WO2023061415A1 - Dérivés de thiadiazolyle, compositions et utilisations de ceux-ci - Google Patents

Dérivés de thiadiazolyle, compositions et utilisations de ceux-ci Download PDF

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Publication number
WO2023061415A1
WO2023061415A1 PCT/CN2022/124933 CN2022124933W WO2023061415A1 WO 2023061415 A1 WO2023061415 A1 WO 2023061415A1 CN 2022124933 W CN2022124933 W CN 2022124933W WO 2023061415 A1 WO2023061415 A1 WO 2023061415A1
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methyl
alkyl
thiadiazol
methoxyphenyl
compound
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PCT/CN2022/124933
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English (en)
Inventor
Yao ZHANG
Hongmei Li
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Danatlas Pharmaceuticals Co., Ltd.
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Priority to CN202280062023.8A priority Critical patent/CN118055930A/zh
Publication of WO2023061415A1 publication Critical patent/WO2023061415A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • C07D417/02—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 two hetero rings
    • C07D417/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • 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 disclosure relates to thiadiazolyl derivatives as inhibitor of PolQ.
  • the present disclosure also relates to methods for preparing the thiadiazolyl derivatives, pharmaceutical compositions, and their uses in the treatment of diseases related to the activity of PolQ including, e.g., cancers containing DNA repair defects.
  • Double strand breaks can be repaired by one of three main pathways: homologous recombination (HR) , non-homologous end-joining (NHEJ) and alternative NHEJ (alt-NHEJ) .
  • HR homologous recombination
  • NHEJ non-homologous end-joining
  • alt-NHEJ alternative NHEJ
  • An alternative end joining (alt-NHEJ) also known as microhomology-mediated end-joining (MMEJ) pathway, is commonly considered as a "backup" DSB repair pathway when NHEJ or HR are compromised (Truong et al. PNAS 2013, 110 (19) , 7720-7725) .
  • DDR DNA damage response
  • PRP poly (ADP-ribose) polymerase
  • DNA polymerase theta (UniProtKB-075417 (DPOLQ_HUMAN) is a key protein involved in MMEJ (Kent et al. Nature Structural & Molecular Biology (2015) , 22 (3) , 230-237, Mateos-Gomez et al. Nature (2015) , 518 (7538) , 254-257) .
  • PolQ is distinct among human DNA polymerases, comprising an N-terminal helicase domain (SF2 HEL308-type) and a C-terminal low-fidelity DNA polymerase domain (A-type) (Wood & D.00e DNA Repair (2016) , 44, 22-32) .
  • HRD homologous recombination deficient
  • PolQ can carry out error-prone DNA synthesis at DNA damage sites through alt-NHEJ pathway. It has been shown that the helicase domain of PolQ mediates the removal of RPA protein from ssDNA ends and stimulates annealing. This anti-recombinase activity of PolQ promotes the alt-NHEJ pathway.
  • the helicase domain of PolQ contributes to microhomology-mediated strand annealing (Chan SH et al., PLoS Genet. (2010) ; 6: el001005; and Kawamura K et al., Int. J. Cancer (2004) ; 109: 9-16) .
  • PolQ can promote end joining in alt-NHEJ pathway by employing this annealing activity when ssDNA overhangs contain >2 bp of microhomology (Kent T., et al., Elife (2016) ; 5: el3740) , and Kent T., et al., Nat. Struct. Mol. Biol. (2015) ; 22: 230-237) .
  • This reannealing activity is obtained through coupled actions of Rad51 interaction followed by ATPase-mediated displacement of Rad51 from DSB damage sites. Once annealed, the polymerase domain extends the ssDNA ends and fills the remaining gaps.
  • PolQ The expression of PolQ is low in normal cells but significantly over-expressed in subsets of HRD ovarian, uterine and breast cancers with associated poor prognosis (Higgins et al. Oncotarget (2010) , 1, 175-184, Lemee et al. PNAS (2010) , 107 (30) , 13390-13395, Ceccaldi et al. (2015) , supra) .
  • the present disclosure relates to, inter alia, compounds of Formula (I) ,
  • a pharmaceutical composition comprising a compound of formula (I) , or pharmaceutically acceptable salt, solvate, tautomeric, stereoisomer, atropisomer, isotopic variants or prodrugs thereof and at least one pharmaceutically acceptable carrier.
  • a method of inhibiting PolQ comprising:
  • a method of treating cancers comprising administering to a patient a therapeutically effective amount of a compound of formula (I) , or pharmaceutically acceptable salt, solvate, tautomeric, stereoisomer, atropisomer, isotopic variants or prodrugs thereof.
  • compositions and methods which are described herein in the context of separate aspects, may also be provided in combination in a single aspect.
  • the present disclosure relates to, inter alia, compounds of Formula (I) ,
  • X is N or C
  • Y is NH, NMe, O or S
  • ring A is phenyl, 5-6 membered heteroaryl, 5-6 membered partially saturated heterocycloalkyl containing, inclusive of X, one to four heteroatoms independently selected from nitrogen; and ring A is not pyrazolyl;
  • Ar 1 is C 6 -C 10 aryl, 5-10 membered heteroaryl or 5-10 membered heterocycloalkyl; wherein the C 6 -C 10 aryl, 5-10 membered heteroaryl or 5-10 membered heterocycloalkyl is optionally substituted with R a , R b , and/or R c ;
  • R a , R b and R c are independently selected from H, D, halogen, CN, OR A , C (O) R B , C (O) NR C R D , NR C R D , NR C C (O) R B , S (O) 2 R B , C 1- C 6 alkyl optionally substituted with D, halogen, CN, OH, NH 2 , NO 2 , C 3 -C 6 cycloalkyl, 4-6 membered heterocycloalkyl; or
  • R a and R b when on adjacent ring vertices, combine to form a C 3- C 6 cycloalkyl or 3-6 membered heterocycloalkyl; wherein, the C 3- C 6 cycloalkyl or 4-6 membered heterocycloalkyl optionally substituted with D, halogen, oxo, CN, OH, NH 2 , NO 2 , C 1- C 6 alkyl, C 1- C 6 haloalkyl, -O-C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocycloalkyl;
  • R a and R b when on the same ring vertex, combine to form oxo, C 3- C 6 cycloalkyl or 4-6 membered heterocycloalkyl optionally substituted with D, halogen, oxo, CN, OH, NH 2 , NO 2 , C 1- C 6 alkyl, C 1- C 6 haloalkyl, -O-C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocycloalkyl;
  • Ar 2 is C 6 -C 10 aryl, 5-10 membered heteroaryl; wherein, the C 6 -C 10 aryl or 5-10 membered heteroaryl is optionally substituted with R d , R e and/or R f ;
  • R d and R e are independently selected from H, D, halogen, CN, oxo, OR A , NR C R D , C (O) NR C R D , NR C C (O) R B , OC (O) NR C R D , NR C C (O) NR C R D , C 1 -C 6 alkyl optionally substituted with D, halogen, CN, OH, NH 2 , NO 2 , oxo, C 3- C 6 cycloalkyl, 4-6 membered heterocycloalkyl; or
  • R d and R e together with the atoms to which they are attached form a 4-7 membered heterocycloalkyl optionally substituted with D, OH, oxo, CN, -NH 2 , halo, C 1 -C 4 alkyl, -O-C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 cyanoalkyl;
  • R f is selected from H, D, halogen, CN, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, OR A , NR C R D , C (O) NR C R D , NR C C (O) R B ; wherein, the C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl is optionally substituted with one, two, or three substituents independently selected from D, halogen, CN, OH, NH 2 , NO 2 , oxo, C 1- C 6 alkyl, C 1 -C 6 haloalkyl, -O-C 1 -C 6 alkyl, -OC 1 -C 6 haloalkyl
  • R 1 is independently selected from H, D, CN, NO 2 , SF 5 , halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocycloalkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, OR A , OC (O) NR C R D , NR C R D , NR C C (O) R B , NR C C (O) OR A ; wherein, the C 1- C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3- C 6 cycloalkyl, 4-6 membered heterocycloalkyl, C 6- C 10 aryl, 5-10 membered heteroaryl is optionally substituted with one, two, or three substituents independently selected from D, halogen, CN, OH, NH
  • R 2 is H, D, halo, CN, C 1- C 6 alkyl, C 1 -C 6 haloalkyl, -O-C 1 -C 6 alkyl, -OC 1 -C 6 haloalkyl;
  • R 3 and R 4 are independently selected from H, D, C 1- C 6 alkyl
  • R A is independently selected from H, D, C 1 -C 6 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl; wherein the C 1 -C 6 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocyclalkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, NO 2 , oxo, -NH 2 , -NH (C 1 -C 4 alkyl) , -N (C 1 -C 4 alkyl) 2 , C 1 -C 4 alkyl, C 1
  • R B is independently selected from H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, -NH 2 , CN, SF 5 , halo, oxo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 cyanoalkyl, OC 1 -C 4 al
  • R C and R D are each independently selected from H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, -NH 2 , CN, SF 5 , halo, oxo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 cyanoalkyl, OC 1 -C 4 alkyl, OC 1
  • R C and R D together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, oxo, CN, -NH 2 , -NH (C 1 -C 4 alkyl) , -N (C 1 -C 4 alkyl) 2 , halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 cyanoalkyl, OC 1 -C 4 alkyl, or OC 1 -C 4 haloalkyl.
  • substituents independently selected from D, OH, oxo, CN, -NH 2 , -NH (C 1 -C 4 alkyl) , -N (C 1 -C 4 alkyl) 2 , halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -
  • X is N.
  • X is C.
  • Y is O.
  • Y is S.
  • Y is NH
  • Y is NHCH 3 .
  • ring A is phenyl
  • ring A is a six membered heteroaryl or 6 membered partially saturated heterocycloalkyl comprising one to three heteroatoms independently selected from nitrogen.
  • ring A is pyridinyl, pyrimidinyl, pyridazinyl, pyrazin-2 (1H) -onyl, pyrimidin-2 (1H) -onyl or 1, 2, 4-triazin-5 (4H) -onyl.
  • ring A is:
  • ring A is a five membered heteroaryl comprising one to three heteroatoms independently selected from nitrogen. In some embodiments, ring A is imidazolyl or triazolyl.
  • ring A is:
  • R 1 is independently selected from H, D, CN, NO 2 , SF 5 , halogen, C 1- C 6 alkyl, C 3- C 6 cycloalkyl, 4-6 membered heterocycloalkyl, OR A , OC (O) NR C R D , NR C R D , NR C C (O) R B , or NR C C (O) OR A ; wherein, the C 1- C 6 alkyl, C 3- C 6 cycloalkyl or 4-6 membered heterocycloalkyl is optionally substituted with one, two, or three substituents independently selected from D, halogen, CN, OH, NH 2 , NO 2 , oxo, C 1- C 6 alkyl, C 1 -C 6 haloalkyl, -O-C 1 -C 6 alkyl, -OC 1 -C 6 haloalkyl.
  • R 1 is H, D, CN, SF 5 , halogen, C 1- C 6 alkyl, C 3- C 6 cycloalkyl.
  • R 1 is H, D, CN, SF 5 , fluoro, chloro, methyl, cyclopropanyl.
  • R 2 is H, D, halogen, CN, C 1 -C 6 alkyl. In some embodiments, R 2 is H, D, CN, fluoro, chloro, methyl.
  • Ar 1 is C 6- C 10 aryl optionally substituted with R a , R b , and/or R c .
  • Ar 1 is phenyl optionally substituted with R a , R b , and/or R c .
  • Ar 1 is phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2, 4-dimethoxyphenyl, 2-chlorophenyl, 2-cyanophenyl, 2-cyclopropyloxyphenyl, 2-methoxy-4-fluorophenyl, 2-methoxy-6-fluorophenyl, 2-methoxy-5-chlorophenyl, 2-methoxy-5- (trifluoromethyl) phenyl, 2, 4-dimethoxyphenyl, 2-methoxy-5-cyanophenyl, 2-methoxy-4-cyanophenyl, 2-methoxy-4-cyanophenyl, 2-methoxy-4-cyanophenyl, 2-methoxy-4- (hydroxymethyl) phenyl, 2-methoxy-5-chloro-6-fluorophenyl, 2-methoxy-5-methyl-6-fluorophenyl, 2-methoxy-5-trifluoromethyl-6-fluorophenyl, 2-me
  • Ar 1 is 5-10 membered heteroaryl optionally substituted with R a , R b , and/or R c .
  • Ar 1 is pyrrolyl, pyrazolyl, imidazolyl, 1, 2, 3-triazolyl, furanyl, oxazolyl, thiophenyl, thiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, benzo [d] imidazolyl, benzo [d] [1, 2, 3] triazolyl, benzo [d] thiazolyl, benzo [d] oxazolyl, benzo [d] isoxazolyl, each of the aforementioned ring optionally substituted with R a , R b , and/or R c .
  • Ar 1 is 5-10 membered heterocycloalkyl optionally substituted with R a , R b , and/or R c .
  • Ar 1 is piperidinyl, piperazinyl, morpholinyl, homomorpholinyl, 2-oxopiperazinyl, 2-oxohomopiperazinyl, 3-oxopiperazin-l-yl, 3-oxohomopiperazin-l-yl, 5-oxohomopiperazin-l-yl, tetrahydropyranyl, 3, 6-dihydro-2H-pyranyl, 2-oxo-l, 2-dihydropyridinyl, 5-methylpiperazin-2-onyl, thiomorpholinyl, 1, 1-dioxothiomorpholinyl, 6-oxohexahydropyrrolo [l, 2-a] pyrazin-2 (lH) -yl or 2, 3-dihydro-4H-benzo [b] [l, 4] oxazin-4-yl, 4-oxa-7-azaspiro [2.5] octan-7-yl optional
  • R a and R b are independently selected from H, D, halogen, CN, OR A , NR C R D , C (O) R B , S (O) 2 R B or C 1- C 6 alkyl optionally substituted with D, halogen, CN, OH, NH 2 , NO 2 , C 3- C 6 cycloalkyl, 4-6 membered heterocycloalkyl.
  • R a and R b are independently selected from hydrogen, D, CN, OH, NH 2 , fluoro, chloro, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoroethyl, hydroxymethyl, methylsulfonyl, or methylcarbonyl.
  • R a and R b when on adjacent ring vertices, combine to form a C 3- C 6 cycloalkyl optionally substituted with D, halogen, oxo, CN, OH, NH 2 , NO 2 , C 1- C 6 alkyl, C 1- C 6 haloalkyl, -O-C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocycloalkyl.
  • R a and R b when on adjacent ring vertices, combine to form 4-6 membered heterocycloalkyl optionally substituted with D, halogen, oxo, CN, OH, NH 2 , NO 2 , C 1- C 6 alkyl, C 1- C 6 haloalkyl, -O-C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocycloalkyl.
  • R a and R b when on the same ring vertex, combine to form oxo, C 3- C 6 cycloalkyl or 4-6 membered heterocycloalkyl optionally substituted with D, halogen, oxo, CN, OH, NH 2 , NO 2 , C 1- C 6 alkyl, C 1- C 6 haloalkyl, -O-C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocycloalkyl.
  • R c is selected from H, D, halogen, OR A , NR C R D , C (O) NR C R D , NR C C (O) R B , C 1 -C 6 alkyl optionally substituted with D, halogen, CN, OH, NH 2 , NO 2 , -O-C 1 -C 4 alkyl, C 3- C 6 cycloalkyl, 4-6 membered heterocycloalky.
  • R c is hydrogen, methyl, ethyl, fluoro, chloro, difluoromethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, hydroxy, hydroxymethyl, 2-hydroxyethyl, 2-methoxyethyl, 2-aminoethyl, 2-morpholin-l-yl ethyl, -CONH 2 , methylaminocarbonyl, or dimethylaminocarbonyl.
  • Ar 2 is C 6 -C 10 aryl or 5-10 membered heteroaryl optionally substituted with R d , R e and/or R f .
  • Ar 2 is phenyl, pyridinyl or pyrimidinyl optionally substituted with R d , R e and/or R f .
  • Ar 2 is phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3, 4-dichlorophenyl, 3, 5-dichlorophenyl, 4-cyclopropylphenyl, 4- (trifluoromethyl) phenyl, 4-methoxyphenyl, 4-methylphenyl, 4-cyanophenyl, 4- (trifluoromethoxy) phenyl, 5-cyanopyridinyl, 5-chloropyridinyl.
  • R d and R e are independently selected from H, D, halogen, CN, oxo, OR A , NR C R D or C 1- C 6 alkyl optionally substituted with D, halogen, CN, OH, NH 2 , NO 2 , oxo, C 3- C 6 cycloalkyl, 4-6 membered heterocycloalkyl.
  • R d and R e are independently selected from H, D, fluoro, chloro, CN, OH, NH 2 , methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoroethyl, -N (CH 3 ) 2 .
  • R f is selected from H, D, halogen, CN, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, OR A , NR C R D , C (O) NR C R D , NR C C (O) R B ; wherein, the C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl is optionally substituted with one, two, or three substituents independently selected from D, halogen, CN, OH, NH 2 , NO 2 , oxo, C 1- C 6 alkyl, C 1 -C 6 haloalkyl, -O-C 1 -C 6 alkyl, -OC 1 -C 6 haloalkyl.
  • R 3 and R 4 are independently selected from H or D.
  • R A is H or D.
  • R A is independently selected from C 1 -C 6 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl; wherein the C 1 -C 6 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocyclalkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, NO 2 , oxo, -NH 2 , -NH (C 1 -C 4 alkyl) , -N (C 1 -C 4 alkyl) 2 , C 1 -C 4 alkyl, C 1 -C 4 al
  • R B is H or D.
  • R B is independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, -NH 2 , CN, SF 5 , halo, oxo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 cyanoalkyl, OC 1 -C 4 alkyl,
  • R C and R D are each independently selected from H or D.
  • R C and R D are each independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, -NH 2 , CN, SF 5 , halo, oxo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 cyanoalkyl, OC 1 -C 4 alkyl, OC 1
  • R C and R D together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, oxo, CN, -NH 2 , -NH (C 1 -C 4 alkyl) , -N (C 1 -C 4 alkyl) 2 , halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 cyanoalkyl, OC 1 -C 4 alkyl, or OC 1 -C 4 haloalkyl.
  • the compounds of Formula (I) are represented by compounds of Formula (IIa) , (IIb) , (IIc) , (IId) , (IIe) , (IIf) , (IIg) , (IIh) or (IIi) :
  • Y is O.
  • Y is S.
  • Y is NH
  • Y is NHCH 3 .
  • R 1 is independently selected from H, D, CN, NO 2 , SF 5 , halogen, C 1- C 6 alkyl, C 3- C 6 cycloalkyl, 4-6 membered heterocycloalkyl, OR A , OC (O) NR C R D , NR C R D , NR C C (O) R B , or NR C C (O) OR A ; wherein, the C 1- C 6 alkyl, C 3- C 6 cycloalkyl or 4-6 membered heterocycloalkyl is optionally substituted with one, two, or three substituents independently selected from D, halogen, CN, OH, NH 2 , NO 2 , oxo, C 1- C 6 alkyl, C 1 -C 6 haloalkyl, -O-C 1 -C 6 alkyl, -OC 1 -C 6 haloalkyl.
  • R 1 is H, D, CN, SF 5 , halogen, C 1- C 6 alkyl, C 3- C 6 cycloalkyl.
  • R 1 is H, D, CN, fluoro, chloro, methyl, cyclopropanyl.
  • R 2 is H, D, halogen, CN, C 1- C 6 alkyl.
  • R 2 is H, D, CN, fluoro, chloro, methyl.
  • Ar 1 is C 6- C 10 aryl optionally substituted with R a , R b , and/or R c .
  • Ar 1 is phenyl optionally substituted with R a , R b , and/or R c .
  • Ar 1 is phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2, 4-dimethoxyphenyl, 2-chlorophenyl, 2-cyanophenyl, 2-cyclopropyloxyphenyl, 2-methoxy-4-fluorophenyl, 2-methoxy-6-fluorophenyl, 2-methoxy-5-chlorophenyl, 2-methoxy-5- (trifluoromethyl) phenyl, 2, 4-dimethoxyphenyl, 2-methoxy-5-cyanophenyl, 2-methoxy-4-cyanophenyl, 2-methoxy-4-cyanophenyl, 2-methoxy-4-cyanophenyl, 2-methoxy-4- (hydroxymethyl) phenyl, 2-methoxy-5-chloro-6-fluorophenyl, 2-methoxy-5-methyl-6-fluorophenyl, 2-methoxy-5-trifluoromethyl-6-fluorophenyl, 2-me
  • Ar 1 is 5-10 membered heteroaryl optionally substituted with R a , R b , and/or R c .
  • Ar 1 is pyrrolyl, pyrazolyl, imidazolyl, 1, 2, 3-triazolyl, furanyl, oxazolyl, thiophenyl, thiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, 1H-indolyl, 1H-indazolyl, 1H-benzo [d] imidazolyl, 1H-benzo [d] [1, 2, 3] triazolyl, benzo [d] thiazolyl, benzo [d] oxazolyl, benzo [d] isoxazolyl, each of the aforementioned ring optionally substituted with R a , R b , and/or R c .
  • Ar 1 is 5-10 membered heterocycloalkyl optionally substituted with R a , R b , and/or R c .
  • Ar 1 is piperidinyl, piperazinyl, morpholinyl, homomorpholinyl, 2-oxopiperazinyl, 2-oxohomopiperazinyl, 3-oxopiperazin-l-yl, 3-oxohomopiperazin-l-yl, 5-oxohomopiperazin-l-yl, tetrahydropyranyl, 3, 6-dihydro-2H-pyranyl, 2-oxo-l, 2-dihydropyridinyl, 5-methylpiperazin-2-onyl, thiomorpholinyl, 1, 1-dioxothiomorpholinyl, 6-oxohexahydropyrrolo [l, 2-a] pyrazin-2 (lH) -yl or 2, 3-dihydro-4H-benzo [b] [l, 4] oxazin-4-yl, 4-oxa-7-azaspiro [2.5] octan-7-yl optional
  • Ar 2 is C 6- C 10 aryl or 5-10 membered heteroaryl optionally substituted with R d , R e and/or R f .
  • Ar 2 is phenyl, pyridinyl or pyrimidinyl optionally substituted with R d , R e and/or R f .
  • Ar 2 is phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3, 4-dichlorophenyl, 3, 5-dichlorophenyl, 4-cyclopropylphenyl, 4- (trifluoromethyl) phenyl, 4-methoxyphenyl, 4-methylphenyl, 4-cyanophenyl, 4- (trifluoromethoxy) phenyl, 5-cyanopyridinyl, 5-chloropyridinyl.
  • R 3 and R 4 are independently selected from H or D.
  • the compounds of Formula (I) are represented by compounds of Formula (IIIa) , (IIIb) , (IIIc) , (IIId) , (IIIe) , (IIIf) , (IIIg) , (IIIh) , (IIIi) , (IIIj) or (IIIk) :
  • R 1 is independently selected from H, D, CN, NO 2 , SF 5 , halogen, C 1- C 6 alkyl, C 3- C 6 cycloalkyl, 4-6 membered heterocycloalkyl, OR A , OC (O) NR C R D , NR C R D , NR C C (O) R B , or NR C C (O) OR A ; wherein, the C 1- C 6 alkyl, C 3- C 6 cycloalkyl or 4-6 membered heterocycloalkyl is optionally substituted with one, two, or three substituents independently selected from D, halogen, CN, OH, NH 2 , NO 2 , oxo, C 1- C 6 alkyl, C 1 -C 6 haloalkyl, -O-C 1 -C 6 alkyl, -OC 1 -C 6 haloalkyl.
  • R 1 is H, D, CN, SF 5 , halogen, C 1- C 6 alkyl, C 3- C 6 cycloalkyl.
  • R 1 is H, D, CN, fluoro, chloro, methyl, cyclopropanyl.
  • R 2 is H, D, halogen, CN, C 1- C 6 alkyl.
  • R 2 is H, D, CN, fluoro, chloro, methyl.
  • Ar 1 is C 6- C 10 aryl optionally substituted with R a , R b , and/or R c .
  • Ar 1 is phenyl optionally substituted with R a , R b , and/or R c .
  • Ar 1 is phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2, 4-dimethoxyphenyl, 2-chlorophenyl, 2-cyanophenyl, 2-cyclopropyloxyphenyl, 2-methoxy-4-fluorophenyl, 2-methoxy-6-fluorophenyl, 2-methoxy-5-chlorophenyl, 2-methoxy-5- (trifluoromethyl) phenyl, 2, 4-dimethoxyphenyl, 2-methoxy-5-cyanophenyl, 2-methoxy-4-cyanophenyl, 2-methoxy-4-cyanophenyl, 2-methoxy-4-cyanophenyl, 2-methoxy-4- (hydroxymethyl) phenyl, 2-methoxy-5-chloro-6-fluorophenyl, 2-methoxy-5-methyl-6-fluorophenyl, 2-methoxy-5-trifluoromethyl -6-fluorophenyl, 2-
  • Ar 1 is 5-10 membered heteroaryl optionally substituted with R a , R b , and/or R c .
  • Ar 1 is pyrrolyl, pyrazolyl, imidazolyl, 1, 2, 3-triazolyl, furanyl, oxazolyl, thiophenyl, thiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, 1H-indolyl, 1H-indazolyl, 1H-benzo [d] imidazolyl, 1H-benzo [d] [1, 2, 3] triazolyl, benzo [d] thiazolyl, benzo [d] oxazolyl, benzo [d] isoxazolyl, each of the aforementioned ring optionally substituted with R a , R b , and/or R c .
  • Ar 1 is 5-10 membered heterocycloalkyl optionally substituted with R a , R b , and/or R c .
  • Ar 1 is piperidinyl, piperazinyl, morpholinyl, homomorpholinyl, 2-oxopiperazinyl, 2-oxohomopiperazinyl, 3-oxopiperazin-l-yl, 3-oxohomopiperazin-l-yl, 5-oxohomopiperazin-l-yl, tetrahydropyranyl, 3, 6-dihydro-2H-pyranyl, 2-oxo-l, 2-dihydropyridinyl, 5-methylpiperazin-2-onyl, thiomorpholinyl, 1, 1-dioxothiomorpholinyl, 6-oxohexahydropyrrolo [l, 2-a] pyrazin-2 (lH) -yl or 2, 3-dihydro-4H-benzo [b] [l, 4] oxazin-4-yl, 4-oxa-7-azaspiro [2.5] octan-7-yl optional
  • Ar 2 is C 6- C 10 aryl or 5-10 membered heteroaryl optionally substituted with R d , R e and/or R f .
  • Ar 2 is phenyl, pyridinyl or pyrimidinyl optionally substituted with R d , R e and/or R f .
  • Ar 2 is phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3, 4-dichlorophenyl, 3, 5-dichlorophenyl, 4-cyclopropylphenyl, 4- (trifluoromethyl) phenyl, 4-methoxyphenyl, 4-methylphenyl, 4-cyanophenyl, 4- (trifluoromethoxy) phenyl, 5-cyanopyridinyl, 5-chloropyridinyl.
  • R 3 and R 4 are independently selected from H or D.
  • the compounds of Formula (I) are represented by compounds of Formula (IIIa) , (IIIb) , (IIIc) or (IIIe) :
  • the compound of Formula (I) is:
  • the present disclosure further provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) , or pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.
  • the present disclosure also provides a method for treating and/or preventing a cancer characterized by overexpression of PolQ in a patient comprising administering to the patient a therapeutically effective amount of the compound of the present disclosure, or a pharmaceutical composition comprising a compound disclosed herein.
  • the present disclosure also provides a method of treating and/or preventing of a cancer in a patient, wherein the cancer is characterized by increased dependence upon MMEJ DSB repair, comprising administering to the patient a therapeutically effective amount of the compound of the present disclosure, or a pharmaceutical composition comprising a compound disclosed herein.
  • the present disclosure also provides a method of treating and/or preventing of a cancer in a patient, wherein the cancer is characterized by HR-deficiency, a reduction or absence of expression of HR-associated genes, comprising administering to the patient a therapeutically effective amount of the compound of the present disclosure, or a pharmaceutical composition comprising a compound disclosed herein.
  • the present disclosure also provides a method of treating and/or preventing of a cancer that is lack of 53BP1/Shieldin complex in a patient, comprising administering to the patient a therapeutically effective amount of the compound of the present disclosure, or a pharmaceutical composition comprising a compound disclosed herein.
  • the present disclosure also provides a method of treating and/or preventing of a cancer, following or not following exposure to PARPi medication, which are resistant to PARPi treatment, comprising administering to the patient a therapeutically effective amount of the compound of the present disclosure, or a pharmaceutical composition comprising a compound disclosed herein.
  • the present disclosure also provides a method of treating and/or preventing of a cancer in a patient, wherein the cancer is characterized by NHEJ deficiency, a reduction or absence of expression of NHEJ-associated genes, comprising administering to the patient a therapeutically effective amount of the compound of the present disclosure, or a pharmaceutical composition comprising a compound disclosed herein.
  • the present invention also provides use of the compound or the pharmaceutical composition of the present disclosure in the manufacture of a medicament for treating a disease characterized by overexpression of PolQ in a patient.
  • the present invention also provides use of the compound or the pharmaceutical composition of the present disclosure in the manufacture of a medicament for treating a disease in a patient, wherein the disease is characterized by increased dependence upon MMEJ DSB repair.
  • the present invention also provides use of the compound or the pharmaceutical composition of the present disclosure in the manufacture of a medicament for treating a cancer in a patient, wherein the cancer is characterized by HR-deficiency, a reduction or absence of expression of HR-associated genes.
  • the present invention also provides use of the compound or the pharmaceutical composition of the present disclosure in the manufacture of a medicament for treating a cancer in a patient that is lack of 53BP1/Shieldin complex.
  • the present invention also provides use of the compound or the pharmaceutical composition of the present disclosure in the manufacture of a medicament for treating a cancer in a patient, wherein the cancer, following or not following exposure to PARPi medication, which are resistant to PARPi treatment.
  • the present invention also provides use of the compound or the pharmaceutical composition of the present disclosure in the manufacture of a medicament for treating a cancer in a patient, wherein the cancer is characterized by NHEJ deficiency, a reduction or absence of expression of NHEJ-associated genes.
  • each linking substituent include both the forward and backward forms of the linking substituent.
  • -NR (CR'R") -includes both -NR (CR'R") -and - (CR'R”) NR-and is intended to disclose each of the forms individually.
  • the Markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable list "alkyl” or “aryl” then it is understood that the "alkyl” or “aryl” represents a linking alkylene group or arylene group, respectively.
  • substituted means that an atom or group of atoms formally replaces hydrogen as a "substituent" attached to another group.
  • substituted refers to any level of substitution, e.g., mono-, di-, tri-, tetra-or penta-substitution, where such substitution is permitted.
  • the substituents are independently selected, and substitution may be at any chemically accessible position. It is to be understood that substitution at a given atom is limited by valency.
  • optionally substituted means unsubstituted or substituted.
  • substituted means that a hydrogen atom is removed and replaced by a substituent.
  • a single divalent substituent e.g., oxo, can replace two hydrogen atoms.
  • Cn-Cm indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons.
  • C 1 -C 6 alkyl is specifically intended to individually disclose methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
  • C 0 alkyl refers to a covalent bond.
  • stable refers to a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and preferably capable of formulation into an efficacious therapeutic agent.
  • alkyl by itself or as part of another substituent, is meant to refer to a saturated hydrocarbon group which is straight-chained or branched.
  • An alkyl group can contain from 1 to about 20, from 2 to about 20, from 1 to about 10, from 1 to about 8, from 1 to about 6, from 1 to about 4, or from 1 to about 3 carbon atoms.
  • C 1-8 as in C 1-8 alkyl is defined to identify the group as having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms in a linear or branched arrangement.
  • Example alkyl groups include, but are not limited to, methyl (Me) , ethyl (Et) , propyl (e.g., n-propyl and isopropyl) , butyl (e.g., n-butyl, isobutyl, t-butyl) , pentyl (e.g., n-pentyl, isopentyl, neopentyl) , and the like.
  • Me methyl
  • Et ethyl
  • propyl e.g., n-propyl and isopropyl
  • butyl e.g., n-butyl, isobutyl, t-butyl
  • pentyl e.g., n-pentyl, isopentyl, neopentyl
  • alkenyl refers to an alkyl group having one or more double carbon-carbon bonds.
  • Example alkenyl groups include, but are not limited to, ethenyl, propenyl, and the like.
  • alkynyl refers to an alkyl group having one or more triple carbon-carbon bonds.
  • Example alkynyl groups include, but are not limited to, ethynyl, propynyl, and the like.
  • haloalkyl refers to an alkyl group having one or more halogen substituents.
  • Example haloalkyl groups include, but are not limited to, CF 3 , C 2 F 5 , CHF 2 , CH 2 F, CCl 3 , CHCl 2 , C 2 Cl 5 , and the like.
  • aryl refers to an unsubstituted or substituted monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbons. In some embodiments, aryl groups have from 6 to about 20 carbon atoms. In some embodiments, aryl groups have from 6 to about 14 carbon atoms. In some embodiments, aryl groups have from 6 to about 10 carbon atoms.
  • Example aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and the like.
  • cycloalkyl refers to an unsubstituted or substituted non-aromatic carbocycles including cyclized alkyl, alkenyl, and alkynyl groups.
  • Cycloalkyl groups can include mono-or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems, including fused rings, spirocyclic rings, and bridged rings (e.g., a bridged bicycloalkyl group) .
  • cycloalkyl groups can have from 3 to about 20 carbon atoms, 3 to about 14 carbon atoms, 3 to about 10 carbon atoms, or 3 to 7 carbon atoms.
  • Cycloalkyl groups can further have 0, 1, 2, or 3 double bonds and/or 0, 1, or 2 triple bonds. Cycloalkyl groups can be optionally substituted by oxo or sulfido (e.g., -C (O) -or -C (S) -) . Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo derivatives of pentane, pentene, hexane, and the like. A cycloalkyl group having one or more fused aromatic rings can be attached though either the aromatic or non-aromatic portion.
  • One or more ring-forming carbon atoms of a cycloalkyl group can be oxidized, for example, having an oxo or sulfido substituent.
  • the cycloalkyl is a C 3 -C 7 monocyclic cycloalkyl.
  • the cycloalkyl is a C 4- C 10 spirocycle or bridged cycloalkyl.
  • Example cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, cubane, adamantane, bicyclo [l. l.
  • cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • cycloalkyl are cyclic-containing, non-aromatic hydrocarbon groups having from 3 to 12 carbon atoms ( “C 3- C 12 ” ) , preferably from 3 to 6 carbon atoms ( “C 3 -C 6 ” ) .
  • cycloalkyl groups include, for example, cyclopropyl (C 3; 3-membered) , cyclobutyl (C 4; 4-membered) , cyclopropylmethyl (C 4 ) , cyclopentyl (C 5 ) , cyclohexyl (C 6 ) , 1-methylcyclopropyl (C 4 ) , 2-methylcyclopentyl (C 4 ) , adamantanyl (C 10 ) , and the like.
  • spirocycloalkyl when used alone or as part of a substituent group refers to a non-aromatic hydrocarbon group containing two cycloalkyl rings, and wherein the two cycloalyl rings share a single carbon atom in common.
  • heteroaryl refers to an unsubstituted or substituted aromatic heterocycle having at least one heteroatom ring member such as boron, sulfur, oxygen, or nitrogen.
  • Heteroaryl groups include monocyclic and polycyclic (e.g., having 2, 3 or 4 fused rings) systems. Any ring-forming N atom in a heteroaryl group can also be oxidized to form an N-oxo moiety.
  • heteroaryl groups include without limitation, pyridyl, N-oxopyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1, 2, 4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, and the like.
  • the heteroaryl group has from 1 to about 20 carbon atoms, and in further embodiments from about 3 to about 20 carbon atoms. In some embodiments, the heteroaryl group contains 3 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, the heteroaryl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms.
  • heterocycloalkyl refers to an unsubstituted or substituted monocyclic (saturated or partially unsaturated ring) or polycyclic heterocycles having at least one non-aromatic ring (saturated or partially unsaturated ring) , wherein one or more of the ring-forming carbon atoms of the heterocycloalkyl is replaced by a heteroatom selected from N, O, S and B, and wherein the ring-forming carbon atoms and heteroatoms of the heterocycloalkyl group can be optionally substituted by one or more oxo or sulfido (e.g., C (O) , S (O) , C (S) , or S (O) 2 , etc.
  • oxo or sulfido e.g., C (O) , S (O) , C (S) , or S (O) 2 , etc.
  • Heterocycloalkyl groups include monocyclic and polycyclic (e.g., having 2 fused rings) systems. Included in heterocycloalkyl are monocyclic and polycyclic 3-10, 4-10, 3-7, 4-7, and 5-6 membered heterocycloalkyl groups. Heterocycloalkyl groups can also include spirocycles and bridged rings (e.g., a 5-10 membered bridged biheterocycloalkyl ring having one or more of the ring-forming carbon atoms replaced by a heteroatom independently selected from N, O, S and B) .
  • the heterocycloalkyl group can be attached through a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds.
  • heterocycloalkyl moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the non-aromatic heterocyclic ring, for example, benzo or thienyl derivatives of piperidine, morpholine, azepine, etc.
  • a heterocycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring.
  • the heterocycloalkyl group contains 3 to 10 ring-forming atoms, 4 to 10 ring-forming atoms, 3 to 7 ring-forming atoms, or 5 to 6 ring-forming atoms.
  • the heterocycloalkyl group has 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms or 1 heteroatom.
  • the heterocycloalkyl is a monocyclic 4-6 membered heterocycloalkyl having 1 or 2 heteroatoms independently selected from N, O, S and B and having one or more oxidized ring members.
  • Example heterocycloalkyl groups include, but are not limited to, pyrrolidin-2-one, l, 3-isoxazolidin-2-one, pyranyl, tetrahydropyran, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, benzazapene, 1, 2, 3, 4-tetrahydroisoquinoline, azabicyclo [3.1.0] hexanyl, diazabicyclo [3.
  • heterocycloalkyl refers to any three to ten membered monocyclic or bicyclic, saturated ring structure containing at least one heteroatom selected from the group consisting of O, N and S.
  • the heterocycloalkyl group may be attached at any heteroatom or carbon atom of the ring such that the result is a stable structure.
  • heterocycloalkyl groups include, but are not limited to, azepanyl, aziridinyl, azetidinyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, piperazinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, oxazepanyl, oxiranyl, oxetanyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, and the like.
  • the term “spiroheterocycloalkyl” when used alone or as part of a substituent group refers to a non-aromatic group containing two rings, at least one of which is a heterocycloalkyl ring, and wherein the two rings share a single carbon atom in common.
  • halo or “halogen” includes fluoro, chloro, bromo, and iodo.
  • alkoxy refers to an –O-alkyl group.
  • Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy) , t-butoxy, and the like.
  • hydroxylalkyl refers to an alkyl group substituted by OH.
  • cyanoalkyl refers to an alkyl group substituted by CN.
  • alkoxyalkyl refers to an alkyl group substituted by an alkoxy group.
  • haloalkoxy refers to an —O- (haloalkyl) group.
  • arylalkyl refers to alkyl substituted by aryl and “cycloalkylalkyl” refers to alkyl substituted by cycloalkyl.
  • An example arylalkyl group is benzyl.
  • heteroarylalkyl refers to alkyl substituted by heteroaryl and “heterocycloalkylalkyl” refers to alkyl substituted by heterocycloalkyl.
  • substituted refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent (s) .
  • the compounds described herein can be asymmetric (e.g., having one or more stereocenters) . All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated.
  • Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton.
  • Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge.
  • Example prototropic tautomers include ketone–enol pairs, amide-imidic acid pairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H-and 3H-imidazole, 1H-, 2H-and 4H-1, 2, 4-triazole, 1H-and 2H-isoindole, and 1H-and 2H-pyrazole; certain hydroxy substituted compounds may exist as tautomers as shown below: Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
  • the compounds of the present disclosure may exist as rotational isomers. Descriptions of a compound of the invention that do not indicate a particular rotational isomer are intended to encompass any individual rotational isomers, as well as mixtures of rotational isomers in any proportion. Depiction of a particular rotational isomer is meant to refer to the depicted rotational isomer, substantially free of other rotational isomers.
  • Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium.
  • the compounds of the invention, and salts thereof are substantially isolated.
  • substantially isolated is meant that the compound is at least partially or substantially separated from the environment in which was formed or detected.
  • Partial separation can include, for example, a composition enriched in the compound of the invention.
  • Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99%by weight of the compound of the invention, or salt thereof. Methods for isolating compounds and their salts are routine in the art.
  • the present disclosure also includes pharmaceutically acceptable salts of the compounds described herein.
  • pharmaceutically acceptable salts refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form.
  • examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts of the present disclosure include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • the pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington’s Pharmaceutical Sciences, 17 th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977) , each of which is incorporated herein by reference in its entirety.
  • phrases “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • a “pharmaceutically acceptable excipient” refers to a substance that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as an inert substance, added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of an agent and that is compatible therewith.
  • excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.
  • a “solvate” refers to a physical association of a compound of Formula I with one or more solvent molecules.
  • Subject includes humans.
  • the terms “human, ” “patient, ” and “subject” are used interchangeably herein.
  • Treating” or “treatment” of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof) .
  • “treating” or “treatment” refers to ameliorating at least one physical parameter, which may not be discernible by the subject.
  • “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom) , physiologically, (e.g., stabilization of a physical parameter) , or both.
  • “treating” or “treatment” refers to delaying the onset of the disease or disorder.
  • Compounds of the present disclosure are meant to embrace compounds of Formula I as described herein, as well as its subgenera, which expression includes the stereoisomers (e.g., entaniomers, diastereomers) and constitutional isomers (e.g., tautomers) of compounds of Formula I as well as the pharmaceutically acceptable salts, where the context so permits.
  • stereoisomers e.g., entaniomers, diastereomers
  • constitutional isomers e.g., tautomers
  • isotopic variant refers to a compound that contains proportions of isotopes at one or more of the atoms that constitute such compound that is greater than natural abundance.
  • an “isotopic variant” of a compound can be radiolabeled, that is, contain one or more radioactive isotopes, or can be labeled with non-radioactive isotopes such as for example, deuterium ( 2 H or D) , carbon-13 ( 13 C) , nitrogen-15 ( 15 N) , or the like.
  • any hydrogen may be 2 H/D
  • any carbon may be 13 C
  • any nitrogen may be 15 N, and that the presence and placement of such atoms may be determined within the skill of the art.
  • isomers compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers. ” Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers, ” for example, diastereomers, enantiomers, and atropisomers.
  • the compounds of this disclosure may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R) -or (S) -stereoisomers at each asymmetric center, or as mixtures thereof.
  • compositions of the present invention comprise a compound represented by Formula (I) (or a pharmaceutically acceptable salt thereof) as an active ingredient, and pharmaceutically acceptable excipients.
  • compositions may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs) , for injection use (for example as aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles) , for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions) , for administration by inhalation (for example as a finely divided powder or a liquid aerosol) , for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous
  • the pharmaceutically acceptable excipient (s) can be selected from, for example, carriers (e.g. a solid, liquid or semi-solid carrier) , adjuvants, diluents, fillers or bulking agents, granulating agents, coating agents, release-controlling agents, binding agents, disintegrants, lubricating agents, preservatives, antioxidants, buffering agents, suspending agents, thickening agents, flavouring agents, sweeteners, taste masking agents, stabilisers or any other excipients conventionally used in pharmaceutical compositions.
  • carriers e.g. a solid, liquid or semi-solid carrier
  • adjuvants e.g. a solid, liquid or semi-solid carrier
  • granulating agents e.g. granulating agents, coating agents, release-controlling agents, binding agents, disintegrants, lubricating agents, preservatives, antioxidants, buffering agents, suspending agents, thickening agents, flavouring agents, sweeteners, taste masking agents, stabilisers or any
  • the pharmaceutical carrier employed can be, for example, a solid, liquid, or gas.
  • solid carriers include such as lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
  • liquid carriers include such as sugar syrup, peanut oil, olive oil, and water.
  • gaseous carriers include such as carbon dioxide and nitrogen.
  • oral liquid preparations such as suspensions, elixirs and solutions
  • carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets.
  • oral solid preparations such as powders, capsules and tablets.
  • tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed.
  • tablets may be coated by standard aqueous or nonaqueous techniques.
  • Pharmaceutical dosage forms suitable for oral administration include tablets (coated or uncoated) , capsules (hard or soft shell) , caplets, pills, lozenges, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets, wafers or patches such as buccal patches.
  • tablet compositions can contain a unit dosage of active compound together with an inert diluent or carrier such as a sugar or sugar alcohol, e.g., lactose, sucrose, sorbitol or mannitol; and/or a non-sugar derived diluent such as sodium carbonate, calcium phosphate, calcium carbonate, or a cellulose or derivative thereof such as microcrystalline cellulose (MCC) , methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, and starches such as corn starch.
  • an inert diluent or carrier such as a sugar or sugar alcohol, e.g., lactose, sucrose, sorbitol or mannitol
  • a non-sugar derived diluent such as sodium carbonate, calcium phosphate, calcium carbonate, or a cellulose or derivative thereof such as microcrystalline cellulose (MCC) , methyl cellulose, ethyl cellulose
  • Tablets may also contain such standard ingredients as binding and granulating agents such as polyvinylpyrrolidone, disintegrants (e.g., swellable crosslinked polymers such as crosslinked carboxymethylcellulose) , lubricating agents (e.g., stearates) , preservatives (e.g., parabens) , antioxidants (e.g., BHT) , buffering agents (for example phosphate or citrate buffers) , and effervescent agents such as citrate/bicarbonate mixtures.
  • binding and granulating agents such as polyvinylpyrrolidone, disintegrants (e.g., swellable crosslinked polymers such as crosslinked carboxymethylcellulose) , lubricating agents (e.g., stearates) , preservatives (e.g., parabens) , antioxidants (e.g., BHT) , buffering agents (for example phosphate or citrate buffers)
  • Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent.
  • molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
  • Each tablet preferably contains from about 0.05mg to about 5g of the active ingredient and each cachet or capsule preferably containing from about 0.05mg to about 5g of the active ingredient.
  • a formulation intended for the oral administration to humans may contain from about 0.5 mg to about 5 g of active agent, compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition.
  • Unit dosage forms will generally contain between from about l mg to about 2 g of the active ingredient, typically 25 mg, 50 mg, l00 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or l000 mg.
  • compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water.
  • a suitable surfactant can be included such as, for example, hydroxypropyl cellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.
  • compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions.
  • the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions.
  • the final injectable form must be sterile and must be effectively fluid for easy syringability.
  • the pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol) , vegetable oils, and suitable mixtures thereof.
  • compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, or the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared, utilizing a compound represented by Formula I of this invention, or a pharmaceutically acceptable salt thereof, via conventional processing methods. As an example, a cream or ointment is prepared by admixing hydrophilic material and water, together with about 5 wt%to about 10 wt%of the compound, to produce a cream or ointment having a desired consistency.
  • compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier (s) followed by chilling and shaping in molds.
  • compositions may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
  • compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and/or preservative agents.
  • An effective amount of a compound of Formula (I) or a pharmaceutically salt thereof for use in therapy is an amount sufficient to treat or prevent a proliferative condition referred to herein, slow its progression and/or reduce the symptoms associated with the condition.
  • a formulation intended for oral administration to humans will generally contain, for example, from 0.1 mg to 1000 mg of Formula (I) or a pharmaceutically salt thereof with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
  • the size of the dose for therapeutic or prophylactic purposes of a compound of the Formula (I) will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine.
  • compositions of this invention may include a pharmaceutically acceptable carrier and a compound, or a pharmaceutically acceptable salt, of Formula I.
  • the compounds of Formula I, or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.
  • the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
  • other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient.
  • dosage levels on the order of from about 0.01 mg/kg to about 150 mg/kg of body weight per day are useful in the treatment of the above-indicated conditions, or alternatively about 0.5 mg to about 7 g per patient per day.
  • colon cancer, rectal cancer, mantle cell lymphoma, multiple myeloma, breast cancer, prostate cancer, glioblastoma, squamous cell esophageal cancer, liposarcoma, T-cell lymphoma melanoma, pancreatic cancer, or lung cancer may be effectively treated by the administration of from about 0.01 to 50 mg of the compound per kilogram of body weight per day, or alternatively about 0.5 mg to about 3.5 g per patient per day.
  • compositions and methods for preparing the same are non-limiting exemplary pharmaceutical compositions and methods for preparing the same.
  • the compounds of Formula (I) or a pharmaceutically salt thereof or pharmaceutical compositions comprising these compounds may be administered to a subject by any convenient route of administration, whether systemically/peripherally or topically (i.e., at the site of desired action) .
  • Routes of administration include, but are not limited to, oral (e.g., by ingestion) ; buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc. ) ; transmucosal (including, e.g., by a patch, plaster, etc.
  • intranasal e.g., by nasal spray
  • ocular e.g., by eye drops
  • pulmonary e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose
  • rectal e.g., by suppository or enema
  • vaginal e.g., by pessary
  • parenteral for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrastemal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly.
  • the method typically comprises administering to a subject a therapeutically effective amount of a compound of the invention.
  • the therapeutically effective amount of the subject combination of compounds may vary depending upon the intended application (in vitro or in vivo) , or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
  • the term also applies to a dose that will induce a particular response in target cells, e.g., reduction of proliferation or downregulation of activity of a target protein.
  • the specific dose will vary depending on the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.
  • IC 50 refers to the half maximal inhibitory concentration of an inhibitor in inhibiting biological or biochemical function. This quantitative measure indicates how much of a particular inhibitor is needed to inhibit a given biological process (or component of a process, i.e. an enzyme, cell, cell receptor or microorganism) by half. In other words, it is the half maximal (50%) inhibitory concentration (IC) of a substance (50%IC, or IC 50 ) .
  • the subject methods utilize a PolQ inhibitor with an IC 50 value of about or less than a predetermined value, as ascertained in an in vitro assay.
  • the PolQ inhibitor inhibits PolQ with an IC 50 value of about 1 nM or less, 2 nM or less, 5 nM or less, 7 nM or less, 10 nM or less, 20 nM or less, 30 nM or less, 40 nM or less, 50 nM or less, 60 nM or less, 70 nM or less, 80 nM or less, 90 nM or less, 100 nM or less, 120 nM or less, 140 nM or less, 150 nM or less, 160 nM or less, 170 nM or less, 180 nM or less, 190 nM or less, 200 nM or less, 225 nM or less, 250 nM or less, 275 nM or less, 300 nM or less, 325
  • PolQ inhibitors in the present invention selectively inhibit PolQ with an IC 50 value that is at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100, or 1000 times less (or a number in the range defined by and including any two numbers above) than its IC 50 s value against Pol ⁇ , Pol ⁇ , Pol ⁇ , Pol ⁇ , Pol ⁇ , Pol ⁇ and other DNA polymerases.
  • PolQ inhibitors in the present invention selectively inhibit PolQ with an IC 50 value that is less than about 1 nM, 2 nM, 5 nM, 7 nM, 10 nM, 20 nM, 30 nM, 40 nM, 50 nM, 60 nM, 70 nM, 80 nM, 90 nM, 100 nM, 120 nM, 140 nM, 150 nM, 160 nM, 170 nM, 180 nM, 190 nM, 200 nM, 225 nM, 250 nM, 275 nM, 300 nM, 325 nM, 350 nM, 375 nM, 400 nM, 425 nM, 450 nM, 475 nM, 500 nM, 550 nM, 600 nM, 650 nM, 700 nM, 750 nM, 800 nM, 850 nM, 900 nM,
  • the subject methods are useful for treating a disease condition associated with PolQ. Any disease condition that results directly or indirectly from an abnormal activity or expression level of PolQ can be an intended disease condition.
  • Non-limiting examples of such conditions include but are not limited to breast cancer, invasive ductal carcinoma, invasive lobular carcinoma, Paget's disease of the breast, hereditary breast-ovarian cancer syndrome, medullary breast cancer, mucinous breast cancer, inflammatory breast cancer, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor, gastric cancer, gastric lymphoma, gastrointestinal cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, gastrointestinal stromal tumor, prostate cancer, acinar adenocarcinoma of prostate, prostatic ductal adenocarcinoma, prostate sarcoma, small cell prostate cancer, squamous cell prostate cancer, pancreatic cancer, exocrine pancreatic cancer, neuroendocrine pancreatic cancer, uterine cancer, uterine sarcoma, uterine corpus sarcoma, cervical cancer, squamous cell cervical cancer, cervical adenocar
  • Compounds of the disclosure can be used in the treatment and/or prevention of a disease in a patient, wherein the disease is characterized by overexpression of PolQ.
  • PolyQ overexpression refers to the increased expression or activity of PolQ enzyme in a diseased cell e.g., cancer cell, relative to expression or activity of PolQ enzyme in a control cell (e.g., non-diseased cell of the same type) .
  • the amount of the amount of PolQ overexpression can be at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, PolQ overexpression can be at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 10-fold, at least 20-fold, at least 50-fold, relative to PolQ expression in a control cell.
  • PolQ overexpressing cancers include, but are not limited to, certain ovarian, breast, cervical, uterine, pancreatic, lung, colorectal, gastric, bladder, and prostate cancers.
  • Compounds of the disclosure can be used in the treatment and/or prevention of a disease in a patient, wherein the disease is characterized by increased dependence upon MMEJ DSB repair.
  • Compounds of the disclosure can be used in the treatment and/or prevention of a cancer in a patient, wherein the cancer is characterized by HR-deficiency, a reduction or absence of expression of HR-associated genes, including but not limited to, ATM, ATR, BARD1, BLM, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, CtIP (BCL11A) , ERCC4 (FANCQ) , FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANJ (BRIP1) , FANCL, FANCM, FANCN (PALB2) , FANCP (SLX4) , LIG1, MRE11, NBS1, NBN, PTEN, RAD50, RAD51B, RAD51C, RAD54, RECQL4, RPA1, RPA2, SMARCA2, SMARCA4, WRN, and XRCC2.
  • HR-deficiency a reduction or absence
  • said method is for use in the treatment or prevention of HR-deficient breast cancer, but is not limited to, lobular carcinoma in situ, a ductal carcinoma in situ , an invasive ductal carcinoma, triple negative, HER positive, estrogen receptor positive, progesterone receptor positive, HER and estrogen receptor positive, HER and estrogen and progesterone receptor positive, inflammatory breast cancer, Paget disease of nipple, Phyllodes tumor, angiosarcoma, adenoid cystic carcinoma, low-grade adenosquamous carcinoma, medullary carcinoma, mucinous carcinoma, papillary carcinoma, tubular carcinoma, metaplastic carcinoma, micropapillary carcinoma, and mixed carcinoma.
  • said method is for use in the treatment or prevention of HR-deficient ovarian cancer, but is not limited to, epithelial ovarian carcinomas, maturing teratomas, dysgerminomas, endodermal sinus tumors, granulosa-theca tumors, Sertoli-Leydig cell tumors, and primary peritoneal carcinoma.
  • said method is for use in the treatment or prevention of HR-deficient prostate cancer, but is not limited to, prostate cancer, acinar adenocarcinoma of prostate, prostatic ductal adenocarcinoma, prostate sarcoma, small cell prostate cancer, squamous cell prostate cancer.
  • said method is for use in the treatment or prevention of HR-deficient pancreatic cancer, but is not limited to, pancreatic cancer, exocrine pancreatic cancer, neuroendocrine pancreatic cancer.
  • Compounds of the disclosure can be used in the treatment or prevention of a cancer that is lack of 53BP1/Shieldin complex in a patient.
  • cancers include, but are not limited to, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, lung cancer, bladder cancer, liver cancer, head and neck cancer, gastrointestinal cancer and colorectal cancer.
  • Compounds of the disclosure can be used in the treatment or prevention of a cancer, following or not following exposure to PARPi medication, which are resistant to PARPi treatment.
  • cancers that are resistant to PARP-inhibitors include, but are not limited to, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, lung cancer, bladder cancer, liver cancer, head and neck cancer, gastrointestinal cancer and colorectal cancer.
  • Compounds of the disclosure can be used in the treatment and/or prevention of a cancer in a patient, wherein the cancer is characterized by NHEJ deficiency, a reduction or absence of expression of NHEJ-associated genes, including but not limited to, 53BP1, DCLRE1C, LIG4, NHEJ1, POLL, POLM, PRKDC, RIF1, SHLD1, SHLD2, SHLD3, XRCC4, XRCC5 and XRCC6.
  • said method is for use in the treatment or prevention of lymphoma, soft tissue, rhabdoid, multiple myeloma, uterus, gastric, peripheral nervous system, rhabdomyosarcoma, bone, colorectal, mesothelioma, breast, ovarian, lung, fibroblast, central nervous system, urinary tract, upper aerodigestive, leukemia, kidney, skin, esophagus, and pancreas (data from large scale drop out screens in cancer cell lines indicate that some cell lines from the above cancers are dependent on PolQ for proliferation see https: //depmap. org/portal/) .
  • said method is for treating a disease selected from breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon cancer, ovarian cancer, uterine cancer, or cervical cancer.
  • said method is for treating a disease selected from leukemia such as acute myeloid leukemia (AML) , acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, myelodysplasia, myeloproliferative disorders, chronic myelogenous leukemia (CML) , mastocytosis, chronic lymphocytic leukemia (CLL) , multiple myeloma (MM) , myelodysplastic syndrome (MDS) or epidermoid cancer.
  • AML acute myeloid leukemia
  • CML chronic lymphocytic leukemia
  • CLL chronic lymphocytic leukemia
  • MDS myelodysplastic syndrome
  • Medical therapies include, for example, surgery and radiotherapy (e.g., gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, systemic radioactive isotopes) .
  • radiotherapy e.g., gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, systemic radioactive isotopes
  • compounds of the disclosure as well as pharmaceutical compositions comprising them, can be administered to treat any of the described diseases, alone or in combination with one or more other agents.
  • the compounds of the disclosure as well as pharmaceutical compositions comprising them, can be administered in combination with agonists of nuclear receptors agents.
  • the compounds of the disclosure as well as pharmaceutical compositions comprising them, can be administered in combination with antagonists of nuclear receptors agents.
  • the compounds of the disclosure as well as pharmaceutical compositions comprising them, can be administered in combination with an anti-proliferative agent.
  • the compounds of the present invention may be used as a single agent or combined with other treatments.
  • Such treatment may include one or more of the following categories of cancer therapies: such as surgery, chemotherapies, radiation therapies, targeted therapy (for example growth factor inhibitors, kinase inhibitors, cyclin dependent kinase inhibitors and so on) , other DDR modulators (for example PARP inhibitor, DNA-PK inhibitor, ATM inhibitor, ATR inhibitor, CHK1 inhibitor, WEE1 inhibitor, CDK1 inhibitor, LIG4 inhibitor, HIF-1 inhibitor, HDAC inhibitor, RAD51 inhibitor, WRN inhibitor, PRMT5 inhibitor, MAT2A inhibitor, USP1 inhibitor, PARG inhibitor and PKMYT1 inhibitor and so on) , immunotherapies, and gene and cell therapy approaches.
  • cancer therapies such as surgery, chemotherapies, radiation therapies, targeted therapy (for example growth factor inhibitors, kinase inhibitors, cyclin dependent kinase inhibitors and so on) , other DDR modulators (for example PARP inhibitor,
  • the compounds of the invention can be used in combination with a medical therapy such as surgery, radiotherapy or chemotherapy.
  • a medical therapy such as surgery, radiotherapy or chemotherapy.
  • radiotherapies include gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes.
  • chemotherapeutic agents include one or more of the following categories of anti-tumor agents: other antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas) ; antimetabolites (for example gemcitabine and antifolates such as fluoropyrimi dines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea) ; antitumor antibiotics (for example anthracyclines like bleomycin, doxorubicin, daunomycin, epimbicin, idarubicin, mitomycin-C, dactinomycin and mithramycin)
  • the compounds of the invention can be used in combination with targeted therapies, including inhibitors of growth factor function (for example the anti-erbB2 antibody trastuzumab, the anti-EGFR antibody panitumumab, the anti-erbB antibody cetuximab and any growth factor or growth factor receptor antibodies disclosed by Stem et al. (Critical reviews in oncology/haematology, 2005, Vol.
  • inhibitors also include tyrosine kinase inhibitors (for example inhibitors of the EGFR family tyrosine kinase inhibitors such as gefitinib, erlotinib and Cl 1033) , erbB2 tyrosine kinase inhibitors such as lapatinib; inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; inhibitors of the platelet-derived growth factor family such as imatinib and/or nilotinib; inhibitors of serine/threonine kinases (for example Ras/Raf inhibitors such as sorafenib, tipifamib and lonafamib) ; inhibitors of cell proliferation through MEK and/or AKT kinases; c-kit inhibitors; abl kinase inhibitors; PI3 kinase inhibitors; Flt3 kinase inhibitors, CSF-
  • the reactions for preparing compounds of the invention can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis.
  • suitable solvents can be substantially non-reactive with the starting materials (reactants) , the intermediates or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature.
  • a given reaction can be carried out in one solvent or a mixture of more than one solvent.
  • suitable solvents for a particular reaction step can be selected by the skilled artisan.
  • Preparation of compounds of the invention can involve the protection and deprotection of various chemical groups.
  • the need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art.
  • the chemistry of protecting groups is described, e.g., in Kocienski, Protecting Groups, (Thieme, 2007) ; Robertson, Protecting Group Chemistry, (Oxford University Press, 2000) ; Smith el ah, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th Ed. (Wiley, 2007) ; Peturssion et al, Protecting Groups in Carbohydrate Chemistry, J Chem. Educ., 1997, 74 (11) , 1297; and Wuts et al., Protective Groups in Organic Synthesis, 4th Ed., (Wiley, 2006) .
  • Reactions can be monitored according to any suitable method known in the art.
  • product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C) , infrared spectroscopy, spectrophotometry (e.g., UV-visible) , or mass spectrometry, or by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography.
  • spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C) , infrared spectroscopy, spectrophotometry (e.g., UV-visible) , or mass spectrometry
  • chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography.
  • ambient temperature e.g. a reaction temperature
  • room temperature e.g. a temperature that is about the temperature of the room in which the reaction is carried out, for example, a temperature from about 20 °C to about 30 °C.
  • a series of heterocyclic amide derivatives of formula (I) can be prepared as the methods described in Scheme 1.
  • Compounds (I) can be prepared by reactions of carboxylic acids 1-1 with a substitute 1, 3, 4-thiadiazol-2-amine derivatives 1-2 under standard amide coupling conditions (e.g., in the presence of an activating reagent such as BOP, PyBOP, HATU, HBTU, EDCI, or T 3 P and a base, such as Hunig’s base, Et 3 N, pyridine or DMAP) .
  • treatment of the carboxylic acids 1-1 with the chlorine reagent such as oxalyl dichloride, thionyl chloride, POCl 3 or TCFH can produce the corresponding acid chlorides 1-3 which is subsequently coupled with the appropriate amine 1-2 to yield the corresponding compounds of formula (I) .
  • a series of heterocyclic amide derivatives of formula (I) can be prepared as the methods described in Scheme 2.
  • Compounds 2-3 can be prepared by reactions of carboxylic acids 2-1 with a substitute 1, 3, 4-thiadiazol-2-amine derivatives 2-2in a similar manner as those described in the scheme 1.
  • a palladium catalyst such as Pd (OAc) 2 , Pd (dppf) Cl 2 , Pd 2 (dba) 3 , Pd (PPh 3 ) 4
  • a base such as t-BuOK, t-BuONa, C
  • Suzuki coupling of amide derivatives 2-3 where X is carbon, W is boronic acid or boronic acid ester with Ar 1 -V where V is halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) under standard Suzuki coupling conditions e.g., in the presence of a palladium catalyst, such as Pd (OAc) 2 , Pd (dppf) Cl 2 , Pd 2 (dba) 3 , Pd (PPh 3 ) 4 and a base, such as t-BuOK, t-BuONa, Cs 2 CO 3 , K 2 CO 3 , or Na 2 CO 3
  • a palladium catalyst such as Pd (OAc) 2 , Pd (dppf) Cl 2 , Pd 2 (dba) 3 , Pd (PPh 3 ) 4
  • a base such as t-BuOK, t-BuONa, Cs 2 CO 3 , K 2 CO
  • a palladium catalyst and ligand such as BrettPhos Pd G3, t-BuXphos Pd G3, RuPhos Pd G3 or XantPhos Pd G3 and a base, such as t-BuOK, t-BuONa, Cs 2 CO 3
  • halogen e.g., Cl, Br, or I
  • pseudohalogen e.g., OTf or OMs
  • a copper catalyst such as CuI, CuTC, Cu 2 O or CuCl
  • ligand such as proline, 1, 10-Phenanthroline, BINOL or N, N'-Dimethylethylenediamine
  • Chan-Lam coupling of amide derivatives 2-3 where X is nitrogen, W is hydrogen with Ar 1 -V where V is boronic acid or boronic acid ester under standard Chan-Lam coupling conditions e.g., in the presence of a copper catalyst such as Cu (OAc) 2 , CuCl 2 , or CuBr 2 and base such as DBU, TEA, t-BuOK, or t-BuONa
  • a copper catalyst such as Cu (OAc) 2 , CuCl 2 , or CuBr 2 and base
  • base such as DBU, TEA, t-BuOK, or t-BuONa
  • a series of heterocyclic derivatives of formula (I) can be prepared as the methods described in Scheme 3.
  • Compounds 3-4 can be prepared by reactions of carboxylic acids 3-1 with a substitute 1, 3, 4-thiadiazol-2-amine derivatives 3-2 in a similar manner as those described in the scheme 1.
  • Compounds 3-5 where V is Cl, Br, I, OMs, or OTs can be prepared by treatment of the alcohol 3-4 with the halogen reagent (e.g., SOCl 2 , NBS or PBr 3 ) or pseudohalogen reagent (MsCl, TsCl, or Ms 2 O) .
  • the halogen reagent e.g., SOCl 2 , NBS or PBr 3
  • pseudohalogen reagent MsCl, TsCl, or Ms 2 O
  • Compounds of formula (I) can be prepared by reactions of compounds 3-5 with a Ar 2 Y-H under a base (e.g., Hunig’s base, Et 3 N, DBU, NaH, NaHMDS, t-BuOK or LDA) .
  • a base e.g., Hunig’s base, Et 3 N, DBU, NaH, NaHMDS, t-BuOK or LDA
  • W is the halogen (e.g., F, Cl, Br or I) or pseudohalogen group (OMs, OTf, or OTs)
  • a base e.g., Hunig’s base, Et 3 N, DBU, NaH, NaHMDS, t-BuOK or LDA
  • Heterocyclic acid intermediates of formula 4-3 can be prepared as the methods described in Scheme 4.
  • C-C or C-N bond coupling of compounds 4-1 and Ar 1 -V can provide ester compounds 4-2 by the methods Suzuki coupling, Buchwald coupling, Ullmann coupling and Cham-Lam coupling described in Scheme 2.
  • Saponification of the compounds 4-2 can yield the corresponding acid 4-3 under a base such as LiOH, NaOH, KOH or Me 3 SnOH.
  • some carboxylic acids 4-4 and Ar 1 -V can directly provide corresponding acid 4-3 by the methods Suzuki coupling, Buchwald coupling, Ullmann coupling and Cham-Lam coupling described in Scheme 2.
  • 1, 3, 4-thiadiazol-2-amine derivatives 5-3 can be prepared as the methods described in Scheme 5. Substitution of ICH 2 COONa and BrCN by Ar 2 Y-H under a base such as such as t-BuOK, t-BuONa, Cs 2 CO 3 , K 2 CO 3 , Na 2 CO 3 , NaH, NaHMDS, or LDA can provide carboxylic acids 5-1 and cyanide 5-2. 1, 3, 4-thiadiazol-2-amine derivatives 5-3 can be prepared by treatment of thiosemicarbazide under a dehydrant such as POCl 3 , TFA, PCl 5 , P 2 O 5 or PPA.
  • a dehydrant such as POCl 3 , TFA, PCl 5 , P 2 O 5 or PPA.
  • Step 1 ethyl 1- (2-methoxyphenyl) -1H-imidazole-5-carboxylate
  • Step 2 1- (2-methoxyphenyl) -1H-imidazole-5-carboxylic acid
  • Step 4 N- (5- ( (4-chlorophenoxy) methyl) -1, 3, 4-thiadiazol-2-yl) -1- (2-methoxyphenyl) -1H-imidazole-5-carboxamide
  • Step 4 5- ( ( (4-chlorophenyl) amino) methyl) -1, 3, 4-thiadiazol-2-amine
  • POCl 3 (33.0 g, 215 mmol) was added to a mixture of (4-chlorophenyl) glycine (5.00 g, 26.9 mmol) and hydrazinecarbothioamide (2.46 g, 26.9 mmol) .
  • the reaction mixture was stirred at 65 °Cunder N 2 atmosphere for 1 h.
  • the mixture was poured into ice-water (100 mL) and stirred at 0 °Cfor 20 min., and extracted with EtOAc (10 mL ⁇ 3) .
  • the combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • Step 5 5- ( ( (4-chlorophenyl) amino) methyl) -1, 3, 4-thiadiazol-2-amine)
  • Step 1 methyl N- (4-chlorophenyl) -N-methylglycinate
  • Step 2 N- (5- ( ( (4-chlorophenyl) (methyl) amino) methyl) -1, 3, 4-thiadiazol-2-yl) -3- (2-methoxyphenyl) isonicotinamide
  • Step 2 methyl 4- (2-methoxyphenyl) -6-methylnicotinate
  • Step 3 4- (2-methoxyphenyl) -6-methylnicotinic acid
  • Step 4 N- (5- ( (4-chlorophenoxy) methyl) -1, 3, 4-thiadiazol-2-yl) -4- (2-methoxyphenyl) -6-methylnicotinamide
  • Example 3 Step 2 This compound was prepared using procedures analogous to those described for Example 5 Step 4 using intermediate 5- ( (4-chlorophenoxy) methyl) -1, 3, 4-thiadiazol-2-amine (Example 1 Step 3) and 3- (2-methoxyphenyl) isonicotinic acid (Example 3 Step 2) as the starting material.
  • Step 1 methyl 3- (2-fluoro-6-methoxyphenyl) isonicotinate
  • Step 3 N- (5- ( (4-chlorophenoxy) methyl) -1, 3, 4-thiadiazol-2-yl) -3- (2-fluoro-6-methoxy phenyl) isonicotinamide
  • Step 2 5- ( (4-cyclopropylphenoxy) methyl) -1, 3, 4-thiadiazol-2-amine
  • Step 3 N- (5- ( (4-cyclopropylphenoxy) methyl) -1, 3, 4-thiadiazol-2-yl) -4- (2-methoxyphenyl) -6-methylnicotinamide
  • Example 10 4- (5-Chloro-2-methoxyphenyl) -N- (5- ( (4-chlorophenoxy) methyl) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
  • Example 12 4- (2-Methoxyphenyl) -6-methyl-N- (5- ( (4- (trifluoromethyl) phenoxy) methyl) -1, 3, 4-thiadiazol-2-yl) nicotinamide
  • Step 1 5- ( (4- (trifluoromethoxy) phenoxy) methyl) -1, 3, 4-thiadiazol-2-amine
  • Step 2 4- (2-methoxyphenyl) -6-methyl-N- (5- ( (4- (trifluoromethyl) phenoxy) methyl) -1, 3, 4-thiadiazol -2-yl) nicotinamide
  • This compound was prepared using procedures analogous to those described for Example 5 Step 4 using intermediate 4- (2-methoxyphenyl) -6-methylnicotinic acid (Example 5 Step 3) and 5- ( (4- (trifluoromethoxy) phenoxy) methyl) -1, 3, 4-thiadiazol-2-amine as the starting material.
  • Example 13 4- (2-Methoxyphenyl) -6-methyl-N- (5- ( (4- (trifluoromethoxy) phenoxy) methyl) -1, 3, 4-thiadiazol-2-yl) nicotinamide
  • Step 1 5- ( (4- (trifluoromethoxy) phenoxy) methyl) -1, 3, 4-thiadiazol-2-amine
  • Step 2 4- (2-methoxyphenyl) -6-methyl-N- (5- ( (4- (trifluoromethoxy) phenoxy) methyl) -1, 3, 4-thiadiazol-2-yl) nicotinamide
  • This compound was prepared using procedures analogous to those described for Example 5 Step 4 using intermediate 4- (2-methoxyphenyl) -6-methylnicotinic acid (Example 5 Step 3) and 5- ( (4- (trifluoromethoxy) phenoxy) methyl) -1, 3, 4-thiadiazol-2-amine as the starting material.
  • Step 1 4- ( (5-amino-1, 3, 4-thiadiazol-2-yl) methoxy) benzonitrile
  • thiosemicarbazide 1.2 g, 6.3 mmol
  • 2- (4-cyanophenoxy) acetic acid 900 mg, 5.0 mmol
  • POCl 3 8 mL was added dropwise into the mixture at 0 °C. The mixture was stirred at 75 °C for 1 h. The reaction mixture was cooled and poured into the ice water 30 mL at 0 °C and stirred for 2 h.
  • Step 2 N- (5- ( (4-cyanophenoxy) methyl) -1, 3, 4-thiadiazol-2-yl) -4- (2-methoxyphenyl) -6-methylnicotinamide
  • This compound was prepared using procedures analogous to those described for Example 5 Step 4 using intermediate 4- ( (5-amino-1, 3, 4-thiadiazol-2-yl) methoxy) benzonitrile and 4- (2-methoxyphenyl) -6-methylnicotinic acid (Example 5 Step 3) as the starting material.
  • Step 1 4- (5-cyano-2-methoxyphenyl) -6-methylnicotinic acid
  • Step 2 N- (5- ( (4-chlorophenoxy) methyl) -1, 3, 4-thiadiazol-2-yl) -4- (5-cyano-2-methoxyphenyl) -6-methylnicotinamide
  • This compound was prepared using procedures analogous to those described for Example 5 Step 4 using intermediate 5- ( (4-chlorophenoxy) methyl) -1, 3, 4-thiadiazol-2-amine (Example 1 Step 3) and 4- (5-cyano-2-methoxyphenyl) -6-methylnicotinic acid as the starting material.
  • Step 1 6-cyano-4- (5-fluoro-2-methoxyphenyl) nicotinic acid
  • Step 2 5- ( ( (tert-butyldimethylsilyl) oxy) methyl) -1, 3, 4-thiadiazol-2-amine
  • Step 3 N- (5- ( ( (tert-butyldimethylsilyl) oxy) methyl) -1, 3, 4-thiadiazol-2-yl) -6-cyano-4- (5-fluoro-2-methoxyphenyl) nicotinamide
  • Step 4 6-cyano-4- (5-fluoro-2-methoxyphenyl) -N- (5- (hydroxymethyl) -1, 3, 4-thiadiazol-2-yl) -nicotinamide
  • Step 5 6-cyano-N- (5- ( ( (5-cyanopyridin-2-yl) oxy) methyl) -1, 3, 4-thiadiazol-2-yl) -4- (5-fluoro-2-methoxyphenyl) nicotinamide
  • Step 1 6-cyano-4- (2-methoxyphenyl) nicotinic acid
  • Step 2 N- (5- ( (4-chlorophenoxy) methyl) -1, 3, 4-thiadiazol-2-yl) -6-cyano-4- (2-methoxyphenyl) nicotinamide
  • This compound was prepared using procedures analogous to those described for Example 5 Step 4 using intermediate 5- ( (4-chlorophenoxy) methyl) -1, 3, 4-thiadiazol-2-amine (Example 1 Step 3) and 6-cyano-4- (2-methoxyphenyl) nicotinic acid as the starting material.
  • Example 19 4- (5-Cyano-2-methoxyphenyl) -N- (5- ( ( (5-cyanopyridin-2-yl) oxy) methyl) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
  • Step 1 N- (5- ( ( (tert-butyldimethylsilyl) oxy) methyl) -1, 3, 4-thiadiazol-2-yl) -4- (5-cyano-2-methoxyphenyl) -6-methylnicotinamide
  • Example 17 Step 2 This compound was prepared using procedures analogous to those described for Example 17 Step 3 using intermediate 4- (5-cyano-2-methoxyphenyl) -6-methylnicotinic acid (Example 15 Step 2) and 5- ( ( (tert-butyldimethylsilyl) oxy) methyl) -1, 3, 4-thiadiazol-2-amine (Example 17 Step 2) .
  • Step 2 4- (5-cyano-2-methoxyphenyl) -N- (5- (hydroxymethyl) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
  • Step 3 4- (5-cyano-2-methoxyphenyl) -N- (5- ( ( (5-cyanopyridin-2-yl) oxy) methyl) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
  • Example 21 4- (3-Chloro-2-fluoro-6-methoxyphenyl) -N- (5- ( (4-chlorophenoxy) methyl) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
  • Step 1 (3-chloro-2-fluoro-6-methoxyphenyl) boronic acid
  • the combined organic layers were washed with brine (40 mL) , dried over Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • the residue was purified by flash chromatography on a silica gel column eluting with EtOAc/PE (0%to 20%) to yield (3-chloro-2-fluoro-6-methoxyphenyl) boronic acid (1.6 g) as an off-white solid.
  • Step 2 methyl 4- (3-chloro-2-fluoro-6-methoxyphenyl) -6-methylnicotinate
  • Step 3 4- (3-cyano-2-fluoro-6-methoxyphenyl) -6-methylnicotinic acid
  • Step 4 4- (3-chloro-2-fluoro-6-methoxyphenyl) -N- (5- ( (4-chlorophenoxy) methyl) -1, 3, 4-thiadiazol -2-yl) -6-methylnicotinamide
  • This compound was prepared using procedures analogous to those described for Example 5 Step 4 using intermediate 5- ( (4-chlorophenoxy) methyl) -1, 3, 4-thiadiazol-2-amine (Example 1 Step 3) and 4- (3-cyano-2-fluoro-6-methoxyphenyl) -6-methylnicotinic acid as the starting material.
  • Example 22 N- (5- ( (4-Cyanophenoxy) methyl) -1, 3, 4-thiadiazol-2-yl) -4- (2-fluoro-6-methoxy-3- (trifluoromethyl) phenyl) -6-methylnicotinamide
  • Step 1 2-fluoro-6-methoxy-3- (trifluoromethyl) phenyl) boronic acid
  • Step 2 methyl 4- (2-fluoro-6-methoxy-3- (trifluoromethyl) phenyl) -6-methylnicotinate
  • Step 3 4- (2-fluoro-6-methoxy-3- (trifluoromethyl) phenyl) -6-methylnicotinic acid
  • Step 4 4- ( (5-amino-1, 3, 4-thiadiazol-2-yl) methoxy) benzonitrile
  • Step 5 N- (5- ( (4-cyanophenoxy) methyl) -1, 3, 4-thiadiazol-2-yl) -4- (2-fluoro-6-methoxy-3- (trifluoromethyl) phenyl) -6-methylnicotinamide
  • Example 14 Step 1 This compound was prepared using procedures analogous to those described for Example 5 Step 4 using 4- (2-fluoro-6-methoxy-3- (trifluoromethyl) phenyl) -6-methylnicotinic acid 4- ( (5-amino-1, 3, 4-thiadiazol-2-yl) methoxy) benzonitrile (Example 14 Step 1) to give the title compound as white solid.
  • Example 23 Step 3 This compound was prepared using procedures analogous to those described for Example 1 Step 4 using intermediate 5- ( (4-chlorophenoxy) methyl) -1, 3, 4-thiadiazol-2-amine. (Example 1 Step 3) and 4- (2-fluoro-6-methoxy-3- (trifluoromethyl) phenyl) -6-methylnicotinic acid (Example 23 Step 3) .
  • Step 1 (3-cyano-2-fluoro-6-methoxyphenyl) boronic acid
  • the combined organic layers were washed with brine (40 mL) , dried over Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • the residue was purified by column chromatography on a silica gel column eluting with EtOAc/PE (1%-20%) to yield (3-cyano-2-fluoro-6-methoxyphenyl) boronic acid (1.20 g) as an off-white solid.
  • Step 2 N- (5- ( (4-chlorophenoxy) methyl) -1, 3, 4-thiadiazol-2-yl) -4- (2, 3-difluoro-6-methoxyphenyl) -6-methylnicotinamide
  • Step 1 (2-fluoro-4-methoxy-3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) methanol
  • Step 2 N- (5- ( (4-chlorophenoxy) methyl) -1, 3, 4-thiadiazol-2-yl) -4- (2-fluoro-3- (hydroxymethyl) -6-methoxyphenyl) -6-methylnicotinamide
  • This compound was prepared using procedures analogous to those described for Example 5 Step 2-4 using (2-fluoro-4-methoxy-3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) methanol to replace 2-methoxyphenylboronic acid in Step 2.
  • Example 28 4- (3-Chloro-2-fluoro-6-methoxyphenyl) -6-methyl-N- (5- ( ( (2-oxo-2, 3-dihydrobenzo [d] oxazol-5-yl) oxy) methyl) -1, 3, 4-thiadiazol-2-yl) nicotinamide
  • Step 1 2- ( (2-oxo-2, 3-dihydrobenzo [d] oxazol-5-yl) oxy) acetonitrile
  • Step 2 5- ( (5-amino-1, 3, 4-thiadiazol-2-yl) methoxy) benzo [d] oxazol-2 (3H) -one
  • Step 3 4- (3-chloro-2-fluoro-6-methoxyphenyl) -6-methyl-N- (5- ( ( (2-oxo-2, 3-dihydrobenzo [d] oxazol -5-yl) oxy) methyl) -1, 3, 4-thiadiazol-2-yl) nicotinamide
  • Step 1 5-methoxy-6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-indole
  • Step 2 methyl 4- (5-methoxy-1H-indol-6-yl) -6-methylnicotinate
  • Step 3 4- (5-methoxy-1H-indol-6-yl) -6-methylnicotinic acid
  • Step 4 N- (5- ( (4-chlorophenoxy) methyl) -1, 3, 4-thiadiazol-2-yl) -4- (5-methoxy-1H-indol-6-yl) -6-methylnicotinamide
  • Step 1 methyl 4- (5-methoxy-1-methyl-1H-indol-6-yl) -6-methylnicotinate
  • Step 2 4- (5-methoxy-1-methyl-1H-indol-6-yl) -6-methylnicotinic acid
  • Step 3 N- (5- ( (4-chlorophenoxy) methyl) -1, 3, 4-thiadiazol-2-yl) -4- (5-methoxy-1-methyl-1H-indol-6-yl) -6-methylnicotinamide
  • Step 1 5- ( (3-chlorophenoxy) methyl) -1, 3, 4-thiadiazol-2-amine
  • Step 2 N- (5- ( (3-chlorophenoxy) methyl) -1, 3, 4-thiadiazol-2-yl) -4- (2-methoxyphenyl) -6-methylnicotinamide
  • This compound was prepared using procedures analogous to those described for Example 5 Step 4 using intermediate 4- (2-methoxyphenyl) -6-methylnicotinic acid (Example 5 Step 3) and 5- ( (3-chlorophenoxy) methyl) -1, 3, 4-thiadiazol-2-amine as the starting material.
  • Step 1 5- ( (3, 4-dichlorophenoxy) methyl) -1, 3, 4-thiadiazol-2-amine
  • Step 2 N- (5- ( (3, 4-dichlorophenoxy) methyl) -1, 3, 4-thiadiazol-2-yl) -4- (2-methoxyphenyl) -6-methylnicotinamide
  • This compound was prepared using procedures analogous to those described for Example 5 Step 4 using intermediate 4- (2-methoxyphenyl) -6-methylnicotinic acid (Example 5 Step 3) and 5- ( (3, 4-dichlorophenoxy) methyl) -1, 3, 4-thiadiazol-2-amine as the starting material.
  • Step 1 5- ( (2-chlorophenoxy) methyl) -1, 3, 4-thiadiazol-2-amine
  • Step 2 N- (5- ( (2-chlorophenoxy) methyl) -1, 3, 4-thiadiazol-2-yl) -4- (2-methoxyphenyl) -6-methylnicotinamide#
  • This compound was prepared using procedures analogous to those described for Example 5 Step 4 using intermediate 4- (2-methoxyphenyl) -6-methylnicotinic acid (Example 5 Step 3) and 5- ( (2-chlorophenoxy) methyl) -1, 3, 4-thiadiazol-2-amine as the starting material.
  • Step 1 ethyl 6-chloro-4- (2-methoxyphenyl) nicotinate
  • Step 2 ethyl 6-cyclopropyl-4- (2-methoxyphenyl) nicotinate
  • Step 3 6-cyclopropyl-4- (2-methoxyphenyl) nicotinic acid
  • Step 4 N- (5- ( (4-chlorophenoxy) methyl) -1, 3, 4-thiadiazol-2-yl) -6-cyclopropyl-4- (2-methoxyphenyl) nicotinamide
  • This compound was prepared using procedures analogous to those described for Example 5 Step 4 using intermediate 5- ( (4-chlorophenoxy) methyl) -1, 3, 4-thiadiazol-2-amine (Example 1 Step 3) and 6-cyclopropyl-4- (2-methoxyphenyl) nicotinic acid as the starting material.
  • Example 36 N- (5- ( (4-Chlorophenoxy) methyl) -1, 3, 4-thiadiazol-2-yl) -4- (3-methoxyphenyl) -6-methylnicotinamide
  • Step 1 5- ( (3, 5-dichlorophenoxy) methyl) -1, 3, 4-thiadiazol-2-amine
  • Step 2 N- (5- ( (3, 5-dichlorophenoxy) methyl) -1, 3, 4-thiadiazol-2-yl) -4- (2-methoxyphenyl) -6-methylnicotinamide
  • This compound was prepared using procedures analogous to those described for Example 5 Step 4 using intermediate 4- (2-methoxyphenyl) -6-methylnicotinic acid (Example 5 Step 3) and 5- ( (3, 5-dichlorophenoxy) methyl) -1, 3, 4-thiadiazol-2-amine as the starting material.
  • Example 38 N- (5- ( (4-Fluorophenoxy) methyl) -1, 3, 4-thiadiazol-2-yl) -4- (2-methoxyphenyl) -6-methylnicotinamide
  • Step 1 5- ( (4-fluorophenoxy) methyl) -1, 3, 4-thiadiazol-2-amine
  • Step 2 N- (5- ( (4-fluorophenoxy) methyl) -1, 3, 4-thiadiazol-2-yl) -4- (2-methoxyphenyl) -6-methylnicotinamide
  • This compound was prepared using procedures analogous to those described for Example 5 Step 4 using intermediate 4- (2-methoxyphenyl) -6-methylnicotinic acid (Example 5 Step 3) and 5- ( (4-fluorophenoxy) methyl) -1, 3, 4-thiadiazol-2-amine as the starting material.
  • Step 1 5- ( (4-methoxyphenoxy) methyl) -1, 3, 4-thiadiazol-2-amine
  • Step 2 N- (5- ( (4-methoxyphenoxy) methyl) -1, 3, 4-thiadiazol-2-yl) -4- (2-methoxyphenyl) -6-methylnicotinamide
  • This compound was prepared using procedures analogous to those described for Example 5 Step 4 using intermediate 4- (2-methoxyphenyl) -6-methylnicotinic acid (Example 5 Step 3) and 5- ( (4-methoxyphenoxy) methyl) -1, 3, 4-thiadiazol-2-amine as the starting material.
  • Example 40 4- (2-Methoxyphenyl) -6-methyl-N- (5- ( (p-tolyloxy) methyl) -1, 3, 4-thiadiazol-2-yl) nicotinamide
  • Step 1 5- ( (p-tolyloxy) methyl) -1, 3, 4-thiadiazol-2-amine
  • Step 2 4- (2-methoxyphenyl) -6-methyl-N- (5- ( (p-tolyloxy) methyl) -1, 3, 4-thiadiazol-2-yl) nicotinamide
  • This compound was prepared using procedures analogous to those described for Example 5 Step 4 using intermediate 4- (2-methoxyphenyl) -6-methylnicotinic acid (Example 5 Step 3) and 5- ( (p-tolyloxy) methyl) -1, 3, 4-thiadiazol-2-amine as the starting material.
  • Step 3 methyl 6-cyano-2- (2-methoxyphenyl) nicotinate
  • Step 4 6-cyano-2- (2-methoxyphenyl) nicotinic acid
  • Step 4 N- (5- ( (4-chlorophenoxy) methyl) -1, 3, 4-thiadiazol-2-yl) -6-cyano-2- (2-methoxyphenyl) nicotinamide
  • This compound was prepared using procedures analogous to those described for Example 1 Step 4 using intermediate 5- ( (4-chlorophenoxy) methyl) -1, 3, 4-thiadiazol-2-amine (Example 1 Step 3) and 6-cyano-2- (2-methoxyphenyl) nicotinic acid as the starting material.
  • Example 17 Step 1 This compound was prepared using procedures analogous to those described for Example 1 Step 4 using intermediate 5- ( (4-chlorophenoxy) methyl) -1, 3, 4-thiadiazol-2-amine (Example 1 Step 3) and 6-cyano-4- (5-fluoro-2-methoxyphenyl) nicotinic acid (Example 17 Step 1) as the starting material.
  • Step 1 1- (2, 4-dimethoxyphenyl) -1H-imidazole-5-carboxylic acid
  • Step 2 N- (5- ( (4-chlorophenoxy) methyl) -1, 3, 4-thiadiazol-2-yl) -1- (2, 4-dimethoxyphenyl) -1H-imidazole-5-carboxamide
  • This compound was prepared using procedures analogous to those described for Example 1 Step 4 using intermediate 5- ( (4-chlorophenoxy) methyl) -1, 3, 4-thiadiazol-2-amine (Example 1 Step 3) and 1- (2, 4-dimethoxyphenyl) -1H-imidazole-5-carboxylic acid as the starting material.
  • Step 2 N- (5- ( (4-chlorophenoxy) methyl) -1, 3, 4-thiadiazol-2-yl) -3- (4-cyano-2-methoxyphenyl) isonicotinamide
  • Example 1 Step 4 This compound was prepared using procedures analogous to those described for Example 1 Step 4 using intermediate 5- ( (4-chlorophenoxy) methyl) -1, 3, 4-thiadiazol-2-amine. (Example 1 Step 3) and 3- (4-cyano-2-methoxyphenyl) isonicotinic acid as the starting material.
  • Step 1 8- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2H-benzo [b] [1, 4] oxazin-3 (4H) -one
  • Step 2 methyl 3- (3-oxo-3, 4-dihydro-2H-benzo [b] [1, 4] oxazin-8-yl) isonicotinate
  • Step 3 3- (3-oxo-3, 4-dihydro-2H-benzo [b] [1, 4] oxazin-8-yl) isonicotinic acid
  • Step 4 N- (5- ( (4-chlorophenoxy) methyl) -1, 3, 4-thiadiazol-2-yl) -3- (3-oxo-3, 4-dihydro-2H-benzo [b] [1, 4] oxazin-8-yl) isonicotinamide
  • Step 2 N- (5- ( (4-chlorophenoxy) methyl) -1, 3, 4-thiadiazol-2-yl) -6-methyl-4-morpholinonicotinamide
  • Step 1 4-bromo-N- (5- ( (4-chlorophenoxy) methyl) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
  • Step 2 N- (5- ( (4-chlorophenoxy) methyl) -1, 3, 4-thiadiazol-2-yl) -6-methyl-4- (4-oxa-7-azaspiro [2.5] octan-7-yl) nicotinamide
  • Example 48 N- (5- ( (4-Chlorophenoxy) methyl) -1, 3, 4-thiadiazol-2-yl) -2- (2-methyl-5-oxopiperazin-1-yl) nicotinamide
  • Step 1 N- (5- ( (4-chlorophenoxy) methyl) -1, 3, 4-thiadiazol-2-yl) -2-fluoronicotinamide
  • Step 2 N- (5- ( (4-chlorophenoxy) methyl) -1, 3, 4-thiadiazol-2-yl) -2- (2-methyl-5-oxopiperazin-1-yl) nicotinamide
  • the comparative compound above was synthesized by referring to the method desdcribed in WO2020243459A1 Example 183.
  • Example A Biological evaluation
  • PolQ ATPase activity was determined by ADP-Glo assay. 10-point dilution series of compounds were used in a 384 well format for the inhibition assays.
  • Pol theta (1-899) (1 nM) in assay buffer (20 mM Tris HCl (pH 8.0) , 80 mM KCl, 10 mM MgCl 2 , 1 mM DTT, 0.01%BSA, 0.01%Tween, 5%glycerol) was transferred to the test wells (20 uL) , except the low control wells (20 ⁇ L of assay buffer was added to the low control wells) . The plate was then incubated at room temperature for 30 min.
  • %Inhibition Signal Max -Signal Compound ) / (Signal Max -Signal Min ) *100%) , where “Max” is the high control (DMSO) and “Min” is the no enzyme control.
  • Example No. IC 50 (nM) Example No. IC 50 (nM) Example No. IC 50 (nM) Example No. IC 50 (nM) Example No. IC 50 (nM) 1 193 17 * 33 *** 2 694 18 * 34 *** 3 843 19 * 35 ** 4 1412 20 * 36 *** 5 36 21 * 37 *** 6 * 22 * 38 *** 7 * 23 * 39 *** 8 * 24 * 40 ** 9 * 25 * 41 *** 10 * 26 * 42 ** 11 * 27 * 43 ** 12 * 28 ** 44 *** 13 * 29 *** 45 *** 14 * 30 *** 46 *** 15 * 31 *** 47 *** 16 * 32 *** 48 ***
  • All the compounds of the present disclosure have good potency to inhibit ATPase activity of PolQ, and most of the compounds inhibited ATPase activity with IC 50 ⁇ 100 nM.
  • Blood samples were collected at 5 min., 15min., 30 min., 1 h., 2 h., 4 h., 6 h., 8 h. and 24 h. after IV administration (anticoagulant: EDTA-K2) , Blood samples were collected at 15 min., 30 min., 1 h., 2 h., 4 h., 6h., 8 h. and 24 h.
  • the compounds of the present disclosure demonstrated a longer time of maximum plasma concentration and a higher plasma exposure AUC last associated with a higher C max compared with the reference compound 1 by oral administration. Furthermore, the compounds of the present disclosure had a lower clearance and a higher plasma exposure AUC last compared with the reference compound 1 by injection. Meanwhile, the compounds of the present disclosure had improved pharmacological properties.

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Abstract

L'invention concerne des dérivés de thiadiazolyle tels que représentés dans la formule (I), des compositions pharmaceutiques les comprenant, un procédé pour leur préparation, et leur utilisation en tant qu'agents thérapeutiques.
PCT/CN2022/124933 2021-10-15 2022-10-12 Dérivés de thiadiazolyle, compositions et utilisations de ceux-ci WO2023061415A1 (fr)

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WO2024099337A1 (fr) * 2022-11-10 2024-05-16 Danatlas Pharmaceuticals Co., Ltd. Dérivés de thiadiazolyle, compositions et utilisations associées

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