WO2024099336A1 - Thiadiazolyl derivatives, compositions and uses thereof - Google Patents

Thiadiazolyl derivatives, compositions and uses thereof Download PDF

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WO2024099336A1
WO2024099336A1 PCT/CN2023/130324 CN2023130324W WO2024099336A1 WO 2024099336 A1 WO2024099336 A1 WO 2024099336A1 CN 2023130324 W CN2023130324 W CN 2023130324W WO 2024099336 A1 WO2024099336 A1 WO 2024099336A1
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alkyl
compound
haloalkyl
independently selected
och
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PCT/CN2023/130324
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French (fr)
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Jincong Zhuo
Yao ZHANG
Wenlai Zhou
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Danatlas Pharmaceuticals Co., Ltd.
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  • the present disclosure relates to thiadiazolyl derivatives as PolQ inhibitors.
  • the present disclosure also relates to methods for preparing the thiadiazolyl derivatives, pharmaceutical compositions, and their uses in the treatment of a PolQ-mediated disease, e.g., cancer containing a DNA repair defect.
  • 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 alt-NHEJ also known as microhomology-mediated end-joining (MMEJ) , is commonly considered as a “backup” DSB repair pathway when NHEJ or HR is compromised.
  • MMEJ microhomology-mediated end-joining
  • DDR DNA damage response
  • PRP poly (ADP-ribose) polymerase
  • DNA polymerase theta is a key protein involved in MMEJ. Kent et al. Nat. Struct. Mol. Biol. 2015, 22, 230-7; Mateos-Gomez et al. Nature 2015, 518, 254-7. 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 and D bountye, DNA Repair (Amst) . 2016, 44, 22-32.
  • PolQ can carry out error-prone DNA synthesis at DNA damage sites through the alt-NHEJ pathway. It has been shown that the helicase domain of PolQ mediates the removal of a replication (RPA) protein from single-stranded (ssDNA) ends and stimulates annealing. This anti-recombinase activity of PolQ promotes the alt-NHEJ pathway. In addition, the helicase domain of PolQ contributes to microhomology-mediated strand annealing. Chan et al., PLoS Genet. 2010, 6, e1001005; Kawamura et al., Int. J. Cancer 2004, 109, 9-16.
  • PolQ can promote end joining in the alt-NHEJ pathway by employing this annealing activity when ssDNA overhangs contain >2 base pair (bp) of microhomology. Kent et al., Elife 2016, 5, e13740; Kent, et al., Nat. Struct. Mol. Biol. 2015, 22, 230-7.
  • This reannealing activity is achieved 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, 175-84; Lemee et al., Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 13390-5; Ceccaldi et al., Nature 2015, 518, 258-62. Recent studies suggest that cancer cells with deficiency in HR, NHEJ, or ATM are highly dependent on PolQ expression. Ceccaldi et al., 2015, supra; Mateos-Gomez et al., 2015, supra; Wyatt et al., Mol.
  • PolQ inhibition could conceivably prevent the MMEJ-dependent functional reversion of BRCA1-or BRCA2-mutations that underlies the emergence of cisplatin and PARPi resistance in tumors. Zatreanu et al., Nat. Commun. 2021, 12, 3636) . Therefore, PolQ is an attractive target for synthetic lethal therapy in cancer containing a DNA repair defect.
  • 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 variant, prodrug, N-oxide, or deuterated compound thereof and at least one pharmaceutically acceptable carrier.
  • a method of inhibiting PolQ comprising: contacting a PolQ with a compound of formula (I) , or pharmaceutically acceptable salt, solvate, tautomeric, stereoisomer, atropisomer, isotopic variant, prodrug, N-oxide, or deuterated compound thereof.
  • 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 variant, prodrug, N-oxide, or deuterated compound thereof.
  • each divalent linking group includes both the forward and backward forms of the divalent linking group.
  • –NR (CR’ R” ) includes both the forward and backward forms of the divalent linking group.
  • –NR (CR’ R” ) includes both the forward and backward forms of the divalent linking group.
  • –NR (CR’ R” ) includes both the forward and backward forms of the divalent linking group.
  • –NR (CR’ R” ) includes both the forward and backward forms of the divalent linking group.
  • –NR (CR’ R” ) includes both the forward and backward forms of the divalent linking group.
  • –NR (CR’ R” ) includes both the forward and backward forms of the divalent linking group.
  • –NR (CR’ R” ) includes both the forward and backward forms of the divalent linking group.
  • –NR (CR’ R” ) includes both the forward and backward forms of the divalent linking group.
  • —NR (CR’ R” ) includes both the forward and back
  • 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
  • substituents include, but are not limited to, D, halo, oxo, C 1 -C -6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl-NR c R d , – (CH 2 CH 2 O) o C 1 -C 6 alkyl wherein o is 1-10; C 2-6 alkenyl-NR c R d , C 2-6 alkynyl-NR c R d , –OC 2-6 alkyl-NR c R d , –CN, –NO 2 , –N 3 , –OR a , –SR a , –C (O) R b , –C (O) NR c R d , –CH 2 C (
  • C n -C m 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 is meant to refer to a saturated hydrocarbon group which is straight-chained or branched.
  • An alkyl group can contain from about 1 to about 20, from about 2 to about 20, from about 1 to about 10, from about 1 to about 8, from about 1 to about 6, from about 1 to about 4, or from about 1 to about 3 carbon atoms.
  • alkyl can include any number of carbons, such as C 1 -C 2 alkyl, C 1 -C 3 alkyl, C 1 -C 4 alkyl, C 1 -C 5 alkyl, C 1 -C 6 alkyl, C 1 -C 7 alkyl, C 1 -C 8 alkyl, C 1 -C 9 alkyl, C 1 -C 10 alkyl, C 2 -C 3 alkyl, C 2 -C 4 alkyl, C 2 -C 5 alkyl, C 2 -C 6 alkyl, C 3 -C 4 alkyl, C 3 -C 5 alkyl, C 3 -C 6 alkyl, C 4 -C 5 alkyl, C 4 -C 6 alkyl, and C 5 -C 6 alkyl.
  • C 1 -C 2 alkyl C 1 -C 3 alkyl, C 1 -C 4 alkyl, C 1 -C 5 alkyl, C 1 -C 6 alkyl
  • C 1 -C 8 as in C 1 -C 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.
  • 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, and t-butyl) , pentyl (e.g., n-pentyl, isopentyl, and neopentyl) , hexyl, heptyl, and octyl.
  • alkenyl is meant to refer to a hydrocarbon group having one or more double carbon-carbon bonds.
  • Alkenyl can include any number of carbons, such as C 2 -C 3 alkenyl, C 2 -C 4 alkenyl, C 2 -C 5 alkenyl, C 2 -C 6 alkenyl, C 2 -C 7 alkenyl, C 2 -C 8 alkenyl, C 2 -C 9 alkenyl, C 2 -C 10 alkenyl, C 3 -C 4 alkenyl, C 3 -C 5 alkenyl, C 3 -C 6 alkenyl, C 4 -C 5 alkenyl, C 4 -C 6 alkenyl and C 5 -C 6 alkenyl.
  • alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.
  • alkynyl is meant to refer to a hydrocarbon group having one or more triple carbon-carbon bonds.
  • Alkynyl can include any number of carbons, such as C 2 -C 3 alkynyl, C 2 -C 4 alkynyl, C 2 -C 5 alkynyl, C 2 -C 6 alkynyl, C 2 -C 7 alkynyl, C 2 -C 8 alkynyl, C 2 -C 9 alkynyl, C 2 -C 10 alkynyl, C 3 -C 4 alkynyl, C 3 -C 5 alkynyl, C 3 -C 6 alkynyl, C 4 -C 5 alkynyl, C 4 -C 6 alkynyl, and C 5 -C 6 alkynyl.
  • alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, and
  • haloalkyl is meant to refer to an alkyl group having one or more halo as substituents.
  • haloalkyl groups include, but are not limited to, –CF 3 , –C 2 F 5 , –CHF 2 , –CH 2 F, –CCl 3 , –CHCl 2 , and –C 2 Cl 5 .
  • aryl is meant to refer to an unsubstituted or substituted monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) aromatic hydrocarbon.
  • aryl groups have from about 6 to about 20 carbon atoms.
  • aryl groups have from about 6 to about 14 carbon atoms.
  • aryl groups have from about 6 to about 10 carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, and indenyl.
  • Cycloalkyl is meant to refer to an unsubstituted or substituted nonaromatic carbocycle.
  • Cycloalkyl groups can include mono-or polycyclic (e.g., having 2, 3, or 4 rings) ring systems, including fused rings, spirocyclic rings, and bridged rings (e.g., a bridged bicycloalkyl group) .
  • cycloalkyl groups can have from about 3 to about 20 carbon atoms, from about 3 to about 14 carbon atoms, from about 3 to about 10 carbon atoms, or from about 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.
  • the cycloalkyl is C 3 -C 7 monocyclic cycloalkyl.
  • the cycloalkyl is C 4- C 10 spiro or bridged cycloalkyl.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcaranyl, cubanyl, adamantanyl, bicyclo [1.1.1] pentyl, bicyclo [2.1.1] hexyl, bicyclo [2.2.1] heptanyl, bicyclo2[3.1.1] -heptanyl, bicyclo [2.2.2] octanyl, and spiro [3.3] heptanyl.
  • heteroaryl is meant to refer 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, are not limited to, pyridyl, N-oxopyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuryl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1, 2, 4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, and indolinyl.
  • the heteroaryl group has from about 1 to about 20 carbon atoms or from about 3 to about 20 carbon atoms. In certain embodiments, the heteroaryl group contains from about 3 to about 14, from about 3 to about 7, about 5, or about 6 ring-forming atoms. In certain embodiments, the heteroaryl group has from about 1 to about 4, from about 1 to about 3, about 1, or about 2 heteroatoms.
  • Heterocycloalkyl groups include monocyclic and polycyclic (e.g., having 2 fused rings) systems.
  • heterocycloalkyl 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 spirocyclic and bridged rings (e.g., a 5-10 membered bridged biheterocycloalkyl) .
  • the heterocycloalkyl group contains 0 to 3 double bonds. In certain embodiments, the heterocycloalkyl group contains 0 to 2 double bonds.
  • heterocycloalkyl moieties that have one or more aromatic rings fused to the non-aromatic heterocyclic ring, for example, benzo or thienyl derivatives of piperidine, morpholine, azepine, etc.
  • 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.
  • heterocycloalkyl groups include, but are not limited to, pyrrolidin-2-onyl, l, 3-isoxazolidin-2-onyl, pyranyl, tetrahydropyranyl, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, benzazepinyl, 1, 2, 3, 4-tetrahydroisoquinolinyl, azabicyclo [3.1.0] hexanyl, diazabicyclo [3.
  • heterocycloalkyl is meant to refer 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, and piperazinyl.
  • halo or halogen is meant to refer to fluoro, chloro, bromo, and iodo.
  • alkoxy is meant to refer to an –O-alkyl group.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy) , and t-butoxy.
  • hydroxylalkyl is meant to refer to an alkyl group substituted by —OH.
  • cyanoalkyl is meant to refer to an alkyl group substituted by —CN.
  • alkoxyalkyl is meant to refer to an alkyl group substituted by an alkoxy group.
  • haloalkoxy is meant to refer to an —O- (haloalkyl) group.
  • arylalkyl or “aralkyl” is meant to refer to alkyl substituted by aryl.
  • An example of the arylalkyl group is benzyl.
  • cycloalkylalkyl is meant to refer to alkyl substituted by cycloalkyl.
  • heteroarylalkyl is meant to refer to alkyl substituted by heteroaryl.
  • heterocycloalkylalkyl is meant to refer to alkyl substituted by heterocycloalkyl.
  • the compounds of the disclosure, 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.
  • 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 disclosure, or a salt thereof.
  • 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.
  • 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.
  • solvate refers to a physical association of a compound with one or more solvent molecules.
  • subject refers to an animal, including, but not limited to, a primate (e.g., human) , cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse.
  • primate e.g., human
  • subject and patient are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject. In one embodiment, the subject is a human.
  • treating or “treatment” of a 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.
  • 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.
  • X 1 is N or CR 1 ;
  • X 2 is N or CR 2 ;
  • X 3 is N or CR 3 ;
  • X 1 , X 2 and X 3 are not N at the same time;
  • n 1, 2, 3, 4 or 5;
  • Cy is C 6 -C 10 aryl or 5-10 membered heteroaryl
  • R is selected from OH, or
  • R 1 and R 2 are independently selected from H, D, CN, NO 2 , N 3 , oxo, 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, phenyl, 5-6 membered heteroaryl, OR A , SR A , C (O) R B , C (O) NR C R D , C (O) OR A , OC (O) R B , OC (O) NR C R D , NR C R D , NR C C (O) R B , NR C C (O) OR A , S (O) R B , S (O) 2 R B ; wherein, the C 1- C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3- C 6 cycl
  • R 1 and R 2 together with the carbon atoms to which they are attached form C 4 -C 7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; wherein, the C 4 -C 7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl is optionally substituted by 1, 2, 3 or 4 substituents independently selected from D, halo, CN, NO 2 , OH, NH 2 , C 1- C 6 alkyl, C 1 -C 6 haloalkyl, -O-C 1 -C 6 alkyl, -OC 1 -C 6 haloalkyl, NHC 1 -C 4 alkyl, or N (C 1 -C 4 alkyl) 2 ;
  • R 3 is selected from H, D, CN, NO 2 , -N 3 , oxo, SF 5 , halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocycloalkyl, OR A , SR A , C (O) R B , C (O) NR C R D , C (O) OR A , OC (O) R B , OC (O) NR C R D , NR C R D , NR C C (O) R B , NR C C (O) OR A , S (O) R B , S (O) 2 R B ; wherein, the C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3- C 6 cycloalkyl, 4-6 membered heterocycloal
  • each R 4A is independently selected from D, halogen, CN, OH, NH 2 , oxo, C 1- C 6 alkyl, OC 1- C 6 alkyl, C 1- C 6 haloalkyl, OC 1- C 6 haloalkyl, NHC 1- C 3 alkyl, N (C 1- C 3 alkyl) 2 , C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocycloalkyl; wherein, the C 3- C 6 cycloalkyl or 4-6 membered heterocycloalkyl is optionally substituted with D, halogen, CN, OH, NH 2 , C 1- C 6 alkyl, C 1- C 6 haloalkyl, -O-C 1 -C 6 alkyl, -O-C 1- C 6 haloalkyl;
  • C 4- C 7 cycloalkyl or 4-7 membered heterocycloalkyl wherein, the C 4- C 7 cycloalkyl or 4-7 membered heterocycloalkyl is 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 6 alkyl, -O-C 1- C 6 haloalkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocycloalkyl; wherein, the C 3- C 6 cycloalkyl or 4-6 membered heterocycloalkyl is optionally substituted with D, halogen, CN, OH, NH 2 , C 1- C 6 alkyl, C 1- C 6 haloalkyl, -O-C 1 -C 6 alkyl, -
  • R 5 and R 6 are each independently selected from H, D, halo, CN, NO 2 , C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 1 -C 8 haloalkyl, C 1 -C 8 alkyl-O-C 1 -C 8 alkyl, C 1 -C 8 alkyl-O-C 1 -C 8 haloalkyl, C 1 -C 8 alkyl-OH, C 1 -C 8 alkyl-CN;
  • R 7 is independently selected from H, D, CN, halo, NO 2 , N 3 , SF 5 , Si (R 8 ) 3 , C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl or adamantanyl; wherein, the C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl or adamantanyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from D, -halo, -CN, -NO 2 , -N 3 , SF 5 , oxo, -NR C R D , -OR A , -SR A , SiR G R H R I , -B (OR C ) (OR D ) , -C (O) R B , -C (O) OR A , -OC (O) R B , -C (O)
  • each R 8 is independently selected from C 1 -C 4 alkyl or phenyl
  • each R A 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, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl; 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 heterocyclalkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected
  • each 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, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl; 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, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently
  • 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, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl; 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, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, OH,
  • 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, 3, 4 or 5 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;
  • R a and R a1 are each independently selected from H, D, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl, C 3 -C 7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl, wherein the C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl, C 3- C 7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halo, OH, CN, -NH 2 , -NH (C 1 -C 4 alkyl) , -N (C 1 -C 4 alkyl) 2 , C 1 -C 4 alkyl, OC 1 -C 4 alkyl, C
  • R b and R b1 are each independently selected from H, D, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl, C 3- C 7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl; wherein, the C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl, C 3- C 7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, OH, CN
  • R c and R d are each independently selected from H, D, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 6- C 10 aryl, 5-10 membered heteroaryl, C 3- C 10 cycloalkyl, 4-10 membered heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkyl, arylheterocycloalkyl, arylheteroaryl, biaryl, heteroarylcycloalkyl, heteroarylheterocycloalkyl, heteroarylaryl, or biheteroaryl; wherein, the C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 6- C 10 aryl, 5-10 membered
  • 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, 3, 4 or 5 substituents independently selected from D, OH, 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 alkoxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, C 1 -C 4 hydroxyalkyl, C 1 -C 4 cyanoalkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, C 1 -C 4 alkoxy-C 1 -C 4 alkyl or C 1 -C 4 alkoxy-C 1 -C 4 alkoxy;
  • R E and R e are each independently selected from H, D, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 2 -C 4 alkenyl, (C 1 -C 4 alkoxy) -C 1 -C 4 alkyl, C 2 -C 4 alkynyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -C 10 aryl-C 1 -C 4 alkyl, C 3 -C 10 cycloalkyl-C 1 -C 4 alkyl, 5-10 membered heteroaryl-C 1 -C 4 alkyl, or 4-10 membered heterocycloalkyl-C 1 -C 4 alkyl;
  • R F and R f are each independently selected from H, D, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, C 3 -C 10 cycloalkyl, or 4-10 membered heterocycloalkyl;
  • R G , R H and R I are each independently selected from C 1 -C 4 alkyl or phenyl.
  • X 1 is CR 1
  • X 2 is CR 2
  • X 3 is CR 3 .
  • X 1 is N
  • X 2 is CR 2
  • X 3 is CR 3 .
  • X 1 is CR 1
  • X 2 is N
  • X 3 is CR 3 .
  • X 1 is CR 1
  • X 2 is CR 2
  • X 3 is N.
  • the compounds of Formula (I) are represented by compounds of Formula (IIa) , (IIb) , (IIc) or (IId) :
  • the compounds of Formula (I) are represented by compounds of Formula (IIa) or (IIb) :
  • Cy is C 6- C 10 aryl, 5-10 membered heteroaryl.
  • Cy is C 6- C 10 aryl. In some embodiments, Cy is phenyl or naphthalenyl. In some embodiments, Cy is phenyl.
  • Cy is 5-10 membered heteroaryl. In some embodiments, Cy is 5 membered heteroaryl. In some embodiments, Cy is 6 membered heteroaryl. In some embodiments, Cy is 8 membered heteroaryl. In some embodiments, Cy is 9 membered heteroaryl. In some embodiments, Cy is 10 membered heteroaryl.
  • Cy is pyrrolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, tetrazolyl, pyrazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, indolizinyl, benzofuranyl, isobenzofuranyl, benzo [b] thiophenyl, benzo [c] thiophenyl, indazolyl, benzo [d] imidazolyl, pyrrolo [3, 2-b] pyridinyl, pyrrolo [3, 2-c] pyridinyl, pyrrolo [2, 3-c] pyridinyl, pyrrolo [2, 3-b] pyridinyl, pyrrolo [3, 4-b
  • Cy is phenyl or 6-membered heteroaryl. In some embodiments, Cy is phenyl or pyridin-4-yl. In some embodiments, Cy is phenyl.
  • the moiety has the structure of wherein, Y 1 is N or CR 4 ; Y 2 is N or CR 4 ; and each R 4 is same or different and as defined herein.
  • Y 1 is CR 4
  • Y 2 is CR 4
  • Y 1 is CH
  • Y 2 is CH.
  • Y 1 is CR 4
  • Y 2 is N
  • Y 1 is N
  • Y 2 is CR 4 .
  • the moiety has the structure of wherein each R 2 is as defined herein.
  • the moiety has the structure of In some embodiments, the moiety has the structure of In some embodiments, the moiety has the structure of In some embodiments, the moiety has the structure of wherein each R 2 is as defined herein.
  • the moiety has the structure of
  • the compounds of Formula (I) are represented by compounds of Formula (IIIa) , or (IIIb) :
  • R, R 1 , R 2 , R 3 , R 4 , Y 1 and Y 2 are as defined herein.
  • R is OH
  • R is
  • the compounds of Formula (I) are represented by compounds of Formula (IVa) or (IVb) :
  • the compounds of Formula (I) are represented by compounds of Formula (Va) , or (Vb) :
  • the compounds of Formula (I) are represented by compounds of Formula (VIa) , or (VIb) :
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , Y 1 and Y 2 are as defined herein.
  • the compounds of Formula (I) are represented by compounds of Formula (VIIa) , or (VIIb) :
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , Y 1 and Y 2 are as defined herein.
  • the compounds of Formula (I) are represented by compounds of Formula (VIIIa) , or (VIIIb) :
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , Y 1 and Y 2 are as defined herein.
  • R 1 is selected from H, D, CN, NO 2 , N 3 , oxo, 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, phenyl, 5-6 membered heteroaryl, OR A , SR A , C (O) R B , C (O) NR C R D , C (O) OR A , OC (O) R B , OC (O) NR C R D , NR C R D , NR C C (O) R B , NR C C (O) OR A , S (O) R B , S (O) 2 R B ; wherein, the C 1- C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3- C 6 cycloalkyl
  • R 1 is selected from H, D, CN, NO 2 , N 3 , oxo, SF 5 , halogen, OR A , SR A , C (O) R B , C (O) NR C R D , C (O) OR A , OC (O) R B , OC (O) NR C R D , NR C R D , NR C C (O) R B , NR C C (O) OR A , S (O) R B , S (O) 2 R B .
  • R 1 is H.
  • R 1 is D.
  • R 1 is CN.
  • R 1 is NO 2 .
  • R 1 is N 3 . In some embodiments, R 1 is SF 5 . In some embodiments, R 1 is halogen. In some embodiments, R 1 is F, Cl, Br or I. In some embodiments, R 1 is F. In some embodiments, R 1 is Cl. In some embodiments, R 1 is Br. In some embodiments, R 1 is I. In some embodiments, R 1 is OR A . In some embodiments, R 1 is OH, OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH (CH 3 ) 2 , OCH 2 F, OCHF 2 , OCF 3 , In some embodiments, R 1 is SR A . In some embodiments, R 1 is C (O) R B .
  • R 1 is C (O) NR C R D . In some embodiments, R 1 is C (O) OR A . In some embodiments, R 1 is OC (O) R B . In some embodiments, R 1 is OC (O) NR C R D . In some embodiments, R 1 is NR C R D . In some embodiments, R 1 is NR C C (O) R B . In some embodiments, R 1 is NR C C (O) OR A . In some embodiments, R 1 is S (O) R B . In some embodiments, R 1 is S (O) 2 R B .
  • R 1 is selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4-6 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 6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halogen, CN, OH, NH 2 , NO 2 , oxo, C 1- C 4 alkyl, C 1 -C 4 haloalkyl, -O-C 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl, C 3 -C 6 cycl
  • R 1 is C 1 -C 6 alkyl (such as C 1 -C 5 alkyl, C 1 -C 4 alkyl, C 1 -C 3 alkyl, C 1 -C 2 alkyl) optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halogen, CN, OH, NH 2 , NO 2 , oxo, -O-C 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocycloalkyl.
  • C 1 -C 6 alkyl such as C 1 -C 5 alkyl, C 1 -C 4 alkyl, C 1 -C 3 alkyl, C 1 -C 2 alkyl
  • substituents independently selected from D, halogen, CN, OH, NH 2 , NO 2 , oxo, -O-C 1 -C 4 alkyl, -
  • R 1 is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 .
  • R 1 is C 2 -C 6 alkenyl (such as C 2 -C 5 alkenyl, C 2 -C 4 alkenyl, C 2 -C 3 alkenyl) optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halogen, CN, OH, NH 2 , NO 2 , oxo, -O-C 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocycloalkyl.
  • C 2 -C 6 alkenyl such as C 2 -C 5 alkenyl, C 2 -C 4 alkenyl, C 2 -C 3 alkenyl
  • substituents independently selected from D, halogen, CN, OH, NH 2 , NO 2 , oxo, -O-C 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl
  • R 1 is C 2 -C 6 alkynyl (such as C 2 -C 5 alkynyl, C 2 -C 4 alkynyl, C 2 -C 3 alkynyl) optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halogen, CN, OH, NH 2 , NO 2 , oxo, -O-C 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocycloalkyl.
  • substituents independently selected from D, halogen, CN, OH, NH 2 , NO 2 , oxo, -O-C 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocycloalkyl.
  • R 1 is C 3 -C 6 cycloalkyl optionally substituted with 1, 2, 3, 4 or 5 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 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; each is optionally substituted with 1, 2, 3, 4 or 5 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 cyclopropyl.
  • R 1 is 4-6 membered heterocycloalkyl optionally substituted with 1, 2, 3, 4 or 5 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 azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl; each is optionally substituted with 1, 2, 3, 4 or 5 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 phenyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halogen, CN, OH, NH 2 , NO 2 , oxo, C 1- C 4 alkyl, C 1 -C 4 haloalkyl, -O-C 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocycloalkyl.
  • R 1 is 5-6 membered heteroaryl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halogen, CN, OH, NH 2 , NO 2 , oxo, C 1- C 4 alkyl, C 1 -C 4 haloalkyl, -O-C 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocycloalkyl.
  • substituents independently selected from D, halogen, CN, OH, NH 2 , NO 2 , oxo, C 1- C 4 alkyl, C 1 -C 4 haloalkyl, -O-C 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocycloalkyl.
  • R 1 is selected from H, D, CN, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, OR A , SR A , NR C R D ; wherein, the C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halogen, CN, OH, NH 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 selected from H, D, CN, NO 2 , SF 5 , halogen, OH, OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH (CH 3 ) 2 , OCH 2 F, OCHF 2 , OCF 3 , methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CH 2 CHF 2 , or CH 2 CF 3 .
  • R 2 is selected from H, D, CN, NO 2 , N 3 , oxo, 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, phenyl, 5-6 membered heteroaryl, OR A , SR A , C (O) R B , C (O) NR C R D , C (O) OR A , OC (O) R B , OC (O) NR C R D , NR C R D , NR C C (O) R B , NR C C (O) OR A , S (O) R B , S (O) 2 R B ; wherein, the C 1- C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3- C 6 cycl
  • R 2 is selected from H, D, CN, NO 2 , N 3 , oxo, SF 5 , halogen, OR A , SR A , C (O) R B , C (O) NR C R D , C (O) OR A , OC (O) R B , OC (O) NR C R D , NR C R D , NR C C (O) R B , NR C C (O) OR A , S (O) R B , S (O) 2 R B .
  • R 2 is H.
  • R 2 is D.
  • R 2 is CN.
  • R 2 is NO 2 .
  • R 2 is N 3 . In some embodiments, R 2 is SF 5 . In some embodiments, R 2 is halogen. In some embodiments, R 2 is F, Cl, Br or I. In some embodiments, R 2 is F. In some embodiments, R 2 is Cl. In some embodiments, R 2 is Br. In some embodiments, R 2 is I.
  • R 2 is OR A .
  • R 2 is OH, OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH (CH 3 ) 2 , OCH 2 F, OCHF 2 , OCF 3 ,
  • R 2 is SR A . In some embodiments, R 2 is C (O) R B . In some embodiments, R 2 is C (O) NR C R D . In some embodiments, R 2 is C (O) OR A . In some embodiments, R 2 is OC (O) R B . In some embodiments, R 2 is OC (O) NR C R D . In some embodiments, R 2 is NR C R D . In some embodiments, R 2 is NR C C (O) R B . In some embodiments, R 2 is NR C C (O) OR A . In some embodiments, R 2 is S (O) R B . In some embodiments, R 2 is S (O) 2 R B .
  • R 2 is selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4-6 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 6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halogen, CN, OH, NH 2 , NO 2 , oxo, C 1- C 4 alkyl, C 1 -C 4 haloalkyl, -O-C 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl, C 3 -C 6 cycl
  • R 2 is C 1 -C 6 alkyl (such as C 1 -C 5 alkyl, C 1 -C 4 alkyl, C 1 -C 3 alkyl, C 1 -C 2 alkyl) optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halogen, CN, OH, NH 2 , NO 2 , oxo, -O-C 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocycloalkyl.
  • C 1 -C 6 alkyl such as C 1 -C 5 alkyl, C 1 -C 4 alkyl, C 1 -C 3 alkyl, C 1 -C 2 alkyl
  • substituents independently selected from D, halogen, CN, OH, NH 2 , NO 2 , oxo, -O-C 1 -C 4 alkyl, -
  • R 2 is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 .
  • R 2 is methyl.
  • R 2 is ethyl.
  • R 2 is CH 2 F.
  • R 2 is CHF 2 .
  • R 2 is CF 3 .
  • R 2 is C 2 -C 6 alkenyl (such as C 2 -C 5 alkenyl, C 2 -C 4 alkenyl, C 2 -C 3 alkenyl) optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halogen, CN, OH, NH 2 , NO 2 , oxo, -O-C 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocycloalkyl.
  • C 2 -C 6 alkenyl such as C 2 -C 5 alkenyl, C 2 -C 4 alkenyl, C 2 -C 3 alkenyl
  • substituents independently selected from D, halogen, CN, OH, NH 2 , NO 2 , oxo, -O-C 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl
  • R 2 is C 2 -C 6 alkynyl (such as C 2 -C 5 alkynyl, C 2 -C 4 alkynyl, C 2 -C 3 alkynyl) optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halogen, CN, OH, NH 2 , NO 2 , oxo, -O-C 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocycloalkyl.
  • substituents independently selected from D, halogen, CN, OH, NH 2 , NO 2 , oxo, -O-C 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocycloalkyl.
  • R 2 is C 3 -C 6 cycloalkyl optionally substituted with 1, 2, 3, 4 or 5 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 2 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; each is optionally substituted with 1, 2, 3, 4 or 5 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 2 is 4-6 membered heterocycloalkyl optionally substituted with 1, 2, 3, 4 or 5 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 azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl; each is optionally substituted with 1, 2, 3, 4 or 5 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 2 is phenyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halogen, CN, OH, NH 2 , NO 2 , oxo, C 1- C 4 alkyl, C 1 -C 4 haloalkyl, -O-C 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocycloalkyl.
  • R 2 is 5-6 membered heteroaryl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halogen, CN, OH, NH 2 , NO 2 , oxo, C 1- C 4 alkyl, C 1 -C 4 haloalkyl, -O-C 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocycloalkyl.
  • substituents independently selected from D, halogen, CN, OH, NH 2 , NO 2 , oxo, C 1- C 4 alkyl, C 1 -C 4 haloalkyl, -O-C 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocycloalkyl.
  • R 2 is selected from H, D, CN, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, OR A , SR A , NR C R D ; wherein, the C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halogen, CN, OH, NH 2 , oxo, C 1- C 6 alkyl, C 1 -C 6 haloalkyl, -O-C 1 -C 6 alkyl, -OC 1 -C 6 haloalkyl.
  • R 2 is selected from H, D, CN, NO 2 , SF 5 , halogen, OH, OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH (CH 3 ) 2 , OCH 2 F, OCHF 2 , OCF 3 , methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 .
  • R 1 and R 2 together with the carbon atoms to which they are attached form C 4 -C 7 cycloalkyl optionally substituted by 1, 2, 3 or 4 substituents independently selected from D, halo, CN, NO 2 , OH, NH 2 , C 1- C 6 alkyl, C 1 -C 6 haloalkyl, -O-C 1 -C 6 alkyl, -OC 1 -C 6 haloalkyl, NHC 1 -C 4 alkyl, or N (C 1 -C 4 alkyl) 2 .
  • R 1 and R 2 together with the carbon atoms to which they are attached form 4-7 membered heterocycloalkyl optionally substituted by 1, 2, 3 or 4 substituents independently selected from D, halo, CN, NO 2 , OH, NH 2 , C 1- C 6 alkyl, C 1 -C 6 haloalkyl, -O-C 1 -C 6 alkyl, -OC 1 -C 6 haloalkyl, NHC 1 -C 4 alkyl, or N (C 1 -C 4 alkyl) 2 .
  • substituents independently selected from D, halo, CN, NO 2 , OH, NH 2 , C 1- C 6 alkyl, C 1 -C 6 haloalkyl, -O-C 1 -C 6 alkyl, -OC 1 -C 6 haloalkyl, NHC 1 -C 4 alkyl, or N (C 1 -C 4 alkyl) 2 .
  • R 1 and R 2 together with the carbon atoms to which they are attached form phenyl optionally substituted by 1, 2, 3 or 4 substituents independently selected from D, halo, CN, NO 2 , OH, NH 2 , C 1- C 6 alkyl, C 1 -C 6 haloalkyl, -O-C 1 -C 6 alkyl, -OC 1 -C 6 haloalkyl, NHC 1 -C 4 alkyl, or N (C 1 -C 4 alkyl) 2 .
  • substituents independently selected from D, halo, CN, NO 2 , OH, NH 2 , C 1- C 6 alkyl, C 1 -C 6 haloalkyl, -O-C 1 -C 6 alkyl, -OC 1 -C 6 haloalkyl, NHC 1 -C 4 alkyl, or N (C 1 -C 4 alkyl) 2 .
  • R 1 and R 2 together with the carbon atoms to which they are attached form 5-6 membered heteroaryl independently selected from D, halo, CN, NO 2 , OH, NH 2 , C 1- C 6 alkyl, C 1 -C 6 haloalkyl, -O-C 1 -C 6 alkyl, -OC 1 -C 6 haloalkyl, NHC 1 -C 4 alkyl, or N (C 1 -C 4 alkyl) 2 .
  • R 3 is selected from H, D, CN, NO 2 , SF 5 , halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocycloalkyl, OR A , SR A , C (O) R B , C (O) NR C R D , C (O) OR A , OC (O) R B , OC (O) NR C R D , NR C R D , NR C C (O) R B , NR C C (O) OR A , S (O) R B , S (O) 2 R B ; wherein, the C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3- C 6 cycloalkyl, 4-6 membered heterocycloalkyl, is optionally substitute
  • R 3 is selected from H, D, CN, NO 2 , -N 3 , oxo, SF 5 , halogen, OR A , SR A , C (O) R B , C (O) NR C R D , C (O) OR A , OC (O) R B , OC (O) NR C R D , NR C R D , NR C C (O) R B , NR C C (O) OR A , S (O) R B , S (O) 2 R B .
  • R 3 is H.
  • R 3 is D.
  • R 3 is CN.
  • R 3 is NO 2 .
  • R 3 is N 3 . In some embodiments, R 3 is SF 5 . In some embodiments, R 3 is halogen. In some embodiments, R 3 is F, Cl, Br or I. In some embodiments, R 3 is F. In some embodiments, R 3 is Cl. In some embodiments, R 3 is Br. In some embodiments, R 3 is I.
  • R 3 is OR A . In some embodiments, R 3 is OH, OCH 3 , OCH 2 CH 3 , OCF 3 or
  • R 3 is SR A .
  • R 1 is C (O) R B .
  • R 1 is C (O) NR C R D .
  • R 1 is C (O) OR A .
  • R 1 is OC (O) R B .
  • R 3 is OC (O) NR C R D .
  • R 3 is NR C R D .
  • R 3 is NR C C (O) R B .
  • R 3 is NR C C (O) OR A .
  • R 3 is S (O) R B .
  • R 3 is S (O) 2 R B .
  • R 3 is selected from C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocycloalkyl; wherein, the C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halogen, CN, OH, NH 2 , NO 2 , oxo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -O-C 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocycloalkyl.
  • R 3 is C 1 -C 4 alkyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halogen, CN, OH, NH 2 , NO 2 , oxo, -O-C 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocycloalkyl.
  • R 3 is methyl, ethyl, CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 .
  • R 3 is C 2 -C 4 alkenyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halogen, CN, OH, NH 2 , NO 2 , oxo, -O-C 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocycloalkyl.
  • R 3 is C 2 -C 4 alkynyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halogen, CN, OH, NH 2 , NO 2 , oxo, -O-C 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocycloalkyl.
  • R 3 is C 3 -C 6 cycloalkyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halogen, CN, OH, NH 2 , NO 2 , oxo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -O-C 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocycloalkyl.
  • R 3 is 4-6 membered heterocycloalkyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halogen, CN, OH, NH 2 , NO 2 , oxo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -O-C 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocycloalkyl.
  • R 3 is selected from H, D, CN, SF 5 , halogen, OR A , or SR A , C 1 -C 4 alkyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halogen, CN, OH, -O-C 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl.
  • R 3 is selected from H, D, CN, SF 5 , halogen, OH, OCH 3 , OCH 2 CH 3 , OCF 3 , methyl, ethyl, CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CH 2 CHF 2 , or CH 2 CF 3 .
  • each R 4 is independently selected from D, halogen, -CN, -NO 2 , -SF 5 , -OR A , -SR A .
  • each R 4 is independently selected from D. In some embodiments, each R 4 is independently selected from halogen. In some embodiments, each R 4 is independently selected from F, Cl, Br, I. In some embodiments, each R 4 is F. In some embodiments, each R 4 is Cl. In some embodiments, each R 4 is Br. In some embodiments, each R 4 is I.
  • each R 4 is independently selected from CN. In some embodiments, each R 4 is independently selected from NO 2 . In some embodiments, each R 4 is independently selected from SF 5 .
  • each R 4 is independently selected from OR A . In some embodiments, each R 4 is independently selected from OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH 2 (CH 3 ) 2 , OCH 2 F, OCHF 2 , OCF 3 , OCH 2 CH 2 F, OCH 2 CHF 2 , OCH 2 CF 3 , -CH (OH) CH 3 , OCH 2 CN, OCH 2 CONH 2 . In some embodiments, each R 4 is independently selected from OCH 3 . In some embodiments, each R 4 is independently selected from OCH 2 CH 3 . In some embodiments, each R 4 is independently selected from OCH (CH 3 ) 2 .
  • each R 4 is independently selected from OCF 3 . In some embodiments, each R 4 is independently selected from OCHF 2 . In some embodiments, each R 4 is independently selected from OCH 2 F. In some embodiments, each R 4 is independently selected from OCF 3 . In some embodiments, each R 4 is independently selected from OCH 2 CH 2 F. In some embodiments, each R 4 is independently selected from OCH 2 CHF 2 . In some embodiments, each R 4 is independently selected from OCH 2 CF 3 . In some embodiments, each R 4 is independently selected from OCH 2 CN. In some embodiments, each R 4 is independently selected from OCH 2 CONH 2 .
  • each R 4 is independently selected from SR A . In some embodiments, each R 4 is independently selected from SCH 3 . In some embodiments, each R 4 is independently selected from SCH 2 CH 3 .
  • each R 4 is independently selected from C (O) R B . In some embodiments, each R 4 is independently selected from C (O) NR C R D . In some embodiments, each R 4 is independently selected from -C (O) OR A . In some embodiments, each R 4 is independently selected from -OC (O) R B . In some embodiments, each R 4 is independently selected from NR C R D . In some embodiments, each R 4 is independently selected from NR C C (O) R B . In some embodiments, each R 4 is independently selected from S (O) R B . In some embodiments, each R 4 is independently selected from S (O) 2 R B .
  • each R 4 is independently selected from C 1- C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; 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, phenyl or 5-6 membered heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 4A .
  • each R 4 is independently selected from C 1- C 6 alkyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 4A .
  • each R 4 is independently selected from CH 3 , CH 2 CH 3 , n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 , CH 2 OH, -CH (OH) CH 3 , CH 2 CH 2 OH, -CH 2 OCH 3 , -CH 2 OCH 2 F, -CH 2 OCHF 2 , -CH 2 OCF 3 , -CH (OCH 3 ) CH 3 , CH 2 CH 2 NH 2 , -CH (NH 2 ) CH 3 , CH 2 N (CH 3 ) 2 , CH 2 CH 2 N (CH 3 ) 2 , CH 2 CN.
  • each R 4 is independently selected from C 2 -C 6 alkenyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 4A .
  • each R 4 is independently selected from C 2 -C 6 alkynyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 4A .
  • each R 4 is independently selected from -C ⁇ CH, -C ⁇ CCH 3
  • each R 4 is independently selected from C 3 -C 6 cycloalkyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 4A .
  • each R 4 is independently selected from 4-6 membered heterocycloalkyl having 1 or 2 heteroatoms selected from N, O, S and B, and wherein the heteroatoms can be optionally substituted by one or more oxo (e.g., S (O) , or S (O) 2 ) optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 4A .
  • oxo e.g., S (O) , or S (O) 2
  • each R 4 is independently selected from phenyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 4A .
  • each R 4 is independently selected from 5-6 membered heteroaryl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 4A .
  • two adjacent R 4 together with the atoms to which they are attached form C 4- C 7 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 6 alkyl, -O-C 1- C 6 haloalkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocycloalkyl; wherein, the C 3- C 6 cycloalkyl or 4-6 membered heterocycloalkyl is optionally substituted with D, halogen, CN, OH, NH 2 , C 1- C 6 alkyl, C 1- C 6 haloalkyl, -O-C 1 -C 6 alkyl, -O-C 1- C 6 haloalkyl.
  • two adjacent R 4 together with the atoms to which they are attached form 4-7 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 6 alkyl, -O-C 1- C 6 haloalkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocycloalkyl; wherein, the C 3- C 6 cycloalkyl or 4-6 membered heterocycloalkyl is optionally substituted with D, halogen, CN, OH, NH 2 , C 1- C 6 alkyl, C 1- C 6 haloalkyl, -O-C 1 -C 6 alkyl, -O-C 1- C 6 haloalkyl.
  • each R 4 is independently (i) H, D, halo, or –OR A ; or (ii) C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl; each is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 4A ; wherein R A and R 4A are each as defined herein.
  • each R 4 is independently H, –F, –Cl, –CH 3 , –CF 3 , or –OCH 3 .
  • one of the R 4 groups is –F. In some embodiments, one of the R 4 groups is H, F, –Cl, –CH 3 , –CF 3 –OCH 3 , or ethynyl. In some embodiments, one of the R 4 groups is –OCH 3 .
  • two of the R 4 groups are not H. In some embodiments, two of the R 4 groups are not H; the first of the two is –F; the second of the two is –OCH 3 .
  • three of the R 4 groups are not H. In some embodiments, three of the R 4 groups are not H; the first of the three is –F; the second of the three is F, –Cl, –CH 3 , –CF 3 –OCH 3 , or ethynyl; and the third of the three is –OCH 3 . In some embodiments, three of the R 4 groups are not H; the first of the three is –F; the second of the three is –Cl; and the third of the three is –OCH 3 .
  • R 5 is independently selected from H, D, halo, CN, NO 2 , C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 1 -C 8 haloalkyl, C 1 -C 8 alkyl-O-C 1 -C 8 alkyl, OC 1 -C 8 haloalkyl, C 1 -C 8 alkyl-OH, C 1 -C 8 alkyl-CN.
  • R 5 is H.
  • R 5 is D.
  • R 5 is halo (such as F, Cl, Br, I) .
  • R 5 is CN.
  • R 5 is NO 2 . In some embodiments, R 5 is C 1 -C 8 alkyl. In some embodiments, R 5 is C 2 -C 8 alkenyl. In some embodiments, R 5 is C 2 -C 8 alkynyl. In some embodiments, R 5 is C 1 -C 8 haloalkyl. In some embodiments, R 5 is C 1 -C 8 alkyl-O-C 1 -C 8 alkyl. In some embodiments, R 5 is C 1 -C 8 alkyl-OH.In some embodiments, R 5 is C 1 -C 8 alkyl-CN.
  • R 6 is independently selected from H, D, halo, CN, NO 2 , C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 1 -C 8 haloalkyl, C 1 -C 8 alkyl-O-C 1 -C 8 alkyl, C 1 -C 8 alkyl-OH, C 1 -C 8 alkyl-CN.
  • R 6 is H.
  • R 6 is D.
  • R 6 is halo (such as F, Cl, Br, I) .
  • R 6 is CN.
  • R 6 is NO 2 .
  • R 6 is C 1 -C 8 alkyl. In some embodiments, R 6 is C 2 -C 8 alkenyl. In some embodiments, R 6 is C 2 -C 8 alkynyl. In some embodiments, R 6 is C 1 -C 8 haloalkyl. In some embodiments, R 6 is C 1 -C 8 alkyl-O-C 1 -C 8 alkyl. In some embodiments, R 6 is C 1 -C 8 alkyl-OH. In some embodiments, R 6 is C 1 -C 8 alkyl-CN.
  • R 7 is independently selected from H, D, CN, halo, NO 2 , N 3 , SF 5 , Si (R 8 ) 3 , C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl or adamantanyl; wherein, the C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl or adamantanyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from D, -halo, -CN, -NO 2 , -N 3 , SF 5 , oxo, -NR C R D , -OR A , -SR A , SiR G R H R I , -B (OR C ) (OR D ) , -C (O) R B , -C (O) OR A , -OC (O) R B , -C
  • R 7 is independently selected from H, D, CN, halo, NO 2 , N 3 , SF 5 , Si (R 8 ) 3 .
  • R 7 is H.
  • R 7 is D.
  • R 7 is halo.
  • R 7 is CN.
  • R 7 is NO 2 .
  • R 7 is N 3 .
  • R 7 is SF 5 .
  • R 7 is Si (R 8 ) 3 , such as R 7 is Si (CH 3 ) 3 .
  • R 7 is C 1 -C 8 alkyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from D, -halo, -CN, -NO 2 , -N 3 , SF 5 , oxo, -NR C R D , -OR A , -SR A , SiR G R H R I , -C (O) R B , -C (O) OR A , -OC (O) R B , -C (O) NR C R D , -OC (O) NR C R D , -NR C C (O) R B , -NR C C (O) NR C R D , -NR C C C (O) OR A , -S (O) R B , -S (O) 2 R B , -S (O) NR C R D , -NR C S (O) 2 R D , -S (O) 2 NR C R D , -NR C R D
  • R 7 is methyl, ethyl, propyl, butyl, pentyl, hexyl; each is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from D, -halo, -CN, -NO 2 , -N 3 , oxo, -NR C R D , -OR A , -SR A , SiR G R H R I , -C (O) R B , -C (O) NR C R D , -OC (O) NR C R D , -NR C C (O) R B , -NR C C (O) NR C R D , -NR C C (O) OR A , -S (O) R B , -S (O) 2 R B , -S (O) NR C R D , -NR C S (O) 2 R D , -S (O) 2 NR C R D , -NR C S (O) (O)
  • R 7 is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, CH 2 C (CH 3 ) 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 , CH 2 OH, CH 2 CH 2 OH, CH (CH 3 ) OH, CH 2 CH (CH 3 ) OH, CH 2 CH (CH 3 ) OH, CH 2 CH (CH 3 ) OH, CH 2 OCH 3 , CH 2 CH 2 OCH 3 , CH 2 OCH 2 CH 3 , CH 2 CH 2 OCH 2 CH 3 , CH 2 CH 2 OCH 2 CH 2 OCH 3 , CH 2 CH 2 OCH 2 CH 2 OCH 2 CH 3 , CH 2 CH 2 OCH 2 CH 2 OCH 2 CH 3 , CH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 OH, CH 2 CH 2 OCH 2 CH 2
  • R 7 is C 2 -C 8 alkenyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from D, -halo, -CN, -NO 2 , -N 3 , oxo, -NR C R D , -OR A , -SR A , -SiR G R H R I 3 , -C (O) R B , -C (O) NR C R D , -OC (O) NR C R D , -NR C C (O) R B , -NR C C (O) NR C R D , -NR C C (O) OR A , -S (O) R B , -S (O) 2 R B , -S (O) NR C R D , -NR C S (O) 2 R D , -S (O) 2 NR C R D , -NR C S (O) 2 NR C R D , -NR C S (O) 2 NR
  • R 7 is C 2 alkenyl, C 3 alkenyl, C 4 alkenyl, C 5 alkenyl, or C 6 alkenyl; wherein, each is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from D, -halo, -CN, -NO 2 , -N 3 , oxo, -NR C R D , -OR A , -SR A , SiR G R H R I , -C (O) R B , -C (O) NR C R D , -OC (O) NR C R D , -NR C C (O) R B , -NR C C (O) NR C R D , -NR C C (O) OR A , -S (O) R B , -S (O) 2 R B , -S (O) NR C R D , -NR C S (O) 2 R D , -S (O) 2 NR C
  • R 7 is C 2 -C 8 alkynyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from D, -halo, -CN, -NO 2 , -N 3 , oxo, -NR C R D , -OR A , -SR A , -SiR G R H R I , -C (O) R B , -C (O) NR C R D , -OC (O) NR C R D , -NR C C (O) R B , -NR C C (O) NR C R D , -NR C C (O) OR A , -S (O) R B , -S (O) 2 R B , -S (O) NR C R D , -NR C S (O) 2 R D , -S (O) 2 NR C R D , -NR C S (O) 2 NR C R D , -NR C S (O) 2 NR
  • R 7 is adamantanyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from D, halo, CN, NO 2 , N 3 , oxo, NR C R D , OR A , SR A , SiR G R H R I , B (OR C ) (OR D ) , C (O) R B , C (O) NR C R D , OC (O) NR C R D , NR C C (O) R B , NR C C (O) NR C R D , NR C C (O) OR A , S (O) R B , S (O) 2 R B , S (O) NR C R D , NR C S (O) R D , NR C S (O) 2 R D , S (O) 2 NR C R D , NR C S (O) 2 , S (O) 2 NR C R D , NR C S (O) 2 NR C R D ,
  • the moiety has the structure of
  • each R 8 is independently selected from C 1 -C 4 alkyl or phenyl.
  • R 8 is C 1 -C 4 alkyl or phenyl. In some embodiments, R 8 is methyl, ethyl, propyl (such as n-propyl, i-propyl) , butyl (n-butyl, i-butyl, t-butyl) or phenyl.
  • each R A is independently selected from H, D.
  • each R A 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, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl; 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 heterocyclalkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected
  • each R B is independently selected from H, D.
  • each 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, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl; 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, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected
  • R C and R D are each independently selected from H, 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, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl; 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, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, OH,
  • 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, 3, 4 or 5 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.
  • each R a is independently selected from H, D.
  • each R a is independently selected from C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl, C 3 -C 7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl, wherein, the C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl, C 3- C 7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halo, OH, CN, -NH 2 , -NH (C 1 -C 4 alkyl) , -N (C 1 -C 4 alkyl) 2 , C 1 -C 4 alkyl, OC 1 -C 4 alkyl, C 1 -C
  • each R a1 is independently selected from H, D.
  • each R a1 is independently selected from C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl, C 3 -C 7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl, wherein the C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl, C 3- C 7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halo, OH, CN, -NH 2 , -NH (C 1 -C 4 alkyl) , -N (C 1 -C 4 alkyl) 2 , C 1 -C 4 alkyl, OC 1 -C 4 alkyl, C 1 -C
  • each R b is each independently selected from H, D.
  • each R b is each independently selected from C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl, C 3- C 7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl; wherein the C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl, C 3- C 7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, OH, CN, -NH
  • each R b1 is each independently selected from H, D.
  • each R b1 is each independently selected from C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl, C 3- C 7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl; wherein, the C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl, C 3- C 7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, OH, CN,
  • R c and R d are each independently selected from H, D.
  • R c and R d are each independently selected from C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 6- C 10 aryl, 5-10 membered heteroaryl, C 3- C 10 cycloalkyl, 4-10 membered heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkyl, arylheterocycloalkyl, arylheteroaryl, biaryl, heteroarylcycloalkyl, heteroarylheterocycloalkyl, heteroarylaryl, or biheteroaryl; wherein the C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 6- C 10 aryl, 5-10 membered heteroaryl, C
  • 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, 3, 4 or 5 substituents independently selected from D, OH, 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 alkoxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, C 1 -C 4 hydroxyalkyl, C 1 -C 4 cyanoalkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, C 1 -C 4 alkoxy-C 1 -C 4 alkyl, or C 1 -C 4 alkoxy-C 1 -C 4 alkoxy.
  • each R E is independently selected from H, D.
  • each R E is independently selected from C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 2 -C 4 alkenyl, (C 1 -C 4 alkoxy) -C 1 -C 4 alkyl, C 2 -C 4 alkynyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -C 10 aryl-C 1 -C 4 alkyl, C 3 -C 10 cycloalkyl-C 1 -C 4 alkyl, 5-10 membered heteroaryl-C 1 -C 4 alkyl, or 4-10 membered heterocycloalkyl-C 1 -C 4 alkyl.
  • each R F is independently selected from H, D.
  • each R F is independently selected from C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, C 3 -C 10 cycloalkyl, or 4-10 membered heterocycloalkyl.
  • each R e is independently selected from C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 2 -C 4 alkenyl, (C 1 -C 4 alkoxy) -C 1 -C 4 alkyl, C 2 -C 4 alkynyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -C 10 aryl-C 1 -C 4 alkyl, C 3 -C 10 cycloalkyl-C 1 -C 4 alkyl, 5-10 membered heteroaryl-C 1 -C 4 alkyl, or 4-10 membered heterocycloalkyl-C 1 -C 4 alkyl.
  • each R f is independently selected from H, D.
  • each R f is independently selected from C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, C 3 -C 10 cycloalkyl, or 4-10 membered heterocycloalkyl.
  • R G , R H and R I are each independently selected from C 1 -C 4 alkyl or phenyl.
  • R G is C 1 -C 4 alkyl (such as C 1 alkyl, C 2 alkyl, C 3 alkyl, C 4 alkyl) or phenyl. In some embodiments, R G is methyl, ethyl, propyl (such as n-propyl, i-propyl) , butyl (n-butyl, i-butyl, t-butyl) or phenyl.
  • R H is C 1 -C 4 alkyl (such as C 1 alkyl, C 2 alkyl, C 3 alkyl, C 4 alkyl) or phenyl. In some embodiments, R H is methyl, ethyl, propyl (such as n-propyl, i-propyl) , or butyl (n-butyl, i-butyl, t-butyl) or phenyl.
  • R I is C 1 -C 4 alkyl (such as C 1 alkyl, C 2 alkyl, C 3 alkyl, C 4 alkyl) or phenyl. In some embodiments, R I is methyl, ethyl, propyl (such as n-propyl, i-propyl) , or butyl (n-butyl, i-butyl, t-butyl) or phenyl.
  • the compound of Formula (I) is:
  • the compounds provided herein can be asymmetric (e.g., having one or more stereocenters) . All stereoisomers, such as enantiomers and diastereomers, are contemplated unless otherwise indicated.
  • Cis and trans geometric isomers of the compounds provided herein are described and may be isolated as a mixture of isomers or as separated isomeric forms. Furthermore, atropisomers and mixtures thereof such as those resulting from restricted rotation about two aromatic or heteroaromatic rings bonded to one another are encompassed within the scope of the disclosure.
  • the compounds provided herein also include tautomeric forms.
  • Prototropic 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.
  • prototropic tautomers examples 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: etc. 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 disclosure 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 disclosure 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 present disclosure also includes pharmaceutically acceptable salts of the compounds provided herein.
  • 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.
  • 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. Lists of suitable salts are found in Remington’s Pharmaceutical Sciences, 17 th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and J. Pharm. Sci. 1977, 66, 2, each of which is incorporated herein by reference in its entirety.
  • a pharmaceutical composition comprising a compound provided herein, e.g., a compound of Formula (I) , or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic variant, prodrug, or deuterated compound thereof; and a pharmaceutically acceptable excipient.
  • compositions can be formulated in a form suitable for oral administration (for example, as tablets, lozenges, hard or soft capsules, aqueous or oil suspensions, emulsions, dispersible powders or granules, syrups, or elixirs) , for injection (for example, as aqueous or oil suspensions, emulsions, elixirs, or a sterile aqueous solution) , for topical application (for example, as creams, ointments, gels, or aqueous or oil solutions or suspensions) , for inhalation (for example, as a finely divided powder or a liquid aerosol) , for insufflation (for example, as a finely divided powder) , or for parenteral administration (for example, as a sterile aqueous or oil solution for intravenous, subcutaneous, intramuscular, intraperitoneal, or intramuscular dosing, or as a suppository for rectal dos
  • the pharmaceutically acceptable excipient (s) can be, 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, flavoring agents, sweeteners, taste masking agents, or stabilizers.
  • 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, flavoring agents, sweeteners, taste masking agents, or stabilizers.
  • the pharmaceutical carrier employed can be, for example, a solid, liquid, or gas.
  • solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
  • liquid carriers include sugar syrup, peanut oil, olive oil, and water.
  • gaseous carriers include carbon dioxide and nitrogen.
  • water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents may be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents may be used to form oral solid preparations, such as powders, capsules, and tablets.
  • 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, suspensions, sublingual tablets, wafers, or patches such as buccal patches.
  • tablet compositions can contain a unit dosage of an 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, and 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, eth
  • 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)
  • compositions of the present disclosure 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 disclosure 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, 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 disclosure can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, or dusting powder. Further, the compositions can be in a form suitable for use in transdermal devices.
  • the pharmaceutical formulations described herein may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, and preservatives (including antioxidants) .
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, and preservatives (including antioxidants) .
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, and preservatives (including antioxidants) .
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, and preservatives (including antioxidants) .
  • preservatives including antioxidants
  • provided herein is a method for treating or preventing cancer in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I) , or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic variant, prodrug, or deuterated compound thereof; or a pharmaceutical composition provided herein.
  • a compound provided herein e.g., a compound of Formula (I) , or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic variant, prodrug, or deuterated compound thereof; or a pharmaceutical composition provided herein.
  • the cancer is characterized by PolQ overexpression. In certain embodiments, the cancer is the characterized by increased dependence on MMEJ DSB repair. In certain embodiments, the cancer is characterized by HR-deficiency. In certain embodiments, the cancer is characterized by a reduction or absence of expression of a HR-associated gene. In certain embodiments, the cancer lacks a 53BP1/Shieldin complex. In certain embodiments, the cancer is resistant to PARPi treatment. In certain embodiments, the cancer is characterized by NHEJ deficiency. In certain embodiments, the cancer is a reduction or absence of expression of an NHEJ-associated gene.
  • a method for treating or preventing a disease characterized by PolQ overexpression in a subject comprising administering to the subject in need thereof a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I) , or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic variant, prodrug, or deuterated compound thereof; or a pharmaceutical composition provided herein.
  • a compound provided herein e.g., a compound of Formula (I) , or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic variant, prodrug, or deuterated compound thereof; or a pharmaceutical composition provided herein.
  • PolQ overexpression refers to the increased expression or activity of a PolQ enzyme in a diseased cell, e.g., cancer cell, relative to the expression or activity of a PolQ enzyme in a control cell (e.g., non-diseased cell of the same type) .
  • the PolQ overexpression is at least 2-fold, at least 3-fold, at least 4-fold, at least 6-fold, at least 10-fold, at least 20-fold, or at least 50-fold relative to the PolQ expression in a control cell.
  • PolQ overexpressing cancer include, but are not limited to, certain ovarian, breast, cervical, uterine, pancreatic, lung, colorectal, gastric, bladder, and prostate cancer.
  • a method for treating or preventing a disease characterized by increased dependence upon MMEJ DSB repair in a subject comprising administering to the subject in need thereof a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I) , or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic variant, prodrug, or deuterated compound thereof; or a pharmaceutical composition provided herein.
  • a compound provided herein e.g., a compound of Formula (I) , or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic variant, prodrug, or deuterated compound thereof; or a pharmaceutical composition provided herein.
  • a method for treating or preventing a disease characterized by HR-deficiency, a reduction or absence of the expression of an HR-associated gene in a subject comprising administering to the subject in need thereof a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I) , or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic variant, prodrug, or deuterated compound thereof; or a pharmaceutical composition provided herein.
  • a compound provided herein e.g., a compound of Formula (I) , or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic variant, prodrug, or deuterated compound thereof; or a pharmaceutical composition provided herein.
  • the HR-associated gene is 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, or XRCC2.
  • a method for treating or preventing a disease lacking a 53BP1/Shieldin complex in a subject comprising administering to the subject in need thereof a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I) , or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic variant, prodrug, or deuterated compound thereof; or a pharmaceutical composition provided herein.
  • a compound provided herein e.g., a compound of Formula (I) , or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic variant, prodrug, or deuterated compound thereof; or a pharmaceutical composition provided herein.
  • a method for treating or preventing a disease resistant to PARPi treatment in a subject comprising administering to the subject in need thereof a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I) , or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic variant, prodrug, or deuterated compound thereof; or a pharmaceutical composition provided herein.
  • a compound provided herein e.g., a compound of Formula (I) , or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic variant, prodrug, or deuterated compound thereof; or a pharmaceutical composition provided herein.
  • a method for treating or preventing a disease characterized by NHEJ deficiency, or a reduction or absence of expression of an NHEJ-associated gene in a subject comprising administering to the subject in need thereof a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I) , or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic variant, prodrug, or deuterated compound thereof; or a pharmaceutical composition provided herein.
  • a compound provided herein e.g., a compound of Formula (I) , or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic variant, prodrug, or deuterated compound thereof; or a pharmaceutical composition provided herein.
  • the NHEJ-associated gene is 53BP1, DCLRE1C, LIG4, NHEJ1, POLL, POLM, PRKDC, RIF1, SHLD1, SHLD2, SHLD3, XRCC4, XRCC5, or XRCC6.
  • the subject is a mammal. In certain embodiments, the subject is a human.
  • the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 100 mg/kg/day, from about 0.1 to about 50 mg/kg/day, from about 0.1 to about 25 mg/kg/day, from about 0.1 to about 20 mg/kg/day, from about 0.1 to about 15 mg/kg/day, from about 0.1 to about 10 mg/kg/day, or from about 0.1 to about 5 mg/kg/day.
  • the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 100 mg/kg/day.
  • the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 50 mg/kg/day.
  • the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 25 mg/kg/day. In yet another embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 20 mg/kg/day. In yet another embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 15 mg/kg/day. In yet another embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 10 mg/kg/day. In still another embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 5 mg/kg/day.
  • the administered dose can also be expressed in units other than mg/kg/day.
  • doses for parenteral administration can be expressed as mg/m 2 /day.
  • doses for parenteral administration can be expressed as mg/m 2 /day.
  • One of ordinary skill in the art would readily know how to convert doses from mg/kg/day to mg/m 2 /day to given either the height or weight of a subject or both. For example, a dose of 1 mg/m 2 /day for a 65 kg human is approximately equal to 58 mg/kg/day.
  • a compound provided herein may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, CIV, intracisternal injection or infusion, subcutaneous injection, or implant) , inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or local) routes of administration.
  • parenteral e.g., intramuscular, intraperitoneal, intravenous, CIV, intracisternal injection or infusion, subcutaneous injection, or implant
  • inhalation nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or local) routes of administration.
  • a compound provided herein may be formulated in suitable dosage unit with a pharmaceutically acceptable excipient, carrier, adjuvant, or vehicle, appropriate for each route of administration.
  • a compound provided herein is administered orally. In another embodiment, a compound provided herein is administered parenterally. In yet another embodiment, a compound provided herein is administered intravenously. In yet another embodiment, a compound provided herein is administered intramuscularly. In yet another embodiment, a compound provided herein is administered subcutaneously. In still another embodiment, a compound provided herein is administered topically.
  • a compound provided herein can be delivered as a single dose such as, e.g., a single bolus injection, or oral tablets or pills; or over time such as, e.g., continuous infusion over time or divided bolus doses over time.
  • a compound provided herein can be administered repetitively, if necessary, for example, until the subject experiences stable disease or regression, or until the subject experiences disease progression or unacceptable toxicity.
  • a compound provided herein can be administered once daily (QD) or divided into multiple daily doses such as twice daily (BID) , and three times daily (TID) .
  • the administration can be continuous, i.e., every day, or intermittently.
  • the term “intermittent” or “intermittently” as used herein is intended to mean stopping and starting at either regular or irregular intervals.
  • intermittent administration of a compound provided herein is administration for one to six days per week, administration in cycles (e.g., daily administration for two to eight consecutive weeks, then a rest period with no administration for up to one week) , or administration on alternate days.
  • a compound provided herein can also be combined or used in combination with other therapeutic agents useful in the treatment and/or prevention of a disease described herein.
  • the compounds provided herein, including salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes, such as those exemplified herein.
  • 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, 8th Ed. (Wiley, 2019) ; Peturssion et al, “Protecting Groups in Carbohydrate Chemistry” , J Chem. Educ., 1997, 74 (11) , 1297; and Wuts et al., Protective Groups in Organic Synthesis, 5th Ed., (Wiley, 2014) .
  • 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 from about 20 °C to about 30 °C.
  • heterocyclic amide derivatives of formula (I) can be prepared as the methods described in Scheme 1.
  • Heterocyclic amide derivatives (I) can be prepared by reactions of carboxylic acids 1-1 with suitable 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) .
  • an activating reagent such as BOP, PyBOP, HATU, HBTU, EDCI, or T 3 P
  • a base such as Hunig’s base, Et 3 N, pyridine or DMAP
  • 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 suitable 1, 3, 4-thiadiazol-2-amine derivatives 2-2 in 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 )
  • Heterocyclic acid intermediates of formula 3-5 can be prepared as the methods described in Scheme 3.
  • C-C coupling of compounds 3-1 with 3-3 can provide ester compounds 3-4 by the methods of Suzuki coupling or Stille coupling as described in Scheme 2. Saponification of the compounds 3-4 can yield the corresponding acid 3-5 under a base such as LiOH, NaOH, KOH or Me 3 SnOH.
  • Suzuki coupling of carboxylic acids 3-2 with compounds 3-3 can directly provide the corresponding acids 3-5 under standard Suzuki coupling conditions or Stille coupling conditions as described in Scheme 3.
  • 1,3, 4-thiadiazol-2-amine derivatives 4-3 can be prepared as the methods described in Scheme 4. Treatment of carboxylic acids 4-1 or cyanide 4-2 and thiosemicarbazide with a dehydrant such as POCl 3 , TFA, PCl 5 , P 2 O 5 or PPA can provide the 1, 3, 4-thiadiazol-2-amine derivatives 4-3.
  • a dehydrant such as POCl 3 , TFA, PCl 5 , P 2 O 5 or PPA
  • 1, 3, 4-thiadiazol-2-amine derivatives 5-4 can be prepared as the methods described in Scheme 5. Substitution of 5-bromo-1, 3, 4-thiadiazol-2-amine by alcohols 5-1 in the presence of a base such as t-BuOK, t-BuONa, Cs 2 CO 3 , K 2 CO 3 , Na 2 CO 3 , NaH, NaHMDS, or LDA in a suitable solvent THF, DMF or DMSO can provide 1, 3, 4-thiadiazol-2-amine derivatives 5-4.
  • a base such as t-BuOK, t-BuONa, Cs 2 CO 3 , K 2 CO 3 , Na 2 CO 3 , NaH, NaHMDS, or LDA
  • THF, DMF or DMSO a suitable solvent
  • dithiocarbonate 5-2 can be prepared by reaction of alcohols 5-1 with CS 2 and iodomethane in the presence of a base such as NaH, t-BuOK, t-BuONa or NaHMDS in a suitable solvent such as THF. Hydrazinolysis of dithiocarbonate 5-2 with hydrazine hydrate can afford compounds 5-3 which can be transformed into 1, 3, 4-thiadiazol-2-amine derivatives 5-4 by treatment of BrCN in the presence of a base such as Hunig’s base or TEA.
  • a base such as NaH, t-BuOK, t-BuONa or NaHMDS
  • Example 1 4- (2-Fluoro-6-methoxyphenyl) -6-methyl-N- (5- (neopentyloxy) -1, 3, 4-thiadiazol-2-yl) nicotinamide
  • Step 1 5- (neopentyloxy) -1, 3, 4-thiadiazol-2-amine
  • Step 2 4- (2-fluoro-6-methoxyphenyl) -6-methyl-N- (5- (neopentyloxy) -1, 3, 4-thiadiazol-2-yl) nicotinamide
  • Example 7 4- (2-Fluoro-6-methoxyphenyl) -6-methyl-N- (5- (2, 2, 2-trifluoroethoxy) -1, 3, 4-thiadiazol-2-yl) nicotinamide
  • Step 1 5- (2, 2, 2-trifluoroethoxy) -1, 3, 4-thiadiazol-2-amine
  • Step 2 4- (2-fluoro-6-methoxyphenyl) -6-methyl-N- (5- (2, 2, 2-trifluoroethoxy) -1, 3, 4-thiadiazol-2-yl) nicotinamide
  • Example 8 4- (2-Fluoro-6-methoxyphenyl) -N- (5- ( (-3-hydroxyadamantan-1-yl) methoxy) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
  • Example 11 4- (2-Fluoro-6-methoxyphenyl) -N- (5- (2-methoxypropoxy) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
  • Step 3 4- (2-fluoro-6-methoxyphenyl) -N- (5- (2-methoxypropoxy) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
  • Example 12 4- (2-Fluoro-6-methoxyphenyl) -N- (5- ( (S) -2-methoxypropoxy) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
  • Example 13 4- (2-Fluoro-6-methoxyphenyl) -N- (5- ( (R) -2-methoxypropoxy) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
  • Example 14 4- (2, 3-Difluoro-6-methoxyphenyl) -N- (5-ethoxy-1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
  • Step 2 4- (2, 3-difluoro-6-methoxyphenyl) -N- (5-ethoxy-1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
  • Example 15 4- (2, 3-Difluoro-6-methoxyphenyl) -N- (5- (2-methoxypropoxy) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
  • Example 16 4- (2, 3-Difluoro-6-methoxyphenyl) -6-methyl-N- (5- (2, 2, 2-trifluoroethoxy) -1, 3, 4-thiadiazol-2-yl) nicotinamide
  • Example 17 4- (3-Chloro-2-fluoro-6-methoxyphenyl) -N- (5-ethoxy-1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
  • Example 18 4- (3-Chloro-2-fluoro-6-methoxyphenyl) -N- (5- (2-methoxypropoxy) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
  • Example 19 4- (3-Chloro-2-fluoro-6-methoxyphenyl) -6-methyl-N- (5- (2, 2, 2-trifluoroethoxy) -1, 3, 4-thiadiazol-2-yl) nicotinamide
  • Example 20 4- (3-Chloro-2-fluoro-6-methoxyphenyl) -N- (5- (2-methoxyethoxy) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
  • Step 1 5- (2-methoxyethoxy) -1, 3, 4-thiadiazol-2-amine
  • Step 2 4- (3-chloro-2-fluoro-6-methoxyphenyl) -N- (5- (2-methoxyethoxy) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
  • Example 21 4- (3-Chloro-2-fluoro-6-methoxyphenyl) -N- (5- (2- (2-methoxyethoxy) ethoxy) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
  • Step 1 5- (2- (2-methoxyethoxy) ethoxy) -1, 3, 4-thiadiazol-2-amine
  • Step 2 4- (3-chloro-2-fluoro-6-methoxyphenyl) -N- (5- (2- (2-methoxyethoxy) ethoxy) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
  • Example 22 4- (3-Chloro-2-fluoro-6-methoxyphenyl) -N- (5- (2-cyclobutoxyethoxy) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
  • Step 2 5- (2-cyclobutoxyethoxy) -1, 3, 4-thiadiazol-2-amine
  • Step 3 4- (3-chloro-2-fluoro-6-methoxyphenyl) -N- (5- (2-cyclobutoxyethoxy) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
  • Step 1 (E) -5- (but-2-en-1-yloxy) -1, 3, 4-thiadiazol-2-amine
  • Step 2 (E) -N- (5- (but-2-en-1-yloxy) -1, 3, 4-thiadiazol-2-yl) -4- (3-chloro-2-fluoro-6-methoxyphenyl) -6-methylnicotinamide
  • Example 24 4- (3-Chloro-2-fluoro-6-methoxyphenyl) -N- (5- ( (2- (methoxymethyl) allyl) oxy) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
  • Step 2 5- ( (2- (methoxymethyl) allyl) oxy) -1, 3, 4-thiadiazol-2-amine
  • Step 3 4- (3-chloro-2-fluoro-6-methoxyphenyl) -N- (5- ( (2- (methoxymethyl) allyl) oxy) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
  • Example 25 4- (3-Chloro-2-fluoro-6-methoxyphenyl) -6-methyl-N- (5- ( (2-methylallyl) oxy) -1, 3, 4-thiadiazol-2-yl) nicotinamide
  • Step 1 5- ( (2-methylallyl) oxy) -1, 3, 4-thiadiazol-2-amine
  • Step 2 4- (3-chloro-2-fluoro-6-methoxyphenyl) -6-methyl-N- (5- ( (2-methylallyl) oxy) -1, 3, 4-thiadiazol-2-yl) nicotinamide
  • Example 26 4- (3-Chloro-2-fluoro-6-methoxyphenyl) -6-methyl-N- (5- ( (trimethylsilyl) methoxy) -1, 3, 4-thiadiazol-2-yl) nicotinamide
  • Step 1 S-methyl O- ( (trimethylsilyl) methyl) carbonodithioate
  • Step 2 O- ( (trimethylsilyl) methyl) hydrazinecarbothioate
  • Step 4 4- (3-chloro-2-fluoro-6-methoxyphenyl) -6-methyl-N- (5- ( (trimethylsilyl) methoxy) -1, 3, 4-thiadiazol-2-yl) nicotinamide
  • This compound was prepared using procedures analogous to those described for Example 17 using intermediate 4- (3-chloro-2-fluoro-6-methoxyphenyl) -6-methylnicotinic acid (Int-1) and 5- ( (trimethylsilyl) methoxy) -1, 3, 4-thiadiazol-2-amine.
  • Step 1 methyl 2'-chloro-5'-methoxy-6-methyl- [4, 4'-bipyridine] -3-carboxylate
  • Step 2 2'-chloro-5'-methoxy-6-methyl- [4, 4'-bipyridine] -3-carboxylic acid
  • Step 3 2'-chloro-5'-methoxy-6-methyl-N- (5- ( (trimethylsilyl) methoxy) -1, 3, 4-thiadiazol-2-yl) - [4, 4'-bipyridine] -3-carboxamide
  • Example 28 4- (3-Chloro-2-fluoro-6-methoxyphenyl) -6-methyl-N- (5- (2- (methylthio) ethoxy) -1, 3, 4-thiadiazol-2-yl) nicotinamide
  • Step 1 5- (2- (methylthio) ethoxy) -1, 3, 4-thiadiazol-2-amine
  • Step 2 4- (3-chloro-2-fluoro-6-methoxyphenyl) -6-methyl-N- (5- (2- (methylthio) ethoxy) -1, 3, 4-thiadiazol-2-yl) nicotinamide
  • Example 29 4- (3-Chloro-2-fluoro-6-methoxyphenyl) -6-methyl-N- (5- (2- (methylsulfinyl) ethoxy) -1, 3, 4-thiadiazol-2-yl) nicotinamide
  • Step 1 5- (2-azidoethoxy) -1, 3, 4-thiadiazol-2-amine
  • Step 2 N- (5- (2-azidoethoxy) -1, 3, 4-thiadiazol-2-yl) -4- (3-chloro-2-fluoro-6-methoxyphenyl) -6-methylnicotinamide
  • Example 31 4- (3-Chloro-2-fluoro-6-methoxyphenyl) -6-methyl-N- (5- (2- (N-methylacetamido) ethoxy) -1, 3, 4-thiadiazol-2-yl) nicotinamide
  • Step 1 N- (2- ( (5-amino-1, 3, 4-thiadiazol-2-yl) oxy) ethyl) -N-methylacetamide
  • Step 2 4- (3-chloro-2-fluoro-6-methoxyphenyl) -6-methyl-N- (5- (2- (N-methylacetamido) ethoxy) -1, 3, 4-thiadiazol-2-yl) nicotinamide
  • Example 32 4- (3-Chloro-2-fluoro-6-methoxyphenyl) -6-methyl-N- (5- (2- (N-methylmethylsulfonamido) ethoxy) -1, 3, 4-thiadiazol-2-yl) nicotinamide
  • Step 1 N- (2- ( (5-amino-1, 3, 4-thiadiazol-2-yl) oxy) ethyl) -N-methylmethanesulfonamide
  • Step 2 4- (3-chloro-2-fluoro-6-methoxyphenyl) -6-methyl-N- (5- (2- (N-methylmethylsulfonamido) ethoxy) -1, 3, 4-thiadiazol-2-yl) nicotinamide
  • Step 1 2- (2- ( (5-amino-1, 3, 4-thiadiazol-2-yl) oxy) ethyl) isoindoline-1, 3-dione
  • Step 2 4- (3-chloro-2-fluoro-6-methoxyphenyl) -N- (5- (2- (1, 3-dioxoisoindolin-2-yl) ethoxy) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
  • Step 3 N- (5- (2-aminoethoxy) -1, 3, 4-thiadiazol-2-yl) -4- (3-chloro-2-fluoro-6-methoxyphenyl) -6-methylnicotinamide
  • Step 4 N- (5- (2-acetamidoethoxy) -1, 3, 4-thiadiazol-2-yl) -4- (3-chloro-2-fluoro-6-methoxyphenyl) -6- methylnicotinamide
  • Example 34 4- (3-Chloro-2-fluoro-6-methoxyphenyl) -6-methyl-N- (5- (2- (methylsulfonamido) ethoxy) -1, 3, 4-thiadiazol-2-yl) nicotinamide
  • Example 36 4- (2-Fluoro-6-methoxy-3-methylphenyl) -N- (5- (2-methoxypropoxy) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
  • Example 37 4- (2-Fluoro-6-methoxy-3-methylphenyl) -6-methyl-N- (5- (2, 2, 2-trifluoroethoxy) -1, 3, 4-thiadiazol-2-yl) nicotinamide
  • Example 38 N- (5-Ethoxy-1, 3, 4-thiadiazol-2-yl) -4- (2-fluoro-6-methoxy-3- (trifluoromethyl) phenyl) -6-methylnicotinamide
  • Example 39 4- (2-Fluoro-6-methoxy-3- (trifluoromethyl) phenyl) -N- (5- (2-methoxypropoxy) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
  • Example 40 4- (2-Fluoro-6-methoxy-3- (trifluoromethyl) phenyl) -6-methyl-N- (5- (2, 2, 2-trifluoroethoxy) -1, 3, 4-thiadiazol-2-yl) nicotinamide
  • Example 41 4- (2-Fluoro-6-methoxy-3- (trifluoromethyl) phenyl) -N- (5- (2-methoxyethoxy) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
  • Example 43 4- (2-Fluoro-6-methoxy-3- (trifluoromethyl) phenyl) -N- (5- ( (2- (methoxymethyl) allyl) oxy) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
  • Example 44 4- (2-Fluoro-6-methoxy-3- (trifluoromethyl) phenyl) -6-methyl-N- (5- ( (2-methylallyl) oxy) -1, 3, 4-thiadiazol-2-yl) nicotinamide
  • Example 45 4- (2-Fluoro-6-methoxy-3- (trifluoromethyl) phenyl) -6-methyl-N- (5- ( (trimethylsilyl) methoxy) -1, 3, 4-thiadiazol-2-yl) nicotinamide
  • Example 46 4- (2-Fluoro-6-methoxy-3- (trifluoromethyl) phenyl) -N- (5-hydroxy-1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
  • Example 47 4- (3-Chloro-2-fluoro-6-methoxyphenyl) -N- (5-hydroxy-1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
  • Example 48 5'-Fluoro-2', 3'-dimethoxy-6-methyl-N- (5- (trimethylsilyl) methoxy) -1, 3, 4-thiadiazol-2-yl) - [4, 4'-bipyridine] -3-carboxamide
  • Step 3 methyl 5'-fluoro-2', 3'-dimethoxy-6-methyl- [4, 4'-bipyridine] -3-carboxylate
  • Step 4 5'-fluoro-2', 3'-dimethoxy-6-methyl- [4, 4'-bipyridine] -3-carboxylic acid
  • Step 5 5'-fluoro-2', 3'-dimethoxy-6-methyl-N- (5- (trimethylsilyl) methoxy) -1, 3, 4-thiadiazol-2-yl) - [4, 4'-bipyridine] -3-carboxamide
  • Example 49 4- (3-Ethynyl-2-fluoro-6-methoxyphenyl) -N- (5- (2-methoxyethoxy) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
  • Step 1 methyl 4- (3-bromo-2-fluoro-6-methoxyphenyl) -6-methylnicotinate
  • Step 2 methyl 4- (2-fluoro-6-methoxy-3- ( (trimethylsilyl) ethynyl) phenyl) -6-methylnicotinate
  • Step 3 4- (3-ethynyl-2-fluoro-6-methoxyphenyl) -6-methylnicotinic acid
  • Step 4 4- (3-ethynyl-2-fluoro-6-methoxyphenyl) -N- (5- (2-methoxyethoxy) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
  • Example 50 4- (3-Chloro-2-fluoro-6-methoxyphenyl) -6-methyl-N- (5- (2- ( ( (R) -tetrahydrofuran-3-yl) oxy) ethoxy) -1, 3, 4-thiadiazol-2-yl) nicotinamide
  • Example 51 4- (3-Chloro-2-fluoro-6-methoxyphenyl) -6-methyl-N- (5- (2- ( ( (S) -tetrahydrofuran-3-yl) oxy) ethoxy) -1, 3, 4-thiadiazol-2-yl) nicotinamide
  • Step 1 5- (allyl) oxy-1, 3, 4-thiadiazol-2-amine
  • Step 2 N- (5- (allyloxy) -1, 3, 4-thiadiazol-2-yl) -4- (3-chloro-2-fluoro-6-methoxyphenyl) -6-methylnicotinamide
  • Example 53 4- (3-Chloro-2-fluoro-6-methoxyphenyl) -N- (5- (2, 2-dihydroxyethoxy) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
  • Example 54 4- (3-Chloro-2-fluoro-6-methoxyphenyl) -6-methyl-N- (5- (2- (oxetan-3-yloxy) ethoxy) -1, 3, 4-thiadiazol-2-yl) nicotinamide
  • Example 55 4- (3-Chloro-2-fluoro-6-methoxyphenyl) -N- (5- (2- (2- (2-methoxyethoxy) ethoxy) ethoxy) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
  • Example 56 4- (3-Chloro-2-fluoro-6-methoxyphenyl) -N- (5- (2- (2- (2-hydroxyethoxy) ethoxy) ethoxy) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
  • Step 1 2, 2-dimethyl-3, 3-diphenyl-4, 7, 10-trioxa-3-siladodecan-12-ol
  • Step 2 O- (2, 2-dimethyl-3, 3-diphenyl-4, 7, 10-trioxa-3-siladodecan-12-yl) S-methyl carbonodithioate
  • Step 3 O- (2, 2-dimethyl-3, 3-diphenyl-4, 7, 10-trioxa-3-siladodecan-12-yl) hydrazinecarbothioate
  • Step 4 5- ( (2, 2-dimethyl-3, 3-diphenyl-4, 7, 10-trioxa-3-siladodecan-12-yl) oxy) -1, 3, 4-thiadiazol-2-amine
  • Step 5 4- (3-chloro-2-fluoro-6-methoxyphenyl) -N- (5- ( (2, 2-dimethyl-3, 3-diphenyl-4, 7, 10-trioxa-3-siladodecan-12-yl) oxy) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
  • Step 6 4- (3-chloro-2-fluoro-6-methoxyphenyl) -N- (5- (2- (2- (2-hydroxyethoxy) ethoxy) ethoxy) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
  • Step 1 (3-chloro-2-fluoro-6-methoxyphenyl) boronic acid
  • Step 2 methyl 4- (3-chloro-2-fluoro-6-methoxyphenyl) -6-methylnicotinate
  • Step 3 4- (3-chloro-2-fluoro-6-methoxyphenyl) -6-methylnicotinic acid
  • Step 1 methyl 4- (2-fluoro-6-methoxyphenyl) -6-methylnicotinate
  • Step 2 4- (2-fluoro-6-methoxyphenyl) -6-methylnicotinic acid
  • Step 1 methyl 4- (2, 3-difluoro-6-methoxyphenyl) -6-methylnicotinate
  • Step 2 4- (2, 3-difluoro-6-methoxyphenyl) -6-methylnicotinic acid
  • Step 1 methyl 4- (2-fluoro-6-methoxy-3-methylphenyl) -6-methylnicotinate
  • Step 2 4- (2-fluoro-6-methoxy-3-methylphenyl) -6-methylnicotinic acid
  • Step 1 2- (3-fluoro-4- (trifluoromethyl) phenyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane
  • Step 4 (2-fluoro-6-methoxy-3- (trifluoromethyl) phenyl) boronic acid
  • Step 5 methyl 4- (2-fluoro-6-methoxy-3- (trifluoromethyl) phenyl) -6-methylnicotinate
  • Step 6 4- (2-fluoro-6-methoxy-3- (trifluoromethyl) phenyl) -6-methylnicotinic acid
  • 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.
  • PolQ (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.
  • IC 50 values were determined by fitting the data to the standard 4 parameters with Hill Slope using GraphPad Prism software. IC 50 : * ⁇ 10nM, 10nM ⁇ ** ⁇ 100nM, 100nM ⁇ *** ⁇ 500nM, ****>500nM. The experimental results of the compounds are described in Table 1.

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Abstract

The disclosure relates to thiadiazolyl derivatives as shown in Formula (I), to pharmaceutical compositions comprising them, to a process for their preparation, and their use as therapeutic agents.

Description

THIADIAZOLYL DERIVATIVES, COMPOSITIONS AND USES THEREOF
CROSS REFERENCES TO RELATED APPLICATIONS
This application claims the benefit of the priority of International Application No. PCT/CN2022/131231, filed November 10, 2022, International Application No. PCT/CN2023/079231, filed March 02, 2023, International Application No. PCT/CN2023/082593, filed March 20, 2023, International Application No. PCT/CN2023/088519, filed April 14, 2023, each of which is hereby incorporated in its entirety.
TECHNICAL FIELD
The present disclosure relates to thiadiazolyl derivatives as PolQ inhibitors. The present disclosure also relates to methods for preparing the thiadiazolyl derivatives, pharmaceutical compositions, and their uses in the treatment of a PolQ-mediated disease, e.g., cancer containing a DNA repair defect.
BACKGROUND
DNA damage repair processes are critical for genome maintenance and cell viability. Double strand breaks (DSBs) can be repaired by one of three main pathways: homologous recombination (HR) , non-homologous end-joining (NHEJ) , and alternative NHEJ (alt-NHEJ) . An alt-NHEJ, also known as microhomology-mediated end-joining (MMEJ) , is commonly considered as a “backup” DSB repair pathway when NHEJ or HR is compromised. Truong et al., Proc. Natl. Acad. Sci. U.S.A. 2013, 110, 7720-5.
An aberrant DNA damage response (DDR) often can sensitize cancer cells to specific types of DNA damage. Thus, a defective DDR can be developed into targeted cancer therapies. Targeting DNA repair deficiencies has become a proven and effective strategy in cancer treatment, for example, the success of poly (ADP-ribose) polymerase (PARP) inhibitors in treating BRCA-deficient breast, ovarian, prostate, and pancreatic cancer. Audeh et al., Lancet 2010, 376, 245-51.
Numerous genetic, cell biological, and biochemical studies have demonstrated that DNA polymerase theta (PolQ) is a key protein involved in MMEJ. Kent et al. Nat. Struct. Mol. Biol. 2015, 22, 230-7; Mateos-Gomez et al. Nature 2015, 518, 254-7. 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 and Doublie, DNA Repair (Amst) . 2016, 44, 22-32. In homologous recombination deficient (HRD) cells, PolQ can carry out error-prone DNA synthesis at DNA damage sites through the alt-NHEJ pathway. It has been shown that the helicase domain of PolQ mediates the removal of a replication (RPA) protein from single-stranded (ssDNA) ends and stimulates annealing. This anti-recombinase activity of PolQ promotes the alt-NHEJ pathway. In addition, the helicase domain of PolQ contributes to microhomology-mediated strand annealing. Chan et al., PLoS Genet. 2010, 6, e1001005; Kawamura et al., Int. J. Cancer 2004, 109,  9-16. PolQ can promote end joining in the alt-NHEJ pathway by employing this annealing activity when ssDNA overhangs contain >2 base pair (bp) of microhomology. Kent et al., Elife 2016, 5, e13740; Kent, et al., Nat. Struct. Mol. Biol. 2015, 22, 230-7. This reannealing activity is achieved 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.
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, 175-84; Lemee et al., Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 13390-5; Ceccaldi et al., Nature 2015, 518, 258-62. Recent studies suggest that cancer cells with deficiency in HR, NHEJ, or ATM are highly dependent on PolQ expression. Ceccaldi et al., 2015, supra; Mateos-Gomez et al., 2015, supra; Wyatt et al., Mol. Cell. 2016, 63, 662-73. Thus, PolQ inhibition could conceivably prevent the MMEJ-dependent functional reversion of BRCA1-or BRCA2-mutations that underlies the emergence of cisplatin and PARPi resistance in tumors. Zatreanu et al., Nat. Commun. 2021, 12, 3636) . Therefore, PolQ is an attractive target for synthetic lethal therapy in cancer containing a DNA repair defect.
SUMMARY
The present disclosure relates to, inter alia, compounds of Formula (I) ,
or a pharmaceutically acceptable salt, solvate, tautomeric, stereoisomer, atropisomer, isotopic variant, prodrug, N-oxide, or deuterated compound thereof; wherein the variables are as defined below.
In another aspect, provided herein is a pharmaceutical composition comprising a compound of formula (I) , or pharmaceutically acceptable salt, solvate, tautomeric, stereoisomer, atropisomer, isotopic variant, prodrug, N-oxide, or deuterated compound thereof and at least one pharmaceutically acceptable carrier.
In another aspect, provided herein is a method of inhibiting PolQ comprising: contacting a PolQ with a compound of formula (I) , or pharmaceutically acceptable salt, solvate, tautomeric, stereoisomer, atropisomer, isotopic variant, prodrug, N-oxide, or deuterated compound thereof.
In another aspect, provided herein is 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 variant, prodrug, N-oxide, or deuterated compound thereof.
The details of one or more embodiments are set forth in the description below. Other features, objects, and advantages will be apparent from the description and from the claims.
Detailed description
Definitions
To facilitate understanding of the disclosure set forth herein, a number of terms are defined herein.
Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, biochemistry, biology, and pharmacology described herein are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.
As used herein, the singular forms “a” and “an” include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology such as “solely” , “only” , and the like in connection with the recitation of claim elements, or use of a “negative” limitation.
At various places in the present specification, variables defining divalent linking groups are described. It is specifically intended that each divalent linking group includes both the forward and backward forms of the divalent linking group. For example, –NR (CR’ R” ) –includes both –NR (CR’ R” ) –and – (CR’ R” ) NR–. Where a structure requires a linking group, 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 lists “alkyl” or “aryl” , then it is understood that the “alkyl” or “aryl” represents a linking alkylene group or arylene group, respectively.
The term “substituted” means that an atom or group of atoms formally replaces hydrogen as a “substituent” attached to another group. The term “substituted” , unless otherwise indicated, 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. The phrase “optionally substituted” means unsubstituted or substituted. The term “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. Examples of substituents include, but are not limited to, D, halo, oxo, C1-C-6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkyl-NRcRd, – (CH2CH2O) oC1-C6alkyl wherein o is 1-10; C2-6 alkenyl-NRcRd, C2-6 alkynyl-NRcRd, –OC2-6 alkyl-NRcRd, –CN, –NO2, –N3, –ORa, –SRa, –C (O) Rb, –C (O) NRcRd, –CH2C (O) NRcRd, –C (O) ORa, –OC (O) Rb, –OC (O) NRcRd, –NRcRd, –NRcC (O) Rb, –NRcC (O) NRcRd, –NRcC (O) ORa, –C (=NRc) NRcRd, –NRcC (=NRc) NRcRd, –P (Rf) 2, –P (ORe) 2, –P (O) ReRf, –P (O) OReORf, –S (O) Rb, –SO (=NRb) , –S (O) NRcRd, –S (O) 2Rb, –NRcS (O) 2Rb, –S (O) 2NRcRd; aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are each optionally substituted with D, halo, oxo, C1-C-6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6  alkyl-NRcRd, C2-6 alkenyl-NRcRd, C2-6 alkynyl-NRcRd, –OC2-6 alkyl-NRcRd, –CN, –NO2, –N3, –ORa, –SRa, –C (O) Rb, –C (O) NRcRd, –CH2C (O) NRcRd, –C (O) ORa, –OC (O) Rb, –OC (O) NRcRd, –NRcRd, –NRcC (O) Rb, –NRcC (O) NRcRd, –NRcC (O) ORa, –C (=NRc) NRcRd, –NRcC (=NRc) NRcRd, –P (Rf) 2, –P (ORe) 2, –P (O) ReRf, –P (O) OReORf, –S (O) Rb, –S (O) NRcRd, –S (O) 2Rb, –NRcS (O) 2Rb, or –S (O) 2NRcRd; wherein each Ra, Rb, Rc, Rd, Re, and Rf are each as described herein.
The term “Cn-Cm” indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons. For example, the term “C1-C6 alkyl” is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl. The term “C0 alkyl” refers to a covalent bond.
It is further intended that the compounds of the disclosure are stable. As used herein “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.
It is further appreciated that certain features of the disclosure, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the disclosure which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable sub-combination.
As used herein, the term “alkyl” is meant to refer to a saturated hydrocarbon group which is straight-chained or branched. An alkyl group can contain from about 1 to about 20, from about 2 to about 20, from about 1 to about 10, from about 1 to about 8, from about 1 to about 6, from about 1 to about 4, or from about 1 to about 3 carbon atoms. For example, alkyl can include any number of carbons, such as C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C1-C5 alkyl, C1-C6 alkyl, C1-C7 alkyl, C1-C8 alkyl, C1-C9 alkyl, C1-C10 alkyl, C2-C3 alkyl, C2-C4 alkyl, C2-C5 alkyl, C2-C6 alkyl, C3-C4 alkyl, C3-C5 alkyl, C3-C6 alkyl, C4-C5 alkyl, C4-C6 alkyl, and C5-C6 alkyl. Similarly, C1-C8 as in C1-C8 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. Examples of 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, and t-butyl) , pentyl (e.g., n-pentyl, isopentyl, and neopentyl) , hexyl, heptyl, and octyl.
As used herein, the term “alkenyl” is meant to refer to a hydrocarbon group having one or more double carbon-carbon bonds. Alkenyl can include any number of carbons, such as C2-C3 alkenyl, C2-C4 alkenyl, C2-C5 alkenyl, C2-C6 alkenyl, C2-C7 alkenyl, C2-C8 alkenyl, C2-C9 alkenyl, C2-C10 alkenyl, C3-C4 alkenyl, C3-C5 alkenyl, C3-C6 alkenyl, C4-C5 alkenyl, C4-C6 alkenyl and C5-C6 alkenyl. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.
As used herein, the term “alkynyl” is meant to refer to a hydrocarbon group having one or more triple carbon-carbon bonds. Alkynyl can include any number of carbons, such as C2-C3 alkynyl, C2-C4 alkynyl, C2-C5 alkynyl, C2-C6 alkynyl, C2-C7 alkynyl, C2-C8 alkynyl, C2-C9 alkynyl, C2-C10 alkynyl, C3-C4 alkynyl, C3-C5 alkynyl, C3-C6 alkynyl, C4-C5 alkynyl, C4-C6 alkynyl, and C5-C6 alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, and pentynyl.
As used herein, the term “haloalkyl” is meant to refer to an alkyl group having one or more  halo as substituents. Examples of haloalkyl groups include, but are not limited to, –CF3, –C2F5, –CHF2, –CH2F, –CCl3, –CHCl2, and –C2Cl5.
As used herein, the term “aryl” is meant to refer to an unsubstituted or substituted monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) aromatic hydrocarbon. In certain embodiments, aryl groups have from about 6 to about 20 carbon atoms. In certain embodiments, aryl groups have from about 6 to about 14 carbon atoms. In certain embodiments, aryl groups have from about 6 to about 10 carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, and indenyl.
As used herein, the term “cycloalkyl” is meant to refer to an unsubstituted or substituted nonaromatic carbocycle. Cycloalkyl groups can include mono-or polycyclic (e.g., having 2, 3, or 4 rings) ring systems, including fused rings, spirocyclic rings, and bridged rings (e.g., a bridged bicycloalkyl group) . In certain embodiments, cycloalkyl groups can have from about 3 to about 20 carbon atoms, from about 3 to about 14 carbon atoms, from about 3 to about 10 carbon atoms, or from about 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 (=O) or sulfido (=S) . In certain embodiments, the cycloalkyl is C3-C7 monocyclic cycloalkyl. In certain embodiments, the cycloalkyl is C4-C10 spiro or bridged cycloalkyl. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcaranyl, cubanyl, adamantanyl, bicyclo [1.1.1] pentyl, bicyclo [2.1.1] hexyl, bicyclo [2.2.1] heptanyl, bicyclo2[3.1.1] -heptanyl, bicyclo [2.2.2] octanyl, and spiro [3.3] heptanyl.
As used herein, the term “heteroaryl” is meant to refer 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. Examples of heteroaryl groups include, are not limited to, pyridyl, N-oxopyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuryl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1, 2, 4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, and indolinyl. In certain embodiments, the heteroaryl group has from about 1 to about 20 carbon atoms or from about 3 to about 20 carbon atoms. In certain embodiments, the heteroaryl group contains from about 3 to about 14, from about 3 to about 7, about 5, or about 6 ring-forming atoms. In certain embodiments, the heteroaryl group has from about 1 to about 4, from about 1 to about 3, about 1, or about 2 heteroatoms.
As used herein, the term “heterocycloalkyl” is meant to refer to an unsubstituted or substituted monocyclic (saturated or partially unsaturated ring) or polycyclic heterocycle having at least one non-aromatic ring (saturated or partially unsaturated ring) and at least one heteroatom ring member such as N, O, S, Si, and B; wherein the ring-forming carbon atoms and heteroatoms of the heterocycloalkyl group can be optionally substituted by one or more oxo (=O) or sulfido (=S) . 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 spirocyclic and bridged rings (e.g., a 5-10 membered bridged biheterocycloalkyl) . In certain embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In certain embodiments, the heterocycloalkyl group contains 0 to 2 double bonds.
Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused to the non-aromatic heterocyclic ring, for example, benzo or thienyl derivatives of piperidine, morpholine, azepine, etc. In certain embodiments, 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. In certain embodiments, the heterocycloalkyl group has 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms or 1 heteroatom. In certain embodiments, the heterocycloalkyl is a monocyclic 4-6 membered heterocycloalkyl having 1 or 2 heteroatoms.
Examples of heterocycloalkyl groups include, but are not limited to, pyrrolidin-2-onyl, l, 3-isoxazolidin-2-onyl, pyranyl, tetrahydropyranyl, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, benzazepinyl, 1, 2, 3, 4-tetrahydroisoquinolinyl, azabicyclo [3.1.0] hexanyl, diazabicyclo [3. l. 0] hexanyl, oxabicyclo-[2.1.l] hexanyl, azabicyclo [2.2.l] heptanyl, diazabicyclo [2.2.1] heptanyl, azabicyclo [3.1.l] heptanyl, diazabicyclo [3.1.l] heptanyl, azabicyclo [3.2.l] octanyl, diazabicyclo [3.2.1] octanyl, oxabicyclo [2.2.2] -octanyl, azabicyclo [2.2.2] octanyl, diazabicyclo [2.2.2] octanyl, azaadamantanyl, diazaadamantanyl, oxaadamantanyl, azaspiro [3.3] heptanyl, diazaspiro [3.3] heptanyl, oxaazaspiro [3.3] heptanyl, azaspiro [3.4] octanyl, diazaspiro [3.4] octanyl, oxaazaspiro [3.4] octanyl, oxaazaspiro [3.5] nonanyl, azaspiro [2.5] octanyl, diazaspiro [2.5] octanyl, azaspiro [4.4] nonanyl, diazaspiro [4.4] nonanyl, oxa-azaspiro [4.4] nonanyl, azaspiro [4.5] decanyl, diazaspiro [4.5] decanyl, diazaspiro [4.4] nonanyl, oxa-diazaspiro [4.4] nonanyl, and octahydropyrrolo [3, 4-c] pyrrolyl.
In certain embodiments, heterocycloalkyl is meant to refer 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. Examples of suitable 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, and piperazinyl.
As used herein, the term “halo” or “halogen” is meant to refer to fluoro, chloro, bromo, and iodo.
As used herein, the term “alkoxy” is meant to refer to an –O-alkyl group. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy) , and t-butoxy.
As used herein, the term “hydroxylalkyl” is meant to refer to an alkyl group substituted by –OH.
As used herein, the term “cyanoalkyl” is meant to refer to an alkyl group substituted by –CN.
As used herein, the term “alkoxyalkyl” is meant to refer to an alkyl group substituted by an alkoxy group.
As used herein, the term “haloalkoxy” is meant to refer to an –O- (haloalkyl) group.
As used herein, the term “arylalkyl” or “aralkyl” is meant to refer to alkyl substituted by aryl. An example of the arylalkyl group is benzyl.
As used herein, the term “cycloalkylalkyl” is meant to refer to alkyl substituted by cycloalkyl.
As used herein, the term “heteroarylalkyl” is meant to refer to alkyl substituted by heteroaryl.
As used herein, the term “heterocycloalkylalkyl” is meant to refer to alkyl substituted by heterocycloalkyl.
In certain embodiments, the compounds of the disclosure, and salts thereof, are substantially isolated. By “substantially isolated” is meant that the compound is at least partially or substantially separated from the environment in which was formed or detected. 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 disclosure, or a salt thereof.
The phrase “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.
The term “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. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.
The term “solvate” refers to a physical association of a compound with one or more solvent molecules.
The term “subject” refers to an animal, including, but not limited to, a primate (e.g., human) , cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms “subject” and “patient” are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject. In one embodiment, the subject is a human.
The term “treating” or “treatment” of a 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) . In another embodiment, “treating” or “treatment” refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, “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. In yet another embodiment, “treating” or “treatment” refers to  delaying the onset of the disease or disorder.
As used herein, the term “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. For example, 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 (2H or D) , carbon-13 (13C) , nitrogen-15 (15N) , or the like. It will be understood that, in a compound where such isotopic substitution is made, the following atoms, where present, may vary, so that, for example, any hydrogen may be 2H/D, any carbon may be 13C, or any nitrogen may be 15N, and that the presence and placement of such atoms may be determined within the skill of the art.
Compounds
In one embodiment, provided herein is a compound of Formula (I) ,
or a pharmaceutically acceptable salt, solvate, tautomeric, stereoisomer, atropisomer, isotopic variant, prodrug, N-oxide, or deuterated compound thereof; wherein:
X1 is N or CR1;
X2 is N or CR2;
X3 is N or CR3;
X1, X2 and X3 are not N at the same time;
m is 1, 2, 3, 4 or 5;
Cy is C6-C10 aryl or 5-10 membered heteroaryl;
R is selected from OH, or
R1 and R2 are independently selected from H, D, CN, NO2, N3, oxo, SF5, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, ORA, SRA, C (O) RB, C (O) NRCRD, C (O) ORA, OC (O) RB, OC (O) NRCRD, NRCRD, NRCC (O) RB, NRCC (O) ORA, S (O) RB, S (O) 2RB; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halogen, CN, OH, NH2, NO2, oxo, C1-C4 alkyl, C1-C4 haloalkyl, -O-C1-C4 alkyl, -OC1-C4 haloalkyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl;
or R1 and R2 together with the carbon atoms to which they are attached form C4-C7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; wherein, the C4-C7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl is optionally substituted by 1, 2, 3 or 4 substituents independently selected from D, halo, CN, NO2, OH, NH2, C1-C6 alkyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, -OC1-C6 haloalkyl, NHC1-C4 alkyl, or N (C1-C4 alkyl) 2;
R3 is selected from H, D, CN, NO2, -N3, oxo, SF5, halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl, ORA, SRA, C (O) RB, C (O) NRCRD, C (O) ORA, OC (O) RB, OC (O) NRCRD, NRCRD, NRCC (O) RB, NRCC (O) ORA, S (O) RB, S (O) 2RB; wherein, the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halogen, CN, OH, NH2, NO2, oxo, C1-C4 alkyl, C1-C4 haloalkyl, -O-C1-C4 alkyl, -OC1-C4 haloalkyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl;
each R4 is independently selected from D, halogen, -CN, -NO2, -SF5, -ORA, -SRA, -C (O) RB, -C (O) NRCRD, -C (O) ORA, -OC (O) RB, -NRCRD, -NRCC (O) RB, -S (O) RB, -S (O) 2RB, -S (O) NRCRD, -NRCS (O) 2RD, -S (O) 2NRCRD, -NRCS (O) 2NRCRD, -NRCS (O) (=NRB) RB, -P (O) RERF, -P (O) OREORF, -OP (O) OREORF, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R4A;
each R4A is independently selected from D, halogen, CN, OH, NH2, oxo, C1-C6 alkyl, OC1-C6 alkyl, C1-C6 haloalkyl, OC1-C6 haloalkyl, NHC1-C3 alkyl, N (C1-C3 alkyl) 2, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl; wherein, the C3-C6 cycloalkyl or 4-6 membered heterocycloalkyl is optionally substituted with D, halogen, CN, OH, NH2, C1-C6 alkyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl;
or two adjacent R4 together with the atoms to which they are attached form C4-C7 cycloalkyl or 4-7 membered heterocycloalkyl; wherein, the C4-C7 cycloalkyl or 4-7 membered heterocycloalkyl is optionally substituted with D, halogen, oxo, CN, OH, NH2, NO2, C1-C6 alkyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl; wherein, the C3-C6 cycloalkyl or 4-6 membered heterocycloalkyl is optionally substituted with D, halogen, CN, OH, NH2, C1-C6 alkyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl;
R5 and R6 are each independently selected from H, D, halo, CN, NO2, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 haloalkyl, C1-C8 alkyl-O-C1-C8 alkyl, C1-C8 alkyl-O-C1-C8 haloalkyl, C1-C8 alkyl-OH, C1-C8 alkyl-CN;
R7 is independently selected from H, D, CN, halo, NO2, N3, SF5, Si (R8) 3, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or adamantanyl; wherein, the C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or adamantanyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from D, -halo, -CN, -NO2, -N3, SF5, oxo, -NRCRD, -ORA, -SRA, SiRGRHRI, -B (ORC) (ORD) , -C (O) RB, -C (O) ORA, -OC (O) RB, -C (O) NRCRD, -OC (O) NRCRD, -NRCC (O) RB, -NRCC (O) NRCRD, -NRCC (O) ORA, -S (O) RB, -S (O) 2RB, -S (O) NRCRD, -NRCS (O) RD, -NRCS (O) 2RD, -S (O) 2NRCRD, -NRCS (O) 2NRCRD, -NRCS (O) (=NRB) RB;
each R8 is independently selected from C1-C4 alkyl or phenyl;
each RA is independently selected from H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocyclalkyl, C6-C10 aryl, 5-10 membered  heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, CN, halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkyl-OH, C1-C4 alkyl-CN, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, NO2, oxo, ORa, SRa, SF5, NHORa, C (O) Rb, C (O) NRcRd, C (O) ORa, OC (O) Rb, OC (O) NRcRd, NRcRd, NRcC (O) Rb, NRcC (O) NRcRd, NRcC (O) ORa, B (ORc) (ORd) , C (=NRc) NRcRd, NRdC (=NRc) NRcRd, NRdC (=NRc) Rb, P (O) ReRf, P (O) OReORf, OP (O) OReORf, S (O) Rb, S (O) NRcRd, S (O) 2Rb, NRcS (O) 2Rb, S (O) 2NRcRd, NRcS (O) 2NRcRd, or NRcS (O) (=NRb) Rb;
each RB is independently selected from H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, OH, CN, halo, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, SF5, C (O) Rb, OC (O) NRcRd, NRcRd, NRcC (O) Rb, NRcC (O) NRcRd, NRcC (O) ORa, S (O) Rb, S (O) NRcRd, S (O) 2Rb, NRcS (O) 2Rb, S (O) 2NRcRd, NRcS (O) 2NRcRd, or B (ORc) (ORd) ;
RC and RD are each independently selected from H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, OH, CN, halo, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, SF5, OC (O) NRcRd, NRcRd, NRcC (O) Rb, S (O) NRcRd, S (O) 2Rb, NRcS (O) 2Rb, S (O) 2NRcRd, NRcS (O) 2NRcRd or B (ORc) (ORd) ;
or RC and RD together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, OH, oxo, CN, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, or OC1-C4 haloalkyl;
Ra and Ra1 are each independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C3-C7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl, wherein the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C3-C7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halo, OH, CN, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, C1-C4 alkyl, OC1-C4 alkyl, C1-C4 haloalkyl, or OC1-C4 haloalkyl;
Rb and Rb1 are each independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C3-C7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl; wherein, the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C3-C7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered  heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, OH, CN, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C6-C10 aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl;
Rc and Rd are each independently selected from H, D, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkyl, arylheterocycloalkyl, arylheteroaryl, biaryl, heteroarylcycloalkyl, heteroarylheterocycloalkyl, heteroarylaryl, or biheteroaryl; wherein, the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkyl, arylheterocycloalkyl, arylheteroaryl, biaryl, heteroarylcycloalkyl, heteroarylheterocycloalkyl, heteroarylaryl, or biheteroaryl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, OH, CN, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 hydroxyalkyl, C1-C4 cyanoalkyl, C6-C10 aryl, 5-10 membered heteroaryl, C (O) ORa1, C (O) Rb1, S (O) 2Rb1, C1-C4 alkyl-O-C1-C4 alkyl or C1-C4 alkyl-O-C1-C4 alkyl-O-;
or Rc and Rd together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, OH, CN, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 hydroxyalkyl, C1-C4 cyanoalkyl, C6-C10 aryl, 5-10 membered heteroaryl, C1-C4 alkoxy-C1-C4 alkyl or C1-C4 alkoxy-C1-C4 alkoxy;
RE and Re are each independently selected from H, D, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, (C1-C4 alkoxy) -C1-C4 alkyl, C2-C4 alkynyl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl-C1-C4 alkyl, C3-C10 cycloalkyl-C1-C4 alkyl, 5-10 membered heteroaryl-C1-C4 alkyl, or 4-10 membered heterocycloalkyl-C1-C4 alkyl;
RF and Rf are each independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, or 4-10 membered heterocycloalkyl;
RG, RH and RI are each independently selected from C1-C4 alkyl or phenyl.
In some embodiments, X1 is CR1, X2 is CR2, and X3 is CR3.
In some embodiments, X1 is N, X2 is CR2, and X3 is CR3.
In some embodiments, X1 is CR1, X2 is N, and X3 is CR3.
In some embodiments, X1 is CR1, X2 is CR2, and X3 is N.
In some embodiments, the compounds of Formula (I) are represented by compounds of Formula (IIa) , (IIb) , (IIc) or (IId) :

or a pharmaceutically acceptable salt, solvate, tautomeric, stereoisomer, atropisomer, isotopic variant, prodrug, N-oxide, or deuterated compound thereof;
wherein, Cy, R, R1, R2, R3, R4, and m are as defined herein.
In some embodiments, the compounds of Formula (I) are represented by compounds of Formula (IIa) or (IIb) :
or a pharmaceutically acceptable salt, solvate, tautomeric, stereoisomer, atropisomer, isotopic variant, prodrug, N-oxide, or deuterated compound thereof;
wherein, Cy, R, R1, R2, R3, R4, and m are as defined herein.
In some embodiments, Cy is C6-C10 aryl, 5-10 membered heteroaryl.
In some embodiments, Cy is C6-C10 aryl. In some embodiments, Cy is phenyl or naphthalenyl. In some embodiments, Cy is phenyl.
In some embodiments, Cy is 5-10 membered heteroaryl. In some embodiments, Cy is 5 membered heteroaryl. In some embodiments, Cy is 6 membered heteroaryl. In some embodiments, Cy is 8 membered heteroaryl. In some embodiments, Cy is 9 membered heteroaryl. In some embodiments, Cy is 10 membered heteroaryl.
In some embodiments, Cy is pyrrolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, tetrazolyl, pyrazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, indolizinyl, benzofuranyl, isobenzofuranyl, benzo [b] thiophenyl, benzo [c] thiophenyl, indazolyl, benzo [d] imidazolyl, pyrrolo [3, 2-b] pyridinyl, pyrrolo [3, 2-c] pyridinyl, pyrrolo [2, 3-c] pyridinyl, pyrrolo [2, 3-b] pyridinyl, pyrrolo [3, 4-b] pyridinyl, pyrrolo [3, 4-c] pyridinyl, benzo [d] isoxazolyl, benzo [d] oxazolyl, furo [3, 2-b] pyridinyl, furo [3, 2-c] pyridinyl, furo [2, 3-c] pyridinyl, furo [2, 3-b] pyridinyl, benzo [c] isoxazolyl, furo [3, 4-b] pyridinyl, furo [3, 4-c] pyridinyl, benzo [d] isothiazolyl, benzo [d] thiazolyl, thieno [3, 2-b] pyridinyl, thieno [3, 4-c] pyridinyl, benzo [d] [1, 2, 3] triazolyl, pyrazolo [4, 3-b] pyridinyl, pyrazolo [4, 3-c] pyridinyl, pyrazolo [3, 4-c] pyridinyl, pyrazolo [3, 4-b] pyridinyl, imidazo [4, 5-b] pyridinyl, imidazo [4, 5-c] pyridinyl, imidazo [4, 5-c] pyridinyl, imidazo [4, 5-b] pyridinyl, pyrrolo [3, 2-c] pyridazinyl, pyrrolo [3, 2-d] pyrimidinyl, pyrrolo [2, 3-b] pyrazinyl, pyrrolo [2, 3-d] pyridazinyl, pyrrolo [2, 3-d] pyrimidinyl, pyrrolo [2, 3-c] pyridazinyl, pyrrolo [3, 4-c] pyridazinyl, pyrrolo [3, 4-d] pyrimidinyl, pyrrolo [3, 4-b] pyrazinyl, pyrrolo [3, 4-d] pyridazinyl, pyrrolo [3, 4-d] pyrimidinyl, 6H-pyrrolo [3, 4-c] pyridazinyl.
In some embodiments, Cy is phenyl or 6-membered heteroaryl. In some embodiments, Cy is phenyl or pyridin-4-yl. In some embodiments, Cy is phenyl.
In some embodiments, the moietyhas the structure ofwherein, Y1 is N or CR4; Y2 is N or CR4; and each R4 is same or different and as defined herein.
In some embodiments, Y1 is CR4, and Y2 is CR4. In some embodiments, Y1 is CH, and Y2 is CH.
In some embodiments, Y1 is CR4, and Y2 is N.
In some embodiments, Y1 is N, and Y2 is CR4.
In some embodiments, the moietyhas the structure of wherein each R2 is as defined herein.
In some embodiments, the moietyhas the structure ofIn some embodiments, the moietyhas the structure ofIn some embodiments, the moietyhas the structure ofIn some embodiments, the moietyhas the structure ofwherein each R2 is as defined herein.
In some embodiments, the moietyhas the structure of
In some embodiments, the compounds of Formula (I) are represented by compounds of Formula (IIIa) , or (IIIb) :
or a pharmaceutically acceptable salt, solvate, tautomeric, stereoisomer, atropisomer, isotopic variant, prodrug, N-oxide, or deuterated compound thereof;
wherein, R, R1, R2, R3, R4, Y1 and Y2 are as defined herein.
In some embodiments, R is OH.
In some embodiments, R is
In some embodiments, the compounds of Formula (I) are represented by compounds of Formula (IVa) or (IVb) :
or a pharmaceutically acceptable salt, solvate, tautomeric, stereoisomer, atropisomer, isotopic variant, prodrug, N-oxide, or deuterated compound thereof;
wherein, Cy, R1, R2, R3, R4, R5, R6, R7, and m are as defined herein.
In some embodiments, the compounds of Formula (I) are represented by compounds of Formula (Va) , or (Vb) :
or a pharmaceutically acceptable salt, solvate, tautomeric, stereoisomer, atropisomer, isotopic variant, prodrug, N-oxide, or deuterated compound thereof;
wherein, Cy, R1, R2, R3, R4, R7, and m are as defined herein.
In some embodiments, the compounds of Formula (I) are represented by compounds of Formula (VIa) , or (VIb) :
or a pharmaceutically acceptable salt, solvate, tautomeric, stereoisomer, atropisomer, isotopic variant, prodrug, N-oxide, or deuterated compound thereof;
wherein, R1, R2, R3, R4, R5, R6, R7, Y1 and Y2 are as defined herein.
In some embodiments, the compounds of Formula (I) are represented by compounds of Formula (VIIa) , or (VIIb) :
or a pharmaceutically acceptable salt, solvate, tautomeric, stereoisomer, atropisomer, isotopic variant, prodrug, N-oxide, or deuterated compound thereof;
wherein, R1, R2, R3, R4, R5, R6, R7, Y1 and Y2 are as defined herein.
In some embodiments, the compounds of Formula (I) are represented by compounds of Formula (VIIIa) , or (VIIIb) :
or a pharmaceutically acceptable salt, solvate, tautomeric, stereoisomer, atropisomer, isotopic variant, prodrug, N-oxide, or deuterated compound thereof;
wherein, R1, R2, R3, R4, R5, R6, R7, Y1 and Y2 are as defined herein.
In some embodiments, R1 is selected from H, D, CN, NO2, N3, oxo, SF5, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, ORA, SRA, C (O) RB, C (O) NRCRD, C (O) ORA, OC (O) RB, OC (O) NRCRD, NRCRD, NRCC (O) RB, NRCC (O) ORA, S (O) RB, S (O) 2RB; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halogen, CN, OH, NH2, NO2, oxo, C1-C4 alkyl, C1-C4 haloalkyl, -O-C1-C4 alkyl, -OC1-C4 haloalkyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl.
In some embodiments, R1 is selected from H, D, CN, NO2, N3, oxo, SF5, halogen, ORA, SRA, C (O) RB, C (O) NRCRD, C (O) ORA, OC (O) RB, OC (O) NRCRD, NRCRD, NRCC (O) RB, NRCC (O) ORA, S (O) RB, S (O) 2RB. In some embodiments, R1 is H. In some embodiments, R1 is D. In some embodiments, R1 is CN. In some embodiments, R1 is NO2. In some embodiments, R1 is N3. In some embodiments, R1 is SF5. In some embodiments, R1 is halogen. In some embodiments, R1 is F, Cl, Br or I. In some embodiments, R1 is F. In some embodiments, R1 is Cl. In some embodiments, R1 is Br. In some embodiments, R1 is I. In some embodiments, R1 is ORA. In some embodiments, R1 is OH, OCH3, OCH2CH3, OCH2CH2CH3, OCH (CH3) 2, OCH2F, OCHF2, OCF3, In some embodiments, R1 is SRA. In some embodiments, R1 is C (O) RB. In some embodiments, R1 is C (O) NRCRD. In some embodiments, R1 is C (O) ORA. In some embodiments, R1 is OC (O) RB. In  some embodiments, R1 is OC (O) NRCRD. In some embodiments, R1 is NRCRD. In some embodiments, R1 is NRCC (O) RB. In some embodiments, R1 is NRCC (O) ORA. In some embodiments, R1 is S (O) RB. In some embodiments, R1 is S (O) 2RB.
In some embodiments, R1 is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halogen, CN, OH, NH2, NO2, oxo, C1-C4 alkyl, C1-C4 haloalkyl, -O-C1-C4 alkyl, -OC1-C4 haloalkyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl.
In some embodiments, R1 is C1-C6 alkyl (such as C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl) optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halogen, CN, OH, NH2, NO2, oxo, -O-C1-C4 alkyl, -OC1-C4 haloalkyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl. In some embodiments, R1 is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, CH2F, CHF2, CF3, CH2CH2F, CH2CHF2, CH2CF3.
In some embodiments, R1 is C2-C6 alkenyl (such as C2-C5 alkenyl, C2-C4 alkenyl, C2-C3 alkenyl) optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halogen, CN, OH, NH2, NO2, oxo, -O-C1-C4 alkyl, -OC1-C4 haloalkyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl.
In some embodiments, R1 is C2-C6 alkynyl (such as C2-C5 alkynyl, C2-C4 alkynyl, C2-C3 alkynyl) optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halogen, CN, OH, NH2, NO2, oxo, -O-C1-C4 alkyl, -OC1-C4 haloalkyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl.
In some embodiments, R1 is C3-C6 cycloalkyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halogen, CN, OH, NH2, NO2, oxo, C1-C6 alkyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, -OC1-C6 haloalkyl. In some embodiments, R1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; each is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halogen, CN, OH, NH2, NO2, oxo, C1-C6 alkyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, -OC1-C6 haloalkyl. In some embodiments, R1 is cyclopropyl.
In some embodiments, R1 is 4-6 membered heterocycloalkyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halogen, CN, OH, NH2, NO2, oxo, C1-C6 alkyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, -OC1-C6 haloalkyl. In some embodiments, R1 is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl; each is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halogen, CN, OH, NH2, NO2, oxo, C1-C6 alkyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, -OC1-C6 haloalkyl.
In some embodiments, R1 is phenyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halogen, CN, OH, NH2, NO2, oxo, C1-C4 alkyl, C1-C4 haloalkyl, -O-C1-C4 alkyl, -OC1-C4 haloalkyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl.
In some embodiments, R1 is 5-6 membered heteroaryl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halogen, CN, OH, NH2, NO2, oxo, C1-C4 alkyl, C1-C4 haloalkyl, -O-C1-C4 alkyl, -OC1-C4 haloalkyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl.
In some embodiments, R1 is selected from H, D, CN, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, ORA, SRA, NRCRD; wherein, the C1-C6 alkyl or C3-C6 cycloalkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halogen, CN, OH, NH2, oxo, C1-C6 alkyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, -OC1-C6 haloalkyl.
In some embodiments, R1 is selected from H, D, CN, NO2, SF5, halogen, OH, OCH3, OCH2CH3, OCH2CH2CH3, OCH (CH3) 2, OCH2F, OCHF2, OCF3, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, CH2F, CHF2, CF3, CH2CH2F, CH2CHF2, or CH2CF3.
In some embodiments, R2 is selected from H, D, CN, NO2, N3, oxo, SF5, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, ORA, SRA, C (O) RB, C (O) NRCRD, C (O) ORA, OC (O) RB, OC (O) NRCRD, NRCRD, NRCC (O) RB, NRCC (O) ORA, S (O) RB, S (O) 2RB; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halogen, CN, OH, NH2, NO2, oxo, C1-C4 alkyl, C1-C4 haloalkyl, -O-C1-C4 alkyl, -OC1-C4 haloalkyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl.
In some embodiments, R2 is selected from H, D, CN, NO2, N3, oxo, SF5, halogen, ORA, SRA, C (O) RB, C (O) NRCRD, C (O) ORA, OC (O) RB, OC (O) NRCRD, NRCRD, NRCC (O) RB, NRCC (O) ORA, S (O) RB, S (O) 2RB. In some embodiments, R2 is H. In some embodiments, R2 is D. In some embodiments, R2 is CN. In some embodiments, R2 is NO2. In some embodiments, R2 is N3. In some embodiments, R2 is SF5. In some embodiments, R2 is halogen. In some embodiments, R2 is F, Cl, Br or I. In some embodiments, R2 is F. In some embodiments, R2 is Cl. In some embodiments, R2 is Br. In some embodiments, R2 is I.
In some embodiments, R2 is ORA. In some embodiments, R2 is OH, OCH3, OCH2CH3, OCH2CH2CH3, OCH (CH3) 2, OCH2F, OCHF2, OCF3, 
In some embodiments, R2 is SRA. In some embodiments, R2 is C (O) RB. In some embodiments, R2 is C (O) NRCRD. In some embodiments, R2 is C (O) ORA. In some embodiments, R2 is OC (O) RB. In some embodiments, R2 is OC (O) NRCRD. In some embodiments, R2 is NRCRD. In some embodiments, R2 is NRCC (O) RB. In some embodiments, R2 is NRCC (O) ORA. In some embodiments, R2 is S (O) RB. In some embodiments, R2 is S (O) 2RB.
In some embodiments, R2 is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halogen, CN, OH, NH2, NO2, oxo, C1-C4 alkyl, C1-C4 haloalkyl, -O-C1-C4 alkyl, -OC1-C4 haloalkyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl.
In some embodiments, R2 is C1-C6 alkyl (such as C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl) optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halogen, CN, OH, NH2, NO2, oxo, -O-C1-C4 alkyl, -OC1-C4 haloalkyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl.
In some embodiments, R2 is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, CH2F, CHF2, CF3, CH2CH2F, CH2CHF2, CH2CF3. In some embodiments, R2 is methyl. In some embodiments, R2 is ethyl. In some embodiments, R2 is CH2F. In some embodiments, R2 is CHF2. In some embodiments, R2 is CF3.
In some embodiments, R2 is C2-C6 alkenyl (such as C2-C5 alkenyl, C2-C4 alkenyl, C2-C3 alkenyl) optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halogen, CN, OH, NH2, NO2, oxo, -O-C1-C4 alkyl, -OC1-C4 haloalkyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl.
In some embodiments, R2 is C2-C6 alkynyl (such as C2-C5 alkynyl, C2-C4 alkynyl, C2-C3 alkynyl) optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halogen, CN, OH, NH2, NO2, oxo, -O-C1-C4 alkyl, -OC1-C4 haloalkyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl.
In some embodiments, R2 is C3-C6 cycloalkyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halogen, CN, OH, NH2, NO2, oxo, C1-C6 alkyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, -OC1-C6 haloalkyl. In some embodiments, R2 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; each is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halogen, CN, OH, NH2, NO2, oxo, C1-C6 alkyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, -OC1-C6 haloalkyl.
In some embodiments, R2 is 4-6 membered heterocycloalkyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halogen, CN, OH, NH2, NO2, oxo, C1-C6 alkyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, -OC1-C6 haloalkyl. In some embodiments, R1 is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl; each is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halogen, CN, OH, NH2, NO2, oxo, C1-C6 alkyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, -OC1-C6 haloalkyl.
In some embodiments, R2 is phenyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halogen, CN, OH, NH2, NO2, oxo, C1-C4 alkyl, C1-C4 haloalkyl, -O-C1-C4 alkyl, -OC1-C4 haloalkyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl.
In some embodiments, R2 is 5-6 membered heteroaryl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halogen, CN, OH, NH2, NO2, oxo, C1-C4 alkyl, C1-C4 haloalkyl, -O-C1-C4 alkyl, -OC1-C4 haloalkyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl.
In some embodiments, R2 is selected from H, D, CN, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, ORA, SRA, NRCRD; wherein, the C1-C6 alkyl or C3-C6 cycloalkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halogen, CN, OH, NH2, oxo, C1-C6 alkyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, -OC1-C6 haloalkyl.
In some embodiments, R2 is selected from H, D, CN, NO2, SF5, halogen, OH, OCH3, OCH2CH3, OCH2CH2CH3, OCH (CH3) 2, OCH2F, OCHF2, OCF3, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, CH2F, CHF2, CF3, CH2CH2F, CH2CHF2, CH2CF3.
In some embodiments, R1 and R2 together with the carbon atoms to which they are attached form C4-C7 cycloalkyl optionally substituted by 1, 2, 3 or 4 substituents independently selected  from D, halo, CN, NO2, OH, NH2, C1-C6 alkyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, -OC1-C6 haloalkyl, NHC1-C4 alkyl, or N (C1-C4 alkyl) 2.
In some embodiments, R1 and R2 together with the carbon atoms to which they are attached form 4-7 membered heterocycloalkyl optionally substituted by 1, 2, 3 or 4 substituents independently selected from D, halo, CN, NO2, OH, NH2, C1-C6 alkyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, -OC1-C6 haloalkyl, NHC1-C4 alkyl, or N (C1-C4 alkyl) 2.
In some embodiments, R1 and R2 together with the carbon atoms to which they are attached form phenyl optionally substituted by 1, 2, 3 or 4 substituents independently selected from D, halo, CN, NO2, OH, NH2, C1-C6 alkyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, -OC1-C6 haloalkyl, NHC1-C4 alkyl, or N (C1-C4 alkyl) 2.
In some embodiments, R1 and R2 together with the carbon atoms to which they are attached form 5-6 membered heteroaryl independently selected from D, halo, CN, NO2, OH, NH2, C1-C6 alkyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, -OC1-C6 haloalkyl, NHC1-C4 alkyl, or N (C1-C4 alkyl) 2.
In some embodiments, R3 is selected from H, D, CN, NO2, SF5, halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl, ORA, SRA, C (O) RB, C (O) NRCRD, C (O) ORA, OC (O) RB, OC (O) NRCRD, NRCRD, NRCC (O) RB, NRCC (O) ORA, S (O) RB, S (O) 2RB; wherein, the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl, is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halogen, CN, OH, NH2, NO2, oxo, C1-C6 alkyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, -OC1-C6 haloalkyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl.
In some embodiments, R3 is selected from H, D, CN, NO2, -N3, oxo, SF5, halogen, ORA, SRA, C (O) RB, C (O) NRCRD, C (O) ORA, OC (O) RB, OC (O) NRCRD, NRCRD, NRCC (O) RB, NRCC (O) ORA, S (O) RB, S (O) 2RB. In some embodiments, R3 is H. In some embodiments, R3 is D. In some embodiments, R3 is CN. In some embodiments, R3 is NO2. In some embodiments, R3 is N3. In some embodiments, R3 is SF5. In some embodiments, R3 is halogen. In some embodiments, R3 is F, Cl, Br or I. In some embodiments, R3 is F. In some embodiments, R3 is Cl. In some embodiments, R3 is Br. In some embodiments, R3 is I.
In some embodiments, R3 is ORA. In some embodiments, R3 is OH, OCH3, OCH2CH3, OCF3 or
In some embodiments, R3 is SRA. In some embodiments, R1 is C (O) RB. In some embodiments, R1 is C (O) NRCRD. In some embodiments, R1 is C (O) ORA. In some embodiments, R1 is OC (O) RB. In some embodiments, R3 is OC (O) NRCRD. In some embodiments, R3 is NRCRD. In some embodiments, R3 is NRCC (O) RB. In some embodiments, R3 is NRCC (O) ORA. In some embodiments, R3 is S (O) RB. In some embodiments, R3 is S (O) 2RB.
In some embodiments, R3 is selected from C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl; wherein, the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halogen, CN, OH, NH2, NO2, oxo, C1-C4 alkyl, C1-C4 haloalkyl, -O-C1-C4 alkyl, -OC1-C4 haloalkyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl.
In some embodiments, R3 is C1-C4 alkyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halogen, CN, OH, NH2, NO2, oxo, -O-C1-C4 alkyl, -OC1-C4 haloalkyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl. In some embodiments, R3 is methyl, ethyl, CH2F, CHF2, CF3, CH2CH2F, CH2CHF2, CH2CF3.
In some embodiments, R3 is C2-C4 alkenyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halogen, CN, OH, NH2, NO2, oxo, -O-C1-C4 alkyl, -OC1-C4 haloalkyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl.
In some embodiments, R3 is C2-C4 alkynyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halogen, CN, OH, NH2, NO2, oxo, -O-C1-C4 alkyl, -OC1-C4 haloalkyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl.
In some embodiments, R3 is C3-C6 cycloalkyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halogen, CN, OH, NH2, NO2, oxo, C1-C4 alkyl, C1-C4 haloalkyl, -O-C1-C4 alkyl, -OC1-C4 haloalkyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl.
In some embodiments, R3 is 4-6 membered heterocycloalkyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halogen, CN, OH, NH2, NO2, oxo, C1-C4 alkyl, C1-C4 haloalkyl, -O-C1-C4 alkyl, -OC1-C4 haloalkyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl.
In some embodiments, R3 is selected from H, D, CN, SF5, halogen, ORA, or SRA, C1-C4 alkyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halogen, CN, OH, -O-C1-C4 alkyl, -OC1-C4 haloalkyl.
In some embodiments, R3 is selected from H, D, CN, SF5, halogen, OH, OCH3, OCH2CH3, OCF3, methyl, ethyl, CH2F, CHF2, CF3, CH2CH2F, CH2CHF2, or CH2CF3.
In some embodiments, each R4 is independently selected from D, halogen, -CN, -NO2, -SF5, -ORA, -SRA, -C (O) RB, -C (O) NRCRD, -C (O) ORA, -OC (O) RB, -NRCRD, -NRCC (O) RB, -S (O) RB, -S (O) 2RB, -S (O) NRCRD, -NRCS (O) 2RD, -S (O) 2NRCRD, -NRCS (O) 2NRCRD, -NRCS (O) (=NRB) RB, -P (O) RERF, -P (O) OREORF, -OP (O) OREORF, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halogen, CN, OH, NH2, oxo, C1-C6 alkyl, OC1-C6 alkyl, C1-C6 haloalkyl, OC1-C6 haloalkyl, NHC1-C3 alkyl, N (C1-C3 alkyl) 2, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl; wherein, the C3-C6 cycloalkyl or 4-6 membered heterocycloalkyl is optionally substituted with D, halogen, CN, OH, NH2, C1-C6 alkyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl.
In some embodiments, each R4 is independently selected from D, halogen, -CN, -NO2, -SF5, -ORA, -SRA.
In some embodiments, each R4 is independently selected from D. In some embodiments, each R4 is independently selected from halogen. In some embodiments, each R4 is independently selected from F, Cl, Br, I. In some embodiments, each R4 is F. In some embodiments, each R4 is Cl. In some  embodiments, each R4 is Br. In some embodiments, each R4 is I.
In some embodiments, each R4 is independently selected from CN. In some embodiments, each R4 is independently selected from NO2. In some embodiments, each R4 is independently selected from SF5.
In some embodiments, each R4 is independently selected from ORA. In some embodiments, each R4 is independently selected from OCH3, OCH2CH3, OCH2CH2CH3, OCH2 (CH3) 2, OCH2F, OCHF2, OCF3, OCH2CH2F, OCH2CHF2, OCH2CF3, -CH (OH) CH3, OCH2CN, OCH2CONH2. In some embodiments, each R4 is independently selected from OCH3. In some embodiments, each R4 is independently selected from OCH2CH3. In some embodiments, each R4 is independently selected from OCH (CH3) 2. In some embodiments, each R4 is independently selected from OCF3. In some embodiments, each R4 is independently selected from OCHF2. In some embodiments, each R4 is independently selected from OCH2F. In some embodiments, each R4 is independently selected from OCF3. In some embodiments, each R4 is independently selected from OCH2CH2F. In some embodiments, each R4 is independently selected from OCH2CHF2. In some embodiments, each R4 is independently selected from OCH2CF3. In some embodiments, each R4 is independently selected from OCH2CN. In some embodiments, each R4 is independently selected from OCH2CONH2.
In some embodiments, each R4 is independently selected from SRA. In some embodiments, each R4 is independently selected from SCH3. In some embodiments, each R4 is independently selected from SCH2CH3.
In some embodiments, each R4 is independently selected from -C (O) RB, -C (O) NRCRD, -C (O) ORA, -OC (O) RB, -NRCRD, -NRCC (O) RB, -S (O) RB, -S (O) 2RB, -S (O) NRCRD, -NRCS (O) 2RD, -S (O) 2NRCRD, -NRCS (O) 2NRCRD, -NRCS (O) (=NRB) RB, -P (O) RERF, -P (O) OREORF, -OP (O) OREORF. In some embodiments, each R4 is independently selected from C (O) RB. In some embodiments, each R4 is independently selected from C (O) NRCRD. In some embodiments, each R4 is independently selected from -C (O) ORA. In some embodiments, each R4 is independently selected from -OC (O) RB. In some embodiments, each R4 is independently selected from NRCRD. In some embodiments, each R4 is independently selected from NRCC (O) RB. In some embodiments, each R4 is independently selected from S (O) RB. In some embodiments, each R4 is independently selected from S (O) 2RB. In some embodiments, each R4 is independently selected from S (O) NRCRD. In some embodiments, each R4 is independently selected from -NRCS (O) 2RD. In some embodiments, each R4 is independently selected from -S (O) 2NRCRD. In some embodiments, each R4 is independently selected from -NRCS (O) 2NRCRD. In some embodiments, each R4 is independently selected from -NRCS (O) (=NRB) RB. In some embodiments, each R4 is independently selected from -P (O) RERF. In some embodiments, each R4 is independently selected from -P (O) OREORF. In some embodiments, each R4 is independently selected from -OP (O) OREORF.
In some embodiments, each R4 is independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R4A.
In some embodiments, each R4 is independently selected from C1-C6 alkyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R4A.
In some embodiments, each R4 is independently selected from CH3, CH2CH3, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, CH2F, CHF2, CF3, CH2CH2F, CH2CHF2, CH2CF3, CH2OH, -CH (OH) CH3, CH2CH2OH, -CH2OCH3, -CH2OCH2F, -CH2OCHF2, -CH2OCF3, -CH (OCH3) CH3, CH2CH2NH2, -CH (NH2) CH3, CH2N (CH3) 2, CH2CH2N (CH3) 2, CH2CN.
In some embodiments, each R4 is independently selected from C2-C6 alkenyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R4A.
In some embodiments, each R4 is independently selected from -CH=CH2, -CH=CHCH3.
In some embodiments, each R4 is independently selected from C2-C6 alkynyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R4A.
D, halogen, CN, OH, NH2, oxo, C1-C6 alkyl, OC1-C6 alkyl, C1-C6 haloalkyl, OC1-C6 haloalkyl, NHC1-C3 alkyl, N (C1-C3 alkyl) 2, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl; wherein, the C3-C6 cycloalkyl or 4-6 membered heterocycloalkyl is optionally substituted with D, halogen, CN, OH, NH2, C1-C6 alkyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl. In some embodiments, each R4 is independently selected from -C≡CH, -C≡CCH3.
In some embodiments, each R4 is independently selected from C3-C6 cycloalkyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R4A.
In some embodiments, each R4 is independently selected from 4-6 membered heterocycloalkyl having 1 or 2 heteroatoms selected from N, O, S and B, and wherein the heteroatoms can be optionally substituted by one or more oxo (e.g., S (O) , or S (O) 2) optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R4A.
In some embodiments, each R4 is independently selected from phenyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R4A.
In some embodiments, each R4 is independently selected from 5-6 membered heteroaryl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R4A.
In some embodiments, each R4 is independently selected from D, CN, OH, NH2, F, Cl, Br, CH3, CH2CH3, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, -CH=CH2, -CH=CHCH3, -C≡CH, -C≡CCH3, OCH3, OCH2CH3, OCH2CH2CH3, OCH2 (CH3) 2, CH2F, CHF2, CF3, CH2CH2F, CH2CHF2, CH2CF3, CH2OH, SCH3, SCH2CH3, S (O) CH3, S (O) CH2CH3, S (O) 2CH3, S (O) 2CH2CH3, S (O) 2NH2, S (O) 2NHCH3, S (O) 2N (CH3) 2, NHS (O) 2CH3, C (O) CH3, C (O) CH2CH3, OCH2F, OCHF2, OCF3, OCH2CH2F, OCH2CHF2, OCH2CF3, -CH (OH) CH3, CH2CH2OH, -CH2OCH3, -CH2OCH2F, -CH2OCHF2, -CH2OCF3, -CH (OCH3) CH3, OCH2CN, OCH2CONH2, NHCH3, N (CH3) 2, CH2CH2NH2, -CH (NH2) CH3, CH2N (CH3) 2, CH2CH2N (CH3) 2, CH2CN, -COOH, -CONH2, -CONHCH3, -CON (CH3) 2, -P (O) (CH3) 2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, CHO, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, 1, 4-diazocanyl, 1, 4-diazepanyl, azepanyl.
In some embodiments, two adjacent R4 together with the atoms to which they are attached form C4-C7 cycloalkyl optionally substituted with D, halogen, oxo, CN, OH, NH2, NO2, C1-C6 alkyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl; wherein, the C3-C6 cycloalkyl or 4-6 membered heterocycloalkyl is optionally substituted with D, halogen, CN, OH, NH2, C1-C6 alkyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl.
In some embodiments, two adjacent R4 together with the atoms to which they are attached form 4-7 membered heterocycloalkyl optionally substituted with D, halogen, oxo, CN, OH, NH2, NO2, C1-C6 alkyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl; wherein, the C3-C6 cycloalkyl or 4-6 membered heterocycloalkyl is optionally substituted with D, halogen, CN, OH, NH2, C1-C6 alkyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl.
In some embodiments, each R4 is independently (i) H, D, halo, or –ORA; or (ii) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl; each is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R4A; wherein RA and R4A are each as defined herein. In some embodiments, each R4 is independently H, –F, –Cl, –CH3, –CF3, or –OCH3.
In some embodiments, one of the R4 groups is –F. In some embodiments, one of the R4 groups is H, F, –Cl, –CH3, –CF3 –OCH3, or ethynyl. In some embodiments, one of the R4 groups is –OCH3.
In some embodiments, two of the R4 groups are not H. In some embodiments, two of the R4 groups are not H; the first of the two is –F; the second of the two is –OCH3.
In some embodiments, three of the R4 groups are not H. In some embodiments, three of the R4 groups are not H; the first of the three is –F; the second of the three is F, –Cl, –CH3, –CF3 –OCH3, or ethynyl; and the third of the three is –OCH3. In some embodiments, three of the R4 groups are not H; the first of the three is –F; the second of the three is –Cl; and the third of the three is –OCH3.
In some embodiments, R5 is independently selected from H, D, halo, CN, NO2, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 haloalkyl, C1-C8 alkyl-O-C1-C8 alkyl, OC1-C8 haloalkyl, C1-C8 alkyl-OH, C1-C8 alkyl-CN. In some embodiments, R5 is H. In some embodiments, R5 is D. In some embodiments, R5 is halo (such as F, Cl, Br, I) . In some embodiments, R5 is CN. In some embodiments, R5 is NO2. In some embodiments, R5 is C1-C8 alkyl. In some embodiments, R5 is C2-C8 alkenyl. In some embodiments, R5 is C2-C8 alkynyl. In some embodiments, R5 is C1-C8 haloalkyl. In some embodiments, R5 is C1-C8 alkyl-O-C1-C8 alkyl. In some embodiments, R5 is C1-C8 alkyl-OH.In some embodiments, R5 is C1-C8 alkyl-CN.
In some embodiments, R6 is independently selected from H, D, halo, CN, NO2, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 haloalkyl, C1-C8 alkyl-O-C1-C8 alkyl, C1-C8 alkyl-OH, C1-C8 alkyl-CN. In some embodiments, R6 is H. In some embodiments, R6 is D. In some embodiments, R6 is halo (such as F, Cl, Br, I) . In some embodiments, R6 is CN. In some embodiments, R6 is NO2. In some embodiments, R6 is C1-C8 alkyl. In some embodiments, R6 is C2-C8 alkenyl. In some embodiments, R6 is C2-C8 alkynyl. In some embodiments, R6 is C1-C8 haloalkyl. In some embodiments, R6 is C1-C8 alkyl-O-C1-C8 alkyl. In some embodiments, R6 is C1-C8 alkyl-OH. In some embodiments, R6 is C1-C8 alkyl-CN.
In some embodiments, R7 is independently selected from H, D, CN, halo, NO2, N3, SF5, Si (R8) 3, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or adamantanyl; wherein, the C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or adamantanyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from D, -halo, -CN, -NO2, -N3, SF5, oxo, -NRCRD, -ORA, -SRA, SiRGRHRI, -B (ORC) (ORD) , -C (O) RB, -C (O) ORA, -OC (O) RB, -C (O) NRCRD, -OC (O) NRCRD, -NRCC (O) RB, -NRCC (O) NRCRD, -NRCC (O) ORA, -S (O) RB, -S (O) 2RB, -S (O) NRCRD, -NRCS (O) RD, -NRCS (O) 2RD, -S (O) 2NRCRD, -NRCS (O) 2NRCRD, -NRCS (O) (=NRB) RB.
In some embodiments, R7 is independently selected from H, D, CN, halo, NO2, N3, SF5, Si (R8) 3. In some embodiments, R7 is H. In some embodiments, R7 is D. In some embodiments, R7 is halo. In some embodiments, R7 is CN. In some embodiments, R7 is NO2. In some embodiments, R7 is N3. In some embodiments, R7 is SF5. In some embodiments, R7 is Si (R8) 3, such as R7 is Si (CH3) 3.
In some embodiments, R7 is C1-C8 alkyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from D, -halo, -CN, -NO2, -N3, SF5, oxo, -NRCRD, -ORA, -SRA, SiRGRHRI, -C (O) RB, -C (O) ORA, -OC (O) RB, -C (O) NRCRD, -OC (O) NRCRD, -NRCC (O) RB, -NRCC (O) NRCRD, -NRCC (O) ORA, -S (O) RB, -S (O) 2RB, -S (O) NRCRD, -NRCS (O) 2RD, -S (O) 2NRCRD, -NRCS (O) 2NRCRD, -NRCS (O) (=NRB) RB. In some embodiments, R7 is methyl, ethyl, propyl, butyl, pentyl, hexyl; each is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from D, -halo, -CN, -NO2, -N3, oxo, -NRCRD, -ORA, -SRA, SiRGRHRI, -C (O) RB, -C (O) NRCRD, -OC (O) NRCRD, -NRCC (O) RB, -NRCC (O) NRCRD, -NRCC (O) ORA, -S (O) RB, -S (O) 2RB, -S (O) NRCRD, -NRCS (O) 2RD, -S (O) 2NRCRD, -NRCS (O) 2NRCRD, -NRCS (O) (=NRB) RB.
In some embodiments, R7 is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, CH2C (CH3) 3, CH2F, CHF2, CF3, CH2CH2F, CH2CHF2, CH2CF3, CH2OH, CH2CH2OH, CH (CH3) OH, CH2CH (CH3) OH, CH2OCH3, CH2CH2OCH3, CH2OCH2CH3, CH2CH2OCH2CH3, CH2CH2OCH2CH2OCH3, CH2CH2OCH2CH2OCH2CH3, CH2CH2OCH2CH2OCH2CH2OH, CH2CH2OCH2CH2OCH2CH2OCH3, CH2CH2OCH2CH2OCH2CH2OCH2CH3, CH2CH2OCH2CH2SCH3, CH2CH2OCH2CH2SCH2CH3, CH (CH3) OCH3, CH2CH (CH3) OCH3, CH (CH3) CN, C (CH3) 2CN, CH2C (CH3) 2CN, CH (CH3) F, C (CH3) 2F, CH2C (CH3) 2F, CH (CH3) OH, C (CH3) 2OH, CH2C (CH3) 2OH, CH (CH3) OCH3, C (CH3) 2OCH3, CH2C (CH3) OCH3, CH (CH3) CH2OH, C (CH3) 2CH2OH, CH2C (CH3) 2CH2OH, CH2SCH3, CH2CH2SCH3, CH2S (O) CH3, CH2CH2S (O) CH3, CH2S (O) 2CH3, CH2CH2S (O) 2CH3, CH2C (O) CH3, CH2CH2C (O) CH3, CH2N3, CH2CH2N3, Si (CH3) 3, CH2Si (CH3) 3, CH2NHCH3, CH2CH2NHCH3, CH2N (CH3) 2, CH2CH2N (CH3) 2, CH2NHC (O) CH3, CH2CH2NHC (O) CH3, CH2N (CH3) C (O) CH3, CH2CH2N (CH3) C (O) CH3, CH2NHS (O) CH3, CH2CH2NHS (O) CH3, CH2N (CH3) S (O) CH3, CH2CH2N (CH3) S (O) CH3, CH2NHS (O) 2CH3, CH2CH2NHS (O) 2CH3, CH2N (CH3) S (O) 2CH3, CH2CH2N (CH3) S (O) 2CH3, 
In some embodiments, R7 is C2-C8 alkenyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from D, -halo, -CN, -NO2, -N3, oxo, -NRCRD, -ORA, -SRA, -SiRGRHRI 3, -C (O) RB, -C (O) NRCRD, -OC (O) NRCRD, -NRCC (O) RB, -NRCC (O) NRCRD, -NRCC (O) ORA, -S (O) RB, -S (O) 2RB, -S (O) NRCRD, -NRCS (O) 2RD, -S (O) 2NRCRD, -NRCS (O) 2NRCRD, -NRCS (O) (=NRB) RB. In some embodiments, R7 is C2 alkenyl, C3 alkenyl, C4 alkenyl, C5 alkenyl, or C6 alkenyl; wherein, each is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from D, -halo, -CN, -NO2, -N3, oxo, -NRCRD, -ORA, -SRA, SiRGRHRI, -C (O) RB, -C (O) NRCRD, -OC (O) NRCRD, -NRCC (O) RB, -NRCC (O) NRCRD, -NRCC (O) ORA, -S (O) RB, -S (O) 2RB, -S (O) NRCRD, -NRCS (O) 2RD, -S (O) 2NRCRD, -NRCS (O) 2NRCRD, -NRCS (O) (=NRB) RB.
In some embodiments, R7 is -CH=CH2, -CH=CHCH3, -CH=CHCH2CH3, -C (=CH2) CH3, -C (=CH2) CH2CH3, -C (=CH2) CH2OCH3, -C (=CH2) CH2OCH3, -C (=CH2) CH2SCH3, -C (=CH2) CH2SCH3, -CH=CF2, -CH=CFCH3, -CH=CFCH2CH3, -C (=CF2) CH3, -C (=CF2) CH2CH3, -C (=CF2) CH2OCH3, -C (=CF2) CH2OCH3, -C (=CF2) CH2SCH3, or -C (=CF2) CH2SCH3.
In some embodiments, R7 is C2-C8 alkynyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from D, -halo, -CN, -NO2, -N3, oxo, -NRCRD, -ORA, -SRA, -SiRGRHRI, -C (O) RB, -C (O) NRCRD, -OC (O) NRCRD, -NRCC (O) RB, -NRCC (O) NRCRD, -NRCC (O) ORA, -S (O) RB, -S (O) 2RB, -S (O) NRCRD, -NRCS (O) 2RD, -S (O) 2NRCRD, -NRCS (O) 2NRCRD, -NRCS (O) (=NRB) RB.
In some embodiments, R7 is adamantanyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from D, halo, CN, NO2, N3, oxo, NRCRD, ORA, SRA, SiRGRHRI, B (ORC) (ORD) , C (O) RB, C (O) NRCRD, OC (O) NRCRD, NRCC (O) RB, NRCC (O) NRCRD, NRCC (O) ORA, S (O) RB, S (O) 2RB, S (O) NRCRD, NRCS (O) RD, NRCS (O) 2RD, S (O) 2NRCRD, NRCS (O) 2NRCRD, NRCS (O) (=NRB) RB. In some embodiments, R7 is
In some embodiments, the moietyhas the structure of
In some embodiments, each R8 is independently selected from C1-C4 alkyl or phenyl.
In some embodiments, R8 is C1-C4 alkyl or phenyl. In some embodiments, R8 is methyl, ethyl, propyl (such as n-propyl, i-propyl) , butyl (n-butyl, i-butyl, t-butyl) or phenyl.
In some embodiments, each RA is independently selected from H, D.
In some embodiments, each RA is independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocyclalkyl, C6-C10 aryl, 5-10 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, OH, CN, halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkyl-OH, C1-C4 alkyl-CN, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, NO2, oxo, ORa, SRa, SF5, NHORa, C (O) Rb, C (O) NRcRd, C (O) ORa, OC (O) Rb, OC (O) NRcRd, NRcRd, NRcC (O) Rb, NRcC (O) NRcRd, NRcC (O) ORa, B (ORc) (ORd) , C (=NRc) NRcRd, NRdC (=NRc) NRcRd, NRdC (=NRc) Rb, P (O) ReRf, P (O) OReORf, OP (O) OReORf, S (O) Rb, S (O) NRcRd, S (O) 2Rb, NRcS (O) 2Rb, S (O) 2NRcRd, NRcS (O) 2NRcRd, or NRcS (O) (=NRb) Rb.
In some embodiments, each RB is independently selected from H, D.
In some embodiments, each RB is independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, OH, CN, halo, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, SF5, C (O) Rb, OC (O) NRcRd, NRcRd, NRcC (O) Rb, NRcC (O) NRcRd, NRcC (O) ORa, S (O) Rb, S (O) NRcRd, S (O) 2Rb, NRcS (O) 2Rb, S (O) 2NRcRd, NRcS (O) 2NRcRd, or B (ORc) (ORd) .
In some embodiments, RC and RD are each independently selected from H, D.
In some embodiments, RC and RD are each independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, OH, CN, halo,  oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, SF5, OC (O) NRcRd, NRcRd, NRcC (O) Rb, S (O) NRcRd, S (O) 2Rb, NRcS (O) 2Rb, S (O) 2NRcRd, NRcS (O) 2NRcRd, or B (ORc) (ORd) .
In some embodiments, RC and RD together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, OH, oxo, CN, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, or OC1-C4 haloalkyl.
In some embodiments, each Ra is independently selected from H, D.
In some embodiments, each Ra is independently selected from C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C3-C7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl, wherein, the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C3-C7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halo, OH, CN, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, C1-C4 alkyl, OC1-C4 alkyl, C1-C4 haloalkyl, or OC1-C4 haloalkyl.
In some embodiments, each Ra1 is independently selected from H, D.
In some embodiments, each Ra1 is independently selected from C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C3-C7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl, wherein the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C3-C7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halo, OH, CN, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, C1-C4 alkyl, OC1-C4 alkyl, C1-C4 haloalkyl, or OC1-C4 haloalkyl.
In some embodiments, each Rb is each independently selected from H, D.
In some embodiments, each Rb is each independently selected from C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C3-C7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl; wherein the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C3-C7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, OH, CN, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C6-C10 aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl.
In some embodiments, each Rb1 is each independently selected from H, D.
In some embodiments, each Rb1 is each independently selected from C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C3-C7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl; wherein, the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C3-C7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, OH, CN, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C6-C10 aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl.
In some embodiments, Rc and Rd are each independently selected from H, D.
In some embodiments, Rc and Rd are each independently selected from C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkyl, arylheterocycloalkyl, arylheteroaryl, biaryl, heteroarylcycloalkyl, heteroarylheterocycloalkyl, heteroarylaryl, or biheteroaryl; wherein the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkyl, arylheterocycloalkyl, arylheteroaryl, biaryl, heteroarylcycloalkyl, heteroarylheterocycloalkyl, heteroarylaryl, or biheteroaryl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, OH, CN, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 hydroxyalkyl, C1-C4 cyanoalkyl, C6-C10 aryl, 5-10 membered heteroaryl, C (O) ORa1, C (O) Rb1, S (O) 2Rb1, C1-C4 alkyl-O-C1-C4 alkyl, and C1-C4 alkyl-O-C1-C4 alkyl-O-.
In some embodiments, Rc and Rd together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, OH, CN, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 hydroxyalkyl, C1-C4 cyanoalkyl, C6-C10 aryl, 5-10 membered heteroaryl, C1-C4 alkoxy-C1-C4 alkyl, or C1-C4 alkoxy-C1-C4 alkoxy.
In some embodiments, each RE is independently selected from H, D.
In some embodiments, each RE is independently selected from C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, (C1-C4 alkoxy) -C1-C4 alkyl, C2-C4 alkynyl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl-C1-C4 alkyl, C3-C10 cycloalkyl-C1-C4 alkyl, 5-10 membered heteroaryl-C1-C4 alkyl, or 4-10 membered heterocycloalkyl-C1-C4 alkyl.
In some embodiments, each RF is independently selected from H, D.
In some embodiments, each RF is independently selected from C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, or 4-10 membered heterocycloalkyl.
In some embodiments, each Re is independently selected from C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, (C1-C4 alkoxy) -C1-C4 alkyl, C2-C4 alkynyl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl-C1-C4 alkyl, C3-C10 cycloalkyl-C1-C4 alkyl, 5-10 membered heteroaryl-C1-C4 alkyl, or 4-10 membered heterocycloalkyl-C1-C4 alkyl.
In some embodiments, each Rf is independently selected from H, D.
In some embodiments, each Rf is independently selected from C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, or 4-10 membered heterocycloalkyl.
In some embodiments, RG, RH and RI are each independently selected from C1-C4 alkyl or phenyl.
In some embodiments, RG is C1-C4 alkyl (such as C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl) or phenyl. In some embodiments, RG is methyl, ethyl, propyl (such as n-propyl, i-propyl) , butyl (n-butyl, i-butyl, t-butyl) or phenyl.
In some embodiments, RH is C1-C4 alkyl (such as C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl) or phenyl. In some embodiments, RH is methyl, ethyl, propyl (such as n-propyl, i-propyl) , or butyl (n-butyl, i-butyl, t-butyl) or phenyl.
In some embodiments, RI is C1-C4 alkyl (such as C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl) or phenyl. In some embodiments, RI is methyl, ethyl, propyl (such as n-propyl, i-propyl) , or butyl (n-butyl, i-butyl, t-butyl) or phenyl.
In some embodiments, the compound of Formula (I) is:


or a pharmaceutically acceptable salt thereof.
The compounds provided herein can be asymmetric (e.g., having one or more stereocenters) . All stereoisomers, such as enantiomers and diastereomers, are contemplated unless otherwise indicated. The compounds provided herein that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds provided herein, and all such stable isomers are contemplated unless otherwise indicated. Cis and trans geometric isomers of the compounds provided herein are described and may be isolated as a mixture of isomers or as separated isomeric forms. Furthermore, atropisomers and mixtures thereof such as those resulting from restricted rotation about two aromatic or heteroaromatic rings bonded to one another are encompassed within the scope of the disclosure.
The compounds provided herein also include tautomeric forms. Prototropic 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. Examples of 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: etc. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
In certain embodiments, the compounds of the present disclosure may exist as rotational isomers. Descriptions of a compound of the disclosure 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 disclosure 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. For example, isotopes of hydrogen include tritium and deuterium.
The present disclosure also includes pharmaceutically acceptable salts of the compounds provided herein. 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. 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. Lists of suitable salts are found in Remington’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and J. Pharm. Sci. 1977, 66, 2, each of which is incorporated herein by reference in its entirety.
Pharmaceutical Compositions
In one embodiment, provided herein is a pharmaceutical composition comprising a compound provided herein, e.g., a compound of Formula (I) , or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic variant, prodrug, or deuterated compound thereof; and a pharmaceutically acceptable excipient.
The pharmaceutical compositions can be formulated in a form suitable for oral administration (for example, as tablets, lozenges, hard or soft capsules, aqueous or oil suspensions, emulsions, dispersible powders or granules, syrups, or elixirs) , for injection (for example, as aqueous or oil suspensions, emulsions, elixirs, or a sterile aqueous solution) , for topical application (for example, as creams, ointments, gels, or aqueous or oil solutions or suspensions) , for inhalation (for example, as a finely divided powder or a liquid aerosol) , for insufflation (for example, as a finely divided powder) , or for parenteral administration (for example, as a sterile aqueous or oil solution for intravenous, subcutaneous, intramuscular, intraperitoneal, or intramuscular dosing, or as a suppository for rectal dosing) .
The pharmaceutically acceptable excipient (s) can be, 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, flavoring agents, sweeteners, taste masking agents, or stabilizers.
The pharmaceutical carrier employed can be, for example, a solid, liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers include sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen. In preparing the compositions for oral dosage form, any convenient pharmaceutical media may be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents may be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents may be used to form oral solid preparations, such as powders, capsules, and  tablets.
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, suspensions, sublingual tablets, wafers, or patches such as buccal patches.
Thus, tablet compositions can contain a unit dosage of an 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, and hydroxypropyl methyl cellulose, and starches such as corn starch. 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.
Pharmaceutical compositions of the present disclosure 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.
Pharmaceutical compositions of the present disclosure suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, 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, 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.
Pharmaceutical compositions of the present disclosure can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, or dusting powder. Further, the compositions can be in a form suitable for use in transdermal devices.
In addition to the aforementioned carrier ingredients, the pharmaceutical formulations described herein may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, and preservatives (including antioxidants) . Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient.
Methods of Use
In one embodiment, provided herein is a method for treating or preventing cancer in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I) , or a pharmaceutically acceptable salt,  solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic variant, prodrug, or deuterated compound thereof; or a pharmaceutical composition provided herein.
In certain embodiments, the cancer is characterized by PolQ overexpression. In certain embodiments, the cancer is the characterized by increased dependence on MMEJ DSB repair. In certain embodiments, the cancer is characterized by HR-deficiency. In certain embodiments, the cancer is characterized by a reduction or absence of expression of a HR-associated gene. In certain embodiments, the cancer lacks a 53BP1/Shieldin complex. In certain embodiments, the cancer is resistant to PARPi treatment. In certain embodiments, the cancer is characterized by NHEJ deficiency. In certain embodiments, the cancer is a reduction or absence of expression of an NHEJ-associated gene.
In another embodiment, provided herein is a method for treating or preventing a disease characterized by PolQ overexpression in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I) , or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic variant, prodrug, or deuterated compound thereof; or a pharmaceutical composition provided herein.
The term “PolQ overexpression” refers to the increased expression or activity of a PolQ enzyme in a diseased cell, e.g., cancer cell, relative to the expression or activity of a PolQ enzyme in a control cell (e.g., non-diseased cell of the same type) . In certain embodiments, the PolQ overexpression is at least 2-fold, at least 3-fold, at least 4-fold, at least 6-fold, at least 10-fold, at least 20-fold, or at least 50-fold relative to the PolQ expression in a control cell. Examples of PolQ overexpressing cancer include, but are not limited to, certain ovarian, breast, cervical, uterine, pancreatic, lung, colorectal, gastric, bladder, and prostate cancer.
In yet another embodiment, provided herein is a method for treating or preventing a disease characterized by increased dependence upon MMEJ DSB repair in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I) , or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic variant, prodrug, or deuterated compound thereof; or a pharmaceutical composition provided herein.
In yet another embodiment, provided herein is a method for treating or preventing a disease characterized by HR-deficiency, a reduction or absence of the expression of an HR-associated gene in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I) , or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic variant, prodrug, or deuterated compound thereof; or a pharmaceutical composition provided herein.
In certain embodiments, the HR-associated gene is 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, or XRCC2.
In yet another embodiment, provided herein is a method for treating or preventing a disease lacking a 53BP1/Shieldin complex in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I) , or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic variant, prodrug, or deuterated compound thereof; or a pharmaceutical composition provided herein.
In yet another embodiment, provided herein is a method for treating or preventing a disease resistant to PARPi treatment in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I) , or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic variant, prodrug, or deuterated compound thereof; or a pharmaceutical composition provided herein.
In still another embodiment, provided herein is a method for treating or preventing a disease characterized by NHEJ deficiency, or a reduction or absence of expression of an NHEJ-associated gene in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I) , or a pharmaceutically acceptable salt, solvate, N-oxide, tautomer, stereoisomer, atropisomer, isotopic variant, prodrug, or deuterated compound thereof; or a pharmaceutical composition provided herein.
In certain embodiments, the NHEJ-associated gene is 53BP1, DCLRE1C, LIG4, NHEJ1, POLL, POLM, PRKDC, RIF1, SHLD1, SHLD2, SHLD3, XRCC4, XRCC5, or XRCC6.
In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a human.
In certain embodiments, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 100 mg/kg/day, from about 0.1 to about 50 mg/kg/day, from about 0.1 to about 25 mg/kg/day, from about 0.1 to about 20 mg/kg/day, from about 0.1 to about 15 mg/kg/day, from about 0.1 to about 10 mg/kg/day, or from about 0.1 to about 5 mg/kg/day. In one embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 100 mg/kg/day. In another embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 50 mg/kg/day. In yet another embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 25 mg/kg/day. In yet another embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 20 mg/kg/day. In yet another embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 15 mg/kg/day. In yet another embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 10 mg/kg/day. In still another embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 5 mg/kg/day.
It is understood that the administered dose can also be expressed in units other than mg/kg/day. For example, doses for parenteral administration can be expressed as mg/m2/day. One of ordinary skill in the art would readily know how to convert doses from mg/kg/day to mg/m2/day to given  either the height or weight of a subject or both. For example, a dose of 1 mg/m2/day for a 65 kg human is approximately equal to 58 mg/kg/day.
Depending on the disorder, disease, or condition to be treated and the subject’s condition, a compound provided herein may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, CIV, intracisternal injection or infusion, subcutaneous injection, or implant) , inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or local) routes of administration. A compound provided herein may be formulated in suitable dosage unit with a pharmaceutically acceptable excipient, carrier, adjuvant, or vehicle, appropriate for each route of administration.
In one embodiment, a compound provided herein is administered orally. In another embodiment, a compound provided herein is administered parenterally. In yet another embodiment, a compound provided herein is administered intravenously. In yet another embodiment, a compound provided herein is administered intramuscularly. In yet another embodiment, a compound provided herein is administered subcutaneously. In still another embodiment, a compound provided herein is administered topically.
A compound provided herein can be delivered as a single dose such as, e.g., a single bolus injection, or oral tablets or pills; or over time such as, e.g., continuous infusion over time or divided bolus doses over time. A compound provided herein can be administered repetitively, if necessary, for example, until the subject experiences stable disease or regression, or until the subject experiences disease progression or unacceptable toxicity.
A compound provided herein can be administered once daily (QD) or divided into multiple daily doses such as twice daily (BID) , and three times daily (TID) . In addition, the administration can be continuous, i.e., every day, or intermittently. The term “intermittent” or “intermittently” as used herein is intended to mean stopping and starting at either regular or irregular intervals. For example, intermittent administration of a compound provided herein is administration for one to six days per week, administration in cycles (e.g., daily administration for two to eight consecutive weeks, then a rest period with no administration for up to one week) , or administration on alternate days.
A compound provided herein can also be combined or used in combination with other therapeutic agents useful in the treatment and/or prevention of a disease described herein.
Synthesis
The compounds provided herein, including salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes, such as those exemplified herein.
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. Depending on the particular reaction step,  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, 8th Ed. (Wiley, 2019) ; Peturssion et al, “Protecting Groups in Carbohydrate Chemistry” , J Chem. Educ., 1997, 74 (11) , 1297; and Wuts et al., Protective Groups in Organic Synthesis, 5th Ed., (Wiley, 2014) .
Reactions can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1H or 13C) , infrared spectroscopy, spectrophotometry (e.g., UV-visible) , or mass spectrometry, or by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography.
The expressions, “ambient temperature” , “room temperature” and “r.t. ” as used herein, are understood in the art, and refer generally to a temperature, e.g., a reaction temperature, that is about the temperature of the room in which the reaction is carried out, for example, a temperature from about 20 ℃ to about 30 ℃.
Compounds of the invention can be prepared according to numerous preparatory routes known in the literature. The Schemes below provide general guidance in connection with preparing the compounds of the invention. One skilled in the art would understand that the preparations shown in the Schemes can be modified or optimized using general knowledge of organic chemistry to prepare various compounds of the invention. Example synthetic methods for preparing compounds of the invention are provided in the Schemes below.
The following Examples are provided to illustrate some of the concepts described within this disclosure. While the Examples are considered to provide an embodiment, it should not be considered to limit the more general embodiments described herein.
Abbreviations


General Synthetic Schemes
A series of heterocyclic amide derivatives of formula (I) can be prepared as the methods described in Scheme 1. Heterocyclic amide derivatives (I) can be prepared by reactions of carboxylic acids 1-1 with suitable 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 T3P and a base, such as Hunig’s base, Et3N, pyridine or DMAP) . Alternatively, treatment of the carboxylic acids 1-1 with the chlorine reagent such as oxalyl dichloride, thionyl chloride, POCl3 or TCFH can produce the corresponding acid chlorides 1-3 which is subsequently coupled with appropriate amines 1-2 to afford the corresponding heterocyclic amide derivatives of formula (I) .
Scheme 1
Alternatively, 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 suitable 1, 3, 4-thiadiazol-2-amine derivatives 2-2 in a similar manner as those described in the Scheme 1. Suzuki coupling of amide derivatives 2-3 where W is halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) with compounds 2-5 where V is boronic acid, boronic acid ester, trimethylstannyl or tributylstannyl under standard Suzuki coupling conditions or Stille coupling conditions (e.g., in the presence of a palladium catalyst, such as Pd (OAc) 2, Pd (dppf) Cl2, Pd2 (dba) 3, Pd(PPh3) 4 and a base, such as t-BuOK, t-BuONa, Cs2CO3, K2CO3, or Na2CO3) can provide heterocyclic amide derivatives (I) .
Or Suzuki coupling of amide derivatives 2-3 where W is boronic acid, boronic acid ester , trimethylstannyl or tributylstannyl with compounds 2-5 where V is halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) under standard Suzuki coupling conditions or Stille coupling conditions (e.g., in the presence of a palladium catalyst, such as Pd (OAc) 2, Pd (dppf) Cl2, Pd2 (dba) 3, Pd (PPh3) 4 and a base, such as t-BuOK, t-BuONa, Cs2CO3, K2CO3, or Na2CO3) can also provide heterocyclic amide derivatives (I) .
Scheme 2
Heterocyclic acid intermediates of formula 3-5 can be prepared as the methods described in Scheme 3. C-C coupling of compounds 3-1 with 3-3 can provide ester compounds 3-4 by the methods of Suzuki coupling or Stille coupling as described in Scheme 2. Saponification of the compounds 3-4 can yield the corresponding acid 3-5 under a base such as LiOH, NaOH, KOH or Me3SnOH. Alternatively, Suzuki coupling of carboxylic acids 3-2 with compounds 3-3 can directly provide the corresponding acids 3-5 under standard Suzuki coupling conditions or Stille coupling conditions as described in Scheme 3.
Scheme 3 
1,3, 4-thiadiazol-2-amine derivatives 4-3 can be prepared as the methods described in Scheme 4. Treatment of carboxylic acids 4-1 or cyanide 4-2 and thiosemicarbazide with a dehydrant such as POCl3, TFA, PCl5, P2O5 or PPA can provide the 1, 3, 4-thiadiazol-2-amine derivatives 4-3.
Scheme 4
1, 3, 4-thiadiazol-2-amine derivatives 5-4 can be prepared as the methods described in Scheme 5. Substitution of 5-bromo-1, 3, 4-thiadiazol-2-amine by alcohols 5-1 in the presence of a base such as t-BuOK, t-BuONa, Cs2CO3, K2CO3, Na2CO3, NaH, NaHMDS, or LDA in a suitable solvent THF, DMF or DMSO can provide 1, 3, 4-thiadiazol-2-amine derivatives 5-4.
Alternatively, dithiocarbonate 5-2 can be prepared by reaction of alcohols 5-1 with CS2 and iodomethane in the presence of a base such as NaH, t-BuOK, t-BuONa or NaHMDS in a suitable solvent such as THF. Hydrazinolysis of dithiocarbonate 5-2 with hydrazine hydrate can afford compounds 5-3 which can be transformed into 1, 3, 4-thiadiazol-2-amine derivatives 5-4 by treatment of BrCN in the presence of a base such as Hunig’s base or TEA.
Scheme 5
Examples
Example 1: 4- (2-Fluoro-6-methoxyphenyl) -6-methyl-N- (5- (neopentyloxy) -1, 3, 4-thiadiazol-2-yl) nicotinamide
Step 1: 5- (neopentyloxy) -1, 3, 4-thiadiazol-2-amine
To a solution of neopentyl alcohol (0.88 g, 10 mmol) and 5-bromo-1, 3, 4-thiadiazol-2-amine (0.9 g, 5 mmol) in DMF (10 mL) was added NaH (0.6 g, 15 mmol, 60%suspension in mineral oil) at 0 ℃. The mixture was stirred at r.t. overnight. The reaction mixture was quenced with water (30 mL) and then extracted with EtOAc (20 mL x 4) . The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a C18 column eluting with MeCN/H2O (0 -15%) to afford the title compound (110 mg) as yellow oil. LCMS calc. for C7H14N3OS [M+H] -: m/z = 188.1; Found: 188.0.
Step 2: 4- (2-fluoro-6-methoxyphenyl) -6-methyl-N- (5- (neopentyloxy) -1, 3, 4-thiadiazol-2-yl) nicotinamide
To a solution of 4- (2-fluoro-6-methoxyphenyl) -6-methylnicotinic acid (Int-2) (53 mg, 0.2 mmol) , TCFH (84 mg, 0.3 mmol) and NMI (33 mg, 0.4 mmol) in DMF (2 mL) was added 5-(neopentyloxy) -1, 3, 4-thiadiazol-2-amine (38 mg, 0.2 mmol) . The mixture was stirred at r.t. for 5 h., and then concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column eluting with MeCN/H2O (15 -45%) to afford the title compound (46.2 mg) as white solid. LCMS calc. for C21H24FN4O3S [M+H] +: m/z = 431.2; Found: 431.1.
Example 2: N- (5-Ethoxy-1, 3, 4-thiadiazol-2-yl) -4- (2-fluoro-6-methoxyphenyl) -6-methylnicotinamide
This compound was prepared using procedures analogous to those described for Example 1 Step 1-2 using anhydrous ethanol to replace neopentyl alcohol in Step 1. LCMS calc. for C18H18FN4O3S [M+H] +: m/z = 389.1; Found: 389.1.
Example 3: 4- (2-Fluoro-6-methoxyphenyl) -N- (5- (3-hydroxy-2, 2-dimethylpropoxy) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
This compound was prepared using procedures analogous to those described for Example 1 Step 1-2 using 2, 2-dimethylpropane-1, 3-diol to replace neopentyl alcohol in Step 1. LCMS calc. for C21H24FN4O4S [M+H] +: m/z = 447.1; Found: 447.1.
Example 4: 4- (2-Fluoro-6-methoxyphenyl) -N- (5- (2-methoxyethoxy) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
This compound was prepared using procedures analogous to those described for Example 1 Step 1-2 using 2-methoxyethan-1-ol to replace neopentyl alcohol in Step 1. LCMS calc. for C19H20FN4O4S [M+H] +: m/z = 419.1; Found: 419.1.
Example 5: 4- (2-Fluoro-6-methoxyphenyl) -N- (5- (2-hydroxy-2-methylpropoxy) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
This compound was prepared using procedures analogous to those described for Example 1 Step 1-2 using 2-methylpropane-1, 2-diol to replace neopentyl alcohol in Step 1. LCMS calc. for C20H22FN4O4S [M+H] +: m/z = 433.1; Found: 433.1.
Example 6: 4- (2-Fluoro-6-methoxyphenyl) -N- (5- (2-methoxy-2-methylpropoxy) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
This compound was prepared using procedures analogous to those described for Example 1 Step 1-2 using 2-methoxy-2-methylpropan-1-ol to replace neopentyl alcohol in Step 1. LCMS calc. for C21H24FN4O4S [M+H] +: m/z = 447.1; Found: 447.1.
Example 7: 4- (2-Fluoro-6-methoxyphenyl) -6-methyl-N- (5- (2, 2, 2-trifluoroethoxy) -1, 3, 4-thiadiazol-2-yl) nicotinamide
Step 1: 5- (2, 2, 2-trifluoroethoxy) -1, 3, 4-thiadiazol-2-amine 
This compound was prepared using procedures analogous to those described for Example 1 Step 1 using 2, 2, 2-trifluoroethanol to replace neopentyl alcohol. LCMS calc. for C4H5F3N3OS [M+H] +: m/z = 200.0; Found: 200.0.
Step 2: 4- (2-fluoro-6-methoxyphenyl) -6-methyl-N- (5- (2, 2, 2-trifluoroethoxy) -1, 3, 4-thiadiazol-2-yl) nicotinamide
This compound was prepared using procedures analogous to those described for Example 1 Step 2 using 5- (2, 2, 2-trifluoroethoxy) -1, 3, 4-thiadiazol-2-amine to replace 5- (neopentyloxy) -1, 3, 4-thiadiazol-2-amine. LCMS calc. for C18H15F4N4O3S [M+H] +: m/z = 443.1; Found: 443.0.
Example 8: 4- (2-Fluoro-6-methoxyphenyl) -N- (5- ( (-3-hydroxyadamantan-1-yl) methoxy) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
This compound was prepared using procedures analogous to those described for Example 1 Step 1-2 using 3- (hydroxymethyl) adamantan-1-ol to replace neopentyl alcohol in Step 1. LCMS calc. for C27H30FN4O4S [M+H] +: m/z = 525.2; Found: 525.2.
Example 9: N- (5- (2-Fluoro-2-methylpropoxy) -1, 3, 4-thiadiazol-2-yl) -4- (2-fluoro-6-methoxyphenyl) -6-methylnicotinamide
This compound was prepared using procedures analogous to those described for Example 1 Step 1-2 using 2-fluoro-2-methylpropan-1-ol to replace neopentyl alcohol in Step 1. LCMS calc. for C20H21F2N4O3S [M+H] +: m/z = 435.1; Found: 435.1.
Example 10: N- (5- (2-Cyano-2-methylpropoxy) -1, 3, 4-thiadiazol-2-yl) -4- (2-fluoro-6-methoxyphenyl) -6-methylnicotinamide
This compound was prepared using procedures analogous to those described for Example 1 Step 1-2 using 3-hydroxy-2, 2-dimethylpropanenitrile to replace neopentyl alcohol in Step 1. LCMS  calc. for C21H21FN5O3S [M+H] +: m/z = 442.1; Found: 442.2.
Example 11: 4- (2-Fluoro-6-methoxyphenyl) -N- (5- (2-methoxypropoxy) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
Step 1: 2-methoxypropan-1-ol
To a solution of 2-methoxypropanoic acid (1.04 g, 10 mmol) in THF (10 mL) was added BH3-THF complex (15 mL, 1.0 M in THF) , then the mixture was stirred at 70 ℃ overnight. The reaction mixture was cooled with ice-water bath, and then quenched by MeOH (20 mL) for 2 h.. The resulting mixture was evaporated under reduced pressure to afford 2-methoxypropan-1-ol without further purification.
Step 2: 5- (2-methoxypropoxy) -1, 3, 4-thiadiazol-2-amine
To a mixture of 2-methoxypropan-1-ol (1.0 g, 10.0 mmol) and 5-bromo-1, 3, 4-thiadiazol-2-amine (0.9 g, 5.0 mmol) in DMF (10 mL) was added NaH (0.6 g, 15.0 mmol 60%suspension in mineral oil) at 0 ℃. The mixture was stirred at r.t. overnight, quenced with water (30 mL) , and then extracted with EtOAc (20 mL x 4) . The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a C18 column eluting with MeCN/H2O (2 -15%) to afford the the title compound (230 mg, 14%yield) as yellow oil. LCMS calc. for C6H12N3O2S [M+H] +: m/z = 190.1; Found: 190.1.
Step 3: 4- (2-fluoro-6-methoxyphenyl) -N- (5- (2-methoxypropoxy) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
To a mixture of 4- (2-fluoro-6-methoxyphenyl) -6-methylnicotinic acid (Int-2) (106 mg, 0.4 mmol) , TCFH (168 mg, 0.6 mmol) and NMI (66 mg, 0.8 mmol) in DMF (3 mL) was added 5- (2-methoxypropoxy) -1, 3, 4-thiadiazol-2-amine (80 mg, 0.4 mmol) . The reaction mixture was stirred at r.t. for 5 h., and then concentrated under reduced pressure. The residue was purified by prep-HPLC eluting on a C18 column with MeCN/H2O (15 -45%) to afford the title compound (82.9 mg, 48%yield) as white solid. LCMS calc. for C20H22FN4O4S [M+H] +: m/z = 433.1; Found: 433.2.
Example 12: 4- (2-Fluoro-6-methoxyphenyl) -N- (5- ( (S) -2-methoxypropoxy) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
This compound was prepared using procedures analogous to those described for Example 11 Step 1-3 using (S) -2-methoxypropanoic acid to replace 2-methoxypropanoic acid in Step 1. LCMS calc. for C20H22FN4O4S [M+H] +: m/z = 433.1; Found: 433.2.
Example 13: 4- (2-Fluoro-6-methoxyphenyl) -N- (5- ( (R) -2-methoxypropoxy) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
This compound was prepared using procedures analogous to those described for Example 11 Step 1-3 using (R) -2-methoxypropanoic acid to replace 2-methoxypropanoic acid in Step 1. LCMS calc. for C20H22FN4O4S [M+H] +: m/z = 433.1; Found: 433.2.
Example 14: 4- (2, 3-Difluoro-6-methoxyphenyl) -N- (5-ethoxy-1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
Step 1: 5-ethoxy-1, 3, 4-thiadiazol-2-amine
This compound was prepared using procedures analogous to those described for Example 1 Step 1 using anhydrous ethanol to replace neopentyl alcohol. LCMS calc. for C4H8N3OS [M+H] +: m/z = 146.0; Found: 146.1.
Step 2: 4- (2, 3-difluoro-6-methoxyphenyl) -N- (5-ethoxy-1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
To a mixture of 4- (2, 3-difluoro-6-methoxyphenyl) -6-methylnicotinic acid (70 mg, 0.25 mmol, Int-3) , TCFH (112 mg, 0.4 mmol) and NMI (66 mg, 0.5 mmol) in DMF (3 mL) was added 5-ethoxy-1, 3, 4-thiadiazol-2-amine (44 mg, 0.3 mmol) . The reaction mixture was stirred at r.t. for 4 h., and then concentrated under reduced pressure. The residue was purified by prep-HPLC eluting on a C18 column with MeCN/H2O (15-45%) to afford the title compound (40.9 mg, 40%yield) as white solid. LCMS calc. for C18H17F2N4O3S [M+H] +: m/z = 407.1; Found: 407.1.
Example 15: 4- (2, 3-Difluoro-6-methoxyphenyl) -N- (5- (2-methoxypropoxy) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
This compound was prepared using procedures analogous to those described for Example 14 Step 2 using the intermediate 4- (2, 3-difluoro-6-methoxyphenyl) -6-methylnicotinic acid (Int-3) and 5- (2-methoxypropoxy) -1, 3, 4-thiadiazol-2-amine (Example 11 Step 2) . LCMS calc. for C20H21F2N4O4S [M+H] +: m/z = 451.1; Found: 451.2.
Example 16: 4- (2, 3-Difluoro-6-methoxyphenyl) -6-methyl-N- (5- (2, 2, 2-trifluoroethoxy) -1, 3, 4-thiadiazol-2-yl) nicotinamide
This compound was prepared using procedures analogous to those described for Example 14 Step 2 using the intermediate 4- (2, 3-difluoro-6-methoxyphenyl) -6-methylnicotinic acid (Int-3) and 5- (2, 2, 2-trifluoroethoxy) -1, 3, 4-thiadiazol-2-amine (Example 7 Step 1) . LCMS calc. for C18H14F5N4O3S [M+H] +: m/z = 461.1; Found: 461.1.
Example 17: 4- (3-Chloro-2-fluoro-6-methoxyphenyl) -N- (5-ethoxy-1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
To a solution of 4- (3-chloro-2-fluoro-6-methoxyphenyl) -6-methylnicotinic acid (60 mg, 0.2 mmol, Int-1) , TCFH (84 mg, 0.3 mmol) and NMI (33 mg, 0.4 mmol) in DMF (2 mL) was added 5-ethoxy-1, 3, 4-thiadiazol-2-amine (45 mg, 0.3 mmol, Example 14 Step 1) . The mixture was stirred at r.t. for 5 h., and then concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column eluting with MeCN/H2O (10 -30%) to afford the title compound (38 mg) as white solid. LCMS calc. for C18H17ClFN4O3S [M+H] +: m/z = 423.1; Found: 423.1.
Example 18: 4- (3-Chloro-2-fluoro-6-methoxyphenyl) -N- (5- (2-methoxypropoxy) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
This compound was prepared using procedures analogous to those described for Example 17  using the intermediate 4- (3-chloro-2-fluoro-6-methoxyphenyl) -6-methylnicotinic acid (Int-1) and 5- (2-methoxypropoxy) -1, 3, 4-thiadiazol-2-amine (Example 11 Step 2) . LCMS calc. for C20H21ClFN4O4S [M+H] +: m/z = 467.1; Found: 467.1.
Example 19: 4- (3-Chloro-2-fluoro-6-methoxyphenyl) -6-methyl-N- (5- (2, 2, 2-trifluoroethoxy) -1, 3, 4-thiadiazol-2-yl) nicotinamide
This compound was prepared using procedures analogous to those described for Example 17 using the intermediate 4- (3-chloro-2-fluoro-6-methoxyphenyl) -6-methylnicotinic acid (Int-1) and 5- (2, 2, 2-trifluoroethoxy) -1, 3, 4-thiadiazol-2-amine (Example 7 Step 1) . LCMS calc. for C18H14ClF4N4O3S [M+H] +: m/z = 477.0; Found: 477.1.
Example 20: 4- (3-Chloro-2-fluoro-6-methoxyphenyl) -N- (5- (2-methoxyethoxy) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
Step 1: 5- (2-methoxyethoxy) -1, 3, 4-thiadiazol-2-amine
This compound was prepared using procedures analogous to those described for Example 1 Step 1 using 2-methoxyethanol to replace neopentyl alcohol. LCMS calc. for C5H10N3O2S [M+H] +: m/z = 176.0; Found: 176.1.
Step 2: 4- (3-chloro-2-fluoro-6-methoxyphenyl) -N- (5- (2-methoxyethoxy) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
This compound was prepared using procedures analogous to those described for Example 17 using the intermediate 4- (3-chloro-2-fluoro-6-methoxyphenyl) -6-methylnicotinic acid (Int-1) and 5- (2-methoxyethoxy) -1, 3, 4-thiadiazol-2-amine. LCMS calc. for C19H19ClFN4O4S [M+H] +: m/z = 453.1; Found: 453.1.
Example 21: 4- (3-Chloro-2-fluoro-6-methoxyphenyl) -N- (5- (2- (2-methoxyethoxy) ethoxy) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
Step 1: 5- (2- (2-methoxyethoxy) ethoxy) -1, 3, 4-thiadiazol-2-amine
To a solution of 2- (2-methoxyethoxy) ethan-1-ol (1.2 g, 10 mmol) and 5-bromo-1, 3, 4-thiadiazol-2-amine (0.9 g, 5 mmol) in DMF (10 mL) was added NaH (0.6 g, 15 mmol, 60%suspension in mineral oil) at 0 ℃. The mixture was stirred at r.t. overnight. The reaction mixture was quenched with water (30 mL) and then extracted with EtOAc (20 mL x 4) . The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a C18 column eluting with MeCN/H2O (5 -15%) to afford the title compound (130 mg) as yellow oil. LCMS calc. for C7H14N3O3S [M+H] +: m/z = 220.1; Found: 220.1.
Step 2: 4- (3-chloro-2-fluoro-6-methoxyphenyl) -N- (5- (2- (2-methoxyethoxy) ethoxy) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
To a solution of 4- (3-chloro-2-fluoro-6-methoxyphenyl) -6-methylnicotinic acid (59 mg, 0.2 mmol, Int-1) , TCFH (84 mg, 0.3 mmol) and NMI (33 mg, 0.4 mmol) in DMF (2 mL) was added 5- (2- (2-methoxyethoxy) ethoxy) -1, 3, 4-thiadiazol-2-amine (44 mg, 0.2 mmol) . The mixture was stirred at r.t. for 5 h., and concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column eluting with MeCN/H2O (0 -10%) to afford the title compound (60 mg) as white solid. LCMS calc. for C21H23ClFN4O5S [M+H] +: m/z = 497.1; Found: 497.1.
Example 22: 4- (3-Chloro-2-fluoro-6-methoxyphenyl) -N- (5- (2-cyclobutoxyethoxy) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
Step 1: 2-cyclobutoxyethan-1-ol
To a solution of cyclobutanol (2.6 g, 36 mmol) in THF (40 mL) was added n-BuLi solution (36 mmol, 2.5 M in hexane, 14.4 mL) at 0 ℃. The mixture was stirred at 0 ℃ for 30 min., then 1, 3, 2-dioxathiolane 2, 2-dioxide (4.5 g, 36 mmol) in 30 mL THF was added at 0 ℃. The resulting mixture was stirred at r.t. overnight, quenched with water (50 mL) , and then extracted with EtOAc (100 mL x 3) . The organic layer was washed with brine, dried over Na2SO4, and then concentrated under reduced pressure to afford the title compound (2.5 g) as yellow oil. TLC Rf = 0.25 (EtOAc, I2) .
Step 2: 5- (2-cyclobutoxyethoxy) -1, 3, 4-thiadiazol-2-amine
To a solution of 2-cyclobutoxyethan-1-ol (2.3 g, 20 mmol) and 5-bromo-1, 3, 4-thiadiazol-2-amine (1.8 g, 10 mmol) in DMF (20 mL) was added NaH (1.2 g, 30 mmol, 60%suspension in mineral oil) at 0 ℃. The mixture was stirred at r.t. overnight, quenched with water (60 mL) and extracted with EtOAc (80 mL x 4) . The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a C18 column eluting with MeCN/H2O (20 -40%) to afford the title compound (300 mg) as yellow oil. LCMS calc. for C8H14N3O2S [M+H] +: m/z = 216.1; Found: 216.1.
Step 3: 4- (3-chloro-2-fluoro-6-methoxyphenyl) -N- (5- (2-cyclobutoxyethoxy) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
To a solution of 4- (3-chloro-2-fluoro-6-methoxyphenyl) -6-methylnicotinic acid (120 mg, 0.4 mmol, Int-1) , TCFH (168 mg, 0.6 mmol) and NMI (66 mg, 0.8 mmol) in DMF (2 mL) was added 5- (2-cyclobutoxyethoxy) -1, 3, 4-thiadiazol-2-amine (108 mg, 0.5 mmol) . The mixture was stirred at r.t. for 5 h., and then concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column eluting with MeCN/H2O (20 -30%) to afford the title compound (67 mg) as white solid. LCMS calc. for C22H23ClFN4O4S [M+H] +: m/z = 493.1; Found: 493.1.
Example 23: (E) -N- (5- (But-2-en-1-yloxy) -1, 3, 4-thiadiazol-2-yl) -4- (3-chloro-2-fluoro-6-methoxyphenyl) -6-methylnicotinamide
Step 1: (E) -5- (but-2-en-1-yloxy) -1, 3, 4-thiadiazol-2-amine
This compound was prepared using procedures analogous to those described for Example 1 Step 1 using (E) -but-2-en-1-ol to replace neopentyl alcohol. LCMS calc. for C6H10N3OS [M+H] +: m/z = 172.1; Found: 172.1.
Step 2: (E) -N- (5- (but-2-en-1-yloxy) -1, 3, 4-thiadiazol-2-yl) -4- (3-chloro-2-fluoro-6-methoxyphenyl) -6-methylnicotinamide
This compound was prepared using procedures analogous to those described for Example 17 using the intermediate 4- (3-chloro-2-fluoro-6-methoxyphenyl) -6-methylnicotinic acid (Int-1) and (E) -5- (but-2-en-1-yloxy) -1, 3, 4-thiadiazol-2-amine. LCMS calc. for C20H19ClFN4O3S [M+H] +: m/z = 449.1; Found: 449.1.
Example 24: 4- (3-Chloro-2-fluoro-6-methoxyphenyl) -N- (5- ( (2- (methoxymethyl) allyl) oxy) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
Step 1: 2- (methoxymethyl) prop-2-en-1-ol
To a solution of 2-methylenepropane-1, 3-diol (1.3 g, 15.0 mol) in dry THF (30 mL) was added NaH (0.6 g, 15 mmol, 60%suspension in mineral oil) at 0 ℃. After being stirred at the same temperature for 1 h., MeI (2.13 g, 15 mmol) was added at 0 ℃. The reaction mixture was stirred at r.t. overnight. The mixture was quenched by aq. HCl (1 M, 20 mL) at 0 ℃, stirred for 30 min., and extracted with EtOAc (40 mL x 3) . The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc/PE (10 -20%) to afford the title compoud (0.5 g, 31%) as yellow oil. TLC Rf = 0.45 (EtOAc/PE = 1/1, iodine) .
Step 2: 5- ( (2- (methoxymethyl) allyl) oxy) -1, 3, 4-thiadiazol-2-amine
This compound was prepared using procedures analogous to those described for Example 1 Step 1 using 2- (methoxymethyl) prop-2-en-1-ol to replace neopentyl alcohol. LCMS calc. for C7H12N3O2S [M+H] +: m/z = 202.1; Found: 202.1.
Step 3: 4- (3-chloro-2-fluoro-6-methoxyphenyl) -N- (5- ( (2- (methoxymethyl) allyl) oxy) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
This compound was prepared using procedures analogous to those described for Example 17 using the intermediate 4- (3-chloro-2-fluoro-6-methoxyphenyl) -6-methylnicotinic acid (Int-1) and 5- ( (2- (methoxymethyl) allyl) oxy) -1, 3, 4-thiadiazol-2-amine. LCMS calc. for C21H21ClFN4O4S [M+H] +: m/z = 479.1; Found: 479.1.
Example 25: 4- (3-Chloro-2-fluoro-6-methoxyphenyl) -6-methyl-N- (5- ( (2-methylallyl) oxy) -1, 3, 4-thiadiazol-2-yl) nicotinamide
Step 1: 5- ( (2-methylallyl) oxy) -1, 3, 4-thiadiazol-2-amine
This compound was prepared using procedures analogous to those described for Example 1  Step 1 using 2-methylprop-2-en-1-ol to replace neopentyl alcohol. LCMS calc. for C6H10N3OS [M+H] +: m/z = 172.1; Found: 172.1.
Step 2: 4- (3-chloro-2-fluoro-6-methoxyphenyl) -6-methyl-N- (5- ( (2-methylallyl) oxy) -1, 3, 4-thiadiazol-2-yl) nicotinamide
This compound was prepared using procedures analogous to those described for Example 17 using the intermediate 4- (3-chloro-2-fluoro-6-methoxyphenyl) -6-methylnicotinic acid (Int-1) and 5- ( (2-methylallyl) oxy) -1, 3, 4-thiadiazol-2-amine. LCMS calc. for C20H19ClFN4O3S [M+H] +: m/z = 449.1; Found: 449.1.
Example 26: 4- (3-Chloro-2-fluoro-6-methoxyphenyl) -6-methyl-N- (5- ( (trimethylsilyl) methoxy) -1, 3, 4-thiadiazol-2-yl) nicotinamide
Step 1: S-methyl O- ( (trimethylsilyl) methyl) carbonodithioate
To a solution of (trimethylsilyl) methanol (3.12 g, 30 mmol) in THF (50 mL) was added NaH (2.4 g, 60 mmol, 60%suspension in mineral oil) at 0 ℃. The resulting mixture was stirred for 30 min., and CS2 (3.43 g, 45.0 mmol) was added to the above minxture at 0 ℃. After stirring for 10 min., MeI (5.54 g, 39.0 mmol) was added dropwise at 0 ℃. The reaction mixture was allowed to stirred at r.t. for 16 h., and then quenched with aq. NH4Cl (50 mL) . The aqueous phase was extracted with EtOAc (50 mL x 4) . The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford S-methyl O- ( (trimethylsilyl) methyl) carbonodithioate as crude product without further purification.
Step 2: O- ( (trimethylsilyl) methyl) hydrazinecarbothioate
To a solution of S-methyl O- ( (trimethylsilyl) methyl) carbonodithioate (5.83 g, 30 mmol) in MeOH (50 mL) was added hydrazine hydrate solution (2.81 g, 45 mmol, 80%purity) at r.t.. The reaction mixture was stirred at r.t. for 30 min., and then concentrated under reduced pressure to afford O- ( (trimethylsilyl) methyl) hydrazinecarbothioate as crude product without further purification. LCMS calc. for C5H15N2OSSi [M+H] +: m/z = 179.1; Found: 179.1.
Step 3: 5- ( (trimethylsilyl) methoxy) -1, 3, 4-thiadiazol-2-amine
To a mixture of O- ( (trimethylsilyl) methyl) hydrazinecarbothioate (5.34 g, 30 mmol) and BrCN  (3.82 g, 36 mmol) in MeOH (30 mL) was added TEA (6.1 g, 60 mmol) at 0 ℃. The mixture was stirred at r.t. for 1 h., and then concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc/PE (0 -20%) to afford the title compound (3.8 g, 62%yield) as colorless oil. LCMS calc. for C6H14N3OSSi [M+H] +: m/z = 204.1; Found: 204.1.
Step 4: 4- (3-chloro-2-fluoro-6-methoxyphenyl) -6-methyl-N- (5- ( (trimethylsilyl) methoxy) -1, 3, 4-thiadiazol-2-yl) nicotinamide
This compound was prepared using procedures analogous to those described for Example 17 using intermediate 4- (3-chloro-2-fluoro-6-methoxyphenyl) -6-methylnicotinic acid (Int-1) and 5- ( (trimethylsilyl) methoxy) -1, 3, 4-thiadiazol-2-amine. 1H NMR: (400 MHz, DMSO-d6) δ 12.82 (s, 1H) , 8.84 (s, 1H) , 7.59 (t, J = 8.0 Hz, 1H) , 7.38 (s, 1H) , 6.93 (d, J = 8.0 Hz, 6H) , 4.20 (s, 2H) , 3.58 (s, 3H) , 2.57 (s, 3H) , 0.10 (s, 9H) . LCMS calc. for C20H23ClFN4O3SSi [M+H] +: m/z = 481.1; Found: 481.1.
Example 27: 2'-Chloro-5'-methoxy-6-methyl-N- (5- ( (trimethylsilyl) methoxy) -1, 3, 4-thiadiazol-2-yl) - [4, 4'-bipyridine] -3-carboxamide
Step 1: methyl 2'-chloro-5'-methoxy-6-methyl- [4, 4'-bipyridine] -3-carboxylate
A mixture of methyl 4-chloro-6-methylnicotinate (1.5 g, 8 mmol) , (2-chloro-5-methoxypyridin-4-yl) boronic acid (0.94 g, 5 mmol) , K2CO3 (4.4 g, 16 mmol) and Pd (dppf) Cl2 (0.34 g, 0.5 mmol) in 1, 4-dioxane (24 mL) and H2O (3 mL) was degassed and recharged with nitrogen for 3 cycles, and then stirred at 80 ℃ for 16 h. . The mixture was diluted with EtOAc (80 mL) , washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc/PE (50 -70%) to give the title compound (0.3 g) as yellow solid. LCMS calc. for C14H14ClN2O3 [M+H] +: m/z = 293.1; Found: 293.1.
Step 2: 2'-chloro-5'-methoxy-6-methyl- [4, 4'-bipyridine] -3-carboxylic acid
To a solution of methyl 2'-chloro-5'-methoxy-6-methyl- [4, 4'-bipyridine] -3-carboxylate (0.3 g, 1.0 mmol) in THF (2 mL) and H2O (2 mL) was added LiOH. H2O (0.12 g, 3.0 mmol) . After it was stirred at r.t. overnight, the reaction mixture was diluted with water and adjusted to pH～2 -3 with aq.  HCl (2 M) , and then concentrated under reduced pressure. The residue was purified by flash chromatography on a C18 column eluting with MeCN/H2O (10 -15%) to afford the title compound as yellow oil. LCMS calc. for C13H12ClN2O3 [M+H] +: m/z = 279.1; Found: 279.1.
Step 3: 2'-chloro-5'-methoxy-6-methyl-N- (5- ( (trimethylsilyl) methoxy) -1, 3, 4-thiadiazol-2-yl) - [4, 4'-bipyridine] -3-carboxamide
To a solution of 2'-chloro-5'-methoxy-6-methyl- [4, 4'-bipyridine] -3-carboxylic acid (56 mg, 0.2 mmol) , TCFH (84 mg, 0.3 mmol) and NMI (33 mg, 0.4 mmol) in DMF (2 mL) was added 5- ( (trimethylsilyl) methoxy) -1, 3, 4-thiadiazol-2-amine (40 mg, 0.2 mmol, Example 26 Step 3) . The mixture was stirred at r.t. for 2 h., and then concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column eluting with MeCN/H2O (0 -10%) to afford the title compound (47 mg) as white solid. . LCMS calc. for C19H23ClN5O3SSi [M+H] +: m/z = 464.1; Found: 464.1.
Example 28: 4- (3-Chloro-2-fluoro-6-methoxyphenyl) -6-methyl-N- (5- (2- (methylthio) ethoxy) -1, 3, 4-thiadiazol-2-yl) nicotinamide
Step 1: 5- (2- (methylthio) ethoxy) -1, 3, 4-thiadiazol-2-amine
This compound was prepared using procedures analogous to those described for Example 1 Step 1 using 2- (methylthio) ethanol to replace neopentyl alcohol. LCMS calc. for C5H10N3OS2 [M+H] +: m/z = 192.0; Found: 192.1.
Step 2: 4- (3-chloro-2-fluoro-6-methoxyphenyl) -6-methyl-N- (5- (2- (methylthio) ethoxy) -1, 3, 4-thiadiazol-2-yl) nicotinamide
This compound was prepared using procedures analogous to those described for Example 17 using intermediate 4- (3-chloro-2-fluoro-6-methoxyphenyl) -6-methylnicotinic acid (Int-1) and 5- (2- (methylthio) ethoxy) -1, 3, 4-thiadiazol-2-amine. LCMS calc. for C19H19ClFN4O3S2 [M+H] +: m/z = 469.1; Found: 469.1.
Example 29: 4- (3-Chloro-2-fluoro-6-methoxyphenyl) -6-methyl-N- (5- (2- (methylsulfinyl) ethoxy) -1, 3, 4-thiadiazol-2-yl) nicotinamide
To a solution of 4- (3-chloro-2-fluoro-6-methoxyphenyl) -6-methyl-N- (5- (2- (methylthio) ethoxy) -1, 3, 4-thiadiazol-2-yl) nicotinamide (47 mg, 0.1 mmol, Example 28) in MeCN  (5 mL) was added aq. NaClO (1.0 mL, 1.3 mmol, 10%) at r.t. . The reaction mixture was stirred at r.t. for 5 h., and concentrated under reduced pressure. The residue was purified by prep-HPLC eluting with MeCN/H2O (20 -50%) to afford the title compound (8.4 mg, 18%yield) as white solid. LCMS calc. for C19H19ClFN4O4S2 [M+H] +: m/z = 485.0; Found: 485.1.
Example 30: N- (5- (2-Azidoethoxy) -1, 3, 4-thiadiazol-2-yl) -4- (3-chloro-2-fluoro-6-methoxyphenyl) -6-methylnicotinamide
Step 1: 5- (2-azidoethoxy) -1, 3, 4-thiadiazol-2-amine
This compound was prepared using procedures analogous to those described for Example 1 Step 1 using 2-azidoethanol to replace neopentyl alcohol. LCMS calc. for C4H7N6OS [M+H] +: m/z = 187.0; Found: 187.1.
Step 2: N- (5- (2-azidoethoxy) -1, 3, 4-thiadiazol-2-yl) -4- (3-chloro-2-fluoro-6-methoxyphenyl) -6-methylnicotinamide
This compound was prepared using procedures analogous to those described for Example 17 using intermediate 4- (3-chloro-2-fluoro-6-methoxyphenyl) -6-methylnicotinic acid (Int-1) and 5- (2-azidoethoxy) -1, 3, 4-thiadiazol-2-amine. LCMS calc. for C18H16ClFN7O3S [M+H] +: m/z = 464.1; Found: 464.1.
Example 31: 4- (3-Chloro-2-fluoro-6-methoxyphenyl) -6-methyl-N- (5- (2- (N-methylacetamido) ethoxy) -1, 3, 4-thiadiazol-2-yl) nicotinamide
Step 1: N- (2- ( (5-amino-1, 3, 4-thiadiazol-2-yl) oxy) ethyl) -N-methylacetamide
To a solution of N- (2-hydroxyethyl) -N-methylacetamide (1.17 g, 10.0 mmol) and 5-bromo-1, 3, 4-thiadiazol-2-amine (0.9 g, 5.0 mmol) in DMF (10 mL) was added NaH (0.6 g, 15 mmol, 60%suspension in mineral oil) at 0 ℃. The mixture was stirred at r.t. overnight, quenched with water (30 mL) , and then extracted with EtOAc (20 mL x 4) . The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a C18 column eluting with MeCN/H2O (5 -10%) to afford the title compound (110 mg) as yellow oil. LCMS calc. for C7H13N4O2S [M+H] +: m/z = 217.1; Found:  217.1.
Step 2: 4- (3-chloro-2-fluoro-6-methoxyphenyl) -6-methyl-N- (5- (2- (N-methylacetamido) ethoxy) -1, 3, 4-thiadiazol-2-yl) nicotinamide
To a solution of 4- (3-chloro-2-fluoro-6-methoxyphenyl) -6-methylnicotinic acid (59 mg, 0.2 mmol, Int-1) , TCFH (84 mg, 0.3 mmol) and NMI (33 mg, 0.4 mmol) in DMF (2 mL) was added N- (2- ( (5-amino-1, 3, 4-thiadiazol-2-yl) oxy) ethyl) -N-methylacetamide (65 mg, 0.3 mmol) . The mixture was stirred at r.t. for 5 h., and then concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column eluting with MeCN/H2O (20 -25%) to afford the title compound (27 mg) as white solid. LCMS calc. for C21H22ClFN5O4S [M+H] +: m/z = 494.1; Found: 494.1.
Example 32: 4- (3-Chloro-2-fluoro-6-methoxyphenyl) -6-methyl-N- (5- (2- (N-methylmethylsulfonamido) ethoxy) -1, 3, 4-thiadiazol-2-yl) nicotinamide
Step 1: N- (2- ( (5-amino-1, 3, 4-thiadiazol-2-yl) oxy) ethyl) -N-methylmethanesulfonamide
To a solution of N- (2-hydroxyethyl) -N-methylmethanesulfonamide (1.53 g, 10.0 mmol) and 5-bromo-1, 3, 4-thiadiazol-2-amine (0.9 g, 5.0 mmol) in DMF (10 mL) was added NaH (0.6 g, 15 mmol, 60%suspension in mineral oil) at 0 ℃. The mixture was stirred at r.t. overnight, quenched with water (30 mL) , and then extracted with EtOAc (50 mL x 4) . The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a C18 column eluting with MeCN/H2O (15 -35%) to afford the title compound (110 mg) as yellow oil. LCMS calc. for C6H13N4O3S2 [M+H] +: m/z = 253.0; Found: 253.0.
Step 2: 4- (3-chloro-2-fluoro-6-methoxyphenyl) -6-methyl-N- (5- (2- (N-methylmethylsulfonamido) ethoxy) -1, 3, 4-thiadiazol-2-yl) nicotinamide
To a solution of 4- (3-chloro-2-fluoro-6-methoxyphenyl) -6-methylnicotinic acid (59 mg, 0.2 mmol, Int-1) , TCFH (84 mg, 0.3 mmol) and NMI (33 mg, 0.4 mmol) in DMF (2 mL) was added N- (2- ( (5-amino-1, 3, 4-thiadiazol-2-yl) oxy) ethyl) -N-methylmethanesulfonamide (76 mg, 0.3 mmol) . The mixture was stirred at r.t. for 5 h., and then concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column eluting with MeCN/H2O (20 -25%) to afford the title compound (8 mg) as white solid. LCMS calc. for C20H22ClFN5O5S2 [M+H] +: m/z = 530.1; Found: 530.1.
Example 33: N- (5- (2-Acetamidoethoxy) -1, 3, 4-thiadiazol-2-yl) -4- (3-chloro-2-fluoro-6-methoxyphenyl) -6-methylnicotinamide
Step 1: 2- (2- ( (5-amino-1, 3, 4-thiadiazol-2-yl) oxy) ethyl) isoindoline-1, 3-dione
To a solution of 2- (2-hydroxyethyl) isoindoline-1, 3-dione (1.91 g, 10 mmol) and 5-bromo-1, 3, 4-thiadiazol-2-amine (0.9 g, 5 mmol) in DMF (10 mL) was added NaH (0.6 g, 15 mmol, 60%suspension in mineral oil) at 0 ℃. The mixture was stirred at r.t. overnight, quenched with water (30 mL) , and then extracted with EtOAc (50 mL x 2) . The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc/PE (60 -85%) to afford the title compound (120 mg) as yellow oil. LCMS calc. for C12H11N4O3S [M+H] +: m/z =291.1; Found: 291.1.
Step 2: 4- (3-chloro-2-fluoro-6-methoxyphenyl) -N- (5- (2- (1, 3-dioxoisoindolin-2-yl) ethoxy) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
To a solution of 4- (3-chloro-2-fluoro-6-methoxyphenyl) -6-methylnicotinic acid (118 mg, 0.4 mmol, Int-1) , TCFH (168 mg, 0.6 mmol) and NMI (66 mg, 0.8 mmol) in DMF (2 mL) was added 2- (2- ( (5-amino-1, 3, 4-thiadiazol-2-yl) oxy) ethyl) isoindoline-1, 3-dione (120 mg, 0.41 mmol) . The mixture was stirred at r.t. for 3 h., and then concentrated under reduced pressure. The residue was purified by flash chromatography on a C18 column eluting with MeCN/H2O (40 -55%) to afford the title compound (92 mg) as yellow solid. LCMS calc. for C26H20ClFN5O5S [M+H] +: m/z = 568.1; Found: 568.1.
Step 3: N- (5- (2-aminoethoxy) -1, 3, 4-thiadiazol-2-yl) -4- (3-chloro-2-fluoro-6-methoxyphenyl) -6-methylnicotinamide
A mixture of 4- (3-chloro-2-fluoro-6-methoxyphenyl) -N- (5- (2- (1, 3-dioxoisoindolin-2-yl) ethoxy) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide (92 mg, 0.16 mmol) and hydrazine hydrate solution (0.1 mL, 80%purity) in EtOH (3 mL) was heated to 80 ℃ for 4 h. . The reaction mixture was concentrated under reduced pressure to afford the title compound (70 mg) as yellow oil. LCMS calc. for C18H18ClFN5O3S [M+H] +: m/z = 438.1; Found: 438.1.
Step 4: N- (5- (2-acetamidoethoxy) -1, 3, 4-thiadiazol-2-yl) -4- (3-chloro-2-fluoro-6-methoxyphenyl) -6- methylnicotinamide
To a mixture of N- (5- (2-aminoethoxy) -1, 3, 4-thiadiazol-2-yl) -4- (3-chloro-2-fluoro-6-methoxyphenyl) -6-methylnicotinamide (35 mg, 0.08 mmol) and NaHCO3 (68 mg, 0.8 mmol) in THF (2 mL) and water (2 mL) was added acetic anhydride (50 mg, 0.4 mmol) . The reaction mixture was stirred at r.t. for 2 h., and then concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column eluting with MeCN/H2O (15 -25%) to afford the title compound (22 mg) as white solid. LCMS calc. for C20H20ClFN5O4S [M+H] +: m/z = 480.1; Found: 480.1.
Example 34: 4- (3-Chloro-2-fluoro-6-methoxyphenyl) -6-methyl-N- (5- (2- (methylsulfonamido) ethoxy) -1, 3, 4-thiadiazol-2-yl) nicotinamide
To a mixture of N- (5- (2-aminoethoxy) -1, 3, 4-thiadiazol-2-yl) -4- (3-chloro-2-fluoro-6-methoxyphenyl) -6-methylnicotinamide (35 mg, 0.08 mmol, Example 33 Step 3) and NaHCO3 (68 mg, 0.8 mmol) in THF (2 mL) and water (2 mL) was added methanesulfonic anhydride (70 mg, 0.4 mmol) . The reaction mixture was stirred at r.t. for 1 h., and then concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column eluting with MeCN/H2O (20 -40%) to afford the title compound (8 mg) as white solid. LCMS calc. for C19H20ClFN5O5S2 [M+H] +: m/z = 516.1; Found: 516.1.
Example 35: N- (5-Ethoxy-1, 3, 4-thiadiazol-2-yl) -4- (2-fluoro-6-methoxy-3-methylphenyl) -6-methylnicotinamide
To a mixture of 4- (2-fluoro-6-methoxy-3-methylphenyl) -6-methylnicotinic acid (68 mg, 0.25 mmol, Int-4) , TCFH (112 mg, 0.4 mmol) and NMI (66 mg, 0.5 mmol) in DMF (3 mL) was added 5-ethoxy-1, 3, 4-thiadiazol-2-amine (44 mg, 0.3 mmol, Example 14 Step 1) . The reaction mixture was stirred at r.t. for 4 h., and then concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column eluting with MeCN/H2O (15 -50%) to afford the title compound (30 mg) as white solid. LCMS calc. for C19H20FN4O3S [M+H] +: m/z = 403.1; Found: 403.2.
Example 36: 4- (2-Fluoro-6-methoxy-3-methylphenyl) -N- (5- (2-methoxypropoxy) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
This compound was prepared using procedures analogous to those described for Example 35 using the intermediate 4- (2-fluoro-6-methoxy-3-methylphenyl) -6-methylnicotinic acid (Int-4) and 5- (2-methoxypropoxy) -1, 3, 4-thiadiazol-2-amine (Example 11 Step 2) . LCMS calc. for C21H24FN4O4S [M+H] +: m/z = 447.1; Found: 447.2.
Example 37: 4- (2-Fluoro-6-methoxy-3-methylphenyl) -6-methyl-N- (5- (2, 2, 2-trifluoroethoxy) -1, 3, 4-thiadiazol-2-yl) nicotinamide
This compound was prepared using procedures analogous to those described for Example 35 using the intermediate 4- (2-fluoro-6-methoxy-3-methylphenyl) -6-methylnicotinic acid (Int-4) and 5- (2, 2, 2-trifluoroethoxy) -1, 3, 4-thiadiazol-2-amine (Example 7 Step 1) . LCMS calc. for C19H17F4N4O3S [M+H] +: m/z = 457.1; Found: 457.1.
Example 38: N- (5-Ethoxy-1, 3, 4-thiadiazol-2-yl) -4- (2-fluoro-6-methoxy-3- (trifluoromethyl) phenyl) -6-methylnicotinamide
To a mixture of 4- (2-fluoro-6-methoxy-3- (trifluoromethyl) phenyl) -6-methylnicotinic acid (83 mg, 0.25 mmol, Int-5) , TCFH (112 mg, 0.4 mmol) and NMI (66 mg, 0.5 mmol) in DMF (3 mL) was added 5-ethoxy-1, 3, 4-thiadiazol-2-amine (44 mg, 0.3 mmol, Example 14 Step 1) . The reaction mixture was stirred at r.t. for 4 h., and then concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column eluting with MeCN/H2O (25 -50%) to afford the title compound (43.0 mg, 38%yield) as white solid. LCMS calc. for C19H17F4N4O3S [M+H] +: m/z = 457.1; Found: 457.1.
Example 39: 4- (2-Fluoro-6-methoxy-3- (trifluoromethyl) phenyl) -N- (5- (2-methoxypropoxy) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
This compound was prepared using procedures analogous to those described for Example 38 using the intermediate 4- (2-fluoro-6-methoxy-3- (trifluoromethyl) phenyl) -6-methylnicotinic acid (Int-5) and 5- (2-methoxypropoxy) -1, 3, 4-thiadiazol-2-amine (Example 11 Step 2) . LCMS calc. for C21H21F4N4O4S [M+H] +: m/z = 501.1; Found: 501.2.
Example 40: 4- (2-Fluoro-6-methoxy-3- (trifluoromethyl) phenyl) -6-methyl-N- (5- (2, 2, 2-trifluoroethoxy) -1, 3, 4-thiadiazol-2-yl) nicotinamide
This compound was prepared using procedures analogous to those described for Example 38 using the intermediate 4- (2-fluoro-6-methoxy-3- (trifluoromethyl) phenyl) -6-methylnicotinic acid (Int-5) and 5- (2, 2, 2-trifluoroethoxy) -1, 3, 4-thiadiazol-2-amine (Example 7 Step 1) . LCMS calc. for C19H14F7N4O3S [M+H] +: m/z = 511.1; Found: 511.2.
Example 41: 4- (2-Fluoro-6-methoxy-3- (trifluoromethyl) phenyl) -N- (5- (2-methoxyethoxy) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
This compound was prepared using procedures analogous to those described for Example 38 using the intermediate 4- (2-fluoro-6-methoxy-3- (trifluoromethyl) phenyl) -6-methylnicotinic acid (Int-5) and 5- (2-methoxyethoxy) -1, 3, 4-thiadiazol-2-amine (Example 20 Step 1) . LCMS calc. for C20H19F4N4O4S [M+H] +: m/z = 487.1; Found: 487.1.
Example 42: (E) -N- (5- (But-2-en-1-yloxy) -1, 3, 4-thiadiazol-2-yl) -4- (2-fluoro-6-methoxy-3- (trifluoromethyl) phenyl) -6-methylnicotinamide
This compound was prepared using procedures analogous to those described for Example 38 using the intermediate 4- (2-fluoro-6-methoxy-3- (trifluoromethyl) phenyl) -6-methylnicotinic acid (Int-5) and (E) -5- (but-2-en-1-yloxy) -1, 3, 4-thiadiazol-2-amine (Example 23 Step 1) . LCMS calc. for C21H19F4N4O3S [M+H] +: m/z = 483.1; Found: 483.1.
Example 43: 4- (2-Fluoro-6-methoxy-3- (trifluoromethyl) phenyl) -N- (5- ( (2- (methoxymethyl) allyl) oxy) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
This compound was prepared using procedures analogous to those described for Example 38 using the intermediate 4- (2-fluoro-6-methoxy-3- (trifluoromethyl) phenyl) -6-methylnicotinic acid (Int-5) and 5- ( (2- (methoxymethyl) allyl) oxy) -1, 3, 4-thiadiazol-2-amine (Example 24 Step 2) . LCMS calc. for C22H21F4N4O4S [M+H] +: m/z = 513.1; Found: 513.1.
Example 44: 4- (2-Fluoro-6-methoxy-3- (trifluoromethyl) phenyl) -6-methyl-N- (5- ( (2-methylallyl) oxy) -1, 3, 4-thiadiazol-2-yl) nicotinamide
This compound was prepared using procedures analogous to those described for Example 38 using the intermediate 4- (2-fluoro-6-methoxy-3- (trifluoromethyl) phenyl) -6-methylnicotinic acid (Int-5) and 5- ( (2-methylallyl) oxy) -1, 3, 4-thiadiazol-2-amine (Example 25 Step 1) . LCMS calc. for C21H19F4N4O3S [M+H] +: m/z = 483.1; Found: 483.1.
Example 45: 4- (2-Fluoro-6-methoxy-3- (trifluoromethyl) phenyl) -6-methyl-N- (5- ( (trimethylsilyl) methoxy) -1, 3, 4-thiadiazol-2-yl) nicotinamide
This compound was prepared using procedures analogous to those described for Example 38 using intermediate 4- (2-fluoro-6-methoxy-3- (trifluoromethyl) phenyl) -6-methylnicotinic acid (Int-5) and 5- ( (trimethylsilyl) methoxy) -1, 3, 4-thiadiazol-2-amine (Example 26 Step 3) . LCMS calc. for C21H23F4N4O3SSi [M+H] +: m/z = 515.1; Found: 515.2.
Example 46: 4- (2-Fluoro-6-methoxy-3- (trifluoromethyl) phenyl) -N- (5-hydroxy-1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
A solution of N- (5-ethoxy-1, 3, 4-thiadiazol-2-yl) -4- (2-fluoro-6-methoxy-3- (trifluoromethyl) phenyl) -6-methylnicotinamide (Example 38, 23 mg, 0.05 mmol) in HCl (4 M in  1, 4-dioxane, 10 mL) was stirred at 60 ℃ for 6 h., and then concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column eluting with MeCN/H2O (10 -30%with 0.05%TFA) to afford the title compound (3.2 mg, 15%yield) as white solid. LCMS calc. for C17H13F4N4O3S [M+H] +: m/z = 429.1; Found: 429.1.
Example 47: 4- (3-Chloro-2-fluoro-6-methoxyphenyl) -N- (5-hydroxy-1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
This compound was prepared using procedures analogous to those described for Example 46 using 4- (3-chloro-2-fluoro-6-methoxyphenyl) -N- (5-ethoxy-1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide (Example 17) . LCMS calc. for C16H13ClFN4O3S [M+H] +: m/z = 395.0; Found: 395.0.
Example 48: 5'-Fluoro-2', 3'-dimethoxy-6-methyl-N- (5- ( (trimethylsilyl) methoxy) -1, 3, 4-thiadiazol-2-yl) - [4, 4'-bipyridine] -3-carboxamide
Step 1: 5-fluoro-2, 3-dimethoxypyridine
To a solution of 2, 3, 5-trifluoropyridine (1.50 g, 11.3 mmol) in DMSO (60 mL) was added MeONa (1.34 g, 24.8 mmol) . The mixture was stirred at 80 ℃ for 2 h. . The reaction mixture was diluted with EtOAc and washed with H2O and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc/PE (0 -15%) to afford the title compound (1.15 g, 64%yield) as white solid. LCMS calc. for C7H9FNO2 [M+H] +: m/z = 158.0; Found: 158.0.
Step 2: 5-fluoro-4-iodo-2, 3-dimethoxypyridine
To a solution of 5-fluoro-2, 3-dimethoxypyridine (500 mg, 3.18 mmol) in THF (2 mL) was added n-BuLi (2.5 M in hexane, 1.5 mL) and stirred at -78 ℃ for 1 h., and then I2 (888 mg, 3.50 mmol) was added in portions. The reaction mixture was stirred at 25 ℃ for 2 h., and quenched with water (50 mL) . The mixture was extracted with EtOAc (50 mL x 3) . The combined organic layers  were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc/PE (0 -5%) to afford the title compound (700 mg, 77%yield) as white solid. 1H NMR (400 MHz, DMSO-d6) δ7.87 (s, 1H) , 3.90 (s, 3H) , 3.79 (s, 3H) . LCMS calc. for C7H8FINO2 [M+H] +: m/z = 284.0; Found: 283.8.
Step 3: methyl 5'-fluoro-2', 3'-dimethoxy-6-methyl- [4, 4'-bipyridine] -3-carboxylate
To a solution of 5-fluoro-4-iodo-2, 3-dimethoxypyridine (200 mg, 0.71 mmol) in dioxane (10 mL) and H2O (0.5 mL) was added methyl 6-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) nicotinate (215 mg, 0.77 mmol) and K2CO3 (293 mg, 2.12 mmol) and Pd (dppf) Cl2 (58 mg, 0.071 mmol) . The reaction was stirred at 90 ℃ overnight. The mixture was diluted with water (50 mL) , extracted with EtOAc (50 mL x 3) . The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC eluting with EtOAc/PE (20%) to afford the title compound (120 mg, 44%yield) as yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H) , 8.02 (s, 1H) , 7.39 (s, 1H) , 3.95 (s, 3H) , 3.70 (s, 3H) , 3.59 (s, 3H) , 2.59 (s, 3H) . LCMS calc. for C15H16FN2O4 [M+H] +: m/z = 307.1; Found: 307.0.
Step 4: 5'-fluoro-2', 3'-dimethoxy-6-methyl- [4, 4'-bipyridine] -3-carboxylic acid
To a solution of methyl 5'-fluoro-2', 3'-dimethoxy-6-methyl- [4, 4'-bipyridine] -3-carboxylate (50 mg, 0.16 mmol) in THF (2 mL) was added aq. NaOH (2 M, 1.5 mL) . The mixture was stirred at r.t. overnight, and adjusted pH～7 with aq. HCl (1 M) . The mixture was concentrated under reduced pressure. The residue was washed with EtOAc (5 mL) and DCM (10 mL) , and filtered to afford the title compound (40 mg, 85%yield) as white solid. LCMS calc. for C14H14FN2O4 [M+H] +: m/z =293.1; Found: 293.0.
Step 5: 5'-fluoro-2', 3'-dimethoxy-6-methyl-N- (5- ( (trimethylsilyl) methoxy) -1, 3, 4-thiadiazol-2-yl) - [4, 4'-bipyridine] -3-carboxamide
A mixture of 5'-fluoro-2', 3'-dimethoxy-6-methyl- [4, 4'-bipyridine] -3-carboxylic acid (40 mg, 0.14 mmol) , 5- ( (trimethylsilyl) methoxy) -1, 3, 4-thiadiazol-2-amine (28 mg, 0.14 mmol, Example 26 Step 3) , HATU (68 mg, 0.18 mmol) and DIEA (53 mg, 0.42 mmol) in ACN (3 mL) was stirred at r.t. overnight. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column eluting with ACN/water (10 -95%with 1%NH4HCO3) to afford the title compound (10 mg, 15%yield) as white solid. 1H NMR (400 MHz, DMSO-d6) δ 13.04 (s, 1H) , 8.98  (s, 1H) , 8.00 (s, 1H) , 7.37 (s, 1H) , 4.20 (s, 2H) , 3.93 (s, 3H) , 3.57 (s, 3H) , 2.59 (s, 3H) , 0.10 (s, 9H) . LCMS calc. for C20H25FN5O4SSi [M+H] +: m/z = 478.1; Found: 478.2.
Example 49: 4- (3-Ethynyl-2-fluoro-6-methoxyphenyl) -N- (5- (2-methoxyethoxy) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
Step 1: methyl 4- (3-bromo-2-fluoro-6-methoxyphenyl) -6-methylnicotinate
To a solution of methyl 4- (2-fluoro-6-methoxyphenyl) -6-methylnicotinate (1.1 g, 4.0 mmol) in ACN (40 mL) was added NBS (0.8 g, 4.5 mmol) . The reaction mixture was stirred at 30 ℃overnight. After it was concentrated under reduced pressure, the residue was purified by flash chromatography on a silica gel column eluting with EtOAc/PE (40 -60%) to afford the title compound (0.85 g) as yellow solid LCMS calc. for C15H14BrFNO3 [M+H] +: m/z = 354.0; Found: 354.0.
Step 2: methyl 4- (2-fluoro-6-methoxy-3- ( (trimethylsilyl) ethynyl) phenyl) -6-methylnicotinate
To a mixture of methyl 4- (3-bromo-2-fluoro-6-methoxyphenyl) -6-methylnicotinate (353 mg, 1.0 mmol) , trimethylsilylacetylene (148 mg, 1.5 mmol) and TEA (1.01 g, 10.0 mL) in DMF (1 mL) was added CuI (19 mg, 0.1 mmol) and Pd (PPh3) 2Cl2 (70 mg, 0.1 mmol) . The reaction mixture was stirred at 50 ℃ for 4 h. . The mixture was diluted with EtOAc (40 mL) , washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc/PE (5 -30%) to afford the title compound (230 mg) as yellow oil. LCMS calc. for C20H23FNO3Si [M+H] +: m/z = 372.1; Found: 372.1.
Step 3: 4- (3-ethynyl-2-fluoro-6-methoxyphenyl) -6-methylnicotinic acid
To a solution of methyl 4- (2-fluoro-6-methoxy-3- ( (trimethylsilyl) ethynyl) phenyl) -6- methylnicotinate (74 mg, 0.2 mmol) in MeOH (2 mL) and H2O (2 mL) was added KOH. (56 mg, 1.0 mmol) . After it was stirred at r.t. overnight, the reaction mixture was diluted with water (20 mL) adjusted to pH～3 -4 with HCl aq. (2 M) , and then extracted with DCM (10 mL x 5) . The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude product (60 mg) as yellow oil which was used in the next step without further purification. LCMS calc. for C16H13FNO3 [M+H] +: m/z = 286.1; Found: 286.1.
Step 4: 4- (3-ethynyl-2-fluoro-6-methoxyphenyl) -N- (5- (2-methoxyethoxy) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
To a solution of 4- (3-ethynyl-2-fluoro-6-methoxyphenyl) -6-methylnicotinic acid (60 mg, 0.21 mmol) , TCFH (84 mg, 0.3 mmol) and NMI (33 mg, 0.4 mmol) in DMF (2 mL) was added 5- (2-methoxyethoxy) -1, 3, 4-thiadiazol-2-amine (40 mg, 0.23 mmol, Example 20 Step 1) . The mixture was stirred at r.t. for 2 h., and then concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column eluting with MeCN/H2O (10 -20%) to afford the title compound (62 mg) as white solid. LCMS calc. for C21H20FN4O4S [M+H] +: m/z = 443.1; Found: 443.1.
Example 50: 4- (3-Chloro-2-fluoro-6-methoxyphenyl) -6-methyl-N- (5- (2- ( ( (R) -tetrahydrofuran-3-yl) oxy) ethoxy) -1, 3, 4-thiadiazol-2-yl) nicotinamide
This compound was prepared by procedures analogous to those described for Example 22 Step 1-3 using (R) -tetrahydrofuran-3-ol to replace cyclobutanol in Step 1. LCMS calc. for C22H23ClFN4O5S [M+H] +: m/z = 509.1; Found: 509.1.
Example 51: 4- (3-Chloro-2-fluoro-6-methoxyphenyl) -6-methyl-N- (5- (2- ( ( (S) -tetrahydrofuran-3-yl) oxy) ethoxy) -1, 3, 4-thiadiazol-2-yl) nicotinamide
This compound was prepared by procedures analogous to those described for Example 22 Step 1-3 using (S) -tetrahydrofuran-3-ol to replace cyclobutanol in Step 1. LCMS calc. for C22H23ClFN4O5S [M+H] +: m/z = 509.1; Found: 509.1.
Example 52: N- (5- (Allyloxy) -1, 3, 4-thiadiazol-2-yl) -4- (3-chloro-2-fluoro-6-methoxyphenyl) -6-methylnicotinamide
Step 1: 5- (allyl) oxy-1, 3, 4-thiadiazol-2-amine
This compound was prepared using procedures analogous to those described for Example 1 Step 1 using prop-2-en-1-ol to replace neopentyl alcohol. LCMS calc. for C5H8N3O2S [M+H] +: m/z = 158.0; Found: 158.0.
Step 2: N- (5- (allyloxy) -1, 3, 4-thiadiazol-2-yl) -4- (3-chloro-2-fluoro-6-methoxyphenyl) -6-methylnicotinamide
This compound was prepared by procedures analogous to those described for Example 17 using 4- (3-chloro-2-fluoro-6-methoxyphenyl) -6-methylnicotinic acid (Int-1) and 5- (allyl) oxy-1, 3, 4-thiadiazol-2-amine. LCMS calc. for C19H17ClFN4O3S [M+H] +: m/z = 435.1; Found: 435.1.
Example 53: 4- (3-Chloro-2-fluoro-6-methoxyphenyl) -N- (5- (2, 2-dihydroxyethoxy) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
To a mixture of N- (5- (allyloxy) -1, 3, 4-thiadiazol-2-yl) -4- (3-chloro-2-fluoro-6-methoxyphenyl) -6-methylnicotinamide (22 mg, 0.2 mmol, Example 52) , NaIO4 (173 mg, 0.8 mmol) in 1, 4-dioxane (2 mL) and water (1 mL) was added potassium osmate (VI) dihydrate (1 mg) . The reaction mixture was stirred at r.t. overnight, and then concentrated under reduced pressure. The residue was purified by flash chromatography on a C18 column eluting with ACN/water (30 -50%) to afford the title compound (2.2 mg) as off-white solid. LCMS calc. for C18H17ClFN4O5S [M+H] +: m/z = 455.1; Found: 455.1.
Example 54: 4- (3-Chloro-2-fluoro-6-methoxyphenyl) -6-methyl-N- (5- (2- (oxetan-3-yloxy) ethoxy) -1, 3, 4-thiadiazol-2-yl) nicotinamide
This compound was prepared by procedures analogous to those described for Example 22 Step 1-3 using oxetan-3-ol to replace cyclobutanol in Step 1. LCMS calc. for C21H21ClFN4O5S [M+H] +: m/z = 495.1; Found: 495.1.
Example 55: 4- (3-Chloro-2-fluoro-6-methoxyphenyl) -N- (5- (2- (2- (2-methoxyethoxy) ethoxy) ethoxy) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
This compound was prepared by procedures analogous to those described for Example 21 Step 1-2 using 2- (2- (2-methoxyethoxy) ethoxy) ethan-1-ol to replace 2- (2-methoxyethoxy) ethan-1-ol in Step 1. LCMS calc. for C23H27ClFN4O6S [M+H] +: m/z = 541.1; Found: 541.1.
Example 56: 4- (3-Chloro-2-fluoro-6-methoxyphenyl) -N- (5- (2- (2- (2-hydroxyethoxy) ethoxy) ethoxy) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
Step 1: 2, 2-dimethyl-3, 3-diphenyl-4, 7, 10-trioxa-3-siladodecan-12-ol
To a mixture of triethylene glycol (20 g, 133 mmol) and 1H-imidazole (9.1 g, 133 mmol) in DCM (400 mL) was added TBDPSCl (25.6 g, 93.1 mmol) at 0 ℃. The reaction mixture was stirred at r.t. overnight, diluted with H2O (200 mL) and extracted with DCM (200 mL x 2) . The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with MeOH/DCM (0 -1%) to afford the title compound (20 g) as yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.70-7.67 (m, 4H) , 7.45-7.35 (m, 6H) , 3.83-3.80 (m, 2H) , 3.73-3.71 (m, 2H) , 3.66 (s, 4H) , 3.62-3.59 (m, 4H) , 2.21 (brs, 1H) , 1.05 (s, 9H) . TLC: Rf = 0.7 (DCM/MeOH = 10: 1) .
Step 2: O- (2, 2-dimethyl-3, 3-diphenyl-4, 7, 10-trioxa-3-siladodecan-12-yl) S-methyl carbonodithioate
To a solution of 2, 2-dimethyl-3, 3-diphenyl-4, 7, 10-trioxa-3-siladodecan-12-ol (3.0 g, 7.73 mmol) in THF (90 mL) was added NaH (0.62 g, 15.5 mmol, 60%suspension in mineral oil) at 0 ℃. The resulting mixture was stirred at 0 ℃ for 1 h., CS2 (1.29 g, 17 mmol) was added at 0 ℃ and stirred for an additional 1 h. . MeI (1.42 g, 10 mmol) was added dropwise at 0 ℃. The reaction mixture was stirred at r.t. for 14 h. . The resulting mixture was quenched with saturated aq. NH4Cl, and extracted with EtOAc (100 mL x 2) . The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc/PE = (0 -1.5%) to afford the title compound (2.4 g) as yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.69-7.67 (m, 4H) , 7.40-7.36 (m, 6H) , 4.72 (t, J = 4.8 Hz, 2H) , 3.84-3.80 (m, 4H) , 3.65-3.60 (m, 6H) , 2.55 (s, 3H) , 1.05 (s, 9H) . TLC: Rf = 0.6 (PE/EtOAc = 10: 1) .
Step 3: O- (2, 2-dimethyl-3, 3-diphenyl-4, 7, 10-trioxa-3-siladodecan-12-yl) hydrazinecarbothioate
To a solution of O- (2, 2-dimethyl-3, 3-diphenyl-4, 7, 10-trioxa-3-siladodecan-12-yl) S-methyl carbonodithioate (1.8 g, 3.77 mmol) in MeOH (18 mL) was added hydrazine hydrate solution (283 mg, 5.66 mmol, 80%purity) at r.t. . The reaction mixture was stirred at r.t. for 30 min., and then concentrated under reduced pressure to afford the title compound (1.70 g) as white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.66-7.64 (m, 4H) , 7.48-7.42 (m, 6H) , 4.65-4.56 (m, 1H) , 3.76-3.74 (m, 2H) , 3.53-3.41 (m, 8H) , 3.24 (s, 2H) , 0.99 (s, 9H) . TLC: Rf = 0.6 (DCM/MeOH = 10: 1) .
Step 4: 5- ( (2, 2-dimethyl-3, 3-diphenyl-4, 7, 10-trioxa-3-siladodecan-12-yl) oxy) -1, 3, 4-thiadiazol-2-amine
To a mixture of O- (2, 2-dimethyl-3, 3-diphenyl-4, 7, 10-trioxa-3-siladodecan-12-yl) hydrazinecarbothioate (1.70 g, 3.7 mmol) and BrCN (0.78 g, 7.36 mmol) in MeOH (34 mL) was added TEA (1.11 g, 11 mmol) at 0 ℃. The mixture was stirred at r.t. for 1 h., and then concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with MeOH/DCM (0 -10%) to afford the title compound (1 g) as yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.69-7.67 (m, 4H) , 7.46-7.35 (m, 6H) , 4.74 (s, 2H) , 3.56-3.53 (m, 2H) , 3.81-3.80 (m, 4H) , 3.66-3.59 (m, 6H) , 1.05 (s, 9H) . LCMS calc. for C24H34N3O4SSi [M+H] +: m/z = 488.2; Found: 488.1.
Step 5: 4- (3-chloro-2-fluoro-6-methoxyphenyl) -N- (5- ( (2, 2-dimethyl-3, 3-diphenyl-4, 7, 10-trioxa-3-siladodecan-12-yl) oxy) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
To a mixture of 5- ( (2, 2-dimethyl-3, 3-diphenyl-4, 7, 10-trioxa-3-siladodecan-12-yl) oxy) -1, 3, 4-thiadiazol-2-amine (200 mg, 0.41 mmol) , 4- (3-chloro-2-fluoro-6-methoxyphenyl) -6-methylnicotinic acid (121 mg, 0.41 mmol, Int-1) and TEA (208 mg, 2.1 mmol) in DMF (6 mL) was added HOBT (72 mg, 0.53 mmol ) and EDCI (102 mg, 0.53 mmol) . The reaction mixture was stirred for 16 h. at r.t. . The resulting mixture was diluted with H2O and extracted with EtOAc (20 mL x 3) . The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with MeOH/DCM (0 -2%) to afford the title compound (180 mg) as yellow solid. LCMS calc. for C38H43ClFN4O6SSi [M+H] +: m/z = 765.2; Found: 765.2.
Step 6: 4- (3-chloro-2-fluoro-6-methoxyphenyl) -N- (5- (2- (2- (2-hydroxyethoxy) ethoxy) ethoxy) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide
To a solution of 4- (3-chloro-2-fluoro-6-methoxyphenyl) -N- (5- ( (2, 2-dimethyl-3, 3-diphenyl-4, 7, 10-trioxa-3-siladodecan-12-yl) oxy) -1, 3, 4-thiadiazol-2-yl) -6-methylnicotinamide (170 mg, 0.22 mmol) in THF (3 mL) was added TBAF solution (6.7 mL, 67 mmol, 1.0 M in THF) and stirred for 6  h. at r.t. . The reaction mixture was diluted with H2O and extracted with EtOAc (20 mL x 2) . The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC eluting with MeOH/DCM (10%) to afford the title compound (50 mg) as white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.9 (brs, 1H) , 8.84 (s, 1H) , 7.59 (t, J = 8.8 Hz, 1H) , 7.39 (s, 1H) , 6.93 (d, J = 8.8 Hz, 1H) , 4.58 (s, 1H) , 4.53-4.51 (m, 2H) , 3.37 (s, 2H) , 3.52-3.41 (m, 9H) , 3.33 (s, 2H) , 2.57 (s, 3H) . LCMS calc. for C22H25ClFN4O6S [M+H] +: m/z = 527.1; Found: 527.1.
Int-1: 4- (3-Chloro-2-fluoro-6-methoxyphenyl) -6-methylnicotinic acid
Step 1: (3-chloro-2-fluoro-6-methoxyphenyl) boronic acid
To a solution of 1-chloro-2-fluoro-4-methoxybenzene (2.00 g, 12.5 mmol) in dry THF (20 mL) was added LDA (2.0 M in THF, 12.5 mL) at -70 ℃ under N2 atmosphere. The mixture was stirred at -70 ℃ for 1 h., and then triisopropyl borate (4.70 g, 25.0 mmol) was added at -70 ℃. The resulting mixture was stirred at -70 ℃ for 2 h., and quenched by saturated aq. NH4Cl (50 mL) at 0 ℃. The aqueous layer was adjusted to pH～2 -3 with HCl (1 M) , and extracted with EtOAc (40 mL x 5) . The combined organic layers were washed with brine (40 mL) , dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc/PE (0 -10%) to afford (3-chloro-2-fluoro-6-methoxyphenyl) boronic acid (1.6 g) as off-white solid.
Step 2: methyl 4- (3-chloro-2-fluoro-6-methoxyphenyl) -6-methylnicotinate
A mixture of methyl 4-chloro-6-methylnicotinate (3.0 g, 16 mmol) , (3-chloro-2-fluoro-6-methoxyphenyl) boronic acid (3.2 g, 16 mmol) , K2CO3 (4.4 g, 32 mmol) and Pd (dppf) Cl2 (1.1 g, 1.6 mmol) in 1, 4-dioxane (24 mL) and H2O (3 mL) was degassed and recharged with nitrogen for 3 cycles. The mixture was stirred at 80 ℃ for 16 h. . The mixture was diluted with EtOAc (80 mL) , washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc/PE (0 -20%) to give the title compound (2.8 g) as yellow solid. LCMS calc. for C15H14FClNO3 [M+H] +: m/z = 310.1; Found: 310.0.
Step 3: 4- (3-chloro-2-fluoro-6-methoxyphenyl) -6-methylnicotinic acid
To a solution of methyl 4- (3-chloro-2-fluoro-6-methoxyphenyl) -6-methylnicotinate (70 mg, 0.23 mmol) in MeOH (2 mL) and H2O (2 mL) was added LiOH. H2O (40 mg, 1.0 mmol) . After it was stirred at r.t. overnight, the reaction mixture was diluted with water and adjusted to pH～3 -4 with aq. HCl (2 M) , extracted with DCM (20 mL x 5) . The combined organic layers were washed with brine (15 mL) , dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude product (50 mg) as yellow oil which was used in the next step without further purification. LCMS calc. for C14H12FClNO3 [M+H] +: m/z = 296.0; Found: 296.0.
Int-2: 4- (2-Fluoro-6-methoxyphenyl) -6-methylnicotinic acid
Step 1: methyl 4- (2-fluoro-6-methoxyphenyl) -6-methylnicotinate
This compound was prepared as yellow solid by procedures analogous to those described for Int-1 Step 2 using 2-fluoro-6-methoxyphenylboronic acid to replace (3-chloro-2-fluoro-6-methoxyphenyl) boronic acid. LCMS calc. for C15H15FNO3 [M+H] +: m/z = 276.1; Found: 276.0.
Step 2: 4- (2-fluoro-6-methoxyphenyl) -6-methylnicotinic acid
This compound was prepared as off-white solid by procedures analogous to those described for Int-1 Step 3 using methyl 4- (2-fluoro-6-methoxyphenyl) -6-methylnicotinate . LCMS calc. for C14H13FNO3 [M+H] +: m/z = 261.1; Found: 261.0.
Int-3: 4- (2, 3-Difluoro-6-methoxyphenyl) -6-methylnicotinic acid
Step 1: methyl 4- (2, 3-difluoro-6-methoxyphenyl) -6-methylnicotinate
This compound was prepared as yellow solid by procedures analogous to those described for  Int-1 Step 2 using (2, 3-difluoro-6-methoxyphenyl) boronic acid to replace (3-chloro-2-fluoro-6-methoxyphenyl) boronic acid. LCMS calc. for C15H14F2NO3 [M+H] +: m/z = 294.1; Found: 294.1.
Step 2: 4- (2, 3-difluoro-6-methoxyphenyl) -6-methylnicotinic acid
This compound was prepared as off-white solid by procedures analogous to those described for Int-1 Step 3 using methyl 4- (2, 3-difluoro-6-methoxyphenyl) -6-methylnicotinate. LCMS calc. for C14H12F2NO3 [M+H] +: m/z = 280.1; Found: 280.1.
Int-4: 4- (2-Fluoro-6-methoxy-3-methylphenyl) -6-methylnicotinic acid
Step 1: methyl 4- (2-fluoro-6-methoxy-3-methylphenyl) -6-methylnicotinate
This compound was prepared as white solid by procedures analogous to those described for Int-1 Step 2 using 2-fluoro-6-methoxy-3-methylphenylboronic acid to replace (3-chloro-2-fluoro-6-methoxyphenyl) boronic acid. LCMS calc. for C16H17FNO3 [M+H] +: m/z = 290.1; Found: 290.1.
Step 2: 4- (2-fluoro-6-methoxy-3-methylphenyl) -6-methylnicotinic acid
This compound was prepared as off-white solid by procedures analogous to those described for Int-1 Step 3 using methyl 4- (2-fluoro-6-methoxy-3-methylphenyl) -6-methylnicotinate. LCMS calc. for C15H15FNO3 [M+H] +: m/z = 275.1; Found: 275.1.
Int-5: 4- (2-Fluoro-6-methoxy-3- (trifluoromethyl) phenyl) -6-methylnicotinic acid
Step 1: 2- (3-fluoro-4- (trifluoromethyl) phenyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane
A mixture of 4-bromo-2-fluoro-1- (trifluoromethyl) benzene (9.7 g, 40 mmol) , bis (pinacolato) diboron (12.7 g, 50 mmol) , KOAc (9.8 g, 100 mmol) and Pd (dppf) Cl2 (0.87 g, 1.2 mmol) in 1, 4-dioxane (120 mL) was degassed and recharged with nitrogen for 3 cycles. The reaction mixture was stirred at 100 ℃ for 16 h. . The reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (300 mL) , washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was disolved in PE and fitered through a short pad of a silica gel to afford the title compound (11.5 g,  99%yield) as yellow oil. TLC Rf = 0.4 (EtOAc/PE = 1/50, UV 254 nm) .
Step 2: 3-fluoro-4- (trifluoromethyl) phenol
To a cooled (ice-water bath) mixture of 2- (3-fluoro-4- (trifluoromethyl) phenyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (11.5 g, 40 mmol) and NaOH (6.4 g, 160 mmol) in THF (400 mL) and water (20 mL) was added aq. H2O2 (16 mL, 33%) . The reaction mixture was stirred at 0 ℃ for 4 h., and concentrated under reduced pressure. The residue was diluted with PE (300 mL) and filtered. The filtrate was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title compound (7.0 g, 97%yield) as yellow oil. LCMS calc. for C7H3F4O [M-H] +: m/z = 179.0; Found: 179.0. TLC Rf = 0.45 (EtOAc/PE = 1/25, UV 254 nm) .
Step 3: 2-fluoro-4-methoxy-1- (trifluoromethyl) benzene
To a mixture of 3-fluoro-4- (trifluoromethyl) phenol (7.0 g, 38.9 mmol) , K2CO3 (13.8 g, 100 mmol) in MeCN (40 mL) was added MeI (8.5 g, 60 mmol) The reaction mixture was stirred at 40 ℃ for 4 h., and concentrated under reduced pressure. The residue was diluted with PE (200 mL) and filtered. The filtrate was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc/PE (0 -5%) to afford the title compound (4.2 g, 56%yield) as colorless oil. TLC Rf = 0.55 (EtOAc/PE = 1/25, UV 254 nm) .
Step 4: (2-fluoro-6-methoxy-3- (trifluoromethyl) phenyl) boronic acid
To a solution of 2-fluoro-4-methoxy-1- (trifluoromethyl) benzene (3.9 g, 20 mmol) in THF (40 mL) was added n-BuLi (10 mL, 2.5 M in hexane) at -60 ℃. After being stirred for 1 h., 2-isopropoxy-4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (4.6 g, 25 mmol) was added at -60 ℃. The reaction mixture was stirred at r.t. for 1 h. . The reaction mixture was quenched by aq. HCl (2 M) solution (20 mL) at 0 ℃, stirred for 30 min., and extracted with EtOAc (40 mL x 5) . The combined organic layers were washed with brine (40 mL) , dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title compoud (2.0 g, 42%) as yellow oil without further purification.
Step 5: methyl 4- (2-fluoro-6-methoxy-3- (trifluoromethyl) phenyl) -6-methylnicotinate
This compound was prepared as yellow solid by procedures analogous to those described for Int-1 Step 2 using (2-fluoro-6-methoxy-3- (trifluoromethyl) phenyl) boronic acid to replace (3-chloro- 2-fluoro-6-methoxyphenyl) boronic acid. LCMS calc. for C16H14F4NO3 [M+H] +: m/z = 344.1; Found: 344.1.
Step 6: 4- (2-fluoro-6-methoxy-3- (trifluoromethyl) phenyl) -6-methylnicotinic acid
This compound was prepared as white solid by procedures analogous to those described for Int-1 Step 3 using methyl 4- (2-fluoro-6-methoxy-3- (trifluoromethyl) phenyl) -6-methylnicotinate. LCMS calc. for C15H12F4NO3 [M+H] +: m/z = 330.1; Found: 330.1.
Example A: Biological evaluation
The ability of the compounds of the present disclosure to inhibit ATPase activity of PolQ (1-899) was determined using the assay described below.
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. PolQ (1-899) (1 nM) in assay buffer (20 mM Tris HCl (pH 8.0) , 80 mM KCl, 10 mM MgCl2, 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 μL of assay buffer was added to the low control wells) . The plate was then incubated at room temperature for 30 min. An equal volume (20 μL) of 100 μM ATP, 150 nM ssDNA containing 50 thymine bases in assay buffer was added to all the test wells. The plates were covered and left to incubate for 60 min. at room temperature before the addition of the ADP Glo detection reagents. After 60 min. incubation, transfer 5 μL reaction mix to another 384-well plate and add 5 μL ADP Glo and plates incubated for 60 min. before addition of 10 μL kinase detection reagent. After the addition of the kinase detection reagent, the plates were covered and incubated for 60 min. and read luminescence on Envision.
Percent inhibition was calculated as follows: %Inhibition= (SignalMax-SignalCompound) /(SignalMax-SignalMin) *100%) , where “Max” is the high control (DMSO) and “Min” is the no enzyme control.
IC50 values were calculated using a four-parameter logistic curve fit using the following formula:
Y=LowerBound+ ( (UpperBound-LowerBound) / (1+ ( (IC50/x) ^Hill) ) ) .
IC50 values were determined by fitting the data to the standard 4 parameters with Hill Slope using GraphPad Prism software. IC50: *≤10nM, 10nM＜**≤100nM, 100nM＜***≤500nM, ****＞500nM. The experimental results of the compounds are described in Table 1.
Table 1. PolQ ATPase assay

Although the present invention has been comprehensively described through its embodiments, it is worth noting that various changes and modifications are obvious to those skilled in the art. Such changes and modifications should be included in the scope of the appended claims of the present invention.

Claims (54)

  1. A compound of Formula (I) , or a pharmaceutically acceptable salt, solvate, tautomeric, stereoisomer, atropisomer, isotopic variant, prodrug, N-oxide, or deuterated compound thereof; wherein:
    X1 is N or CR1;
    X2 is N or CR2;
    X3 is N or CR3;
    X1, X2 and X3 are not N at the same time;
    m is 1, 2, 3, 4 or 5;
    Cy is C6-C10 aryl or 5-10 membered heteroaryl;
    R is selected from OH, or
    R1 and R2 are independently selected from H, D, CN, NO2, N3, oxo, SF5, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, ORA, SRA, C (O) RB, C (O) NRCRD, C (O) ORA, OC (O) RB, OC (O) NRCRD, NRCRD, NRCC (O) RB, NRCC (O) ORA, S (O) RB, S (O) 2RB; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halogen, CN, OH, NH2, NO2, oxo, C1-C6 alkyl, C1-C6 haloalkyl, -O-C1-C4 alkyl, -OC1-C4 haloalkyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl; or
    R1 and R2 together with the carbon atoms to which they are attached form C4-C7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; wherein, the C4-C7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl is optionally substituted by 1, 2, 3 or 4 substituents independently selected from D, halo, CN, NO2, OH, NH2, C1-C6 alkyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, -OC1-C6 haloalkyl, NHC1-C4 alkyl, or N (C1-C4 alkyl) 2;
    R3 is selected from H, D, CN, NO2, -N3, oxo, SF5, halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl, ORA, SRA, C (O) RB, C (O) NRCRD, C (O) ORA, OC (O) RB, OC (O) NRCRD, NRCRD, NRCC (O) RB, NRCC (O) ORA, S (O) RB, S (O) 2RB; wherein, the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halogen, CN, OH, NH2, NO2, oxo, C1-C4 alkyl, C1-C4 haloalkyl, -O-C1-C4 alkyl, -OC1-C4 haloalkyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl;
    each R4 is independently selected from D, halogen, -CN, -NO2, -SF5, -ORA, -SRA, -C (O) RB, -C (O) NRCRD, -C (O) ORA, -OC (O) RB, -NRCRD, -NRCC (O) RB, -S (O) RB, -S (O) 2RB, -S (O) NRCRD, -NRCS (O) 2RD, -S (O) 2NRCRD, -NRCS (O) 2NRCRD, -NRCS (O) (=NRB) RB, -P (O) RERF, -P (O) OREORF, -OP (O) OREORF, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R4A;
    each R4A is independently selected from D, halogen, CN, OH, NH2, oxo, C1-C6 alkyl, OC1-C6 alkyl, C1-C6 haloalkyl, OC1-C6 haloalkyl, NHC1-C3 alkyl, N (C1-C3 alkyl) 2, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl; wherein, the C3-C6 cycloalkyl or 4-6 membered heterocycloalkyl is optionally substituted with D, halogen, CN, OH, NH2, C1-C6 alkyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl; or
    two adjacent R4 together with the atoms to which they are attached form C4-C7 cycloalkyl or 4-7 membered heterocycloalkyl; wherein, the C4-C7 cycloalkyl or 4-7 membered heterocycloalkyl is optionally substituted with D, halogen, oxo, CN, OH, NH2, NO2, C1-C6 alkyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl; wherein, the C3-C6 cycloalkyl or 4-6 membered heterocycloalkyl is optionally substituted with D, halogen, CN, OH, NH2, C1-C6 alkyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl;
    R5 and R6 are independently selected from H, D, halo, CN, NO2, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 haloalkyl, C1-C8 alkyl-O-C1-C8 alkyl, C1-C8 alkyl-O-C1-C8 haloalkyl, C1-C8 alkyl-OH, C1-C8 alkyl-CN;
    R7 is independently selected from H, D, CN, halo, NO2, N3, SF5, Si (R8) 3, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or adamantanyl; wherein, the C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or adamantanyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from D, -halo, -CN, -NO2, -N3, SF5, oxo, -NRCRD, -ORA, -SRA, SiRGRHRI, -B (ORC) (ORD) , -C (O) RB, -C (O) ORA, -OC (O) RB, -C (O) NRCRD, -OC (O) NRCRD, -NRCC (O) RB, -NRCC (O) NRCRD, -NRCC (O) ORA, -S (O) RB, -S (O) 2RB, -S (O) NRCRD, -NRCS (O) RD, -NRCS (O) 2RD, -S (O) 2NRCRD, -NRCS (O) 2NRCRD, -NRCS (O) (=NRB) RB;
    each R8 is independently selected from C1-C4 alkyl or phenyl;
    each RA is independently selected from H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocyclalkyl, C6-C10 aryl, 5-10 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, CN, halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkyl-OH, C1-C4 alkyl-CN, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, NO2, oxo, ORa, SRa, SF5, NHORa, C (O) Rb, C (O) NRcRd, C (O) ORa, OC (O) Rb, OC (O) NRcRd, NRcRd, NRcC (O) Rb,  NRcC (O) NRcRd, NRcC (O) ORa, B (ORc) (ORd) , C (=NRc) NRcRd, NRdC (=NRc) NRcRd, NRdC (=NRc) Rb, P (O) ReRf, P (O) OReORf, OP (O) OReORf, S (O) Rb, S (O) NRcRd, S (O) 2Rb, NRcS (O) 2Rb, S (O) 2NRcRd, NRcS (O) 2NRcRd, or NRcS (O) (=NRb) Rb;
    each RB is independently selected from H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, OH, CN, halo, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, SF5, C (O) Rb, OC (O) NRcRd, NRcRd, NRcC (O) Rb, NRcC (O) NRcRd, NRcC (O) ORa, S (O) Rb, S (O) NRcRd, S (O) 2Rb, NRcS (O) 2Rb, S (O) 2NRcRd, NRcS (O) 2NRcRd, or B (ORc) (ORd) ;
    RC and RD are each independently selected from H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, OH, CN, halo, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, SF5, OC (O) NRcRd, NRcRd, NRcC (O) Rb, S (O) NRcRd, S (O) 2Rb, NRcS (O) 2Rb, S (O) 2NRcRd, NRcS (O) 2NRcRd or B (ORc) (ORd) ; or
    RC and RD together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, OH, oxo, CN, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, or OC1-C4 haloalkyl;
    Ra and Ra1 are each independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C3-C7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl, wherein the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C3-C7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halo, OH, CN, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, C1-C4 alkyl, OC1-C4 alkyl, C1-C4 haloalkyl, or OC1-C4 haloalkyl;
    Rb and Rb1 are each independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C3-C7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl; wherein, the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C3-C7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently  selected from D, OH, CN, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C6-C10 aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl;
    Rc and Rd are each independently selected from H, D, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkyl, arylheterocycloalkyl, arylheteroaryl, biaryl, heteroarylcycloalkyl, heteroarylheterocycloalkyl, heteroarylaryl, or biheteroaryl; wherein, the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkyl, arylheterocycloalkyl, arylheteroaryl, biaryl, heteroarylcycloalkyl, heteroarylheterocycloalkyl, heteroarylaryl, or biheteroaryl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, OH, CN, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 hydroxyalkyl, C1-C4 cyanoalkyl, C6-C10 aryl, 5-10 membered heteroaryl, C (O) ORa1, C (O) Rb1, S (O) 2Rb1, C1-C4 alkyl-O-C1-C4 alkyl or C1-C4 alkyl-O-C1-C4 alkyl-O-; or
    Rc and Rd together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, OH, CN, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 hydroxyalkyl, C1-C4 cyanoalkyl, C6-C10 aryl, 5-10 membered heteroaryl, C1-C4 alkoxy-C1-C4 alkyl or C1-C4 alkoxy-C1-C4 alkoxy;
    RE and Re are each independently selected from H, D, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, (C1-C4 alkoxy) -C1-C4 alkyl, C2-C4 alkynyl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl-C1-C4 alkyl, C3-C10 cycloalkyl-C1-C4 alkyl, 5-10 membered heteroaryl-C1-C4 alkyl, or 4-10 membered heterocycloalkyl-C1-C4 alkyl;
    RF and Rf are each independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, or 4-10 membered heterocycloalkyl;
    RG, RH and RI are each independently selected from C1-C4 alkyl or phenyl.
  2. The compound of claim 1, wherein, X1 is CR1, X2 is CR2, and X3 is CR3; X1 is N, X2 is CR2, and X3 is CR3; X1 is CR1, X2 is N, and X3 is CR3; or X1 is CR1, X2 is CR2, and X3 is N.
  3. The compound of claim 1 or 2, wherein, the compounds of Formula (I) are represented by compounds of Formula (IIa) , (IIb) , (IIc) or (IId) :

    or a pharmaceutically acceptable salt, solvate, tautomeric, stereoisomer, atropisomer, isotopic variant, prodrug, N-oxide, or deuterated compound thereof.
  4. The compound of claim 3, wherein, the compounds of Formula (I) are represented by compounds of Formula (IIa) or (IIb) :
    or a pharmaceutically acceptable salt, solvate, tautomeric, stereoisomer, atropisomer, isotopic variant, prodrug, N-oxide, or deuterated compound thereof.
  5. The compound of anyone of claim 1-4, wherein, Cy is phenyl or 6-membered heteroaryl.
  6. The compound of claim 5, wherein, Cy is phenyl or pyridin-4-yl.
  7. The compound of anyone of claim 1-6, wherein, the moietyhas the structure ofwherein, Y1 is N or CR4; Y2 is N or CR4.
  8. The compound of claim 7, wherein, Y1 is CR4, and Y2 is CR4; Y1 is CR4, and Y2 is N; or Y1 is N, and Y2 is CR4.
  9. The compound of claim 8, wherein, Y1 is CH, and Y2 is CH.
  10. The compound of anyone of claim 1-9, wherein, the moietyhas the structure ofwherein each R2 is as defined herein.
  11. The compound of claim 10, wherein, the moietyhas the structure of 
  12. The compound of anyone of claim 1-11, wherein, the compounds of Formula (I) are represented by compounds of Formula (IIIa) , or (IIIb) :
    or a pharmaceutically acceptable salt, solvate, tautomeric, stereoisomer, atropisomer, isotopic variant, prodrug, N-oxide, or deuterated compound thereof.
  13. The compound of anyone of claim 1-12, wherein, R is OH.
  14. The compound of anyone of claim 1-12, wherein, R is
  15. The compound of anyone of claim 1-14, wherein, the compounds of Formula (I) are represented by compounds of Formula (IVa) or (IVb) :
    or a pharmaceutically acceptable salt, solvate, tautomeric, stereoisomer, atropisomer, isotopic variant, prodrug, N-oxide, or deuterated compound thereof.
  16. The compound of claim 15, wherein, the compounds of Formula (I) are represented by compounds of Formula (Va) , or (Vb) :
    or a pharmaceutically acceptable salt, solvate, tautomeric, stereoisomer, atropisomer, isotopic variant, prodrug, N-oxide, or deuterated compound thereof.
  17. The compound of claim 16, wherein, the compounds of Formula (I) are represented by compounds of Formula (VIa) , or (VIb) :
    or a pharmaceutically acceptable salt, solvate, tautomeric, stereoisomer, atropisomer, isotopic variant, prodrug, N-oxide, or deuterated compound thereof.
  18. The compound of claim 17, wherein, the compounds of Formula (I) are represented by compounds of Formula (VIIa) , or (VIIb) :
    or a pharmaceutically acceptable salt, solvate, tautomeric, stereoisomer, atropisomer, isotopic variant, prodrug, N-oxide, or deuterated compound thereof.
  19. The compound of claim 17, wherein, the compounds of Formula (I) are represented by compounds of Formula (VIIIa) , or (VIIIb) :
    or a pharmaceutically acceptable salt, solvate, tautomeric, stereoisomer, atropisomer, isotopic variant, prodrug, N-oxide, or deuterated compound thereof.
  20. The compound of anyone of claim 1-19, wherein, R1 and R2 are selected from H, D, CN, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, ORA, SRA, NRCRD; wherein, the C1-C6 alkyl or C3-C6 cycloalkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halogen, CN, OH, NH2, oxo, C1-C6 alkyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, -OC1-C6 haloalkyl.
  21. The compound of claim 20, wherein, R1 and R2 are selected from H, D, CN, halogen, OH, NH2, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, CH2F, CHF2, CF3, CH2CH2F, CH2CHF2, CH2CF3, OCH3, OCH2CH3, OCH2CH2CH3, OCH (CH3) 2, OCH2F, OCHF2, OCF3, 
  22. The compound of claim 21, wherein, R1 is H.
  23. The compound of claim 21, wherein, R2 is CH3.
  24. The compound of any one of claim 1-23, wherein, R3 is selected from H, D, CN, SF5, halogen, ORA, or SRA, C1-C4 alkyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halogen, CN, OH, -O-C1-C4 alkyl, -OC1-C4 haloalkyl.
  25. The compound of claim 24, wherein, R3 is selected from H, D, CN, SF5, halogen, OH, OCH3, OCH2CH3, OCF3, methyl, ethyl, CH2F, CHF2, CF3, CH2CH2F, CH2CHF2, CH2CF3.
  26. The compound of claim 25, wherein, R3 is H.
  27. The compound of any one of claim 1-26, wherein, each R4 is independently (i) H, D, halo, or –ORA; or (ii) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl; each is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R4A.
  28. The compound of claim 27, wherein, each R4 is independently H, –F, –Cl, –CH3, –CF3, or –OCH3.
  29. The compound of claim 27 or 28, wherein, one of the R4 groups is –F.
  30. The compound of any one of claim 27-29, wherein, one of the R4 groups is H, F, –Cl, –CH3, –CF3 –OCH3, or ethynyl.
  31. The compound of any one of claim 27-30, wherein, one of the R4 groups is –OCH3.
  32. The compound of any one of claim 27-31, wherein, one of the R4 groups is F, –Cl, –CH3, –CF3 –OCH3, or ethynyl; one of the R4 groups is –OCH3; and remaining R4 groups are H.
  33. The compound of any one of claim 1-32, wherein, R5 is selected from H, D, halo, CN, NO2, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 haloalkyl, C1-C8 alkyl-O-C1-C8 alkyl, OC1-C8 haloalkyl, C1-C8 alkyl-OH, C1-C8 alkyl-CN.
  34. The compound of claim 33, wherein, R5 is H.
  35. The compound of any one of claim 1-34, wherein, R6 is selected from H, D, halo, CN, NO2, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 haloalkyl, C1-C8 alkyl-O-C1-C8 alkyl, C1-C8 alkyl-OH, C1-C8 alkyl-CN.
  36. The compound of claim 35, wherein, R6 is H.
  37. The compound of any one of claim 1-36, wherein, R7 is H, D, CN, halo, Si (R8) 3, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, each is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from D, -halo, -CN, -NO2, SF5, -N3, oxo, -NRCRD, -ORA, -SRA, SiRGRHRI, -C (O) RB, -C (O) ORA, -OC (O) RB, -C (O) NRCRD, -OC (O) NRCRD, -NRCC (O) RB, -NRCC (O) NRCRD, -NRCC (O) ORA, -S (O) RB, -S (O) 2RB, -S (O) NRCRD, -NRCS (O) 2RD, -S (O) 2NRCRD, -NRCS (O) 2NRCRD, -NRCS (O) (=NRB) RB.
  38. The compound of claim 37, wherein, R7 is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, CH2C (CH3) 3, CH2F, CHF2, CF3, CH2CH2F, CH2CHF2, CH2CF3, CH2OH, CH2CH2OH, CH (CH3) OH, CH2CH (CH3) OH, CH2OCH3, CH2CH2OCH3, CH2OCH2CH3, CH2CH2OCH2CH3, CH2CH2OCH2CH2OCH3, CH2CH2OCH2CH2OCH2CH3, CH2CH2OCH2CH2OCH2CH2OH, CH2CH2OCH2CH2OCH2CH2OCH3, CH2CH2OCH2CH2OCH2CH2OCH2CH3, CH2CH2OCH2CH2SCH3, CH2CH2OCH2CH2SCH2CH3, CH (CH3) OCH3, CH2CH (CH3) OCH3, CH (CH3) CN, C (CH3) 2CN, CH2C (CH3) 2CN, CH (CH3) F, C (CH3) 2F, CH2C (CH3) 2F, CH (CH3) OH, C (CH3) 2OH, CH2C (CH3) 2OH, CH (CH3) OCH3, C (CH3) 2OCH3, CH2C (CH3) OCH3, CH (CH3) CH2OH, C (CH3) 2CH2OH, CH2C (CH3) 2CH2OH, CH2SCH3, CH2CH2SCH3, CH2S (O) CH3, CH2CH2S (O) CH3, CH2S (O) 2CH3, CH2CH2S (O) 2CH3, CH2C (O) CH3, CH2CH2C (O) CH3, CH2N3, CH2CH2N3, Si (CH3) 3, CH2Si (CH3) 3, CH2NHCH3, CH2CH2NHCH3, CH2N (CH3) 2, CH2CH2N (CH3) 2, CH2NHC (O) CH3, CH2CH2NHC (O) CH3, CH2N (CH3) C (O) CH3, CH2CH2N (CH3) C (O) CH3, CH2NHS (O) CH3, CH2CH2NHS (O) CH3, CH2N (CH3) S (O) CH3, CH2CH2N (CH3) S (O) CH3, CH2NHS (O) 2CH3, CH2CH2NHS (O) 2CH3, CH2N (CH3) S (O) 2CH3, CH2CH2N (CH3) S (O) 2CH3, -CH=CH2, -CH=CHCH3, -CH=CHCH2CH3, -C (=CH2) CH3, -C (=CH2) CH2CH3, -C (=CH2) CH2OCH3, -C (=CH2) CH2OCH3, -C (=CH2) CH2SCH3, -C (=CH2) CH2SCH3, -CH=CF2, -CH=CFCH3, -CH=CFCH2CH3, -C (=CF2) CH3, -C (=CF2) CH2CH3, -C (=CF2) CH2OCH3, -C (=CF2) CH2OCH3, -C (=CF2) CH2SCH3, or -C (=CF2) CH2SCH3, 
  39. The compound of any one of claim 1-36, wherein, R7 is adamantanyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from D, halo, CN, NO2, N3, SF5, oxo, NRCRD, ORA, SRA, SiRGRHRI, B (ORC) (ORD) , C (O) RB, -C (O) ORA, -OC (O) RB, C (O) NRCRD, OC (O) NRCRD, NRCC (O) RB, NRCC (O) NRCRD, NRCC (O) ORA, S (O) RB, S (O) 2RB, S (O) NRCRD, NRCS (O) RD, NRCS (O) 2RD, S (O) 2NRCRD, NRCS (O) 2NRCRD, NRCS (O) (=NRB) RB.
  40. The compound of any one of claim 1-39, wherein, the moietyhas the structure of 
  41. The compound of any one of claim 1-40, wherein, the compound is:


    or a pharmaceutically acceptable salt thereof.
  42. A pharmaceutical composition comprising a compound of anyone of claim 1-41, or  pharmaceutically acceptable salt, solvate, tautomeric, stereoisomer, atropisomer, isotopic variant, prodrug, N-oxide, or deuterated compound thereof and at least one pharmaceutically acceptable excipient.
  43. 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 anyone of claim 1-41, or a pharmaceutical composition of claim 42.
  44. 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 anyone of claim 1-41, or a pharmaceutical composition of claim 42.
  45. 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 anyone of claim 1-41, or a pharmaceutical composition of claim 42.
  46. 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 anyone of claim 1-41, or a pharmaceutical composition of claim 42.
  47. 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 anyone of claim 1-41, or a pharmaceutical composition of claim 42.
  48. 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 anyone of claim 1-41, or a pharmaceutical composition of claim 42.
  49. Use of the compound of anyone of claim 1-41 or the pharmaceutical composition of claim 42 in the manufacture of a medicament for treating a disease characterized by overexpression of PolQ in a patient.
  50. Use of the compound of anyone of claim 1-41 or the pharmaceutical composition of claim 42 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.
  51. Use of the compound of anyone of claim 1-41 or the pharmaceutical composition of claim 42 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.
  52. Use of the compound of anyone of claim 1-41 or the pharmaceutical composition of claim 42 in the manufacture of a medicament for treating a cancer in a patient that is lack of 53BP1/Shieldin complex.
  53. Use of the compound of anyone of claim 1-41 or the pharmaceutical composition of claim 42 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.
  54. Use of the compound of anyone of claim 1-41 or the pharmaceutical composition of claim 42 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.
PCT/CN2023/130324 2022-11-10 2023-11-08 Thiadiazolyl derivatives, compositions and uses thereof WO2024099336A1 (en)

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Application Number Priority Date Filing Date Title
CNPCT/CN2022/131231 2022-11-10
CN2022131231 2022-11-10
CNPCT/CN2023/079231 2023-03-02
CN2023079231 2023-03-02
CNPCT/CN2023/082593 2023-03-20
CN2023082593 2023-03-20
CNPCT/CN2023/088519 2023-04-14
CN2023088519 2023-04-14

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020243459A1 (en) * 2019-05-31 2020-12-03 Ideaya Biosciences, Inc. Thiadiazolyl derivatives as dna polymerase theta inhibitors
WO2022118210A1 (en) * 2020-12-02 2022-06-09 Ideaya Biosciences, Inc. Substituted thiadiazolyl derivatives as dna polymerase theta inhibitors
WO2022259204A1 (en) * 2021-06-11 2022-12-15 Ideaya Biosciences, Inc. O-linked thiadiazolyl compounds as dna polymerase theta inhibitors
WO2023134708A1 (en) * 2022-01-12 2023-07-20 Beigene , Ltd. Thiazolopyridyl amide derivatives as dna polymerase theta inhibitors
WO2023202623A1 (en) * 2022-04-20 2023-10-26 南京再明医药有限公司 Polq inhibitor compound and use thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020243459A1 (en) * 2019-05-31 2020-12-03 Ideaya Biosciences, Inc. Thiadiazolyl derivatives as dna polymerase theta inhibitors
WO2022118210A1 (en) * 2020-12-02 2022-06-09 Ideaya Biosciences, Inc. Substituted thiadiazolyl derivatives as dna polymerase theta inhibitors
WO2022259204A1 (en) * 2021-06-11 2022-12-15 Ideaya Biosciences, Inc. O-linked thiadiazolyl compounds as dna polymerase theta inhibitors
WO2023134708A1 (en) * 2022-01-12 2023-07-20 Beigene , Ltd. Thiazolopyridyl amide derivatives as dna polymerase theta inhibitors
WO2023202623A1 (en) * 2022-04-20 2023-10-26 南京再明医药有限公司 Polq inhibitor compound and use thereof

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