydroxyalkyl.
44. A compound of structural Formula (VI): or a salt thereof, wherein: X is chosen from N and CR ; Y is chosen from N and CR ; R and R are independently chosen from C alkyl, C haloalkyl, C cycloalkyl, C 1-4 1-4 3-6 3-6 heterocycloalkyl, C aryl, and 5-10 membered heteroaryl, any of which is optionally 5 1 2 substituted with one or more R groups, or R and R , together with the sulfur to which they are both attached, form a 4, 5, 6, or 7-membered heterocycloalkyl ring which is optionally substituted with one or more R groups; R is chosen from C alkyl, and C haloalkyl; 1-6 1-6 5 8 9 each R is independently chosen from NR R , halogen, cyano, hydroxy, oxo, alkyl, haloalkyl, C cycloalkyl, 3-6 membered heterocycloalkyl, hydroxyalkyl, OR , 7 8 7 8 7 8 9 8 8 8 9 NR C(O)R , NR C(O)OR , NR C(O)NR R , C(O)R , C(O)OR , and C(O)NR R ; 6a 6b 11 12 R and R are independently chosen from H, NR R , halogen, cyano, hydroxy, oxo, alkyl, haloalkyl, C cycloalkyl, 3-6 membered heterocycloalkyl, hydroxyalkyl, 11 10 11 10 11 10 11 12 11 11 OR , NR C(O)R , NR C(O)OR , NR C(O)NR R , C(O)R , C(O)OR , and 11 12 C(O)NR R , 6a 6b or R and R , together with the intervening atoms, combine to form a heteroaryl ring, which is optionally substituted with one or more R groups; 6c 6d 11 12 each R and R is independently chosen from H, NR R , halogen, cyano, hydroxy, oxo, alkyl, haloalkyl, C cycloalkyl, 3-6 membered heterocycloalkyl, hydroxyalkyl, 11 10 11 10 11 10 11 12 11 11 OR , NR C(O)R , NR C(O)OR , NR C(O)NR R , C(O)R , C(O)OR , and 11 12 C(O)NR R ; 6 11 12 R is chosen from NR R , halogen, cyano, hydroxy, oxo, alkyl, haloalkyl, C 11 10 11 cycloalkyl, 3-6 membered heterocycloalkyl, hydroxyalkyl, OR , NR C(O)R , 10 11 10 11 12 11 11 11 12 NR C(O)OR , NR C(O)NR R , C(O)R , C(O)OR , and C(O)NR R ; 7 8 9 each R , R and R is independently chosen from hydrogen, C alkyl, C cycloalkyl, 1-4 3-6 and 3-6 membered heterocycloalkyl, any of which is optionally substituted with halo, 7 8 9 hydroxy, C alkyl, C haloalkyl, and C alkoxy; or any two of R , R and R , together 1-3 1-3 1-3 with the atom to which they are both attached can form a 3-7 membered cycloalkyl or heterocycloalkyl ring; and 10 11 12 each R , R and R is independently chosen from hydrogen, C alkyl, C 1-4 3- 6cycloalkyl, and 3-6 membered heterocycloalkyl, any of which is optionally substituted 10 11 with one or more groups chosen from halo, hydroxy and alkoxy; or any two of R , R and R , together with the atom to which they are both attached, can form a 3-7 membered cycloalkyl or heterocycloalkyl ring. 6a 6b
45. The compound as recited in claim 33, or a salt thereof, wherein R and R , together with the intervening atoms, combine to form a pyridyl ring. 6c 6d
46. The compound as recited in claim 34, or a salt thereof, wherein each R and R is independently chosen from H, alkyl, haloalkyl, C cycloalkyl, 3-6 membered heterocycloalkyl, and hydroxyalkyl.
47. A compound of structural Formula (VII): (VII) or a salt thereof, wherein: X is chosen from N and CR ; Y is chosen from N and CR ; R and R are independently chosen from C alkyl, C haloalkyl, C cycloalkyl, C 1-4 1-4 3-6 3-6 heterocycloalkyl, C5-10aryl, and 5-10 membered heteroaryl, any of which is optionally 5 1 2 substituted with one or more R groups, or R and R , together with the sulfur to which they are both attached, form a 4, 5, 6, or 7-membered heterocycloalkyl ring which is optionally substituted with one or more R groups; R is chosen from C alkyl, and C haloalkyl; 1-6 1-6 5 8 9 each R is independently chosen from NR R , halogen, cyano, hydroxy, oxo, alkyl, haloalkyl, C cycloalkyl, 3-6 membered heterocycloalkyl, hydroxyalkyl, OR , 7 8 7 8 7 8 9 8 8 8 9 NR C(O)R , NR C(O)OR , NR C(O)NR R , C(O)R , C(O)OR , and C(O)NR R ; 6a 6b 11 12 R and R are independently chosen from H, NR R , halogen, cyano, hydroxy, oxo, alkyl, haloalkyl, C cycloalkyl, 3-6 membered heterocycloalkyl, hydroxyalkyl, 11 10 11 10 11 10 11 12 11 11 OR , NR C(O)R , NR C(O)OR , NR C(O)NR R , C(O)R , C(O)OR , and 11 12 C(O)NR R , 6a 6b or R and R , together with the intervening atoms, combine to form a heteroaryl ring, which is optionally substituted with one or more R groups; 6c 6d 11 12 each R and R is independently chosen from H, NR R , halogen, cyano, hydroxy, oxo, alkyl, haloalkyl, C cycloalkyl, 3-6 membered heterocycloalkyl, hydroxyalkyl, 11 10 11 10 11 10 11 12 11 11 OR , NR C(O)R , NR C(O)OR , NR C(O)NR R , C(O)R , C(O)OR , and 11 12 C(O)NR R ; 6 11 12 R is chosen from NR R , halogen, cyano, hydroxy, oxo, alkyl, haloalkyl, C 11 10 11 cycloalkyl, 3-6 membered heterocycloalkyl, hydroxyalkyl, OR , NR C(O)R , 10 11 10 11 12 11 11 11 12 NR C(O)OR , NR C(O)NR R , C(O)R , C(O)OR , and C(O)NR R ; 7 8 9 each R , R and R is independently chosen from hydrogen, C1-4alkyl, C3-6cycloalkyl, and 3-6 membered heterocycloalkyl, any of which is optionally substituted with halo, 7 8 9 hydroxy, C alkyl, C haloalkyl, and C alkoxy; or any two of R , R and R , together 1-3 1-3 1-3 with the atom to which they are both attached can form a 3-7 membered cycloalkyl or heterocycloalkyl ring; and 10 11 12 each R , R and R is independently chosen from hydrogen, C alkyl, C 1-4 3- cycloalkyl, and 3-6 membered heterocycloalkyl, any of which is optionally substituted 10 11 with one or more groups chosen from halo, hydroxy and alkoxy; or any two of R , R and R , together with the atom to which they are both attached, can form a 3-7 membered cycloalkyl or heterocycloalkyl ring. 6a 6b
48. The compound as recited in claim 47, wherein R and R , together with the intervening atoms, combine to form a phenyl ring, which is optionally substituted with one or two R groups.
49. The compound as recited in claim 47, or a salt thereof, wherein X is CR and Y is N.
50. The compound as recited in claim 47, or a salt thereof, wherein R is chosen from H, alkyl, haloalkyl, C3-6cycloalkyl, 3-6 membered heterocycloalkyl, and hydroxyalkyl.
51. The compound as recited in claim 47, or a salt thereof, wherein R and R are independently chosen from C alkyl, C cycloalkyl, and 3-6 membered heterocycloalkyl. 1-4 3-6
52. The compound as recited in claim 47, or a salt thereof, wherein at least one of R and R is methyl.
53. The compound as recited in claim 47, or a salt thereof, wherein exactly one of R and R is chosen from cyclopropyl and oxetanyl.
54. The compound as recited in claim 47, or a salt thereof, wherein R and R are methyl.
55. The compound as recited in claim 1, wherein the compound is chosen from , , , , , , , , and , or a salt of any of the foregoing.
56. The compound as recited in claim 1, wherein the compound is chosen from , , , , , , .0 .0. NH NH NH £ N N , , , CH3 f NH 'NH 0?SSN NH O' N N , , , .Cl S CH o^"n^n O N N cMnM' nh2 NH , , , .0. .0. .0. I N M NH A ¦ NH ^S'XA O N N O' N N , , , .OCH3 S OCH S OCH O N N O N N NH NH , , , O N N , , , , , , , , , 2- Ll o ¦z.—C' z \__ / O 2—(' O \//Z \__ / \//Z (/) O 2—(' 2 < ° \oZ ¦2 cn 2 V 1 2—y 2' O 2—(Z 2 O 2—v 2 \__ / o 2—(f 2 \__ / o 2— 2 .// ¦ b ¦2 CM ll // 2- O ^ _/f~^ o 2 O 2—(/ Z o 2 2- \__ / \__ / O 2— , , , , , , , , , , , , )----Z CM z /—Z /----Z 0v V s r~( /f-( f vi r~( /f~i \__ / o ) z—(' z o ) 2—(7 2 'v,2 o r-( Jf-C o ¦.>! ll >—z CN /---z v V s r~( _£-( O 2—(' Z X f~( JF~4 O ) 2—O' 2 O > 2—O' 2 \__ / o ) 2—(' 2 \__ / \__ / ¦ V\ \/,z ' * o-^ y—Z cm y-----Z CSJ ll )----Z CM 2 r vi r~( ?-( /-(_?-( r~( _A~i v V s O 2—(' 2 I ^ Jr V o ) 2—O' 2 o ) 2—O' 2 ) 2—(' 2 O 2—(' 2 \__ / \__ / \d \o2 , , , , , , , , , , , , , , , , , , , , , , , , , , , .0. .0. (An^n^nA h H3c h3c .0. .0. °as-j6 °^'Xi nh2 nh2 cAn^iA .0. .0. och3 u \ cA N 0^S ^[\j |\j H3c N 0^S'N 0;S$N nh2 cA>An O' NH O' nh2 /-(_£-{ \___/ o ) z—i' z A \___/ A f~( f Z—v Z X \___/ N__/ ) z—c7 z O z—(Z z o 'x—^ o ¦z CO \//z / *0 d'b ii LM u-% LM ) z—(7 z z rz-A o Z-C7 Jr o z O z—(7 z o O Z—(7 z X \__/ x y LJ- r^,7- o—7 ^'b A \„z CO xz CO ¦z CO / —o o O LM LM z LM LM 7 z Z' o ) z O z—Jr (7 z ) z—<7 : zA' z ZiA z o z o o o o z—(7 z \___/ Q Q z z ; co /~\>r o \>r /—\ CO z CO ¦z z CO /b o —o O O , , , , , , , , , , , , O N N , , , , , , , , , , , , , , , O N N N , , , O N N N O N N N CH CH , , , , , , Li- X /-(_J-{ T )r^ z O Z—(/ Z ^ z^y \' r-( ?% o z—y z w o z—y z N__/ r-( _?-( o z— J-t F< x" / /-C O z—c7 z 3: cTWiz X" \__/ \//Z •*¦ \\ \//z < ° Ll Ll /ft 7ft r-( _J< ^ r~( _,f^C r \ J-~% /-(,?¦% O z—(7 z O z—(7 z O z—<7 z ^ \__/ \__/ \__/ \__/ O z—(7 z \__/ \__/ \//Z \,z V,z CO CO CO CO • \\ •*• \\ \' < ° < ° , , , O N N N , , , , , , , , , xV/ \ '/ \ X LL. A X—(' o X—V X O X—(/ X \//2 X—C' o X CO o X X \__ / / ^ \__/ CO / ^ ll ll /—Z CO x-c'/ o x—(/ x r~( _?-L O X—<7 X O X— CO \__/ • \\ A O X—(/ X x-c'/ \__ / o O X—f X CO CO , , , , , , , , , , , , O N N , , , O N N N , , , O N N , , , S NH S NH O N N O N N Cl Cl , , , , , , r-( F Q z-f r-( J-i. ) ~Z.—(' Z (N CO r-( f-C // Z' ^z ) Z—(' z z— \__/ VJ A f-i rAoz o ) z—v z d'b \//Z CN CN Z co d'b rV§ rvi '/ V-S O z—(/ z r-( f-\ r~( f-i X__/ X 5 Z—(/ Z 5 Z—(' Z O z—(/ z s=< O : \\ \oZ I /'b O N N , , , , , , , and , or a salt of any of the foregoing.
57. A compound as recited in any one of claims 1-56, or a salt thereof, for use as a medicament.
58. A compound as recited in any one of claims 1-56, or a salt thereof, for use in the manufacture of a medicament for the prevention or treatment of a disease ameliorated by the inhibition of ATR kinase.
59. The compound as recited in claim 58, or a salt thereof, wherein the disease is cancer.
60. The compound as recited in claim 59, or a salt thereof, wherein the cancer is a chemotherapy-resistant cancer.
61. The compound as recited in claim 59, or a salt thereof, wherein the cancer is a radiotherapy-resistant cancer.
62. The compound as recited in claim 59, or a salt thereof, wherein the cancer is an ALT- positive cancer.
63. The compound as recited in claim 59, or a salt thereof, wherein the cancer is a sarcoma.
64. The compound as recited in claim 59, or a salt thereof, wherein the cancer is chosen from osteosarcoma and glioblastoma.
65. The compound as recited in claim 59, or a salt thereof, wherein the cancer is chosen from lung cancer, head and neck cancer, pancreatic cancer, gastric cancer, and brain cancer.
66. The compound as recited in claim 59, or a salt thereof, wherein the cancer is chosen from non-small cell lung cancer, small cell lung cancer, pancreatic cancer, biliary tract cancer, head and neck cancer, bladder cancer, colorectal cancer, glioblastoma, esophageal cancer, breast cancer, hepatocellular carcinoma, and ovarian cancer.
67. The compound as recited in claim 59, or a salt thereof, wherein the cancer has a defect in a base excision repair protein.
68. A pharmaceutical composition comprising a compound as recited in any one of claims 1- 56, or a salt thereof, together with a pharmaceutically acceptable carrier.
69. Use of a compound as recited in any one of claims 1-56, or a salt thereof, in the manufacture of a medicament for the treatment of an ATR kinase-mediated disease.
70. The use as recited in claim 69, wherein the disease is cancer.
71. The use as recited in claim 70, wherein the cancer is a chemotherapy-resistant cancer.
72. The use as recited in claim 70, wherein the cancer is a radiotherapy-resistant cancer.
73. The use as recited in claim 70, wherein the cancer is an ALT-positive cancer.
74. The use as recited in claim 70, wherein the cancer is a sarcoma.
75. The use as recited in claim 70, wherein the cancer is chosen from osteosarcoma and glioblastoma.
76. The use as recited in claim 70, wherein the cancer is chosen from lung cancer, head and neck cancer, pancreatic cancer, gastric cancer, and brain cancer.
77. The use as recited in claim 70, wherein the cancer is chosen from non-small cell lung cancer, small cell lung cancer, pancreatic cancer, biliary tract cancer, head and neck cancer, bladder cancer, colorectal cancer, glioblastoma, esophageal cancer, breast cancer, hepatocellular carcinoma, and ovarian cancer.
78. The use as recited in claim 70, wherein the cancer has a defect in a base excision repair protein.
79. The use as recited in claim 70, wherein the cancer has defects in the ATM signaling cascade.
80. The use as recited in claim 79, wherein the defect is altered expression or activity of one or more of the following: TM, p53, CHK2, MRE11, RAD50, NBS 1, 53BP1, MDC1, H2AX, MCPH1 / BRIT1, CTIP, or SMC1.
81. The use as recited in claim 70, wherein the medicament is to be administered with another therapeutic agent, wherein the other therapeutic agent inhibits or modulates a base excision repair protein.
82. Use of: a. a therapeutically effective amount of a compound as recited in any one of claims 1-56, or a salt thereof; and b. another therapeutic agent, in the manufacture of a medicament for the treatment of an ATR kinase-mediated disease.
83. The use as recited in claim 82, wherein the other therapeutic agent is a CHK1 inhibitor.
84. The use as recited in claim 83, wherein the CHK1 inhibitor is chosen from MK-8776, LY2603618, V158411, PF-477736, UCN-01, and AZD7762.
85. The use as recited in claim 82, wherein the other therapeutic agent is a DNA-damaging agent.
86. The use as recited in claim 85, wherein the DNA-damaging agent is chosen from ionizing radiation, radiomimetic neocarzinostatin, a platinating agent, a Topo I inhibitor, a Topo II inhibitor, an antimetabolite, an alkylating agent, an alkyl sulphonate, and an antibiotic.
87. The use as recited in claim 86, wherein the platinating agent is chosen from cisplatin, oxaliplatin, carboplatin, nedaplatin, lobaplatin, triplatin tetranitrate, picoplatin, satraplatin, ProLindac, and aroplatin.
88. The use as recited in claim 86, wherein the Topo I inhibitor is chosen from camptothecin, topotecan, irinotecan / SN38, rubitecan and belotecan.
89. The use as recited in claim 86, wherein the Topo II inhibitor is chosen from etoposide, daunorubicin, doxorubicin, clarubicin, epirubicin, idarubicin, amrubicin, pirarubicin, valrubicin, zorubicin and teniposide.
90. The use as recited in claim 86, wherein the antimetabolite is chosen from aminopterin, methotrexate, pemetrexed, raltitrexed, pentostatin, cladribine, clofarabine, fludarabine, thioguanine, mercaptopurine, fluorouracil, capecitabine, tegafur, carmofur, floxuridine, cytarabine, gemcitabine, azacitidine, and hydroxyurea.
91. The use as recited in claim 86, wherein the alkylating agent is chosen from mechlorethamine, cyclophosphamide, ifosfamide, trofosfamide, chlorambucil, melphalan, prednimustine, bendamustine, uramustine, estramustine, carmustine, lomustine, semustine, fotemustine, nimustine, ranimustine, streptozocin, busulfan, mannosulfan, treosulfan, carboquone, thioTEPA, triaziquone, triethylenemelamine, procarbazine, dacarbazine, temozolomide, altretamine, mitobronitol, actinomycin, bleomycin, mitomycin, and plicamycin.
92. The compound of claim 1, substantially as herein described with reference to any one of the examples thereof.
93. The compound of claim 23, substantially as herein described with reference to any one of the examples thereof.
94. The compound of claim 24, substantially as herein described with reference to any one of the examples thereof.
95. The compound of claim 41, substantially as herein described with reference to any one of the examples thereof.
96. The compound of claim 44, substantially as herein described with reference to any one of the examples thereof.
97. The compound of claim 47, substantially as herein described with reference to any one of the examples thereof.
NZ761374A 2018-07-13 Heterocyclic inhibitors of atr kinase NZ761374B2 (en)

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