WO2023177356A2 - Compounds and method for pkmyt1 inhibition - Google Patents

Compounds and method for pkmyt1 inhibition Download PDF

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WO2023177356A2
WO2023177356A2 PCT/SG2023/050174 SG2023050174W WO2023177356A2 WO 2023177356 A2 WO2023177356 A2 WO 2023177356A2 SG 2023050174 W SG2023050174 W SG 2023050174W WO 2023177356 A2 WO2023177356 A2 WO 2023177356A2
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alkyl
cycloalkyl
compound
pharmaceutically acceptable
acceptable salt
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PCT/SG2023/050174
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French (fr)
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WO2023177356A3 (en
Inventor
Toni Kline
Christine Taylor Brew
Stephen Harrison
Dimitri KHRAKOVSKY
Ojas A. Namjoshi
George L. Trainor
Eric Gordon
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Engine Biosciences Pte. Ltd.
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Publication of WO2023177356A2 publication Critical patent/WO2023177356A2/en
Publication of WO2023177356A3 publication Critical patent/WO2023177356A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the disclosure relates to compounds which function as inhibitors of protein kinase, membrane associated tyrosine/threonine 1 (PKMYT1).
  • PLMYT1 membrane associated tyrosine/threonine 1
  • the WEE1 kinase family consists of three serine/threonine kinases sharing conserved molecular structures and encoded by the following genes: WEE1 (WEE1 G2 Checkpoint Kinase), PKMYT1 (membrane -associated tyrosine- and threonine-specific cdc2 -inhibitory kinase), and WEE1B (WEE2 oocyte meiosis inhibiting kinase).
  • WEE1 and PKMYT1 play a key role in cell cycle regulation and, in particular, they are involved in the entry into mitosis. Their role as regulators is crucial during normal cell cycle progression and in response to DNA damages, as part of the DNA damage response (DDR) pathways.
  • DDR DNA damage response
  • die present disclosure provides tor compounds that function as inhibitors of protein kinase, membrane associated tyrosine/threonine 1 (PKMYT1).
  • PLMYT1 membrane associated tyrosine/threonine 1
  • A, B, and C are each independently N or CR 4 ;
  • D is N, CR 4 , or CR 5 ;
  • E is N, CR 4 , or CR 5 ; wherein one of D or E is CR 5 ;
  • R 1 is hydrogen, Ci-Ce alkyl, Ci-Ce heteroalkyl, G-C'e cycloalkyl, or 4 to 6 membered heterocycloalkyl;
  • W is O or NH; or W and R 1 combine with the atoms to which they are attached to form a 5 to 6-membered heterocycloalkyl or 5 to 6-membered heteroaryl;
  • L is absent or Z-L 1 ,
  • Z is -O- or -NR 3B -; wherein R 3B is hydrogen or Ci-C 3 alkyl;
  • L 1 is absent or Ci-Cg alkylene which is optionally substituted with one, two, or three R 8 ;
  • Q is -OR 11 or -N(R n ) 2 ; ach R 11 is independently hydrogen, Ci-Cg alkyl, Ci-Cg alkylamino, Ci-Cg haloalkyl, or Ci-Cg hydroxyalkyl, each of which is optionally substituted with one, two, or three halogen or Ci-C 3 hydroxyalkyl; m is 0, 1, 2, 3, or 4;
  • R 10 is hydrogen, halogen, -CN, -OH, -NH2, Ci-Cg alkyl, or Ci-Cg haloalkyl; each R a is independently Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, Ci-Cg heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Ci-Cg alkyl(aryl), -Ci-Cg alkyl(heteroaryl), -Ci-Cg alkyl(cycloalkyl), or -Ci-Cg alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-Cg alkyl, or
  • R 3A is hydrogen; and R 1 is CH3.
  • Z is absent; and R 2 is phenyl or 6 membered heteroaryl.
  • R 2 is phenyl, pyridinyl, pyrazinyl, or pyrimidinyl.
  • the compound of Formula (I) has the structure of Formula (II), or a pharmaceutically acceptable salt thereof:
  • X 1 is CH or N
  • R 7A and R 7B are each independently selected from hydrogen, halogen, -CN, -OH, -OR a , -SH, -SR a , - N(R b )2, Ci-Cg alkyl, Ci-Cg aminoalkyl, Ci-Cg haloalkyl, or Ci-Cg hydroxyalkyl.
  • D is CR 5 and E is N or CR 4 .
  • D is N or CR 4 ; and E is CR 5 .
  • C is CH.
  • R 5 is ’
  • X 1 is N or CH
  • W is O
  • R 7A and R 7B are each independently selected from hydrogen, halogen, -CN, -OH, -OR a , -SH, -SR a , - N(R b )2, Ci-Cg alkyl, Ci-Cg aminoalkyl, Ci-Cg haloalkyl, or Ci-Cg hydroxyalkyl;
  • L is absent or Z-L 1 , wherein
  • Z is -O- or -NR 3B -; wherein R 3B is hydrogen or Ci-C 3 alkyl;
  • ring A is a Cg-Cio cycloalkyl or 5 to 10 membered heterocycloalkyl. In some embodiments of Formula (III), ring A is a 5 to 10 membered heterocycloalkyl, wherein the heterocycloalkyl is a monocyclic, bicyclic, or spirocyclic heterocycloalkyl. In some embodiments of Formula (III), ring A is piperidine, piperazine, or morpholine.
  • W is O
  • X 1 is CH orN
  • X 2 is CH orN
  • X 3 and X 5 are each independently CR 6 R 6 , O or NR X ;
  • L is absent or Z-L 1 , wherein
  • Z is -O- or -NR 3B -; wherein R 3B is hydrogen or C1-C3 alkyl;
  • L 1 is absent or C1-C3 alkylene which is optionally substituted with one, two, or three R 8 ; each R 8 is independently halogen, -OH, oxo, Ci-Cg alkyl, Ci-Cg haloalky 1, Ci-Cghydroxyalkyl, or C3- Cg cycloalkyl; each R a is independently Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, Ci-Cg heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Ci-Cg alkyl(aryl), -Ci-Cg alkyl(heteroaryl), -Ci-Cg alkyl(cycloalkyl), or -Ci-Cg alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclo
  • X 2 is CH; X 3 and X 5 are each independently CR 6 R 6 , O, or NR X ; and X 4 is CR 6 R 6 .
  • X 3 and X 5 are each independently O or NR X .
  • X 3 and X 5 are each independently CR 6 R 6 .
  • the compound of Formula (IV) has the structure of Formula (IVa), or a pharmaceutically acceptable salt thereof:
  • each R 6 is independently halogen, -CN, -OH, -OR a , - N(R b )2, oxo, Ci-Cg alkyl, Ci-Cg haloalkyl, or Ci-Cg hydroxyalkyl.
  • two R 6 together with the intervening atoms to which they are attached form a 5 to 8 membered heteroaryl, Cs-Cx cycloalkyl, or 5 to 8 membered heterocycloalkyl.
  • m is 1 or 2. In some embodiments of Formula (IV) or (IVa), m is 0.
  • ring A is 5 to 10-membered heteroaryl. In some embodiments of Formula (III), ring A is a 5 or 6 membered heteroaryl having one, two, or three heteroatoms selected from N, O, and S. In some embodiments of Formula (III), ring A is triazinyl, pyrrolyl, furanyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, or tetrazolyl. In some embodiments of Formula (III), ring A is pyrrolyl, imidazolyl, or pyrazolyl.
  • provided herein is a compound having the structure of Formula (V), or a pharmaceutically acceptable salt thereof:
  • X 1 is CH or N
  • Y 1 is C or N and Y 2 is CH or N, provided that at least one of Y 1 or Y 2 is N;
  • W is O
  • R 6A is hydrogen, halogen, Ci-Cg alkyl, Ci-Cg haloalkyl, or Ci-Cg hydroxy alkyl;
  • R 9 is hydrogen, Ci-Cg alkyl, Ci-Cg haloalkyl, Ci-Cghydroxyalkyl, -Ci-C 3 alkylene(cycloalkyl), -Ci-C 3 alkylene(heterocycloalkyl), C 3 -Cg cycloalkyl, or 4 to 6 membered heterocycloalkyl; or R 6A and R 9 together with the intervening atoms to which they are attached form a 6 to 8 membered heteroaryl or 6 to 8 membered heterocycloalkyl;
  • R 7A and R 7B are each independently selected from hydrogen, halogen, -CN, -OH, -OR a , -SH, -SR a , - N(R b )2, Ci-Cg alkyl, Ci-Cg aminoalkyl, Ci-Cg haloalkyl, or Ci-Cg hydroxyalkyl;
  • L is absent or Z-L 1 , wherein
  • Z is -O- or -NR 3B -; wherein R 3B is hydrogen or Ci-C 3 alkyl;
  • L 1 is absent or Ci-C 3 alkylene which is optionally substituted with one, two, or three R 8 ; each R 8 is independently halogen, -OH, oxo, Ci-Cg alkyl, Ci-Cg haloalkyl, Ci-Cghydroxyalkyl, or C 3 - Cg cycloalkyl; each R a is independently Ci-Cg alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Cg heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Ci-Cg alkyl(aryl), -Ci-Cg alkyl(heteroaryl), -Ci-Cg alkyl(cycloalkyl), or -Ci-Cg alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycl
  • Y 1 is N and Y 2 is N.
  • R 6A is hydrogen; and R 9 is Ci-Cg alkyl, Ci-Cg hydroxyalkyl, -C1-C3 alkylene(cycloalkyl), -C1-C3 alkylene(heterocycloalkyl), C3-Cg cycloalkyl, or 4 to 6 membered heterocycloalkyl.
  • R 9 is methyl, ethyl, -CH2-(C3-Cgcycloalkyl), -CH2-(4 to 6 membered heterocycloalkyl), C3-Cg cycloalkyl, or 4 to 6 membered heterocycloalkyl.
  • R 6A and R 9 together with the intervening atoms form a 6 to 8 membered heteroaryl or 6 to 8 membered heterocycloalkyl.
  • the compound of Formula (V) has the structure of Formula (Va) or Formula (Vb), or a pharmaceutically acceptable salt thereof:
  • X 1 is CH or N; W is O;
  • R 7A and R 7B are each independently selected from hydrogen, halogen, -CN, -OH, -OR a , -SH, -SR a , - N(R b )2, Ci-Cg alkyl, Ci-Cg aminoalkyl, Ci-Cg haloalkyl, or Ci-Cg hydroxyalkyl;
  • Z is -O- or -NR 3B -; wherein R 3B is hydrogen or Ci-C 3 alkyl;
  • L 2 is Ci-Cg alkylene which is optionally substituted with one, two, or three R 8 ; each R 8 is independently halogen, -OH, oxo, Ci-Cg alkyl, Ci-Cg haloalkyl, Ci-Cghydroxyalkyl, or C 3 -Cg cycloalkyl;
  • each R 11 is independently hydrogen, Ci-Cg alkyl, Ci-Cg alkylamino, Ci-Cg haloalkyl, or Ci-Cg hydroxyalkyl, each of which is optionally substituted with one, two, or three halogen or Ci-C 3 hydroxyalkyl; each R a is independently Ci-Cg alkyl, C -Cg alkenyl, CS-Cg alkynyl, Ci-Cg heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Ci-Cg alkyl(aryl), -Ci-Cg alkyl(heteroaryl), -Ci-Cg alkyl(cycloalkyl), or -Ci-Cg alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, heteroalkyl, cycl
  • Q is -OR 11 . In some embodiments of Formula (VI), Q is -N(R n ) 2 .
  • R 7A and R 7B are each independently halogen. In some embodiments of Formula (II), (III), (IV), (IVa), (V), (Va), (Vb), or (VI), R 7A and R 7B are each independently chloro or fluoro. In some embodiments of Formula (II), (III), (IV), (IVa), (V), (Va), (Vb), or (VI), X 1 is N. In some embodiments of Formula (II), (III), (IV), (IVa), (V), (Va), (Vb), or (VI), X 1 is CH.
  • A is CH and B is CH. In some embodiments of Formula (I), (II), (III), (IV), (IVa), (V), (Va), (Vb), or (VI), A is N and B is CH. In some embodiment of Formula (I), (II), (III), (IV), (IVa), (V), (Va), (Vb), or (VI), A is CH and B is N. In some embodiments of Formula (I), (II), (III), (IV), (IVa), (V), (Va), (Vb), or (VI), A is CH and B is N. In some embodiments of Formula (I), (II), (III), (IV), (IVa), (V), (Va), (Vb), or (VI), A is N and B is N. 882S] In another aspects, the disclosure provides a pharmaceutical composition comprising a compound described herein and a pharmaceutically acceptable excipient.
  • the disclosure provides for a method of treating a disease or condition associated with inhibiting protein kinase, membrane associated tyrosine/threonine 1 (PKMYT1) in a patient in need thereof, comprising administering to the patient a compound of compound disclosed herein or a pharmaceutically acceptable salt thereof.
  • the disease or condition is a cancer.
  • the disclosure provides a method of treating a cancer in a patient in need thereof, comprising administering to the patient a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.
  • the cancer is leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia, acute lymphoblastic leukemia (ALL), non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), or multiple myeloma (MM).
  • the cancer is a solid cancer.
  • the cancer is a skin cancer, ocular cancer, gastrointestinal cancer, thyroid cancer, breast cancer, ovarian cancer, central nervous system cancer, laryngeal cancer, cervical cancer, lymphatic system cancer, genitourinary tract cancer, bone cancer, biliary tract cancer, endometrial cancer, liver cancer, lung cancer, prostate cancer, or colon cancer.
  • Carboxyl refers to -C00H.
  • Alkyl refers to a straight-chain, or branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2 -methyl- 1 -propyl, 2 -methyl -2 -propyl, 2- methyl-1 -butyl, 3 -methyl- 1 -butyl, 2-methyl-3 -butyl, 2,2-dimethyl-l -propyl, 2 -methyl- 1 -pentyl, 3-methyl- 1 -pentyl, 4-methyl-l -pentyl, 2 -methyl -2 -pentyl, 3 -methyl -2 -pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l- butyl, 3, 3 -dimethyl- 1 -butyl, 2 -ethyl- 1
  • a numerical range such as “Ci-Ce alkyl” or “Ci-galkyl”, means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated.
  • the alkyl is a Ci-ioalkyl.
  • the alkyl is a Ci-galkyl.
  • the alkyl is a Ci-salkyl.
  • the alkyl is a Ci-4alkyl.
  • the alkyl is a Ci-3alkyl.
  • an alkyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkyl is optionally substituted with halogen, -CN, -OH, or -OMe.
  • the alkyl is optionally substituted with halogen.
  • Alkenyl refers to a straight-chain, or branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms.
  • C2-C6 alkenyl or “C2-6alkenyl”
  • alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated.
  • an alkenyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen.
  • Alkynyl refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and the like.
  • a numerical range such as “C2-C6 alkynyl” or “C2-6alkynyl”, means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated.
  • an alkynyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen.
  • f 042 j “Alkylene” refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe.
  • the alkoxy is optionally substituted with halogen.
  • Aryl refers to a radical derived from an aromatic monocyclic or aromatic multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom.
  • the aromatic monocyclic or aromatic multicyclic hydrocarbon ring system can contain only hydrogen and carbon and from five to eighteen carbon atoms, where at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) K-cIcctron system in accordance with the Htickel theory.
  • the ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene.
  • the aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems.
  • the aryl is a 6- to 10-membered aryl.
  • the aryl is a 6-membered aryl (phenyl).
  • Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene.
  • an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.
  • Carbocycle refers to a saturated, unsaturated, or aromatic rings in which each atom of the ring is carbon.
  • Carbocycle may include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings.
  • Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings.
  • An aromatic ring e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene.
  • carbocyclic Any combination of saturated, unsaturated, and aromatic bicyclic rings, as valence permits, are included in the definition of carbocyclic.
  • exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. Unless stated otherwise specifically in the specification, a carbocycle may be optionally substituted.
  • Cycloalkyl refers to a partially or fully saturated, monocyclic, or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom), spiro, or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated.
  • Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (e.g., C3-C15 fully saturated cycloalkyl or C3-C15 cycloalkenyl), from three to ten carbon atoms (e.g., C3-C10 fully saturated cycloalkyl or C3-C10 cycloalkenyl), from three to eight carbon atoms (e.g., C3-C8 fully saturated cycloalkyl or C3-C8 cycloalkenyl), from three to six carbon atoms (e.g., C3-C6 fully saturated cycloalkyl or C3-C6 cycloalkenyl), from three to five carbon atoms (e.g., C3-C5 fully saturated cycloalkyl or C3-C5 cycloalkenyl), or three to four carbon atoms (e.g., C3-C4 fully saturated cyclo
  • the cycloalkyl is a 3- to 10-membered fully saturated cycloalkyl or a 3- to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3- to 6-membered fully saturated cycloalkyl or a 3- to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5- to 6-membered fully saturated cycloalkyl or a 5 - to 6-membered cycloalkenyl.
  • Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic cycloalkyls include, for example, adamantyl, norbomyl, decalinyl, bicyclo [3.3.0] octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo [2.
  • Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen.
  • Cycloalkenyl refers to an unsaturated non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, preferably having from three to twelve carbon atoms and comprising at least one double bond. In certain embodiments, a cycloalkenyl comprises three to ten carbon atoms.
  • a cycloalkenyl comprises five to seven carbon atoms.
  • the cycloalkenyl may be attached to the rest of the molecule by a single bond.
  • monocyclic cycloalkenyls includes, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • Halo or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.
  • haloalkyl or “haloalkane” refers to an alkyl radical, as defined above, that is substituted by one or more halogen radicals, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, l-fluoromethyl-2-fluoroethyl, and the like.
  • the alkyl part of the fluoroalkyl radical is optionally further substituted.
  • halogen substituted alkanes include halomethane (e.g., chloromethane, bromomethane, fluoromethane, iodomethane), di-and trihalomethane (e.g., trichloromethane, tribromomethane, trifluoromethane, triiodomethane), 1-haloethane, 2-haloethane, 1,2-dihaloethane, 1-halopropane, 2-halopropane, 3- halopropane, 1,2-dihalopropane, 1,3-dihalopropane, 2,3-dihalopropane, 1,2,3-trihalopropane, and any other suitable combinations of alkanes (or substituted alkanes) and halogens (e.g., Cl, Br, F, I, etc.).
  • each halogen may be any other suitable combinations of alkanes (or substituted alkanes) and halogens (e.
  • Fluoroalkyl refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, l-fluoromethyl-2-fluoroethyl, and the like.
  • “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.
  • Aminoalkyl refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.
  • Heteroalkyl refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof.
  • a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • a heteroalkyl is a Ci-Ce heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g.
  • heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • heteroalkyl are, for example, - CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH 3 )OCH 3 , -CH2NHCH3, -CH 2 N(CH3) 2 , - CH2CH2NHCH3, or -CH2CH 2 N(CH3)2.
  • a heteroalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, - OMe, -NH2, or -NO2.
  • a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.
  • Heterocycloalkyl refers to a 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, silicon, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl comprises one to three nitrogens. In some embodiments, the heterocycloalkyl comprises one or two nitrogens.
  • the heterocycloalkyl comprises one nitrogen. In some embodiments, the heterocycloalkyl comprises one nitrogen and one oxygen.
  • the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom), spiro, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized.
  • heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (e.g., C2-C15 fully saturated heterocycloalkyl or C2-C15 heterocycloalkenyl), from two to ten carbon atoms (e.g., C2-C10 fully saturated heterocycloalkyl or C2-C10 heterocycloalkenyl), from two to eight carbon atoms (e.g., C2- Cx fully saturated heterocycloalkyl or C2-C8 heterocycloalkenyl), from two to seven carbon atoms (e.g., C2-C7 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), from two to six carbon atoms (e.g., C2-C6 fully saturated heterocycloalkyl or C2-C6 heterocycloalkenyl), from two to five carbon atoms (e.g., C2-C5 fully saturated heterocycloalkyl or C2-C5 heterocycloal
  • heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyr
  • heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides, and the oligosaccharides.
  • heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring).
  • the heterocycloalkyl is a 3- to 8-membered fully saturated heterocycloalkyl.
  • the heterocycloalkyl is a 3- to 7-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkenyl.
  • the heterocycloalkyl is a 3- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkenyl.
  • a heterocycloalkyl may be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe.
  • the heterocycloalkyl is optionally substituted with halogen.
  • Heteroaryl refers to a 5- to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring.
  • the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.
  • the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen.
  • the heteroaryl comprises one to three nitrogens.
  • the heteroaryl comprises one or two nitrogens.
  • the heteroaryl comprises one nitrogen.
  • the heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized.
  • the heteroaryl is a 5- to 10-membered heteroaryl.
  • the heteroaryl is a 5- to 6-membered heteroaryl.
  • the heteroaryl is a 6-membered heteroaryl.
  • the heteroaryl is a 5 -membered heteroaryl.
  • examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cin
  • a heteroaryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.
  • substituted refers to moieties having substituents replacing a hydrogen on one or more carbons or substitutable heteroatoms, e.g., NH, of the structure.
  • substitution or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • substituted refers to moieties having substituents replacing two hydrogen atoms on the same carbon atom, such as substituting the two hydrogen atoms on a single carbon with an oxo, imino or thioxo group.
  • substituted is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched, and unbranched, carbocyclic, and heterocyclic, aromatic, and non-aromatic substituents of organic compounds.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. f 0 S7 f
  • the term “one or more” when referring to an optional substituent means that the subject group is optionally substituted with one, two, three, or four substituents.
  • the subject group is optionally substituted with one, two, or three substituents. In some embodiments, the subject group is optionally substituted with one or two substituents. In some embodiments, the subject group is optionally substituted with one substituent. In some embodiments, the subject group is optionally substituted with two substituents. fO SSf
  • the term “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
  • “optionally substituted alkyl” means either “alkyl” or “substituted alkyl” as defined above.
  • an optionally substituted group may be un-substituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), mono-substituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH2CHF2, - CH2CF3, -CF2CH3, -CFHCHF2, etc ).
  • salt or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids.
  • Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methane sulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.
  • the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrastemal injection and infusion.
  • 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.
  • phrases “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as com starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydrox
  • an “effective amount” or “therapeutically effective amount” refers to an amount of a compound administered to a mammalian subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.
  • treat may include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically.
  • the present disclosure pro vides for compounds that function as inhibitors of
  • the present disclosure provides for compounds that function as modulators of
  • A, B, and C are each independently N or CR 4 ;
  • D is N, CR 4 , or CR 5 ;
  • E is N, CR 4 , or CR 5 ; wherein one of D or E is CR 5 ;
  • R 1 is hydrogen, Ci-Cg alkyl, Ci-Cg heteroalkyl, C3-C6 cycloalkyl, or 4 to 6 membered heterocycloalkyl;
  • W is O or NH; or W and R 1 combine with the atoms to which they are attached to form a 5 to 6-membered heterocycloalkyl or 5 to 6-membered heteroaryl;
  • L is absent or Z-L 1 , wherein
  • Z is -O- or -NR 3B -; wherein R 3B is hydrogen or C1-C3 alkyl;
  • L 1 is absent or Ci-Cg alkylene which is optionally substituted with one, two, or three R 8 ;
  • Q is -OR 11 or -N(R n ) 2 ; each R 11 is independently hydrogen, Ci-Cg alkyl, Ci-Cg alkylamino, Ci-Cg haloalkyl, or Ci-Cg hydroxyalkyl, each of which is optionally substituted with one, two, or three halogen or C1-C3 hydroxyalkyl; m is 0, 1, 2, 3, or 4;
  • R 10 is hydrogen, halogen, -CN, -OH, -NH2, Ci-Cg alkyl, or Ci-Cg haloalkyl; each R a is independently Ci-Cg alkyl, CS-Cg alkenyl, CS-Cg alkynyl, Ci-Cg heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Ci-Cg alkyl(aryl), -Ci-Cg alkyl(heteroaryl), -Ci-Cg alkyl(cycloalkyl), or -Ci-Cg alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-Cg alkyl
  • a and B are each independently N or CH;
  • D is N, CR 4 , or CR 5 ;
  • E is N, CR 4 , or CR 5 ; wherein one of D or E is CR 5 ;
  • R 1 is hydrogen, methyl, cyclopropyl, cyclopentyl, or 4 membered heterocycloalkyl
  • W is O
  • R 3A is hydrogen
  • L is absent or Z-L 1 , wherein
  • Z is -O- or -NR 3B -; wherein R 3B is hydrogen or methyl;
  • L 1 is absent or Ci-Cg alkylene which is optionally substituted with one, two, or three R 8 ;
  • Q is -OR 11 or -N(R n ) 2 ; each R 11 is independently hydrogen, Ci-Cg alkyl, Ci-Cg alkylamino, Ci-Cg haloalkyl, or Ci-Cg hydroxyalkyl, each of which is optionally substituted with one, two, or three halogen or C1-C3 hydroxyalkyl; m is 0, 1, 2, 3, or 4;
  • R 10 is hydrogen; each R a is independently Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, Ci-Cg heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Ci-Cg alkyl(aryl), -Ci-Cg alkyl(heteroaryl), -Ci-Cg alkyl(cycloalkyl), or -Ci-Cg alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-Cg alkyl, or Ci-Cg haloalkyl; and each R b is independently hydrogen, Ci-Cg alkyl, C2-Cg alkenyl
  • W is O. In some embodiments, W is NH.
  • the compound of Formula (I) has the structure of Formula (la), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
  • W and R 1 combine together with the intervening atoms to which they are attached to form a 5 to 6-membered heterocycle. In some embodiments of Formula (I) or (a), W and R 1 combine together with the intervening atoms to which they are attached to form a 5-membered heterocycle. In some embodiments of Formula (I) or (la), W and R 1 combine together with the intervening atoms to which they are attached form a 6-membered heterocycle. In some embodiments of Formula (I) or (la), W and R 1 combine together with the intervening atoms to which they are attached form a 5 to 6-membered heterocycle comprising one, two, or three N atoms.
  • R 3A is hydrogen. In some embodiments of Formula (I) or (la), R 3A is C1-C3 alkyl. In some embodiments of Formula (I) or (la), R 3A is methyl.
  • R 1 is hydrogen. In some embodiments of Formula (I) or (la), R 1 is Ci-Ce alkyl. In some embodiments, R 1 is Ci-Cg heteroalkyl. In some embodiments of Formula (I) or (la), R 1 is methyl, ethyl, n-propyl, iso-propyl, sec-butyl, iso-butyl, or tert-butyl. In some embodiments of Formula (I) or (la), R 1 is methyl. In some embodiments of Formula (I) or (la), R 1 is C3- Cg cycloalkyl.
  • R 1 is 4 to 6 membered heterocycloalkyl. In some embodiments of Formula (I) or (la), R 1 is cyclopropyl, cyclobutyl, cyclopentyl, or oxetane. In some embodiments of Formula (I) or (la), R 1 is hydrogen, methyl, cyclopropyl, cyclobutyl, cyclopentyl, or 4 membered heterocycloalkyl.
  • R 2 is phenyl, which is optionally substituted with one, two, three, or four R 7 .
  • R 2 is 6 to 10 membered heteroaryl which is optionally substituted with one, two, three, or four R 7 .
  • the heteroaryl is a membered monocyclic heteroaryl or bicyclic having one, two, or three ring heteroatoms independently selected from N, O and S.
  • R 2 is phenyl or 6-memembered heteroaryl each of which are optionally substituted with one, two, three or four R 7 .
  • R 2 is phenyl or 6-memembered heteroaryl each of which are optionally substituted with one, two, or three R 7 .
  • R 2 is phenyl or 6-memembered heteroaryl each of which are optionally substituted with one or two R 7 .
  • R 2 is phenyl, pyridinyl, pyrazinyl, or pyrimidinyl.
  • R 2 is phenyl. In some embodiments of Formula (I) or (la), R 2 is pyridinyl. In some embodiments of Formula (I) or (la), R 2 is pyrazinyl. In some embodiments of Formula (I) or (la), R 2 is pyrimidinyl.
  • each R 7 is independently fluoro, chloro, -OH, -CF 3 , or -CH 3 .
  • each R 7 is independently halogen. In some embodiments of Formula (I) or (la), each R 7 is independently selected from chloro or fluoro. f 076 j In some embodiments of Formula (I) or (la), two R 7 together with the atoms to which they are attached form a 5 to 6-membered heterocycloalkyl. In some embodiments of Formula (I) or (la), two R 7 together with the atoms to which they are attached form a 5 heterocycloalkyl. In some embodiments of Formula (I) or (la), two R 7 together with the atoms to which they are attached form a 6-membered heterocycloalkyl.
  • R 10 is hydrogen, halogen, -CN, -OH, -NH2, Ci-Cg alkyl, or Ci-Cg haloalkyl. In some embodiments of Formula (I) or (la), R 10 is hydrogen, halogen, -CN, Ci- Cg alkyl, or Ci-Cg haloalkyl. In some embodiments of Formula (I) or (la), R 10 is hydrogen or halogen, In some embodiments of Formula (I) or (la), R 10 is Ci-Cg alkyl or Ci-Cg haloalkyl. In some embodiments of Formula (I) or (la), R 10 is hydrogen. W78] In some embodiments, provided herein is a compound has the structure of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
  • A, B, and C are each independently N or CR 4 ;
  • D is N, CR 4 , or CR 5 ;
  • E is N, CR 4 , or CR 5 ; wherein one of D or E is CR 5 ;
  • X 1 is CH or N
  • L is absent or Z-L 1 ,
  • Z is -O- or -NR 3B -; wherein R 3B is hydrogen or C1-C3 alkyl;
  • L 1 is absent or Ci-Cg alkylene which is optionally substituted with one, two, or three R 8 ;
  • Q is -OR 11 or -N(R n ) 2 ; ach R 11 is independently hydrogen, Ci-Cg alkyl, Ci-Cg alkylamino, Ci-Cg haloalkyl, or Ci-Cg hydroxyalkyl, each of which is optionally substituted with one, two, or three halogen or C1-C3 hydroxyalkyl; m is 0, 1, 2, 3, or 4;
  • R 7A and R 7B are each independently selected from hydrogen, halogen, -CN, -OH, -OR a , -N(R b )2, Ci-Cg alkyl, or Ci-Cg haloalkyl; each R a is independently Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, Ci-Cg heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Ci-Cg alkyl(aryl), -Ci-Cg alkyl(heteroaryl), -Ci-Cg alkyl(cycloalkyl), or -Ci-Cg alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one
  • W is O. In some embodiments, W is NH.
  • a compound has the structure of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: Formula (II), wherein,
  • a and B are each independently N or CH;
  • D is N, CR 4 , or CR 5 ;
  • E is N, CR 4 , or CR 5 ; wherein one of D or E is CR 5 ;
  • X 1 is CH or N
  • W is O
  • L is absent or Z-L 1 ,
  • Z is -O- or -NR 3B -; wherein R 3B is hydrogen or Ci-C 3 alkyl;
  • L 1 is absent or Ci-Cg alkylene which is optionally substituted with one, two, or three R 8 ;
  • R 11 is independently hydrogen, Ci-Cg alkyl, Ci-Cg alkylamino, Ci-Cg haloalkyl, or Ci-Cg hydroxyalkyl, each of which is optionally substituted with one, two, or three halogen or Ci-C 3 hydroxyalkyl; m is 0, 1, 2, 3, or 4;
  • R 7A and R 7B are each independently selected from hydrogen or halogen; each R a is independently Ci-Cg alkyl, C 2 -Cg alkenyl, C 2 -Cg alkynyl, Ci-Cg heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Ci-Cg alkyl(aryl), -Ci-Cg alkyl(heteroaryl), -Ci-Cg alkyl(cycloalkyl), or -Ci-Cg alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-Cg alkyl, or Ci-Cg haloalkyl; and each R b is independently hydrogen
  • the compound of Formula (II) has the structure of Formula (Ila), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
  • A is N or CH.
  • L is absent or Z-L 1 , wherein
  • Z is -O- or -NR 3B -; wherein R 3B is hydrogen or C1-C3 alkyl;
  • L is absent or Z-L 1 , wherein
  • Z is -O- or -NR 3B -; wherein R 3B is hydrogen or C1-C3 alkyl;
  • a and B are each independently N or CH;
  • X 1 is N or CH
  • W is O
  • L is absent or Z-L 1 , wherein
  • Z is -O- or -NR 3B -; wherein R 3B is hydrogen or C1-C3 alkyl;
  • L 1 is absent or C1-C3 alkylene which is optionally substituted with one, two, or three R 8 ; each R 8 is independently halogen, -OH, oxo, Ci-Cg alkyl, Ci-Cg haloalky 1, Ci-Cghydroxyalkyl, or C3- Cg cycloalkyl; each R a is independently Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, Ci-Cg heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Ci-Cg alkyl(aryl), -Ci-Cg alkyl(heteroaryl), -Ci-Cg alkyl(cycloalkyl), or -Ci-Cg alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclo
  • ring A is a Cg-Cio cycloalkyl or 5 to 10 membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is monocyclic, bicyclic, polycyclic, or spirocyclic.
  • ring A is a C3-C8 cycloalkyl. In some embodiments of Formula (III), ring A is a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.
  • ring A is a 5 to 10 membered heterocycloalkyl, wherein the heterocycloalkyl is a monocyclic, bicyclic, or spirocyclic heterocycloalkyl.
  • ring A is piperidine, piperazine, or morpholine.
  • ring A is piperidine.
  • ring A is piperazine.
  • ring A is morpholine. f 093 j
  • a compound has the structure of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
  • X 2 is CH orN
  • X 3 and X 5 are each independently CR 6 R 6 , O or NR X ;
  • R 7A and R 7B are each independently selected from hydrogen, halogen, -CN, -OH, -OR a , -SH, -SR a , - N(R b ) 2 , Ci-Cg alkyl, Ci-Cg aminoalkyl, Ci-Cg haloalkyl, or Ci-Cg hydroxyalkyl;
  • L is absent or Z-L 1 , wherein
  • Z is -O- or -NR 3B -; wherein R 3B is hydrogen or Ci-C 3 alkyl;
  • L 1 is absent or Ci-C 3 alkylene which is optionally substituted with one, two, or three R 8 ; each R 8 is independently halogen, -OH, oxo, Ci-Cg alkyl, Ci-Cg haloalkyl, Ci-Cghydroxyalkyl, or C 3 - Cg cycloalkyl; each R a is independently Ci-Cg alkyl, C 2 -Cg alkenyl, C 2 -Cg alkynyl, Ci-Cg heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Ci-Cg alkyl(aryl), -Ci-Cg alkyl(heteroaryl), -Ci-Cg alkyl(cycloalkyl), or -Ci-Cg alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalky
  • X 2 is CH; X 3 and X 5 are each independently CR 6 R 6 , O, or NR x ; and X 4 is CR 6 R 6 .
  • X 3 and X 5 are each independently O or NR X .
  • X 3 and X 5 are each independently CR 6 R 6 .
  • X 3 is CR 6 R 6 .
  • X 3 is O. In some embodiments of Formula (IV), X 3 is NR X . In some embodiments of Formula (IV), X 5 is CR 6 R 6 . In some embodiments of Formula (IV),
  • X 5 is O. In some embodiments of Formula (IV), X 5 is NR X . In some embodiments, the compound of Formula (IV) has the structure of Formula (IVa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
  • Formula (IVa) In some embodiments, provided herein is a compound having the structure of Formula (IVa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: wherein,
  • X 1 is CH or N
  • X 2 is CH or N
  • R 7A and R 7B are each independently selected from hydrogen, halogen, -CN, -OH, -0R a , -SH, -SR a , - N(R b )2, Ci-Cg alkyl, Ci-Cg aminoalkyl, Ci-Cg haloalkyl, or Ci-Cg hydroxyalkyl;
  • L is absent or Z-L 1 , wherein
  • Z is -O- or -NR 3B -; wherein R 3B is hydrogen or C1-C3 alkyl;
  • L 1 is absent or C1-C3 alkylene which is optionally substituted with one, two, or three R 8 ; each R 8 is independently halogen, -OH, oxo, Ci-Cg alkyl, Ci-Cg haloalkyl, Ci-Cghydroxyalkyl, or C3- Cg cycloalkyl; each R a is independently Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, Ci-Cg heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Ci-Cg alkyl(aryl), -Ci-Cg alkyl(heteroaryl), -Ci-Cg alkyl(cycloalkyl), or -Ci-Cg alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycl
  • X 4 is O. In some embodiments of Formula (IV) or (IVa), X 4 is NR X . In some embodiments of Formula (IV) or (IVa), X 4 is CR 6 R 6 .
  • R x is hydrogen, Ci-Cg alkyl, Ci-Cg haloalkyl, or Ci-Cg hydroxyalkyl. In some embodiments of Formula (IV) or (IVa), R x is hydrogen or Ci-Cg alkyl. In some embodiments of Formula (IV) or (IVa), R x is Ci-Cg alkyl. In some embodiments of Formula (IV) or (IVa), R x is methyl or ethyl. In some embodiments of Formula (IV) or (IVa), R x is Ci-Cg hydroxyalkyl.
  • each R Y is independently C1-C3 alkyl. In some embodiments of Formula (IV) or (IVa), each R Y is independently methyl or ethyl. In some embodiments of Formula (IV) or (IVa), each R Y is independently methyl. In some embodiments of Formula (IV) or (IVa), each R Y is independently hydrogen.
  • ring A is 5 to 10-membered heteroaryl. In some embodiments of Formula (III), ring A is a 5 or 6 membered heteroaryl having one, two, or three heteroatoms selected from N, O, and S. In some embodiments of Formula (III), ring A is a 5 or 6 membered heteroaryl having one, two, or three heteroatoms selected from N and O. In some embodiments of Formula (III), ring A is a 5 membered heteroaryl having one, two, or three heteroatoms selected from N and O. In some embodiments of Formula (III), ring A is a 6 membered heteroaryl having one, two, or three heteroatoms selected from N and O.
  • ring A is triazinyl, pyrrolyl, furanyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, or tetrazolyl.
  • ring A is pyrrolyl, imidazolyl, or pyrazolyl.
  • ring A is pyrrolyl.
  • ring A is imidazolyl.
  • ring A is pyrazolyl.
  • ring A is pyridinyl, pyrimidinyl, ortriazinyl. In some embodiments of Formula (III), ring A pyridinyl. In some embodiments of Formula (III), ring A is pyrimidinyl. In some embodiments of Formula (III), ring A is triazinyl.
  • W is O
  • X 1 is CH or N
  • Y 1 is C or N and Y 2 is CH or N, provided that at least one of Y 1 or Y 2 is N;
  • R 6A is hydrogen, halogen, Ci-Cg alkyl, Ci-Cg haloalkyl, or Ci-Cg hydroxy alkyl;
  • R 9 is hydrogen, Ci-Cg alkyl, Ci-Cg haloalkyl, Ci-Cghydroxyalkyl, -Ci-C 3 alkylene(cycloalkyl), -Ci-C 3 alkylene(heterocycloalkyl), C 3 -Cg cycloalkyl, or 4 to 6 membered heterocycloalkyl; or R 6A and R 9 together with the intervening atoms to which they are attached form a 6 to 8 membered heteroaryl or 6 to 8 membered heterocycloalkyl;
  • R 7A and R 7B are each independently selected from hydrogen, halogen, -CN, -OH, -OR a , -SH, -SR a , - N(R b ) 2 , Ci-Cg alkyl, Ci-Cg aminoalkyl, Ci-Cg haloalkyl, or Ci-Cg hydroxyalkyl;
  • L is absent or Z-L 1 , wherein
  • Z is -O- or -NR 3B -; wherein R 3B is hydrogen or Ci-C 3 alkyl;
  • L 1 is absent or Ci-C 3 alkylene which is optionally substituted with one, two, or three R 8 ; each R 8 is independently halogen, -OH, oxo, Ci-Cg alkyl, Ci-Cg haloalkyl, Ci-Cghydroxyalkyl, or C 3 - Cg cycloalkyl; each R a is independently Ci-Cg alkyl, C 2 -Cg alkenyl, C 2 -Cg alkynyl, Ci-Cg heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Ci-Cg alkyl(aryl), -Ci-Cg alkyl(heteroaryl), -Ci-Cg alkyl(cycloalkyl), or -Ci-Cg alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalky
  • Y 1 is N and Y 2 is N. In some embodiments of Formula (V), Y 1 is N and Y 2 is CH. In some embodiments of Formula (V), Y 1 is C and Y 2 is N.
  • R 6A is hydrogen, halogen, Ci-Cg alkyl, Ci-Cg haloalkyl, or Ci-Cghydroxyalkyl. In some embodiments of Formula (V), R 6A is Ci-Cg alkyl, Ci-Cg haloalkyl, or Ci- Cghydroxyalkyl. In some embodiments of Formula (V), R 6A is hydrogen.
  • R 9 is Ci-Cg alkyl, Ci-Cg haloalkyl, Ci-Cg hydroxyalkyl, - Ci-C 3 alkylene(cycloalkyl), -Ci-C 3 alkylene(heterocycloalkyl), C 3 -Cg cycloalkyl, or 4 to 6 membered heterocycloalkyl.
  • R 9 is Ci-Cg alkyl, Ci-Cg haloalkyl, Ci-Cg hydroxyalkyl, -CH 2 -(cycloalkyl), -CH 2 -(heterocycloalkyl), C 3 -Cg cycloalkyl, or 4 to 6 membered heterocycloalkyl.
  • R 9 is Ci-Cg alkyl, Ci-Cg haloalkyl, Ci-Cg hydroxyalkyl, -CH 2 -(C 3 -Cgcycloalkyl), -CH 2 -(4 to 6 membered heterocycloalkyl), C 3 -Cg cycloalkyl, or 4 to 6 membered heterocycloalkyl.
  • R 9 is hydrogen, Ci-Cg alkyl or Ci-Cghaloalkyl.
  • R 9 is Ci-Cg alkyl.
  • R 9 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl. In some embodiments of Formula (V), R 9 is C3-C6 cycloalkyl, or 4 to 6 membered heterocycloalkyl. In some embodiments, R 9 is C3-C6 cycloalkyl. In some embodiments of Formula (V), R 9 is cyclopropyl or cyclobutyl. In some embodiments of Formula (V), R 9 is 4 to 6 membered heterocycloalkyl.
  • R 9 is 4 membered heterocycloalkyl. In some embodiments of Formula (V), R 9 is 5 membered heterocycloalkyl. In some embodiments of Formula (V), R 9 is -C1-C3 alkylene(cycloalkyl) or -C1-C3 alkylene(heterocycloalkyl). In some embodiments of Formula (V), R 9 is - C1-C3 alkylene(C3-Cg cycloalkyl). In some embodiments of Formula (V), R 9 is -C1-C3 alkylene(4 to 6 membered heterocycloalkyl).
  • R 6A is hydrogen; and R 9 is Ci-Cg alkyl, Ci-Cg hydroxyalkyl, -C1-C3 alkylene(cycloalkyl), -C1-C3 alkylene(heterocycloalkyl), C3-Cg cycloalkyl, or 4 to 6 membered heterocycloalkyl.
  • R 6A is hydrogen; and R 9 is Ci-Cg alkyl, Ci-Cg hydroxyalkyl, -CH2-(C3-Cgcycloalkyl), -CH2-(4 to 6 membered heterocycloalkyl), C3-Cg cycloalkyl, or 4 to 6 membered heterocycloalkyl.
  • R 6A is hydrogen; and R 9 is Ci-Cg alkyl. Wi 12] In some embodiments of Formula (V), R 6A and R 9 together with the intervening atoms to which they are attached form a 6 to 8 membered heteroaryl or 6 to 8 membered heterocycloalkyl.
  • R 6A and R 9 together with the intervening atoms to which they are attached form a 5 to 7 membered heteroaryl. In some embodiments of Formula (V), R 6A and R 9 together with the intervening atoms to which they are attached form a 5 -membered heteroaryl. In some embodiments of Formula (V), R 6A and R 9 together with the intervening atoms to which they are attached form a 6-membered heteroaryl In some embodiments of Formula (V), R 6A and R 9 together with the intervening atoms to which they are attached form a 7-membered heteroaryl.
  • R 6A and R 9 together with the intervening atoms to which they are attached form a 5 to 7 membered heterocycloalkyl. In some embodiments of Formula (V), R 6A and R 9 together with the intervening atoms to which they are attached form a 5 -membered heterocycloalkyl. In some embodiments of Formula (V), R 6A and R 9 together with the intervening atoms to which they are attached form a 6-membered heterocycloalkyl. In some embodiments of Formula (V), R 6A and R 9 together with the intervening atoms to which they are attached form a 7-membered heterocycloalkyl. In some embodiments, the compound of Formula (V) has the structure of Formula (Va), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
  • the compound of Formula (V) has the structure of Formula (Vb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
  • R 5 is -Z ⁇ L ⁇ Q, wherein
  • Z is -O- or -NR 3B -; wherein R 3B is hydrogen or C1-C3 alkyl;
  • L 1 is absent or Ci-Cg alkylene which is optionally substituted with one, two, or three R 8 ; each R 8 is independently halogen, -OH, oxo, Ci-Cg alkyl, Ci-Cg haloalkyl, Ci-Cghydroxyalkyl, or C3- Cg cycloalkyl;
  • Q is -OR 11 or -N(R n ) 2 ; and each R 11 is independently hydrogen, Ci-Cg alkyl, Ci-Cg alkylamino, Ci-Cg haloalkyl, or Ci-Cg hydroxyalkyl.
  • X 1 is CH or N
  • W is O
  • R 7A and R 7B are each independently selected from hydrogen, halogen, -CN, -OH, -OR a , -SH, -SR a , - N(R b ) 2 , Ci-Cg alkyl, Ci-Cg aminoalkyl, Ci-Cg haloalkyl, or Ci-Cg hydroxyalkyl; Z is -O- or -NR 3B -; wherein R 3B is hydrogen or C1-C3 alkyl;
  • L 2 is Ci-Cg alkylene which is optionally substituted with one, two, or three R 8 ; each R 8 is independently halogen, -OH, oxo, Ci-Cg alkyl, Ci-Cg haloalky 1, Ci-Cghydroxyalkyl, or C3-C6 cycloalkyl;
  • each R 11 is independently hydrogen, Ci-Cg alkyl, Ci-Cg alkylamino, Ci-Cg haloalkyl, or Ci-Cg hydroxyalkyl, each of which is optionally substituted with one, two, or three halogen or C1-C3 hydroxyalkyl; each R a is independently Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, Ci-Cg heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Ci-Cg alkyl(aryl), -Ci-Cg alkyl(heteroaryl), -Ci-Cg alkyl(cycloalkyl), or -Ci-Cg alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, heteroalkyl, cyclo
  • Q is -OR 11 . In some embodiments of Formula (I), (la), (II), (Ila), or (VI), Q is -N(R n )2.
  • Q is -OH, -OCH3, or -OCH2CH.
  • Q is -NH2, -NHCH3, -N(CH3) 2 , - NH(CH 2 CH 3 ), -N(CH 2 CH 3 )2, or NH(CH 2 CH 2 CH 3 ).
  • L is Z-L 1 .
  • Z is -O-.
  • Z is -NR 3B -.
  • Z 1 is -NH-.
  • Z is -NCH3-.
  • -Z- is absent.
  • R 3B is C1-C3 alkyl. In some embodiments, R 3B is methyl or ethyl. In some embodiments, R 3B is methyl. In some embodiments, R 3B is hydrogen.
  • L 1 is Ci-Cg alkylene which is optionally substituted with one, two, or three R 8 .
  • L 1 is Ci- C4 alkylene.
  • L 1 is C1-C3 alkylene.
  • L 1 is -CH2-, -CH2CH2-, - CH2CH2CH2-, CH2CH2CH2CH2-.
  • L 1 is -CH2-, -CH2CH2-, or -CH2CH2CH2-.
  • L 1 is -CH 2 -.
  • L 1 is -CH2CH2-. In some embodiments, L 1 is - CH2CH2CH2-. In some embodiments of Formula (I), (la), (II), (Ila), (III), (IV), (IVa), (V), (Va), or (Vb), L 1 is absent. In some embodiments of Formula (I), (la), (II), (Ila), or (VI), L 2 is Ci-Cg alkylene which is optionally substituted with one, two, or three R 8 . In some embodiments, L 2 is C1-C4 alkylene. In some embodiments, L 2 is C1-C3 alkylene. In some embodiments, L 2 is -CH2-, -CH2CH2-, -CH2CH2CH2-, - CH2CH2CH2CH2-, or -CH2CH2CH2CH2CH2-.
  • each R 4 is independently hydrogen, halogen, Ci-Cg alkyl, Ci-Cg haloalkyl, Ci-Cg heteroalkyl, or Ci-Cg hydroxyalkyl. In some embodiments, each R 4 is independently Ci- Cg alkyl or Ci-Cg haloalkyl. In some embodiments, each R 4 is independently Ci-Cg alkyl. In some embodiments, each R 4 is independently halogen. In some embodiments, each R 4 is independently chloro or fluoro. In some embodiments, each R 4 is independently fluoro, methyl, -CN, CF3, or CH2CF3.
  • each R 4 is independently a 5 -membered heteroaryl, C3-Cg cycloalkyl, or 4 to 6 membered heterocycloalkyl. In some embodiments, each R 4 is independently a 5 -membered heteroaryl. In some embodiments, each R 4 is independently a C3-Cg cycloalkyl. In some embodiments, each R 4 is independently a 4 to 6 membered heterocycloalkyl.
  • each R 4 is independently hydrogen.
  • two R 4 on adjacent carbon atoms together with the atoms to which they are attached form a 5 to 6-membered heteroaryl. In some embodiments, two R 4 on adjacent carbon atoms together with the atoms to which they are attached form a 5 membered heteroaryl. In some embodiments, two R 4 on adjacent carbon atoms together with the atoms to which they are attached form a 6 membered heteroaryl.
  • each R 6 is independently hydrogen, fluoro, -CH3, -CH2CH3, -C(CH3)3, -CF3, or -CH2CF3. In some embodiments, each R 6 is independently hydrogen or -CH3. In some embodiments, each R 6 is independently fluoro. In some embodiments, each R 6 is independently hydrogen.
  • two R 6 together with the intervening atoms to which they are attached form a 5 to 8 membered heteroaryl, Cs-Cx cycloalkyl, or 5 to 8 membered heterocycloalkyl.
  • two R 6 together with the intervening atoms to which they are attached form a 5 to 8 membered heteroaryl.
  • two R 6 together with the intervening atoms to which they are attached form a Cs-Cx cycloalkyl.
  • two R 6 together with the intervening atoms to which they are attached form a 5 to 8 membered heterocycloalkyl.
  • R 7A and R 7B are each the same. In some embodiments, R 7A and R 7B are each different.
  • R 7A and R 7B are each independently selected from hydrogen, halogen, -CN, -OH, -OR a , -SH, -SR a , -N(R b )2, Ci-Cg alkyl, Ci-Cg aminoalkyl, Ci-Cghaloalkyl, or Ci-Cghydroxyalkyl.
  • R 7A and R 7B are each independently selected from hydrogen, halogen, -CN, -OH, -OR a , -N(R b )2, Ci-Cg alkyl, Ci-Cg aminoalkyl, Ci-Cghaloalkyl, or Ci-Cg hydroxy alkyl.
  • each R 7A and R 7B are each independently halogen, -CN, -OH, -OCH3, -SCH3, -CH3, -NH2, -NHCH3, or -N(CH3)2.
  • each R 7A and R 7B are each independently fluoro, chloro, -OH, -CF3, or -CH3.
  • R 7A and R 7B are each independently halogen.
  • R 7A and R 7B are each independently chloro or fluoro.
  • R 7A and R 7B are each independently chloro.
  • R 7A and R 7B are each independently fluoro.
  • each R 8 is independently -CH3. In some embodiments, each R 8 is independently -CH2CH3 In some embodiments, each R 8 is independently Ci-Cg haloalkyl, or Ci-Cghydroxyalkyl. In some embodiments, each R 8 is independently C9-Cg cycloalkyl. In some embodiments, each R 8 is independently cyclopropyl.
  • each R 11 is independently hydrogen, Ci-Cg alkyl, Ci-Cg alkylamino, Ci-Cg haloalkyl, or Ci-Cg hydroxyalkyl, each of which is optionally substituted with one, two, or three halogen or C1-C3 hydroxyalkyl.
  • each R 11 is independently hydrogen or Ci-Cg alkyl.
  • each R 11 is independently Ci-Cg alkylamino, Ci-Cg haloalkyl, or Ci-Cg hydroxyalkyl.
  • each R 11 is independently Ci-Cg methyl.
  • each R 11 is independently methyl, ethyl, n-propyl, isopropyl, n- butyl, sec-butyl, or tert-butyl.
  • X 1 is CH. In some embodiments, X 1 is N.
  • A is N or CR 4 . In some embodiments, A is CR 4 . In some embodiments A is CH. In some embodiments, A is N. [88147] In some embodiments of Formula (II), (Ila), (III), (IV), (IVa), (V), (Va), (Vb), or (VI), B is N or CR 4 . In some embodiments, B is CR 4 . In some embodiments, B is CH. In some embodiments, B is N.
  • C is N or CR 4 .
  • C is CR 4 .
  • C is CH.
  • C is N.
  • D is N, CR 4 , or CR 5 .
  • D is N or CR 4 .
  • D is CR 4 .
  • D is CH.
  • D is N.
  • D is CR 5 .
  • E is N, CR 4 , or CR 5 ; wherein one of D or E is CR 5 .
  • E is N.
  • E is CR 4 .
  • E is CH.
  • E is CR 5 .
  • A is N or CR 4 ; B is N or CR 4 ; C is CH; D is CR 4 ; and E is CR 5 .
  • A is N or CR 4 ; B is N or CR 4 ; C is CH; D is CR 5 ; and E is N or CR 4 .
  • A is CH and B is CH. In some embodiments, A is N and B is CH. In some embodiments, A is CH and B is N. In some embodiments, A is N and B is N.
  • m is 1, 2, 3, or 4. In some embodiments, m is 1 or 2. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 0.
  • each R a is independently Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, or Ci-Cg heteroalkyl. In some embodiments, each R a is independently cycloalkyl or heterocycloalkyl. In some embodiments, each R a is independently aryl or heteroaryl. In some embodiments, each R a is independently -Ci-Cg alkyl(aryl), -Ci- Cg alkyl(heteroaryl), -Ci-Cg alkyl(cycloalkyl), or -Ci-Cg alkyl (heterocycloalkyl).
  • each R b is independently hydrogen, Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, Ci-Cg heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-Cg alkyl, or Ci-Cg haloalkyl.
  • each R b is independently hydrogen, Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, or Ci-Cg heteroalkyl. In some embodiments, each R b is independently cycloalkyl or heterocycloalkyl. In some embodiments, each R b is independently aryl, or heteroaryl.
  • the compounds made in the examples below are made from racemic starting materials (and/or intermediates) and separated into the individual enantiomers by chiral chromatography as final products or intermediates. Unless otherwise stated, it is understood that the absolute configuration of the separated intermediates and final compounds as drawn is arbitrarily assigned and was not determined.
  • compositions described herein include salts, particularly pharmaceutically acceptable salts, of the compounds described herein.
  • the compounds of the present invention that possess a sufficiently acidic, a sufficiently basic, or both functional groups can react with any of a number of inorganic bases, and inorganic and organic acids, to form a salt.
  • compounds that are inherently charged, such as those with a quaternary nitrogen can form a salt with an appropriate counterion, e.g., a halide such as bromide, chloride, or fluoride, particularly bromide.
  • Chemical entities having carbon-carbon double bonds or carbon-nitrogen double bonds may exist in Z- or E- form (or cis- or trans- form). Furthermore, some chemical entities may exist in various tautomeric forms. Unless otherwise specified, compounds described herein are intended to include all Z-, E- and tautomeric forms as well.
  • a “tautomer” refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible.
  • the compounds presented herein, in certain embodiments exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH.
  • tautomeric equilibrium examples include:
  • the compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of 2 H, 3 H, n C, 13 C and/or 14 C.
  • the compound is deuterated in at least one position.
  • deuterated forms can be made by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997.
  • deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.
  • compounds described herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13 C- or 14 C-enriched carbon are within the scope of the present disclosure.
  • the compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds.
  • the compounds may be labeled with isotopes, such as for example, deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C).
  • the compounds disclosed herein have some or all of the 4 H atoms replaced with 2 H atoms.
  • the methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.
  • Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, HO pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.
  • Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.
  • Compounds of the present invention also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.
  • the compounds described herein may in some cases exist as diastereomers, enantiomers, or other stereoisomeric forms. Where absolute stereochemistry is not specified, the compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Separation of stereoisomers may be performed by chromatography or by forming diastereomers and separating by recrystallization, or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981, herein incorporated by reference for this disclosure). Stereoisomers may also be obtained by stereoselective synthesis.
  • the methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also known as polymorphs).
  • the compounds described herein may be in the form of pharmaceutically acceptable salts.
  • active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure.
  • the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • the solvated forms of the compounds presented herein are also considered to be disclosed herein.
  • compounds or salts of the compounds may be prodrugs, e.g., wherein a hydroxyl in the parent compound is presented as an ester or a carbonate, or carboxylic acid present in the parent compound is presented as an ester.
  • prodrug is intended to encompass compounds which, under physiologic conditions, are converted into pharmaceutical agents of the present disclosure.
  • One method for making a prodrug is to include one or more selected moieties which are hydrolyzed under physiologic conditions to reveal the desired molecule.
  • the prodrug is converted by an enzymatic activity of the host animal such as specific target cells in the host animal.
  • esters or carbonates e.g., esters or carbonates of alcohols or carboxylic acids and esters of phosphonic acids
  • Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a compound as set forth herein are included within the scope of the claims.
  • some of the herein-described compounds may be a prodrug for another derivative or active compound.
  • Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. Prodrugs may help enhance the cell permeability of a compound relative to the parent drug. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug.
  • Prodrugs may be designed as reversible drug derivatives, for use as modifiers to enhance drug transport to site-specific tissues or to increase drug residence inside of a cell.
  • the design of a prodrug increases the lipophilicity of the pharmaceutical agent. In some embodiments, the design of a prodrug increases the effective water solubility. See, e.g., Fedorak etal., Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 31, 87 (1987); J. Larsen et al.. / J.
  • the present disclosure provides methods of producing the above-defined compounds.
  • the compounds may be synthesized using conventional techniques.
  • these compounds are conveniently synthesized from readily available starting materials.
  • compositions comprising a therapeutically effective amount of any compound or salt of any one of Formulas (I), (la) (II), (Ila) (III), (IV), (IVa), (V), (Va), (Vb), or (VI), (also referred to herein as “a pharmaceutical agent”).
  • Pharmaceutical compositions may be formulated using one or more physiologically acceptable carriers including excipients and auxiliaries which facilitate processing of the pharmaceutical agent into preparations which are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • compositions and methods of the present disclosure may be utilized to treat an individual in need thereof.
  • the individual is a mammal such as a human, or a non-human mammal.
  • the composition or the pharmaceutical agent is preferably administered as a pharmaceutical composition comprising, for example, a pharmaceutical agent and a pharmaceutically acceptable carrier or excipient.
  • Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters.
  • the aqueous solution is pyrogen-free, or substantially pyrogen-free.
  • the excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs.
  • Tire pharmaceutical composition can be in dosage unit form such as tablet, capsule, granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like.
  • the composition can also be present in a transdermal delivery system, e.g., a skin patch.
  • the composition can also be present in a solution suitable for topical administration, such as an eye drop.
  • a pharmaceutically acceptable excipient can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a pharmaceutical agent.
  • physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients.
  • Hie choice of a pharmaceutically acceptable excipient, including a physiologically acceptable agent depends, for example, on the route of administration of the composition.
  • the preparation or pharmaceutical composition can be a selfemulsifying drug delivery system or a self microemulsifying drug delivery system.
  • the pharmaceutical composition also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the invention.
  • Liposomes for example, which comprise phospholipids or other iipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.
  • a pharmaceutical composition can be administered to a subject by any of a number of rou tes of administration including, for example, orally, for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules, including sprinkle capsules and gelatin capsules, boluses, powders, granules, pastes for application to the tongue; absorption through the oral mucosa, e.g., sublingually; anally, rectally or vaginally, for example, as a pessary', cream or foam; parenterally, including intramuscularly, intravenously, subcutaneously or intrathecally as, for example, a sterile solution or suspension; nasally; intraperitoneally; subcutaneously; transdermally, for example, as a patch applied to the skin; and topically, for example, as a cream, ointment or spray applied to the skin, or as an eye drop.
  • the compound may also be formulated for inhalation.
  • orally for example,
  • a pharmaceutical composition may be a sterile aqueous or non-aqueous solution, suspension or emulsion, e.g., a microemulsion.
  • excipients described herein are examples and are in no way limiting.
  • An effective amount or therapeutically effective amount refers to an amount of the one or more pharmaceutical agents administered to a subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.
  • Subjects may generally be monitored for therapeutic effectiveness using assays and methods suitable for the condition being treated, which assays will be familiar to those having ordinary skill in the art and are described herein.
  • Pharmacokinetics of a pharmaceutical agent, or one or more metabolites thereof, that is administered to a subject may be monitored by determining the level of the pharmaceutical agent or metabolite in a biological fluid, for example, in the blood, blood fraction, e.g., serum, and/or in the urine, and/or other biological sample or biological tissue from the subject. Any method practiced in the art and described herein to detect the agent may be used to measure the level of the pharmaceutical agent or metabolite during a treatment course.
  • a pharmaceutical agent described herein for treating a disease or disorder may depend upon the subject’s condition, that is, stage of the disease, severity of symptoms caused by the disease, general health status, as well as age, gender, and weight, and other factors apparent to a person skilled in the medical art.
  • Pharmaceutical compositions may be administered in a manner appropriate to the disease to be treated as determined by persons skilled in the medical arts.
  • suitable duration and frequency of administration of the pharmaceutical agent may also be determined or adjusted by such factors as the condition of the patient, the type and severity of the patient’s disease, the particular form of the active ingredient, and the method of administration.
  • Optimal doses of an agent may generally be determined using experimental models and/or clinical trials.
  • the optimal dose may depend upon the body mass, weight, or blood volume of the subject. The use of the minimum dose that is sufficient to provide effective therapy is usually preferred. Design and execution of pre-clinical and clinical studies for a pharmaceutical agent, including when administered for prophylactic benefit, described herein are well within the skill of a person skilled in the relevant art.
  • the optimal dose of each pharmaceutical agent may be different, such as less than when either agent is administered alone as a single agent therapy.
  • two pharmaceutical agents in combination may act synergistically or additively, and either agent may be used in a lesser amount than if administered alone.
  • An amount of a pharmaceutical agent that may be administered per day may be, for example, between about 0.01 mg/kg and 100 mg/kg, e.g., between about 0.1 to 1 mg/kg, between about 1 to 10 mg/kg, between about 10-50 mg/kg, between about 50-100 mg/kg body weight. In other embodiments, the amount of a pharmaceutical agent that may be administered per day is between about 0.01 mg/kg and 1000 mg/kg, between about 100-500 mg/kg, or between about 500-1000 mg/kg body weight.
  • the optimal dose, per day or per course of treatment may be different for the disease or disorder to be treated and may also vary with the administrative route and therapeutic regimen.
  • compositions comprising a pharmaceutical agent can be formulated in a manner appropriate for the delivery method by using techniques routinely practiced in the art.
  • the composition may be in the form of a solid, e.g., tablet, capsule, semi-solid, e.g., gel, liquid, or gas, e.g., aerosol.
  • the pharmaceutical composition is administered as a bolus infusion.
  • Pharmaceutical acceptable excipients are well known in the pharmaceutical art and described, for example, in Rowe et al., Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, 5 th Ed., 2006, and in Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub. Co., Easton, PA (2005)).
  • Exemplary pharmaceutically acceptable excipients include sterile saline and phosphate buffered saline at physiological pH. Preservatives, stabilizers, dyes, buffers, and the like may be provided in the pharmaceutical composition. In addition, antioxidants and suspending agents may also be used. In general, the type of excipient is selected based on the mode of administration, as well as the chemical composition of the active ingredient(s). Alternatively, compositions described herein may be formulated as a lyophilizate. A composition described herein may be lyophilized or otherwise formulated as a lyophilized product using one or more appropriate excipient solutions for solubilizing and/or diluting the pharmaceutical agent(s) of the composition upon administration.
  • the pharmaceutical agent may be encapsulated within liposomes using technology known and practiced in the art.
  • a pharmaceutical agent is not formulated within liposomes for application to a stent that is used for treating highly, though not totally, occluded arteries.
  • Pharmaceutical compositions may be formulated for any appropriate manner of administration described herein and in the art.
  • a pharmaceutical composition e.g., for oral administration or for injection, infusion, subcutaneous delivery, intramuscular delivery, intraperitoneal delivery or other method, may be in the form of a liquid.
  • a liquid pharmaceutical composition may include, for example, one or more of the following: a sterile diluent such as water, saline solution, preferably physiological saline, Ringer’s solution, isotonic sodium chloride, fixed oils that may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents; antioxidants; chelating agents; buffers and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • a parenteral composition can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • physiological saline is preferred, and an injectable pharmaceutical composition is preferably sterile.
  • a liquid pharmaceutical composition may be applied to the eye in the form of eye drops.
  • a liquid pharmaceutical composition may be delivered orally.
  • At least one of the pharmaceutical agents described herein can be used alone or in combination with appropriate additives to make tablets, powders, granules or capsules, and if desired, with diluents, buffering agents, moistening agents, preservatives, coloring agents, and flavoring agents.
  • the pharmaceutical agents may be formulated with a buffering agent to provide for protection of the compound from low pH of the gastric environment and/or an enteric coating.
  • a pharmaceutical agent included in a pharmaceutical composition may be formulated for oral delivery with a flavoring agent, e.g., in a liquid, solid or semi-solid formulation and/or with an enteric coating.
  • a pharmaceutical composition comprising any one of the pharmaceutical agents described herein may be formulated for sustained or slow release, also called timed release or controlled release.
  • Such compositions may generally be prepared using well known technology and administered by, for example, oral, rectal, intradermal, or subcutaneous implantation, or by implantation at the desired target site.
  • Sustained-release formulations may contain the compound dispersed in a carrier matrix and/or contained within a reservoir surrounded by a rate controlling membrane. Excipients for use within such formulations are biocompatible, and may also be biodegradable; preferably the formulation provides a relatively constant level of active component release.
  • the amount of pharmaceutical agent contained within a sustained release formulation depends upon the site of implantation, the rate and expected duration of release, and the nature of the condition, disease or disorder to be treated or prevented.
  • the pharmaceutical compositions comprising a pharmaceutical agent are formulated for transdermal, intradermal, or topical administration.
  • the compositions can be administered using a syringe, bandage, transdermal patch, insert, or syringe-like applicator, as a powder/talc or other solid, liquid, spray, aerosol, ointment, foam, cream, gel, paste.
  • This preferably is in the form of a controlled release formulation or sustained release formulation administered topically or injected directly into the skin adjacent to or within the area to be treated, e.g., intradermally or subcutaneously.
  • the active compositions can also be delivered via iontophoresis.
  • Preservatives can be used to prevent the growth of fungi and other microorganisms.
  • Suitable preservatives include, but are not limited to, benzoic acid, butylparaben, ethyl paraben, methyl paraben, propylparaben, sodium benzoate, sodium propionate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetypyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, thimerosal, and combinations thereof.
  • compositions comprising a pharmaceutical agent can be formulated as emulsions for topical application.
  • An emulsion contains one liquid distributed in the body of a second liquid.
  • the emulsion may be an oil-in-water emulsion or a water-in-oil emulsion.
  • Either or both of the oil phase and the aqueous phase may contain one or more surfactants, emulsifiers, emulsion stabilizers, buffers, and other excipients.
  • the oil phase may contain other oily pharmaceutically approved excipients.
  • Suitable surfactants include, but are not limited to, anionic surfactants, non-ionic surfactants, cationic surfactants, and amphoteric surfactants.
  • Compositions for topical application may also include at least one suitable suspending agent, antioxidant, chelating agent, emollient, or humectant.
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.
  • Liquid sprays may be delivered from pressurized packs, for example, via a specially shaped closure.
  • Oil-in-water emulsions can also be used in the compositions, patches, bandages and articles. These systems are semisolid emulsions, microemulsions, or foam emulsion systems.
  • the pharmaceutical agent described herein can be formulated as in inhalant. Inhaled methods can deliver medication directly to the airway.
  • the pharmaceutical agent can be formulated as aerosols, microspheres, liposomes, or nanoparticles.
  • the pharmaceutical agent can be formulated with solvents, gases, nitrates, or any combinations thereof.
  • Compositions described herein are optionally formulated for delivery as a liquid aerosol or inhalable dry powder.
  • Liquid aerosol formulations are optionally nebulized predominantly into particle sizes that can be delivered to the terminal and respiratory bronchioles.
  • Liquid aerosol and inhalable dry powder formulations are preferably delivered throughout the endobronchial tree to the terminal bronchioles and eventually to the parenchymal tissue.
  • Aerosolized formulations described herein are optionally delivered using an aerosol forming device, such as a jet, vibrating porous plate or ultrasonic nebulizer, preferably selected to allow the formation of aerosol particles having with a mass medium average diameter predominantly between 1 to 5 p.
  • the formulation preferably has balanced osmolarity ionic strength and chloride concentration, and the smallest aerosolizable volume able to deliver effective dose of the pharmaceutical agent.
  • the aerosolized formulation preferably does not impair negatively the functionality of the airways and does not cause undesirable side effects.
  • Aerosolization devices suitable for administration of aerosol formulations described herein include, for example, jet, vibrating porous plate, ultrasonic nebulizers and energized dry powder inhalers, that are able to nebulize the formulation into aerosol particle size predominantly in the size range from 1- 5 p. Predominantly in this application means that at least 70% but preferably more than 90% of all generated aerosol particles are within 1-5 p range.
  • a jet nebulizer works by air pressure to break a liquid solution into aerosol droplets. Vibrating porous plate nebulizers work by using a sonic vacuum produced by a rapidly vibrating porous plate to extrude a solvent droplet through a porous plate.
  • An ultrasonic nebulizer works by a piezoelectric crystal that shears a liquid into small aerosol droplets.
  • suitable devices including, for example, AeroNebTM and AeroDoseTM vibrating porous plate nebulizers (AeroGen, Inc., Sunnyvale, California), Sidestream® nebulizers (Medic-Aid Ltd., West Wales, England), Pari LC® and Pari LC Star® jet nebulizers (Pari Respiratory Equipment, Inc., Richmond, Virginia), and AerosonicTM (DeVilbiss Medizinische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffetechnik (Deutschland) GmbH, Heiden, Germany) and UltraAire® (Omron Healthcare, Inc., Vernon Hills, Illinois) ultrasonic nebulizers.
  • AeroNebTM and AeroDoseTM vibrating porous plate nebulizers (AeroGen, Inc.
  • the pharmaceutical agent(s) can be formulated with oleaginous bases or ointments to form a semisolid composition with a desired shape.
  • these semisolid compositions can contain dissolved and/or suspended bactericidal agents, preservatives and/or a buffer system.
  • a petrolatum component that may be included may be any paraffin ranging in viscosity from mineral oil that incorporates isobutylene, colloidal silica, or stearate salts to paraffin waxes.
  • Absorption bases can be used with an oleaginous system.
  • Additives may include cholesterol, lanolin (lanolin derivatives, beeswax, fatty alcohols, wool wax alcohols, low HLB (hydrophobellipophobe balance) emulsifiers, and assorted ionic and nonionic surfactants, singularly or in combination.
  • lanolin lanolin derivatives, beeswax, fatty alcohols, wool wax alcohols, low HLB (hydrophobellipophobe balance) emulsifiers, and assorted ionic and nonionic surfactants, singularly or in combination.
  • Controlled or sustained release transdermal or topical formulations can be achieved by the addition of time-release additives, such as polymeric structures, matrices, that are available in the art.
  • the compositions may be administered through use of hot-melt extrusion articles, such as bioadhesive hot-melt extruded film.
  • the formulation can comprise a cross-linked polycarboxylic acid polymer formulation.
  • a cross-linking agent may be present in an amount that provides adequate adhesion to allow the system to remain attached to target epithelial or endothelial cell surfaces for a sufficient time to allow the desired release of the compound.
  • An insert, transdermal patch, bandage or article can comprise a mixture or coating of polymers that provide release of the pharmaceutical agents at a constant rate over a prolonged period of time.
  • the article, transdermal patch or insert comprises water-soluble pore forming agents, such as polyethylene glycol (PEG) that can be mixed with water insoluble polymers to increase the durability of the insert and to prolong the release of the active ingredients.
  • PEG polyethylene glycol
  • Transdermal devices may also comprise a water insoluble polymer.
  • Rate controlling polymers may be useful for administration to sites where pH change can be used to effect release. These rate controlling polymers can be applied using a continuous coating film during the process of spraying and drying with the active compound.
  • the coating formulation is used to coat pellets comprising the active ingredients that are compressed to form a solid, biodegradable insert.
  • a polymer formulation can also be utilized to provide controlled or sustained release.
  • Bioadhesive polymers described in the art may be used.
  • a sustained-release gel and the compound may be incorporated in a polymeric matrix, such as a hydrophobic polymer matrix.
  • a polymeric matrix include a microparticle.
  • the microparticles can be microspheres, and the core may be of a different material than the polymeric shell.
  • the polymer may be cast as a thin slab or film, a powder produced by grinding or other standard techniques, or a gel such as a hydrogel.
  • kits with unit doses of one or more of the agents described herein, usually in oral or injectable doses are provided. Such kits may include a container containing the unit dose, an informational package insert describing the use and attendant benefits of the drugs in treating disease, and optionally an appliance or device for delivery of the composition.
  • the compounds described herein can be used in the preparation of medicaments for the prevention or treatment of diseases or conditions.
  • a method for treating any of the diseases or conditions described herein in a subject in need of such treatment involves administration of pharmaceutical compositions containing at least one compound described herein, or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said subject.
  • compositions containing the compound(s) described herein can be administered for prophylactic and/or therapeutic treatments.
  • the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition. Amounts effective for this use will depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician.
  • compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a "prophylactically effective amount or dose.”
  • prophylactically effective amount or dose In this use, the precise amounts also depend on the patient's state of health, weight, and the like. When used in a patient, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.
  • the administration of the compounds may be administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.
  • the amount of a given agent that will correspond to such an amount will vary depending upon factors such as the particular compound, disease or condition and its severity, the identity (e.g., weight) of the subject or host in need of treatment, but can nevertheless be determined in a manner recognized in the field according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.
  • doses employed for adult human treatment will typically be in the range of about 0.02 - about 5000 mg per day, in some embodiments, about 1 - about 1500 mg per day.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example as two, three, four or more sub-doses per day.
  • the pharmaceutical composition described herein may be in unit dosage forms suitable for single administration of precise dosages.
  • the formulation is divided into unit doses containing appropriate quantities of one or more compound.
  • the unit dosage may be in the form of a package containing discrete quantities of the formulation.
  • Non-limiting examples are packaged tablets or capsules, and powders in vials or ampoules.
  • Aqueous suspension compositions can be packaged in single-dose non-recloseable containers.
  • multiple-dose recloseable containers can be used, in which case it is typical to include a preservative in the composition.
  • formulations for parenteral injection may be presented in unit dosage form, which include, but are not limited to ampoules, or in multi -dose containers, with an added preservative.
  • Toxicity and therapeutic efficacy of such therapeutic regimens can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between the toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD50 and ED50.
  • Compounds exhibiting high therapeutic indices are preferred.
  • the data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in human.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with minimal toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • PLMYT1 membrane associated tyrosine/threonine 1
  • a method of inhibiting protein kinase, membrane associated tyrosine/threonine 1 (PKMYT1) activity in a subject comprising administering to the subject a compound described herein, or a pharmaceutically acceptable salt thereof.
  • PLMYT1 membrane associated tyrosine/threonine 1
  • a method of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition described herein.
  • the cancer is associated with PKMYT1 activity.
  • a method for treating a subject having or suspected of having a cancer comprising administering to the subject a therapeutically effective amount of a compounds disclosed herein, or a pharmaceutically acceptable salt thereof, that modulates the expression or activity of PKMYTl.
  • the cancer is a skin cancer, ocular cancer, gastrointestinal cancer, thyroid cancer, breast cancer, ovarian cancer, central nervous system cancer, laryngeal cancer, cervical cancer, lymphatic system cancer, genitourinary tract cancer, bone cancer, biliary tract cancer, endometrial cancer, liver cancer, lung cancer, prostate cancer, or colon cancer.
  • the cancer is leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia, acute lymphoblastic leukemia (ALL), non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), or multiple myeloma (MM).
  • AML acute myeloid leukemia
  • ALL non-Hodgkin lymphoma
  • NHL Hodgkin lymphoma
  • MM multiple myeloma
  • the cancer is a solid cancer.
  • the cancer is not a solid cancer.
  • the cancer is a cancer metastasis.
  • the method comprises administering a second therapeutic agent.
  • the second therapeutic agent is a monoclonal antibody.
  • the second therapeutic agent is an immune checkpoint inhibitor.
  • the second therapeutic is chemotherapy or radiation therapy.
  • a method of identifying a subject having a disease for treatment with a compound disclosed herein comprising determining the presence of a mutation in the expression level of , and/or the activity of one or more biomarkers in a diseased tissue sample obtained from the subject.
  • a method of determining the responsiveness of a subject having a disease or disorder to a compound disclosed herein comprising determining the presence of a mutation in the expression level of, and/or the activity of one of more biomarkers in a diseased tissue sample obtained from the subject.
  • the diseased tissue sample comprises an altered expression level and/or activity of the one or more biomarkers relative to a reference tissue sample. In some embodiments, the expression level and/or activity of the one or more biomarkers is reduced relative to a reference tissue sample.
  • the diseased tissue sample is from a cancer.
  • the cancerous tissue is breast tissue, pancreatic tissue, uterine tissue, bladder tissue, colorectal tissue, prostate tissue, liver tissue, or ovarian tissue.
  • the cancerous tissue is liver tissue.
  • the cancerous tissue is ovarian tissue
  • the subject has a tumor
  • the diseased tissue sample comprises a tumor sample, a circulating tumor DNA sample, a tumor biopsy sample, or a fixed tumor sample.
  • the tumor sample is selected from acute myeloid leukemia (LAML), adrenocortical carcinoma (ACC), bladder urothelial carcinoma (BLCA), brain lower grade glioma (LGG), breast invasive carcinoma (BRCA), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), cholangiocarcinoma (CHOL), chronic myelogenous leukemia (LCML), colon adenocarcinoma (COAD), esophageal carcinoma (ESCA), glioblastoma multiforme (GBM), head and neck squamous cell carcinoma (HNSC), kidney chromophobe (KICH), kidney renal clear cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP), liver
  • LAML acute myeloid leukemia
  • ACC
  • a method of identifying a cancer subject to receive a compound disclosed herein comprising: (i) determining the presence of the mutation in the expression level of, and/or the activity of one or more biomarkers in the tumor sample obtained from the subject; and (ii) administering the compound disclosed herein to the subject based on the presence of a mutation in, a reduced expression level, and/or a reduced activity of the one or more biomarkers relative to a healthy control.
  • the one or more biomarkers is selected from the group consisting of ATM, MAP2K4, TP53, CDC25A, CACNA1H, CDKN1B, DUSP7, FOXO3, FZD3, JAK1, SMAD2, TGFBR2, MAP3K2, PPP3CC, and PPP2R1B.
  • the one or more biomarkers is selected from the group consisting of BIN3, AGPAT5, FGF17, PBK, NOTCH 1, CNTN5, IRF2, ALPK2, CDH19, CHKB, MAPK12, SLC8A1, HDAC2, CDT1, ADCY2, SLK, CDC20B, RPS6KA3, STAG1, CKAP5, RAD51, CKS1B, CCNO, KCNA2, MCM4, PLK4, and CDC16.
  • the one or more biomarkers is selected from the group consisting of ERICH1, TNKS, TDRP, MTUS1, TNFRSF10B, HR, TNFRSF10D, DMTN, ENTPD4, TNFRSF10C, PEBP4, LPL, LGI3, SLC7A2, MTMR9, MSRA, PDLIM2, INTS10, SH2D4A, GFRA2, ZDHHC2, PDGFRL, SPAG11B, PPP1R3B, SPAG11A, REEP4, DEFA5, DEFB136, NRG1, ASAHI, DEFA3, EPHX2, CNOT7, PNMA2, TRIM35, ATRX, INTS9, DNAH3, MAP3K1, RIMS2, NSD1, and SARAF.
  • the one or more biomarker is selected from the group consisting of SLITRK1, ZNF521, CCNB1, CDK7, MYTIL, FZR1, SERF1A, GADD45B, ADGRL2, TTK, NRXN2, UNC13A, ZBTB7A, POLDI, PCDH19, SLC8A2, E2F4, UTS2, KCNN2, CCNH, FRG2C, PLK2, MYO 18 A, and DCAF12L1.
  • the one or more biomarkers is selected from the group consisting of CDKN2B, CSMD3, LRP1B, DMRTA1, PTPRD, ELAVL2, FAT1, CDH1, NF1, PPP6R2, PIM3, MAPK11, CDH10, PCDH15, ALB, OR4F21, LING02, FBN2, CACNA1E, LRRC7, NALCN, ARID1A, ADGRB3, SI, PKHD1L1, TBCID22A, BNIP3L, DEFA1, DEFB103B, DEFB103A, HCN1, RELN, UNC13C, XKR5, CHMP7, CHRNA2, CSGALNACT1, FAM86B2, EGR3, XPO7, TRPS1, KDM6A, NBEA, VPS37A, SCN1A, CSMD2, GTSE1, TRMU, TENM1, DOCK3, VPS13B, RBM10, RYR2, SCARA5, SETBP1,
  • the one or more biomarkers is selected form the group consisting of OR4F16, BUB IB, PLK1, PAXBP 1, CTR9, AR, EIF3A, KIF4A, MAGEBIO, CHEK1, CENPM, AKT1, ADCY1, ATP2B2, HASPIN, CTDSPL2, STAG2, NCAPG, NCAPG, IGF1F, BLM, ATR, AURKB, RBL2, RPS6KA6, GINS2, MAD1L1, ADCY5, CHTF18, SMC1A, BRSK2, BRPF3, FOXD4L4, TGIF2LX, SOX5, POU4F1, UHRF1, PPP2RC, WDR45, FAM120C, BRSK1, EVI5L, NPAS4, MCM10, SUPT5H, MCM5, GALK2, FTSJ1, TRAP1, PAK3, CENPE, TPT1, MAD2L2, FBXO5, CDK16, CDC45,
  • the cancer is associated with cancerous tissue comprising a cell that displays mutations and/or deletions in genes encoding subunits of Protein Phosphatase 2 (PP2A) as compared to a healthy control.
  • P2A Protein Phosphatase 2
  • the presence or absence of the mutations and/or deletions is identified by an assay of cells derived from tissue obtained from the subject.
  • the assay is a next generation sequencing-based assay.
  • the PP2A subunit is selected from the group consisting of 65 kDa regulatory subunit A alpha (PPP2R1A), 65 kDa regulatory subunit A beta (PPP2R1B), 55 kDa regulatory subunit B alpha (PPP2R2A), 55 kDa regulatory subunit B beta (PPP2R2B), 55 kDa regulatory subunit B gamma (PPP2R2C), 55 kDa regulatory subunit B delta (PPP2R2D), 72/130 kDa regulatory subunit B (PPP2R3A), 48 kDa regulatory subunit B (PPP2R3B), regulatory subunit B” subunit gamma (PPP2R3C), regulatory subunit B’ (PPP2R4), 56 kDa regulatory subunit alpha (PPP2R5A), 56 kDa regulatory subunit beta (PPP2R5B), 56 kDa regulatory subunit gamma (PPPPP2R4), 56 kD
  • Step 1 l-ethyl-lH-pyrazol-3-ol
  • Step 2 2-((l-ethyl-lH-pyrazol-3-yl)oxy)-3-methyl-5-nitropyridine ⁇ 88257]
  • l-ethyl-lH-pyrazol-3-ol 0.6 g, 5.35 mmol, 1.0 eq
  • NaH 60 % in mineral oil
  • 2-Chloro-3-methyl-5 -nitropyridine 0.23g, 5.35 mmol, 1.0 eq
  • reaction mixture was quenched with 10 % NH4CI solution (100 mL) and extracted with EtOAc (3x30 mL). The combined organic layer was washed with water, dried over Na2SC>4 and concentrated under vacuum. The crude was purified by column chromatography (230-400 mesh silica gel, 0-20 % EtOAc/hexane) to afford the title compound as a yellow solid (0.6g, 45.17%).
  • Step 2 6-((4,5,6, 7-tetrahydropyrazolo[l,5-a]pyridin-2-yl)oxy)pyridin-3-amine
  • Step 3 6-(2,6-dichlorophenyl)-2-((6-((l-ethyl-lH-pyrazol-3-yl)oxy)-5-fluoropyridin-3- yl)amino)-8-methylpyrido[2,3-d]pyrimidin-7( 8H)-one
  • reaction mixture was quenched with 10 % NH4CI solution (100 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layer was washed with water, dried over Na2SC>4 and concentrated under vacuum. The crude was purified by trituration with n-hexane (15 mL), observed precipitate was filtered and concentrated under vacuum to afford the title compound as a yellow solid (0.270 g, 47. 12 %).
  • Step 3 6-(2,6-dichlorophenyl)-2-((6-(indolizin-2-yloxy)pyridin-3-yl)amino)-8- methylpyrido[2,3-d]pyrimidin- 7( 8H)-on e
  • reaction was quenched with 10 % NaHCC>3 solution (50 mL) and extracted with EtOAc (3x30 mL). The combined organic layers were washed with water, dried over Na2SO4 and concentrated under vacuum.
  • Step 1 tert-butyl 4-(2-((5-nitropyridin-2-yl)oxy)ethyl)piperazine-l-carboxylate
  • Step 3 tert-butyl 4-(2-((5-((6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido [2,3- d]pyrimidin-2-yl)amino)pyridin-2-yl)oxy)ethyl)piperazine-l-carboxylate
  • reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (50 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC to afford the title compound (150 mg, crude) as a yellow oil.
  • Step 4 6-(2,6-dichlorophenyl)-8-methyl-2-((6-(2-(piperazin-l-yl)ethoxy)pyridin-3- yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one
  • COMPOUND-045 6-(2,6-dichlorophenyl)-2-((6-(2-(diethylamino)ethoxy)pyridin-3-yl)amino)-8- methylpyrido[2,3-d]pyrimidin-7(8H)-one hydrochloric acid
  • the title compound was made by the method used for COMPOUND-044 from 2- (diethylamino)ethanol.
  • the crude product was purified by RP-HPLC (40 to 70% acetonitrile in water and 0.225% formic acid) to afford the title compound (113 mg, 41%) as a yellow solid.
  • the title compound was made by the method used for COMPOUND-044 from 1-ethylpyrazol- 3-ol.
  • the crude was purified by RP-HPLC (46 to 76% acetonitrile in water and 1% hydrochloric acid) to afford the title compound (21 mg, 10%) as a white solid.
  • Step 4 6-(2,6-dichlorophenyl)-8-methyl-2-((6-(2-thiomorpholinoethoxy)pyridin-3- yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one
  • Step 5 6-(2,6-dichlorophenyl)-8-methyl-2-((6-(2-(l-oxidothiomorpholino)ethoxy)pyridin-3- yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one
  • 6-(2,6-dichlorophenyl)-8-methyl-2-[[6-(2-thiomorpholinoethoxy)-3- pyridyl]amino]pyrido[2,3-d]pyrimidin-7-one 150 mg, 0.276 mmol) in acetone (3 mL) was added Oxone (85 mg, 0.138 mmol) in water (1 mL).
  • the mixture was stirred at 0 °C for 1 hour.
  • the reaction mixture was concentrated directly.
  • the reaction mixture was concentrated and purified by RP-HPLC (18 to 48% acetonitrile in water and 0.225% formic acid) to afford the title compound- (10 mg, 10%) as a yellow solid.
  • Step 4 methyl 2-((6-((l-ethyl-lH-pyrazol-3-yl)oxy)pyridin-3-yl)amino)-8-methyl-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidine-6-carboxylate
  • Step 5 2-( ( 6-( ( I -ethyl-lH-pyrazol-3-yl)oxy)pyridin-3-yl)amino)-8-methyl- 7-oxo- 7, 8- dihydropyrido[2,3-d]pyrimidin e-6-carboxylic acid
  • Step 6 N-(2-aminopyridin-3-yl)-2-((6-((l-ethyl-lH-pyrazol-3-yl)oxy)pyridin-3-yl)amino)-8- methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
  • Step 7 2-((6-((l-ethyl-lH-pyrazol-3-yl)oxy)pyridin-3-yl)amino)-6-(3H-imidazo[4,5- b]pyridin-2-yl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one
  • a solution ofN-(2-amino-3-pyridyl)-2-[[6-(l-ethylpyrazol-3-yl)oxy-3-pyridyl]amino]-8- methyl-7-oxo-pyrido[2,3-d]pyrimidine-6-carboxamide 35 mg, 0.07 mmol
  • acetic acid (1 mb) was heated at 150 °C for 2 hours under microwave.
  • Step 1 tert-butyl 4-(2-((5-((6-bromo-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2- yl)amino)pyridin-2-yl)oxy)ethyl)piperazine-l -carboxylate
  • Step 2 tert-butyl 4-(2-((5-((6-(3,5-difluoropyridin-4-yl)-8-methyl-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-2-yl)oxy)ethyl)piperazine-l-carboxylate [8838.8 [ To a solution of tert-butyl 4-[2-[[5-[(6-bromo-8-methyl-7-oxo-pyrido[2,3-d]pyrimidin-2- yl)amino]-2-pyridyl]oxy]ethyl]piperazine-l -carboxylate (300 mg, 0.53 mmol) in dioxane (4 mL) was added tributyl-(3,5-difluoro-4-pyridyl)stannane (281 mg, 0.69 mmol), copper
  • Step 1 methyl 2-((l-ethyl-lH-pyrazol-3-yl)oxy)-5-nitronicotinate
  • Step 2 methyl 5-amino-2-((l-ethyl-lH-pyrazol-3-yl)oxy)nicotinate
  • Step 3 methyl 5-((6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-2-yl)amino)-2-((l-ethyl-lH-pyrazol-3-yl)oxy)nicotinate
  • Step 4 5-((6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2- yl)amino)-2-((l-ethyl-lH-pyrazol-3-yl)oxy)nicotinamide
  • Step 1 5-((6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2- yl)amino)-2-((l-ethyl-lH-pyrazol-3-yl)oxy)nicotinic acid
  • Step 2 5-((6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2- yl)amino)-2-((l-ethyl-lH-pyrazol-3-yl)oxy)nicotinic acid
  • Step 4 tert-butyl ((5-amino-2-((l-ethyl-lH-pyrazol-3-yl)oxy)pyridin-3-yl)methyl)carbamate [00416)
  • a solution of 5-(aminomethyl)-6-(l-ethylpyrazol-3-yl)oxy-pyridin-3-amine (0.50 g, 2. 14 mmol) in dichloromethane (1 mL) was added di-tert-butyl dicarbonate (234 mg, 1.07 mmol) at 0 °C. Then the mixture was stirred at 20 °C for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure to give a residue.
  • the mixture was stirred at 100 °C for 16 hours.
  • the reaction mixture was concentrated and purified by RP- HPLC (55 to 85% acetonitrile in water and 0.225% formic acid) to afford the title compound (60 mg, 28%) as a white solid.
  • Step 3 6-(2, 6-dichlorophenyl)-2-( (2-( ( 1 -ethyl-lH-pyrazol-3-yl)oxy)pyrimidin-5-yl)amino)-8- methylpyrido[2,3-d]pyrimidin- 7( 8H)-on e
  • Step 3 tert-butyl N-tert-butoxycarbonyl-N-[2-(l-ethylpyrazol-3-yl)oxy-5-nitro-3- pyridyl]carbamate
  • Step 4 tert-butyl N-[5-amino-2-(l-ethylpyrazol-3-yl)oxy-3-pyridyl]-N-tert-butoxycarbonyl- carbamate
  • Step 7 [2-[[5-[[6-(2,6-dichlorophenyl)-8-methyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl]amino]- 2-(l-ethylpyrazol-3-yl)oxy-3-pyridyl]amino]-2-oxo-ethyl] acetate
  • Step 8 N-[5-[[6-(2,6-dichlorophenyl)-8-methyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl]amino]-2- ( 1 -ethylpyrazol-3-yl)oxy-3-pyridyl]-2-hydroxy-acetamide
  • reaction mixture was quenched by addition of formic acid (0.5 mL) and concentrated and purified by RP-HPLC (40 to 60% acetonitrile in water and 0.225% formic acid) to afford the title compound (2.4 mg, 5%) as a yellow solid.
  • Step 2 l-(l,l-dioxo-l,4-thiazinan-4-yl)-2-hydroxy-ethanone
  • Step 3 l-(l,l-dioxo-l,4-thiazinan-4-yl)-2-[(5-nitro-2-pyridyl)oxy]ethenone
  • N,N-dimethylformamide (1 mL) was added sodium hydride (10 mg, 0.26 mmol) at 0 °C. After stirred for
  • Step 4 2-[(5-amino-2-pyridyl)oxy]-l-( 1,1 -dioxo- 1, 4-th iazinan-4-yl)ethenone [88478] To a solution of l-(l,l-dioxo-l,4-thiazinan-4-yl)-2-[(5-nitro-2-pyridyl)oxy]ethanone (45 mg, 0.14 mmol) in methanol (1 mL) was added 10% palladium on carbon (15 mg). The mixture was stirred at 20 °C for 16 hours under hydrogen atmosphere (15 psi). The mixture was filtered and the filtrate was concentrated under reduced pressure.
  • Step 5 6-(2,6-dichlorophenyl)-2-[[6-[2-(l,l-dioxo-l,4-thia nan-4-yl)-2-oxo-ethoxy]-3- pyridyl]amino]-8-methyl-pyrido[2,3-d]pyrimidin-7-one
  • Step 1 methyl 2-[[6-[2-(4-tert-butoxycarbonylpiperazin-l-yl)ethoxy]-3-pyridyl]amino]-8- methyl-7-oxo-pyrido[2,3-d]pyrimidine-6-carboxylate
  • Step 3 tert-butyl 4-[2-[[5-[[8-methyl-7-oxo-6-(4-pyridylmethylcarbamoyl)pyrido[2,3- d]pyrimidin-2-yl]amino]-2-pyridyl]oxy]ethyl]piperazine-l-carboxylate
  • Step 4 8-methyl- 7-oxo-2-[[6-(2-piperazin-l-ylethoxy)-3-pyridyl]amino]-N-(4- pyridylmethyl)pyrido[2,3-d]pyrimidine-6-carboxamide
  • Step 2 5-amino-2-[2-(l,l-dioxo-l,4-thiazinan-4-yl)ethoxy]pyridine-3-carbonitrile pW496 ⁇
  • 2-[2-(l,l-dioxo-l,4-thiazinan-4-yl)ethoxy]-5-nitro-pyridine-3-carbonitrile 900 mg, 2.76 mmol
  • iron 770 mg, 13.79 mmol
  • ammonium chloride 148 mg, 2.76 mmol
  • the mixture was stirred at 80 °C for 1 hour.
  • the reaction solution was concentrated under reduced pressure.
  • the crude reaction mixture was purified by RP-HPLC (21 to 51% acetonitrile in water and 0.225% formic acid) to afford the title compound (8 mg, 17%) as a yellow solid.
  • Step 5 3-((5-((6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2- yl)amino)-2-(( I -(2-morpholinoethyl)-lH-pyrazol-3-yl)oxy)pyridin-3-yl)methyl)-l,l-dimethylurea [88522] The title compound- was made by the method used for COMPOUND-168 from 5-((6-(2,6- dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-2-((l-(2- morpholinoethyl)-lH-pyrazol-3-yl)oxy)nicotinonitrile.
  • Step 1 tert-butyl 4-(2-(3-((5-((6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-2-yl)amino)-3-((3,3-dimethylureido)methyl)pyridin-2-yl)oxy)-lH-pyrazol-l- yl)ethyl)piperazin e-1 -carboxylate
  • Step 2 3-((5-((6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2- yl)amino)-2-((l-(2-(piperazin-l-yl)ethyl)-lH-pyrazol-3-yl)oxy)pyridin-3-yl)methyl)-l,l-dimethylurea
  • Step 3 3-( ( 5-( ( 6-(2, 6-dichlorophenyl)-8-methyl- 7 -oxo- 7, 8-dihydropyrido[2,3-d]pyrimidin-2- yl)amino)-2-((l-(2-(4-methylpiperazin-l-yl)ethyl)-l H-pyraz,ol-3-yl)oxy)pyridin-3-yl)methyl)-l ,1- dimethylurea
  • Step 2 2-nitro-5-((l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-lH-pyrazol-4-yl)oxy)pyridine
  • 2-nitro-5-(lH-pyrazol-4-yloxy)pyridine 534 mg, 2.59 mmol
  • N,N- dimethylformamide 4 mL
  • 4-(2-bromoethyl)tetrahydropyran 500 mg, 2.59 mmol
  • cesium carbonate (2.53 g, 7.77 mmol
  • Step 3 5-((l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-l H-pyraz,ol-4-yl)oxy)pyridin-2-amine
  • 2-nitro-5-[l-(2-tetrahydropyran-4-ylethyl)pyrazol-4-yl]oxy-pyridine 450 mg, 1.41 mmol
  • iron 395 mg, 7.07 mmol
  • ammonium chloride 378 mg, 7.07 mmol
  • Step 4 6-(2,6-dichlorophenyl)-8-methyl-2-((5-((l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-lH- pyrazol-4-yl)oxy)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one
  • reaction mixture was filtered and concentrated under reduced pressure to remove solvent.
  • residue was purified by RP-HPLC (46 to 76% acetonitrile in water and 0.225% formic acid) to afford the title compound (28 mg, 13%) as a white solid.
  • Step 3 5-(l-(tetrahydrofuran-3-yl)cyclopropoxy)pyridin-2-amine
  • 2-nitro-5-(l -tetrahydrofuran-3 -ylcyclopropoxy)pyridine 240 mg, 0.96 mmol
  • ammonium chloride 257 mg, 4.80 mmol
  • iron 268 mg, 4.80 mmol
  • Step 1 2-(6-chloropyridazin-3-yl)oxy-l-(l,l-dioxo-l,4-thiazinan-4-yl)ethenone
  • N,N-dimethylformamide (1 mL) was added sodium hydride (10 mg, 0.26 mmol) at 0 °C. After stirred at 0 °C for 0.5 hour, the mixture was added 3,6-dichloropyridazine (39 mg, 0.26 mmol). Then, the mixture was stirred at 50 °C for 16 hours under nitrogen atmosphere. The mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-TLC to afford the title compound (70 mg, 78%) as a yellow solid.
  • Step 2 6-(2,6-dichlorophenyl)-2-[[6-[2-(l,l-dioxo-l,4-thiazinan-4-yl)-2-oxo- ethoxy]pyridazin-3-yl]amino]-8-methyl-pyrido[2,3-d]pyrimidin-7-one
  • Step 1 tert-butyl 3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3,6-diazabicyclo[3.1.1]heptane-6- carboxylate
  • Step 2 tert-butyl 3-(2-hydroxyethyl)-3,6-diazabicyclo[3.1.1 ]heptane-6-carboxylate
  • Step 4 tert-butyl 3-(2-((6-((6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-2-yl)amino)pyridazin-3-yl)oxy)ethyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (88569) A mixture of tert-butyl 3-[2-(6-chloropyridazin-3-yl)oxyethyl]-3,6-diazabicyclo[3.1. l]heptane-
  • 6-carboxylate 110 mg, 0.310 mmol
  • Step 5 2-((6-(2-(3,6-diazabicyclo[3.1.1 ]heptan-3-yl)etl )xy)pyrida in-3-yl)amino)-6-(2,6- dichlorophenyl)-8-methylpyrido[2,3-d]pyrimidin-7( 8H)-one
  • Step 1 4-(2-((6-chloropyridazin-3-yl)oxy)ethyl)thiomorpholine 1,1-dioxide ] 88587]
  • 2-( 1 , 1 -dioxo- 1 ,4-thiazinan-4-yl)ethanol 150 mg, 0.8 mmol
  • sodium hydride 35 mg, 0.8 mmol
  • the mixture was stirred at 25 °C for 0.5 hour.
  • 3,6-dichloropyridazine 125 mg, 0.8 mmol was added.
  • Step 2 6-(2,6-dichlorophenyl)-2-((6-(2-(l,l-dioxidothiomorpholino)ethoxy)pyridazin-3- yl)amino)-8-methylpyrido[2,3-d]pyrimidin-7( 8H)-one
  • Step 1 4-(2-((6-chloropyridazin-3-yl)oxy)ethyl)thiomorpholine
  • Step 2 4-(2-((6-chloropyridazin-3-yl)oxy)ethyl)thiomorpholine 1-oxide
  • 4-[2-(6-chloropyridazin-3-yl)oxyethyl]thiomorpholine (4.50 g, 17.32 mmol) in methyl alcohol (80 mL) was added a solution of sodium periodate (3.33 g, 6.93 mmol) in water (16 mL) under nitrogen atmosphere at 20 °C.
  • the reaction mixture was stirred at 20 °C for 1 hour.
  • the filtrate was concentrated under reduced pressure.
  • Step 3 4-(2-((6-chloropyridazin-3-yl)oxy)ethyl)-l-iminothiomorpholine 1-oxide
  • Step 4 4-(2-((6-chloropyridazin-3-yl)oxy)ethyl)-l-(methylimino)thiomorpholine 1-oxide
  • Step 4 4-(2-((6-chloropyridazin-3-yl)oxy)ethyl)-l-(methylimino)thiomorpholine 1-oxide
  • To a solution of 4-[2-(6-chloropyridazin-3-yl)oxyethyl]-l-imino-l,4-thiazinane 1-oxide (500 mg, 1.72 mmol) in dioxane (5 mL) was added cupric acetate (468 mg, 2.58 mmol) and pyridine (340 mg, 4.30 mmol) under nitrogen at 20 °C. The mixture was stirred at 20 °C for 30 min.
  • Step 5 6-(2,6-dichlorophenyl)-8-methyl-2-((6-(2-(l-(methylimino)-l- oxidothiomorpholino)ethoxy)pyridazin-3-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one
  • Step 1 tert-butyl ((6-chloro-3-(2-(l,l-dioxidothiomorpholino)ethoxy)pyridazin-4- y I) methyl) carbamate
  • Step 2 tert-butyl ((6-((6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-2-yl)amino)-3-(2-(l,l-dioxidothiomorpholino)ethoxy)pyridazin-4-yl)methyl)carbamate [98619] To a solution of tert-butyl N-[[6-chloro-3-[2-(l, 1 -dioxo- l,4-thiazinan-4-yl)ethoxy]pyridazin-4- yl]methyl]carbamate (240 mg, 0.57 mmol) in dioxane (20 mL) was added 2-amino-6-(2,6- dichlorophenyl)-8-methyl-pyrido[2,3-d]pyrimidin-7-one
  • Step 3 2-((5-(aminomethyl)-6-(2-(l,l-dioxidothiomorpholino)ethoxy)pyridazin-3-yl)amino)- 6-(2, 6-dichlorophenyl)-8-methylpyrido[2,3-d]pyrimidin-7( 8H)-one
  • Step 1 phenyl ((6-((6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-2-yl)amino)-3-(2-(l,l-dioxidothiomorpholino)ethoxy)pyridazin-4-yl)methyl)carbamate [88627] To a solution of 2-[[5-(aminomethyl)-6-[2-(l,l-dioxo-l,4-thiazinan-4-yl)ethoxy]pyridazin-3- yl]amino]-6-(2,6-dichlorophenyl)-8-methyl-pyrido[2,3-d]pyrimidin-7-one (100 mg, 0.17 mmol) in dichloromethane (2 mL) was added phenyl carbonochloridate (28 mg, 0.18 mmol) and N
  • Step 2 3-( ( 6-( ( 6-(2, 6-dichlorophenyl)-8-methyl- 7 -oxo- 7, 8-dihydropyrido[2,3-d]pyrimidin-2- yl)amino)-3-(2-(l,l-dioxidothiomorpholino)ethoxy)pyridazin-4-yl)methyl)-l,l-dimethylurea
  • Step 1 tert-butyl ((6-((6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-2-yl)amino)pyridazin-3-yl)methyl)carbamate
  • tert-butyl N-[(6-chloropyridazin-3-yl)methyl]carbamate 152 mg, 0.62 mmol) in dioxane (2 mb) was added 2-amino-6-(2,6-dichlorophenyl)-8-methyl-pyrido[2,3-d]pyrimidin-7-one (100 mg, 0.3 mmol) and sodium tert-butoxide (90 mg, 0.93 mmol) and tris(dibenzylideneacetone)dipalladium (0) (29 mg, 0.03 mmol) and (5-diphen
  • Step 2 2-((6)-(aminomethyl)pyridaz,in-3-yl)amino)-6-(2,6-dichlorophenyl)-8- methylpyrido[2,3-d]pyrimidin- 7( 8H)-on e
  • Step 3 l-(( 6-( ( 6-(2, 6-dichlorophenyl)-8-methyl- 7-oxo- 7,8-dihydropyrido[2,3-d]pyrimidin-2- yl)amino)pyridazin-3-yl)methyl)-3-methylurea
  • Step 3 4-(2-(3-((6-chloropyridazin-3-yl)oxy)-lH-pyrazol-l-yl)ethyl)morpholine ⁇ 006451
  • 3-chloro-6-(lH-pyrazol-3-yloxy)pyridazine 190 mg, 0.97 mmol
  • 4-(2-bromoethyl)morpholine 187.56 mg, 0.97 mmol
  • cesium carbonate 945 mg, 2.90 mmol
  • the reaction mixture was diluted with dichloromethane (15 mL). The reaction was washed with water (5 mL x 3). The separated organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC to afford the title compound (110 mg, 33%) as a white solid.
  • Step 4 6-(2, 6-dichlorophenyl)-8-methyl-2-( ( 6-( ( l-(2-morpholinoethyl)-lH-pyrazol-3- yl)oxy)pyridazin-3-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one
  • Step 1 3-chloro-6-((l-(2-(piperazin-l-yl)ethyl)-lH-pyrazol-3-yl)oxy)pyridazine
  • Step 2 3-chloro-6-((l-(2-(4-methylpiperazin-l-yl)ethyl)-lH-pyrazol-3-yl)oxy)pyridazine f 0653 j
  • 3-chloro-6-[l-(2-piperazin-l-ylethyl)pyrazol-3-yl]oxy-pyridazine 130 mg, 0.4 mmol
  • methanol 1.5 mL
  • dichloromethane 1.5 mL
  • formaldehyde (1.26 g, 42.10 mmol
  • sodium cyanoborohydride 185 mg, 2.95 mmol
  • Step 1 3-((l-(2-((tert-butyldimetliylsilyl)oxy)etliyl)-lH-pyraz/)l-4-yl)oxy)-6-cliloropyridazine [0065] To a solution of 3-chloro-6-(lH-pyrazol-4-yloxy)pyridazine (500 mg, 2.54 mmol) in N,N- dimethylformamide (5 mL) was added 2-bromoethoxy-tert-butyl-dimethyl-silane (608 mg, 2.54 mmol), cesium carbonate (2.49 g, 7.63 mmol).
  • the mixture was stirred at 80 °C for 1 hour under nitrogen atmosphere.
  • the reaction mixture was diluted with ethyl acetate (30 mL).
  • the reaction was washed with water (10 mL x 3).
  • the separated organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure.
  • the residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 - 30% ethyl acetate in petroleum ether) to afford the title compound (310 mg, 34%) as a colorless oil.
  • Step 2 2-( ( 6-( ( 1 -(2-((tert-butyldimethylsilyl)oxy)ethyl)-lH-pyrazol-4-yl)oxy)pyridazin-3- yl)amino)-6-(2,6-dichlorophenyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one

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Abstract

The disclosure provides for compounds and methods for inhibiting protein kinase, membrane associate tyrosine/threonine 1 (PKMYT1).

Description

COMPOUNDS AND METHOD FOR PKMYT1 INHIBITION
CROSS REFERENCE
Figure imgf000002_0002
This application claims the benefit of U.S. Application No. 63/321,376, filed March 18, 2022, which is hereby incorporated by reference in its entirety.
FIEED OF THE INVENTION
The disclosure relates to compounds which function as inhibitors of protein kinase, membrane
Figure imgf000002_0003
associated tyrosine/threonine 1 (PKMYT1).
BACKGROUND OF THE INVENTION
The WEE1 kinase family consists of three serine/threonine kinases sharing conserved
Figure imgf000002_0004
molecular structures and encoded by the following genes: WEE1 (WEE1 G2 Checkpoint Kinase), PKMYT1 (membrane -associated tyrosine- and threonine-specific cdc2 -inhibitory kinase), and WEE1B (WEE2 oocyte meiosis inhibiting kinase). In eukaryotic somatic cells, WEE1 and PKMYT1 play a key role in cell cycle regulation and, in particular, they are involved in the entry into mitosis. Their role as regulators is crucial during normal cell cycle progression and in response to DNA damages, as part of the DNA damage response (DDR) pathways. PKMYT1 plays a crucial role in DNA damage identification and repair in both nonmalignant and cancer.
SUMMARY OF THE INVENTION
The present disclosure addresses the above need and provides additional advantages as well.
Figure imgf000002_0005
In an aspect, die present disclosure provides tor compounds that function as inhibitors of protein kinase, membrane associated tyrosine/threonine 1 (PKMYT1).
In an aspect, provided herein are compounds represented by Formula (I), or a pharmaceutically
Figure imgf000002_0006
acceptable salt thereof
R10 wherein,
Figure imgf000002_0001
A, B, and C, are each independently N or CR4;
D is N, CR4, or CR5;
E is N, CR4, or CR5; wherein one of D or E is CR5;
R1 is hydrogen, Ci-Ce alkyl, Ci-Ce heteroalkyl, G-C'e cycloalkyl, or 4 to 6 membered heterocycloalkyl;
W is O or NH; or W and R1 combine with the atoms to which they are attached to form a 5 to 6-membered heterocycloalkyl or 5 to 6-membered heteroaryl;
R2 is Cg-Cio aryl or 6 to 10 membered heteroaryl; each of which is optionally substituted with one, two, three, or four R7; each R7 is independently selected from halogen, -CN, -OH, -ORa, -SH, -SRa, -N(Rb)2, -C(=O)Ra, - C(=O)ORb, -C(=O)N(Rb)2, Ci-C6 alkyl, Ci-C6 aminoalkyl, Ci-C6 haloalkyl, or Ci-C6 hydroxyalkyl; or two R7 together with the atoms to which they are attached form a 5 to 6-membered heterocycloalkyl; R3A is hydrogen or Ci-Cg alkyl; each R4 is independently hydrogen, halogen, -CN, -OH, -ORa, -SH, -SRa, -S(=O)Ra, -NO2, -N(Rb)2, - S(=O)2Ra, -NHS(=O)2Ra, -S(=O)2N(Rb)2, -C(=O)Ra, -OC(=O)Ra, -C(=O)ORb, -OC(=O)ORb, - C(O)N(Rb)2, -OC(=O)N(Rb)2, -NRbC(=O)N(Rb)2, -NRbC(=O)Ra, -NRbC(=O)ORb, -Ci-C3 alkylene- NHS(=O)2Ra, -Ci-C3 alkylene-NRbC(=O)Ra, -Ci-C3 alkylene-OC(=O)Ra, -Ci-C3 alkylene- NRbC(=O)N(Rb)2, -Ci-C3 alkylene-NRbC(=O)ORb, -Ci-C3 alkylene-OC(=O)N(Rb)2, Ci-C6 alkyl, Ci- Cg aminoalkyl, Ci-Cg haloalkyl, Ci-Cg hydroxyalkyl, Ci-Cg heteroalkyl, 5-membered heteroaryl, C3- Cx cycloalkyl, or 4 to 8 membered heterocycloalkyl, each of which is optionally substituted with one, two, three, or four halogen, -OH, Ci-C3 alkyl, Ci-C3 haloalkyl, or a 4 to 5-membered heterocycloalkyl; or two R4 on adjacent carbon atoms together with the atoms to which they are attached form a 5 to 6- membered heteroaryl;
Figure imgf000003_0001
wherein
L is absent or Z-L1,
Z is -O- or -NR3B-; wherein R3B is hydrogen or Ci-C3 alkyl;
L1 is absent or Ci-Cg alkylene which is optionally substituted with one, two, or three R8;
L2 is Ci-Cg alkylene which is optionally substituted with one, two, or three R8; each R8 is independently halogen, -OH, oxo, Ci-Cg alkyl, Ci-Cg haloalkyl, Ci-Cghydroxyalkyl, or C3- Cg cycloalkyl; ring A is 5 to 10-membered heteroaryl, Cg-Cio cycloalkyl, or 5 to 10 membered heterocycloalkyl; each R6 is independently hydrogen, halogen, -CN, -OH, -ORa, -N(Rb)2, -S(=O)2Ra, -NHS(=O)2Ra, - S(=O)2N(Rb)2, -C(=O)Ra, -OC(=O)Ra, -C(=O)ORb, -C(=O)N(Rb)2, -NRbC(=O)Ra, oxo, Ci-Cg alkyl, Ci-Cg alkylamino, Ci-Cg haloalkyl, Ci-Cg hydroxyalkyl, Ci-Cg heteroalkyl, C3-Cx cycloalkyl, or 4 to 8 membered heterocycloalkyl; or two R6 together with the intervening atoms to which they are attached form a 5 to 8 membered heteroaryl, Cx-Cx cycloalkyl, or 5 to 8 membered heterocycloalkyl;
Q is -OR11 or -N(Rn)2; ach R11 is independently hydrogen, Ci-Cg alkyl, Ci-Cg alkylamino, Ci-Cg haloalkyl, or Ci-Cg hydroxyalkyl, each of which is optionally substituted with one, two, or three halogen or Ci-C3 hydroxyalkyl; m is 0, 1, 2, 3, or 4;
R10 is hydrogen, halogen, -CN, -OH, -NH2, Ci-Cg alkyl, or Ci-Cg haloalkyl; each Ra is independently Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, Ci-Cg heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Ci-Cg alkyl(aryl), -Ci-Cg alkyl(heteroaryl), -Ci-Cg alkyl(cycloalkyl), or -Ci-Cg alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-Cg alkyl, or Ci-Cg haloalkyl; and each Rb is independently hydrogen, Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, Ci-Cg heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-Cg alkyl, or Ci-Cg haloalkyl. fO GTf In some embodiments of Formula (I), R3A is hydrogen; and R1 is CH3. In some embodiments, Z is absent; and R2 is phenyl or 6 membered heteroaryl. In some embodiments, R2 is phenyl, pyridinyl, pyrazinyl, or pyrimidinyl.
[8888] In some embodiments, the compound of Formula (I) has the structure of Formula (II), or a pharmaceutically acceptable salt thereof:
Figure imgf000004_0001
Formula (II), wherein,
X1 is CH or N;
R7A and R7B are each independently selected from hydrogen, halogen, -CN, -OH, -ORa, -SH, -SRa, - N(Rb)2, Ci-Cg alkyl, Ci-Cg aminoalkyl, Ci-Cg haloalkyl, or Ci-Cg hydroxyalkyl.
[8000] In some embodiments of Formula (I) or (II), D is CR5 and E is N or CR4. In some embodiments of Formula (I) or (II), D is N or CR4; and E is CR5. In some embodiments of Formula (I) or (II), C is CH.
| _ [_ _ f J _ (R )
[8888 In some embodiments of Formula (I) or (II), R5 is ’
[8811 [ In some embodiments, provided herein is a compound having the structure of Formula (III), or a pharmaceutically acceptable salt thereof:
Figure imgf000004_0002
Formula (III), wherein, A and B are each independently N or CH;
X1 is N or CH;
W is O;
Ring A is ring A is a 5 to 10-membered heteroaryl, Cg-Cio cycloalkyl, or 5 to 10 membered heterocycloalkyl; each R4 is independently hydrogen, halogen, -CN, -OH, -ORa, -SH, -SRa, -S(=O)Ra, -NO2, -N(Rb)2, - S(=O)2Ra, -NHS(=O)2Ra, -S(=O)2N(Rb)2, -C(=O)Ra, -OC(=O)Ra, -C(=O)ORb, -OC(=O)ORb, - C(O)N(Rb)2, -OC(=O)N(Rb)2, -NRbC(=O)N(Rb)2, -NRbC(=O)Ra, -NRbC(=O)ORb, -Ci-C3 alkylene- NHS(=O)2Ra, -Ci-C3 alkylene-NRbC(=O)Ra, -Ci-C3 alkylene-OC(=O)Ra, -Ci-C3 alkylene- NRbC(=O)N(Rb)2, -Ci-C3 alkylene-NRbC(=O)ORb, -Ci-C3 alkylene-OC(=O)N(Rb)2, Ci-C6 alkyl, Ci- Cg aminoalkyl, Ci-Cg haloalkyl, Ci-Cg hydroxyalkyl, Ci-Cg heteroalkyl, 5-membered heteroaryl, C3- Cx cycloalkyl, or 4 to 8 membered heterocycloalkyl, each of which is optionally substituted with one, two, three, or four halogen, -OH, Ci-C3 alkyl, Ci-C3 haloalkyl, or a 4 to 5-membered heterocycloalkyl; each R6 is independently hydrogen, halogen, -CN, -OH, -ORa, -N(Rb)2, -S(=O)2Ra, -NHS(=O)2Ra, - S(=O)2N(Rb)2, -C(=O)Ra, -OC(=O)Ra, -C(=O)ORb, -C(=O)N(Rb)2, -NRbC(=O)Ra, oxo (=0), Ci-Cg alkyl, Ci-Cg alkylamino, Ci-Cg haloalkyl, Ci-Cg hydroxyalkyl, Ci-Cg heteroalkyl, C3-Cx cycloalkyl, of 4 to 8 membered heterocycloalkyl; or two R6 together with the intervening atoms to which they are attached form a 5 to 8 membered heteroaryl, Cx-Cx cycloalkyl, or 5 to 8 membered heterocycloalkyl;
R7A and R7B are each independently selected from hydrogen, halogen, -CN, -OH, -ORa, -SH, -SRa, - N(Rb)2, Ci-Cg alkyl, Ci-Cg aminoalkyl, Ci-Cg haloalkyl, or Ci-Cg hydroxyalkyl;
L is absent or Z-L1, wherein
Z is -O- or -NR3B-; wherein R3B is hydrogen or Ci-C3 alkyl;
L1 is absent or Ci-C3 alkylene which is optionally substituted with one, two, or three R8; each R8 is independently halogen, -OH, oxo (=0), Ci-Cg alkyl, Ci-Cg haloalkyl, Ci-Cg hydroxyalkyl, or C3-Cg cycloalkyl; each Ra is independently Ci-Cg alkyl, C -Cg alkenyl, CS-Cg alkynyl, Ci-Cg heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Ci-Cg alkyl(aryl), -Ci-Cg alkyl(heteroaryl), -Ci-Cg alkyl(cycloalkyl), or -Ci-Cg alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-Cg alkyl, or Ci-Cg haloalkyl; each Rb is independently hydrogen, Ci-Cg alkyl, C -Cg alkenyl, C -Cg alkynyl, Ci-Cg heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-Cg alkyl, or Ci-Cg haloalkyl; and m is 0, 1, 2, 3, or 4. ^8012^ In some embodiments of Formula (III), ring A is a Cg-Cio cycloalkyl or 5 to 10 membered heterocycloalkyl. In some embodiments of Formula (III), ring A is a 5 to 10 membered heterocycloalkyl, wherein the heterocycloalkyl is a monocyclic, bicyclic, or spirocyclic heterocycloalkyl. In some embodiments of Formula (III), ring A is piperidine, piperazine, or morpholine.
In some embodiments, provided herein is a compound having the structure of Formula (IV), or a pharmaceutically acceptable salt thereof:
Figure imgf000006_0001
Formula (IV), wherein,
W is O;
X1 is CH orN;
X2 is CH orN;
X3 and X5 are each independently CR6R6, O or NRX;
X4 is CR6R6, O, NRX, S, S(=O), S(=O)2, S(=O)=NRY, or S(=O)ORY;
Rx is hydrogen, -S(=O)2OH, -S(=O)2NH2, Ci-Cg alkyl, Ci-Cg haloalkyl, or Ci-Cg hydroxyalkyl; each RY is independently hydrogen or C1-C3 alkyl;
A and B are each independently N or CH; each R4 is independently hydrogen, halogen, -CN, -OH, -ORa, -SH, -SRa, -S(=O)Ra, -NO2, -N(Rb)2, - S(=O)2Ra, -NHS(=O)2Ra, -S(=O)2N(Rb)2, -C(=O)Ra, -OC(=O)Ra, -C(=O)ORb, -OC(=O)ORb, - C(O)N(Rb)2, -OC(=O)N(Rb)2, -NRbC(=O)N(Rb)2, -NRbC(=O)Ra, -NRbC(=O)ORb, -Ci-C3 alkylene- NHS(=O)2Ra, -Ci-C3 alkylene-NRbC(=O)Ra, -C C3 alkylene-OC(=O)Ra, -C C3 alkylene- NRbC(=O)N(Rb)2, -Ci-C3 alkylene-NRbC(=O)ORb, -C C3 alkylene-OC(=O)N(Rb)2, Ci-C6 alkyl, C Cg aminoalkyl, Ci-Cg haloalkyl, Ci-Cg hydroxyalkyl, Ci-Cg heteroalkyl, 5-membered heteroaryl, C3- Cx cycloalkyl, or 4 to 8 membered heterocycloalkyl, each of which is optionally substituted with one, two, three, or four halogen, -OH, Ci-C3 alkyl, Ci-C3 haloalkyl, or a 4 to 5-membered heterocycloalkyl; each R6 is independently hydrogen, halogen, -CN, -OH, -ORa, -N(Rb)2, -S(=O)2Ra, -NHS(=O)2Ra, - S(=O)2N(Rb)2, -C(=O)Ra, -OC(=O)Ra, -C(=O)ORb, -C(=O)N(Rb)2, -NRbC(=O)Ra, oxo (=0), Ci-Cg alkyl, Ci-Cg alkylamino, Ci-Cg haloalkyl, Ci-Cg hydroxyalkyl, Ci-Cg heteroalkyl, C3-Cx cycloalkyl, or 4 to 8 membered heterocycloalkyl; or two R6 together with the intervening atoms to which they are attached form a 5 to 8 membered heteroaryl, Cx-Cx cycloalkyl, or 5 to 8 membered heterocycloalkyl; R7A and R7B are each independently selected from hydrogen, halogen, -CN, -OH, -ORa, -SH, -SRa, - N(Rb)2, Ci-Cg alkyl, Ci-Cg aminoalkyl, Ci-Cg haloalkyl, or Ci-Cg hydroxyalkyl;
L is absent or Z-L1, wherein
Z is -O- or -NR3B-; wherein R3B is hydrogen or C1-C3 alkyl;
L1 is absent or C1-C3 alkylene which is optionally substituted with one, two, or three R8; each R8 is independently halogen, -OH, oxo, Ci-Cg alkyl, Ci-Cg haloalky 1, Ci-Cghydroxyalkyl, or C3- Cg cycloalkyl; each Ra is independently Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, Ci-Cg heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Ci-Cg alkyl(aryl), -Ci-Cg alkyl(heteroaryl), -Ci-Cg alkyl(cycloalkyl), or -Ci-Cg alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-Cg alkyl, or Ci-Cg haloalkyl; each Rb is independently hydrogen, Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, Ci-Cg heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-Cg alkyl, or Ci-Cg haloalkyl; and m is 0, 1, 2, 3, or 4.
[881 ^ In some embodiments of Formula (IV), X2 is CH; X3 and X5 are each independently CR6R6, O, or NRX; and X4 is CR6R6. In some embodiments of Formula (IV), X3 and X5 are each independently O or NRX. In some embodiments of Formula (IV), X3 and X5 are each independently CR6R6. 8815] In some embodiments, the compound of Formula (IV) has the structure of Formula (IVa), or a pharmaceutically acceptable salt thereof:
Figure imgf000007_0001
Formula (IVa).
In some embodiments of Formula (IV) or (IVa), X4 is X4 is S, S(=O), or S(=O)2. In some embodiments, X4 is S(=O)2. In some embodiments of Formula (IV) or (IVa), X4 is O or NRX. In some embodiments of Formula (IV) or (IVa), X2 is CH. In some embodiments of Formula (IV) or (IVa), X2 is N. In some embodiments of Formula (IV) or (IVa), each R6 is independently halogen, -CN, -OH, -ORa, - N(Rb)2, oxo, Ci-Cg alkyl, Ci-Cg haloalkyl, or Ci-Cg hydroxyalkyl. In some embodiments of Formula (IV) or (IVa), two R6 together with the intervening atoms to which they are attached form a 5 to 8 membered heteroaryl, Cs-Cx cycloalkyl, or 5 to 8 membered heterocycloalkyl. In some embodiments of Formula (IV) or (IVa), m is 1 or 2. In some embodiments of Formula (IV) or (IVa), m is 0. f 17j In some embodiments of Formula (III), ring A is 5 to 10-membered heteroaryl. In some embodiments of Formula (III), ring A is a 5 or 6 membered heteroaryl having one, two, or three heteroatoms selected from N, O, and S. In some embodiments of Formula (III), ring A is triazinyl, pyrrolyl, furanyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, or tetrazolyl. In some embodiments of Formula (III), ring A is pyrrolyl, imidazolyl, or pyrazolyl.
In some embodiments, provided herein is a compound having the structure of Formula (V), or a pharmaceutically acceptable salt thereof:
Figure imgf000008_0001
Formula (V), wherein,
X1 is CH or N;
Y1 is C or N and Y2 is CH or N, provided that at least one of Y1 or Y2 is N;
W is O;
A and B are each independently N or CH; each R4 is independently hydrogen, halogen, -CN, -OH, -ORa, -SH, -SRa, -S(=O)Ra, -NO2, -N(Rb)2, - S(=O)2Ra, -NHS(=O)2Ra, -S(=O)2N(Rb)2, -C(=O)Ra, -OC(=O)Ra, -C(=O)ORb, -OC(=O)ORb, - C(O)N(Rb)2, -OC(=O)N(Rb)2, -NRbC(=O)N(Rb)2, -NRbC(=O)Ra, -NRbC(=O)ORb, -Ci-C3 alkylene- NHS(=O)2Ra, -Ci-C3 alkylene-NRbC(=O)Ra, -C C3 alkylene-OC(=O)Ra, -C C3 alkylene- NRbC(=O)N(Rb)2, -Ci-C3 alkylene-NRbC(=O)ORb, -C C3 alkylene-OC(=O)N(Rb)2, Ci-C6 alkyl, C Cg aminoalkyl, Ci-Cg haloalkyl, Ci-Cg hydroxyalkyl, Ci-Cg heteroalkyl, 5-membered heteroaryl, C3- cycloalkyl, or 4 to 8 membered heterocycloalkyl, each of which is optionally substituted with one, two, three, or four halogen, -OH, Ci-C3 alkyl, Ci-C3 haloalkyl, or a 4 to 5-membered heterocycloalkyl;
R6A is hydrogen, halogen, Ci-Cg alkyl, Ci-Cg haloalkyl, or Ci-Cg hydroxy alkyl;
R9 is hydrogen, Ci-Cg alkyl, Ci-Cg haloalkyl, Ci-Cghydroxyalkyl, -Ci-C3 alkylene(cycloalkyl), -Ci-C3 alkylene(heterocycloalkyl), C3-Cg cycloalkyl, or 4 to 6 membered heterocycloalkyl; or R6A and R9 together with the intervening atoms to which they are attached form a 6 to 8 membered heteroaryl or 6 to 8 membered heterocycloalkyl;
R7A and R7B are each independently selected from hydrogen, halogen, -CN, -OH, -ORa, -SH, -SRa, - N(Rb)2, Ci-Cg alkyl, Ci-Cg aminoalkyl, Ci-Cg haloalkyl, or Ci-Cg hydroxyalkyl;
L is absent or Z-L1, wherein
Z is -O- or -NR3B-; wherein R3B is hydrogen or Ci-C3 alkyl;
L1 is absent or Ci-C3 alkylene which is optionally substituted with one, two, or three R8; each R8 is independently halogen, -OH, oxo, Ci-Cg alkyl, Ci-Cg haloalkyl, Ci-Cghydroxyalkyl, or C3- Cg cycloalkyl; each Ra is independently Ci-Cg alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Cg heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Ci-Cg alkyl(aryl), -Ci-Cg alkyl(heteroaryl), -Ci-Cg alkyl(cycloalkyl), or -Ci-Cg alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-Cg alkyl, or Ci-Cg haloalkyl; and each Rb is independently hydrogen, Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, Ci-Cg heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-Cg alkyl, or Ci-Cg haloalkyl.
[8819[ In some embodiments of Formula (V), Y1 is N and Y2 is N. In some embodiments of Formula (V), R6A is hydrogen; and R9 is Ci-Cg alkyl, Ci-Cg hydroxyalkyl, -C1-C3 alkylene(cycloalkyl), -C1-C3 alkylene(heterocycloalkyl), C3-Cg cycloalkyl, or 4 to 6 membered heterocycloalkyl. In some embodiments of Formula (V), R9 is methyl, ethyl, -CH2-(C3-Cgcycloalkyl), -CH2-(4 to 6 membered heterocycloalkyl), C3-Cg cycloalkyl, or 4 to 6 membered heterocycloalkyl. In some embodiments of Formula (V), R6A and R9 together with the intervening atoms form a 6 to 8 membered heteroaryl or 6 to 8 membered heterocycloalkyl.
[8820] In some embodiments, the compound of Formula (V) has the structure of Formula (Va) or Formula (Vb), or a pharmaceutically acceptable salt thereof:
Figure imgf000009_0001
Formula (Vb).
[8821 [ In some embodiments, provided herein is a compound having the structure of Formula (VI), or a pharmaceutically acceptable salt thereof:
Figure imgf000009_0002
wherein,
X1 is CH or N; W is O;
A and B are each independently N or CH; each R4 is independently hydrogen, halogen, -CN, -OH, -ORa, -SH, -SRa, -S(=O)Ra, -NO2, -N(Rb)2, - S(=O)2Ra, -NHS(=O)2Ra, -S(=O)2N(Rb)2, -C(=O)Ra, -OC(=O)Ra, -C(=O)ORb, -OC(=O)ORb, - C(O)N(Rb)2, -OC(=O)N(Rb)2, -NRbC(=O)N(Rb)2, -NRbC(=O)Ra, -NRbC(=O)ORb, -Ci-C3 alkylene- NHS(=O)2Ra, -Ci-C3 alkylene-NRbC(=O)Ra, -Ci-C3 alkylene-OC(=O)Ra, -Ci-C3 alkylene- NRbC(=O)N(Rb)2, -Ci-C3 alkylene-NRbC(=O)ORb, -Ci-C3 alkylene-OC(=O)N(Rb)2, Ci-C6 alkyl, Ci- Cg aminoalkyl, Ci-Cg haloalkyl, Ci-Cg hydroxyalkyl, Ci-Cg heteroalkyl, 5-membered heteroaryl, C3- cycloalkyl, or 4 to 8 membered heterocycloalkyl, each of which is optionally substituted with one, two, three, or four halogen, -OH, Ci-C3 alkyl, Ci-C3 haloalkyl, or a 4 to 5-membered heterocycloalkyl;
R7A and R7B are each independently selected from hydrogen, halogen, -CN, -OH, -ORa, -SH, -SRa, - N(Rb)2, Ci-Cg alkyl, Ci-Cg aminoalkyl, Ci-Cg haloalkyl, or Ci-Cg hydroxyalkyl;
Z is -O- or -NR3B-; wherein R3B is hydrogen or Ci-C3 alkyl;
L2 is Ci-Cg alkylene which is optionally substituted with one, two, or three R8; each R8 is independently halogen, -OH, oxo, Ci-Cg alkyl, Ci-Cg haloalkyl, Ci-Cghydroxyalkyl, or C3-Cg cycloalkyl;
Q is -OR11 or -N(Rn)2; each R11 is independently hydrogen, Ci-Cg alkyl, Ci-Cg alkylamino, Ci-Cg haloalkyl, or Ci-Cg hydroxyalkyl, each of which is optionally substituted with one, two, or three halogen or Ci-C3 hydroxyalkyl; each Ra is independently Ci-Cg alkyl, C -Cg alkenyl, CS-Cg alkynyl, Ci-Cg heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Ci-Cg alkyl(aryl), -Ci-Cg alkyl(heteroaryl), -Ci-Cg alkyl(cycloalkyl), or -Ci-Cg alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-Cg alkyl, or Ci-Cg haloalkyl; and each Rb is independently hydrogen, Ci-Cg alkyl, C -Cg alkenyl, C -Cg alkynyl, Ci-Cg heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-Cg alkyl, or Ci-Cg haloalkyl.
[0022] In some embodiments of Formula (VI), Q is -OR11. In some embodiments of Formula (VI), Q is -N(Rn)2.
[0823] In some embodiment of Formula (I), (II), (III), (IV), (IVa), (V), (Va), (Vb), or (VI), Z is -O-. In some embodiments of Formula (I), (II), (III), (IV), (IVa), (V), (Va), (Vb), or (VI), Z is - NR3B-. In some embodiments of Formula (I), (II), (III), (IV), (IVa), (V), (Va), or (Vb), L1 is Ci-Cg alkylene which is optionally substituted with one, two, or three R8. In some embodiments of Formula (I), (II), (III), (IV), (IVa), (V), (Va), or (Vb), L1 is absent. [8824] In some embodiments of Formula (III), (IV), (IVa), (V), (Va), (Vb), or (VI), R4 is independently hydrogen, halogen, -CN, -S(=O)Ra, -N(Rb)2, -S(=O)2Ra, -NHS(=O)2Ra, -S(=O)2N(Rb)2, - C(=O)Ra, -C(=O)ORb, -C(O)N(Rb)2, -OC(=O)N(Rb)2, -NRbC(=O)N(Rb)2, -NRbC(=O)Ra, -NRbC(=O)ORb, -Ci-C3 alkylene-NHS(=O)2Ra, -Ci-C3 alkylene-NRbC(=O)Ra, -Ci-C3 alkylene-OC(=O)Ra, -Ci-C3 alkylene-NRbC(=O)N(Rb)2, -Ci-C3 alkylene-NRbC(=O)ORb, -Ci-C3 alkylene-OC(=O)N(Rb)2, Ci-C6 alkyl, Ci-Cg aminoalkyl, Ci-Cg haloalkyl, Ci-Cg hydroxyalkyl, Ci-Cg heteroalkyl, 5-membered heteroaryl, C3-Cx cycloalkyl, or 4 to 8 membered heterocycloalkyl, each of which is optionally substituted with one, two, three, or four halogen, -OH, Ci-C3 alkyl, Ci-C3 haloalkyl, or a 4 to 5-membered heterocycloalkyl. In some embodiments of Formula (III), (IV), (IVa), (V), (Va), (Vb), or (VI), R4 is hydrogen, halogen, -CN, - C(=O)Ra, -C(=O)ORb, -C(O)N(Rb)2, -CH2-NHS(=O)2Ra, -CH2-NRbC(=O)Ra, -CH2-NRbC(=O)N(Rb)2, - CH2-NRbC(=O)ORb, -CH2-OC(=O)N(Rb)2, Ci-C6 alkyl, Ci-C6 haloalkyl, Ci-C6 hydroxyalkyl, Ci-C6 heteroalkyl, 5-membered heteroaryl, C3-Cx cycloalkyl, or 4 to 6 membered heterocycloalkyl. In some embodiments of Formula (II), (III), (IV), (IVa), (V), (Va), (Vb), or (VI), R7A and R7B are each independently halogen. In some embodiments of Formula (II), (III), (IV), (IVa), (V), (Va), (Vb), or (VI), R7A and R7B are each independently chloro or fluoro. In some embodiments of Formula (II), (III), (IV), (IVa), (V), (Va), (Vb), or (VI), X1 is N. In some embodiments of Formula (II), (III), (IV), (IVa), (V), (Va), (Vb), or (VI), X1 is CH. In some embodiments of Formula (I), (II), (III), (IV), (IVa), (V), (Va), (Vb), or (VI), A is CH and B is CH. In some embodiments of Formula (I), (II), (III), (IV), (IVa), (V), (Va), (Vb), or (VI), A is N and B is CH. In some embodiment of Formula (I), (II), (III), (IV), (IVa), (V), (Va), (Vb), or (VI), A is CH and B is N. In some embodiments of Formula (I), (II), (III), (IV), (IVa), (V), (Va), (Vb), or (VI), A is N and B is N. 882S] In another aspects, the disclosure provides a pharmaceutical composition comprising a compound described herein and a pharmaceutically acceptable excipient.
(8826) In another aspect, the disclosure provides for a method of treating a disease or condition associated with inhibiting protein kinase, membrane associated tyrosine/threonine 1 (PKMYT1) in a patient in need thereof, comprising administering to the patient a compound of compound disclosed herein or a pharmaceutically acceptable salt thereof. In some embodiments, the disease or condition is a cancer. 27] In another aspect, the disclosure provides a method of treating a cancer in a patient in need thereof, comprising administering to the patient a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.
[8828] In some embodiments, the cancer is leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia, acute lymphoblastic leukemia (ALL), non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), or multiple myeloma (MM). In some embodiments, the cancer is a solid cancer. In some embodiments, the cancer is a skin cancer, ocular cancer, gastrointestinal cancer, thyroid cancer, breast cancer, ovarian cancer, central nervous system cancer, laryngeal cancer, cervical cancer, lymphatic system cancer, genitourinary tract cancer, bone cancer, biliary tract cancer, endometrial cancer, liver cancer, lung cancer, prostate cancer, or colon cancer. [8829] Additional aspects and advantages of the present disclosure will become readily apparent to those skilled in this art from the following detailed description, wherein only illustrative embodiments of the present disclosure are shown and described. As will be realized, the present disclosure is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects, all without departing from the disclosure. Accordingly, the drawings and description are to be regarded as illustrative in nature, and not as restrictive.
INCORPORATION BY REFERENCE
[8838] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and/or take precedence over any such contradictory material.
DETAILED DESCRIPTION OF THE INVENTION
[8831 [ While various embodiments of the invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions may occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed.
A. Definitions
[8832] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference.
[8833] Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.
[8834] Reference throughout this specification to “some embodiments” or “an embodiment” means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and/or” unless the content clearly dictates otherwise.
[8833] The terms below, as used herein, have the following meanings, unless indicated otherwise: (863^ “oxo” refers to =0.
^0037 i “Carboxyl” refers to -C00H.
(0038 j “Cyano” refers to -CN.
“Alkyl” refers to a straight-chain, or branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2 -methyl- 1 -propyl, 2 -methyl -2 -propyl, 2- methyl-1 -butyl, 3 -methyl- 1 -butyl, 2-methyl-3 -butyl, 2,2-dimethyl-l -propyl, 2 -methyl- 1 -pentyl, 3-methyl- 1 -pentyl, 4-methyl-l -pentyl, 2 -methyl -2 -pentyl, 3 -methyl -2 -pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l- butyl, 3, 3 -dimethyl- 1 -butyl, 2 -ethyl- 1 -butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl and the like. Whenever it appears herein, a numerical range such as “Ci-Ce alkyl” or “Ci-galkyl”, means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, the alkyl is a Ci-ioalkyl. In some embodiments, the alkyl is a Ci-galkyl. In some embodiments, the alkyl is a Ci-salkyl. In some embodiments, the alkyl is a Ci-4alkyl. In some embodiments, the alkyl is a Ci-3alkyl. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -C(=O)OH, - C(=O)OMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen.
“Alkenyl” refers to a straight-chain, or branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms. The group may be in either the cis or trans conformation about the double bond(s), and should be understood to include both isomers. Examples include, but are not limited to ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CHs)=CH2], butenyl, 1,3-butadienyl and the like. Whenever it appears herein, a numerical range such as “C2-C6 alkenyl” or “C2-6alkenyl”, means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkenyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkenyl is optionally substituted with oxo, halogen, -CN, -C(=O)OH, - C(=O)OMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen. “Alkynyl” refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and the like. Whenever it appears herein, a numerical range such as “C2-C6 alkynyl” or “C2-6alkynyl”, means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkynyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkynyl is optionally substituted with oxo, halogen, - CN, -C(=O)OH, C(=O)OMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen. f 042 j “Alkylene” refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkylene is optionally substituted with oxo, halogen, -CN, -C(=O)OH, C(=O)OMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen. “Alkoxy” refers to a radical of the formula -ORa where Ra is an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -C(=O)OH, C(=O)OMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.
[8844^ "Aryl" refers to a radical derived from an aromatic monocyclic or aromatic multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or aromatic multicyclic hydrocarbon ring system can contain only hydrogen and carbon and from five to eighteen carbon atoms, where at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) K-cIcctron system in accordance with the Htickel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. The aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl (phenyl). Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the aryl is optionally substituted with halogen, methyl, ethyl, -CN, - C(=O)OH, C(=O)OMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.
[004S] “Carbocycle” refers to a saturated, unsaturated, or aromatic rings in which each atom of the ring is carbon. Carbocycle may include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. An aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated, and aromatic bicyclic rings, as valence permits, are included in the definition of carbocyclic. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. Unless stated otherwise specifically in the specification, a carbocycle may be optionally substituted.
[884S] “Cycloalkyl” refers to a partially or fully saturated, monocyclic, or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom), spiro, or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (e.g., C3-C15 fully saturated cycloalkyl or C3-C15 cycloalkenyl), from three to ten carbon atoms (e.g., C3-C10 fully saturated cycloalkyl or C3-C10 cycloalkenyl), from three to eight carbon atoms (e.g., C3-C8 fully saturated cycloalkyl or C3-C8 cycloalkenyl), from three to six carbon atoms (e.g., C3-C6 fully saturated cycloalkyl or C3-C6 cycloalkenyl), from three to five carbon atoms (e.g., C3-C5 fully saturated cycloalkyl or C3-C5 cycloalkenyl), or three to four carbon atoms (e.g., C3-C4 fully saturated cycloalkyl or C3-C4 cycloalkenyl). In some embodiments, the cycloalkyl is a 3- to 10-membered fully saturated cycloalkyl or a 3- to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3- to 6-membered fully saturated cycloalkyl or a 3- to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5- to 6-membered fully saturated cycloalkyl or a 5 - to 6-membered cycloalkenyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbomyl, decalinyl, bicyclo [3.3.0] octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo [2. l.l]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7- dimethyl-bicyclo[2.2.1]heptanyl. Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -C(=O)OH, C(=O)OMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen. f 047 j "Cycloalkenyl" refers to an unsaturated non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, preferably having from three to twelve carbon atoms and comprising at least one double bond. In certain embodiments, a cycloalkenyl comprises three to ten carbon atoms. In other embodiments, a cycloalkenyl comprises five to seven carbon atoms. The cycloalkenyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkenyls includes, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
[8048] “Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.
[8849] As used herein, the term "haloalkyl" or “haloalkane” refers to an alkyl radical, as defined above, that is substituted by one or more halogen radicals, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, l-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally further substituted. Examples of halogen substituted alkanes (“haloalkanes”) include halomethane (e.g., chloromethane, bromomethane, fluoromethane, iodomethane), di-and trihalomethane (e.g., trichloromethane, tribromomethane, trifluoromethane, triiodomethane), 1-haloethane, 2-haloethane, 1,2-dihaloethane, 1-halopropane, 2-halopropane, 3- halopropane, 1,2-dihalopropane, 1,3-dihalopropane, 2,3-dihalopropane, 1,2,3-trihalopropane, and any other suitable combinations of alkanes (or substituted alkanes) and halogens (e.g., Cl, Br, F, I, etc.). When an alkyl group is substituted with more than one halogen radicals, each halogen may be independently selected e.g., 1 -chloro, 2-fluoroethane.
[8858] "Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, l-fluoromethyl-2-fluoroethyl, and the like.
[8 S1 [ “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.
[8852] “Aminoalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.
[8853] “Heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a Ci-Ce heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g. - NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyl are, for example, - CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, - CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless stated otherwise specifically in the specification, a heteroalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, - OMe, -NH2, or -NO2. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.
“Heterocycloalkyl” refers to a 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, silicon, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl comprises one to three nitrogens. In some embodiments, the heterocycloalkyl comprises one or two nitrogens. In some embodiments, the heterocycloalkyl comprises one nitrogen. In some embodiments, the heterocycloalkyl comprises one nitrogen and one oxygen. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom), spiro, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized. Representative heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (e.g., C2-C15 fully saturated heterocycloalkyl or C2-C15 heterocycloalkenyl), from two to ten carbon atoms (e.g., C2-C10 fully saturated heterocycloalkyl or C2-C10 heterocycloalkenyl), from two to eight carbon atoms (e.g., C2- Cx fully saturated heterocycloalkyl or C2-C8 heterocycloalkenyl), from two to seven carbon atoms (e.g., C2-C7 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), from two to six carbon atoms (e.g., C2-C6 fully saturated heterocycloalkyl or C2-C6 heterocycloalkenyl), from two to five carbon atoms (e.g., C2-C5 fully saturated heterocycloalkyl or C2-C5 heterocycloalkenyl), or two to four carbon atoms (e.g., C2-C4 fully saturated heterocycloalkyl or C2-C4 heterocycloalkenyl). Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo- thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-l-yl, 3-oxo-l,3- dihydroisobenzofuran-l-yl, methyl-2-oxo-l,3-dioxol-4-yl, and 2-oxo-l,3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides, and the oligosaccharides. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring). In some embodiments, the heterocycloalkyl is a 3- to 8-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkenyl. Unless stated otherwise specifically in the specification, a heterocycloalkyl may be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -C(=O)OH, C(=O)OMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.
^8055^ “Heteroaryl” refers to a 5- to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl comprises one to three nitrogens. In some embodiments, the heteroaryl comprises one or two nitrogens. In some embodiments, the heteroaryl comprises one nitrogen. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl. In some embodiments, the heteroaryl is a 6-membered heteroaryl. In some embodiments, the heteroaryl is a 5 -membered heteroaryl. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1 -phenyl- IH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -C(=O)OH, C(=O)OMe, -CF3, - OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen. f S j The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons or substitutable heteroatoms, e.g., NH, of the structure. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. In certain embodiments, substituted refers to moieties having substituents replacing two hydrogen atoms on the same carbon atom, such as substituting the two hydrogen atoms on a single carbon with an oxo, imino or thioxo group. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched, and unbranched, carbocyclic, and heterocyclic, aromatic, and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. f 0 S7 f The term “one or more” when referring to an optional substituent means that the subject group is optionally substituted with one, two, three, or four substituents. In some embodiments, the subject group is optionally substituted with one, two, or three substituents. In some embodiments, the subject group is optionally substituted with one or two substituents. In some embodiments, the subject group is optionally substituted with one substituent. In some embodiments, the subject group is optionally substituted with two substituents. fO SSf The term “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” means either “alkyl” or “substituted alkyl” as defined above. Further, an optionally substituted group may be un-substituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), mono-substituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH2CHF2, - CH2CF3, -CF2CH3, -CFHCHF2, etc ).
[0059] The term “salt” or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methane sulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.
The phrases “parenteral administration” and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrastemal injection and infusion.
[0 61] 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.
| 0062] The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as com starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.
An “effective amount” or “therapeutically effective amount” refers to an amount of a compound administered to a mammalian subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.
The terms “treat,” “treating” or “treatment,” as used herein, may include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically.
B. Compounds of the disclosure
In an aspect, the present disclosure pro vides for compounds that function as inhibitors of
PKMYT1. In an aspect, the present disclosure provides for compounds that function as modulators of
PKMYT1.
[006^ In an aspect, provided herein is a compound represented by Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000021_0001
Formula (I), wherein,
A, B, and C, are each independently N or CR4;
D is N, CR4, or CR5;
E is N, CR4, or CR5; wherein one of D or E is CR5;
R1 is hydrogen, Ci-Cg alkyl, Ci-Cg heteroalkyl, C3-C6 cycloalkyl, or 4 to 6 membered heterocycloalkyl;
W is O or NH; or W and R1 combine with the atoms to which they are attached to form a 5 to 6-membered heterocycloalkyl or 5 to 6-membered heteroaryl;
R2 is Cg-Cio aryl or 6 to 10 membered heteroaryl; each of which is optionally substituted with one, two, three, or four R7; each R7 is independently selected from halogen, -CN, -OH, -ORa, -SH, -SRa, -N(Rb)2, -C(=O)Ra, - C(=O)ORb, -C(=O)(Nb)2, Ci-Cg alkyl, Ci-Cg aminoalkyl, Ci-Cg haloalkyl, or Ci-Cg hydroxyalkyl; or two R7 together with the atoms to which they are attached form a 5 to 6-membered heterocycloalkyl; R3A is hydrogen or C1-C3 alkyl; each R4 is independently hydrogen, halogen, -CN, -OH, -ORa, -SH, -SRa, -S(=O)Ra, -NO2, -N(Rb)2, - S(=O)2Ra, -NHS(=O)2Ra, -S(=O)2N(Rb)2, -C(=O)Ra, -OC(=O)Ra, -C(=O)ORb, -OC(=O)ORb, - C(O)N(Rb)2, -OC(=O)N(Rb)2, -NRbC(=O)N(Rb)2, -NRbC(=O)Ra, -NRbC(=O)ORb, -Ci-C3 alkylene- NHS(=O)2Ra, -C1-C3 alkylene-NRbC(=O)Ra, -C1-C3 alkylene-OC(=O)Ra, -C1-C3 alkylene- NRbC(=O)N(Rb)2, -C1-C3 alkylene-NRbC(=O)ORb, -C1-C3 alkylene-OC(=O)N(Rb)2, Ci-Cg alkyl, Ci- Cg aminoalkyl, Ci-Cg haloalkyl, Ci-Cg hydroxyalkyl, Ci-Cg heteroalkyl, 5-membered heteroaryl, C3- cycloalkyl, or 4 to 8 membered heterocycloalkyl, each of which is optionally substituted with one, two, three, or four halogen, -OH, C1-C3 alkyl, C1-C3 haloalkyl, or a 4 to 5-membered heterocycloalkyl; or two R4 on adjacent carbon atoms together with the atoms to which they are attached form a 5 to 6- membered heteroaryl;
Figure imgf000022_0001
wherein
L is absent or Z-L1, wherein
Z is -O- or -NR3B-; wherein R3B is hydrogen or C1-C3 alkyl;
L1 is absent or Ci-Cg alkylene which is optionally substituted with one, two, or three R8;
L2 is Ci-Cg alkylene which is optionally substituted with one, two, or three R8; each R8 is independently halogen, -OH, oxo, Ci-Cg alkyl, Ci-Cg haloalky 1, Ci-Cghydroxyalkyl, or C3-C6 cycloalkyl; ring A is 5 to 10-membered heteroaryl, Cg-Cio cycloalkyl, or 5 to 10 membered heterocycloalkyl; each R6 is independently hydrogen, halogen, -CN, -OH, -ORa, -N(Rb)2, -S(=O)2Ra, -NHS(=O)2Ra, - S(=O)2N(Rb)2, -C(=O)Ra, -OC(=O)Ra, -C(=O)ORb, -C(=O)N(Rb)2, -NRbC(=O)Ra, oxo, Ci-Cg alkyl, Ci-Cg alkylamino, Ci-Cghaloalkyl, Ci-Cg hydroxyalkyl, Ci-Cg heteroalkyl, C3-C8 cycloalkyl, or 4 to 8 membered heterocycloalkyl; or two R6 together with the intervening atoms to which they are attached form a 5 to 8 membered heteroaryl, C’s-Cx cycloalkyl, or 5 to 8 membered heterocycloalkyl;
Q is -OR11 or -N(Rn)2; each R11 is independently hydrogen, Ci-Cg alkyl, Ci-Cg alkylamino, Ci-Cg haloalkyl, or Ci-Cg hydroxyalkyl, each of which is optionally substituted with one, two, or three halogen or C1-C3 hydroxyalkyl; m is 0, 1, 2, 3, or 4;
R10 is hydrogen, halogen, -CN, -OH, -NH2, Ci-Cg alkyl, or Ci-Cg haloalkyl; each Ra is independently Ci-Cg alkyl, CS-Cg alkenyl, CS-Cg alkynyl, Ci-Cg heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Ci-Cg alkyl(aryl), -Ci-Cg alkyl(heteroaryl), -Ci-Cg alkyl(cycloalkyl), or -Ci-Cg alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-Cg alkyl, or Ci-Cg haloalkyl; and each Rb is independently hydrogen, Ci-Cg alkyl, CS-Cg alkenyl, CS-Cg alkynyl, Ci-Cg heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-Cg alkyl, or Ci-Cg haloalkyl.
[0067 f In an aspect, provided herein is a compound represented by Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000023_0001
Formula (I), wherein,
A and B are each independently N or CH;
C is CH;
D is N, CR4, or CR5;
E is N, CR4, or CR5; wherein one of D or E is CR5;
R1 is hydrogen, methyl, cyclopropyl, cyclopentyl, or 4 membered heterocycloalkyl;
W is O;
R2 is phenyl or 6 membered heteroaryl, each of which is optionally substituted with one, two, three, or four R7; each R7 is independently selected from halogen, -CN, -OH, -ORa, -N(Rb)2, -C(=O)(Nb)2, Ci-Cg alkyl, or Ci-Cg haloalkyl; or two R7 together with the atoms to which they are attached form a 5 to 6-membered heterocycloalkyl;
R3A is hydrogen;
R4 is hydrogen, halogen, -CN, -C(=O)Ra, -C(=O)ORb, -C(0)N(Rb)2, -0C(=0)N(Rb)2, -NRbC(=0)N(Rb)2, -NRbC(=0)Ra, -NRbC(=0)0Rb, -Ci-C3 alkylene-NHS(=O)2Ra, -Ci-C3 alkylene-NRbC(=O)Ra, -Ci-C3 alkylene-OC(=O)Ra, -Ci-C3 alkylene-NRbC(=O)N(Rb)2, -Ci-C3 alkylene-NRbC(=O)ORb, -Ci-C3 alkylene-OC(=O)N(Rb)2, Ci-Cg alkyl, Ci-Cg aminoalkyl, Ci-Cg haloalkyl, Ci-Cghydroxyalkyl, Ci-Cg heteroalkyl, 5-membered heteroaryl, C3-Cx cycloalkyl, or 4 to 8 membered heterocycloalkyl, each of which is optionally substituted with one, two, three, or four halogen, -OH, Ci-C3 alkyl, Ci-C3 haloalkyl, or a 4 to 5 -membered heterocycloalkyl;
Figure imgf000024_0001
wherein
L is absent or Z-L1, wherein
Z is -O- or -NR3B-; wherein R3B is hydrogen or methyl;
L1 is absent or Ci-Cg alkylene which is optionally substituted with one, two, or three R8;
L2 is Ci-Cg alkylene which is optionally substituted with one, two, or three R8; each R8 is independently halogen, -OH, oxo, Ci-Cg alkyl, Ci-Cg haloalky 1, Ci-Cghydroxyalkyl, or C3-C6 cycloalkyl; ring A is 5 to 10-membered heteroaryl, Cg-Cw cycloalkyl, or 5 to 10 membered heterocycloalkyl; each R6 is independently hydrogen, halogen, -CN, -OH, -ORa, -N(Rb)2, -S(=O)2Ra, -NHS(=O)2Ra, - S(=O)2N(Rb)2, -C(=O)Ra, -OC(=O)Ra, -C(=O)ORb, -C(=O)N(Rb)2, -NRbC(=O)Ra, oxo (=0), C Cg alkyl, Ci-Cg alkylamino, Ci-Cghaloalkyl, Ci-Cghydroxyalkyl, Ci-Cg heteroalkyl, C3-C8 cycloalkyl, or 4 to 8 membered heterocycloalkyl; or
Q is -OR11 or -N(Rn)2; each R11 is independently hydrogen, Ci-Cg alkyl, Ci-Cg alkylamino, Ci-Cg haloalkyl, or Ci-Cg hydroxyalkyl, each of which is optionally substituted with one, two, or three halogen or C1-C3 hydroxyalkyl; m is 0, 1, 2, 3, or 4;
R10 is hydrogen; each Ra is independently Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, Ci-Cg heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Ci-Cg alkyl(aryl), -Ci-Cg alkyl(heteroaryl), -Ci-Cg alkyl(cycloalkyl), or -Ci-Cg alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-Cg alkyl, or Ci-Cg haloalkyl; and each Rb is independently hydrogen, Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, Ci-Cg heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-Cg alkyl, or Ci-Cg haloalkyl.
[8868] In some embodiments of Formula (I), W is O. In some embodiments, W is NH.
[8869] In some embodiments, the compound of Formula (I) has the structure of Formula (la), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000024_0002
Formula (la).
]f8)78] In some embodiments of Formula (I) or (la), W and R1 combine together with the intervening atoms to which they are attached to form a 5 to 6-membered heterocycle. In some embodiments of Formula (I) or (a), W and R1 combine together with the intervening atoms to which they are attached to form a 5-membered heterocycle. In some embodiments of Formula (I) or (la), W and R1 combine together with the intervening atoms to which they are attached form a 6-membered heterocycle. In some embodiments of Formula (I) or (la), W and R1 combine together with the intervening atoms to which they are attached form a 5 to 6-membered heterocycle comprising one, two, or three N atoms.
[8871] In some embodiments of Formula of Formula (I) or (la), R3A is hydrogen. In some embodiments of Formula (I) or (la), R3A is C1-C3 alkyl. In some embodiments of Formula (I) or (la), R3A is methyl.
[8872] In some embodiments, of Formula (I) or (la) R1 is hydrogen. In some embodiments of Formula (I) or (la), R1 is Ci-Ce alkyl. In some embodiments, R1 is Ci-Cg heteroalkyl. In some embodiments of Formula (I) or (la), R1 is methyl, ethyl, n-propyl, iso-propyl, sec-butyl, iso-butyl, or tert-butyl. In some embodiments of Formula (I) or (la), R1 is methyl. In some embodiments of Formula (I) or (la), R1 is C3- Cg cycloalkyl. In some embodiments of Formula (I) or (la), R1 is 4 to 6 membered heterocycloalkyl. In some embodiments of Formula (I) or (la), R1 is cyclopropyl, cyclobutyl, cyclopentyl, or oxetane. In some embodiments of Formula (I) or (la), R1 is hydrogen, methyl, cyclopropyl, cyclobutyl, cyclopentyl, or 4 membered heterocycloalkyl.
[8873] In some embodiments of Formula (I) or (la), R2 is phenyl, which is optionally substituted with one, two, three, or four R7. In some embodiments of Formula (I) or (la), R2 is 6 to 10 membered heteroaryl which is optionally substituted with one, two, three, or four R7. In some embodiments of Formula (I) or (la), the heteroaryl is a membered monocyclic heteroaryl or bicyclic having one, two, or three ring heteroatoms independently selected from N, O and S.
[8874] In some embodiments of Formula (I) or (la), R2 is phenyl or 6-memembered heteroaryl each of which are optionally substituted with one, two, three or four R7. In some embodiments of Formula (I) or (la), R2 is phenyl or 6-memembered heteroaryl each of which are optionally substituted with one, two, or three R7. In some embodiments of Formula (I) or (la), R2 is phenyl or 6-memembered heteroaryl each of which are optionally substituted with one or two R7. In some embodiments of Formula (I) or (la), R2 is phenyl, pyridinyl, pyrazinyl, or pyrimidinyl. In some embodiments of Formula (I) or (la), R2 is phenyl. In some embodiments of Formula (I) or (la), R2 is pyridinyl. In some embodiments of Formula (I) or (la), R2 is pyrazinyl. In some embodiments of Formula (I) or (la), R2 is pyrimidinyl.
[8875] In some embodiments of Formula (I) or (la), each R7 is independently selected from halogen, - CN, -OH, -ORa, -SH, -SRa, -N(Rb)2, -C(=O)Ra, -C(=O)N(Rb)2, -C(=O)ORb, Ci-C6 alkyl, Ci-C6 aminoalkyl, Ci-Cghaloalkyl, or Ci-Cg hydroxy alkyl. In some embodiments of Formula (I) or (la), each R7 is independently selected from halogen, -CN, -OH, -ORa, -N(Rb)2, -C(=O)N(Rb)2, Ci-Cg alkyl, or Ci-Cg haloalkyl. In some embodiments of Formula (I) or (la), each R7 is independently selected from halogen, - CN, -OH, -ORa, -C(=O)N(Rb)2, -N(Rb)2, or Ci-Cg alkyl. In some embodiments of Formula (I) or (la), each R7 is independently halogen, -CN, -OH, -OCH3, -CH3, -NH2, -NHCH3, -N(CH2)2, or -C(=O)NH2. In some embodiments of Formula (I) or (la), each R7 is independently chore, fluoro, -CN, -OH, -CH3, -CF3, -NH2, -NHCH3, -N(CH2)2, or -C(=O)NH2. In some embodiments of Formula (I) or (la), each R7 is independently fluoro, chloro, -OH, -CF3, or -CH3. In some embodiments, each R7 is independently halogen. In some embodiments of Formula (I) or (la), each R7 is independently selected from chloro or fluoro. f 076 j In some embodiments of Formula (I) or (la), two R7 together with the atoms to which they are attached form a 5 to 6-membered heterocycloalkyl. In some embodiments of Formula (I) or (la), two R7 together with the atoms to which they are attached form a 5 heterocycloalkyl. In some embodiments of Formula (I) or (la), two R7 together with the atoms to which they are attached form a 6-membered heterocycloalkyl.
[8877] In some embodiments of Formula (I) or (la), R10 is hydrogen, halogen, -CN, -OH, -NH2, Ci-Cg alkyl, or Ci-Cg haloalkyl. In some embodiments of Formula (I) or (la), R10 is hydrogen, halogen, -CN, Ci- Cg alkyl, or Ci-Cg haloalkyl. In some embodiments of Formula (I) or (la), R10 is hydrogen or halogen, In some embodiments of Formula (I) or (la), R10 is Ci-Cg alkyl or Ci-Cg haloalkyl. In some embodiments of Formula (I) or (la), R10 is hydrogen. W78] In some embodiments, provided herein is a compound has the structure of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000026_0001
Formula (II), wherein,
A, B, and C, are each independently N or CR4;
D is N, CR4, or CR5;
E is N, CR4, or CR5; wherein one of D or E is CR5;
X1 is CH or N;
W is O or NH; each R4 is independently hydrogen, halogen, -CN, -OH, -ORa, -SH, -SRa, -S(=O)Ra, -NO2, -N(Rb)2, - S(=O)2Ra, -NHS(=O)2Ra, -S(=O)2N(Rb)2, -C(=O)Ra, -OC(=O)Ra, -C(=O)ORb, -OC(=O)ORb, - C(O)N(Rb)2, -OC(=O)N(Rb)2, -NRbC(=O)N(Rb)2, -NRbC(=O)Ra, -NRbC(=O)ORb, -Ci-C3 alkylene- NHS(=O)2Ra, -Ci-C3 alkylene-NRbC(=O)Ra, -Ci-C3 alkylene-OC(=O)Ra, -Ci-C3 alkylene- NRbC(=O)N(Rb)2, -Ci-C3 alkylene-NRbC(=O)ORb, -Ci-C3 alkylene-OC(=O)N(Rb)2, Ci-C6 alkyl, Ci- Cg aminoalkyl, Ci-Cg haloalkyl, Ci-Cg hydroxyalkyl, Ci-Cg heteroalkyl, 5-membered heteroaryl, C3- cycloalkyl, or 4 to 8 membered heterocycloalkyl, each of which is optionally substituted with one, two, three, or four halogen, -OH, Ci-C3 alkyl, Ci-C3 haloalkyl, or a 4 to 5-membered heterocycloalkyl; or two R4 on adjacent carbon atoms together with the atoms to which they are attached form a 5 to 6- membered heteroaryl;
Figure imgf000027_0001
wherein
L is absent or Z-L1,
Z is -O- or -NR3B-; wherein R3B is hydrogen or C1-C3 alkyl;
L1 is absent or Ci-Cg alkylene which is optionally substituted with one, two, or three R8;
L2 is Ci-Cg alkylene which is optionally substituted with one, two, or three R8; each R8 is independently halogen, -OH, oxo, Ci-Cg alkyl, Ci-Cg haloalky 1, Ci-Cghydroxyalkyl, or C3- Cg cycloalkyl; ring A is 5 to 10-membered heteroaryl, Cg-Cw cycloalkyl, or 5 to 10 membered heterocycloalkyl; each R6 is independently hydrogen, halogen, -CN, -OH, -ORa, -N(Rb)2, -S(=O)2Ra, -NHS(=O)2Ra, - S(=O)2N(Rb)2, -C(=O)Ra, -OC(=O)Ra, -C(=O)ORb, -C(=O)N(Rb)2, -NRbC(=O)Ra, oxo, Ci-C6 alkyl, Ci-Cg alkylamino, Ci-Cghaloalkyl, Ci-Cg hydroxyalkyl, Ci-Cg heteroalkyl, C3-C8 cycloalkyl, or 4 to 8 membered heterocycloalkyl; or two R6 together with the intervening atoms to which they are attached form a 5 to 8 membered heteroaryl, C’s-Cx cycloalkyl, or 5 to 8 membered heterocycloalkyl;
Q is -OR11 or -N(Rn)2; ach R11 is independently hydrogen, Ci-Cg alkyl, Ci-Cg alkylamino, Ci-Cg haloalkyl, or Ci-Cg hydroxyalkyl, each of which is optionally substituted with one, two, or three halogen or C1-C3 hydroxyalkyl; m is 0, 1, 2, 3, or 4;
R7A and R7B are each independently selected from hydrogen, halogen, -CN, -OH, -ORa, -N(Rb)2, Ci-Cg alkyl, or Ci-Cg haloalkyl; each Ra is independently Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, Ci-Cg heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Ci-Cg alkyl(aryl), -Ci-Cg alkyl(heteroaryl), -Ci-Cg alkyl(cycloalkyl), or -Ci-Cg alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-Cg alkyl, or Ci-Cg haloalkyl; and each Rb is independently hydrogen, Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, Ci-Cg heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-Cg alkyl, or Ci-Cg haloalkyl.
In some embodiments of Formula (II), W is O. In some embodiments, W is NH.
In some embodiments, provided herein is a compound has the structure of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000027_0002
Formula (II), wherein,
A and B are each independently N or CH;
C is CH;
D is N, CR4, or CR5;
E is N, CR4, or CR5; wherein one of D or E is CR5;
X1 is CH or N;
W is O;
R4 is hydrogen, halogen, -CN, -C(=O)Ra, -C(=O)ORb, -C(O)N(Rb)2, -OC(=O)N(Rb)2, -NRbC(=O)N(Rb)2, -NRbC(=O)Ra, -NRbC(=O)ORb, -Ci-C3 alkylene-NHS(=O)2Ra, -Ci-C3 alkylene-NRbC(=O)Ra, -Ci-C3 alkylene-OC(=O)Ra, -Ci-C3 alkylene-NRbC(=O)N(Rb)2, -Ci-C3 alkylene-NRbC(=O)ORb, -Ci-C3 alkylene-OC(=O)N(Rb)2, Ci-Cg alkyl, Ci-Cg aminoalkyl, Ci-Cg haloalky 1, Ci-Cghydroxyalkyl, Ci-Cg heteroalkyl, 5-membered heteroaryl, C3-Cx cycloalkyl, or 4 to 8 membered heterocycloalkyl, each of which is optionally substituted with one, two, three, or four halogen, -OH, Ci-C3 alkyl, Ci-C3 haloalkyl, or a 4 to 5 -membered heterocycloalkyl;
Figure imgf000028_0001
wherein
L is absent or Z-L1,
Z is -O- or -NR3B-; wherein R3B is hydrogen or Ci-C3 alkyl;
L1 is absent or Ci-Cg alkylene which is optionally substituted with one, two, or three R8;
L2 is Ci-Cg alkylene which is optionally substituted with one, two, or three R8; each R8 is independently halogen, -OH, oxo, Ci-Cg alkyl, Ci-Cg haloalkyl, Ci-Cghydroxyalkyl, or C3- Cg cycloalkyl; ring A is 5 to 10-membered heteroaryl, Cg-Cio cycloalkyl, or 5 to 10 membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is monocyclic, bicyclic, polycyclic or spirocyclic; each R6 is independently hydrogen, halogen, -CN, -OH, -ORa, -N(Rb)2, -S(=O)2Ra, -NHS(=O)2Ra, - S(=O)2N(Rb)2, -C(=O)Ra, -OC(=O)Ra, -C(=O)ORb, -C(=O)N(Rb)2, -NRbC(=O)Ra, oxo, Ci-Cg alkyl, Ci-Cg alkylamino, Ci-Cg haloalkyl, Ci-Cg hydroxyalkyl, Ci-Cg heteroalkyl, C3-Cx cycloalkyl, or 4 to 8 membered heterocycloalkyl;
Q is -OR11 or -N R1 Q2; ach R11 is independently hydrogen, Ci-Cg alkyl, Ci-Cg alkylamino, Ci-Cg haloalkyl, or Ci-Cg hydroxyalkyl, each of which is optionally substituted with one, two, or three halogen or Ci-C3 hydroxyalkyl; m is 0, 1, 2, 3, or 4;
R7A and R7B are each independently selected from hydrogen or halogen; each Ra is independently Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, Ci-Cg heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Ci-Cg alkyl(aryl), -Ci-Cg alkyl(heteroaryl), -Ci-Cg alkyl(cycloalkyl), or -Ci-Cg alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-Cg alkyl, or Ci-Cg haloalkyl; and each Rb is independently hydrogen, Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, Ci-Cg heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-Cg alkyl, or Ci-Cg haloalkyl.
(88811 In some embodiments, the compound of Formula (II) has the structure of Formula (Ila), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000029_0001
Formula (Ila).
(88821 In some embodiments of Formula (I), (la), (II), or (Ila), A is N or CH.
(8883] In some embodiments of Formula (I), (la), (II), or (Ila), B is N or CH.
Figure imgf000029_0003
wherein
L is absent or Z-L1, wherein
Z is -O- or -NR3B-; wherein R3B is hydrogen or C1-C3 alkyl;
L1 is absent or Ci-Cg alkylene which is optionally substituted with one, two, or three R8; each R8 is independently halogen, -OH, oxo, Ci-Cg alkyl, Ci-Cg haloalky 1, Ci-Cghydroxyalkyl, or C3- Cg cycloalkyl; ring A is 5 to 10-membered heteroaryl, Cg-Cio cycloalkyl, or 5 to 10 membered heterocycloalkyl; each R6 is independently hydrogen, halogen, -CN, -OH, -ORa, -N(Rb)2, -S(=O)2Ra, -NHS(=O)2Ra, - S(=O)2N(Rb)2, -C(=O)Ra, -OC(=O)Ra, -C(=O)ORb, -C(=O)N(Rb)2, -NRbC(=O)Ra, oxo (=0), Ci- Cg alkyl, Ci-Cg alkylamino, Ci-Cghaloalkyl, Ci-Cghydroxyalkyl, Ci-Cg heteroalkyl, or C3-C8 cycloalkyl; or two R6 together with the atoms to which they are attached form a 5 to 8 membered heteroaryl, C’s-Cx cycloalkyl, or 5 to 8 membered heterocycloalkyl; m is 0, 1, 2, 3, or 4.
(888 ( In some embodiments of Formula (I),
Figure imgf000029_0002
, wherein
L is absent or Z-L1, wherein
Z is -O- or -NR3B-; wherein R3B is hydrogen or C1-C3 alkyl;
L1 is absent or Ci-Cg alkylene which is optionally substituted with one, two, or three R8; each R8 is independently halogen, -OH, oxo, Ci-Cg alkyl, Ci-Cg haloalky 1, Ci-Cghydroxyalkyl, or C3- Cg cycloalkyl; ring A is 5 to 8-membered heteroaryl, Cg-Cio cycloalkyl, Cg-Cio spirocycloalkyl, 5 to 10 membered heterocycloalkyl, or 5 to 10 membered spiroheterocycloalkyl; each R6 is independently hydrogen, halogen, -CN, -OH, -ORa, -N(Rb)2, -S(=O)2Ra, -NHS(=O)2Ra, - S(=O)2N(Rb)2, -C(=O)Ra, -OC(=O)Ra, -C(=O)ORb, -C(=O)N(Rb)2, -NRbC(=O)Ra, oxo (=0), Ci- Cg alkyl, Ci-Cg alkylamino, Ci-Cghaloalkyl, Ci-Cghydroxyalkyl, Ci-Cg heteroalkyl, or C3-C8 cycloalkyl; m is 0, 1, 2, 3, or 4.
[8889^ In some embodiments, provided herein is a compound having the structure of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000030_0001
Formula (III), wherein,
A and B are each independently N or CH;
X1 is N or CH;
W is O;
Ring A is ring A is a 5 to 10-membered heteroaryl, Cg-Cio cycloalkyl, or 5 to 10 membered heterocycloalkyl; each R4 is independently hydrogen, halogen, -CN, -OH, -ORa, -SH, -SRa, -S(=O)Ra, -NO2, -N(Rb)2, - S(=O)2Ra, -NHS(=O)2Ra, -S(=O)2N(Rb)2, -C(=O)Ra, -OC(=O)Ra, -C(=O)ORb, -OC(=O)ORb, - C(=O)N(Rb)2, -OC(=O)N(Rb)2, -NRbC(=0)N(Rb)2, -NRbC(=O)Ra, -NRbC(=O)ORb, -Ci-C3 alkylene- NHS(=O)2Ra, -C1-C3 alkylene-NRbC(=O)Ra, -C1-C3 alkylene-OC(=O)Ra, -C1-C3 alkylene- NRbC(=0)N(Rb)2, -C1-C3 alkylene-NRbC(=O)ORb, -C1-C3 alkylene-OC(=O)N(Rb)2, Ci-Cg alkyl, Ci- Cg aminoalkyl, Ci-Cghaloalkyl, Ci-Cg hydroxyalkyl, Ci-Cg heteroalkyl, 5-membered heteroaryl, C3- Cx cycloalkyl, or 4 to 8 membered heterocycloalkyl, each of which is optionally substituted with one, two, three, or four halogen, -OH, C1-C3 alkyl, C1-C3 haloalkyl, or a 4 to 5-membered heterocycloalkyl; each R6 is independently hydrogen, halogen, -CN, -OH, -ORa, -N(Rb)2, -S(=O)2Ra, -NHS(=O)2Ra, - S(=O)2N(Rb)2, -C(=O)Ra, -OC(=O)Ra, -C(=O)ORb, -C(=O)N(Rb)2, -NRbC(=O)Ra, oxo (=0), Ci-Cg alkyl, Ci-Cg alkylamino, Ci-Cg haloalkyl, Ci-Cg hydroxyalkyl, Ci-Cg heteroalkyl, C3-C8 cycloalkyl, or 4 to 8 membered heterocycloalkyl; or two R6 together with the intervening atoms to which they are attached form a 5 to 8 membered heteroaryl, Cs-Cx cycloalkyl, or 5 to 8 membered heterocycloalkyl; R7A and R7B are each independently selected from hydrogen, halogen, -CN, -OH, -ORa, -SH, -SRa, - N(Rb)2, Ci-Cg alkyl, Ci-Cg aminoalkyl, Ci-Cghaloalkyl, or Ci-Cg hydroxyalkyl;
L is absent or Z-L1, wherein
Z is -O- or -NR3B-; wherein R3B is hydrogen or C1-C3 alkyl;
L1 is absent or C1-C3 alkylene which is optionally substituted with one, two, or three R8; each R8 is independently halogen, -OH, oxo, Ci-Cg alkyl, Ci-Cg haloalky 1, Ci-Cghydroxyalkyl, or C3- Cg cycloalkyl; each Ra is independently Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, Ci-Cg heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Ci-Cg alkyl(aryl), -Ci-Cg alkyl(heteroaryl), -Ci-Cg alkyl(cycloalkyl), or -Ci-Cg alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-Cg alkyl, or Ci-Cg haloalkyl; each Rb is independently hydrogen, Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, Ci-Cg heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-Cg alkyl, or Ci-Cg haloalkyl; and m is 0, 1, 2, 3, or 4.
In some embodiments of Formula (III), ring A is a Cg-Cio cycloalkyl or 5 to 10 membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is monocyclic, bicyclic, polycyclic, or spirocyclic.
^009 Is In some embodiments of Formula (III), ring A is a C3-C8 cycloalkyl. In some embodiments of Formula (III), ring A is a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.
In some embodiments of Formula (III), ring A is a 5 to 10 membered heterocycloalkyl, wherein the heterocycloalkyl is a monocyclic, bicyclic, or spirocyclic heterocycloalkyl. In some embodiments of Formula (III), ring A is piperidine, piperazine, or morpholine. In some embodiments of Formula (III), ring A is piperidine. In some embodiments of Formula (III), ring A is piperazine. In some embodiments of Formula (III), ring A is morpholine. f 093 j In some embodiments, provided herein is a compound has the structure of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000031_0001
Formula (IV), wherein, W is O; X1 is CH orN;
X2 is CH orN;
X3 and X5 are each independently CR6R6, O or NRX;
X4 is CR6R6, O, NRX, S, S(=O), S(O)2, S(=O)=NRY, or S(O)ORY;
Rx is hydrogen, -S(=O)2OH, -S(=O)2NH2, Ci-Cg alkyl, Ci-Cg haloalkyl, or Ci-Cg hydroxyalkyl; each RY is independently hydrogen or C1-C3 alkyl;
A and B are each independently N or CH; each R4 is independently hydrogen, halogen, -CN, -OH, -ORa, -SH, -SRa, -S(=O)Ra, -NO2, -N(Rb)2, - S(=O)2Ra, -NHS(=O)2Ra, -S(=O)2N(Rb)2, -C(=O)Ra, -OC(=O)Ra, -C(=O)ORb, -OC(=O)ORb, - C(=O)N(Rb)2, -OC(=O)N(Rb)2, -NRbC(=O)N(Rb)2, -NRbC(=O)Ra, -NRbC(=O)ORb, -Ci-C3 alkylene- NHS(=O)2Ra, -Ci-C3 alkylene-NRbC(=O)Ra, -Ci-C3 alkylene-OC(=O)Ra, -Ci-C3 alkylene- NRbC(=O)N(Rb)2, -Ci-C3 alkylene-NRbC(=O)ORb, -Ci-C3 alkylene-OC(=O)N(Rb)2, Ci-C6 alkyl, Ci- Cg aminoalkyl, Ci-Cg haloalkyl, Ci-Cg hydroxyalkyl, Ci-Cg heteroalkyl, 5-membered heteroaryl, C3- Cx cycloalkyl, or 4 to 8 membered heterocycloalkyl, each of which is optionally substituted with one, two, three, or four halogen, -OH, Ci-C3 alkyl, Ci-C3 haloalkyl, or a 4 to 5-membered heterocycloalkyl; each R6 is independently hydrogen, halogen, -CN, -OH, -ORa, -N(Rb)2, -S(=O)2Ra, -NHS(=O)2Ra, - S(=O)2N(Rb)2, -C(=O)Ra, -OC(=O)Ra, -C(=O)ORb, -C(=O)N(Rb)2, -NRbC(=O)Ra, oxo, Ci-C6 alkyl, Ci-Cg alkylamino, Ci-Cg haloalkyl, Ci-Cghydroxyalkyl, Ci-Cg heteroalkyl, C3-Cx cycloalkyl, or 4 to 8 membered heterocycloalkyl; or two R6 together with the intervening atoms to which they are attached form a 5 to 8 membered heteroaryl, Cx-Cx cycloalkyl, or 5 to 8 membered heterocycloalkyl;
R7A and R7B are each independently selected from hydrogen, halogen, -CN, -OH, -ORa, -SH, -SRa, - N(Rb)2, Ci-Cg alkyl, Ci-Cg aminoalkyl, Ci-Cg haloalkyl, or Ci-Cg hydroxyalkyl;
L is absent or Z-L1, wherein
Z is -O- or -NR3B-; wherein R3B is hydrogen or Ci-C3 alkyl;
L1 is absent or Ci-C3 alkylene which is optionally substituted with one, two, or three R8; each R8 is independently halogen, -OH, oxo, Ci-Cg alkyl, Ci-Cg haloalkyl, Ci-Cghydroxyalkyl, or C3- Cg cycloalkyl; each Ra is independently Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, Ci-Cg heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Ci-Cg alkyl(aryl), -Ci-Cg alkyl(heteroaryl), -Ci-Cg alkyl(cycloalkyl), or -Ci-Cg alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-Cg alkyl, or Ci-Cg haloalkyl; each Rb is independently hydrogen, Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, Ci-Cg heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-Cg alkyl, or Ci-Cg haloalkyl; and m is 0, 1, 2, 3, or 4. In some embodiments of Formula (IV), X2 is CH; X3 and X5 are each independently CR6R6, O, or NRx; and X4 is CR6R6.
Figure imgf000033_0003
In some embodiments of Formula (IV), X3 and X5 are each independently O or NRX. In some embodiments of Formula (IV), X3 and X5 are each independently CR6R6. In some embodiments of Formula (IV), X3 is CR6R6. In some embodiments of Formula (IV),
Figure imgf000033_0004
X3 is O. In some embodiments of Formula (IV), X3 is NRX.
Figure imgf000033_0005
In some embodiments of Formula (IV), X5 is CR6R6. In some embodiments of Formula (IV),
X5 is O. In some embodiments of Formula (IV), X5 is NRX.
Figure imgf000033_0006
In some embodiments, the compound of Formula (IV) has the structure of Formula (IVa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000033_0001
Formula (IVa). In some embodiments, provided herein is a compound having the structure of Formula (IVa),
Figure imgf000033_0007
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000033_0002
wherein,
X1 is CH or N;
X2 is CH or N;
X4 is CR6R6, O, NRX, S, S(=O), S(=O)2, S(=O)=NRY, or S(=O)ORY;
Rx is hydrogen, -S(=O)2OH, -S(=O)2NH2, Ci-Cg alkyl, Ci-Cg haloalkyl, or Ci-Cg hydroxyalkyl; each RY is independently hydrogen or Ci-C3 alkyl;
A and B are each independently N or CH; each R4 is independently hydrogen, halogen, -CN, -OH, -ORa, -SH, -SRa, -S(=O)Ra, -NO2, -N(Rb)2, - S(=O)2Ra, -NHS(=O)2Ra, -S(=O)2N(Rb)2, -C(=O)Ra, -OC(=O)Ra, -C(=O)ORb, -OC(=O)ORb, - C(=O)N(Rb)2, -OC(=O)N(Rb)2, -NRbC(=O)N(Rb)2, -NRbC(=O)Ra, -NRbC(=O)ORb, -Ci-C3 alkylene- NHS(=O)2Ra, -Ci-C3 alkylene-NRbC(=O)Ra, -Ci-C3 alkylene-OC(=O)Ra, -Ci-C3 alkylene- NRbC(=O)N(Rb)2, -Ci-C3 alkylene-NRbC(=O)ORb, -Ci-C3 alkylene-OC(=O)N(Rb)2, Ci-C6 alkyl, Ci- Cg aminoalkyl, Ci-Cg haloalkyl, Ci-Cg hydroxyalkyl, Ci-Cg heteroalkyl, 5-membered heteroaryl, C3- cycloalkyl, or 4 to 8 membered heterocycloalkyl, each of which is optionally substituted with one, two, three, or four halogen, -OH, C1-C3 alkyl, C1-C3 haloalkyl, or a 4 to 5-membered heterocycloalkyl; each R6 is independently hydrogen, halogen, -CN, -OH, -ORa, -N(Rb)2, -S(=O)2Ra, -NHS(=0)2Ra, - S(=O)2N(Rb)2, -C(=O)Ra, -OC(=O)Ra, -C(=O)ORb, -C(=O)N(Rb)2, -NRbC(=O)Ra, oxo (=0), Ci-C6 alkyl, Ci-Cg alkylamino, Ci-Cg haloalkyl, Ci-Cg hydroxyalkyl, Ci-Cg heteroalkyl, C3-C8 cycloalkyl, or 4 to 8 membered heterocycloalkyl; or two R6 together with the intervening atoms to which they are attached form a 5 to 8 membered heteroaryl, -G cycloalkyl, or 5 to 8 membered heterocycloalkyl;
R7A and R7B are each independently selected from hydrogen, halogen, -CN, -OH, -0Ra, -SH, -SRa, - N(Rb)2, Ci-Cg alkyl, Ci-Cg aminoalkyl, Ci-Cg haloalkyl, or Ci-Cg hydroxyalkyl;
L is absent or Z-L1, wherein
Z is -O- or -NR3B-; wherein R3B is hydrogen or C1-C3 alkyl;
L1 is absent or C1-C3 alkylene which is optionally substituted with one, two, or three R8; each R8 is independently halogen, -OH, oxo, Ci-Cg alkyl, Ci-Cg haloalkyl, Ci-Cghydroxyalkyl, or C3- Cg cycloalkyl; each Ra is independently Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, Ci-Cg heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Ci-Cg alkyl(aryl), -Ci-Cg alkyl(heteroaryl), -Ci-Cg alkyl(cycloalkyl), or -Ci-Cg alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-Cg alkyl, or Ci-Cg haloalkyl; each Rb is independently hydrogen, Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, Ci-Cg heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-Cg alkyl, or Ci-Cg haloalkyl; and m is 0, 1, 2, 3, or 4.
In some embodiments of Formula (IV) or (IVa), X2 is CH. In some embodiments of Formula (IV) or (IVa), X2 is N. sOIG I] In some embodiments of Formula (IV) or (IVa), X4 is O, NRX, S, S(=O), S(=O)2, S(=O)=NRY, or S(=O)ORY. In some embodiments of Formula (IV) or (IVa), X4 is S, S(=O), or S(=O)2. In some embodiments of Formula (IV) or (IVa), X4 is S(=O)2. In some embodiments of Formula (IV) or (IVa), X4 is O or NRX. In some embodiments of Formula (IV) or (IVa), X4 is O. In some embodiments of Formula (IV) or (IVa), X4 is NRX. In some embodiments of Formula (IV) or (IVa), X4 is CR6R6.
^00192^ In some embodiments of Formula (IV) or (IVa), Rx is hydrogen, Ci-Cg alkyl, Ci-Cg haloalkyl, or Ci-Cg hydroxyalkyl. In some embodiments of Formula (IV) or (IVa), Rx is hydrogen or Ci-Cg alkyl. In some embodiments of Formula (IV) or (IVa), Rx is Ci-Cg alkyl. In some embodiments of Formula (IV) or (IVa), Rx is methyl or ethyl. In some embodiments of Formula (IV) or (IVa), Rx is Ci-Cg hydroxyalkyl. In some embodiments of Formula (IV) or (IVa), Rx is -S(=O)2OH or -S(=O)2NH2. In some embodiments of Formula (IV) or (IVa), Rx is -S(=O)2OH. In some embodiments of Formula (IV) or (IVa), Rx is -S(=O)2NH2. In some of Formula (IV) or (IVa), Rx is hydrogen.
[00183] In some embodiments of Formula (IV) or (IVa), each RY is independently C1-C3 alkyl. In some embodiments of Formula (IV) or (IVa), each RY is independently methyl or ethyl. In some embodiments of Formula (IV) or (IVa), each RY is independently methyl. In some embodiments of Formula (IV) or (IVa), each RY is independently hydrogen.
[80104] In some embodiments of Formula (III), ring A is 5 to 10-membered heteroaryl. In some embodiments of Formula (III), ring A is a 5 or 6 membered heteroaryl having one, two, or three heteroatoms selected from N, O, and S. In some embodiments of Formula (III), ring A is a 5 or 6 membered heteroaryl having one, two, or three heteroatoms selected from N and O. In some embodiments of Formula (III), ring A is a 5 membered heteroaryl having one, two, or three heteroatoms selected from N and O. In some embodiments of Formula (III), ring A is a 6 membered heteroaryl having one, two, or three heteroatoms selected from N and O.
[80105] In some embodiments of Formula (III), ring A is triazinyl, pyrrolyl, furanyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, or tetrazolyl. In some embodiments of Formula (III), ring A is pyrrolyl, imidazolyl, or pyrazolyl. In some embodiments of Formula (III), ring A is pyrrolyl. In some embodiments of Formula (III), ring A is imidazolyl. In some embodiments of Formula (III), ring A is pyrazolyl.
[00188] In some embodiments of Formula (III), ring A is pyridinyl, pyrimidinyl, ortriazinyl. In some embodiments of Formula (III), ring A pyridinyl. In some embodiments of Formula (III), ring A is pyrimidinyl. In some embodiments of Formula (III), ring A is triazinyl.
[8 107] In some embodiments, provided herein is a compound having the structure of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000035_0001
Formula (V), wherein,
W is O;
X1 is CH or N;
Y1 is C or N and Y2 is CH or N, provided that at least one of Y1 or Y2 is N;
A and B are each independently N or CH; each R4 is independently hydrogen, halogen, -CN, -OH, -ORa, -SH, -SRa, -S(=O)Ra, -NO2, -N(Rb)2, - S(=O)2Ra, -NHS(=O)2Ra, -S(=O)2N(Rb)2, -C(=O)Ra, -OC(=O)Ra, -C(=O)ORb, -OC(=O)ORb, - C(=O)N(Rb)2, -OC(=O)N(Rb)2, -NRbC(=O)N(Rb)2, -NRbC(=O)Ra, -NRbC(=O)ORb, -Ci-C3 alkylene- NHS(=O)2Ra, -Ci-C3 alkylene-NRbC(=O)Ra, -Ci-C3 alkylene-OC(=O)Ra, -Ci-C3 alkylene- NRbC(=O)N(Rb)2, -Ci-C3 alkylene-NRbC(=O)ORb, -Ci-C3 alkylene-OC(=O)N(Rb)2, Ci-C6 alkyl, Ci- Cg aminoalkyl, Ci-Cg haloalkyl, Ci-Cg hydroxyalkyl, Ci-Cg heteroalkyl, 5-membered heteroaryl, C3- cycloalkyl, or 4 to 8 membered heterocycloalkyl, each of which is optionally substituted with one, two, three, or four halogen, -OH, Ci-C3 alkyl, Ci-C3 haloalkyl, or a 4 to 5-membered heterocycloalkyl;
R6A is hydrogen, halogen, Ci-Cg alkyl, Ci-Cg haloalkyl, or Ci-Cg hydroxy alkyl;
R9 is hydrogen, Ci-Cg alkyl, Ci-Cg haloalkyl, Ci-Cghydroxyalkyl, -Ci-C3 alkylene(cycloalkyl), -Ci-C3 alkylene(heterocycloalkyl), C3-Cg cycloalkyl, or 4 to 6 membered heterocycloalkyl; or R6A and R9 together with the intervening atoms to which they are attached form a 6 to 8 membered heteroaryl or 6 to 8 membered heterocycloalkyl;
R7A and R7B are each independently selected from hydrogen, halogen, -CN, -OH, -ORa, -SH, -SRa, - N(Rb)2, Ci-Cg alkyl, Ci-Cg aminoalkyl, Ci-Cg haloalkyl, or Ci-Cg hydroxyalkyl;
L is absent or Z-L1, wherein
Z is -O- or -NR3B-; wherein R3B is hydrogen or Ci-C3 alkyl;
L1 is absent or Ci-C3 alkylene which is optionally substituted with one, two, or three R8; each R8 is independently halogen, -OH, oxo, Ci-Cg alkyl, Ci-Cg haloalkyl, Ci-Cghydroxyalkyl, or C3- Cg cycloalkyl; each Ra is independently Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, Ci-Cg heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Ci-Cg alkyl(aryl), -Ci-Cg alkyl(heteroaryl), -Ci-Cg alkyl(cycloalkyl), or -Ci-Cg alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-Cg alkyl, or Ci-Cg haloalkyl; and each Rb is independently hydrogen, Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, Ci-Cg heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-Cg alkyl, or Ci-Cg haloalkyl.
[00198 [ In some embodiments of Formula (V), Y1 is N and Y2 is N. In some embodiments of Formula (V), Y1 is N and Y2 is CH. In some embodiments of Formula (V), Y1 is C and Y2 is N.
In some embodiments of Formula (V), R6A is hydrogen, halogen, Ci-Cg alkyl, Ci-Cg haloalkyl, or Ci-Cghydroxyalkyl. In some embodiments of Formula (V), R6A is Ci-Cg alkyl, Ci-Cg haloalkyl, or Ci- Cghydroxyalkyl. In some embodiments of Formula (V), R6A is hydrogen.
[09119[ In some embodiments of Formula (V), R9 is Ci-Cg alkyl, Ci-Cg haloalkyl, Ci-Cg hydroxyalkyl, - Ci-C3 alkylene(cycloalkyl), -Ci-C3 alkylene(heterocycloalkyl), C3-Cg cycloalkyl, or 4 to 6 membered heterocycloalkyl. In some embodiments of Formula (V), R9 is Ci-Cg alkyl, Ci-Cg haloalkyl, Ci-Cg hydroxyalkyl, -CH2-(cycloalkyl), -CH2-(heterocycloalkyl), C3-Cg cycloalkyl, or 4 to 6 membered heterocycloalkyl. In some embodiments of Formula (V), R9 is Ci-Cg alkyl, Ci-Cg haloalkyl, Ci-Cg hydroxyalkyl, -CH2-(C3-Cgcycloalkyl), -CH2-(4 to 6 membered heterocycloalkyl), C3-Cg cycloalkyl, or 4 to 6 membered heterocycloalkyl. In some embodiments of Formula (V), R9 is hydrogen, Ci-Cg alkyl or Ci-Cghaloalkyl. In some embodiments of Formula (V), R9 is Ci-Cg alkyl. In some embodiments of Formula (V), R9 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl. In some embodiments of Formula (V), R9 is C3-C6 cycloalkyl, or 4 to 6 membered heterocycloalkyl. In some embodiments, R9 is C3-C6 cycloalkyl. In some embodiments of Formula (V), R9 is cyclopropyl or cyclobutyl. In some embodiments of Formula (V), R9 is 4 to 6 membered heterocycloalkyl. In some embodiments of Formula (V), R9 is 4 membered heterocycloalkyl. In some embodiments of Formula (V), R9 is 5 membered heterocycloalkyl. In some embodiments of Formula (V), R9 is -C1-C3 alkylene(cycloalkyl) or -C1-C3 alkylene(heterocycloalkyl). In some embodiments of Formula (V), R9 is - C1-C3 alkylene(C3-Cg cycloalkyl). In some embodiments of Formula (V), R9 is -C1-C3 alkylene(4 to 6 membered heterocycloalkyl).
POI 1 In some embodiments of Formula (V), R6A is hydrogen; and R9 is Ci-Cg alkyl, Ci-Cg hydroxyalkyl, -C1-C3 alkylene(cycloalkyl), -C1-C3 alkylene(heterocycloalkyl), C3-Cg cycloalkyl, or 4 to 6 membered heterocycloalkyl. In some embodiments of Formula (V), R6A is hydrogen; and R9 is Ci-Cg alkyl, Ci-Cg hydroxyalkyl, -CH2-(C3-Cgcycloalkyl), -CH2-(4 to 6 membered heterocycloalkyl), C3-Cg cycloalkyl, or 4 to 6 membered heterocycloalkyl. In some embodiments of Formula (V), R6A is hydrogen; and R9 is Ci-Cg alkyl. Wi 12] In some embodiments of Formula (V), R6A and R9 together with the intervening atoms to which they are attached form a 6 to 8 membered heteroaryl or 6 to 8 membered heterocycloalkyl. In some embodiments of Formula (V), R6A and R9 together with the intervening atoms to which they are attached form a 5 to 7 membered heteroaryl. In some embodiments of Formula (V), R6A and R9 together with the intervening atoms to which they are attached form a 5 -membered heteroaryl. In some embodiments of Formula (V), R6A and R9 together with the intervening atoms to which they are attached form a 6-membered heteroaryl In some embodiments of Formula (V), R6A and R9 together with the intervening atoms to which they are attached form a 7-membered heteroaryl. Wi 14) In some embodiments of Formula (V), R6A and R9 together with the intervening atoms to which they are attached form a 5 to 7 membered heterocycloalkyl. In some embodiments of Formula (V), R6A and R9 together with the intervening atoms to which they are attached form a 5 -membered heterocycloalkyl. In some embodiments of Formula (V), R6A and R9 together with the intervening atoms to which they are attached form a 6-membered heterocycloalkyl. In some embodiments of Formula (V), R6A and R9 together with the intervening atoms to which they are attached form a 7-membered heterocycloalkyl. In some embodiments, the compound of Formula (V) has the structure of Formula (Va), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000037_0001
Formula (Va). 1 ] In some embodiments, the compound of Formula (V) has the structure of Formula (Vb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000038_0001
Formula (Vb). In some embodiments of Formula (I), (la), (II), or (Ila), R5 is -Z^L^Q, wherein
Z is -O- or -NR3B-; wherein R3B is hydrogen or C1-C3 alkyl;
L1 is absent or Ci-Cg alkylene which is optionally substituted with one, two, or three R8; each R8 is independently halogen, -OH, oxo, Ci-Cg alkyl, Ci-Cg haloalkyl, Ci-Cghydroxyalkyl, or C3- Cg cycloalkyl;
Q is -OR11 or -N(Rn)2; and each R11 is independently hydrogen, Ci-Cg alkyl, Ci-Cg alkylamino, Ci-Cg haloalkyl, or Ci-Cg hydroxyalkyl.
]8tl 18] In some embodiments, provided herein is a compound having the structure of Formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000038_0002
wherein,
X1 is CH or N;
W is O;
A and B are each independently N or CH; each R4 is independently hydrogen, halogen, -CN, -OH, -ORa, -SH, -SRa, -S(=O)Ra, -NO2, -N(Rb)2, - S(=O)2Ra, -NHS(=O)2Ra, -S(=O)2N(Rb)2, -C(=O)Ra, -OC(=O)Ra, -C(=O)ORb, -OC(=O)ORb, - C(=O)N(Rb)2, -OC(=O)N(Rb)2, -NRbC(=O)N(Rb)2, -NRbC(=O)Ra, -NRbC(=O)ORb, -Ci-C3 alkylene- NHS(=O)2Ra, -C1-C3 alkylene-NRbC(=O)Ra, -C1-C3 alkylene-OC(=O)Ra, -C1-C3 alkylene- NRbC(=O)N(Rb)2, -C1-C3 alkylene-NRbC(=O)ORb, -C1-C3 alkylene-OC(=O)N(Rb)2, Ci-Cg alkyl, Ci- Cg aminoalkyl, Ci-Cg haloalkyl, Ci-Cg hydroxyalkyl, Ci-Cg heteroalkyl, 5-membered heteroaryl, C3- Cx cycloalkyl, or 4 to 8 membered heterocycloalkyl, each of which is optionally substituted with one, two, three, or four halogen, -OH, C1-C3 alkyl, C1-C3 haloalkyl, or a 4 to 5-membered heterocycloalkyl;
R7A and R7B are each independently selected from hydrogen, halogen, -CN, -OH, -ORa, -SH, -SRa, - N(Rb)2, Ci-Cg alkyl, Ci-Cg aminoalkyl, Ci-Cg haloalkyl, or Ci-Cg hydroxyalkyl; Z is -O- or -NR3B-; wherein R3B is hydrogen or C1-C3 alkyl;
L2 is Ci-Cg alkylene which is optionally substituted with one, two, or three R8; each R8 is independently halogen, -OH, oxo, Ci-Cg alkyl, Ci-Cg haloalky 1, Ci-Cghydroxyalkyl, or C3-C6 cycloalkyl;
Q is -OR11 or -N(Rn)2; each R11 is independently hydrogen, Ci-Cg alkyl, Ci-Cg alkylamino, Ci-Cg haloalkyl, or Ci-Cg hydroxyalkyl, each of which is optionally substituted with one, two, or three halogen or C1-C3 hydroxyalkyl; each Ra is independently Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, Ci-Cg heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Ci-Cg alkyl(aryl), -Ci-Cg alkyl(heteroaryl), -Ci-Cg alkyl(cycloalkyl), or -Ci-Cg alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-Cg alkyl, or Ci-Cg haloalkyl; and each Rb is independently hydrogen, Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, Ci-Cg heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-Cg alkyl, or Ci-Cg haloalkyl.
[88119] In some embodiments of Formula (I), (la), (II), (Ila) or (VI), Q is -OR11. In some embodiments of Formula (I), (la), (II), (Ila), or (VI), Q is -N(Rn)2.
[88128] In some embodiments of Formula (I), (la), (II), (Ila), or (VI), Q is -OH, -OCH3, or -OCH2CH. [8812 ] In some embodiments of Formula (I), (la), (II), (Ila), or (VI), Q is -NH2, -NHCH3, -N(CH3)2, - NH(CH2CH3), -N(CH2CH3)2, or NH(CH2CH2CH3).
[891 2] In some embodiments of Formula (I), (la), (II), (Ila), (III), (IV), (IVa), (V), (Va), or (Vb), L is Z-L1.
[88123] In some embodiments of Formula (I), (la), (II), (Ila), (III), (IV), (IVa), (V), (Va), or (Vb), L is absent.
[88 24[ In some embodiments of Formula (I), (la), (II), (Ila), (III), (IV), (IVa), (V), (Va), (Vb), or (VI), Z is -O-. In some embodiments, Z is -NR3B-. In some embodiments, Z1 is -NH-. In some embodiments, Z is -NCH3-. In some embodiments, -Z- is absent.
[89128] In some embodiments of Formula (I), (la), (II), (Ila), (III), (IV), (IVa), (V), (Va), (Vb), or (VI), R3B is C1-C3 alkyl. In some embodiments, R3B is methyl or ethyl. In some embodiments, R3B is methyl. In some embodiments, R3B is hydrogen.
[88126] In some embodiments of Formula (I), (la), (II), (Ila), (III), (IV), (IVa), (V), (Va), or (Vb), L1 is Ci-Cg alkylene which is optionally substituted with one, two, or three R8. In some embodiments, L1 is Ci- C4 alkylene. In some embodiments, L1 is C1-C3 alkylene. In some embodiments, L1 is -CH2-, -CH2CH2-, - CH2CH2CH2-, CH2CH2CH2CH2-. In some embodiments, L1 is -CH2-, -CH2CH2-, or -CH2CH2CH2-. In some embodiments, L1 is -CH2-. In some embodiments, L1 is -CH2CH2-. In some embodiments, L1 is - CH2CH2CH2-. In some embodiments of Formula (I), (la), (II), (Ila), (III), (IV), (IVa), (V), (Va), or (Vb), L1 is
Figure imgf000040_0003
absent. In some embodiments of Formula (I), (la), (II), (Ila), or (VI), L2 is Ci-Cg alkylene which is
Figure imgf000040_0004
optionally substituted with one, two, or three R8. In some embodiments, L2 is C1-C4 alkylene. In some embodiments, L2 is C1-C3 alkylene. In some embodiments, L2 is -CH2-, -CH2CH2-, -CH2CH2CH2-, - CH2CH2CH2CH2-, or -CH2CH2CH2CH2CH2-.
In some embodiments of Formula (I), (la), (II), (Ila), or (VI), -Z^lJ-Q is
Figure imgf000040_0001
Figure imgf000040_0002
[88138] In some embodiments of Formula (I), (la), (II), (Ila), (III), (IV), (IVa), (V), (Va), (Vb), or (VI), each R4 is independently hydrogen, halogen, -CN, -OH, -ORa, -SH, -SRa, -S(=O)Ra, -NO2, -N(Rb)2, - S(=O)2Ra, -NHS(=O)2Ra, -S(=O)2N(Rb)2, -C(=O)Ra, -OC(=O)Ra, -C(=O)ORb, -OC(=O)ORb, - C(O)N(Rb)2, -OC(=O)N(Rb)2, -NRbC(=O)N(Rb)2, -NRbC(=O)Ra, -NRbC(=O)ORb, -Ci-C3 alkylene- NHS(=O)2Ra, -Ci-C3 alkylene-NRbC(=O)Ra, -Ci-C3 alkylene-OC(=O)Ra, -Ci-C3 alkylene- NRbC(=O)N(Rb)2, -Ci-C3 alkylene-NRbC(=O)ORb, -Ci-C3 alkylene-OC(=O)N(Rb)2, Ci-C6 alkyl, Ci-C6 aminoalkyl, Ci-Cg haloalky 1, Ci-Cg hydroxyalkyl, Ci-Cg heteroalkyl, 5-membered heteroaryl, C3-Cx cycloalkyl, or 4 to 8 membered heterocycloalkyl, each of which is optionally substituted with one, two, three, or four halogen, -OH, Ci-C3 alkyl, Ci-C3 haloalkyl, or a 4 to 5-membered heterocycloalkyl. In some embodiments, each R4 is independently hydrogen, halogen, -CN, -ORa, -S(=O)Ra, -N(Rb)2, - S(=O)2Ra, -NHS(=O)2Ra, -S(=O)2N(Rb)2, -C(=O)Ra, -C(=O)ORb, -C(O)N(Rb)2, -OC(=O)N(Rb)2, - NRbC(=O)N(Rb)2, -NRbC(=O)Ra, -NRbC(=O)ORb, -Ci-C3 alkylene-NHS(=O)2Ra, -Ci-C3 alkylene- NRbC(=O)Ra, -Ci-C3 alkylene-OC(=O)Ra, -Ci-C3 alkylene-NRbC(=O)N(Rb)2, -Ci-C3 alkylene- NRbC(=O)ORb, -Ci-C3 alkylene-OC(=O)N(Rb)2, Ci-C6 alkyl, Ci-C6 haloalkyl, Ci-C6 hydroxyalkyl, Ci-C6 heteroalkyl, 5-membered heteroaryl, C3-Cx cycloalkyl, or 4 to 8 membered heterocycloalkyl. In some embodiments, each R4 is independently hydrogen, halogen, -CN, -C(=O)Ra, -C(=O)ORb, -C(O)N(Rb)2, - Ci-C3 alkylene-NHS(=O)2Ra, -Ci-C3 alkylene-NRbC(=O)Ra, -Ci-C3 alkylene-OC(=O)Ra, -Ci-C3 alkylene- NRbC(=O)N(Rb)2, -Ci-C3 alkylene-NRbC(=O)ORb, -Ci-C3 alkylene-OC(=O)N(Rb)2, Ci-C6 alkyl, Ci-C6 haloalkyl, Ci-Cg hydroxyalkyl, Ci-Cg heteroalkyl, 5-membered heteroaryl, C3-Cg cycloalkyl, or 4 to 6 membered heterocycloalkyl. [88131] In some embodiments of Formula (I), (la), (II), (Ila), (III), (IV), (IVa), (V), (Va), (Vb), or (VI), each R4 is independently hydrogen, halogen, -CN, -C(=O)Ra, -C(=O)ORb, -C(O)N(Rb)2, -CH2- NHS(=O)2Ra, -CH2-NRbC(=O)Ra, -CH2-OC(=O)Ra, -CH2-NRbC(=O)N(Rb)2, -CH2-NRbC(=O)ORb, -CH2- OC(=O)N(Rb)2, Ci-Cg alkyl, Ci-Cg haloalkyl, Ci-Cg hydroxyalkyl, Ci-Cg heteroalkyl, 5-membered heteroaryl, C3-C6 cycloalkyl, or 4 to 6 membered heterocycloalkyl, wherein the alkyl, haloalkyl, hydroxyalkyl, heteroaryl, cycloalkyl and heterocycloalkyl is optionally substituted with one, two, three, or four halogen, -OH, C1-C3 alkyl, C1-C3 haloalkyl, or a 4 to 5-membered heterocycloalkyl.
[88132] In some embodiments, each R4 is independently hydrogen, halogen, Ci-Cg alkyl, Ci-Cg haloalkyl, Ci-Cg heteroalkyl, or Ci-Cg hydroxyalkyl. In some embodiments, each R4 is independently Ci- Cg alkyl or Ci-Cg haloalkyl. In some embodiments, each R4 is independently Ci-Cg alkyl. In some embodiments, each R4 is independently halogen. In some embodiments, each R4 is independently chloro or fluoro. In some embodiments, each R4 is independently fluoro, methyl, -CN, CF3, or CH2CF3.
[88133] In some embodiments of Formula (I), (la), (II), (Ila), (III), (IV), (IVa), (V), (Va), (Vb), or (VI), each R4 is independently -C(=O)Ra, -C(=O)ORb, -C(O)N(Rb)2, -C1-C3 alkylene-NHS(=O)2Ra, -C1-C3 alkylene-NRbC(=O)Ra, -C1-C3 alkylene-OC(=O)Ra, -C1-C3 alkylene-NRbC(=O)N(Rb)2, -C1-C3 alkylene- NRbC(=O)ORb, or -C1-C3 alkylene-OC(=O)N(Rb)2. In some embodiments, each R4 is independently - C(=O)Ra, -C(=O)ORb, -C(O)N(Rb)2, -CH2-alkylene-NHS(=O)2Ra, -CH2-NRbC(=O)Ra, -CH2-OC(=O)Ra, - CH2-NRbC(=O)N(Rb)2, -CH2-NRbC(=O)ORb, or -CH2-OC(=O)N(Rb)2. In some embodiments, each R4 is independently -CH2-NRbC(=O)N(Rb)2. In some embodiments, each R4 is independently -CH2- NRbC(=O)Ra.
[88134] In some embodiments of Formula (I), (la), (II), (Ila), (III), (IV), (IVa), (V), (Va), (Vb), or (VI), , each R4 is independently a 5 -membered heteroaryl, C3-Cg cycloalkyl, or 4 to 6 membered heterocycloalkyl. In some embodiments, each R4 is independently a 5 -membered heteroaryl. In some embodiments, each R4 is independently a C3-Cg cycloalkyl. In some embodiments, each R4 is independently a 4 to 6 membered heterocycloalkyl.
[8813S] In some embodiments of Formula (I), (la), (II), (Ila), (III), (IV), (IVa), (V), (Va), (Vb), or (VI), each R4 is independently hydrogen.
[88136] In some embodiments of Formula (I), (la), (II), or (Ila), two R4 on adjacent carbon atoms together with the atoms to which they are attached form a 5 to 6-membered heteroaryl. In some embodiments, two R4 on adjacent carbon atoms together with the atoms to which they are attached form a 5 membered heteroaryl. In some embodiments, two R4 on adjacent carbon atoms together with the atoms to which they are attached form a 6 membered heteroaryl.
[88137] In some embodiments of Formula (I), (la), (II), (Ila), (III), (IV), or (IVa), each R6 is independently hydrogen, halogen, -CN, -OH, -ORa, -N(Rb)2, -S(=O)2Ra, -NHS(=O)2Ra, -S(=O)2N(Rb)2, - C(=O)Ra, -OC(=O)Ra, -C(=O)ORb, -C(=O)N(Rb)2, -NRbC(=O)Ra, oxo (=0), Ci-Cg alkyl, Ci-Cg alkylamino, Ci-Cg haloalkyl, Ci-Cg hydroxyalkyl, Ci-Cg heteroalkyl, C3-C8 cycloalkyl, or 4 to 8 membered heterocycloalkyl. In some embodiments, each R6 is independently hydrogen, halogen, -N(Rb)2, oxo (=0), Ci-Cg alkyl, Ci-Cg alkylamino, Ci-Cg haloalkyl, or Ci-Cg hydroxy alkyl. In some embodiments, each R6 is independently halogen, Ci-Cg alkyl or Ci-Cghaloalkyl. In some embodiments, each R6 is independently Ci-Cg alkyl. In some embodiments, each R6 is independently methyl, ethyl, n-propyl, or isopropyl. In some embodiments, each R6 is independently methyl. In some embodiments, each R6 is independently halogen. In some embodiments, each R6 is independently fluoro or chloro. In some embodiments, each R6 is independently -N(Rb)2. In some embodiments, each R6 is independently -NH2, - NHCH3, -N(CHS)2, or -N(CH2CH3)2. In some embodiments, R6 is oxo (=0). In some embodiments, each R6 is independently C3-C6 cycloalkyl. In some embodiments each R6 is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, each R6 is independently a 4 to 6- membered heterocycloalkyl.
[00138 [ In some embodiments of Formula (I), (la), (II), (Ila), (III), (IV), or (IVa), each R6 is independently hydrogen, fluoro, -CH3, -CH2CH3, -C(CH3)3, -CF3, or -CH2CF3. In some embodiments, each R6 is independently hydrogen or -CH3. In some embodiments, each R6 is independently fluoro. In some embodiments, each R6 is independently hydrogen.
[ 0139] In some embodiments of Formula (I), (la), (II), (Ila), (III), (IV), or (IVa), two R6 together with the intervening atoms to which they are attached form a 5 to 8 membered heteroaryl, Cs-Cx cycloalkyl, or 5 to 8 membered heterocycloalkyl. In some embodiments, two R6 together with the intervening atoms to which they are attached form a 5 to 8 membered heteroaryl. In some embodiments, two R6 together with the intervening atoms to which they are attached form a Cs-Cx cycloalkyl. In some embodiments, two R6 together with the intervening atoms to which they are attached form a 5 to 8 membered heterocycloalkyl.
In some embodiments of Formula (II), (Ila), (III), (IV), (IVa), (V), (Va), (Vb), or (VI), R7A and R7B are each the same. In some embodiments, R7A and R7B are each different.
[ 141 In some embodiments of Formula (II), (Ila), (III), (IV), (IVa), (V), (Va), (Vb), or (VI), R7A and R7B are each independently selected from hydrogen, halogen, -CN, -OH, -ORa, -SH, -SRa, -N(Rb)2, Ci-Cg alkyl, Ci-Cg aminoalkyl, Ci-Cghaloalkyl, or Ci-Cghydroxyalkyl. In some embodiments, R7A and R7B are each independently selected from hydrogen, halogen, -CN, -OH, -ORa, -N(Rb)2, Ci-Cg alkyl, Ci-Cg aminoalkyl, Ci-Cghaloalkyl, or Ci-Cg hydroxy alkyl. In some embodiments, each R7A and R7B are each independently halogen, -CN, -OH, -OCH3, -SCH3, -CH3, -NH2, -NHCH3, or -N(CH3)2. In some embodiments, each R7A and R7B are each independently fluoro, chloro, -OH, -CF3, or -CH3.
[ 0142] In some embodiments of Formula (II), (Ila), (III), (IV), (IVa), (V), (Va), (Vb), or (VI), R7A and R7B are each independently halogen. In some embodiments, R7A and R7B are each independently chloro or fluoro. In some embodiments, R7A and R7B are each independently chloro. In some embodiments, R7A and R7B are each independently fluoro.
[0 !43[ In some embodiments of Formula (I), (la), (II), (Ila), (III), (IV), (IVa), (V), (Va), (Vb), or (IV), each R8 is independently halogen, -OH, oxo (=0), Ci-Cg alkyl, Ci-Cg haloalky 1, or Ci-Cghydroxyalkyl. In some embodiments, each R8 is independently halogen. In some embodiments, each R8 is independently chloro or fluoro. In some embodiments, each R8 is independently Ci-Cg alkyl. In some embodiments, each R8 is independently -CH3, -CH2CH3, -CH(CH3)2, or -C(CH3)3. In some embodiments, each R8 is independently -CH3. In some embodiments, each R8 is independently -CH2CH3 In some embodiments, each R8 is independently Ci-Cg haloalkyl, or Ci-Cghydroxyalkyl. In some embodiments, each R8 is independently C9-Cg cycloalkyl. In some embodiments, each R8 is independently cyclopropyl.
[88144] In some embodiments of Formula (I), (la), (II), (Ila), or (VI) each R11 is independently hydrogen, Ci-Cg alkyl, Ci-Cg alkylamino, Ci-Cg haloalkyl, or Ci-Cg hydroxyalkyl, each of which is optionally substituted with one, two, or three halogen or C1-C3 hydroxyalkyl. In some embodiments, each R11 is independently hydrogen or Ci-Cg alkyl. In some embodiments, each R11 is independently Ci-Cg alkylamino, Ci-Cg haloalkyl, or Ci-Cg hydroxyalkyl. In some embodiments, each R11 is independently Ci-Cg methyl. In some embodiments, each R11 is independently methyl, ethyl, n-propyl, isopropyl, n- butyl, sec-butyl, or tert-butyl.
[88145] In some embodiments of Formula (II), (Ila), (III), (IV), (IVa), (V), (Va), (Vb), or (VI), X1 is CH. In some embodiments, X1 is N.
[88146] In some embodiments of Formula (II), (Ila), (III), (IV), (IVa), (V), (Va), (Vb), or (VI), A is N or CR4. In some embodiments, A is CR4. In some embodiments A is CH. In some embodiments, A is N. [88147] In some embodiments of Formula (II), (Ila), (III), (IV), (IVa), (V), (Va), (Vb), or (VI), B is N or CR4. In some embodiments, B is CR4. In some embodiments, B is CH. In some embodiments, B is N. [88148] In some embodiments of Formula (II), (Ila), (III), (IV), (IVa), (V), (Va), (Vb), or (VI), C is N or CR4. In some embodiments, C is CR4. In some embodiments, C is CH. In some embodiments, C is N. [88149 [ In some embodiments of Formula (II), (Ila), (III), (IV), (IVa), (V), (Va), (Vb), or (VI), D is N, CR4, or CR5. In some embodiments, D is N or CR4. In some embodiments, D is CR4. In some embodiments, D is CH. In some embodiments, D is N. In some embodiments, D is CR5.
[88158] In some embodiments of Formula (II), (Ila), (III), (IV), (IVa), (V), (Va), (Vb), or (VI), E is N, CR4, or CR5; wherein one of D or E is CR5. In some embodiments, E is N. In some embodiments, E is CR4. In some embodiments. E is CH. In some embodiments, E is CR5.
[88151] In some embodiments of Formula (II), (Ila), (III), (IV), (IVa), (V), (Va), (Vb), or (VI), A is N or CR4; B is N or CR4; C is CH; D is CR4; and E is CR5.
[88152 [ In some embodiments of Formula (II), (Ila), (III), (IV), (IVa), (V), (Va), (Vb), or (VI), A is N or CR4; B is N or CR4; C is CH; D is CR5; and E is N or CR4.
[88153] In some embodiments of Formula (II), (Ila), (III), (IV), (IVa), (V), (Va), (Vb), or (VI), A is CH and B is CH. In some embodiments, A is N and B is CH. In some embodiments, A is CH and B is N. In some embodiments, A is N and B is N.
[09154] In some embodiments of Formula (III), (IV), or (IVa), m is 1, 2, 3, or 4. In some embodiments, m is 1 or 2. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 0.
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Cg heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Ci-Cg alkyl(aryl), -Ci-Cg alkyl(heteroaryl), -Ci-Cg alkyl(cycloalkyl), or -Ci-Cg alkyl (heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-Cg alkyl, or Ci-Cg haloalkyl. In some embodiments, each Ra is independently Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, or Ci-Cg heteroalkyl. In some embodiments, each Ra is independently cycloalkyl or heterocycloalkyl. In some embodiments, each Ra is independently aryl or heteroaryl. In some embodiments, each Ra is independently -Ci-Cg alkyl(aryl), -Ci- Cg alkyl(heteroaryl), -Ci-Cg alkyl(cycloalkyl), or -Ci-Cg alkyl (heterocycloalkyl).
In some embodiments, each Rb is independently hydrogen, Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, Ci-Cg heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-Cg alkyl, or Ci-Cg haloalkyl. In some embodiments, each Rb is independently hydrogen, Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, or Ci-Cg heteroalkyl. In some embodiments, each Rb is independently cycloalkyl or heterocycloalkyl. In some embodiments, each Rb is independently aryl, or heteroaryl.
In some embodiments, the compounds made in the examples below are made from racemic starting materials (and/or intermediates) and separated into the individual enantiomers by chiral chromatography as final products or intermediates. Unless otherwise stated, it is understood that the absolute configuration of the separated intermediates and final compounds as drawn is arbitrarily assigned and was not determined.
[W1S2] Non-limiting examples of compounds described herein, are compounds presented in Table 1 and pharmaceutically acceptable salts, solvates, or stereoisomers thereof.
Table 1. Representative compounds of the disclosure
Figure imgf000046_0002
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0002
Included in the present disclosure are salts, particularly pharmaceutically acceptable salts, of the compounds described herein. The compounds of the present invention that possess a sufficiently acidic, a sufficiently basic, or both functional groups, can react with any of a number of inorganic bases, and inorganic and organic acids, to form a salt. Alternatively, compounds that are inherently charged, such as those with a quaternary nitrogen, can form a salt with an appropriate counterion, e.g., a halide such as bromide, chloride, or fluoride, particularly bromide.
[88164] Chemical entities having carbon-carbon double bonds or carbon-nitrogen double bonds may exist in Z- or E- form (or cis- or trans- form). Furthermore, some chemical entities may exist in various tautomeric forms. Unless otherwise specified, compounds described herein are intended to include all Z-, E- and tautomeric forms as well.
Figure imgf000145_0003
A “tautomer” refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. The compounds presented herein, in certain embodiments, exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:
Figure imgf000145_0001
Figure imgf000145_0004
The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of 2H, 3H, nC, 13C and/or 14C. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs. Unless otherwise stated, compounds described herein are intended to include compounds
Figure imgf000145_0005
which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13C- or 14C-enriched carbon are within the scope of the present disclosure. [80168] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium (2H), tritium (3H), iodine-125 (125I) or carbon-14 (14C). Isotopic substitution with 2H, nC, 13C, 14C, 15C, 12N, 13N, 15N, 16N, 16O, 170, 14F, 15F, 16F, 17F, 18F, 33S, 34S, 35S, 36S, 35C1, 37C1, 79Br, 81Br, and 125I are all contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.
[88169] In certain embodiments, the compounds disclosed herein have some or all of the 4H atoms replaced with 2H atoms. The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.
Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, HO pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.
[88171] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.
Compounds of the present invention also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.
[88873] The compounds described herein may in some cases exist as diastereomers, enantiomers, or other stereoisomeric forms. Where absolute stereochemistry is not specified, the compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Separation of stereoisomers may be performed by chromatography or by forming diastereomers and separating by recrystallization, or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981, herein incorporated by reference for this disclosure). Stereoisomers may also be obtained by stereoselective synthesis.
[ 8173 ] The methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also known as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. As well, in some embodiments, active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure. In addition, the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.
]00175] In certain embodiments, compounds or salts of the compounds may be prodrugs, e.g., wherein a hydroxyl in the parent compound is presented as an ester or a carbonate, or carboxylic acid present in the parent compound is presented as an ester. The term “prodrug” is intended to encompass compounds which, under physiologic conditions, are converted into pharmaceutical agents of the present disclosure. One method for making a prodrug is to include one or more selected moieties which are hydrolyzed under physiologic conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal such as specific target cells in the host animal. For example, esters or carbonates (e.g., esters or carbonates of alcohols or carboxylic acids and esters of phosphonic acids) are preferred prodrugs of the present disclosure.
]9G176j Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a compound as set forth herein are included within the scope of the claims. In some cases, some of the herein-described compounds may be a prodrug for another derivative or active compound. [( 77] Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. Prodrugs may help enhance the cell permeability of a compound relative to the parent drug. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. Prodrugs may be designed as reversible drug derivatives, for use as modifiers to enhance drug transport to site-specific tissues or to increase drug residence inside of a cell.
1 (. )178] In some embodiments, the design of a prodrug increases the lipophilicity of the pharmaceutical agent. In some embodiments, the design of a prodrug increases the effective water solubility. See, e.g., Fedorak etal., Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 31, 87 (1987); J. Larsen et al.. / J. Pharmaceutics, 47, 103 (1988); Sinkula / «/.. J. Pharm. Sci., 64: 181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series; and Edward B. Roche, Bioreversihle Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, all incorporated herein for such disclosure). According to another embodiment, the present disclosure provides methods of producing the above-defined compounds. The compounds may be synthesized using conventional techniques.
Advantageously, these compounds are conveniently synthesized from readily available starting materials.
7 ] Synthetic chemistry transformations and methodologies useful in synthesizing the compounds described herein are known in the art and include, for example, those described in R.
Larock, Comprehensive Organic Transformations (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed. (1991); L. Fieser and M. Fieser, Fieser and Fieser ’s Reagents for Organic Synthesis (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995).
C. Pharmaceutical Compositions ^80180) Provided herein, in certain embodiments, are compositions comprising a therapeutically effective amount of any compound or salt of any one of Formulas (I), (la) (II), (Ila) (III), (IV), (IVa), (V), (Va), (Vb), or (VI), (also referred to herein as “a pharmaceutical agent”). Pharmaceutical compositions may be formulated using one or more physiologically acceptable carriers including excipients and auxiliaries which facilitate processing of the pharmaceutical agent into preparations which are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions is found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa., Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins, 1999).
The compositions and methods of the present disclosure may be utilized to treat an individual in need thereof. In certain embodiments, the individual is a mammal such as a human, or a non-human mammal. When administered to an animal, such as a human, the composition or the pharmaceutical agent, is preferably administered as a pharmaceutical composition comprising, for example, a pharmaceutical agent and a pharmaceutically acceptable carrier or excipient. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters. In a preferred embodiment, when such pharmaceutical compositions are for human administration, particularly for invasive routes of administration, e.g., routes, such as injection or implantation, that circumvent transport or diffusion through an epithelial barrier, the aqueous solution is pyrogen-free, or substantially pyrogen-free. The excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs. Tire pharmaceutical composition can be in dosage unit form such as tablet, capsule, granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like. The composition can also be present in a transdermal delivery system, e.g., a skin patch. The composition can also be present in a solution suitable for topical administration, such as an eye drop.
[00183] A pharmaceutically acceptable excipient can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a pharmaceutical agent. Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients. Hie choice of a pharmaceutically acceptable excipient, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition can be a selfemulsifying drug delivery system or a self microemulsifying drug delivery system. The pharmaceutical composition (preparation) also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the invention. Liposomes, for example, which comprise phospholipids or other iipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.
A pharmaceutical composition (preparation) can be administered to a subject by any of a number of rou tes of administration including, for example, orally, for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules, including sprinkle capsules and gelatin capsules, boluses, powders, granules, pastes for application to the tongue; absorption through the oral mucosa, e.g., sublingually; anally, rectally or vaginally, for example, as a pessary', cream or foam; parenterally, including intramuscularly, intravenously, subcutaneously or intrathecally as, for example, a sterile solution or suspension; nasally; intraperitoneally; subcutaneously; transdermally, for example, as a patch applied to the skin; and topically, for example, as a cream, ointment or spray applied to the skin, or as an eye drop. The compound may also be formulated for inhalation. In certain embodiments, a compound may be simply dissolved or suspended in sterile water.
A pharmaceutical composition may be a sterile aqueous or non-aqueous solution, suspension or emulsion, e.g., a microemulsion. The excipients described herein are examples and are in no way limiting. An effective amount or therapeutically effective amount refers to an amount of the one or more pharmaceutical agents administered to a subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect. Subjects may generally be monitored for therapeutic effectiveness using assays and methods suitable for the condition being treated, which assays will be familiar to those having ordinary skill in the art and are described herein. Pharmacokinetics of a pharmaceutical agent, or one or more metabolites thereof, that is administered to a subject may be monitored by determining the level of the pharmaceutical agent or metabolite in a biological fluid, for example, in the blood, blood fraction, e.g., serum, and/or in the urine, and/or other biological sample or biological tissue from the subject. Any method practiced in the art and described herein to detect the agent may be used to measure the level of the pharmaceutical agent or metabolite during a treatment course.
^ )18?| The dose of a pharmaceutical agent described herein for treating a disease or disorder may depend upon the subject’s condition, that is, stage of the disease, severity of symptoms caused by the disease, general health status, as well as age, gender, and weight, and other factors apparent to a person skilled in the medical art. Pharmaceutical compositions may be administered in a manner appropriate to the disease to be treated as determined by persons skilled in the medical arts. In addition to the factors described herein and above related to use of pharmaceutical agent for treating a disease or disorder, suitable duration and frequency of administration of the pharmaceutical agent may also be determined or adjusted by such factors as the condition of the patient, the type and severity of the patient’s disease, the particular form of the active ingredient, and the method of administration. Optimal doses of an agent may generally be determined using experimental models and/or clinical trials. The optimal dose may depend upon the body mass, weight, or blood volume of the subject. The use of the minimum dose that is sufficient to provide effective therapy is usually preferred. Design and execution of pre-clinical and clinical studies for a pharmaceutical agent, including when administered for prophylactic benefit, described herein are well within the skill of a person skilled in the relevant art. When two or more pharmaceutical agents are administered to treat a disease or disorder, the optimal dose of each pharmaceutical agent may be different, such as less than when either agent is administered alone as a single agent therapy. In certain particular embodiments, two pharmaceutical agents in combination may act synergistically or additively, and either agent may be used in a lesser amount than if administered alone. An amount of a pharmaceutical agent that may be administered per day may be, for example, between about 0.01 mg/kg and 100 mg/kg, e.g., between about 0.1 to 1 mg/kg, between about 1 to 10 mg/kg, between about 10-50 mg/kg, between about 50-100 mg/kg body weight. In other embodiments, the amount of a pharmaceutical agent that may be administered per day is between about 0.01 mg/kg and 1000 mg/kg, between about 100-500 mg/kg, or between about 500-1000 mg/kg body weight. The optimal dose, per day or per course of treatment, may be different for the disease or disorder to be treated and may also vary with the administrative route and therapeutic regimen.
Pharmaceutical compositions comprising a pharmaceutical agent can be formulated in a manner appropriate for the delivery method by using techniques routinely practiced in the art. The composition may be in the form of a solid, e.g., tablet, capsule, semi-solid, e.g., gel, liquid, or gas, e.g., aerosol. In other embodiments, the pharmaceutical composition is administered as a bolus infusion. Pharmaceutical acceptable excipients are well known in the pharmaceutical art and described, for example, in Rowe et al., Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, 5th Ed., 2006, and in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)). Exemplary pharmaceutically acceptable excipients include sterile saline and phosphate buffered saline at physiological pH. Preservatives, stabilizers, dyes, buffers, and the like may be provided in the pharmaceutical composition. In addition, antioxidants and suspending agents may also be used. In general, the type of excipient is selected based on the mode of administration, as well as the chemical composition of the active ingredient(s). Alternatively, compositions described herein may be formulated as a lyophilizate. A composition described herein may be lyophilized or otherwise formulated as a lyophilized product using one or more appropriate excipient solutions for solubilizing and/or diluting the pharmaceutical agent(s) of the composition upon administration. In other embodiments, the pharmaceutical agent may be encapsulated within liposomes using technology known and practiced in the art. In certain particular embodiments, a pharmaceutical agent is not formulated within liposomes for application to a stent that is used for treating highly, though not totally, occluded arteries. Pharmaceutical compositions may be formulated for any appropriate manner of administration described herein and in the art. A pharmaceutical composition, e.g., for oral administration or for injection, infusion, subcutaneous delivery, intramuscular delivery, intraperitoneal delivery or other method, may be in the form of a liquid. A liquid pharmaceutical composition may include, for example, one or more of the following: a sterile diluent such as water, saline solution, preferably physiological saline, Ringer’s solution, isotonic sodium chloride, fixed oils that may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents; antioxidants; chelating agents; buffers and agents for the adjustment of tonicity such as sodium chloride or dextrose. A parenteral composition can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. The use of physiological saline is preferred, and an injectable pharmaceutical composition is preferably sterile. In another embodiment, for treatment of an ophthalmological condition or disease, a liquid pharmaceutical composition may be applied to the eye in the form of eye drops. A liquid pharmaceutical composition may be delivered orally.
[99191] For oral formulations, at least one of the pharmaceutical agents described herein can be used alone or in combination with appropriate additives to make tablets, powders, granules or capsules, and if desired, with diluents, buffering agents, moistening agents, preservatives, coloring agents, and flavoring agents. The pharmaceutical agents may be formulated with a buffering agent to provide for protection of the compound from low pH of the gastric environment and/or an enteric coating. A pharmaceutical agent included in a pharmaceutical composition may be formulated for oral delivery with a flavoring agent, e.g., in a liquid, solid or semi-solid formulation and/or with an enteric coating.
[99192] A pharmaceutical composition comprising any one of the pharmaceutical agents described herein may be formulated for sustained or slow release, also called timed release or controlled release. Such compositions may generally be prepared using well known technology and administered by, for example, oral, rectal, intradermal, or subcutaneous implantation, or by implantation at the desired target site. Sustained-release formulations may contain the compound dispersed in a carrier matrix and/or contained within a reservoir surrounded by a rate controlling membrane. Excipients for use within such formulations are biocompatible, and may also be biodegradable; preferably the formulation provides a relatively constant level of active component release. The amount of pharmaceutical agent contained within a sustained release formulation depends upon the site of implantation, the rate and expected duration of release, and the nature of the condition, disease or disorder to be treated or prevented.
[99193] In certain embodiments, the pharmaceutical compositions comprising a pharmaceutical agent are formulated for transdermal, intradermal, or topical administration. The compositions can be administered using a syringe, bandage, transdermal patch, insert, or syringe-like applicator, as a powder/talc or other solid, liquid, spray, aerosol, ointment, foam, cream, gel, paste. This preferably is in the form of a controlled release formulation or sustained release formulation administered topically or injected directly into the skin adjacent to or within the area to be treated, e.g., intradermally or subcutaneously. The active compositions can also be delivered via iontophoresis. Preservatives can be used to prevent the growth of fungi and other microorganisms. Suitable preservatives include, but are not limited to, benzoic acid, butylparaben, ethyl paraben, methyl paraben, propylparaben, sodium benzoate, sodium propionate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetypyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, thimerosal, and combinations thereof.
[99194] Pharmaceutical compositions comprising a pharmaceutical agent can be formulated as emulsions for topical application. An emulsion contains one liquid distributed in the body of a second liquid. The emulsion may be an oil-in-water emulsion or a water-in-oil emulsion. Either or both of the oil phase and the aqueous phase may contain one or more surfactants, emulsifiers, emulsion stabilizers, buffers, and other excipients. The oil phase may contain other oily pharmaceutically approved excipients. Suitable surfactants include, but are not limited to, anionic surfactants, non-ionic surfactants, cationic surfactants, and amphoteric surfactants. Compositions for topical application may also include at least one suitable suspending agent, antioxidant, chelating agent, emollient, or humectant.
|W 19S] Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. Liquid sprays may be delivered from pressurized packs, for example, via a specially shaped closure. Oil-in-water emulsions can also be used in the compositions, patches, bandages and articles. These systems are semisolid emulsions, microemulsions, or foam emulsion systems.
[99199] In some embodiments, the pharmaceutical agent described herein can be formulated as in inhalant. Inhaled methods can deliver medication directly to the airway. The pharmaceutical agent can be formulated as aerosols, microspheres, liposomes, or nanoparticles. The pharmaceutical agent can be formulated with solvents, gases, nitrates, or any combinations thereof. Compositions described herein are optionally formulated for delivery as a liquid aerosol or inhalable dry powder. Liquid aerosol formulations are optionally nebulized predominantly into particle sizes that can be delivered to the terminal and respiratory bronchioles. Liquid aerosol and inhalable dry powder formulations are preferably delivered throughout the endobronchial tree to the terminal bronchioles and eventually to the parenchymal tissue.
Aerosolized formulations described herein are optionally delivered using an aerosol forming device, such as a jet, vibrating porous plate or ultrasonic nebulizer, preferably selected to allow the formation of aerosol particles having with a mass medium average diameter predominantly between 1 to 5 p. Further, the formulation preferably has balanced osmolarity ionic strength and chloride concentration, and the smallest aerosolizable volume able to deliver effective dose of the pharmaceutical agent. Additionally, the aerosolized formulation preferably does not impair negatively the functionality of the airways and does not cause undesirable side effects.
[09198] Aerosolization devices suitable for administration of aerosol formulations described herein include, for example, jet, vibrating porous plate, ultrasonic nebulizers and energized dry powder inhalers, that are able to nebulize the formulation into aerosol particle size predominantly in the size range from 1- 5 p. Predominantly in this application means that at least 70% but preferably more than 90% of all generated aerosol particles are within 1-5 p range. A jet nebulizer works by air pressure to break a liquid solution into aerosol droplets. Vibrating porous plate nebulizers work by using a sonic vacuum produced by a rapidly vibrating porous plate to extrude a solvent droplet through a porous plate. An ultrasonic nebulizer works by a piezoelectric crystal that shears a liquid into small aerosol droplets. A variety of suitable devices are available, including, for example, AeroNeb™ and AeroDose™ vibrating porous plate nebulizers (AeroGen, Inc., Sunnyvale, California), Sidestream® nebulizers (Medic-Aid Ltd., West Sussex, England), Pari LC® and Pari LC Star® jet nebulizers (Pari Respiratory Equipment, Inc., Richmond, Virginia), and Aerosonic™ (DeVilbiss Medizinische Produkte (Deutschland) GmbH, Heiden, Germany) and UltraAire® (Omron Healthcare, Inc., Vernon Hills, Illinois) ultrasonic nebulizers. In some embodiments, the pharmaceutical agent(s) can be formulated with oleaginous bases or ointments to form a semisolid composition with a desired shape. In addition to the pharmaceutical agent, these semisolid compositions can contain dissolved and/or suspended bactericidal agents, preservatives and/or a buffer system. A petrolatum component that may be included may be any paraffin ranging in viscosity from mineral oil that incorporates isobutylene, colloidal silica, or stearate salts to paraffin waxes. Absorption bases can be used with an oleaginous system. Additives may include cholesterol, lanolin (lanolin derivatives, beeswax, fatty alcohols, wool wax alcohols, low HLB (hydrophobellipophobe balance) emulsifiers, and assorted ionic and nonionic surfactants, singularly or in combination.
[88288] Controlled or sustained release transdermal or topical formulations can be achieved by the addition of time-release additives, such as polymeric structures, matrices, that are available in the art. For example, the compositions may be administered through use of hot-melt extrusion articles, such as bioadhesive hot-melt extruded film. The formulation can comprise a cross-linked polycarboxylic acid polymer formulation. A cross-linking agent may be present in an amount that provides adequate adhesion to allow the system to remain attached to target epithelial or endothelial cell surfaces for a sufficient time to allow the desired release of the compound.
[88281] An insert, transdermal patch, bandage or article can comprise a mixture or coating of polymers that provide release of the pharmaceutical agents at a constant rate over a prolonged period of time. In some embodiments, the article, transdermal patch or insert comprises water-soluble pore forming agents, such as polyethylene glycol (PEG) that can be mixed with water insoluble polymers to increase the durability of the insert and to prolong the release of the active ingredients.
[88282] Transdermal devices (inserts, patches, bandages) may also comprise a water insoluble polymer. Rate controlling polymers may be useful for administration to sites where pH change can be used to effect release. These rate controlling polymers can be applied using a continuous coating film during the process of spraying and drying with the active compound. In one embodiment, the coating formulation is used to coat pellets comprising the active ingredients that are compressed to form a solid, biodegradable insert.
[88283] A polymer formulation can also be utilized to provide controlled or sustained release. Bioadhesive polymers described in the art may be used. By way of example, a sustained-release gel and the compound may be incorporated in a polymeric matrix, such as a hydrophobic polymer matrix. Examples of a polymeric matrix include a microparticle. The microparticles can be microspheres, and the core may be of a different material than the polymeric shell. Alternatively, the polymer may be cast as a thin slab or film, a powder produced by grinding or other standard techniques, or a gel such as a hydrogel. The polymer can also be in the form of a coating or part of a bandage, stent, catheter, vascular graft, or other device to facilitate delivery of the pharmaceutical agent. The matrices can be formed by solvent evaporation, spray drying, solvent extraction and other methods known to those skilled in the art. [88284] Kits with unit doses of one or more of the agents described herein, usually in oral or injectable doses, are provided. Such kits may include a container containing the unit dose, an informational package insert describing the use and attendant benefits of the drugs in treating disease, and optionally an appliance or device for delivery of the composition.
D. Methods of Treatment
The compounds described herein can be used in the preparation of medicaments for the prevention or treatment of diseases or conditions. In addition, a method for treating any of the diseases or conditions described herein in a subject in need of such treatment, involves administration of pharmaceutical compositions containing at least one compound described herein, or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said subject.
[8 286] The compositions containing the compound(s) described herein can be administered for prophylactic and/or therapeutic treatments. In therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition. Amounts effective for this use will depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician.
[88287] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a "prophylactically effective amount or dose." In this use, the precise amounts also depend on the patient's state of health, weight, and the like. When used in a patient, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.
[88288] In the case wherein the patient’s condition does not improve, upon the doctor’s discretion the administration of the compounds may be administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.
[88289] Once improvement of the patient's conditions has occurred, a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, can be reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. Patients can, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms.
[88218] The amount of a given agent that will correspond to such an amount will vary depending upon factors such as the particular compound, disease or condition and its severity, the identity (e.g., weight) of the subject or host in need of treatment, but can nevertheless be determined in a manner recognized in the field according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated. In general, however, doses employed for adult human treatment will typically be in the range of about 0.02 - about 5000 mg per day, in some embodiments, about 1 - about 1500 mg per day. The desired dose may conveniently be presented in a single dose or as divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example as two, three, four or more sub-doses per day.
[80211] The pharmaceutical composition described herein may be in unit dosage forms suitable for single administration of precise dosages. In unit dosage form, the formulation is divided into unit doses containing appropriate quantities of one or more compound. The unit dosage may be in the form of a package containing discrete quantities of the formulation. Non-limiting examples are packaged tablets or capsules, and powders in vials or ampoules. Aqueous suspension compositions can be packaged in single-dose non-recloseable containers. Alternatively, multiple-dose recloseable containers can be used, in which case it is typical to include a preservative in the composition. By way of example only, formulations for parenteral injection may be presented in unit dosage form, which include, but are not limited to ampoules, or in multi -dose containers, with an added preservative.
[88 1 ] Toxicity and therapeutic efficacy of such therapeutic regimens can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD50 and ED50. Compounds exhibiting high therapeutic indices are preferred. The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with minimal toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
[80213] In an aspect, disclosed herein in a method of modulating protein kinase, membrane associated tyrosine/threonine 1 (PKMYT1) activity in a subject, comprising administering to the subject a compound described herein, or a pharmaceutically acceptable salt thereof.
](.0)214] In an aspect, disclosed herein is a method of inhibiting protein kinase, membrane associated tyrosine/threonine 1 (PKMYT1) activity in a subject, comprising administering to the subject a compound described herein, or a pharmaceutically acceptable salt thereof.
[80215] In an aspect, disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition described herein.
[(0) 18] In some embodiments, the cancer is associated with PKMYT1 activity.
[ (.0)217] In an aspect, disclosed herein is a method for treating a subject having or suspected of having a cancer, comprising administering to the subject a therapeutically effective amount of a compounds disclosed herein, or a pharmaceutically acceptable salt thereof, that modulates the expression or activity of PKMYTl.
In some embodiments, the cancer is a skin cancer, ocular cancer, gastrointestinal cancer, thyroid cancer, breast cancer, ovarian cancer, central nervous system cancer, laryngeal cancer, cervical cancer, lymphatic system cancer, genitourinary tract cancer, bone cancer, biliary tract cancer, endometrial cancer, liver cancer, lung cancer, prostate cancer, or colon cancer.
[88228] In some embodiments, the cancer is leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia, acute lymphoblastic leukemia (ALL), non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), or multiple myeloma (MM). In some embodiments, the cancer is acute myeloid leukemia (AML). In some embodiments, the cancer is chronic myeloid leukemia. In some embodiments, the cancer is acute lymphoblastic leukemia (ALL). In some embodiments, the cancer is non-Hodgkin lymphoma (NHL). In some embodiments, the cancer is Hodgkin lymphoma (HL). In some embodiments, the cancer is multiple myeloma (MM).
[88220] In some embodiments, the cancer is a solid cancer.
[88222] In some embodiments, the cancer is not a solid cancer.
[88222] In some embodiments, the cancer is a cancer metastasis.
[88223] In some embodiments, the method comprises administering a second therapeutic agent. In some embodiments, the second therapeutic agent is a monoclonal antibody. In some embodiments, the second therapeutic agent is an immune checkpoint inhibitor. In some embodiments, the second therapeutic is chemotherapy or radiation therapy.
E. Biomarkers
[88223] In another aspect, provided herein is a method of identifying a subject having a disease for treatment with a compound disclosed herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof), the method comprising determining the presence of a mutation in the expression level of , and/or the activity of one or more biomarkers in a diseased tissue sample obtained from the subject.
[ 8:228] In another aspect, provided herein is a method of determining the responsiveness of a subject having a disease or disorder to a compound disclosed herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof), the method comprising determining the presence of a mutation in the expression level of, and/or the activity of one of more biomarkers in a diseased tissue sample obtained from the subject.
[88226] In some embodiments, the diseased tissue sample comprises an altered expression level and/or activity of the one or more biomarkers relative to a reference tissue sample. In some embodiments, the expression level and/or activity of the one or more biomarkers is reduced relative to a reference tissue sample.
[88227] In some embodiments, the diseased tissue sample is from a cancer. In some embodiments, the cancerous tissue is breast tissue, pancreatic tissue, uterine tissue, bladder tissue, colorectal tissue, prostate tissue, liver tissue, or ovarian tissue. In some embodiments, the cancerous tissue is liver tissue. In some embodiments, the cancerous tissue is ovarian tissue
(< )22-8| In some embodiments, the subject has a tumor, and wherein the diseased tissue sample comprises a tumor sample, a circulating tumor DNA sample, a tumor biopsy sample, or a fixed tumor sample. In some embodiments, the tumor sample is selected from acute myeloid leukemia (LAML), adrenocortical carcinoma (ACC), bladder urothelial carcinoma (BLCA), brain lower grade glioma (LGG), breast invasive carcinoma (BRCA), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), cholangiocarcinoma (CHOL), chronic myelogenous leukemia (LCML), colon adenocarcinoma (COAD), esophageal carcinoma (ESCA), glioblastoma multiforme (GBM), head and neck squamous cell carcinoma (HNSC), kidney chromophobe (KICH), kidney renal clear cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP), liver hepatocellular carcinoma (LIHC), lung adenocarcinoma (LU AD), lung squamous cell carcinoma (LUSC), lymphoid neoplasm diffuse large B- cell lymphoma (DLBC), mesothelioma (MESO), ovarian serous cystadenocarcinoma (OV), pancreatic adenocarcinoma (PAAD), pheochromocytoma and paraganglioma (PCPG), prostate adenocarcinoma (PRAD), rectum adenocarcinoma (READ), sarcoma (SARC), skin cutaneous melanoma (SKCM), testicular germ cell tumors (TGCT), thymoma (THYM), thyroid carcinoma (THCA), uterine carcinosarcoma (UCS), uterine corpus endometrial carcinoma (UCEC), and uveal melanoma (UVM). ( 0229^ In some embodiments, the healthy control is from one or more subjects that do not exhibit the cancer or tumor (e.g., liver or ovarian cancer).
(fW230j In another aspect, provided herein is a method of identifying a cancer subject to receive a compound disclosed herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof), the method comprising: (i) determining the presence of the mutation in the expression level of, and/or the activity of one or more biomarkers in the tumor sample obtained from the subject; and (ii) administering the compound disclosed herein to the subject based on the presence of a mutation in, a reduced expression level, and/or a reduced activity of the one or more biomarkers relative to a healthy control.
(99231 j In some embodiments, the one or more biomarkers is selected from the group consisting of ATM, MAP2K4, TP53, CDC25A, CACNA1H, CDKN1B, DUSP7, FOXO3, FZD3, JAK1, SMAD2, TGFBR2, MAP3K2, PPP3CC, and PPP2R1B.
(09232 ] In some embodiments, the one or more biomarkers is selected from the group consisting of BIN3, AGPAT5, FGF17, PBK, NOTCH 1, CNTN5, IRF2, ALPK2, CDH19, CHKB, MAPK12, SLC8A1, HDAC2, CDT1, ADCY2, SLK, CDC20B, RPS6KA3, STAG1, CKAP5, RAD51, CKS1B, CCNO, KCNA2, MCM4, PLK4, and CDC16.
(99233( In some embodiments, the one or more biomarkers is selected from the group consisting of ERICH1, TNKS, TDRP, MTUS1, TNFRSF10B, HR, TNFRSF10D, DMTN, ENTPD4, TNFRSF10C, PEBP4, LPL, LGI3, SLC7A2, MTMR9, MSRA, PDLIM2, INTS10, SH2D4A, GFRA2, ZDHHC2, PDGFRL, SPAG11B, PPP1R3B, SPAG11A, REEP4, DEFA5, DEFB136, NRG1, ASAHI, DEFA3, EPHX2, CNOT7, PNMA2, TRIM35, ATRX, INTS9, DNAH3, MAP3K1, RIMS2, NSD1, and SARAF. [88234] In some embodiments, the one or more biomarker is selected from the group consisting of SLITRK1, ZNF521, CCNB1, CDK7, MYTIL, FZR1, SERF1A, GADD45B, ADGRL2, TTK, NRXN2, UNC13A, ZBTB7A, POLDI, PCDH19, SLC8A2, E2F4, UTS2, KCNN2, CCNH, FRG2C, PLK2, MYO 18 A, and DCAF12L1.
[88235] In some embodiments, the one or more biomarkers is selected from the group consisting of CDKN2B, CSMD3, LRP1B, DMRTA1, PTPRD, ELAVL2, FAT1, CDH1, NF1, PPP6R2, PIM3, MAPK11, CDH10, PCDH15, ALB, OR4F21, LING02, FBN2, CACNA1E, LRRC7, NALCN, ARID1A, ADGRB3, SI, PKHD1L1, TBCID22A, BNIP3L, DEFA1, DEFB103B, DEFB103A, HCN1, RELN, UNC13C, XKR5, CHMP7, CHRNA2, CSGALNACT1, FAM86B2, EGR3, XPO7, TRPS1, KDM6A, NBEA, VPS37A, SCN1A, CSMD2, GTSE1, TRMU, TENM1, DOCK3, VPS13B, RBM10, RYR2, SCARA5, SETBP1, DYSF, NLGN4X, EPHA3, FBLN1, ADAMTS20, IFT74, KLKB1, ACVR2A, ZFHX4, WWC2, M0B3B, DMXL1, ELAC1, RBPMS, ANK1, CADM2, C9orf72, MTNR1A, PLAA, NIPBL, ADPM, GABRB3, CTNN3, CNTN3, PPFIA2, FN1, HECW1, DMXL2, ZFP36L2, UPK3A, SMC1B, SMARCA4, LRFN5, TG, CTNND2, CHD1, LSAMP, PRR5, NPAP1, SNTG1, MDGA2, BNC2, SCN2A, HERC2, SCN3A, TRPM1, FSTL5, ASH1L, PRKDC, TCF4, SVIL, CHD4, PCDH9, NRXN3, SNX25, MPDZ, TLL1, EPHA6, FER, NFASC, USP34, SPEF2, CHD8, ABCA12, ARID2, KCNIP4, and NFIB.
[88234[ In some embodiments, the one or more biomarkers is selected form the group consisting of OR4F16, BUB IB, PLK1, PAXBP 1, CTR9, AR, EIF3A, KIF4A, MAGEBIO, CHEK1, CENPM, AKT1, ADCY1, ATP2B2, HASPIN, CTDSPL2, STAG2, NCAPG, NCAPG, IGF1F, BLM, ATR, AURKB, RBL2, RPS6KA6, GINS2, MAD1L1, ADCY5, CHTF18, SMC1A, BRSK2, BRPF3, FOXD4L4, TGIF2LX, SOX5, POU4F1, UHRF1, PPP2RC, WDR45, FAM120C, BRSK1, EVI5L, NPAS4, MCM10, SUPT5H, MCM5, GALK2, FTSJ1, TRAP1, PAK3, CENPE, TPT1, MAD2L2, FBXO5, CDK16, CDC45, USP27X, MAPK8, PRR20A, ADCY4, RRM1, TBR1, PAK2, KIF11, WDHD1, MELK, CHERP, CENPF, BUB1, PRMTG, EIF1AX, SMPD2, CASP8AP2, SFN, WEE1, ESPL1, OTUD5, DMRTC1B, TSSK2, ANAPC10, FOXM1, EXO1, CHEK2, KIFC1, ANKRD52, SPAG5, PPP2R2B, ZNF331, PAK1, TNP02, LDB1, CDK14, CDC25B, KCNV1, CPEB1, ZNF777, RPS6KA1, PSG7, CD177, CCNG1, PRAMEF8, ZBTB17, CCNF, E2F2, HDAC1, CCNB2, KIF15, AGPAT3, PEC8, RECQL4, ZNF853, SRSF4, PPP2R5A, ZBTB12, MMP12, KIF2C, HSP90AA1, PPP2R2D, CDC7, NANS, MOS, RBX1, NAGED4B, KIP23, SCLM1, SPANXA2, TRIM28, SRRM5, MEGEA1, ACTR3B, EBLN1, TP53TG3C, INS, ORC1, HSP90AB1, CHAF1B, MCM7, CPSF6, NACC1, WEE2, MYC, MCM6, ADCY6, TPX2, MYBL2, CDC23, RRM2, MAPK1, PRKACA, DDK, MEM01, IGF1, SKP1, PPIAL4C, PPIAL4D, SLC9A6, ARPP19, NOVA2, CTAG1B, CCNA2, CDC6, MEGEA9, F8A3, ARL17A, CTAG1A, MAD2L1, HSFX1, BNIP3, MRGPRG, ANAPC2, and RAD2.
[88237] In some embodiments, the cancer is associated with cancerous tissue comprising a cell that displays mutations and/or deletions in genes encoding subunits of Protein Phosphatase 2 (PP2A) as compared to a healthy control. In some embodiments, the presence or absence of the mutations and/or deletions is identified by an assay of cells derived from tissue obtained from the subject. In some embodiments, the assay is a next generation sequencing-based assay.
[0 238] In some embodiments, the PP2A subunit is selected from the group consisting of 65 kDa regulatory subunit A alpha (PPP2R1A), 65 kDa regulatory subunit A beta (PPP2R1B), 55 kDa regulatory subunit B alpha (PPP2R2A), 55 kDa regulatory subunit B beta (PPP2R2B), 55 kDa regulatory subunit B gamma (PPP2R2C), 55 kDa regulatory subunit B delta (PPP2R2D), 72/130 kDa regulatory subunit B (PPP2R3A), 48 kDa regulatory subunit B (PPP2R3B), regulatory subunit B” subunit gamma (PPP2R3C), regulatory subunit B’ (PPP2R4), 56 kDa regulatory subunit alpha (PPP2R5A), 56 kDa regulatory subunit beta (PPP2R5B), 56 kDa regulatory subunit gamma (PPP2R5C), 56 kDa regulatory subunit delta (PPP2R5D), 56 kDa regulatory subunit epsilon (PPP2R5E), catalytic subunit alpha (PPP2CA), and catalytic subunit beta (PPP2CB). In some embodiments, the PP2A subunit is PPP2R2.
EXAMPLES
[0239] The following examples are offered to illustrate, but not to limit the claimed invention. The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope.
[0240] The following synthetic schemes are provided for purposes of illustration, not limitation. The following examples illustrate the various methods of making compounds described herein. It is understood that one skilled in the art may be able to make these compounds by similar methods or by combining other methods known to one skilled in the art. It is also understood that one skilled in the art would be able to make, in a similar manner as described below by using the appropriate starting materials and modifying the synthetic route as needed. In general, starting materials and reagents can be obtained from commercial vendors or synthesized according to sources known to those skilled in the art or prepared as described herein.
[0241] The compounds and salts of Formulas (I), (la), (II), (Ila), (III), (IV), (IVa), (V), (Va), (Vb), or (VI) can be synthesized according to one or more illustrative schemes herein and/or techniques known in the art. Materials used herein are either commercially available or prepared by synthetic methods generally known in the art. These schemes are not limited to the compounds listed in the examples or by any particular substituents, which are employed for illustrative purposes. Although various steps are described and depicted in the synthesis schemes below, the steps in some cases may be performed in a different order than the order shown below. Numberings or R groups in each scheme do not necessarily correspond to that of the claims or other schemes or tables herein.
Example 1. Synthesis of Common Intermediate 1
Scheme 1.
Figure imgf000160_0001
^4)24 1 Step 1: 6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one
To a stirred solution of 2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (8 g, 41.40 mmol, 1.0 eq) in dry DMF (80 mL), NBS (7.37 g, 41.40 mmol, 1.0 eq) in DMF (20 mL) was added drop wise to the reaction mixture at room temperature under N2 and allowed to stir at room temperature for 16 h. After completion of reaction as indicated by TLC, the reaction mixture was poured into ice cold water (500 mL). The solid was filtered and dried under vacuum to afford the title compound as an off-white solid (8 g, 71.01 %). LCMS: m/z 272.5, 274.5 (M& M+2); ‘H NMR (DMSO-t/tf, 400 MHz): 5 12.92 (s, 1H), 8.84 (s, 1H), 8.48 (s, 1H), 2.56 (s, 3H).
^4)2461 Step 2: 6-bromo-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one 14)247] To a stirred solution of 6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (16 g, 58.80 mmol, 1.0 eq) in DCM (100 mL), CS2CO3 (38.46 g, 118.08 mmol, 2.0 eq) was added at room temperature and stirred for 15 min. Me2SC>4 (8.88 g, 70.56 mmol, 1.2 eq) was added drop wise to the reaction mixture and stirred the reaction mixture for additional 3h. After completion of reaction as indicated by TLC, the reaction mixture was filtered and filtrate was washed with saturated NaHCCF solution (400 mL). The organic layer was dried over Na2SC>4 and concentrated under vacuum to afford the title compound as an off white solid (15 g, 89.15 %). LCMS: m/z 286.5, 288.5 (M& M+2); ’H NMR (DMSO-d6, 400 MHz): 5 8.86 (s, 1H), 8.52 (s, 1H), 3.65 (s, 3H), 2.60 (s, 3H). 14)248^ Step 3: 6-(2,6-dichlorophenyl)-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one pW49^ To a solution of 6-bromo-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (7.5 g, 26.22 mmol 1.0 eq) and (2,6-dichlorophenyl)boronic acid (17.5 g, 91.78 mmol, 3.5 eq) in dioxane: water (8:2, 100 mL), K2CO3 (12.65 g, 91.73 mmol, 3.5 eq) was added and the reaction mixture was purged with N2 for 30 min. Pd2(dba)3 (3.6 g, 3.93 mmol, 0.15 eq) and Sphos (2.15 g, 5.24 mmol, 0.2 eq) were added to the reaction mixture and stirred at 110°C for 4h. After completion of reaction, the reaction mixture was filtered through Celite and washed with EtOAc. The filtrate was treated with water (100 mL) and the organic payer was separated and further extracted with EtOAc (3 x 50 mL). The combined organic layer was dried over Na2SO4 and concentrated under vacuum. The crude was triturated with diethyl ether (50 mL) and dried under vacuum to afforded title compound as a brown solid (5 g, 54.16 %). LCMS: m/z 352.5, 354.7 (M& M+2); ’H NMR (DMSO-t/tf, 400 MHz): 5 8.95 (s, 1H), 8.06 (s, 1H), 7.61 (d, J = 8.0 Hz, 2H), 7.51 - 7.47 (m, 1H), 3.68 (s, 3H), 2.64 (s, 3H).
^00250^ Step 4: 6-(2,6-dichlorophenyl)-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin -7(8H)~ one (Intermediate 1)
To a stirred solution of 6-(2,6-dichlorophenyl)-8-methyl-2-(methylthio)pyrido[2,3- d]pyrimidin-7(8H)-one (10 g, 28.40 mmol, 1.0 eq) in chloroform (150 mL), m-CPBA(70 %) (20.99 g, 85.22 mmol, 3.0 eq) was added and stirred the reaction mixture for 16h at room temperature. After completion of reaction, the reaction mixture was quenched with 10 % NaHCC>3 solution (500 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layer was dried over Na2SC>4 and concentrated under vacuum. The crude was triturated with ethanol (100 mL) and resulted solid was filtered and dried under vacuum to afforded the title compound as a light brown solid. (5 g, 45.84%).
LCMS: m/z 384.6 (M+H)+; ‘H NMR (DMSO-t/tf, 400 MHz): 5 9.36 (s, 1H), 8.29 (s, 1H), 7.64 (d, J = 8.0
Hz, 2H), 7.55-7.61 (m, 1H), 3.74 (s, 3H), 3.50 (s, 3H).
[00232] Example 2. Synthesis of COMPOUND-090
[0 233] Scheme 2.
Figure imgf000161_0001
[00254] Step 1: l-ethyl-lH-pyrazol-3-ol
[00255] To a solution of methyl 2-chloroacrylate (10 g, 82.90 mmol, 1.0 eq) and ethyl hydrazine oxalate (18.70 g, 124.40 mmol, 1.5 eq) in THF (30 mL), trimethylamine (23 mL, 165.80 mmol, 2.0 eq) was added and stirred the reaction mixture for 16h. After completion of reaction, the reaction mixture was quenched with 10% NaHCC>3 solution (100 mL) and extracted with EtOAc (3x100 mL). The combined organic layer was washed with water, dried over Na2SO4 and concentrated under vacuum. The crude was purified by column chromatography (230-400 mesh silica gel, 0 to 4 % MeOH/DCM) to afford the title compound as an orange semi solid (7g, 75.24 %). LCMS: m/z 113.1(M+H)+; 'H NMR (DMSO- tf, 400 MHz): 5 9.49 (s, 1H), 7.35 (d, J=2.0 Hz, 1H), 5.38 (d, J= 2Hz, 1H), 3.84 (q, 2H), 1.28 (t, J= 1.2 z, 3H).
[00256] Step 2: 2-((l-ethyl-lH-pyrazol-3-yl)oxy)-3-methyl-5-nitropyridine ^88257] To a stirred solution of l-ethyl-lH-pyrazol-3-ol (0.6 g, 5.35 mmol, 1.0 eq) in DMF (6 mL) at 0 °C, NaH (60 % in mineral oil) (0.428 g, 10.70 mmol, 2.0 eq) was added portion wise and stirred for 30 min. 2-Chloro-3-methyl-5 -nitropyridine (0.923g, 5.35 mmol, 1.0 eq) was added to the reaction mixture and allowed to stir at room temperature for 2h. After completion of the reaction as indicated by TLC, the reaction mixture was quenched with 10 % NH4CI solution (100 mL) and extracted with EtOAc (3x30 mL). The combined organic layer was washed with water, dried over Na2SC>4 and concentrated under vacuum. The crude was purified by column chromatography (230-400 mesh silica gel, 0-20 % EtOAc/hexane) to afford the title compound as a yellow solid (0.6g, 45.17%). LCMS: m/z 249.0(M+H); ‘H NMR (DMSO- tf, 400 MHz): 5 8.86 (s, 1H), 8.56 (s, 1H), 7.73 (d, J = 2.2 Hz, 1H), 6.06 (d, J = 2.3 Hz, 1H), 4.05 (q, J = 12 Hz, 2H), 2.39 (s, 3H), 1.36 (t, J = 12 Hz, 3H).
Step 3: 6-((l-ethyl-lH-pyrazol-3-yl)oxy)-5-methylpyridin-3-amine
To a stirred solution of 2-((l-ethyl-lH-pyrazol-3-yl)oxy)-3-methyl-5-nitropyridine (0.6 g, 2.41 mmol, 1.0 eq) in EtOH (20 mL) and water (10 mL), NH4CI (0.77 g, 14.50 mmol, 6.0 eq) and iron powder (0.81 g, 14.50 mmol, 6.0 eq) were added and heated the reaction mixture at 70 °C for Ih. After completion of the reaction as indicated by TLC, the reaction mixture was filtered through Celite and washed with EtOAc (3 x 10 ml). The filtrated was concentrated and water (100 mL) was added. The product was extracted with EtOAc (3 x3 0 mL), dried over Na2SO4 and concentrated under vacuum to afford the title compound as a black solid (0.4g, 75.82 %). The crude was used in next step without further purification. LCMS: m/z 219.5 (M+H)+; ’H NMR (DMSO-t/tf, 400 MHz): 5 7.54 (d, J= 2.4 Hz, IH), 7.32 (d, J= 2.8 Hz, IH), 6.90 (d, J = 2.4 Hz, IH), 5.67 (d, J =2.0 Hz, IH), 4.96 (s, 2H), 3.96 (q, J = 12 z, 2H), 2.10 (s, 3H), 1.31 (t, J = 12 Hz, 3H).
88268^ Step 4: 6-(2, 6-dichlorophenyl)-2-( ( 6-( ( 1 -ethyl-lH-pyrazol-3-yl)oxy)-5-methylpyridin-3- yl)amino)-8-methylpyrido[2,3-d]pyrimidin-7( 8H)-one
[882S1] To a stirred solution of 6-(2,6-dichlorophenyl)-8-methyl-2-(methylsulfonyl)pyrido[2,3- d]pyrimidin-7(8H)-one (0.150 g, 0.39 mmol, 1.0 eq) and 6-((l-ethyl-lH-pyrazol-3-yl)oxy)-5- methylpyridin-3 -amine (0.085g, 0.39 mmol, 1.0 eq) in 1,4-dioxane (3 mL), TFA (0.004 g, 0.039 mmol, 0.1 eq) was added and stirred at 100 °C for 5h. After completion of the reaction as indicated by TLC, the reaction was quenched with 10 % NaHCCF solution (100 mL) and extracted with EtOAc (3x30 mL). The combined organic layer was washed with water, dried over Na2SO4 and concentrated under vacuum. The crude was purified by reverse phase column chromatography (47 % ACN in water) to afford the title compound as a brown solid (0.033g, 16.22 %). LCMS: (m/z) 523.04 (M & M+2); 'H NMR: (DMSO- d, 400 MHz): 5 10.27 (br s, IH), 8.85 (s, IH), 8.42 (br s, IH), 8.10 (s, IH), 7.92 (s, IH), 7.65 (d, J = 2.4 Hz, IH), 7.59 (d, J = 8.0 Hz, 2H), 7.49-7.45 (m, IH), 5.91 (d, J = 2.4 Hz, IH), 4.01 (q, J = 12 Hz, 2H), 3.64 (s, 3H), 2.30 (s, 3H), 1.34 (t, J = 12 Hz, 3H).
Example 3. Synthesis of COMPOUND-092
Scheme 3.
Figure imgf000163_0001
100°C, 16h COMPOUND 092
[66264] Step 1: 2-((5-nitropyridin-2-yl)oxy)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyridine
[00265] To a stirred solution of 4,5,6,7-tetrahydropyrazolo[l,5-a]pyridin-2-ol (0.050 g, 0.36 mmol, 1.0 eq) in DMF (1 mL) at room temperature, K2CO3 (0.250 g, 1.8 mmol, 5.0 eq) was added and stirred for 30 min. 2-chloro-5-nitropyridine (0.086 g, 0.54 mmol, 1.5 eq) was added to the reaction mixture and allowed to stir at room temperature for additional 16h. After completion of the reaction as indicated by TLC, the reaction mixture was quenched with water (20 mL) and extracted with EtOAc (3x10 mL). The combined organic layer was washed with water, dried over Na2SC>4 and concentrated under vacuum. The crude was purified by column chromatography (230-400 mesh silica gel, 0-20 % EtOAc/hexane) to afford the title compound as a brown liquid (0.070g, 74.33%). LCMS: m/z 261.55 (M+H)+. H \\1R (DMSO- tf, 400 MHz): 5 9.06 (d, J = 2.8Hz, 1H), 8.60 (dd, J = 9.2, 2.8 Hz, 1H),7.25 (d, J = 9.2Hz, 1H), 5.84 (s, 1H), 3.96 (t, J = 6.0 Hz, 2H), 2.74 (t, J = 6.4 Hz, 2H), 2.00-1.95 (m, 2H), 1.82-1.75 (m, 2H).
[00266] Step 2: 6-((4,5,6, 7-tetrahydropyrazolo[l,5-a]pyridin-2-yl)oxy)pyridin-3-amine
[00267] To a stirred solution of 2-((5-nitropyridin-2-yl)oxy)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyridine (0.350 g, 13.4 mmol, 1.0 eq) in EtOH (8 mL) and water (2 mL), NH4CI (0.435 g, 8.0 mmol, 6.0 eq) and iron powder (0.451 g, 8.0 mmol, 6.0 eq) were added and heated the reaction mixture at 70 °C for 16h. After completion of the reaction as indicated by TLC, the reaction mixture was filtered through Celite and washed with EtOAc (3 x 10 ml). The filtrated was concentrated and water (100 mL) was added. The product was extracted with EtOAc (3 x3 0 mL), dried over Na2SO4 and concentrated under vacuum. The crude was purified by column chromatography using silica gel (230-400 mesh and 6 % MeOH/DCM) afford the title compound as a brown solid (0.250g, 80.73 %). The crude was used in next step without further purification. LCMS: m/z 231.5 (M+H)+; ’H NMR (DMSO-t/tf, 400 MHz): 5 7.49 (d, J = 2.8Hz, 1H), 7.02 (dd, J = 8.4, 2.8 Hz, 1H), 6.72 (d, J = 8.4Hz, 1H), 5.50 (s, 1H), 5.04 (s, 2H), 3.87 (t, J =6.0 Hz, 2H), 2.66 (t, J = 6.4 Hz, 2H), 2.00-1.90 (m,2H), 1.80-1.70(m, 2H).
[ 66 8 ] Step 3: 6-(2, 6-dichloroph enyl)-8-methyl-2-( (6-((4,5, 6, 7-tetrahydropyrazolo[ 1, 5-a]pyridin-2- yl)oxy)pyridin-3-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one [88289) To a stirred solution of 6-((4,5,6,7-tetrahydropyrazolo[l,5-a]pyridin-2-yl)oxy)pyridin-3-amine (0.150 g, 0.65 mmol, 1.0 eq) and 6-(2,6-dichlorophenyl)-8-methyl-2-(methylsulfonyl)pyrido[2,3- d]pyrimidin-7(8H)-one (0.250 g, 0.65 mmol, 1.0 eq) in dioxane (1 mL), TFA (0.009 g, 0.065 mmol, 0.01 eq) was added and stirred at 100 °C for 16h. After completion of the reaction as indicated by TLC, the reaction was quenched with 10 % NaHCCF solution (50 mL) and extracted with EtOAc (3x30 mL). The combined organic layer was washed with water, dried over Na2SO4 and concentrated under vacuum. The crude was purified by column chromatography using silica gel (230-400 mesh and 60 % EtOAc/Hexane) to afford the title compound as a yellow solid (0.035 g, 10.05 %). LCMS: m/z 235.26 (M+H)+. ’H NMR (DMSO- tf, 400 MHz): 1H NMR (400 MHz, DMSO) 5 10.33 (br s, 1H), 8.85 (s, 1H), 8.60 (s, 1H), 8.24 (d, J= 8.4 Hz, 1H), 7.92 (s, 1H), 7.59 (d, J= 8.0 Hz, 2H), 7.46 (dd, J= 8.4 Hz, 1H), 7.06 (d, J= 8.8 Hz, 1H), 5.72 (s, 1H), 3.93 (t, J= 6.0 Hz, 2H), 3.63 (s, 3H), 2.72 (t, J= 6.4 Hz, 2H), 1.98-1.95 (m, 2H), 1.79- 1.76 (m, 2H).
[88278} Example 4. Synthesis of COMPOUND-097
[88271} Scheme 4.
Figure imgf000164_0001
p-TSA, Dioxane COMPOUND 097 80°C,16h
[80272} Step 1: 2-((l-ethyl-lH-pyrazol-3-yl)oxy)-3-fluoro-5-nitropyridine
[88273[ To a stirred solution of l-ethyl-lH-pyrazol-3-ol (1.0 g, 8.91 mmol, 1.0 eq) in DMF (10 mL) at 0 °C, NaH (60% in mineral oil) (0.71 g, 17.82 mmol, 2.0 eq) was added portion wise and stirred for 30 min. 2-chloro-3-fluoro-5 -nitropyridine (0.457 g, 8.91 mmol, 1.0 eq) was added to the reaction mixture and allowed to stir at room temperature for 2h. After completion of the reaction as indicated by TLC, the reaction mixture was quenched with 10 % NH4CI solution (100 mL) and extracted with EtOAc (3x30 mL). The combined organic layer was washed with water, dried over Na2SC>4 and concentrated under vacuum. The crude was purified by column chromatography (230-400 mesh silica gel, 0-10 % EtOAc/hexane) to afford the title compound as a yellow solid (1.5g, 66.69 %). LCMS: m/z 253.15 (M+H)+. ’H NMR (DMSO- tf, 400 MHz) 5 8.91 (d, J = 2.4 z, 1H), 8.78 (dd, J = 9.6 Hz, 2.4 Hz, 1H), 7.77 (d, J= 2.4 Hz, 1H), 6.14 (d, J = 2.4 Hz, 1H), 4.06 (q, J = 7.2 Hz, 2H), 1.35 (t, J = 7.2 Hz, 3H).
[88274} Step 2: 6-((l-ethyl-lH-pyrazol-3-yl)oxy)-5-fluoropyridin-3-amine [88278] To a stirred solution of 2-((l-ethyl-lH-pyrazol-3-yl)oxy)-3-fluoro-5-nitropyridine (0.5 g, 1.98 mmol, 1.0 eq) in EtOH (8 mL) and water (2 mL), NH4CI (0.636 g, 11.89 mmol, 6.0 eq) and iron powder (0.664 g, 11.89 mmol, 6.0 eq) were added into reaction mixture and heated at 70 °C for 4h. After completion of the reaction as indicated by TLC, the reaction mixture was filtered through Celite and washed with EtOAc (3 x 30 ml). The filtrated was concentrated and water (100 mL) was added. The product was extracted with EtOAc (3 x3 0 mL), dried over Na2SC>4 and concentrated under vacuum. The crude was purified by column chromatography (230-400 mesh, 6 % MeOH/DCM) to afford the title as brown a solid (0.4g, 90.80 %). LCMS: m/z 223.15 (M+H)+. ‘H NMR (DMSO-t/tf, 400 MHz): 5 7.57 (d, J = 2.4 Hz, 1H), 7.35 (d, J = 2.0 Hz, 1H), 6.96 (dd, J = 2.4 Hz, 12Hz, 1H), 5.73 (d, J = 2.0Hz, 1H), 5.42
(br s, 2H), 3.96 (q, J = 12 Hz, 2H), 1.30 (t, J = 8.0 Hz, 3H).
[80276] Step 3: 6-(2,6-dichlorophenyl)-2-((6-((l-ethyl-lH-pyrazol-3-yl)oxy)-5-fluoropyridin-3- yl)amino)-8-methylpyrido[2,3-d]pyrimidin-7( 8H)-one
[88277] To a stirred solution of 6-((l -ethyl- lH-pyrazol-3-yl)oxy)-5-fluoropyridin-3 -amine (0.130 g, 0.58 mmol, 2.0 eq) and 2-chloro-6-(2,6-dichlorophenyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (0.1 g, 0.29 mmol, 1.0 eq) in dioxane (1 mL), PTSA (0.004 g, 0.029 mmol, 0.01 eq) was added and stirred at 80 °C for 16h. After completion of the reaction as indicated by TLC, the reaction was quenched with 10 % NaHCCL solution (50 mL) and extracted with EtOAc (3x30 mL). The combined organic layer was washed with water, dried over NajSOi and concentrated under vacuum. The crude was purified by column chromatography (silica gel, 230-400 mesh, 70 % EtOAc/hexane) to afford the title compound as a yellow solid (0.044 g, 28.58 %). LCMS: m/z 525.8 (M+H)+; 1 H NMR (DMSO-t/tf, 400 MHz): 5 10.53 (s, 1H), 8.89 (s, 1H), 8.40-8.34 (m, 2H), 7.95 (s, 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.59 (d, J = 8.1 Hz, 2H),
7.50-7.45 (m, 1H), 5.97 (d, J = 2.4 Hz, 1H), 4.02 (q, J = 12 Hz, 2H), 3.66 (s, 3H), 1.33 (t, J = 12 Hz,
3H).
[88278] Example 5. Synthesis of COMPOUND-102
Figure imgf000165_0001
[88288] Step 1: 2-((5-nitropyridin-2-yl)oxy)indolizine [88281] To a stirred solution of pyrazolo[l,5-a]pyridin-2-ol (0.30 g, 2.23 mmol, 1.0 eq) in DMF (10 mL) at 0 °C, 60 % sodium hydride (0.089 g, 2.23 mmol, 1.0 eq) was added portion wise and stirred for 15 min. 2-chloro-5 -nitropyridine (0.353 g, 2.23 mmol, 1.0 eq) was added to the reaction mixture and allowed to stir at room temperature for 6h. After completion of the reaction as indicated by TLC, the reaction mixture was quenched with 10 % NH4CI solution (100 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layer was washed with water, dried over Na2SC>4 and concentrated under vacuum. The crude was purified by trituration with n-hexane (15 mL), observed precipitate was filtered and concentrated under vacuum to afford the title compound as a yellow solid (0.270 g, 47. 12 %).
LCMS: m/z 257.50 (M+H)+; ‘H NMR (DMSO-t/tf, 400 MHz): 5 9.09 (s, 1H), 8.67 (dd, J = 8.8 Hz, 2.8 Hz, 1H), 8.60 (d, J = 7.2 Hz, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.40 (d, J = 9.2 Hz, 1H), 7.30 (t, J = 6.8 Hz, 1H), 6.93 (t, J = 6.8 Hz, 1H), 6.49 (s, 1H).
[(8)282-] Step 2: 6-(indolizin-2-yloxy)pyridin-3-amine
[(.8)28.3] To a stirred solution of 2-((5-nitropyridin-2-yl)oxy)indolizine (0.26 g, 1.014 mmol, 1.0 eq) in Ethanol: water (8:2) (10 ml), NH4CI (0.325 g, 6.088 mmol, 6.0 eq) and iron powder (0.340 g, 6.088 mmol, 6.0 eq) were added and heated the reaction mixture at 100 °C for 3h. After completion of the reaction as indicated by TLC, the reaction mixture was filtered through Celite and washed with EtOAc (3 x 50 ml). The filtrate was concentrated and water (100 mL) was added. The product was extracted with EtOAc (3 x30 mL), dried over Na2SO4 and concentrated under vacuum. The crude was diluted with diethyl ether (15 mL), observed precipitate was filtered and solid was concentrated under vacuum to afford the title compound as a yellow solid (0.105 g, 65.34 %). LCMS: m/z 227.45 (M+H)+; *H NMR (DMSO- tf, 400 MHz): 5 8.48 (d, J = 6.8, 1H), 7.56-7.49 (m, 2H), 7.19 (t, J = 7.6 Hz, 1H), 7.08 (dd, J = 2.8 Hz, 8.8 Hz, 1H), 6.88-6.77 (m, 2H), 6.05 (s, 1H), 5.17 (br s, 2H).
[88284] Step 3: 6-(2,6-dichlorophenyl)-2-((6-(indolizin-2-yloxy)pyridin-3-yl)amino)-8- methylpyrido[2,3-d]pyrimidin- 7( 8H)-on e
[88285] To a stirred solution of 6-(indolizin-2-yloxy)pyridin-3-amine (0.100 g, 0.442 mmol, 1.0 eq) and 6-(2,6-dichlorophenyl)-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (0.169g, 0.442 mmol, 1.0 eq) in 1,4-dioxane (3 mL), TFA (0.005 g, 0.045 mmol, 0.1 eq) was added and stirred at 100 °C for 16h. After completion of the reaction as indicated by TLC, the reaction was quenched with 10 % NaHCC>3 solution (50 mL) and extracted with EtOAc (3x30 mL). The combined organic layers were washed with water, dried over Na2SO4 and concentrated under vacuum. The crude was purified by reverse phase column chromatography (0-20 % ACN in water) to afford the title compound as a pale yellow solid (0.015 g, 6.38 %) LCMS: m/z 529.60 (M+H)+; ‘NMR: (DMDO-t/tf, 400 MHz): 5 10.41 (s, 1H), 8.87 (s, 1H), 8.67 (s, 1H), 8.55 (d, J = 6.8 Hz, 1H), 8.31 (d, J = 8.4 Hz, lH), 7.93 (s, 1H), 7.59 (d, J = 8.4 Hz, 3H), 7.49-7.45 (m, 1H), 7.27-7.21 (m, 2H), 6.86 (t, J = 5.6 Hz, 1H), 6.31 (s, 1H), 3.64 (s, 3H).
[18)288] Example 6. Synthesis of COMPOUND-137
[(8)287] Scheme 6.
Figure imgf000167_0001
288} Step 1: Tert-butyl 3-(3-((5-nitropyridin-2-yl)oxy)-lH-pyrazol-l-yl)azetidine-l-carboxylate [ 0289} To a stirred solution of tert-butyl 3 -iodoazetidine- 1 -carboxylate (1 g, 3.5 mmol, 1.0 eq) in EtOH (10 mL) was added NH2NH2.H2O (1.76 g, 35.0 mmol, 10.0 eq) at room temperature. The reaction was stirred at reflux for 16 h. After completion of the reaction as indicated by TLC, the reaction mixture was concentrated under vacuum to afforded tert-butyl 3 -hydrazinylazetidine-1 -carboxylate as an off- white liquid (0.7 g, 100 %). LCMS: m/z 188.10 (M+H)+.
[88298} To a stirred solution of tert-butyl 3 -hydrazinylazetidine-1 -carboxylate (5.39 g, 28.8 mmol, 1.2 eq) in THF (60 mL), Et3N (8 mL, 57.6 mmol, 2 eq) followed by ethyl 2-chloroacrylate (2.88 g, 24.0 mmol, 1.0 eq) were added and stirred at room temperature for 24h. After completion of the reaction as indicated by TLC, the reaction mixture was quenched with ice cold water (500 mL) and extracted with EtOAc (3x200 mL). The combined organic layer was washed with water, dried over Na2SC>4 and concentrated under vacuum. The crude was purified by column chromatography (silica gel, 230-400 mesh, 6 to 8 % EtOAc/hexane) to afford tert-butyl 3-(3-hydroxy-lH-pyrazol-l-yl)azetidine-l-carboxylate as an off-white liquid (1.2 g, 17.42 %). LCMS: m/z 240.1 (M+H)+.
[1)8291 } To a stirred solution of tert-butyl 3-(3-hydroxy-lH-pyrazol-l-yl)azetidine-l-carboxylate (3.1 g, 12.9 mmol, 1.0 eq) in DMF (10 mL) at 0 °C, NaH (60 % in mineral oil) (1.03 g, 25.8 mmol, 2.0 eq) was added portion wise and stirred for 15 min. 2-chloro-5 -nitropyridine (2.05 g, 12.9 mmol, 1.0 eq) was added to the reaction mixture and allowed to stir at room temperature for 3.5h. After completion of the reaction as indicated by TLC, the reaction mixture was quenched with 10 % NH4CI solution (100 mL) and extracted with EtOAc (3x30 mL). The combined organic layer was washed with water, dried over Na2SC>4 and concentrated under vacuum. The crude was purified by column chromatography (230-400 mesh silica gel, 30-40 % EtOAc/hexane) to afford the title compound as a yellow solid (2.5 g, 53.40 %). LCMS: m/z 362.17 (M+H)+. ‘H NMR (DMSO-tA 400 MHz): 5 9.07(d, J = 2.8 Hz, 1H), 8.64 (dd, J = 9.2 Hz, 2.8 Hz, 1H), 7.93 (d, J = 2.4 Hz, 1H), 7.29 (d, J = 9.2 Hz, 1H), 6.18 (d, J = 2,4 Hz, 1H), 5.18- 5.21 (m, 1H), 4.27 (t, J = 7.6 Hz, 2H), 4.08-4.03 (m, 2H), 1.38 (s, 9H).
(88292) Step 2: 6-((l-(l-ethylazetidin-3-yl)-lH-pyrazol-3-yl)oxy)pyridin-3-amine
(88293) To a stirred solution of tert-butyl 3-(3-((5-nitropyridin-2-yl)oxy)-lH-pyrazol-l-yl)azetidine-l- carboxylate (2.5 g, 6.92 mmol, 1.0 eq) in DCM (25 mL) at 0 °C, TFA (25mL) was added drop wise to the reaction mixture and stirred at room temperature for 1.5 h. After completion of the reaction as indicated by TLC, the reaction mixture was concentrated under vacuum. The crude compound was triturated with diethyl ether to afforded the title compound as an off white solid (2.5 g, 100%). LCMS: m/z 262.10 (M+H)+.
(88294) To a mixture of 2-((l-(azetidin-3-yl)-lH-pyrazol-3-yl)oxy)-5-nitropyridine (2.5 g, 9.57 mmol, 1.0 eq) and 40 % acetaldehyde (5.18 g, 117.80 mmol, 12.31 eq) in DCM (25 mL). The reaction mixture was stirred at room temperature for 30 min. NaCNEftL (1.20 g, 19.14 mmol, 2.0 eq) was added at 0°C and stirred at room temperature for 4h. The reaction mixture was diluted with ice cold water (100 mL) and extracted with DCM (3x100 mL). The combined organic layer was dried over Na2SC>4, filtered and concentrated under vacuum. The crude was purified by column chromatography using silica gel (230-400 mesh, 10 % MeOH in DCM) to afford 2-((l-(l-ethylazetidin-3-yl)-lH-pyrazol-3-yl)oxy)-5-nitropyridine as brown liquid (1.0 g, 49.53%). LCMS: m/z 290.16 (M++H).
(88298) To a stirred solution of 2-((l-(l-ethylazetidin-3-yl)-lH-pyrazol-3-yl)oxy)-5-nitropyridine (0.2 g, 0.69 mmol, 1.0 eq) in Ethanol: water (8:2) (4 ml), NH4CI (0.220 g, 4.15 mmol, 6.0 eq) and Iron powder ((0.231 g, 4.15 mmol, 6.0 eq) were added and heated the reaction mixture at 70 °C for 2h. After completion of the reaction as indicated by TLC, the reaction mixture was filtered through Celite and washed with EtOAc (3 x 20 ml). The filtrated was concentrated and water (50 mL) was added. The product was extracted with EtOAc (3 x30 mL), dried over Na2SO4 and concentrated under vacuum to afford a crude product. The crude product was diluted with diethyl ether (15 mL), an observed precipitate was filtered and the solid was concentrated under vacuum to afford the title compound as a yellow solid (0.102 g, 56.90 %). LCMS: m/z 260.20 (M+H)+; ’H NMR (DMSO-t/tf, 400 MHz): 5 7.71 (d, J = 2.0 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.04 (dd, J = 8.8 Hz, 2.8 Hz, 1H), 6.74 (d, J = 8.8 Hz, 1H), 5.79 (d, J = 2.4 Hz, 1H), 5.07 (bs, 2H), 4.80 (quint, 1H), 3.60 (t, J =12 Hz, 2H),3.22 (t, J = 6.8, 2H), 2.45-2.42 (m, 2H), 0.88 (t, J = 7.2 Hz, 3H).
( 98298) Step 3: 6-(2, 6-dichlorophenyl)-2-( ( 6-( (1-(1 -ethylazetidin-3-yl)-lH-pyrazol-3-yl)oxy)pyridin-3- yl) amino)-8-methylpyrido[2,3-d]pyrimidin- 7(8H)-one [88297] After completion of the reaction as indicated by TLC, the reaction was quenched with 10 % NaHCCF solution (100 mL) and extracted with EtOAc (3x30 mL). The combined organic layer was washed with water, dried over Na2SO4 and concentrated under vacuum. The crude was purified by reverse phase column chromatography (47 % ACN in water) to afford the title compound as brown solid (0.033g, 16.22 %). LCMS: (m/z) 523.04 (M& M+2).
[96298] To a stirred solution of 6-((l-(l-ethylazetidin-3-yl)-lH-pyrazol-3-yl)oxy)pyridin-3-amine (0.100 g, 0.38 mmol, 1.0 eq) and 2-chloro-6-(2,6-dichlorophenyl)-8-methylpyrido[2,3-d]pyrimidin- 7(8H)-one (0.130 g, 0.38 mmol, 1.0 eq) in dioxane (2 mL), TFA (0.004 g, 0.038 mmol, 0.1 eq) was added stirred at 100 °C for 16 h. After completion of the reaction as indicated by TLC, the reaction was quenched with 10 % NaHCCh solution (10 mL) and extracted with EtOAc (3x10 mL). The combined organic layer was washed with water, dried over Na2SO4 and concentrated under vacuum. The crude was purified by prep HPLC (using 0.05 % TFA in water-ACN) to afford the title compound as a yellow solid (0.009 g, 4.14 %) LCMS: m/z 562.80 (M+H)+; 1H NMR: (DMSO-t/tf, 400 MHz): 5 10.36 (br s, 1H), 8.87 (s, 1H), 8.63 (s, 1H), 8.28 (dd, J= 8.8, 2.7 Hz, 1H), 7.93 (s, 1H), 7.85 (d, J = 2.4Hz, 1H), 7.60 (d, J= 8.0 Hz, 2H), 7.49-7.45 (m, 1H), 7.15 (d, J= 8.9 Hz, 1H), 6.11 (d, J= 2.4 Hz, 1H), 5.23 (bs, 1H), 4.40 (br s, 2H), 4.20 (br s, 2H), 3.65 (s, 3H), 3.18 (q, 2H), 1.11 (t, J= 7.2 Hz, 3H).
[8829 ] Example 7. Synthesis of COMPOUND-044
[88309] Scheme 7.
Figure imgf000169_0001
[88391] Step 1: tert-butyl 4-(2-((5-nitropyridin-2-yl)oxy)ethyl)piperazine-l-carboxylate
[88382] To a mixture of tert-butyl 4-(2-hydroxyethyl)piperazine- 1 -carboxylate (1.00 g, 4.34 mmol) in tetrahydrofuran (12 mL) was added to n-butyl lithium (2.5 M in tetrahydrofuran, 1.74 mL) at -78 °C and stirred for 1 hour. The reaction mixture was then added a solution of 2-fluoro-5 -nitro-pyridine (308 mg, 2.17 mmol) in tetrahydrofuran (3 mL). The reaction mixture was stirred at -78 °C for 1 hour. The reaction mixture was quenched by addition of water (30 mL) and extracted with ethyl acetate (200 mL). The combined organic layers were washed with brine (30 mb), dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 - 100% ethyl acetate in petroleum ether) to afford the title compound (145 mg, 16%) as a yellow oil. LCMS RT = 0.702 min, m/z = 353.2 [M + H]+ .
[00303[ Step 2: tert-butyl 4-(2-((5-aminopyridin-2-yl)oxy)ethyl)piperazine-l-carboxylate
[00304^ To a mixture of tert-butyl 4-[2-[(5-nitro-2-pyridyl)oxy]ethyl]piperazine-l-carboxylate (145 mg, 0.41 mmol) in methyl alcohol (5 mL) was added 10% palladium on carbon (50 mg) at 25 °C and purged with hydrogen (15 psi) and stirred for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to give the crude title compound (69 mg, 100%) as a yellow oil.
[00395 [ Step 3: tert-butyl 4-(2-((5-((6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido [2,3- d]pyrimidin-2-yl)amino)pyridin-2-yl)oxy)ethyl)piperazine-l-carboxylate
[00306[ To a mixture of tert-butyl 4-[2-[(5-amino-2-pyridyl)oxy]ethyl]piperazine-l-carboxylate (69 mg, 0.21 mmol) in 1 -methyl -2 -pyrrolidone (2 mL) was added 2-chloro-6-(2,6-dichlorophenyl)-8-methyl- pyrido[2,3-d]pyrimidin-7-one (73 mg, 0.21 mmol) and potassium fluoride (37 mg, 0.64 mmol) at 25 °C. The reaction mixture was stirred at 50 °C for 12 hours. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (50 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC to afford the title compound (150 mg, crude) as a yellow oil.
[0039? | Step 4: 6-(2,6-dichlorophenyl)-8-methyl-2-((6-(2-(piperazin-l-yl)ethoxy)pyridin-3- yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one
[90308[ To a mixture of tert-butyl 4-[2-[[5-[[6-(2,6-dichlorophenyl)-8-methyl-7-oxo-pyrido [2,3- d]pyrimidin-2-yl]amino]-2-pyridyl]oxy]ethyl]piperazine-l-carboxylate (150 mg, 0.24 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL) at 25 °C and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by RP-HPLC (44 to 74% acetonitrile in water and 10 mM ammonium bicarbonate) to afford the title compound (17 mg, 13%) as a yellow solid. 1 H NMR (400 MHz, CD3OD) d 8.77 (s, 1H), 8.54 (s, 1H), 8.17-8.10 (m, 1H), 7.80 (s, 1H), 7.52 (d, J= 9.2 Hz, 2H), 7.43-7.35 (m, 1H), 6.88 (d, J= 9.2 Hz, 1H), 4.60 (s, 1H),4.48 (t, J= 5.6 Hz, 2H), 3.77 (s, 3H), 3.00 (t, J= 5.2 Hz, 4H), 2.87 (t, J= 5.6 Hz, 2H), 2.70 (s, 4H). LCMS RT = 1.865 min, m/z = 526.1 [M + H]+.
[00309[ Example 8. Synthesis of COMPOUND-177
Figure imgf000170_0001
[00 10 [ N-(( 5-( ( 6-(2, 6-dichlorophenyl)-8-methyl- 7 -oxo- 7, 8-dihydropyrido[2,3-d]pyrimidin-2- yl)amino)-2-((l-ethyl-lH-pyrazol-3-yl)oxy)pyridin-3-yl)methyl)methanesulfonamide
Figure imgf000171_0003
( ] To a solution of 6-(2,6-dichlorophenyl)-8-methyl-2-[[6-(2-piperazin-l-ylethoxy)-3- pyridyl]amino]pyrido[2,3-d]pyrimidin-7-one (200 mg, 379.93 pmol) in methanol (3 mb) was added N,N- dimethylmethanamine sulfur trioxide (264 mg, 1.90 mmol). Then the mixture was stirred at 0 °C for 2 hours. The reaction mixture was fdtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (25 to 55% acetonitrile in water and 0.225% formic acid) to afford the title compound (0.7 mg, 0.3%) was obtained as a white solid. rH NMR (400 MHz, DMSO-t/g) 3 10.25 (s, 1H), 9.38 (s, 1H), 8.39 (s, 1H), 8.63 (s, 1H), 8.13 (s, 1H), 7.91(s, 1H), 7.62-7.52 (m, 2H), 7.50-7.43 (m, 1H), 7.05-6.81 (m, 1H), 4.65-4.48 (m, 2H), 3.64 (s, 3H), 3.63-3.49 (m, 4H), 3.26-3.05 (m, 4H), 2.86-2.67 (m, 2H). LCMS RT = 1.448 min, m/z = 606.3 [M + H]+ Example 9. Synthesis of COMPOUND-045
Figure imgf000171_0004
Figure imgf000171_0001
6-(2,6-dichlorophenyl)-2-((6-(2-(diethylamino)ethoxy)pyridin-3-yl)amino)-8-
Figure imgf000171_0005
methylpyrido[2,3-d]pyrimidin-7(8H)-one hydrochloric acid The title compound was made by the method used for COMPOUND-044 from 2-
Figure imgf000171_0006
(diethylamino)ethanol. The crude product was purified by RP-HPLC (40 to 70% acetonitrile in water and 0.225% formic acid) to afford the title compound (113 mg, 41%) as a yellow solid. ’H NMR (400 MHz, CD3OD) 3 8.89 (s, 1H), 8.83 (d, J= 2.4 Hz, 1H), 8.41-8.34 (m, 1H), 7.93 (s, 1H), 7.58-7.51 (m, 2H), 7.47-7.38 (m, 2H), 4.88-4.82 (m, 2H), 3.75 (s, 3H), 3.49-3.36 (m, 4H), 3.34-3.37 (m, 2H), 1.45 (t, J = 7.2 Hz, 6H). LCMS RT = 0.782 min, m/z = 513.2 [M + H]+
] 8831 S ] Example 10. Synthesis of COMPOUND-046
Figure imgf000171_0002
Figure imgf000171_0007
6-(2,6-dichlorophenyl)-2-((6-((l-ethyl-lH-pyrazol-3-yl)oxy)pyridin-3-yl)amino)-8- methylpyrido[2,3-d]pyrimidin- 7( 8H)-on e hydroch loride
(88317] The title compound was made by the method used for COMPOUND-044 from 1-ethylpyrazol- 3-ol. The crude was purified by RP-HPLC (46 to 76% acetonitrile in water and 1% hydrochloric acid) to afford the title compound (21 mg, 10%) as a white solid. ’H NMR (400 MHz, CD3OD) 3 8.84 (s, 1H), 8.77 (d, J= 2.4 Hz, 1H), 8.41-8.34 (m, 1H), 7.85 (s, 1H), 7.66 (d, J= 2.4 Hz, 1H), 7.60 (d, J= 5.6 Hz, 1H), 7.51 (s, 1H), 7.46-7.39 (m, 1H), 7.24 (d, J= 8.8 Hz, 1H), 6.06 (d, J= 2.4 Hz, 1H), 4.17 (q, J= 7.2 Hz, 2H), 3.79 (s, 3H), 1.50 (t, J= 7.2 Hz, 3H). LCMS RT = 0.879 min, m/z = 508.1 [M + H]+. Example 11. Synthesis of COMPOUND-047
Figure imgf000171_0008
Figure imgf000172_0001
(R)-6-(2,6-dichlorophenyl)-2-((6-((l-ethylpyrrolidin-2-yl)methoxy)pyridin-3-yl)amino)-8-
Figure imgf000172_0003
methylpyrido[2,3-d]pyrimidin- 7( 8H)-on e
[C 32 ] The title compound was made by the method used for COMPOUND-044 from tert-butyl (2R)- 2-(hydroxymethyl)pyrrolidine-l-carboxylate. The crude was purified by RP-HPLC (49 to 79% acetonitrile in water and 0.05% ammonium hydrate and 10 mM ammonium bicarbonate) to afford the title compound (12 mg 7%) as a yellow solid. rH NMR (400 MHz, CD3OD) 68.76 (s, 1H), 8.53 (s, 1H), 8.14 (d, J= 9.2 Hz, 1H), 7.80 (s, 1H), 7.55-7.48 (m, 2H), 7.44-7.37 (m, 1H), 6.89 (d, J= 8.8 Hz, 1H), 4.60 (s, 1H), 4.40-4.33 (m, 1H), 4.29 ( s, 1H), 3.77 (s, 3H), 3.3-3.13 (m, 2H), 3.03-2.87 (m, 1H), 2.52- 2.41 (m, 2H), 2.21-2.03 (m, 1H), 1.82-1.74 (m, 3H), 1.22 ( t, J= 7.2 Hz, 3H). LCMS RT = 2.363 min, m/z = 525.1 [M + H]+ Example 12. Synthesis of COMPOUND-049
Figure imgf000172_0004
Figure imgf000172_0002
(S)-6-(2,6-dichlorophenyl)-2-((6-((l-ethylpyrrolidin-2-yl)methoxy)pyridin-3-yl)amino)-8-
Figure imgf000172_0005
methylpyrido[2,3-d]pyrimidin- 7( 8H)-on e
(98323( The title compound was made by the method used for COMPOUND-044 from tert-butyl (2S)- 2-(hydroxymethyl)pyrrolidine-l-carboxylate. The crude was purified by RP-HPLC (53 to 83% acetonitrile in water and 0.05% ammonium hydrate and 10 mM ammonium bicarbonate) to afford the title compound (24 mg, 8%) as a yellow solid. *HNMR (400 MHz, CD3OD) 6 8.77 (s, 1H), 8.54 (s, 1H), 8.15-8.12 (m, 1H), 7.80 (s, 1H), 7.54-7.49 (m, 2H), 7.41-7.33 (m, 1H), 6.89 (d, J= 9.2 Hz, 1H), 4.41- 4.33 (m, 1H), 4.31-4.25 (m, 1H), 3.77 (s, 3H), 3.30-3.22(m, 2H), 3.20-3.10 (m, 1H), 2.14-2.06 (m, 2H), 1.91-1.83 (m, 1H), 1.82-1.65 (m, 3H), 1.21 (t, J= 7.2 Hz, 3H). LCMS RT = 0.785 min, m/z = 525.2 [M + H]+ Example 13. Synthesis of COMPOUND-123
Figure imgf000172_0006
Scheme 8.
Figure imgf000173_0001
COMPOUND 123
[88326] 6-(2,6-dichlorophenyl)-2-((6-(2-(l,l-dioxidothiomorpholino)ethoxy)pyridin-3-yl)amino)-8- methylpyrido[2,3-d]pyrimidin- 7( 8H)-on e
[88327] The title compound was made by the method used for COMPOUND-044 from 2-chloro-5- nitro-pyridine and 2-( 1,1 -dioxo- l,4-thiazinan-4-yl)ethanol. The crude was purified by RP-HPLC (35 to 55% acetonitrile in water and 0.225% formic acid) to afford the title compound- (7.7 mg, 17%) as a yellow solid. ’H NMR (400 MHz, CD3OD) 3 8.75 (s, 1H), 8.52 (s, 1H), 8.40 (dd, J= 2.4, 2.8 Hz, 1H), 7.79 (s, 1H), 7.50 (d, J= 8.4 Hz, 2H), 7.41-7.32 (m, 1H), 6.87 (d, J= 8.8 Hz,lH), 4.46 (t, J= 5.2 Hz, 2H), 3.76 (s, 3H), 3.17-3.06 (m, 8H),3.01 (t, J= 5.2 Hz, 2H). LCMS RT = 0.482 min, m/z = 575.1 [M + H]+.
[ 88328 ] Example 14. Synthesis of COMPOUND-196
[88329] Scheme 9.
Figure imgf000173_0002
[88338] Step 1: 2-thiomorpholinoethanol
[00331 [ To a solution of thiomorpholine (10.0 g, 96.91 mmol), 2-bromoethanol (19.4 g, 155.06 mmol), potassium carbonate (40.0 g, 290.74 mmol) in N,N-dimethylformamide (30 mL). The mixture was stirred at 80 °C for 10 hours. The reaction mixture was quenched by water (150 mL). The mixture was extracted with ethyl acetate (100 mL x 3). The combined organic layers were dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 - 25% ethyl acetate in petroleum ether) to afford the title compound (13.0 g, 90%) as a white solid. ’H NMR (400 MHz, CDCh) d 3.61 (t, J= 5.4 Hz, 2H), 2.83-2.77 (m, 4H), 2.73-2.66 (m, 4H), 2.57 (t, J= 5.2 Hz, 2H).
[08332 [ Step 2: 4-(2-((5-nitropyridin-2-yl)oxy)ethyl)thiomorpholine
[88333] To a solution of 2-thiomorpholinoethanol (2.0 g, 13.58 mmol) in N,N-dimethylformamide (40 mL) was added cesium carbonate (13.3 g, 40.75 mmol) and 2-chloro-5-nitro-pyridine (2.2 g, 13.58 mmol). The mixture was stirred at 20 °C for 2 hours. The reaction mixture was quenched by water (50 mL). The mixture was extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 - 25% ethyl acetate in petroleum ether) to afford the title compound (2.6 g, 88%) as a yellow solid. LCMS RT = 0.781 min, m/z = 21Q2 [M + H]+.
[08334 [ Step 3: 6-(2-thiomorpholinoethoxy)pyridin-3-amine
[08335] To a solution of 4-[2-[(5-nitro-2-pyridyl)oxy]ethyl]thiomorpholine (1.8 g, 6.68 mmol) in tetrahydrofuran (20 mL) and water (7 mL) was added iron (2.3 g, 40.10 mmol) and ammonium chloride (2.2 g, 40.10 mmol). The mixture was stirred at 55 °C for 10 hours. The reaction mixture was quenched by water (30 mL). The mixture was extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 - 100% ethyl acetate in petroleum ether) to afford the title compound (1.5 g, 91%) as a yellow oil. LCMS RT = 0.129 min, m/z = 240.0 [M + H]+.
[88336] Step 4: 6-(2,6-dichlorophenyl)-8-methyl-2-((6-(2-thiomorpholinoethoxy)pyridin-3- yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one
[88337] To a solution of 6-(2-thiomorpholinoethoxy)pyridin-3-amine (200 mg, 0.836 mmol) and 2- chloro-6-(2,6-dichlorophenyl)-8-methyl-pyrido[2,3-d]pyrimidin-7-one (284 mg, 0.835 mmol) in 1- methylpyrrolidin-2-one (4 mL) was added potassium fluoride (146 mg, 2.51 mmol). The mixture was stirred at 100 °C for 16 hours. The reaction mixture was quenched by water (10 mL). The mixture was extracted with ethyl acetate (10 mL x 3). The combined organic layers were dried over sodium sulphate, fdtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 - 40% ethyl acetate in petroleum ether) to afford the title compound (290 mg, 90%) as a yellow solid. LCMS RT = 0.485 min, m/z = 544.8 [M + H]+.
[88338] Step 5: 6-(2,6-dichlorophenyl)-8-methyl-2-((6-(2-(l-oxidothiomorpholino)ethoxy)pyridin-3- yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one [88339] To a solution of 6-(2,6-dichlorophenyl)-8-methyl-2-[[6-(2-thiomorpholinoethoxy)-3- pyridyl]amino]pyrido[2,3-d]pyrimidin-7-one (150 mg, 0.276 mmol) in acetone (3 mL) was added Oxone (85 mg, 0.138 mmol) in water (1 mL). The mixture was stirred at 0 °C for 1 hour. The reaction mixture was concentrated directly. The reaction mixture was concentrated and purified by RP-HPLC (18 to 48% acetonitrile in water and 0.225% formic acid) to afford the title compound- (10 mg, 10%) as a yellow solid. ‘H NMR (400 MHz, CD3OD) 3 8.75 (s, 1H), 8.52 (s, 1H), 8.12-8.10 (m, 1H), 7.78 (s, 1H), 7.56- 7.44 (m, 2H), 7.41-7.34 (m, 1H), 6.87 (d, J= 8.8 Hz, 1H), 4.46 (t, J= 5.6 Hz, 2H), 3.75 (s, 3H), 3.23- 3.12 (m, 2H), 3.05-2.98 (m, 2H), 2.96-2.88 (m, 6H). LCMS RT = 1.414 min, m/z = 559.3 [M + H]+
[88348] Example 15. Synthesis of COMPOUND-122
Figure imgf000175_0001
[88341] 6-(2,6-dichlorophenyl)-2-((6-(2-(l,l-dioxidothiomorpholino)ethoxy)-5-fluoropyridin-3- yl)amino)-8-methylpyrido[2,3-d]pyrimidin-7( 8H)-one
[C 342] The title compound was made by the method used for COMPOUND-044 from 2-chloro-3- fluoro-5 -nitro-pyridine and 2-( 1,1 -dioxo- l,4-thiazinan-4-yl)ethanol. The crude was purified by RP-HPLC (25 to 75% acetonitrile in water and 0.05% ammonium hydrate and 10 mM ammonium bicarbonate) to afford the title compound (3 mg, 6%) as a yellow solid.
[88343] ’H NMR (400 MHz, CDCh) d 8.61 (s, 1H), 8.15-8.05 (m, 2H), 7.57 (s, 1H), 7.44 (s, 1H), 7.42 (s, 1H), 7.36-7.28 (m, 1H), 7.29 (s, 1H), 7.59 (s, 2H), 3.79 (s, 3H), 3.29-3.09 (m, 10H). LCMS RT = 2.125 min, m/z = 593.1 [M + H]+
Example 16. Synthesis of COMPOUND-106
Scheme 10.
Figure imgf000176_0001
(88348} Step 1: 2-((l-ethyl-lH-pyrazol-3-yl)oxy)-5-nitropyridine
(88347} To a solution of l-ethylpyrazol-3-ol (500 mg, 4.46 mmol) in acetonitrile (5 mL) was added 2- chloro-5 -nitro-pyridine (848 mg, 5.35 mmol) and potassium carbonate (1.85 g, 13.38 mmol) and stirred at 20 °C for 15 minutes. The mixture was stirred at 60 °C for 4 hours. The mixture was poured into water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over sodium sulphate, fdtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 - 20% ethyl acetate in petroleum ether) to afford the title compound (760 mg, 71%) as a brown oil. LCMS RT = 0.481 min, m/z = 235.0 [M + H]+
[88348} Step 2: 6-((l-ethyl-lH-pyrazol-3-yl)oxy)pyridin-3-amine
(80349} To a solution of 2-(l-ethylpyrazol-3-yl)oxy-5 -nitro-pyridine (760 mg, 3.24 mmol) in methyl alcohol (10 mL) was added 10% palladium on carbon (345 mg). The mixture was stirred at 25 °C for 2 hours under hydrogen atmosphere (15 psi). The mixture was filtered and concentrated under reduced pressure to afford the title compound (600 mg, 91%) as brown oil. rH NMR (400 MHz, CDCL) 3 7.75- 7.62 (m, 1 H), 7.35-7.23 (m, 1 H), 7.02-7.01 (m, 1 H), 6.90 - 6.80 (m, 1 H), 5.98-5.90 (m, 1 H), 4.15- 4.01 (m, 2 H), 3.55-3.42 (m, 2 H), 1.53-1.41 (m, 3 H). [88358] Step 3: 6-bromo-2-(( 6-( ( 1 -ethyl-lH-pyrazol-3-yl)oxy)pyridin-3-yl)amino)-8- methylpyrido[2,3-d]pyrimidin- 7( 8H)-on e
[8835) [ To a solution of 6-bromo-2-chloro-8-methyl-pyrido[2,3-d]pyrimidin-7-one (400 mg, 1.46 mmol) in n-butyl alcohol (4 mL) was added trifluoroacetic acid (498 mg, 4.37 mmol) and 6-(l- ethylpyrazol-3-yl)oxypyridin-3 -amine (357 mg, 1.75 mmol). The mixture was stirred at 100 °C for 16 hours. The mixture was adjusted to pH = 8 with saturated aqueous sodium bicarbonate, then extracted with ethyl acetate (20 mL x 3). The organic extracts were dried over anhydrous sodium sulphate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 - 5% methanol in dichloromethane) to afford the title compound (560 mg, 76%) as a yellow solid. LCMS RT = 0.486 min, m/z = 443.9 [M + H]+.
[88352] Step 4: methyl 2-((6-((l-ethyl-lH-pyrazol-3-yl)oxy)pyridin-3-yl)amino)-8-methyl-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidine-6-carboxylate
[8835.3] To a solution of 6-bromo-2-[[6-(l-ethylpyrazol-3-yl)oxy-3-pyridyl]amino]-8-methyl- pyrido[2,3-d]pyrimidin-7-one (560 mg, 1.27 mmol) in methyl alcohol (6 mL) and N,N- dimethylformamide (1 mL) was added triethylamine (141 mg, 1.39 mmol), 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride (93 mg, 0.13 mmol). The mixture was stirred at 80 °C for 16 hours under carbon monoxide atmosphere (50 psi). The mixture was filtered and the filtrated was concentrated under reduced pressure. The crude reaction mixture was purified by prep-TLC to afford the title compound (260 mg, 40%) as a brown solid. LCMS RT = 0.459 min, m/z = 422.1 [M + H]+.
[1)8354] Step 5: 2-( ( 6-( ( I -ethyl-lH-pyrazol-3-yl)oxy)pyridin-3-yl)amino)-8-methyl- 7-oxo- 7, 8- dihydropyrido[2,3-d]pyrimidin e-6-carboxylic acid
[88355] To a solution of methyl 2-[[6-(l-ethylpyrazol-3-yl)oxy-3-pyridyl]amino]-8-methyl-7-oxo- pyrido [2,3 -d]pyrimidine-6-carboxy late (260 mg, 0.62 mmol) in methyl alcohol (3 mL) was added sodium hydroxide (123 mg, 3.08 mmol) in water (0.3 mL). The mixture was stirred at 50 °C for 1 hour. The mixture was concentrated under reduced pressure, adjusted to pH = 3 with hydrochloric acid (1 M), extracted with ethyl acetate (10 mL x 3). The organic extracts were dried over anhydrous sodium sulphate and filtered. The filtrate was concentrated under reduced pressure. The crude reaction mixture was purified by prep-TLC to afford the title compound (200 mg, 61%) as a brown solid. LCMS RT = 0.471 min, m/z = 408.1 [M + H]+.
[88338] Step 6: N-(2-aminopyridin-3-yl)-2-((6-((l-ethyl-lH-pyrazol-3-yl)oxy)pyridin-3-yl)amino)-8- methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide
[88357] To a solution of 2-[[6-(l-ethylpyrazol-3-yl)oxy-3-pyridyl]amino]-8-methyl-7-oxo-pyrido[2,3- d]pyrimidine-6-carboxylic acid (100 mg, 0.25 mmol) in N,N-dimethylformamide (1 mL) was added N- ethyl-N-isopropylpropan-2-amine (95 mg, 0.74 mmol), O-(7-azabenzotriazol-l-yl)-N,N,N’,N’- tetramethyluronium hexafluorophosphate (103 mg, 0.27 mmol), pyridine-2,3-diamine (27 mg, 0.25 mmol). The mixture was stirred at 20 °C for 16 hours. The mixture was concentrated under reduced pressure. The crude reaction mixture was purified by prep-TLC to afford the title compound- (35 mg, 22%) as a brown solid. LCMS RT = 0.425 min, m/z = 499.2 [M + H]+.
Figure imgf000178_0002
[ ] Step 7: 2-((6-((l-ethyl-lH-pyrazol-3-yl)oxy)pyridin-3-yl)amino)-6-(3H-imidazo[4,5- b]pyridin-2-yl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one
Figure imgf000178_0003
A solution ofN-(2-amino-3-pyridyl)-2-[[6-(l-ethylpyrazol-3-yl)oxy-3-pyridyl]amino]-8- methyl-7-oxo-pyrido[2,3-d]pyrimidine-6-carboxamide (35 mg, 0.07 mmol) in acetic acid (1 mb) was heated at 150 °C for 2 hours under microwave. The mixture was concentrated under reduced pressure and purified by RP-HPLC (32 to 42% acetonitrile in water and 0.225% formic acid) to afford the title compound (2 mg, 4%) as a yellow solid. 1 H NMR (400 MHz, DMSO-t/g) 3 10.53 (s, 1H), 9. 12 (s, 1H), 9.06 (s, 1H), 8.62 (s, 1H), 8.40 (d, J= 4.0 Hz, 1H), 8.26 (d, J= 8.8 Hz, 1H), 8.06 (d, J= 8.0 Hz, 1H), 7.69 (d, J= 2.4 Hz, 1H), 7.28-7.25 (m, 1H), 7.08 (d, J= 8.8 Hz, 1H), 5.96 (d, J= 2.0 Hz, 1H), 4.07-4.01 (m, 2H), 3.73 (s, 3H), 1.36 (t, J= 7.2 Hz, 3H). LCMS RT = 1.462 min, m/z = 481.2 [M + H]+.
[ 88368 [ Example 17. Synthesis of COMPOUND-107
Figure imgf000178_0001
Figure imgf000178_0004
[88361 6-( lH-benzo[d]imidazol-2-yl)-2-(( 6-( ( 1 -ethyl-lH-pyrazol-3-yl)oxy)pyridin-3-yl)amino)-8- methylpyrido[2,3-d]pyrimidin- 7( 8H)-on e
[80362] The title compound was made by the method used for COMPOUND-106 from benzene- 1,2- diamine. The crude product was purified by RP-HPLC (15 to 45% acetonitrile in water and 0.225% formic acid) to afford the title compound (1 mg, 4%) as a yellow solid. rH NMR (400 MHz, CD3OD) 3 8.92 (s, 1H), 8.80 (s, 1H), 9.06 (s, 1H), 8.47 (s, 1H), 8.35-8.25 (m, 1H), 7.71-7.58 (m, 3H), 7.32-7.22 (m, 2H), 7.08 (d, J= 9.2 Hz, 1H), 5.99 (d, J= 2.4 Hz, 1H), 5.19 (s, 2H), 4.15-4.09 (m, 2H), 3.84 (s, 3H), 1.47 (t, J= 7.2 Hz, 3H). LCMS RT = 0.449 min, m/z = 480.2 [M + H]+ Example 18. Synthesis of COMPOUND-112 Scheme 11.
Figure imgf000178_0005
Figure imgf000179_0001
^803651 Step 1: tert-butyl 4-(2-((5-((6-bromo-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2- yl)amino)pyridin-2-yl)oxy)ethyl)piperazine-l -carboxylate
^88366^ To a solution of 6-bromo-2-chloro-8-methyl-pyrido[2,3-d]pyrimidin-7-one (1.00 g, 3.64 mmol) in N-methyl-2-pyrrolidinone (10 mL) was added potassium fluoride (635 mg, 10.93 mmol) and tert-butyl 4-[2-[(5-amino-2-pyridyl)oxy]ethyl]piperazine-l-carboxylate (1.41 g, 4.37 mmol). The mixture was stirred at 100 °C for 16 hours. The mixture was poured into water (20 mL) and extracted with dichloromethane (20 mL x 3). The organic extracts were dried over anhydrous sodium sulphate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 - 4% methanol in dichloromethane) to afford the title compound (1.80 g, 71%) as a white solid. LCMS RT = 0.456 min, m/z = 560.2 [M + H]+.
^8836'7^ Step 2: tert-butyl 4-(2-((5-((6-(2,6-difluorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-2-yl)amino)pyridin-2-yl)oxy)ethyl)piperazine-l-carboxylate
[883S8] To a solution of (2,6-difhrorophenyl)boronic acid (169 mg, 1.07 mmol) in toluene (3 mL) was added tert-butyl 4-[2-[[5-[(6-bromo-8-methyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-2- pyridyl]oxy]ethyl]piperazine-l -carboxylate (300 mg, 0.54 mmol), tris(dibenzylideneacetone)dipalladium (0) (25 mg, 0.03 mmol), potassium carbonate (222 mg, 1.61 mmol) and 2-dicyclohexylphosphino-2',6'- dimethoxybiphenyl (22 mg, 0.05 mmol). The mixture was stirred at 100 °C for 16 hours under nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 - 6% methanol in dichloromethane) to afford the title compound (170 mg, 20%) as a yellow solid. LCMS RT = 1.660 min, m/z = 594.3 [M + H]+.
(88369) Step 3: 6-(2,6-difluorophenyl)-8-methyl-2-((6-(2-(piperazin-l-yl)ethoxy)pyridin-3- yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one
(00378^ To a solution of tert-butyl 4-[2-[[5-[[6-(2,6-difluorophenyl)-8-methyl-7-oxo-pyrido[2,3- d]pyrimidin-2-yl]amino]-2-pyridyl]oxy]ethyl]piperazine-l-carboxylate (165 mg, 0.28 mmol) in dichoromethane was added trifluoroacetic acid (2 mL). The mixture was stirred at 20 °C for 0.5 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by RP-HPLC (15 to 45% acetonitrile in water and 0.225% formic acid) to afford the title compound (59 mg, 42%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) 5 10.21 (s, 1H), 8.83 (s, 1H), 8.59 (s, 1H), 8.13-8.02 (m, 1H), 8.03 (s, 1H), 7.58-7.47 (m, 1H), 7.25-7.16 (m, 2H), 6.86 (d, J= 8.8 Hz, 1H), 4.35 (t, J= 5.6 Hz, 2H), 3.63 (s, 3H), 2.98 (s, 4H), 2.74 (t, J= 5.6 Hz, 2H), 2.61 (s, 4H). LCMS RT = 0.416 min, m/z = 494.2 [M + H]+
(8 3? 1 ) Example 19. Synthesis of COMPOUND-113
Figure imgf000180_0001
(88372( 8-methyl-2-((6-(2-(piperazin-l-yl)ethoxy)pyridin-3-yl)amino)-6-(pyridin-4-yl)pyrido[2,3- d]pyrimidin- 7(8H)-one
(88373( The title compound was made by the method used for COMPOUND-112 from 4- pyridylboronic acid. The crude was purified by RP-HPLC (0 to 30% acetonitrile in water and 0.225% formic acid) to afford the title compound (42 mg, 60%) as a yellow solid. 1 H NMR (400 MHz, DMSO- d6) d 10.22 (s, 1H), 8.86 (s, 1H), 8.66-8.45 (m, 3H), 8.33-8.14 (m, 1H), 8.26 (s, 1H), 8.07 (d, J = 2.0, 8.8 Hz, 1H), 7.77-7.63 (m, 2H), 6.86 (d, J = 9.2 Hz, 1H), 4.34 (t, J= 6.0 Hz, 2H), 3.64 (s, 3H), 2.92-2.76 (m, 4H), 2.69 (t, J= 6.0 Hz, 2H), 2.62-2.35(m, 4H). LCMS RT = 0.354 min, m/z = 459.2 [M + H]+
( 88374 ( Example 20. Synthesis of COMPOUND-114
(88373( Scheme 12.
Figure imgf000180_0002
(88378( Step 1: 6-bromo-8-methyl-2-((6-(2-morpholinoethoxy)pyridin-3-yl)amino)pyrido[2,3- djpyrimidin- 7(8H)-one
(88377( To a solution of 6-bromo-2-chloro-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (310 mg, 1.13 mmol) and 6-(2 -morpholinoethoxy )pyridin-3 -amine (303 mg, 1.36 mmol) in N-methyl-2-pyrrolidinone (8 mL) was added potassium fluoride (197 mg, 3.39 mmol). The mixture was stirred at 100 °C for 6 hours. The mixture was diluted with water (50 mL) and extracted with dichloromethane/methanol (10: 1, 40 mL x 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 - 9% ethyl acetate in petroleum ether) to afford the title compound (500 mg, 96%) as a yellow solid. LCMS RT = 0.893 min, m/z = 463.2 [M + H]+.
[003?8[ Step 2: 6-(2,6-dichlorophenyl)-8-methyl-2-((6-(2-morpholinoethoxy)pyridin-3- yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one
[88379} A mixture of 6-bromo-8-methyl-2-[[6-(2-morpholinoethoxy)-3-pyridyl]amino]pyrido[2,3- d]pyrimidin-7-one (200 mg, 0.43 mmol), (2,6-dichlorophenyl)boronic acid (99 mg, 0.05 mmol), tris(dibenzylideneacetone)dipalladium (0) (50 mg, 0.10 mmol), cesium carbonate (283 mg, 0.86 mmol) and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (71 mg, 0.17 mmol) in toluene (2 mL) and water (0.1 mL) was stirred at 130 °C for 1.5 hours under microwave. The reaction mixture was concentrated and purified by RP-HPLC (15 to 45% acetonitrile in water and 0.225% formic acid) to afford the title compound (3 mg, 1%) as a light yellow solid. ’H NMR (400 MHz, CD3OD) 3 10. 18 (s, 1H), 8.83 (s, 1H), 8.58 (s, 1H), 8.07 (d, J= 2.8 Hz, 1H), 7.90 (s, 1H), 7.60 (s, 1H), 7.58 (s, 1H), 7.49-7.44 (m, 1H), 6.86 (d, J= 2.0 Hz, 1H), 4.36 (t, J= 5.6 Hz, 2H), 3.66-3.56 (m, 7H), 2.68 (t, J= 5.6 Hz, 2H), 2.54-2.46 (m, 4H). LCMS RT = 0.450 min, m/z = 527. 1 [M + H]+
(80388} Example 21. Synthesis of COMPOUND-115
Figure imgf000181_0001
[80381 [ 6-(3,5-dichloropyridin-4-yl)-8-methyl-2-((6-(2-morpholinoethoxy)pyridin-3- yl)amino)pyrido[2,3-d]pyrimidin- 7( 8H)-one formate
(88382} To a solution of lithium diisopropylamide (2 M in tetrahydrofuran, 3.38 ml) in tetrahydrofuran (10 mL) was added 3, 5 -dichloropyridine (1.00 g, 6.76 mmol) in tetrahydrofuran (2 mL) at -65 °C. The mixture was stirred at -65 °C for 1.5 hours. Then tributyl(chloro)stannane (1.73 g, 5.31 mmol) was added. The mixture was stirred at 20 °C for 2 hours. The mixture was quenched with water (2 mL) and concentrated under reduced pressure. The mixture was diluted with ethyl acetate (40 mL). The organic layer was washed with water (25 mL) and brine (20 mL). The organic layer was dried over sodium sulphate. The reaction mixture was concentrated to afford the crude 3,5-dichloro-4- (tributylstannyl)pyridine (1.50 g, 60%) as yellow oil which was used directly. To a solution of 6-bromo- 8-methyl-2-[[6-(2-morpholinoethoxy)-3-pyridyl]amino]pyrido[2,3-d]pyrimidin-7-one (70 mg, 0.15 mmol) and tributyl-(3,5-dichloro-4-pyridyl)stannane (99 mg, 0.23 mmol) in dioxane (1.5 mL) was added copper iodide (9 mg, 0.10 mmol) and bis(triphenylphosphine)palladium(II) dichloride (11 mg, 0.10 mmol). The mixture was stirred at 100 °C for 12 hours. The mixture was quenched by addition of saturated aqueous potassium fluoride (1 mL) and concentrated under reduced pressure. The residue was concentrated and purified by RP-HPLC (15 to 45% acetonitrile in water and 0.225% formic acid) to afford the title compound (0.85 mg, 1%) as a yellow solid. rH NMR (400 MHz, CD3OD) 3 8.73 (s, 2H), 8.68 (s, 1H), 8.16 (d, J= 2.4 Hz, 1H), 7.86 (d, J= 92 Hz, 2H), 6.92 (d, J= 92 Hz, 1H), 6.54 (d, J= 92 Hz, 1H), 4.52 (t, J= 5.6 Hz, 2H), 3.74 (t, J= 4.4 Hz, 4H), 3.48 (s, 3H), 2.93 (t, J= 5.6 Hz, 2H), 2.27 (s, 4H). LCMS RT = 0.423 min, m/z = 528.1 [M + H]+
[ 88383 [ Example 22. Synthesis of COMPOUND-121
Figure imgf000182_0001
121-3 COMPOUND 121
[88385] Step 1: 3,5-difluoro-4-(tributylstannyl)pyridine
[88386] To a solution of lithium diisopropylamide (2 M in tetrahydrofuran, 4.34 mL) in tetrahydrofuran (10 mL) was added 3,5-difluoropyridine (1.00 g, 8.69 mmol) in tetrahydrofuran (2 mL) at -65 °C. The mixture was stirred at -65 °C for 1.5 hours. Then tributyl(chloro)stannane (2.01 g, 6.18 mmol) was added. The mixture was stirred at 20 °C for 2 hours. The mixture was quenched by addition of water (2 mL) and concentrated under reduced pressure. Then the mixture was diluted with ethyl acetate (40 mL), washed with water (40 mL) and brine (20 mL). The organic layer was dried over sodium sulfate and concentrated to afford the title compound (2.50 g, 90%) as a yellow solid. LCMS RT = 1.379 min, m/z = 406.0 [M + H]+
(88387] Step 2: tert-butyl 4-(2-((5-((6-(3,5-difluoropyridin-4-yl)-8-methyl-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-2-yl)oxy)ethyl)piperazine-l-carboxylate [8838.8 [ To a solution of tert-butyl 4-[2-[[5-[(6-bromo-8-methyl-7-oxo-pyrido[2,3-d]pyrimidin-2- yl)amino]-2-pyridyl]oxy]ethyl]piperazine-l -carboxylate (300 mg, 0.53 mmol) in dioxane (4 mL) was added tributyl-(3,5-difluoro-4-pyridyl)stannane (281 mg, 0.69 mmol), copper iodide (31 mg, 0.16 mmol) and bis(triphenylphosphine)palladium(II) dichloride (38 mg, 0.10 mmol). The mixture was stirred at 130 °C for 1.5 hours under microwave. The mixture was concentrated under reduced pressure. The residue was purified by prep-TLC to afford the title compound (150 mg, 72%) as a yellow solid. LCMS RT = 0.457 min, m/z = 595.3 [M + H]+ [88389] Step 3: 6-(3,5-difluoropyridin-4-yl)-8-methyl-2-((6-(2-(piperazin-l-yl)ethoxy)pyridin-3- yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one
[88398] A solution of tert-butyl 4-[2-[[5-[[6-(3,5-difluoro-4-pyridyl)-8-methyl-7-oxo-pyrido[2,3- d]pyrimidin-2-yl]amino]-2-pyridyl]oxy]ethyl]piperazine-l-carboxylate (100 mg, 0.17 mmol) in hydrochloride solution (4 M in dioxane, 10 mL) was stirred at 20 °C for 0.5 hour. The reaction mixture was concentrated and purified by RP-HPLC (0 to 60% acetonitrile in water and 0.225% formic acid) to afford the title compound (11 mg, 12%) as a yellow solid. rH NMR (400 MHz, CD3OD) 6 8.81 (s, 1H), 8.62 (s, 1H), 8.51 (s, 2H), 8.26-8.17 (m, 1H), 8.10 (s, 1H), 7.07 (d, J= 8.8 Hz, 1H), 4.78 (t, J= 5.6 Hz, 2H), 3.77 (s, 9H), 3.66 (s, 4H). LCMS RT = 0.843 min, m/z = 495.4 [M + H]+
[88391 ] Example 23. Synthesis of COMPOUND-131
[88392J Scheme 14.
Figure imgf000183_0001
[88393] Step 1: methyl 2-((l-ethyl-lH-pyrazol-3-yl)oxy)-5-nitronicotinate
[88394] A mixture of methyl 2-chloro-5-nitro-pyridine-3 -carboxylate (940 mg, 4.34 mmol), 1- ethylpyrazol-3-ol (535 mg, 4.77 mmol) and sodium carbonate (1.38 g, 13.02 mmol) in acetonitrile (15 mL) was stirred at 25 °C for 2 hours under nitrogen atmosphere. The mixture was filtered and the filtrate was concentrated to afford the title compound (1.20 g, 99%) as yellow oil. LCMS RT = 0.488 min, m/z = 293.0 [M + H]+.
[8839:3] Step 2: methyl 5-amino-2-((l-ethyl-lH-pyrazol-3-yl)oxy)nicotinate
[88398] To a solution of methyl 2-((l-ethyl-lH-pyrazol-3-yl)oxy)-5-nitronicotinate (700 mg, 2.40 mmol) in methanol (9 mL) and water (3 mL) was added ammonium chloride (128 mg, 2.40 mmol) and iron (669 mg, 11.98 mmol). The mixture was stirred at 70 °C for 2 hours. The mixture was diluted with sodium carbonate water (10 mL) and extracted with ethyl acetate (10 mL x 2), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 - 8% methanol in dichloromethane) to afford the title compound (600 mg, 96%) as a yellow solid. LCMS RT = 0.396 min, m/z = 263.1 [M + H]+. [88397] Step 3: methyl 5-((6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-2-yl)amino)-2-((l-ethyl-lH-pyrazol-3-yl)oxy)nicotinate
[88398] To a solution of methyl 5-amino-2-((l-ethyl-lH-pyrazol-3-yl)oxy)nicotinate (150 mg, 0.57 mmol) in tertiary butanol (1 mL) was added 2-chloro-6-(2,6-dichlorophenyl)-8-methylpyrido[2,3- d]pyrimidin-7(8H)-one (195 mg, 0.57 mmol) and trifluoroacetic acid (65 mg, 0.57 mmol). The mixture was stirred at 100 °C for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 - 60% ethyl acetate in petroleum ether) to afford the title compound (150 mg, 46%) as a yellow solid. LCMS RT = 0.551 min, m/z = 566.2 [M + H]+
[08399] Step 4: 5-((6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2- yl)amino)-2-((l-ethyl-lH-pyrazol-3-yl)oxy)nicotinamide
[98488] A solution of methyl 5-((6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-2-yl)amino)-2-((l-ethyl-lH-pyrazol-3-yl)oxy)nicotinate (50 mg, 0.10 mmol) and liquid ammonia (1 mL) in methanol (2 mL) was stirred at 60 °C for 16 hours in sealed tube. The mixture was concentrated under reduced pressure. The reaction mixture was concentrated and purified by prep-TLC (dichloromethane: methanol = 20: 1) to afford the title compound (6 mg, 12%) as a white solid. rH NMR (400 MHz, CD3OD) 3 9.05 (s, 1H), 8.80 (s, 1H), 8.64 (d, J= 2.8 Hz, 1H), 7.81 (s, 1H), 7.63 (d, J= 2.4 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.43-7.34 (m, 1H), 6.12 (d, J= 2.4 Hz, 1H), 4.13 (q, J= 2.4 Hz, 2H), 3.80 (s, 3H),1.47 (t, J= 7.2 Hz, 3H). LCMS RT = 1.797 min, m/z = 551.3 [M + H]+
[8848 ] Example 24. Synthesis of COMPOUND-136
[98482] Scheme 15.
Figure imgf000184_0001
COMPOUND 136
[98483] Step 1: 5-((6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2- yl)amino)-2-((l-ethyl-lH-pyrazol-3-yl)oxy)nicotinic acid
[99484] To a solution of methyl 5-((6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-2-yl)amino)-2-((l-ethyl-lH-pyrazol-3-yl)oxy)nicotinate (100 mg, 0.17 mmol) in methanol (1 mL) and water (1 mL) was added lithium hydrate (15 mg, 0.35 mmol). The mixture was stirred at 25 °C for 4 hours. The reaction was diluted with hydrochloric acid (1 mL), water (5 mL) and extracted with ethyl acetate (20 mL). The combined organic layers were washed with brine (60 mb), dried over sodium sulfate. The reaction mixture was concentrated to give the crude title compound (50 mg, 51%) as a white solid. LCMS RT = 0.514 min, m/z = 552.1 [M + H]+
[88485] Step 2: 5-((6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2- yl)amino)-2-((l-ethyl-lH-pyrazol-3-yl)oxy)nicotinic acid
[88488] To a solution of 5-((6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-2-yl)amino)-2-((l-ethyl-lH-pyrazol-3-yl)oxy)nicotinic acid (40 mg, 0.10 mmol) in N,N- dimethylformamide (2 mL) was added N-methylmethanamine;hydrochloride (6 mg, 0.10 mmol), diisopropylethylamine (28 mg, 0.21 mmol) and tetramethyluronium hexafluorophosphate (30 mg, 0.10 mmol). The mixture was stirred at 20 °C for 4 hours. The mixture was concentrated under reduced pressure. The residue was purified by RP-HPLC (45 to 65% acetonitrile in water and 0.225% formic acid) to afford the title compound (12 mg, 28%) as a white solid. rH NMR (400 MHz, CD3OD) 38.80 (s, 1H), 8.64 (s, 1H), 8.36 (d, J= 2.8 Hz, 1H), 7.82 (s, 1H), 7.59 (d, J= 2.4 Hz, 1H), 7.49 (d, J= 8.0 Hz, 2H), 7.37 (t, J= 1.2 Hz, 1H), 6.04 (d, J= 2.4 Hz, 1H), 4.17-4.07 (m, 2H), 3.77 (s, 3H), 3.15 (s, 3H) ,3.08 (s, 3H), 1.46 (t, J= 7.6 Hz, 3H). LCMS RT = 1.860 min, m/z = 579.1 [M + H]+
[88407] Example 25. Synthesis of COMPOUND-133
[88408] Scheme 16.
Figure imgf000185_0001
[88488] Step 1: 2-((l-ethyl-lH-pyrazol-3-yl)oxy)-5-nitronicotinonitrile
[88418] To a mixture of 2-chloro-5-nitro-pyridine-3-carbonitrile (1.00 g, 5.45 mmol) in N,N- dimethylformamide (15 mL) was added cesium fluoride (2.48 g, 16.34 mmol) and l-ethylpyrazol-3-ol (671 mg, 5.99 mmol) was stirred at 20 °C for 12 hours. The reaction mixture was diluted with water (150 mL). The reaction was washed with ethyl acetate (100 mL x 3). The separated organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 - 25% ethyl acetate in petroleum ether) to afford the title compound (1.26 g, 89%) as a yellow solid. LCMS RT = 0.492 min, m/z = 260.0 [M + H]+ [00411) Step 2: 5-amino-2-((l-ethyl-lH-pyrazol-3-yl)oxy)nicotinonitrile
[80412) To a solution of 2-((l -ethyl- lH-pyrazol-3-yl)oxy)-5-nitronicotinonitrile (1.20 g, 4.63 mmol) in ethyl acetate (30 mL) was added stannous chloride (5.22 g, 23.15 mmol). Then the mixture was stirred at 60 °C for 2 hours. The reaction mixture was filtered and concentrated to give a residue. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 50 - 75% ethyl acetate in petroleum ether) to afford the title compound (700 mg, 66%) as a white solid. LCMS RT = 0.420 min, m/z = 230.0 [M + H]+
[0041.3) Step 3: 5-(aminomethyl)-6-((l-ethyl-lH-pyrazol-3-yl)oxy)pyridin-3-amine [00414) To a solution of 5-amino-2-((l-ethyl-lH-pyrazol-3-yl)oxy)nicotinonitrile (0.70 g, 3.05 mmol) in methanol (15 mL) was added 10% palladium on carbon (325 mg) and trifluoroacetic acid (3.09 g, 30.54 mmol). The mixture was stirred at 40 °C under hydrogen atmosphere (50 psi) for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC to afford the title compound (500 mg, 70%) as a white solid. LCMS RT = 0.236 min, m/z = 234.0 [M + H]+
[00415) Step 4: tert-butyl ((5-amino-2-((l-ethyl-lH-pyrazol-3-yl)oxy)pyridin-3-yl)methyl)carbamate [00416) A solution of 5-(aminomethyl)-6-(l-ethylpyrazol-3-yl)oxy-pyridin-3-amine (0.50 g, 2. 14 mmol) in dichloromethane (1 mL) was added di-tert-butyl dicarbonate (234 mg, 1.07 mmol) at 0 °C. Then the mixture was stirred at 20 °C for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC to afford the title compound (480 mg, 67%) was as a white solid. LCMS RT = 0.449 min, m/z = 334.2 [M + H]+ [004 7) Step 5: tert-butyl ((5-((6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-2-yl)amino)-2-((l-ethyl-lH-pyrazol-3-yl)oxy)pyridin-3-yl)methyl)carbamate
[00418) To a solution of 2-chloro-6-(2,6-dichlorophenyl)-8-methyl-pyrido[2,3-d]pyrimidin-7-one (153 mg, 0.45 mmol) and tert-butyl ((5-amino-2-((l-ethyl-lH-pyrazol-3-yl)oxy)pyridin-3- yl)methyl)carbamate (150 mg, 0.45 mmol) in l-methylpyrrolidin-2-one (5 mL) was added potassium fluoride (78 mg, 1.35 mmol). Then the mixture was stirred at 100 °C for 12 hours. The reaction mixture was concentrated to give the crude title compound- (200 mg, 100%) as a yellow oil which was used directly for next step without further purification. LCMS RT = 2. 110 min, m/z = 637.2 [M + H]+ [ GG 19 [ Step 6: 2-((5-( aminomethyl)-6-( ( I -ethyl-lH-pyrazol-3-yl)oxy)pyridin-3-yl)amin o)-6-( 2, 6- dichlorophenyl)-8-methylpyrido[2,3-d]pyrimidin-7( 8H)-one
[00420) A solution of tert-butyl ((5-((6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-2-yl)amino)-2-((l-ethyl-lH-pyrazol-3-yl)oxy)pyridin-3-yl)methyl)carbamate (190 mg, 0.30 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (167 mg, 1.49 mmol) and stirred at 20 °C for 1 hour. The mixture was adjusted to pH = 9 with saturated aqueous sodium bicarbonate solution. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, fdtered and concentrated under reduced pressure to give the crude title compound (150 mg, 94%) as a yellow oil which was used directly for next step without further purification. LCMS RT = 0.463 min, m/z = 537.1 [M + H]+
[8842 H Step 7: N-((5-((6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2- yl)amino)-2-((l-ethyl-lH-pyrazol-3-yl)oxy)pyridin-3-yl)methyl)acrylamide
[88422] To a solution of prop-2 -enoyl chloride (10 mg, 0.11 mmol) and 2-((5-(aminomethyl)-6-((l- ethyl-lH-pyrazol-3-yl)oxy)pyridin-3-yl)amino)-6-(2,6-dichlorophenyl)-8-methylpyrido[2,3-d]pyrimidin- 7(8H)-one (60 mg, 0.11 mmol) in dichloromethane (1 mL) was added triethylamine (11 mg, 0.11 mmol). Then the mixture was stirred at 20 °C for 12 hours. The reaction mixture was concentrated and purified by RP-HPLC (35 to 65% acetonitrile in water and 0.225% formic acid) to afford the title compound (5.8 mg, 9%) as a white solid. ’H NMR (400 MHz, DMSO- 6) d 10.34 (s, 1H), 8.84 (s, 1H), 8.73 (t, J= 6.0 Hz, 1H), 8.44 (d, J= 2.4 Hz, 1H), 8.19 (s, 1H), 7.91 (s, 1H), 7.67 (d, J= 2.4 Hz, 1H), 7.62-7.54 (m, 2H), 7.50-7.43 (m, 1H), 6.41-6.29 (m, 1H), 6.22-6.10 (m, 1H), 5.95 (d, J= 2.4 Hz, 1H), 5.67 (dd, J= 2.0, 10.0 Hz, 1H), 4.44 (d, J= 5.6 Hz, 2H), 4.03 (q, J= 7.2 Hz, 2H), 3.60 (s, 3H), 1.36 (t, J= 7.2 Hz, 3H). LCMS RT = 1.866 min, m/z = 591.4 [M + H]+
[80423 [ Example 26. Synthesis of COMPOUND-139
Figure imgf000187_0001
[88424] N-(( 5-( ( 6-(2, 6-dichlorophenyl)-8-methyl- 7 -oxo- 7, 8-dihydropyrido[2,3-d]pyrimidin-2- yl)amino)-2-((l-ethyl-lH-pyrazol-3-yl)oxy)pyridin-3-yl)methyl)acrylamide
[88425] To a solution of butyryl chloride (12 mg, 0.11 mmol) and 2-((5-(aminomethyl)-6-((l-ethyl-lH- pyrazol-3-yl)oxy)pyridin-3-yl)amino)-6-(2,6-dichlorophenyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (60 mg, 0.11 mmol) in dichloromethane (1 mL) was added triethylamine (11.30 mg, 0.11 mmol), then the mixture was stirred at 20 °C for 12 hours. The reaction mixture was concentrated and purified by RP- HPLC (35 to 65% acetonitrile in water and 0.225% formic acid) to afford the title compound (5.8 mg, 8%) as a white solid. ‘H NMR (400 MHz, DMSO-t/6) d 10.32 (s, 1H), 8.84 (s, 1H), 8.46 (s, 1H), 8.39 (t, J = 5.6 Hz, 1H), 8.08 (d, J= 1.6 Hz, 1H), 7.92 (s, 1H), 7.66 (d, J= 2.0 Hz, 1H), 7.59 (d, J= 8.0 Hz, 2H), 7.53-7.43 (m, 1H), 5.94 (d, J= 2.0 Hz, 1H), 4.34 (d, J= 5.6 Hz, 2H), 4.03 (q, J= 7.2 Hz, 2H), 3.63 (s, 3H), 2.17 (t, J= 7.2 Hz, 2H), 1.62-1.48 (m, 2H), 1.35 (t, J= 7.2 Hz, 3H), 0.85 (t, J= 7.2 Hz, 3H). LCMS RT = 1.967 min, m/z = 607.4 [M + H]+
[08426] Example 27. Synthesis of COMPOUND-134
Figure imgf000188_0001
|W 42-7 [5-[[6-(2,6-dichlorophenyl)-8-methyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl]amino]-2-(l- ethylpyrazol-3-yl)oxy-3-pyridyl]methylurea
[C 428] To a solution of 2-[[5-(aminomethyl)-6-(l-ethylpyrazol-3-yl)oxy-3-pyridyl]amino]-6-(2,6- dichlorophenyl)-8-methyl-pyrido[2,3-d]pyrimidin-7-one (15 mg, 0.03 mmol) in dichloromethane (1 mL) was added carbonyl diimidazole (6 mg, 0.04 mmol) at 0 °C and stirred for 5 min. Then the mixture was added triethylamine (12 mg, 0.12 mmol). After stirred for 1 hour, the mixture was added ammonium hydroxide (39 mg, 0.28 mmol) and stirred at 20 °C for 12 hours. The reaction mixture was concentrated and purified by RP-HPLC (20 to 80% acetonitrile in water and 0.225% formic acid) to afford the title compound (3 mg, 18%) as a yellow solid. ‘H NMR (400 MHz, CD3OD) 3 8.77 (s, 1H), 8.40 (d, J= 2.8 Hz, 1H), 8.37 (s, 1H), 7.80 (s, 1H), 7.59 (d, J= 2.4 Hz, 1H), 7.50 (d, J= 8.0 Hz, 2H), 7.43-7.34 (m, 1H), 6.01 (d, J= 2.4 Hz, 1H), 4.46 (s, 2H), 4.11 (q, J = 7.2 Hz, 2H), 3.80 (s, 3H), 1.46 (t, J = 7.2 Hz, 3H). LCMS RT = 1.721 min, m/z = 580.1 [M + H]+
[00429] Example 28. Synthesis of COMPOUND-160
Figure imgf000188_0002
[G8430] N-(( 5-( ( 6-(2, 6-dichlorophenyl)-8-methyl- 7 -oxo- 7, 8-dihydropyrido[2,3-d]pyrimidin-2- yl)amino)-2-((l-ethyl-lH-pyrazol-3-yl)oxy)pyridin-3-yl)methyl)methanesulfonamide
[00431 [ To a solution of 2-((5-(aminomethyl)-6-((l-ethyl-lH-pyrazol-3-yl)oxy)pyridin-3-yl)amino)-6- (2,6-dichlorophenyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (80 mg, 148.86 pmol) in dichloromethane (2 mL) was added triethylamine (45 mg, 446.59 pmol,) in one portion. The mixture was stirred at 0°C for 5 min, then added p-methyl benzene sulfonic chloride (19 mg, 163.75 pmol). Then the mixture was stirred at 20 °C for 1 hour. The residue was purified by prep-HPLC (36 to 56% acetonitrile in water and 0.225% formic acid) to afford the title compound (7.8 mg, 8%) as a yellow solid. 1 H NMR (400 MHz, CD3OD) 3 8.79 (s, 1H), 8.62 (s, 1H), 8.41 (d, J= 2.8 Hz, 1H), 7.81 (s, 1H), 7.60 (d, J= 2.4 Hz, 1H), 7.57-7.48 (m, 2H), 7.43-7.38 (m, 1H), 6.04 (d, J= 2.4 Hz, 1H), 4.44 (s, 2H), 4.12 (q, J= 7.2 Hz, 2H), 3.82 (s, 3H), 3.01 (s, 3H), 1.48-1.45(m, 3H). LCMS RT = 1.795 min, m/z = 615.3 [M + H]+ [0 432] Example 29. Synthesis of COMPOUND-161
Figure imgf000189_0001
3-f ( 5-( ( 6-(2, 6-dichlorophenyl)-8-methyl- 7 -oxo- 7,8-dihydropyrido[2,3-d]pyrimidin-2-
Figure imgf000189_0003
yl)amino)-2-(( 1 -ethyl-lH-pyrazol-3-yl)oxy)pyridin-3-yl)methyl)oxazolidin-2-one
Figure imgf000189_0004
To a solution of 2 -chloroethyl carbonochloridate (19 mg, 130.26 pmol) and 2-[[5- (aminomethyl)-6-(l-ethylpyrazol-3-yl)oxy-3-pyridyl]amino]-6-(2,6-dichlorophenyl)-8-methyl- pyrido[2,3-d]pyrimidin-7-one (70 mg, 130.26 pmol) in acetonitrile (2 mL) was added potassium carbonate (54 mg, 390.77 pmol). Then the mixture was stirred at 85 °C for 12 hours. The reaction mixture was fdtered and concentrated under reduced pressure to give a residue. The residue was purified by RP-HPLC (30 to 75% acetonitrile in water and 0.225% formic acid) to afford the title compound (1.7 mg, 2%) was obtained as a yellow solid. rH NMR (400 MHz, CD3OD) 0 8.79 (s, 1H), 8.51 (d, J= 2.4 Hz, 1H), 8.39 (d, J= 2.4 Hz, 1H), 7.81 (s, 1H), 7.59 (d, J= 2.0 Hz, 1H), 7.55-7.45 (m, 2H), 7.43-7.34 (m, 1H), 6.01 (d, J= 2.4 Hz, 1H), 4.61 (s, 2H), 4.40 (t, J= 7.6 Hz, 2H), 4.11 (q, J= 7.2 Hz, 2H), 3.78 (s, 3H), 3.72 (t, J= 8.0 Hz, 2H), 1.46 (t, J= 7.6 Hz, 3H). LCMS RT = 1.952 min, m/z = 607.1 [M + H]+
[<XM35] Example 30. Synthesis of COMPOUND-132 Scheme 17.
Figure imgf000189_0005
Figure imgf000189_0002
Step 1: 2-((l-ethyl-lH-pyrazol-3-yl)oxy)-5-nitro-3-(trifluoromethyl)pyridine
Figure imgf000189_0006
To a solution of 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (300 mg, 1.32 mmol) and 1- ethylpyrazol-3-ol (148 mg, 1.32 mmol) in N,N-dimethylformamide (4 mL) was added potassium carbonate (549 mg, 3.97 mmol) in one portion. The mixture was stirred at 20 °C for 1 hour. The reaction mixture was added water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (80 mL), dried over sodium sulphate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 - 20% ethyl acetate in petroleum ether) to afford the title compound (260 mg, 53%) as a yellow solid. LCMS RT = 0.537 min, m/z = 302.9 [M + H]+
[00439^ Step 2: 6-((l-ethyl-lH-pyrazol-3-yl)oxy)-5-(trifluoromethyl)pyridin-3-amine
[1M 48] To a solution of 2-(l-ethylpyrazol-3-yl)oxy-5-nitro-3-(trifluoromethyl)pyridine (260 mg, 0.86 mmol) in methyl alcohol (3 mL) and water (1 mL) in one portion was added ammonium chloride (46 mg, 0.86 mmol) and iron (384 mg, 6.88 mmol). The mixture was stirred at 80 °C for 4 hours. The reaction solution was fdtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 - 2% methanol in dichloromethane) to afford the title compound (225 mg, 68%) as a yellow solid. LCMS RT = 0.476 min, m/z = 273.0 [M + H]+.
[99441 [ Step 3: 6-(2,6-dichlorophenyl)-2-((6-((l-ethyl-lH-pyrazol-3-yl)oxy)-5- (trifluoromethyl)pyridin-3-yl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one [96442] To a solution of 6-(l-ethylpyrazol-3-yl)oxy-5-(trifluoromethyl)pyridin-3 -amine (100 mg, 0.37 mmol) and 2-chloro-6-(2,6-dichlorophenyl)-8-methyl-pyrido[2,3-d]pyrimidin-7-one (100 mg, 0.29 mmol) in dioxane (1 mL) in one portion was added p-toluenesulfonic acid (6 mg, 0.03 mmol). The mixture was stirred at 100 °C for 16 hours. The reaction mixture was concentrated and purified by RP- HPLC (55 to 85% acetonitrile in water and 0.225% formic acid) to afford the title compound (60 mg, 28%) as a white solid. 1H NMR (400 MHz, DMSO- 6) S 10.59 (s, 1H), 8.91 (s, 1H), 8.81 (s, 1H), 8.77 (s, 1H), 7.96 (s, 1H), 7.72-7.71 (m, 1H), 7.62-7.57 (m, 1H), 7.51-7.44 (m, 1H), 7.46 (s, 1H), 6.02 (d, J = 2.4 Hz, 1H), 4.08-4.02 (m, 2H), 3.65 (s, 3H), 1.36 (t, J= 7.2 Hz, 3H). LCMS RT = 2.195 min, m/z = 576.0 [M + H]+
[ 99443 ] Example 31. Synthesis of COMPOUND-135
[99444] Scheme 18.
Figure imgf000190_0001
[86445] Step 1: 2-((l-ethyl-lH-pyrazol-3-yl)oxy)-5-nitropyrimidine
[98449] To a solution of 2-chloro-5-nitro-pyrimidine (600 mg, 3.76 mmol) and l-ethylpyrazol-3-ol (422 mg, 3.76 mmol) in N,N-dimethylformamide (10 mL) in one portion was added cesium fluoride (1.71 g, 11.28 mmol). The mixture was stirred at 20 °C for 1 hour under nitrogen atmosphere. The reaction mixture was added water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (80 mL), dried over sodium sulphate, fdtered and concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 - 30% ethyl acetate in petroleum ether) to afford the title compound (700 mg, 73%) as a yellow solid. LCMS RT = 0.457 min, m/z = 236.0 [M + H]+ [88447] Step 2: 2-((l-ethyl-lH-pyrazol-3-yl)oxy)pyrimidin-5-amine
[08448] To a solution of 2-(l-ethylpyrazol-3-yl)oxy-5 -nitro-pyrimidine (600 mg, 2.55 mmol) in ethyl acetate (6 mL) was added stannous chloride (2.88 g, 12.76 mmol) in one portion. The mixture was stirred at 60 °C for 0.5 hour. The residue was added saturated aqueous sodium bicarbonate (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over sodium sulphate, fdtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 - 30% methanol in dichloromethane) to afford the title compound (220 mg, 41%) as a yellow solid. LCMS RT = 0.359 min, m/z = 206.0 [M + H]+.
[08449 ] Step 3: 6-(2, 6-dichlorophenyl)-2-( (2-( ( 1 -ethyl-lH-pyrazol-3-yl)oxy)pyrimidin-5-yl)amino)-8- methylpyrido[2,3-d]pyrimidin- 7( 8H)-on e
[88458] To a solution of 2-(l-ethylpyrazol-3-yl)oxypyrimidin-5 -amine (100 mg, 0.49 mmol) and 2- chloro-6-(2,6-dichlorophenyl)-8-methyl-pyrido[2,3-d]pyrimidin-7-one (133 mg, 0.39 mmol) in tertiary butanol (2 mL) in one portion was added trifluoroacetic acid (56 mg, 0.49 mmol). The mixture was stirred at 100 °C for 16 hours. The reaction mixture was concentrated under reduced pressure. The reaction mixture was concentrated and purified by RP-HPLC (40 to 80% acetonitrile in water and 0.05% ammonium hydrate and 10 mM ammonium bicarbonate) to afford the title compound (2 mg, 1%) as a white solid. XH NMR (400 MHz, CDCh) d 9.01-8.91 (m, 2H), 8.61 (s, 1H), 7.57 (s, 1H), 7.46-7.36 (m, 3H), 7.33-7.18 (m, 1H), 6.09 (s, 1H), 4.18-4.07 (m, 2H), 3.76 (s, 3H), 1.53 (t, J = 7.6 Hz, 3H). LCMS RT = 1.996 min, m/z = 509.1 [M + H]+
] 98451 ] Example 32. Synthesis of COMPOUND-142 ]994S2] Scheme 19.
Figure imgf000191_0001
[88453] Step 1: 2-(l-ethylpyrazol-3-yl)oxy-3,5-dinitro-pyridine
[08454] To a solution of l-ethylpyrazol-3-ol (606 mg, 5.40 mmol) in acetonitrile (10 mL) was added 2- chloro-3,5-dinitro-pyridine (1.00 g, 4.91 mmol) and potassium carbonate (679 mg, 4.91 mmol). The mixture was stirred at 20 °C for 16 hours. The mixture was filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 - 5% ethyl acetate in petroleum ether) to afford the title compound (1.30 g, 88%) as a yellow solid. LCMS RT = 0.511 min, m/z = 280.0 [M + H]+
[88455] Step 2: 2-(l-ethylpyrazol-3-yl)oxy-5-nitro-pyridin-3-amine
[88456] To a solution of 2-(l-ethylpyrazol-3-yl)oxy-3,5-dinitro-pyridine (1.30 g, 4.66 mmol) in methyl alcohol (10 mL) and water (3 mL) was added ammonium chloride (249 mg, 4.66 mmol) and iron (1.30 g, 23.30 mmol). The mixture was stirred at 80 °C for 2 hours. The mixture was filtered and the filtrates were concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 - 1% methanol in dichloromethane) to afford the title compound (477 mg, 41%) as a yellow solid. ’H NMR (400 MHz, DMSO- 6) 8.17 (d, J= 2.8 Hz, 1 H), 7.75-7.68 (m, 2 H), 6.04 (d, J= 2.4 Hz, 1 H), 6.02 (s, 2 H), 4.05 (q, J= 7.2 Hz, 2 H), 1.35 (t, J= 7.2 Hz, 3 H). LCMS RT = 0.476 min, m/z = 250.0 [M + H]+
[88457] Step 3: tert-butyl N-tert-butoxycarbonyl-N-[2-(l-ethylpyrazol-3-yl)oxy-5-nitro-3- pyridyl]carbamate
[88458] To a solution of 2-(l-ethylpyrazol-3-yl)oxy-5-nitro-pyridin-3 -amine (422 mg, 1.69 mmol) in dichloromethane (5 mL) was added ', '-4-dimcthylaminopyridinc (21 mg, 0.17 mmol), triethylamine (343 mg, 3.39 mmol) and tert-butyl (2-methylpropan-2-yl)oxycarbonyl carbonate (739 mg, 3.39 mmol). The mixture was stirred at 20 °C for 1 hour. The mixture was fdtered and concentrated under reduced pressured. The residue was purified by prep-TLC to afford the title compound (477 mg, 46%) as a yellow oil. LCMS RT = 0.586 min, m/z = 350.0 [M + H]+
[88459] Step 4: tert-butyl N-[5-amino-2-(l-ethylpyrazol-3-yl)oxy-3-pyridyl]-N-tert-butoxycarbonyl- carbamate
[88458] To a solution of tert-butyl N-tert-butoxycarbonyl-N-[2-(l-ethylpyrazol-3-yl)oxy-5-nitro-3- pyridyl]carbamate (477 mg, 1.06 mmol) in methyl alcohol (5 mL) and water (1.6 mL) was added iron (296 mg, 5.31 mmol) and ammonium chloride (57 mg, 1.06 mmol). The mixture was stirred at 80 °C for 1 hour. The mixture was filtered and concentrated under reduced pressured. The residue was purified by prep-TLC (dichloromethane: methanol = 20: 1) to afford the title compound (140 mg, 28%) as a yellow solid. ‘H NMR (400 MHz, CDCh) <5 8. 11 (s, 1 H), 7.32 (s, 1 H), 7.07 (s, 1 H), 6.04 (s, 1 H), 4.08 (q, J= 7.2 Hz, 2 H), 1.55-1.39 (m, 12 H). LCMS RT = 0.565 min, m/z = 420.0 [M + H]+
[88481 [ Step 5: tert-butyl N-[5-[[6-(2,6-dichlorophenyl)-8-methyl-7-oxo-pyrido[2,3-d]pyrimidin-2- yl]amino]-2-(l-ethylpyrazol-3-yl)oxy-3-pyridyl]carbamate
[88462] To a solution of 2-chloro-6-(2,6-dichlorophenyl)-8-methyl-pyrido[2,3-d]pyrimidin-7-one (109 mg, 0.32 mmol) in tert-butyl alcohol (1 mL) was added para-toluene sulfonic acid (6 mg, 0.03 mmol) and tert-butyl N-[5-amino-2-(l-ethylpyrazol-3-yl)oxy-3-pyridyl]-N-tert-butoxycarbonyl-carbamate (134 mg, 0.32 mmol). The mixture was stirred at 100 °C for 16 hours. The mixture was filtered and concentrated under reduced pressured. The residue was purified by prep-TLC (dichloromethane: methanol = 20: 1) to afford the title compound (87 mg, 37%) as a yellow solid. rH NMR (400 MHz, DMSO-t/g) 8 10.35 (s, 1 H), 8.93 (s, 1 H), 8.86 (s, 1 H), 8.74 (s, 1 H), 8.16 (d, J= 2.0 Hz, 1 H), 7.92 (s, 1 H), 7.66 (d, J= 2.0 Hz, 1 H), 7.59 (d, J= 8.4 Hz, 2 H), 7.49-7.41 (m, 1 H), 5.93 (d, J= 2.4 Hz, 1 H), 4.03 (q, J= 7.2 Hz, 2 H), 3.68 (s, 3 H), 1.48 (s, 9 H), 1.35 (t, J= 7.2 Hz, 3 H). LCMS RT = 0.607 min, m/z = 623.2 [M + H]+ 88463] Step 6: 2-[[ 5-amino-6-(l -ethylpyrazol-3-yl)oxy-3-pyridyl]amino]-6-(2, 6-dichlorophenyl)-8- methyl-pyrido[2,3-d]pyrimidin-7-one [88464] To a solution of tert-butyl N-[5-[[6-(2,6-dichlorophenyl)-8-methyl-7-oxo-pyrido[2,3- d]pyrimidin-2-yl]amino]-2-(l-ethylpyrazol-3-yl)oxy-3-pyridyl]carbamate (80 mg, 0.13 mmol) in trifluoroacetic acid (1 mL). The mixture was stirred at 20 °C for 1 hour under nitrogen atmosphere. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford the title compound (67 mg, 99%) as a yellow solid.
[88465] Step 7: [2-[[5-[[6-(2,6-dichlorophenyl)-8-methyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl]amino]- 2-(l-ethylpyrazol-3-yl)oxy-3-pyridyl]amino]-2-oxo-ethyl] acetate
[88466] To a solution of (2 -chloro-2 -oxo-ethyl) acetate (17 mg, 0.13 mmol) in dichloromethane (1 mL) was added 2-[[5-amino-6-(l-ethylpyrazol-3-yl)oxy-3-pyridyl]amino]-6-(2,6-dichlorophenyl)-8-methyl- pyrido[2,3-d]pyrimidin-7-one (67 mg, 0.13 mmol) and triethylamine (13 mg, 0.13 mmol). The mixture was stirred at 30 °C for 16 hours under nitrogen atmosphere. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford the title compound (55 mg, 69%) as a brown solid.
[88467] Step 8: N-[5-[[6-(2,6-dichlorophenyl)-8-methyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl]amino]-2- ( 1 -ethylpyrazol-3-yl)oxy-3-pyridyl]-2-hydroxy-acetamide
[88468] To a solution of [2-[[5-[[6-(2,6-dichlorophenyl)-8-methyl-7-oxo-pyrido[2,3-d]pyrimidin-2- yl]amino]-2-(l-ethylpyrazol-3-yl)oxy-3-pyridyl]amino]-2-oxo-ethyl] acetate (50 mg, 0.08 mmol) in methyl alcohol (1 mL) and water (0.2 mL) was added sodium carbonate (26 mg, 0.24 mmol). The mixture was stirred at 30 °C for 16 hours. The reaction mixture was quenched by addition of formic acid (0.5 mL) and concentrated and purified by RP-HPLC (40 to 60% acetonitrile in water and 0.225% formic acid) to afford the title compound (2.4 mg, 5%) as a yellow solid. 1 H NMR (400 MHz, DMSO-t/g) 3 10.39 (s, 1H), 9.34-9.26 (m, 2H), 8.86 (s, 1H), 8.25 (d, J= 2.4 Hz, 1H), 7.92 (s, 1H), 7.70 (d, J= 2.4 Hz, 1H), 7.59 (d, J= 8.0 Hz, 2H), 7.52-7.42 (m, 1H), 6.20 (s, 1H), 6.01 (d, J= 2.0 Hz, 1H), 4.11-4.01 (m, 4H), 3.67 (s, 3H), 1.36 (t, J= 7.2 Hz, 3H). LCMS RT = 1.807 min, m/z = 581.1 [M + H]+
Example 33. Synthesis of COMPOUND-143
Scheme 20.
Figure imgf000194_0001
COMPOUND 143
[88471 ] Step 1: l-ethylpyrazol-3-ol
[88472] To a solution of 1,4-thiazinane 1,1 -dioxide (200 mg, 1.48 mmol) in dichloromethane (3 ml) was added (2-chloro-2 -oxo-ethyl) acetate (606 mg, 4.44 mmol) and triethylamine (449 mg, 4.44 mmol). The mixture was stirred at 20 °C for 16 hours. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 - 2% methanol in dichloromethane) to afford the title compound (348 mg, 99%) as a white solid. rH NMR (400 MHz, CDCh) d 4.76 (s, 2 H), 4.19-3.88 (m, 4 H), 3.23-3.01 (m, 4 H), 2.25-2.13 (m, 3 H).
[88473] Step 2: l-(l,l-dioxo-l,4-thiazinan-4-yl)-2-hydroxy-ethanone
[88474] To a solution of [2-( 1,1 -dioxo- l,4-thiazinan-4-yl)-2-oxo-ethyl] acetate (348 mg, 1.48 mmol) in methanol (5 mL) and water (1 mL) was added sodium carbonate (784 mg, 7.40 mmol). The mixture was stirred at 20 °C for 16 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (dichloromethane: methanol = 10: 1) to afford the title compound (258 mg, 90%) as a white solid. ’H NMR (400 MHz, CDCh) 84.27 (s, 2 H), 4.19 (s, 2 H), 3.88-3.74 (m, 2 H), 3.18- 3.02 (m, 4 H).
[88473] Step 3: l-(l,l-dioxo-l,4-thiazinan-4-yl)-2-[(5-nitro-2-pyridyl)oxy]ethenone
[88476] To a solution of l-( 1,1 -dioxo- l,4-thiazinan-4-yl)-2 -hydroxy-ethanone (50 mg, 0.26 mmol) in
N,N-dimethylformamide (1 mL) was added sodium hydride (10 mg, 0.26 mmol) at 0 °C. After stirred for
O.5 hour, the mixture was added 2-chloro-5 -nitro-pyridine (41 mg, 0.26 mmol). The mixture was stirred at 20 °C for 16 hours under nitrogen atmosphere. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (dichloromethane: methanol = 10: 1) to afford the title compound (50 mg, 49%) as a yellow solid. LCMS RT = 0.406 min, m/z = 316.0 [M + H]+
Step 4: 2-[(5-amino-2-pyridyl)oxy]-l-( 1,1 -dioxo- 1, 4-th iazinan-4-yl)ethenone [88478] To a solution of l-(l,l-dioxo-l,4-thiazinan-4-yl)-2-[(5-nitro-2-pyridyl)oxy]ethanone (45 mg, 0.14 mmol) in methanol (1 mL) was added 10% palladium on carbon (15 mg). The mixture was stirred at 20 °C for 16 hours under hydrogen atmosphere (15 psi). The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (dichloromethane: methanol = 10: 1) to afford the title compound (35 mg, 70%) as a yellow solid. LCMS RT = 0.163 min, m/z = 308.0 [M + Na]+
|<MM 79] Step 5: 6-(2,6-dichlorophenyl)-2-[[6-[2-(l,l-dioxo-l,4-thia nan-4-yl)-2-oxo-ethoxy]-3- pyridyl]amino]-8-methyl-pyrido[2,3-d]pyrimidin-7-one
[88488] To a solution of 2-chloro-6-(2,6-dichlorophenyl)-8-methyl-pyrido[2,3-d]pyrimidin-7-one (36 mg, 0.11 mmol) in l-methyl-2 -pyrrolidone (1 mL) was added 2-[(5-amino-2-pyridyl)oxy]-l-(l,l-dioxo- l,4-thiazinan-4-yl)ethanone (30 mg, 0.11 mmol) and potassium fluoride (18 mg, 0.32 mmol). The mixture was stirred at 100 °C for 16 hours under nitrogen atmosphere. The reaction mixture was fdtered and concentrated under reduced pressure. The residue was purified by RP-HPLC (30 to 60% acetonitrile in water and 0.225% formic acid) to afford the title compound (3.1 mg, 5%) as a yellow solid. rH NMR (400 MHz, DMSO-t/e) 10.20 (s, 1H), 8.83 (s, 1H), 8.51 (s, 1H), 8.11 (d, J= 6.8 Hz, 1H), 7.90 (s, 1H), 7.59 (d, J= 8.0 Hz, 2H), 7.50-7.40 (m, 1H), 6.95 (d, J= 8.8 Hz, 1H), 5.11 (s, 2H), 3.98-3.70 (m, 4H), 3.63 (s, 3H), 3.1 (s, 4H). LCMS RT = 1.563 min, m/z = 589.3 [M + H]+
[88481 [ Example 34. Synthesis of COMPOUND-119
[88482] Scheme 21.
Figure imgf000195_0001
[08483] Step 1: methyl 2-[[6-[2-(4-tert-butoxycarbonylpiperazin-l-yl)ethoxy]-3-pyridyl]amino]-8- methyl-7-oxo-pyrido[2,3-d]pyrimidine-6-carboxylate
[88484] To a solution of tert-butyl 4-[2-[[5-[(6-bromo-8-methyl-7-oxo-pyrido[2,3-d]pyrimidin-2- yl)amino]-2-pyridyl]oxy]ethyl]piperazine-l -carboxylate (300 mg, 0.54 mmol) in methyl alcohol (6 mL) and N,N-dimethylformamide (1.2 mL) was added triethylamine (60 mg, 0.59 mmol) and 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride (39 mg, 0.05 mmol). The mixture was stirred at 80 °C for 16 hours under carbon monoxide atmosphere (50 psi). The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 - 4% methanol in dichloromethane) to afford the title compound (280 mg, 87%) as a yellow solid. LCMS RT = 0.441 min, m/z = 540.3 [M + H]+
[8848S] Step 2: 2-[[6-[2-(4-tert-butoxycarbonylpiperazin-l-yl)ethoxy]-3-pyridyl]amino]-8-methyl-7- oxo-pyrido[2,3-d]pyrimidine-6-carboxylic acid
[88486] To a solution of methyl 2-[[6-[2-(4-tert-butoxycarbonylpiperazin-l-yl)ethoxy]-3- pyridyl]amino]-8-methyl-7-oxo-pyrido[2,3-d]pyrimidine-6-carboxylate (270 mg, 0.50 mmol) in methyl alcohol (3 mL) was added sodium hydroxide (100 mg, 2.50 mmol) in water (0.3 mL). The mixture was stirred at 50 °C for 1 hour. The mixture was diluted with water (10 mL) and adjusted the pH = 6 with citric acid (1 M). The mixture was extracted with ethyl acetate (10 mL x 3). The separated organic layers were dried over sodium sulphate, fdtered and concentrated under reduced pressure to afford the title compound (200 mg, 59%) as a yellow solid. LCMS RT = 0.447 min, m/z = 526.2 [M + H]+
[8848'7] Step 3: tert-butyl 4-[2-[[5-[[8-methyl-7-oxo-6-(4-pyridylmethylcarbamoyl)pyrido[2,3- d]pyrimidin-2-yl]amino]-2-pyridyl]oxy]ethyl]piperazine-l-carboxylate
[88488] To a solution of 2-[[6-[2-(4-tert-butoxycarbonylpiperazin-l-yl)ethoxy]-3-pyridyl]amino]-8- methyl-7-oxo-pyrido[2,3-d]pyrimidine-6-carboxylic acid (100 mg, 0.19 mmol) in N,N- dimethylformamide (1 mL) was added N-ethyl-N-isopropylpropan-2 -amine (74 mg, 0.57 mmol), tetramethylurea hexafluorophosphate (80 mg, 0.21 mmol) and 4-pyridyhnethanamine (21 mg, 0.19 mmol). The mixture was stirred at 20 °C for 1 hour. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 - 6% methanol in dichloromethane) to afford the title compound (70 mg, 51%) as a yellow solid. LCMS RT = 0.406 min, m/z = 616.4 [M + H]+
[88489] Step 4: 8-methyl- 7-oxo-2-[[6-(2-piperazin-l-ylethoxy)-3-pyridyl]amino]-N-(4- pyridylmethyl)pyrido[2,3-d]pyrimidine-6-carboxamide
[88498] To a solution of tert-butyl 4-[2-[[5-[[8-methyl-7-oxo-6-(4-pyridyhnethylcarbamoyl)pyrido[2,3- d]pyrimidin-2-yl]amino]-2-pyridyl]oxy]ethyl]piperazine-l-carboxylate (65 mg, 0.11 mmol) in trifluoroacetic acid (1 mL). The mixture was stirred at 20 °C for 0.5 hour. The reaction mixture was concentrated and purified by RP-HPLC (0 to 35% acetonitrile in water and 0.225% formic acid) to afford the title compound (39 mg, 71%) as a yellow solid. ’H NMR (400 MHz, DMSO-t/g) b 10.56 (s, 1H), 10.12-9.84 (m, 3H), 9.06 (s, 1H), 8.86 (d, J= 6.8 Hz, 2H), 8.74 (s, 1H), 8.65 (s, 1H), 8.15 (d, J= 7.6 Hz, 1H), 7.96 (d, J= 6.4 Hz, 2H), 6.97 (d, J= 8.8 Hz, 1H), 4.85 (d, J= 5.6 Hz, 2H), 4.67 (t, J= 4.0 Hz, 2H), 3.83-3.58 (m, 7H), 3.50 (s, 6H). LCMS RT = 1.299 min, m/z = 516.2 [M + H]+
[88491 [ Example 35. Synthesis of COMPOUND-168
[88492] Scheme 22.
Figure imgf000197_0001
^91494^ To a solution of 2-( 1,1 -dioxo- l,4-thiazinan-4-yl)ethanol (500 mg, 2.79 mmol) in N,N- dimethylformamide (5 mL) was added cesium fluoride (1.3 g, 8.37 mmol) and 2-chloro-5-nitro-pyridine- 3-carbonitrile (512 mg, 2.79 mmol). The mixture was stirred at 20 °C for 1 hour. The mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic extracts were dried over anhydrous sodium sulphate and filtered. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 - 10% methanol in dichloromethane) to afford the title compound (900 mg, 81%) as a yellow solid. LCMS RT = 0.414 min, m/z = 327.0 [M + H]+
Step 2: 5-amino-2-[2-(l,l-dioxo-l,4-thiazinan-4-yl)ethoxy]pyridine-3-carbonitrile pW496^ To a solution of 2-[2-(l,l-dioxo-l,4-thiazinan-4-yl)ethoxy]-5-nitro-pyridine-3-carbonitrile (900 mg, 2.76 mmol) in methanol (10 mL) and water (3 mL) was added iron (770 mg, 13.79 mmol) and ammonium chloride (148 mg, 2.76 mmol). The mixture was stirred at 80 °C for 2 hours. The mixture was filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 - 5% methanol in dichloromethane) to afford the title compound- (600 mg, 71%) as a brown solid. LCMS RT = 0.311 min, m/z = 297.0 [M + H]+ ^<MM9?| Step 3: 5-[[6-(2,6-dichlorophenyl)-8-methyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl]amino]-2-[2- (1,1 -dioxo- 1, 4-th iazin an-4-yl) ethoxy]pyridin e-3-carbon itrile pW498^ To a solution of 2-chloro-6-(2,6-dichlorophenyl)-8-methyl-pyrido[2,3-d]pyrimidin-7-one (200 mg, 0.59 mmol) in dimethyl sulfoxide (3 mL) was added 5-amino-2-[2-(l,l-dioxo-l,4-thiazinan-4- yl)ethoxy]pyridine-3-carbonitrile (191 mg, 0.65 mmol) and cesium carbonate (574 mg, 1.76 mmol). The mixture was stirred at 100 °C for 16 hours under nitrogen atmosphere. The mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic extracts were dried over anhydrous sodium sulphate and filtered. The residue was purified by prep-TLC to afford the title compound (300 mg, crude) as a brown oil. LCMS RT = 0.501 min, m/z = 600.9 [M + H]+
^9 99 Step 4: 2-[[5-(aminomethyl)-6-[2-(l,l-dioxo-l,4-thiazinan-4-yl)ethoxy]-3-pyridyl]amino]-6- (2,6-dichlorophenyl)-8-methyl-pyrido[2,3-d]pyrimidin-7-one [88588] To a solution of 5-[[6-(2,6-dichlorophenyl)-8-methyl-7-oxo-pyrido[2,3-d]pyrimidin-2- yl]amino]-2-[2-(l,l-dioxo-l,4-thiazinan-4-yl)ethoxy]pyridine-3-carbonitrile (300 mg, 0.50 mmol) in methanol (5 mL) was added sodium borohydride (57 mg, 1.50 mmol) and dichlorocobalt (195 mg, 1.50 mmol) at 0 °C. The mixture was stirred at 20 °C for 16 hours under nitrogen atmosphere. The mixture was quenched with hydrochloric acid (I N) and concentrated under reduced pressure. The mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic extracts were dried over anhydrous sodium sulphate and fdtered. The residue was purified by prep-TLC (dichloromethane: methanol = 5: 1) to afford the title compound (30 mg, 9%) as a yellow solid. LCMS RT = 0.451 min, m/z = 604.1 [M + H]+
[88S81 [ Step 5: phenyl N-[[5-[[6-(2,6-dichlorophenyl)-8-methyl-7-oxo-pyrido[2,3-d]pyrimidin-2- yl]amino]-2-[2-(l,l-dioxo-l,4-thiazinan-4-yl)ethoxy]-3-pyridyl]methyl]carbamate
[88582] To a solution of phenyl carbonochloridate (9 mg, 0.06 mmol) in dichloromethane (1 mL) was added 2-[[5-(aminomethyl)-6-[2-(l,l-dioxo-l,4-thiazinan-4-yl)ethoxy]-3-pyridyl]amino]-6-(2,6- dichlorophenyl)-8-methyl-pyrido[2,3-d]pyrimidin-7-one (30 mg, 0.05 mmol) and triethylamine (10 mg, 0.10 mmol). The mixture was stirred at 20 °C for 0.5 hour. The mixture was concentrated under reduced pressure to afford the title compound (15 mg, 42%) as a yellow solid and used for next step immediately.
[88583] Step 6: [5-[[6-(2,6-dichlorophenyl)-8-methyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl]amino]-2-[2- (l,l-dioxo-l,4-thiazinan-4-yl)ethoxy]-3-pyridyl]methylurea
[885CM] To a solution of phenyl N-[[5-[[6-(2,6-dichlorophenyl)-8-methyl-7-oxo-pyrido[2,3- d]pyrimidin-2-yl]amino]-2-[2-( 1 , 1 -dioxo- 1 ,4-thiazinan-4-yl)ethoxy]-3-pyridyl]methyl]carbamate (15 mg, 20.70 mmol) in ethyl alcohol (1 mL) was added ammonium hydroxide (15 mg, 0.10 mmol). The mixture was stirred at 80 °C for 4 hours. The mixture was fdtered and concentrated under reduced pressure. The residue was purified by RP-HPLC (20 to 50% acetonitrile in water and 1% hydrochloric acid) to afford the title compound (3.4 mg, 25%) as a yellow solid. rH NMR (400 MHz, DMSO-t/g) b 10.27 (s, 1H), 8.83 (s, 1H), 8.41 (d, J= 2.8 Hz, 1H), 8.14 (s, 1H), 7.90 (s, 1H), 7.58 (d, J= 8.0 Hz, 2H), 7.50-7.42 (m, 1H), 7.08-6.41 (m, 1H), 4.75-4.61 (m, 2H), 4.23 (s, 2H), 3.79-3.72 (m, 8H), 3.64 (s, 3H), 2.53-2.51 (m, 4 H). LCMS RT = 1.453 min, m/z = 647.1 [M + H]+.
[88585] Example 36. Synthesis of COMPOUND- 178
Figure imgf000198_0001
[88586 [ 3-( ( 5-( ( 6-(2, 6-dichlorophenyl)-8-methyl- 7 -oxo- 7,8-dihydropyrido[2,3-d]pyrimidin-2- yl)amino)-2-(2-(l,l-dioxidothiomorpholino)ethoxy)pyridin-3-yl)methyl)-l,l-dimethylurea [88587] To a solution of phenyl N-[[5-[[6-(2,6-dichlorophenyl)-8-methyl-7-oxo-pyrido[2,3- d]pyrimidin-2-yl]amino]-2-[2-(l,l-dioxo-l,4-thiazinan-4-yl)ethoxy]-3-pyridyl]methyl]carbamate (50 mg, 0.07 mmol) in ethyl alcohol (1 mL) was added dimethylamine aqueous solution (39 mg, 0.35 mmol) in one portion. The mixture was stirred at 80 °C for 1 hour. The reaction solution was concentrated under reduced pressure. The crude reaction mixture was purified by RP-HPLC (21 to 51% acetonitrile in water and 0.225% formic acid) to afford the title compound (8 mg, 17%) as a yellow solid. 1 H NMR (400 MHz, DMSO- 6) S 10.20 (s, 1H), 8.82 (s, 1H), 8.50 (s, 1H), 7.91-7.90 (m, 2H), 7.60 (s, 1H), 7.58 (s, 1H), 7.48-7.44 (m,lH), 6.80 (t, J= 5.6 Hz, 1H), 4.41 (t, J= 5.2 Hz, 2H), 4.18 (d, J= 5.6 Hz, 2H), 3.61 (s, 3H), 3.07-3.06 (m, 8H), 2.95 (t, J= 5.2 Hz, 2H), 2.85 (s, 6H). LCMS RT = 1.480 min, m/z = 675.4 [M + H]+.
[88588] Example 37. Synthesis of COMPOUND- 179
Figure imgf000199_0001
[88S89| l-((5-((6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2- yl)amino)-2-(2-(l,l-dioxidothiomorpholino)ethoxy)pyridin-3-yl)methyl)-3-methylurea
](. )518] To a solution of phenyl N-[[5-[[6-(2,6-dichlorophenyl)-8-methyl-7-oxo-pyrido[2,3- d]pyrimidin-2-yl]amino]-2-[2-(l,l-dioxo-l,4-thiazinan-4-yl)ethoxy]-3-pyridyl]methyl]carbamate (50 mg, 0.07 mmol) in ethyl alcohol (1 mb) was added methylamine water solution (32 mg, 0.35 mmol) in one portion. The mixture was stirred at 80 °C for 1 hour. The reaction solution was concentrated under reduced pressure. The crude reaction mixture was purified by RP-HPLC (21 to 51% acetonitrile in water and 0.225% formic acid) to afford the title compound (4 mg, 8%) as a yellow solid. rH NMR (400 MHz, DMSO-t/6) 5 10.22 (s, 1H), 8.82 (s, 1H), 8.38-8.37 (m, 1H), 8.07 (s, 1H), 7.90 (s, 1H), 7.60 (s, 1H), 7.58 (s, 1H), 7.48-7.44 (m, 1H), 6.33 (t, J= 6.0 Hz, 1H), 5.98-5.95 (m, 1H), 4.40 (t, J= 5.6 Hz, 2H), 4.16 (d, J= 5.6 Hz, 2H), 3.61 (s, 3H), 3.07-3.06 (m, 8H), 2.95 (t, J= 5.6 Hz, 2H), 2.57 (d, J= 4.8 Hz, 3H). LCMS RT = 1.461 min, m/z = 661.4 [M + H]+.
[88511 ] Example 38. Synthesis of COMPOUND-291 [88512] Scheme 23.
Figure imgf000199_0002
[88513] Step 1: tert-butyl 3-((5-bromo-3-cyanopyridin-2-yl)oxy)-lH-pyrazole-l-carboxylate
[08S14] To a solution of tert-butyl 3 -hydroxypyrazole-1 -carboxylate (13.0 g, 70.58 mmol) and 5- bromo-2-chloro-pyridine-3-carbonitrile (15.0 g, 70.58 mmol) in N,N-dimethylformamide (50 mL) was added potassium carbonate (29.0 g, 211.74 mmol) in one portion. The mixture was stirred at 25 °C for 2 hours. The mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were washed with brine (10 mL x 2) and dried over anhydrous sodium sulphate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 - 40% ethyl acetate in petroleum ether) to afford the title compound (22.0 g, 73%) as a white solid. LCMS RT = 0.577 min, m/z = 264.9 [M + H]+.
[08S15] Step 2: 2-((lH-pyrazol-3-yl)oxy)-5-bromonicotinonitrile
[< )S16[ To a solution of tert-butyl 3-[(5-bromo-3-cyano-2-pyridyl)oxy]pyrazole-l-carboxylate (20.0 g, 54.77 mmol) in dichloromethane (100 mL) was added trifluoroacetic acid (18.0 g, 164.30 mmol) in one portion. The mixture was stirred at 25 °C for 2 hours under nitrogen atmosphere. The reaction mixture was adjusted to pH = 8 by addition of saturated aqueous sodium bicarbonate. Then the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 - 40% ethyl acetate in petroleum ether) to afford the title compound (13.0 g, 85%) as a white solid. LCMS RT = 0.453 min, m/z = 266.8 [M + H]+.
[08S17^ Step 3: 5-bromo-2-((l-(2-morpholinoethyl)-lH-pyrazol-3-yl)oxy)nicotinonitrile
[88S18] To a solution of 5-bromo-2-(lH-pyrazol-3-yloxy)pyridine-3-carbonitrile (7.0 g, 26.41 mmol) and 4-(2-bromoethyl)morpholine (7.0 g, 39.61 mmol) in N,N-dimethylformamide (20 mL) was added potassium carbonate (10.0 g, 79.23 mmol) in one portion. The mixture was stirred at 50°C for 16 hours under nitrogen atmosphere. The mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were washed with brine (10 mL x 2) and dried over anhydrous sodium sulphate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 - 40% ethyl acetate in petroleum ether) to afford the title compound (2.0 g, 89%) as a yellow solid. LCMS RT = 0.420 min, m/z = 379.8 [M + H]+.
[ 80S 19 [ Step 4: 5-((6-(2, 6-dich loroph enyl)-8-methyl- 7 -oxo- 7, 8-dihydropyrido[2,3-d]pyrimidin-2- yl)amino)-2-((l-(2-morpholinoethyl)-lH-pyrazol-3-yl)oxy)nicotinonitrile
[88320] To a solution of 5-bromo-2-[l-(2-morpholinoethyl)pyrazol-3-yl]oxy-pyridine-3-carbonitrile (750 mg, 1.98 mmol) and 2-amino-6-(2,6-dichlorophenyl)-8-methyl-pyrido[2,3-d]pyrimidin-7-one (424 mg, 1.32 mmol) in dioxane (2 mL) was added tertiary butyl alcohol (381 mg, 3.97 mmol), Xantphos (153 mg, 0.264 mmol) and tris(dibenzylideneacetone)dipalladium (0) (121 mg, 0.132 mmol) in one portion. The mixture was stirred at 130 °C for 3 hours under microwave. The reaction mixture was concentrated directly. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 - 10% methanol in dichloromethane) to afford the title compound (450 mg, 95%) as a white solid. LCMS RT = 0.495 min, m/z = 618.2 [M + H]+.
[88321] Step 5: 3-((5-((6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2- yl)amino)-2-(( I -(2-morpholinoethyl)-lH-pyrazol-3-yl)oxy)pyridin-3-yl)methyl)-l,l-dimethylurea [88522] The title compound- was made by the method used for COMPOUND-168 from 5-((6-(2,6- dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-2-((l-(2- morpholinoethyl)-lH-pyrazol-3-yl)oxy)nicotinonitrile. The crude product was purified by RP-HPLC (24 to 44% acetonitrile in water and 0.225% formic acid) to give the title compound (7.8 mg, 99%). rH NMR (400 MHz, DMSO-t/6) 5 10.55 (s, 1H), 8.89-8.88 (m, 2H), 8.27-8.24 (m, 2H), 7.95 (s, 1H), 7.60 (d, J= 8.0 Hz, 2H), 7.50-7.45 (m, 1H), 6.80 (t, J= 5.6 Hz, 1H), 6.05 (d, J= 2.4 Hz, 1H), 4.54 (d, J= 4.8 Hz, 2H), 4.30 (t, J= 5.6 Hz, 2H), 3.68 (s, 3H), 3.59-3.57 (m, 4H), 2.86 (s, 6H), 2.70 (t, J= 5.2 Hz, 2H) 2.47 (s, 4H). LCMS RT = 1.535 min, m/z = 693.2 [M + H]+.
[88523] Example 39. Synthesis of COMPOUND-319
[88524] Scheme 24.
Figure imgf000201_0001
[88525] Step 1: tert-butyl 4-(2-(3-((5-((6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-2-yl)amino)-3-((3,3-dimethylureido)methyl)pyridin-2-yl)oxy)-lH-pyrazol-l- yl)ethyl)piperazin e-1 -carboxylate
[88326] The title compound- was made by the method used for COMPOUND-291 from tert-butyl 4- (2-bromoethyl)piperazine-l -carboxylate in 85% yield.
[88527] Step 2: 3-((5-((6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2- yl)amino)-2-((l-(2-(piperazin-l-yl)ethyl)-lH-pyrazol-3-yl)oxy)pyridin-3-yl)methyl)-l,l-dimethylurea
[88528] A solution of tert-butyl 4-(2-(3-((5-((6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8- dihydropyrido [2,3 -d]pyrimidin-2-yl)amino)-3 -((3 ,3 -dimethylureido)methyl)pyridin-2-yl)oxy)- 1H- pyrazol-l-yl)ethyl)piperazine-l -carboxylate (200 mg, 0.1 mmol) in dichloromethane (1 m ) and trifluoroacetic acid (0.3 m ). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated directly. The residue was purified by prep-HPLC (18 to 38% acetonitrile in water and 0.225% formic acid) afford the title compound (50 mg, 28%) as a yellow solid. LCMS RT = 1.404 min, m/z = 692.2 [M + H]+
[88529] Step 3: 3-( ( 5-( ( 6-(2, 6-dichlorophenyl)-8-methyl- 7 -oxo- 7, 8-dihydropyrido[2,3-d]pyrimidin-2- yl)amino)-2-((l-(2-(4-methylpiperazin-l-yl)ethyl)-l H-pyraz,ol-3-yl)oxy)pyridin-3-yl)methyl)-l ,1- dimethylurea
[18)538] To a solution of 3-((5-((6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-2-yl)amino)-2-(( 1 -(2-(piperazin- 1 -yl)ethyl)- lH-pyrazol-3 -yl)oxy)pyridin-3 -yl)methyl)- 1,1- dimethylurea (40 mg, 0.1 mmol) in acetonitrile (1 mb) was added formaldehyde (910 mg, 0.1 mmol, 37% purity) , sodium triacetoxyboranuide (37 mg, 0.1 mmol) and triethylamine (18 mg, 0.11 mmol). The mixture was stirred at 25 °C for 1 hour .The reaction mixture was concentrated under reduced pressure. The residue was purified by RP-HPLC (18 to 38% acetonitrile in water and 0.225% formic acid) to afford the title compound (9 mg, 22%) as a light yellow solid. 1 H NMR (400 MHz, DMSO-t/g) 8 10.31 (d, J= 0.4 Hz, 1H), 8.84 (s, 1H), 8.53-8.43 (m, 1H), 8.09 (s, 1H), 7.91 (s, 1H), 7.66 (d, J= 2.4 Hz, 1H), 7.61-7.54 (m, 2H), 7.50-7.42 (m, 1H), 6.95-6.85 (m, 1H), 5.93 (d, J= 2.4 Hz, 1H), 4.30 (d, J= 6.0 Hz, 2H), 4.09 (t, J= 6.8 Hz, 2H), 3.61 (s, 3H), 2.86 (s, 6H), 2.67 (s, 6H), 2.36-2.26 (m, 4H), 2.14 (s, 3H). LCMS RT = 1.447 min, m/z = 706.3 [M + H]+ Example 40. Synthesis of COMPOUND-293 Scheme 25.
Figure imgf000202_0002
Figure imgf000202_0001
COMPOUND 293
| Step 1: 5-((lH-pyrazol-4-yl)oxy)-2-nitropyridine
[ To a solution of tert-butyl 4-[(6-nitro-3-pyridyl)oxy]pyrazole-l-carboxylate (1.5 g, 4.90 mmol)
Figure imgf000202_0003
in methanol (5 mb) was added hydrogen chloride (5 mb, 4 M in dioxane) at 20 °C. Then the mixture was stirred at 20 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to afford the title compound- (1.0 g, 99%) as a white solid. LCMS RT = 0.715 min, m/z = 207.0 [M + H]+. Step 2: 2-nitro-5-((l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-lH-pyrazol-4-yl)oxy)pyridine To a solution of 2-nitro-5-(lH-pyrazol-4-yloxy)pyridine (534 mg, 2.59 mmol) in N,N-
Figure imgf000202_0004
dimethylformamide (4 mL) was added 4-(2-bromoethyl)tetrahydropyran (500 mg, 2.59 mmol) and cesium carbonate (2.53 g, 7.77 mmol) at 20 °C. Then the mixture was stirred at 80 °C for 2 hours. The reaction mixture was diluted with water (50 mL) and was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 - 45% ethyl acetate in petroleum ether) to afford the title compound (450 mg, 55%) as a yellow oil. LCMS RT = 0.878 min, m/z = 319.0 [M + H]+. Step 3: 5-((l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-l H-pyraz,ol-4-yl)oxy)pyridin-2-amine
Figure imgf000202_0005
[88538] To a solution of 2-nitro-5-[l-(2-tetrahydropyran-4-ylethyl)pyrazol-4-yl]oxy-pyridine (450 mg, 1.41 mmol) in tetrahydrofuran (3 mL) and water (1 mL) was added iron (395 mg, 7.07 mmol) and ammonium chloride (378 mg, 7.07 mmol) at 20 °C, then the mixture was stirred at 60 °C for 3 hr. The reaction mixture was diluted with saturation sodium hydrogencarbonate (5 mL) and was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 10% methanol in dichloromethane) to afford the title compound (380 mg, 93%) as a yellow oil. LCMS RT = 0.725 min, m/z = 289.1 [M + H]+.
[88539] Step 4: 6-(2,6-dichlorophenyl)-8-methyl-2-((5-((l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-lH- pyrazol-4-yl)oxy)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one
[88548] To a solution of 2-chloro-6-(2,6-dichlorophenyl)-8-methyl-pyrido[2,3-d]pyrimidin-7-one (118 mg, 0.35 mmol) in dioxane (2 mL) was added 5-[l-(2-tetrahydropyran-4-ylethyl)pyrazol-4- yl]oxypyridin-2-amine (100 mg, 0.35 mmol), (5-diphenylphosphanyl-9,9-dimethylxanthen-4-yl)- diphenylphosphane (40 mg, 0.07 mmol), cesium carbonate (339 mg, 1.04 mmol) and tris(dibenzylideneacetone)dipalladium (0) (32 mg, 0.03 mmol) at 20 °C, then the mixture was stirred at 120 °C for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to remove solvent. The residue was purified by RP-HPLC (46 to 76% acetonitrile in water and 0.225% formic acid) to afford the title compound (28 mg, 13%) as a white solid. rH NMR (400 MHz, DMSO-t/g) <5 10.49 (s, 1H), 8.89 (s, 1H), 8.29 (d, J= 8.8 Hz, 1H), 8.17 (d, J= 3.2 Hz, 1H), 7.94 (s, 1H), 7.88 (s, 1H), 7.63-7.59 (m, 2H), 7.57-7.43 (m, 3H), 4.11 (t, J= 7.2 Hz, 2H), 3.88-3.74 (m, 2H), 3.66 (s, 3H), 3.29-3.19 (m, 2H), 1.73 (q, J= 6.8 Hz, 2H), 1.58 (d, J= 14.4 Hz, 2H), 1.49-1.27 (m, 1H), 1.26-1.11 (m, 2H). LCMS RT = 3.137 min, m/z = 592.4 [M + H]+
(8854 ; ] Example 41. Synthesis of COMPOUND-292
Figure imgf000203_0001
[88542] 2-((5-((l-(2-(azetidin-3-yl)ethyl)-lH-pyrazol-4-yl)oxy)pyridin-2-yl)amino)-6-(2,6- dichlorophenyl)-8-methylpyrido[2,3-d]pyrimidin-7( 8H)-one
[88543] To a solution of tert-butyl 3-[2-[4-[[6-[[6-(2,6-dichlorophenyl)-8-methyl-7-oxo-pyrido[2,3- d]pyrimidin-2-yl]amino]-3-pyridyl]oxy]pyrazol-l-yl]ethyl]azetidine-l-carboxylate (20 mg, 0.03 mmol) which was made by the method used for COMPOUND-293 from tert-butyl 3-(2-iodoethyl)azetidine-l- carboxylate in dichloromethane (2 mL) and trifluoroacetic acid (0.2 mL). Then the mixture was stirred at 20 °C for 0.5 hour. The mixture was fdtered and the fdtrate was concentrated under reduced pressure. The residue was purified by RP-HPLC (0 to 50% acetonitrile in water and 0.225% formic acid) to afford the title compound (0.6 mg, 34%) as a yellow solid. ’H NMR (400 MHz, CD3OD) 3 8.89-8.85 (m, 1H), 8.72-8.68 (m, 1H), 8.59-8.51 (m, 2H), 8.03-8.01 (m, 1H), 7.89-7.84 (m, 1H), 7.54-7.48 (m, 3H), 7.44- 7.37 (m, 1H), 4.18-4.10 (m, 2H), 4.08-4.03 (m, 2H), 3.97-3.89 (m, 2H), 3.86-3.82 (m, 3H), 3.24-3.16 (m, 1H), 2.19-2.10 (m, 2H). LCMS RT = 1.520 min, m/z = 563.1 [M + H]+.
D S44 Example 42. Synthesis of COMPOUND-419
^0054S Scheme 26.
Figure imgf000204_0001
^00546^ Step 1: l-(tetrahydrofuran-3-yl)cyclopropanol
^ )54?| To a solution of methyl tetrahydrofuran-3 -carboxylate (3.0 g, 23.05 mmol) in tetrahydrofuran (10 mL) was added ethylmagnesium bromide (2 M, 29 mb), Ti(i-PrO)4 (1.64 g, 5.76 mmol). The mixture was stirred at 20 °C for 16 hours under nitrogen atmosphere. The mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL x 3). The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 - 50% ethyl acetate in petroleum ether) to afford the title compound 1.40 g, 47%) as a yellow oil. 1HNMR (400 MHz, DMSO-t/tf) 35.15 (s, 1 H), 3.78-3.65 (m, 2 H), 3.64-3.56 (m, 1 H), 3.54-3.46 (m, 1 H), 2.13-2.04 (m, 1 H), 1.89-1.78 (m, 1 H), 1.78-1.66 (m, 1 H), 0.55-0.50 (m, 2 H), 0.40-0.35 (m, 2 H).
^< )S48| Step 2: 2-nitro-5-(l-(tetrahydrofuran-3-yl)cyclopropoxy)pyridine
|(M. 49^ To a solution of 5-fluoro-2-nitro-pyridine (166 mg, 1.17 mmol) in N,N-dimethylformamide (2 mL) was added 1 -tetrahydrofuran-3 -ylcyclopropanol (150 mg, 1.17 mmol) and cesium carbonate (1.14 g, 3.51 mmol). The mixture was stirred at 60 °C for 1 hour under nitrogen atmosphere. The mixture was fdtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 - 5% methanol in dichloromethane) to afford the title compound (250 mg, 85%) as a yellow oil. LCMS RT = 0.483 min, m/z = 251.0 [M + H]+
Step 3: 5-(l-(tetrahydrofuran-3-yl)cyclopropoxy)pyridin-2-amine To a solution of 2-nitro-5-(l -tetrahydrofuran-3 -ylcyclopropoxy)pyridine (240 mg, 0.96 mmol) in tetrahydrofuran (3 mL) and water (1 mL) was added ammonium chloride (257 mg, 4.80 mmol) and iron (268 mg, 4.80 mmol). The mixture was stirred at 60°C for 1 hour under nitrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 - 5% methanol in dichloromethane) to afford the title compound (150 mg, 71%) as a yellow oil. ’H NMR (400 MHz, DMSO-t/g) S 7.65 (d, J= 2.8 Hz, 1 H), 7.14 (dd, J= 8.8, 2.8 Hz, 1 H), 6.40 (d, J= 8.8 Hz, 1 H), 5.50 (s, 2 H), 3.75-3.70 (m, 2 H), 3.64-3.52 (m, 2 H), 2.87-2.82 (m, 1 H), 1.93-1.86 (m, 1 H), 1.53-1.46 (m, 1 H), 0.80-0.84 (m, 2 H), 0.78-0.74 (m, 2 H).
[1W552J Step 4: 6-(2,6-dichlorophenyl)-8-methyl-2-((5-(l-(tetrahydrofuran-3- yl)cyclopropoxy)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one
[0 533) To a solution of 2-chloro-6-(2,6-dichlorophenyl)-8-methyl-pyrido[2,3-d]pyrimidin-7-one (98 mg, 0.29 mmol) in dioxane (2 mL) was added 5-(l-tetrahydrofuran-3-ylcyclopropoxy)pyridin-2-amine (70 mg, 0.32 mmol), tris(dibenzylideneacetone)dipalladium (26 mg, 0.029 mmol), 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (33 mg, 0.058 mmol) and cesium carbonate (282 mg, 0.87 mmol) in one portion under nitrogen atmosphere. The mixture was stirred at 120°C for 2 hours under microwave. The reaction mixture was fdtered and concentrated under reduced pressure to give a residue. The residue was purified by RP-HPLC (25 to 65% acetonitrile in water and 1% hydrochloric acid) to afford the title compound (5.3 mg, 3% yield) as a white solid. 1H NMR (400 MHz, DMSO-t/g) S 11.25 (s, 1 H), 8.98 (s, 1 H), 8.19 (d, J= 2.8 Hz, 1 H), 8.08-7.98 (m, 2 H), 7.87-7.82 (m, 1 H), 7.64-7.58 (m, 2 H), 7.52-7.46 (m, 1 H), 3.77 (s, 2 H), 3.69 (s, 3 H), 3.64-3.57 (m, 1 H), 3.40-3.35 (m, 1 H), 3.02-2.93 (m, 1 H), 2.03- 1.93 (m, 1 H), 1.59-1.48 (m, 1 H), 0.94 (s, 4 H). LCMS RT = 1.386 min, m/z = 524.2 [M + H]+
[00554 [ Example 43. Synthesis of COMPOUND-154
[00555) Scheme 27.
Figure imgf000205_0001
COMPOUND 154
[00556) Step 1: 2-(6-chloropyridazin-3-yl)oxy-l-(l,l-dioxo-l,4-thiazinan-4-yl)ethenone
[00557) To a solution of l-( 1,1 -dioxo- l,4-thiazinan-4-yl)-2 -hydroxy-ethanone (50 mg, 0.26 mmol) in
N,N-dimethylformamide (1 mL) was added sodium hydride (10 mg, 0.26 mmol) at 0 °C. After stirred at 0 °C for 0.5 hour, the mixture was added 3,6-dichloropyridazine (39 mg, 0.26 mmol). Then, the mixture was stirred at 50 °C for 16 hours under nitrogen atmosphere. The mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-TLC to afford the title compound (70 mg, 78%) as a yellow solid. LCMS RT = 0.365 min, m/z = 305.9 [M + H]+
[00558) Step 2: 6-(2,6-dichlorophenyl)-2-[[6-[2-(l,l-dioxo-l,4-thiazinan-4-yl)-2-oxo- ethoxy]pyridazin-3-yl]amino]-8-methyl-pyrido[2,3-d]pyrimidin-7-one
[00559) A mixture of 2-amino-6-(2,6-dichlorophenyl)-8-methyl-pyrido[2,3-d]pyrimidin-7-one (20 mg,
O.06 mmol), 2-(6-chloropyridazin-3-yl)oxy-l -(1,1 -dioxo- l,4-thiazinan-4-yl)ethanone (48 mg, 0.16 mmol), tris(dibenzylideneacetone)dipalladium (0) (6 mg, 0.01 mmol), potassium carbonate (26 mg, 0.19 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (7 mg, 0.01 mmol) in dioxane (1 mL) was stirred at 130 °C for 3 hours in microwave under nitrogen atmosphere. The reaction mixture was fdtered and the fdtrate was concentrated under reduced pressure. The residue was purified by RP-HPLC (32 to 62% acetonitrile in water and 0.225% formic acid) to afford the title compound (8.3 mg, 21%) as a yellow solid. ’H NMR (400 MHz, DMSO-t/6) 5 10.87 (s, 1H), 8.89 (s, 1H), 8.43 (d, J= 9.2 Hz, 1H), 7.96 (s, 1H), 7.59 (d, J= 8.0 Hz, 2H), 7.52-7.41 (m, 1H), 7.40 (d, J = 9.6 Hz, 1H), 5.31 (s, 2H), 3.96-3.83 (m, 4H), 3.63 (s, 3H), 3.37-3.13 (m, 4H). LCMS RT = 1.527 min, m/z = 590.0 [M + H]+
[88568] Example 44. Synthesis of COMPOUND-205
[80561] Scheme 28.
Figure imgf000206_0001
[88562] Step 1: tert-butyl 3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3,6-diazabicyclo[3.1.1]heptane-6- carboxylate
[88563] To a solution of tert-butyl 3,6-diazabicyclo[3.1 . l]heptane-6-carboxylate (500 mg, 2.52 mmol) in acetonitrile (15 mL) was added potassium carbonate (1.05 g, 7.57 mmol) and 2-bromoethoxy-tert- butyl-dimethyl-silane (664 mg, 2.77 mmol). The mixture was stirred at 80 °C for 16 hours. The reaction mixture was concentrated and the residue was diluted with water (50 mL) and extracted with ethyl acetate (70 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 - 15% ethyl acetate in petroleum ether) to give the title compound (730 mg, 81%) as a colorless oil.
[88564] Step 2: tert-butyl 3-(2-hydroxyethyl)-3,6-diazabicyclo[3.1.1 ]heptane-6-carboxylate
[88565] To a solution of tert-butyl 3-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3,6- diazabicyclo[3.1.1]heptane-6-carboxylate (0.80 g, 2.24 mmol) in tetrahydrofuran (15 mL) was added tetrabutylammonium fluoride (1 M, 4.5 mL) at 0 °C. The mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated and the residue was diluted with ethyl acetate (100 mL) and washed with saturated aqueous ammonium chloride (50 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (500 mg, 92%) as a yellow oil. [0C5S6] Step 3: tert-butyl 3-(2-((6-chloropyridazin-3-yl)oxy)ethyl)-3,6-diazabicyclo[3.1.1]heptane-6- carboxylate
To a solution of tert-butyl 3-(2-hydroxyethyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (350 mg, 1.44 mmol) in tetrahydrofuran (10 mL) was added sodium hydride (116 mg, 2.89 mmol, 60% purity) at 0 °C. The mixture was stirred at 0 °C for 0.2 hour, and then the 3,6-dichloropyridazine (323 mg, 2.17 mmol) was added. The mixture was stirred at 20 °C for 1.8 hour. The reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (60 mL), dried over anhydrous sodium sulfate, fdtered and concentrated. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 - 56% ethyl acetate in petroleum ether) to give the title compound (310 mg, 60%) as a yellow oil. rH NMR (400 MHz, CDCh) d 1.45 (s, 9H), 1.67-1.74 (m, 1H), 2.37-2.46 (m, 1H), 2.85-3.02 (m, 2H), 3.03-3.09 (m, 2H), 3.13-3.36 (m, 2H), 4.04-4.12 (m, 2H), 4.66 (t, J= 5.2 Hz, 2H), 6.99 (d, J= 9.2 Hz, 1H), 7.38 (d, J= 9.2 Hz, 1H).
Step 4: tert-butyl 3-(2-((6-((6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-2-yl)amino)pyridazin-3-yl)oxy)ethyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (88569) A mixture of tert-butyl 3-[2-(6-chloropyridazin-3-yl)oxyethyl]-3,6-diazabicyclo[3.1. l]heptane-
6-carboxylate (110 mg, 0.310 mmol), 2-amino-6-(2,6-dichlorophenyl)-8-methyl-pyrido[2,3-d]pyrimidin-
7-one (100 mg, 0.310 mmol), tris(dibenzylideneacetone)dipalladium (0) (28 mg, 0.031 mmol), 9,9- dimethyl-4,5-bis(diphenylphosphino)xanthene (36 mg, 0.062 mmol) and sodium tert-butoxide (89 mg, 0.93 mmol) in dioxane (4 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 130 °C for 3 hours under microwave. The reaction mixture was concentrated and the residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 - 75% ethyl acetate in petroleum ether) to give the title compound (115 mg, 58%) as a yellow solid. LCMS RT = 1.263 min, m/z = 639.2 [M + H]+.
(88578] Step 5: 2-((6-(2-(3,6-diazabicyclo[3.1.1 ]heptan-3-yl)etl )xy)pyrida in-3-yl)amino)-6-(2,6- dichlorophenyl)-8-methylpyrido[2,3-d]pyrimidin-7( 8H)-one
(18)571 To a solution of tert-butyl 3-[2-[6-[[6-(2,6-dichlorophenyl)-8-methyl-7-oxo-pyrido[2,3- d]pyrimidin-2-yl]amino]pyridazin-3-yl]oxyethyl]-3,6-diazabicyclo[3.1. l]heptane-6-carboxylate (35 mg, 0.055 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.5 mL). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated and the residue was purified by RP-HPLC (15 to 45% acetonitrile in water and 0.225% formic acid) to afford the title compound (9.50 mg, 32%) as a white solid. ‘HNMR (400 MHz, DMSO-t/6) b 10.87 (s, 1H), 8.90 (s, 1H), 8.41 (d, J= 9.2 Hz, 1H), 7.96 (s, 1H), 7. 65-7.55 (m, 2H), 7.51-7.45 (m, 1H), 7.31 (d, J= 10.0 Hz, 1H), 4.59 (t, J= 6.0 Hz, 2H), 3.87- 3.82 (m, 2H), 3.63 (s, 3H), 3.24-3.19 (m, 2H), 3.05 (t, J= 5.6 Hz, 2H), 2.94 (d, J= 11.2 Hz, 2H), 2.45- 2.42 (m, 1H), 1.91 (d, J= 8.4 Hz, 1H). LCMS RT = 1.019 min, m/z = 539.1 [M + H]+
|W 572] Example 45. Synthesis of COMPOUND-207
Figure imgf000208_0001
[00S73| 6-(2,6-dichlorophenyl)-8-methyl-2-((6-(2-(6-methyl-3,6-diazabicyclo[3.1.1]heptan-3- yl)ethoxy)pyridazin-3-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one
[ 574] To a solution of 2-[[6-[2-(3,6-diazabicyclo[3.1. l]heptan-3-yl)ethoxy]pyridazin-3-yl]amino]-6- (2,6-dichlorophenyl)-8-methyl-pyrido[2,3-d]pyrimidin-7-one (60 mg, 0.11 mmol) in methanol (2 mL) was added N,N-diisopropylethylamine (14 mg, 0.11 mmol). After stirred at 25 °C for 0.5 hour, the mixture was added acetic acid (7 mg, 0.11 mmol) and formaldehyde (45 mg, 0.56 mmol, 37% purity) and stirred at 25 °C for 0.5 hour. Then the sodium cyanoborohydride (21 mg, 0.33 mmol) was added and the mixture was stirred at 25 °C for another 1 hour. The reaction mixture was concentrated and the residue was purified by RP-HPLC (15 to 45% acetonitrile in water and 0.225% formic acid) to afford the title compound (22.2 mg, 33%) as a yellow solid. ‘H NMR (400 MHz, DMSO-t/6) b 10.88 (s, 1H), 8.89 (s, 1H), 8.41 (d, J= 9.6 Hz, 1H), 7.96 (s, 1H), 7.65-7.56 (m, 2H), 7.52-7.43 (m, 1H), 7.31 (d, J= 9.6 Hz, 1H), 4.57 (t, J= 5.6 Hz, 2H), 3.62 (s, 3H), 3.54-3.50 (m, 2H), 3.12-3.01 (m, 5H), 3.00-2.87 (m, 2H), 2.54-2.52 (m, 1H), 2.22-2.01 (m, 2H), 1.91-1.76 (m, 1H). LCMS RT = 1.033 min, m/z = 553.2 [M + H]+.
[005?5[ Example 46. Synthesis of COMPOUND-187
Figure imgf000208_0002
[00576] 2-((6-(2-(4-acetylpiperazin-l-yl)ethoxy)pyridazin-3-yl)amino)-6-(2,6-dichlorophenyl)-8- methylpyrido[2,3-d]pyrimidin- 7( 8H)-on e
[00S77[ To a solution of 6-(2,6-dichlorophenyl)-8-methyl-2-[[6-(2-piperazin-l-ylethoxy)pyridazin-3- yl]amino]pyrido[2,3-d]pyrimidin-7-one (100 mg, 0.19 mmol) which was made by the method used for COMPOUND-205 from tert-butyl piperazine- 1 -carboxylate in dichloromethane (2 mL) was added acetyl acetate (21 mg, 0.21 mmol) and N,N-diethylethanamine(58 mg, 0.57 mmol) at 20 °C. The mixture was stirred at 20 °C for 16 hour. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by RP-HPLC (10 to 40% acetonitrile in water and 0.225% formic acid) to afford the title compound (30 mg, 28%) as a white solid. ’H NMR (400 MHz, DMSO-t/g) b 10.86 (s, 1H), 8.89 (s, 1H), 8.40 (d, J= 9.6 Hz, 1H), 7.95 (s, 1H), 7.60 (d, J= 8.4 Hz, 2H), 7.51-7.43 (m, 1H), 7.30 (d, J= 9.6 Hz, 1H), 4.53 (t, J= 6.0 Hz, 2H), 3.62 (s, 3H), 3.45-3.33 (m, 4H), 2.78 (t, J= 5.6 Hz, 2H), 2.46-2.41 (m, 4H), 1.98 (s, 3H). LCMS RT = 1.343 min, m/z = 5692 [M + H]+
[88S78] Example 47. Synthesis of COMPOUND-191
Figure imgf000209_0001
[8857 ] 6-(2,6-dichlorophenyl)-2-((6-(2-(4-(2-hydroxyethyl)piperazin-l-yl)ethoxy)pyridazin-3- yl)amino)-8-methylpyrido[2,3-d]pyrimidin-7( 8H)-one
[88588[ To a solution of 6-(2,6-dichlorophenyl)-8-methyl-2-[[6-(2-piperazin-l-ylethoxy)pyridazin-3- yl]amino]pyrido[2,3-d]pyrimidin-7-one (150 mg, 0.3 mmol) which was made by the method used for COMPOUND-205 from tert-butyl piperazine- 1 -carboxylate, 2-bromoethanol (36 mg, 0.3 mmol), potassium carbonate (118 mg, 0.9 mmol) in acetonitrile (1 mb) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 20 °C for 18 hours. The mixture was fdtered and the fdtrate was concentrated under reduced pressure. The residue was purified by RP-HPLC (14 to 34% acetonitrile in water and 0.225% formic acid) to afford the title compound (2.8 mg, 2%) as a yellow solid. ‘H NMR (400 MHz, CH3OD) 3 8.90-8.80 (m, 1H), 8.64-8.56 (m, 1H), 7.89-7.82 (m, 1H), 7.53- 7.49 (m, 2H), 7.43-7.37 (m, 1H), 7.29-7.26 (m, 1H), 4.65-4.59 (m, 5H), 3.80-3.76 (m, 3H), 3.75-3.69 (m, 2H), 2.97-2.90 (m, 2H), 2.83-2.62 (m, 9H). LCMS RT = 1.307 min, m/z = 571.1 [M + H]+
[88581] Example 48. Synthesis of COMPOUND-212
Figure imgf000209_0002
[88582] 2-((6-(2-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)ethoxy)pyridazin-3-yl)amino)-6-(2,6- dichlorophenyl)-8-methylpyrido[2,3-d]pyrimidin-7( 8H)-one
[08S83] The title compound- was made by the method used for COMPOUND-205 from6-oxa-3- azabicyclo[3.1.1]heptane;hydrochloride. The crude was purified by RP-HPLC (24 to 54% acetonitrile in water and 0.05% ammonium hydrate and 10 mM ammonium bicarbonate) to afford the title compound (21 mg, 10%) as a white solid. ‘H NMR (400 MHz, DMSO-A) 3 10.89 (s, 1H), 8.90 (s, 1H), 8.41 (d, J = 9.6 Hz, 1H), 7.96 (s, 1H), 7.64-7.56 (m, 2H), 7.53-7.44 (m, 1H), 7.32 (d, J= 9.6 Hz, 1H), 4.59 (t, J= 5.6 Hz, 2H), 4.43 (d, J= 6.4 Hz, 2H), 3.62 (s, 3 H), 3.17-3.10 (m, 2H), 3.01 (t, J= 6.0 Hz, 2H), 2.88-2.80 (m, 1H), 2.80-2.73 (m, 2H), 2.16 (d, J= 8.0 Hz, 1H). LCMS RT = 1.161 min, m/z = 540.1 [M + H]+ [88584] Example 49. Synthesis of COMPOUND-155
[00585] Scheme 29.
Figure imgf000210_0001
155-1 155-2 COMPOUND 155
[00586] Step 1: 4-(2-((6-chloropyridazin-3-yl)oxy)ethyl)thiomorpholine 1,1-dioxide ] 88587] To a solution of 2-( 1 , 1 -dioxo- 1 ,4-thiazinan-4-yl)ethanol (150 mg, 0.8 mmol) in tetrahydrofuran (5 mL) was added sodium hydride (35 mg, 0.8 mmol) at 0 °C. The mixture was stirred at 25 °C for 0.5 hour. Then 3,6-dichloropyridazine (125 mg, 0.8 mmol) was added. The mixture was stirred at 25 °C for 1 hour followed by 65 °C for 1 hour. The mixture was fdtered and concentrated to dryness. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 - 10% methanol in dichloromethane) to afford the title compound (210 mg, 86%) as a white solid. LCMS RT = 0.693 min, m/z = 292.0 [M + H]+
[88588] Step 2: 6-(2,6-dichlorophenyl)-2-((6-(2-(l,l-dioxidothiomorpholino)ethoxy)pyridazin-3- yl)amino)-8-methylpyrido[2,3-d]pyrimidin-7( 8H)-one
[88589] To a solution of 2-amino-6-(2,6-dichlorophenyl)-8-methyl-pyrido[2,3-d]pyrimidin-7-one (25 mg, 0.1 mmol) and 4-[2-(6-chloropyridazin-3-yl)oxyethyl]-l,4-thiazinane 1,1-dioxide (56 mg, 0.1 mol) in dioxane (1 mL) was added tris(dibenzylideneacetone)dipalladium (0) (7 mg, 0.1 mmol), 9,9-dimethyl- 4,5-bis(diphenylphosphino)xanthene (9 mg, 0.1 mmol) and cesium carbonate (76 mg, 1 mmol). The mixture was stirred at 130 °C for 3 hours under microwave. The reaction mixture was concentrated directly. The reaction mixture was concentrated and purified by RP-HPLC (30 to 60% acetonitrile in water and 0.225% formic acid) to afford the title compound (15 mg, 34%) as a white solid. rH NMR (400 MHz, CD3C1) 3 8.74-8.64 (m, 2H), 7.60 (s, 1H), 7.42 (d, J= 8.0 Hz, 2H), 7.34-7.28(m, 1H), 7.12 (d, J= 9.2 Hz, 1H), 4.67 (t, J= 5.2 Hz, 2H), 3.81 (s, 3H), 3.26-2.99 (m, 10H). LCMS RT = 1.315 min, m/z = 576.3 [M + H]+
[88598] Example 50. Synthesis of COMPOUND-211
Figure imgf000210_0002
[88591] 6-(2,6-dichlorophenyl)-2-((6-(2-(l,l-dioxidothiomorpholino)ethoxy)-5-(lH-tetrazol-5- yl)pyridazin-3-yl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one [88592] To a solution of 6-((6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-2-yl)amino)-3-(2-(l, l-dioxidothiomorpholino)ethoxy)pyridazine-4-carbonitrile (130 mg, 0.2 mmol) which was made by the method used for COMPOUND-155 from 3,6-dichloropyridazine-4- carbonitrile in N,N-dimethylformamide (5 mL) was added sodium azide (44 mg, 0.6 mmol). The mixture was stirred at 120 °C for 12 hour. The residue was added water (20 mL) and extracted with ethyl acetate (20 mL). The combined organic layers were washed with brine (60 mL), dried over sodium sulphate and concentrated under reduced pressure to give a residue. The residue was purified by RP-HPLC (10 to 60% acetonitrile in water and 1% hydrochloric acid) to give the title compound (18.9 mg, 14%) as a white solid. 1H NMR (400 MHz, DMSO- 6) <5 11.25 (s, 1H), 9.30 (s, 1H), 9.03-8.82 (m, 1H), 8.10-7.90 (m, 1H), 7.67-7.54 (m, 2H), 7.53-7.42 (m, 1H), 7.10 (s, 1H), 4.84 (t, J= 5.2 Hz, 2H), 3.71 (s, 3H), 3.34 (s, 10H). LCMS RT = 1.471 min, m/z = 644.3 [M + H]+.
[ 88893 ] Example 51. Synthesis of COMPOUND-251 'M. 94] Scheme 30.
Figure imgf000211_0001
COMPOUND 251
[88595] Step 1: 4-(2-((6-chloropyridazin-3-yl)oxy)ethyl)thiomorpholine
[88596] To a solution of 3,6-dichloropyridazine (6.0 g, 40.27 mmol) and 2-thiomorpholinoethanol (5.9 g, 40.27 mmol)in N,N-dimethylformamide (40 mL) was added cesium carbonate (32.8 g, 100.69 mmol). The mixture was stirred at 50 °C for 16 hours. The reaction mixture was diluted with ethyl acetate (200 mL). The reaction was washed with water (100 mL x 3). The separated organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 - 25% ethyl acetate in petroleum ether) to afford the title compound (7.0 g, 54%) as a yellow oil. LCMS RT = 0.631 min, m/z = 260.2 [M + H]+
[88597] Step 2: 4-(2-((6-chloropyridazin-3-yl)oxy)ethyl)thiomorpholine 1-oxide [88598] To a solution of 4-[2-(6-chloropyridazin-3-yl)oxyethyl]thiomorpholine (4.50 g, 17.32 mmol) in methyl alcohol (80 mL) was added a solution of sodium periodate (3.33 g, 6.93 mmol) in water (16 mL) under nitrogen atmosphere at 20 °C. The reaction mixture was stirred at 20 °C for 1 hour. The filtrate was concentrated under reduced pressure. The residue was washed with saturated aqueous sodium sulfite (35 ml) at 0 °C. The collected solid cake was purified by column chromatography (silica gel, 100 - 200 mesh, 0 - 10% methanol in dichloromethane) to afford the title compound (2.9 g, 61%) as a yellow solid. LCMS RT = 0.634 min, m/z = 276. 1 [M + H]+
[88599] Step 3: 4-(2-((6-chloropyridazin-3-yl)oxy)ethyl)-l-iminothiomorpholine 1-oxide
[88688] To a solution of 4-[2-(6-chloropyridazin-3-yl)oxyethyl]-l,4-thiazinane 1-oxide (2.6 g, 9.43 mmol) in methyl alcohol (5 mL) was added carbamic acid (1.7 g, 28.29 mmol) and iodosobenzene diacetate (9.11 g, 28.29 mmol) under nitrogen at 20 °C. The reaction mixture was stirred at 20 °C for 1 hour. The reaction mixture was filtered and concentrated to give the crude title compound (2.5 g, crude) as a yellow solid which was used in next step directly without further purification. LCMS RT = 0.532 min, m/z = 291.1 [M + H]+
[88681] Step 4: 4-(2-((6-chloropyridazin-3-yl)oxy)ethyl)-l-(methylimino)thiomorpholine 1-oxide [88682] To a solution of 4-[2-(6-chloropyridazin-3-yl)oxyethyl]-l-imino-l,4-thiazinane 1-oxide (500 mg, 1.72 mmol) in dioxane (5 mL) was added cupric acetate (468 mg, 2.58 mmol) and pyridine (340 mg, 4.30 mmol) under nitrogen at 20 °C. The mixture was stirred at 20 °C for 30 min. To this mixture was added methylboronic acid (206 mg, 3.44 mmol). The reaction mixture was heated at 100 °C for 1.5 hour. The reaction mixture was filtered and concentrated to give the residue. The residue was purified by RP- HPLC to afford the title compound (85 mg, 16%) as a white solid. LCMS RT = 0.630 min, m/z = 304.9 [M + H]+
[88685] Step 5: 6-(2,6-dichlorophenyl)-8-methyl-2-((6-(2-(l-(methylimino)-l- oxidothiomorpholino)ethoxy)pyridazin-3-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one
[88684] To a solution of 2-amino-6-(2,6-dichlorophenyl)-8-methyl-pyrido[2,3-d]pyrimidin-7-one (30 mg, 0.09 mmol) in dioxane (1 mL) was added 4-[2-(6-chloropyridazin-3-yl)oxyethyl]-l-methylimino- 1,4-thiazinane 1-oxide (43 mg, 0.140 mmol), tris(dibenzylideneacetone)dipalladium (0) (9 mg, 0.009 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (11 mg, 0.019 mmol) and tert-butoxide potassium (37 mg, 0.327 mmol) in one portion under nitrogen atmosphere. The mixture was stirred at 130 °C for 3 hours under microwave. The reaction mixture was filtered and concentrated to give the residue. The residue was purified by RP-HPLC (0 to 50% acetonitrile in water and 0.225% formic acid) to afford the title compound (4 mg, 7%) as a white solid. rH NMR (400 MHz, DMSO-t/g) 8 10.87 (s, 1H), 8.89 (s, 1H), 8.41 (d, J= 9.6 Hz, 1H), 7.96 (s, 1H), 7.66-7.53 (m, 2H), 7.51-7.44 (m, 1H), 7.30 (d, J = 9.6 Hz, 1H), 4.52 (t, J= 5.6 Hz, 2H), 3.62 (s, 3H), 3.11-2.90 (m, 10H), 2.61 (s, 3H). LCMS RT = 0.630 min, m/z = 304.9 [M + H]+
[88685] Example 52. Synthesis of COMPOUND-195
Figure imgf000213_0001
[88686] 6-(2,6-dichlorophenyl)-8-methyl-2-((6-(2-(l-oxidothiomorpholino)ethoxy)pyridazin-3- yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one
[88687] To a solution of 4-[2-(6-chloropyridazin-3-yl)oxyethyl]-l,4-thiazinane 1-oxide (250 mg, 0.9 mmol) and 2-amino-6-(2,6-dichlorophenyl)-8-methyl-pyrido[2,3-d]pyrimidin-7-one (292 mg, 0.9 mmol) in dioxane (3 mL) was added sodium tert-butoxide (262 mg, 2.72 mmol), tris(dibenzylideneacetone)dipalladium (0) (83 mg, 0.09 mmol) and 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (105 mg, 0.18 mmol). The mixture was stirred at 140 °C for 3 hours under microwave. The reaction mixture was concentrated directly and purified by RP-HPLC (10 to 40% acetonitrile in water and 0.225% formic acid) to afford the title compound (10 mg, 99.6%) as a yellow solid. ’H NMR (400 MHz, CD3OD) 3 8.85 (s, 1H), 8.60 (d, J= 9.6 Hz, 1H), 7.85 (s, 1H), 7.55-7.48 (m, 2H), 7.44-7.37 (m, 1H), 7.28 (d, J= 9.6 Hz, 1H), 4.59 (s, 4H), 3.78 (s, 3H), 3.21-3.14 (m, 2H), 3.05- 2.90 (m, 8H). LCMS RT = 1.232 min, m/z = 560.3 [M + H]+
[88686] Example 53. Synthesis of COMPOUND-198
Figure imgf000213_0002
[68689] 6-(2,6-dichlorophenyl)-2-((6-(2-(4-ethoxy-4-oxido-l,4-azaphosphinan-l-yl)ethoxy)pyridazin- 3-yl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one
[88618] To a solution of 1-divinylphosphoryloxyethane (10 mg, 0.07 mmol) in ethyl alcohol (10 mL) was added 2-[[6-(2-aminoethoxy)pyridazin-3-yl]amino]-6-(2,6-dichlorophenyl)-8-methyl-pyrido[2,3- d]pyrimidin-7-one (30 mg, 0.7 mmol) which was made by the method used for COMPOUND-207 from tert-butyl N-(2-hydroxyethyl)carbamate and triethylamine (7 mg, 0.07 mmol) in one portion at 20 °C. The mixture was stirred at 100 °C for 60 hours under nitrogen atmosphere. The reaction mixture was concentrated and purified by RP-HPLC (5 to 50% acetonitrile in water and 0.225% formic acid) to afford the title compound (2 mg, 6%) as a white solid. ’H NMR (400 MHz, CD3OD) 39.11 (s, 1H), 8.08 (d, J = 9.6 Hz, 1H), 8.03 (s, 1H), 7.91 (d, J = 9.6 Hz, 1H), 7.56-7.51 (m, 2H), 7.48-7.41 (m, 1H), 4.95-4.90 (m, 2H), 4.25-4.20 (m, 2H), 4.04-3.87 (m, 2H), 3.86-3.82 (m, 5H), 3.80-3.62 (m, 2H), 2.57-2.40 (m, 4H), 1.42 (t, J= 7.2 Hz, 3H). LCMS RT = 1.413 min, m/z = 604.0 [M + H]+.
[88611 ] Example 54. Synthesis of COMPOUND-253
Figure imgf000214_0001
[08612[ 6-((6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3- (2-(l,l-dioxidothiomorpholino)ethoxy)pyridazine-4-carboxylic acid
[8861.3] To a solution of methyl 6-[[6-(2,6-dichlorophenyl)-8-methyl-7-oxo-pyrido[2,3-d]pyrimidin-2- yl]amino]-3-[2-(l,l-dioxo-l,4-thiazinan-4-yl)ethoxy]pyridazine-4-carboxylate (150 mg, 0.24 mmol) which was made by the method used for COMPOUND-155 from 3,6-dichloropyridazine-4-carboxylate, lithium hydroxide (12 mg, 0.3 mmol) in water (1 mb) and tetrahydrofuran (1 mb) was degassed and purged with nitrogen for 3 times and then the mixture was stirred at 45 °C for 2 hour under nitrogen atmosphere. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by RP-HPLC (0 to 60% acetonitrile in water and 1% hydrochloric acid) to afford the title compound (8.9 mg, 6%) as a yellow solid. rH NMR (400 MHz, DMSO-t/g) <5 11.19 (s, 1H), 8.98- 8.81 (m, 2H), 7.98 (s, 1H), 7.64-7.56 (m, 2H), 7.53-7.42 (m, 1H), 4.74 (s, 2H), 3.63 (s, 3H), 3.59-3.49 (m, 8H), 3.09 (m, 2H). LCMS RT = 1.343 min, m/z = 620.3 [M + H]+
[88614] Example 55. Synthesis of COMPOUND-248
[88615] Scheme 31.
Figure imgf000214_0002
[886 6] Step 1: tert-butyl ((6-chloro-3-(2-(l,l-dioxidothiomorpholino)ethoxy)pyridazin-4- y I) methyl) carbamate
[88617] To a solution of tert-butyl N-[(3,6-dichloropyridazin-4-yl)methyl]carbamate (1.0 g, 3.60 mmol) and 2-( 1,1 -dioxo- l,4-thiazinan-4-yl)ethanol (644 mg, 3.60 mmol) in hexane (16 mL) was stirred at 70 °C for 0.5 hour. Then aqueous sodium hydroxide (10 M, 0.4 mL) solution was added and the mixture was stirred at 70 °C for 1.5 hour. The mixture was filtered and concentrated under reduced pressure. The residue was purified by RP-HPLC (25 to 55% acetonitrile in water and 0.225% formic acid) to afford the title compound (340 mg, 23%) as a light yellow solid. LCMS RT = 1.092 min, m/z = 421. 1 [M + H]+ [88618] Step 2: tert-butyl ((6-((6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-2-yl)amino)-3-(2-(l,l-dioxidothiomorpholino)ethoxy)pyridazin-4-yl)methyl)carbamate [98619] To a solution of tert-butyl N-[[6-chloro-3-[2-(l, 1 -dioxo- l,4-thiazinan-4-yl)ethoxy]pyridazin-4- yl]methyl]carbamate (240 mg, 0.57 mmol) in dioxane (20 mL) was added 2-amino-6-(2,6- dichlorophenyl)-8-methyl-pyrido[2,3-d]pyrimidin-7-one (146 mg, 0.46 mmol), tris(dibenzylideneacetone)dipalladium (0) (52 mg, 0.06 mmol), (5-diphenylphosphanyl-9,9- dimethylxanthen-4-yl)-diphenylphosphane (66 mg, 0.1 mmol) and cesium carbonate (557 mg, 1.71 mmol) at 20 °C under nitrogen atmosphere. Then the mixture was stirred at 130 °C for 3 hours. The mixture was filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 - 5% methanol in dichloromethane) to afford the title compound (290 mg, 72%) as a white solid. LCMS RT = 1.342 min, m/z = 705.2 [M + H]+
[88628] Step 3: 2-((5-(aminomethyl)-6-(2-(l,l-dioxidothiomorpholino)ethoxy)pyridazin-3-yl)amino)- 6-(2, 6-dichlorophenyl)-8-methylpyrido[2,3-d]pyrimidin-7( 8H)-one
[88621] To a solution of tert-butyl N-[[6-[[6-(2,6-dichlorophenyl)-8-methyl-7-oxo-pyrido[2,3- d]pyrimidin-2-yl]amino]-3-[2-( 1 , 1 -dioxo- 1 ,4-thiazinan-4-yl)ethoxy]pyridazin-4-yl]methyl]carbamate (280 mg, 0.4 mmol) in methanol (2 mL) was added hydrochloric acid (4 M in dioxane, 4 mL) at 20 °C. Then the mixture was stirred at 20 °C for 1 hour. The mixture was filtered and concentrated under reduced pressure to afford the title compound (310 mg, 98%) as a yellow solid. LCMS RT = 0.792 min, m/z = 605.0 [M + H]+.
[88622] Step 4: N-((6-((6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2- yl)amino)-3-(2-(l,l-dioxidothiomorpholino)ethoxy)pyridazin-4-yl)methyl)methanesulfonamide [88623] To a solution of 2-[[5-(aminomethyl)-6-[2-(l,l-dioxo-l,4-thiazinan-4-yl)ethoxy]pyridazin-3- yl]amino]-6-(2,6-dichlorophenyl)-8-methyl-pyrido[2,3-d]pyrimidin-7-one (100 mg, 0.17 mmol) in dichloromethane (2 mL) was added methanesulfonyl chloride (38 mg, 0.33 mmol) and N,N- diethylethanamine (84 mg, 0.83 mmol) at 0 °C. The mixture was stirred at 20 °C for 2 hours. The reaction was quenched by addition of ice water (10 mL), then was extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate filtered and concentrated under reduced pressure. The residue was purified by RP-HPLC (10 to 50% acetonitrile in water and 1% hydrochloric acid) to afford the title compound (9.37 mg, 8%) as a white solid. 1H NMR (400 MHz, DMSO-t/6) b 11.17 (s, 1H), 8.99-8.92 (m, 1H), 8.66-8.57 (m, 1H), 8.04-7.97 (m, 1H), 7.81 (t, J= 6.4 Hz, 1H), 7.65-7.57 (m, 2H), 7.52-7.46 (m, 1H), 4.87-4.79 (m, 2H), 4.40-4.34 (m, 2H), 3.91-3.82 (m, 4H), 3.81-3.73 (m, 6H), 3.69-3.68 (m, 3H), 3.09-3.06 (m, 3H). LCMS RT = 1.380 min, m/z = 683.1 [M + H]+.
Example 56. Synthesis of COMPOUND-247
Scheme 32.
Figure imgf000216_0001
[80626] Step 1: phenyl ((6-((6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-2-yl)amino)-3-(2-(l,l-dioxidothiomorpholino)ethoxy)pyridazin-4-yl)methyl)carbamate [88627] To a solution of 2-[[5-(aminomethyl)-6-[2-(l,l-dioxo-l,4-thiazinan-4-yl)ethoxy]pyridazin-3- yl]amino]-6-(2,6-dichlorophenyl)-8-methyl-pyrido[2,3-d]pyrimidin-7-one (100 mg, 0.17 mmol) in dichloromethane (2 mL) was added phenyl carbonochloridate (28 mg, 0.18 mmol) and N,N- diethylethanamine (84 mg, 0.82 mmol) at 0 °C. Then the mixture was stirred at 20 °C for 1 hour. The reaction mixture was concentrated to afford the title compound (100 mg, 84%) as a yellow solid. LCMS RT = 0.912 min, m/z = 725.0 [M + H]+.
[80628] Step 2: 3-( ( 6-( ( 6-(2, 6-dichlorophenyl)-8-methyl- 7 -oxo- 7, 8-dihydropyrido[2,3-d]pyrimidin-2- yl)amino)-3-(2-(l,l-dioxidothiomorpholino)ethoxy)pyridazin-4-yl)methyl)-l,l-dimethylurea
[88629] To a solution of phenyl N-[[6-[[6-(2,6-dichlorophenyl)-8-methyl-7-oxo-pyrido[2,3- d]pyrimidin-2-yl]amino]-3-[2-( 1 , 1 -dioxo- 1 ,4-thiazinan-4-yl)ethoxy]pyridazin-4-yl]methyl]carbamate (100 mg, 0.14 mmol) in ethanol (2 mL) was added N-methylmethanamine (31 mg, 0.28 mmol, 40% purity) at 20 °C. Then the mixture was stirred at 80 °C for 2 hour. The reaction mixture was fdtered and concentrated under reduced pressure. The residue was purified by RP-HPLC (10 to 50% acetonitrile in water and 1% hydrochloric acid) to afford the title compound (7.3 mg, 8%) as a white solid. rH NMR (400 MHz, DMSO-t/6) b 9.14-9.10 (m, 1H), 8.06-8.01 (m, 1H), 7.86-7.83 (m, 1H), 7.54 (d, J= 1.2 Hz, 1H), 7.47-7.41 (m, 1H), 4.96-4.93 (m, 2H), 4.59 (s, 2H), 4.07-4.00 (m, 4H), 3.93-3.89 (m, 2H), 3.84- 3.82 (m, 3H), 3.79-3.69 (m, 4H), 3.05-3.00 (m, 6H). LCMS RT = 1.257 min, m/z = 6762 [M + H]+.
[88638] Example 57. Synthesis of COMPOUND-197
[88631] Scheme 33.
Figure imgf000216_0002
COMPOUND 197
[88632] Step 1: tert-butyl ((6-((6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-2-yl)amino)pyridazin-3-yl)methyl)carbamate [88633] To a solution of tert-butyl N-[(6-chloropyridazin-3-yl)methyl]carbamate (152 mg, 0.62 mmol) in dioxane (2 mb) was added 2-amino-6-(2,6-dichlorophenyl)-8-methyl-pyrido[2,3-d]pyrimidin-7-one (100 mg, 0.3 mmol) and sodium tert-butoxide (90 mg, 0.93 mmol) and tris(dibenzylideneacetone)dipalladium (0) (29 mg, 0.03 mmol) and (5-diphenylphosphanyl-9,9- dimethylxanthen-4-yl)-diphenylphosphane (36 mg, 0.06 mmol). The mixture was stirred at 130 °C for 3 hours. The reaction mixture was filtered and concentrated under reduced pressure to remove solvent. The residue was purified by prep-TLC (10% methanol in dichloromethane) to afford the title compound (70 mg, 43%) as a yellow solid. LCMS RT = 0.528 min, m/z = 528.1 [M + H]+
[88634] Step 2: 2-((6)-(aminomethyl)pyridaz,in-3-yl)amino)-6-(2,6-dichlorophenyl)-8- methylpyrido[2,3-d]pyrimidin- 7( 8H)-on e
[88635] To a solution of tert-butyl N-[[6-[[6-(2,6-dichlorophenyl)-8-methyl-7-oxo-pyrido[2,3- d]pyrimidin-2-yl]amino]pyridazin-3-yl]methyl]carbamate (50 mg, 0.09 mmol) in 1, 1,1, 3,3,3- hexafluoropropan-2-ol (1 mL) was added trifluoroacetic acid (11 mg, 0.09 mmol). The mixture was stirred at 20 °C for 0.5 hour. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford the title compound (40 mg, 99%) as a yellow oil. LCMS RT = 0.440 min, m/z = 428.0 [M + H]+
[88636] Step 3: l-(( 6-( ( 6-(2, 6-dichlorophenyl)-8-methyl- 7-oxo- 7,8-dihydropyrido[2,3-d]pyrimidin-2- yl)amino)pyridazin-3-yl)methyl)-3-methylurea
[88637] The title compound- was made by the method used for COMPOUND-168 from 2-((6- (aminomethyl)pyridazin-3-yl)amino)-6-(2,6-dichlorophenyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one. The crude product was purified by RP-HPLC (0 to 50% acetonitrile in water and 0.225% formic acid) to afford the title compound (3 mg, 11%) as a white solid. rH NMR (400 MHz, DMSO-t/g) d 11.07 (s, 1H), 8.93 (s, 1H), 8.52 (d, J= 9.2 Hz, 1H), 7.98 (s, 1H), 7.67-7.55 (m, 3H), 7.50-7.43 (m, 1H), 3.82 (t, J= 6.0 Hz, 1H), 6.02 (d, J= 4.4 Hz, 2H), 4.45 (d, J= 6.0 Hz, 2H), 3.65 (s, 3H), 2.60-2.51 (m, 3H). LCMS RT = 1.498 min, m/z = 485.1 [M + H]+
Example 58. Synthesis of COMPOUND-186
Scheme 34.
Figure imgf000218_0001
COMPOUND 186
^XM49| Step 1: tert-butyl 3-((6-chloropyridazin-3-yl)oxy)-lH-pyrazole-l-carboxylate
To a solution of tert-butyl 3 -hydroxypyrazole- 1 -carboxylate (1.0 g, 5.43 mmol) in dimethyl sulfoxide (20 mL) was added 3,6-dichloropyridazine (970 mg, 6.51 mmol) and potassium carbonate (2.25 g, 16.29 mmol) in one portion. The mixture was stirred at 60 °C for 4 hours. The reaction mixture was diluted with ethyl acetate (60 mL) and water (20 mL). The separated organic layer was dried over sodium sulphate, fdtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 - 20% ethyl acetate in petroleum ether) to afford the title compound (900 mg, 46%) as a white solid. LCMS RT = 0.514 min, m/z = 240.9 [M + H-56]+ i42J Step 2: 3-((lH-pyrazol-3-yl)oxy)-6-chloropyridazine |(M?64.3^ To a solution of tert-butyl 3-(6-chloropyridazin-3-yl)oxypyrazole-l-carboxylate (500 mg, 1.69 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1.92 g, 16.85 mmol) at 20 °C. The mixture was stirred at 20 °C for 2 hours. The reaction mixture was filtered and concentrated to give the crude title compound (200 mg, 59%) as a yellow oil which was used in next step directly without further purification. LCMS RT = 0.390 min, m/z = 197.0 [M + H-56]+
^00644^ Step 3: 4-(2-(3-((6-chloropyridazin-3-yl)oxy)-lH-pyrazol-l-yl)ethyl)morpholine ^006451 To a solution of 3-chloro-6-(lH-pyrazol-3-yloxy)pyridazine (190 mg, 0.97 mmol) in N,N- dimethyl formamide (2 mL) was added 4-(2-bromoethyl)morpholine (187.56 mg, 0.97 mmol) and cesium carbonate (945 mg, 2.90 mmol) at 25 °C. The mixture was stirred at 25 °C for 1 hour. The reaction mixture was diluted with dichloromethane (15 mL). The reaction was washed with water (5 mL x 3). The separated organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC to afford the title compound (110 mg, 33%) as a white solid. ‘H NMR (400 MHz, CDCh) d 7.53 (d, J= 6.8 Hz, 1 H), 7.49 (d, J= 2.0 Hz, 1 H), 7.30 (d, J= 2.8 Hz, 1 H), 6.23 (d, J= 2.4 Hz, 1 H), 4.22 (t, J= 6.4 Hz, 2 H), 3.74 (t, J= 4.4 Hz, 4 H), 2.88 (t, J= 6.8 Hz, 2 H), 2.53 (t, J= 4.8 Hz, 4 H). LCMS RT = 0.491 min, m/z = 308.9 [M+H]+.
[00646 [ Step 4: 6-(2, 6-dichlorophenyl)-8-methyl-2-( ( 6-( ( l-(2-morpholinoethyl)-lH-pyrazol-3- yl)oxy)pyridazin-3-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one
[08647] To a solution of 4-[2-[3-(6-chloropyridazin-3-yl)oxypyrazol-l-yl]ethyl]morpholine (40 mg, 0.13 mmol) in dioxane (3 mL) was added 2-amino-6-(2,6-dichlorophenyl)-8-methyl-pyrido[2,3- d]pyrimidin-7-one (28 mg, 0.09 mmol), tris(dibenzylideneacetone)dipalladium (0) (8 mg, 0.01 mmol, 0.1 eq), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (10 mg, 0.02 mmol) and sodium tert-butoxide (25 mg, 0.26 mmol) in one portion under nitrogen atmosphere. The mixture was stirred at 130 °C for 3 hours under microwave. The reaction mixture filtered and concentrated under reduced pressure to give a residue. The residue was purified by RP-HPLC (0 to 50% acetonitrile in water and 0.225% formic acid) to afford the title compound (20 mg, 37%) as a white solid. 1 H NMR (400 MHz, DMSO-t/g) <5 11.04 (s, 1H), 8.92 (s, 1H), 8.58 (d, J= 9.6 Hz, 1H), 7.97 (s, 1H), 7.75 (d, J= 2.4 Hz, 1H), 7.63-7.56 (m, 2H), 7.54-7.44 (m, 2H), 6.07 (d, J= 2.4 Hz, 1H), 4.15 (t, J= 6.4 Hz, 2H), 3.64 (s, 3H), 3.58-3.53 (m, 4H), 2.73-2.63 (m, 2H), 2.43-2.38 (m, 4H). LCMS RT = 1.544 min, m/z = 594.2 [M + H]+
[00648] Example 59. Synthesis of COMPOUND-181
[00649] Scheme 35.
Figure imgf000219_0001
COMPOUND 181
[00650] Step 1: 3-chloro-6-((l-(2-(piperazin-l-yl)ethyl)-lH-pyrazol-3-yl)oxy)pyridazine
[00651 ] To a solution of tert-butyl 4-[2-[3-(6-chloropyridazin-3-yl)oxypyrazol-l-yl]ethyl]piperazine-l- carboxylate (200 mg, 0.49 mmol) which was made by the method used for COMPOUND-186 from 4- (2-bromoethyl)morpholine in dichloromethane (3 mL) was added trifluoroacetic acid (0.3 mL) in one portion. The mixture was stirred at 20 °C for 0.5 hour. The mixture was concentrated under reduced pressure to afford the title compound (130 mg, 82%) as a yellow oil. LCMS RT = 0.345 min, m/z = 309. 1 [M + H]+.
[0065 [ Step 2: 3-chloro-6-((l-(2-(4-methylpiperazin-l-yl)ethyl)-lH-pyrazol-3-yl)oxy)pyridazine f 0653 j To a solution of 3-chloro-6-[l-(2-piperazin-l-ylethyl)pyrazol-3-yl]oxy-pyridazine (130 mg, 0.4 mmol) in methanol (1.5 mL) and dichloromethane (1.5 mL) was added formaldehyde (1.26 g, 42.10 mmol) and sodium cyanoborohydride (185 mg, 2.95 mmol) in one portion at 0 °C. The mixture was stirred at 20 °C for 1 hour under nitrogen atmosphere. The mixture was poured into water (10 mL) and extracted with dichloromethane (10 mL x 3). The organics were washed with brine (10 mL x 2) and dried over anhydrous sodium sulphate. The fdtrate was concentrated under reduced pressure. The residue was purified by prep-TLC to afford the title compound (70 mg, 49%) was obtained as a yellow solid. LCMS RT = 0.382 min, m/z = 323.1 [M + H]+. f< 65 j Step 3: 6-(2,6-dichlorophenyl)-8-methyl-2-((6-((l-(2-(4-methylpiperazin-l-yl)ethyl)-lH- pyrazol-3-yl)oxy)pyridazin-3-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one
[88655] To a mixture of 3-chloro-6-[l-[2-(4-methylpiperazin-l-yl)ethyl]pyrazol-3-yl]oxy-pyridazine (60 mg, 0.2 mmol), 2-amino-6-(2,6-dichlorophenyl)-8-methyl-pyrido[2,3-d]pyrimidin-7-one (30 mg, 0.09 mmol), tris(dibenzylideneacetone)dipalladium (0) (9 mg, 0.01 mmol), (5-diphenylphosphanyl-9,9- dimethylxanthen-4-yl)-diphenylphosphane (11 mg, 0.02 mmol) and cesium carbonate (91 mg, 0.3 mmol) in dioxane (3 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 130 °C for 3 hours under microwave. The mixture was concentrated under reduced pressure. The residue was purified by RP-HPLC (0 to 50% acetonitrile in water and 0.225% formic acid) to afford the title compound (7.8 mg, 99%) as a yellow solid. ’H NMR (400 MHz, CDC13) 8 8.79 (d, J= 9.2 Hz, 1H), 8.72 (s, 1H), 8.68 (s, 1H), 7.61 (s, 1H), 7.45 (s, 1H), 7.43-7.41 (m, 2H), 7.38 (d, J= 9.6 Hz, 1H), 7.33-7.28 (m, 1H), 6.18 (d, J = 2.4 Hz, 1H), 4.19 (t, J = 6.0 Hz, 2H), 3.82 (s, 3H), 3.00-2.93 (m, 2H), 3.02-2.75 (m, 8H), 2.61 (s, 3H). LCMS RT = 1.453 min, m/z = 607.1 [M + H]+
[00656] Example 60. Synthesis of COMPOUND-208
[00657[ Scheme 36.
Figure imgf000220_0001
[80658] Step 1: 3-((l-(2-((tert-butyldimetliylsilyl)oxy)etliyl)-lH-pyraz/)l-4-yl)oxy)-6-cliloropyridazine [0065 [ To a solution of 3-chloro-6-(lH-pyrazol-4-yloxy)pyridazine (500 mg, 2.54 mmol) in N,N- dimethylformamide (5 mL) was added 2-bromoethoxy-tert-butyl-dimethyl-silane (608 mg, 2.54 mmol), cesium carbonate (2.49 g, 7.63 mmol). The mixture was stirred at 80 °C for 1 hour under nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate (30 mL). The reaction was washed with water (10 mL x 3). The separated organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 - 30% ethyl acetate in petroleum ether) to afford the title compound (310 mg, 34%) as a colorless oil. ‘H NMR (400 MHz, CD3OD) 37.93 (s, 1 H), 7.76 (d, J= 9.2 Hz, 1 H), 7.60 (s, 1 H), 7.43 (d, J= 9.2 Hz, 1 H), 4.22 (t, J= 5.2 Hz, 2 H), 3.97 (t, J= 5.2 Hz, 2 H), 0.84 (s, 9 H), -0.03 (s, 6 H). LCMS RT = 0.595 min, m/z = 355.1 [M + H]+
[88668] Step 2: 2-( ( 6-( ( 1 -(2-((tert-butyldimethylsilyl)oxy)ethyl)-lH-pyrazol-4-yl)oxy)pyridazin-3- yl)amino)-6-(2,6-dichlorophenyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one
[88661 [ To a solution of tert-butyl-[2-[4-(6-chloropyridazin-3-yl)oxypyrazol-l-yl]ethoxy]-dimethyl- silane (300 mg, 0.85 mmol) in dioxane (3 mL) was added 2-amino-6-(2,6-dichlorophenyl)-8-methyl- pyrido[2,3-d]pyrimidin-7-one (200 mg, 0.62 mmol), sodium tert-butoxide (180 mg, 1.87 mmol), 9,9- dimethyl-4,5-bis(diphenylphosphino)xanthene (72 mg, 0.12 mmol) and tris(dibenzylideneacetone)dipalladium (0) (57 mg, 0.06 mmol) under nitrogen atmosphere. The mixture was stirred at 130 °C for 3 hours under microwave. The reaction mixture was filtered and concentrated to give the residue. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 - 10% methanol in dichloromethane) to afford the title compound (50 mg, 13%) as a yellow solid. LCMS RT = 0.607 min, m/z = 639.2 [M + H]+
[1J8662J Step 3: 6-(2,6-dichlorophenyl)-2-((6-((l-(2-hydroxyethyl)-l H-pyraz,ol-4-yl)oxy)pyridazin-3- yl)amino)-8-methylpyrido[2,3-d]pyrimidin-7( 8H)-one
[88663] To a solution of 2-[[6-[l-[2-[tert-butyl(dimethyl)silyl]oxyethyl]pyrazol-4-yl]oxypyridazin-3- yl]amino]-6-(2,6-dichlorophenyl)-8-methyl-pyrido[2,3-d]pyrimidin-7-one (50 mg, 0.08 mmol) in tetrahydrofuran (3 mL) was added tetrabutylammonium fluoride (I M, 0.08 mL) in one portion. The mixture was stirred at 20 °C for 1 hour under nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate (15 mL). The reaction was washed with water (5 mL x 3). The separated organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by RP-HPLC (10 to 60% acetonitrile in water and 0.225% formic acid) to afford the title compound (12 mg, 30%) as a white solid. ‘H NMR (400 MHz, CD3OD) 3 8.87 (s, 1H), 8.76 (d, J= 9.6 Hz, 1H), 7.91 (s, 1H), 7.86 (s, 1H), 7.59 (s, 1H), 7.53-7.46 (m, 3H), 7.41 (d, J= 8.0 Hz, 1H), 4.23 (t, J= 5.2 Hz, 2H), 3.91 (t, J= 5.2 Hz, 2H), 3.80 (s, 3H). LCMS RT = 1.622 min, m/z = 525.0 [M + H]+
[88664] Example 61. Synthesis of COMPOUND-203
Figure imgf000221_0001
[88865] 2-((6-((l-(2-(azetidin-3-yl)ethyl)-lH-pyrazol-4-yl)oxy)pyridazin-3-yl)amino)-6-(2,6- dichlorophenyl)-8-methylpyrido[2,3-d]pyrimidin-7( 8H)-one [88666] To a solution of tert-butyl 3-[2-[4-[6-[[6-(2,6-dichlorophenyl)-8-methyl-7-oxo-pyrido[2,3- d]pyrimidin-2-yl]amino]pyridazin-3-yl]oxypyrazol-l-yl]ethyl]azetidine-l-carboxylate (120 mg, 0.18 mmol) which was made by the method used for COMPOUND-208 from tert-butyl 3-(2- bromoethyl)azetidine-l -carboxylate in dichloromethane (4 mL) was added trifluoroacetic acid (206 mg, 1.81 mmol) in one portion under nitrogen atmosphere. The mixture was stirring at 20 °C for 1 hour under nitrogen atmosphere. The reaction was concentrated under reduced pressure. The residue was purified by RP-HPLC (10 to 40% acetonitrile in water and 1% hydrochloric acid) to afford the title compound (24 mg, 23%) as a white solid. ’H NMR (400 MHz, DMSO-t/6) 5 11.12-11.06 (m, 1H), 8.93 (d, J= 2.4 Hz, 1H), 8.67-8.43 (m, 1H), 8.04 (s, 1H), 7.97-7.80 (m, 1H), 7.64-7.51 (m, 4H), 7.52-7.42 (m, 1H), 4.10 (t, J= 6.4 Hz, 2H), 3.93-3.81 (m, 2H), 3.64 (s, 3H), 3.46-3.44 (m, 3H), 2.80-2.66 (m, 1H), 2.11 (q, J= 6.8 Hz, 2H). LCMS RT = 1.492 min, m/z = 564.4 [M + H]+
[88667] Example 62. Synthesis of COMPOUND-204
Figure imgf000222_0001
[88668] The title compound- was made by the method used for COMPOUND-208 from 4-(2- bromoethyl)tetrahydropyran. The crude was purified by RP-HPLC (38 to 75% acetonitrile in water and 0.225% ammonium bicarbonate) to afford the title compound (13.1 mg, 4%) as a white solid. ’H NMR (400 MHz, DMSO-t/e) d 11.01 (s, 1H), 8.91 (s, 1H), 8.55 (d, J = 9.6 Hz, 1H), 8.00 (d, J = 18.0 Hz, 2H), 7.65-7.57 (m, 2H), 7.55-7.44 (m, 3H), 4.14 (t, J = 7.2 Hz, 2H), 3.84-3.80 (m, 2H), 3.64 (s, 3H), 3.29- 3.21 (m, 3H), 1.74 (q, J = 12 Hz, 2H), 1.60 (d, J = 12.8 Hz, 2H), 1.61-1.58 (m, 1H), 1.22-1.14 (m, 2H). LCMS RT = 1.977 min, m/z = 593.4 [M + H]+
[88669] Example 63. Synthesis of COMPOUND-209
[88678] Scheme 37.
Figure imgf000222_0002
[88671] Step 1: 3-chloro-6-[l-[2-(l-methyl-4-piperidyl)ethyl]pyrazol-4-yl]oxy-pyridazine
[88672] To a solution of 3-chloro-6-[l-[2-(4-piperidyl)ethyl]pyrazol-4-yl]oxy-pyridazine (100 mg, 0.324 mmol) which was made by the method used for COMPOUND-208 from tert-butyl 4-(2- bromoethyl)piperidine-l -carboxylate in dichloromethane (1 mL) and methanol (1 mL) was added formaldehyde (316 mg, 3.90 mmol, 37% purity) and sodium cyanoborohydride (316 mg, 0.454 mmol). The mixture was stirred at 20 °C for 1 hour. The mixture was purified by prep-TLC to afford the title compound (50 mg, 48%) as a white solid. LCMS RT = 0.817 min, m/z = 322.0 [M + H]+
[88673] Step 2: 6-(2,6-dichlorophenyl)-8-methyl-2-[[6-[l-[2-(l-methyl-4-piperidyl)ethyl]pyrazol-4- yl]oxypyridazin-3-yl]amino]pyrido[2,3-d]pyrimidin-7-one [88674] To a solution of 3-chloro-6-[l-[2-(l-methyl-4-piperidyl)ethyl]pyrazol-4-yl]oxy-pyridazine (28 mg, 0.087 mmol) in dioxane (2 mL) was added 2-amino-6-(2,6-dichlorophenyl)-8-methyl-pyrido[2,3- d]pyrimidin-7-one (28 mg, 0.087mmol), sodium tert-butoxide (25 mg, 0.261 mmol), 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (10 mg, 0.017 mmol) and tris(dibenzylideneacetone)dipalladium (0) (8 mg, 0.009 mmol). The mixture was stirred at 130 °C for 3 hour under microwave. The mixture was purified by prep-TLC. The residue was purified by RP-HPLC (25 to 45% acetonitrile in water and 0.225% formic acid) to afford the title compound (1.1 mg, 2%) as a white solid. rH NMR (400 MHz, CD3OD) 3 8.86 (s, 1H), 8.74 (d, J = 9.6 Hz, 1H), 7.92 (s, 1H), 7.86 (s, 1H), 7.60-7.35 (m, 5H), 4.20 (t, J = 7.2 Hz, 2H), 3.79 (s, 3H), 2.95 (d, J = 12.0 Hz, 2H), 2.33 (s, 3H), 2.13 (s, 2H), 1.86-1.78 (m, 4H), 1.37-1.27 (m, 4H). LCMS RT = 1.521 min, m/z = 606.4 [M + H]+
[ 88675 ] Example 64. Synthesis of COMPOUND-192 [88878] Scheme 38.
Figure imgf000223_0001
[88877] Step 1: tert-butyl 4-(2-((6-chloro-4-cyanopyridazin-3-yl)oxy)ethyl)piperazine-l-carboxylate [88678] To a solution of 3,6-dichloropyridazine-4-carbonitrile (1.6 g, 9.20 mmol) in N,N- dimethylformamide (10 mL) was added cesium fluoride (4.19 g, 27.59 mmol) and tert-butyl 4-(2- hydroxyethyl)piperazine- 1 -carboxylate (2.12 g, 9.20 mmol). The mixture was stirred at 25 °C for 2 hours and diluted with water (500 mL). The mixture was extracted with ethyl acetate (200 mL x 2). The combined organic layers were washed with brine (60 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 - 10% methanol in dichloromethane) to afford the title compound (800 mg, 24%) as a black oil. LCMS RT = 0.433 min, m/z = 368.0 [M + H]+.
[88879] Step 2: tert-butyl 4-(2-((4-cyano-6-((6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridazin-3-yl)oxy)ethyl)piperazine-l-carboxylate [88688] To a solution of tert-butyl 4-(2-((6-chloro-4-cyanopyridazin-3-yl)oxy)ethyl)piperazine-l- carboxylate (137 mg, 0.3 mmol) in dioxane (2 mL) was added 2-amino-6-(2,6-dichlorophenyl)-8- methylpyrido[2,3-d]pyrimidin-7(8H)-one (80 mg, 0.2 mmol), tris(dibenzylideneacetone)dipalladium (0) (22. mg, 0.1 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (28 mg, 0.1 mmol) and sodium tert-butoxide (71 mg, 0.7 mmol). The mixture was stirred at 130 °C for 3 hours under microwave. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 - 100% ethyl acetate in petroleum ether) to afford the title compound (90 mg, 55%) as a yellow solid. LCMS RT = 0.527 min, m/z = 652.2 [M + H]+.
[88681] Step 3: tert-butyl 4-(2-((6-((6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-2-yl)amino)-4-(lH-tetrazol-5-yl)pyridazin-3-yl)oxy)ethyl)piperazine-l-carboxylate
[88682] To a solution of tert-butyl 4-(2-((4-cyano-6-((6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridazin-3-yl)oxy)ethyl)piperazine-l-carboxylate (60 mg, 0.1 mmol) in N,N-dimethylformamide (2 mL) was added sodium azide (9 mg, 0.1 mmol). The mixture was stirred at 120 °C for 16 hours. The residue was added water (20 mL) and extracted with ethyl acetate (20 mL). The combined organic layers were washed with brine (60 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-TLC to afford the title compound (40 mg, 63%) as a white solid. LCMS RT = 1.206 min, m/z = 595.2 [M + H]+
[88683] Step 4: 6-(2,6-dichlorophenyl)-8-methyl-2-((6-(2-(piperazin-l-yl)ethoxy)-5-(lH-tetrazol-5- yl)pyridazin-3-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one
[88684] To a solution of tert-butyl 4-(2-((6-((6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-4-(lH-tetrazol-5-yl)pyridazin-3-yl)oxy)ethyl)piperazine-l- carboxylate (35 mg, 0. 1 mmol) in hexafluoroisopropanol (2 mL) was added trifluoroacetic acid (6 mg, 0.1 mmol). The mixture was stirred at 25 °C for 0.5 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by RP-HPLC (10 to 50% acetonitrile in water and 0.225% formic acid water) to give the title compound (5 mg, 17%) as a white solid. rH NMR (400 MHz, CD3OD) 8 9.52 (s, 1H), 8.92 (s, 1H), 7.90 (s, 1H), 7.57-7.46 (m, 2H), 7.46-7.34 (m, 1H), 3.87 (s, 3H), 3.50-3.33 (m, 6H), 3.20 (t, J= 5.2 Hz, 2H), 3.07 (s, 4H). LCMS RT = 1.297 min, m/z = 595.2 [M + H]+
[ 18)685 ] Example 65. Synthesis of COMPOUND-420 [88686] Scheme 39.
Figure imgf000224_0001
[88687] Step 1: 3-bromo-6-(l-(tetrahydrofuran-3-yl)cyclopropoxy)pyridazine
[88688] To a solution of l-tetrahydrofuran-3-ylcyclopropanol (100 mg, 0.78 mmol) in tetrahydrofuran (1 mL) was added sodium hydride (62 mg, 1.56 mmol). The mixture was stirred at 0 °C for 0.5 hour under nitrogen atmosphere. Then the mixture was added 3,6-dichloropyridazine (116 mg, 0.78 mmol). The mixture was stirred at 20 °C for 1 hour under nitrogen atmosphere. The mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 3). The residue was purified by prep-TLC to afford the title compound (80 mg, 43%) as a white solid.
[99669} Step 2: 6-(2,6-dichlorophenyl)-8-methyl-2-((6-(l-(tetrahydrofuran-3- yl)cyclopropoxy)pyridazin-3-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one
[99699} To a solution of 2-amino-6-(2,6-dichlorophenyl)-8-methyl-pyrido[2,3-d]pyrimidin-7-one (78 mg, 0.24 mmol) in dioxane (2 mL) was added 3-chloro-6-(l-tetrahydrofuran-3- ylcyclopropoxy)pyridazine (70 mg, 0.29 mmol), tris(dibenzylideneacetone)dipalladium (0) (22 mg, 0.02 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (28 mg, 0.05 mmol) and sodium tert-butoxide (70 mg, 0.73 mmol) under nitrogen atmosphere. The mixture was stirred at 130°C for 3 hours under microwave. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by RP-HPLC (25 to 65% acetonitrile in water and 1% hydrochloric acid) to afford the title compound (33 mg, 25%) as a white solid. rH NMR (400 MHz, DMSO-t/g) <5 11. 17 (s, 1 H), 8.94 (s, 1 H), 8.37 (d, J= 9.6 Hz, 1 H), 8.01 (s, 1 H), 7.64-7.56 (m, 2 H), 7.52-7.44 (m, 1 H), 7.39 (d, J= 9.6 Hz, 1 H), 3.74-3.72 (m, 2 H), 3.64 (s, 3 H), 3.63-3.58 (m, 1 H), 3.47-3.41 (m, 1 H), 3.30-3.21 (m, 1 H), 2.04-1.88 (m, 1 H), 1.62-1.55 (m, 1 H), 1.04-0.87 (m, 4 H). LCMS RT = 1.378 min, m/z = 525.1 [M + H]+
[00691 [ Example 66. Synthesis of COMPOUND-424
[99692J Scheme 40.
Figure imgf000225_0001
[00 93} Step 1: 5-amino-6-(2,6-dichlorophenyl)-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin- 7(8H)-one
[96694} To a solution of 2-(diethylamino)ethanol (197 mg, 1.68 mmol) in tetrahydrofuran (2 mL) was added sodium hydride (134 mg, 3.36 mmol, 60% purity) at 0 °C. The mixture was stirred at 0 °C for 0.5 hour. Then the mixture was added 3,6-dichloropyridazine (250 mg, 1.68 mmol) and then stirred at 20 °C for 2 hour. The mixture was quenched by addition water (5 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 - 2% ethyl acetate in petroleum ether) to afford the title compound (220 mg, 40%) as a white solid. LCMS RT = 0.372 min, m/z = 230. 1 [M + H]+
[99695} Step 2: 5-amino-2-chloro-6-(2,6-dichlorophenyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one [99696} To a solution of 2-(6-chloropyridazin-3-yl)oxy-N,N-diethyl-ethanamine (110 mg, 0.48 mmol) in dioxane (3 mL) was added 2-amino-6-(2,6-dichlorophenyl)-8-methyl-pyrido[2,3-d]pyrimidin-7-one (154 mg, 0.48 mmol), tris(dibenzylideneacetone)dipalladium (0) (44 mg, 0.05 mmol), (5- diphenylphosphanyl-9,9-dimethylxanthen-4-yl)-diphenylphosphane (55 mg, 0.1 mmol) and cesium carbonate (468 mg, 1.44 mmol) and purged with nitrogen for 3 times. The mixture was stirred at 130 °C for 3 hours under microwave. The mixture was fdtered and the fdtrate was concentrated under reduced pressure. The residue was purified by RP-HPLC (10 to 45% acetonitrile in water and 1% hydrochloric acid) to afford the title compound (5.1 mg, 2%) as a white solid. LCMS RT = 1.303 min, m/z = 514.4 [M + H]+
[88697] Step 3: 5-amino-6-(2,6-dichlorophenyl)-2-((6-methoxypyridazin-3-yl)amino)-8- methylpyrido[2,3-d]pyrimidin- 7( 8H)-on e
[88898] To a solution of 5-amino-2-chloro-6-(2,6-dichlorophenyl)-8-methyl-pyrido[2,3-d]pyrimidin-7- one (160 mg, 0.45 mmol) in dioxane (3 mL) was added 6-methoxypyridazin-3 -amine (62 mg, 0.5 mmol), tris(dibenzylideneacetone)dipalladium (0) (41 mg, 0.05 mmol), (5-diphenylphosphanyl-9,9- dimethylxanthen-4-yl)-diphenylphosphane (52 mg, 0.1 mmol) and cesium carbonate (440 mg, 1.35 mmol) at 20 °C. Then the mixture was stirred at 100 °C for 2 hour under nitrogen atmosphere. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by RP-HPLC (20 to 50% acetonitrile in water and 0.225% formic acid) to afford the title compound (2.8 mg, 5%) as a white solid. ’H NMR (400 MHz, DMSO- 6) S 10.62 (s, 1H), 9.16 (s, 1H), 8.41 (d, J= 9.6 Hz, 1H), 7.60-7.48 (m, 2H), 7.44-7.37 (m, 1H), 7.29 (d, J= 9.6 Hz, 1H), 6.44 (s, 2H), 4.00 (s, 3H), 3.48 (s, 3H). LCMS RT = 1.177 min, m/z = 444.3 [M + H]+
[88899 [ Example 67. Synthesis of COMPOUND-450
[88788] Scheme 41.
Figure imgf000226_0001
[88781] Step 1: 2-((6-chloropyridazin-3-yl)oxy)-N,N-diethylethanamine
[88782 [ To a solution of 2-(diethylamino)ethanol (197 mg, 1.68 mmol) in tetrahydrofuran (2 mL) was added sodium hydride (134 mg, 3.36 mmol, 60% purity) at 0 °C. The mixture was stirred at 0 °C for 0.5 hour. Then the mixture was added 3,6-dichloropyridazine (250 mg, 1.68 mmol) and stirred at 20 °C for 2 hours. The mixture was quenched by addition of water (5 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 - 2% ethyl acetate in petroleum ether) to afford the title compound (220 mg, 40%) as a white solid. LCMS RT = 0.372 min, m/z = 230. 1 [M + H]+
[88788] Step 2: 6-(2,6-dichlorophenyl)-2-((6-(2-(diethylamino)ethoxy)pyridazin-3-yl)amino)-8- methylpyrido[2,3-d]pyrimidin- 7( 8H)-on e
[88784[ To a solution of 2-(6-chloropyridazin-3-yl)oxy-N,N-diethyl-ethanamine (110 mg, 0.48 mmol) in dioxane (3 mL) was added 2-amino-6-(2,6-dichlorophenyl)-8-methyl-pyrido[2,3-d]pyrimidin-7-one (154 mg, 0.48 mmol), tris(dibenzylideneacetone)dipalladium (0) (44 mg, 0.05 mmol), (5- diphenylphosphanyl-9,9-dimethylxanthen-4-yl)-diphenylphosphane (55 mg, 0.1 mmol) and cesium carbonate (468 mg, 1.44 mmol) and purged with nitrogen for 3 times, and then the mixture was stirred at 130 °C for 3 hours. The mixture was fdtered and the filtrate was concentrated under reduced pressure. The residue was purified by RP-HPLC (10 to 45% acetonitrile in water and 0.225% hydrogen chloride) to afford the title compound (5.1 mg, 2%) as a white solid. rH NMR (400 MHz, DMSO-t/g) 3 10.98 (s, 1H), 9.83 (s, 1H), 8.91 (s, 1H), 8.48 (d, J = 9.6 Hz, 1H), 7.98 (s, 1H), 7.61 (m, 2H), 7.51-7.46 (m, 1H), 7.38 (d, J = 9.6 Hz, 1H), 4.77 (t, J= 5.6 Hz, 2H), 3.65 (s, 3H), 3.62-3.59 (m, 2H), 3.31-3.21 (m, 4H), 1.29-1.23 (m, 6H). LCMS RT = 1.303 min, m/z = 514.4 [M + H]+ [00795] Example 68. Synthesis of COMPOUND-449 (90796] Scheme 42.
Figure imgf000227_0001
[99797] Step 1: 2-((6-bromopyridin-3-yl)oxy)-N,N-diethylethanamine
[00798] To a solution of 6-bromopyridin-3-ol (200 mg, 1.15 mmol) in toluene (2 mL) was added 2- (diethylamino)ethanol (135 mg, 1.15 mmol), tributylphosphane (1.40 g, 6.90 mmol) and (3E)-3- (dimethylcarbamoylimino)- 1,1 -dimethylurea (792 mg, 4.60 mmol) at 20 °C. Then the mixture was stirred at 100 °C for 1 hour. The reaction mixture was fdtered and concentrated under reduced pressure to remove solvent. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 - 25% ethyl acetate in petroleum ether) to afford the title compound (220 mg, 70%) as a white solid. LCMS RT = 0.837 min, m/z = 273.0 [M + H]+
[181789] Step 2: 6-(2,6-dichlorophenyl)-2-((5-(2-(diethylamino)ethoxy)pyridin-2-yl)amino)-8- methylpyrido[2,3-d]pyrimidin- 7( 8H)-on e
[00719] To a solution of 2-amino-6-(2,6-dichlorophenyl)-8-methyl-pyrido[2,3-d]pyrimidin-7-one (118 mg, 0.37 mmol) in dioxane (5 mL) was added 2-[(6-bromo-3-pyridyl)oxy]-N,N-diethyl-ethanamine (100 mg, 0.37 mmol), tris(dibenzylideneacetone)dipalladium (0) (34 mg, 0.04 mmol), (5-diphenylphosphanyl- 9,9-dimethylxanthen-4-yl)-diphenylphosphane (42 mg, 0.07 mmol) and cesium carbonate (358 mg, 1.10 mmol) and purged with nitrogen for 3 times, and then the mixture was stirred at 100 °C for 2 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by RP-HPLC (5 to 45% acetonitrile in water and 0.225% hydrogen chloride) to afford the title compound (60 mg, 32%) as a white solid. 1 H NMR (400 MHz, CD3OD) 39.12-9.08 (m, 1H), 8.31-8.25 (m, 1H), 8.19 (d, J = 9.6 Hz, 1H), 8.03 (s, 1H), 7.65-7.59 (m, 1H), 7.54-7.48 (m, 2H), 7.46-7.39 (m, 1H), 4.64- 4.54 (m, 2H), 3.83 (s, 3H), 3.76-3.68 (m, 2H), 3.47-3.35 (m, 4H), 1.42 (t, J = 7.2 Hz, 6H). LCMS RT = 1.203 min, m/z = 513 A [M + H]+„
[99711 [ Example 69. Synthesis of COMPOUND-274 [99712] Scheme 43.
Figure imgf000228_0001
[88713] Step 1: 3-chloro-6-((5-methylpyridin-3-yl)methoxy)pyridaz/ine
[88714] To a solution of sodium hydride (36 mg, 0.90 mmol) in tetrahydrofuran (1.5 ml) was added (5-methylpyridin-3-yl)methanol (100 mg, 0.81 mmol) at 0 °C. The mixture was stirred at 20 °C for 0.3 hour and followed by 3,6-dichloropyridazine (109 mg, 0.73 mmol) at 0 °C. The mixture was stirred at 20 °C for 1.7 hours. The mixture was poured into water (20 mL) and the mixture was filtered. The solid cake was collected and dried to afford the crude title compound (100 mg, 52%) as a white solid. LCMS RT = 0.360 min, m/z = 235.9 [M + H]+.
[88715] Step 2: 6-(2,6-dichlorophenyl)-8-methyl-2-((6-((5-methylpyridin-3-yl)methoxy)pyridazin-3- yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one
|W '716 To a solution of 3-chloro-6-((5-methylpyridin-3-yl)methoxy)pyridazine (100 mg, 0.42 mmol) and 2-amino-6-(2,6-dichlorophenyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (136 mg, 0.42 mmol) in dioxane (3 mL) was added sodium tert-butoxide (102 mg, 1.06 mmol), 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (49 mg, 0.085 mmol) and tris(dibenzylideneacetone)dipalladium (39 mg, 0.042 mmol). The mixture was stirred at 130 °C for 2.5 hours under microwave. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by RP-HPLC (30 to 50% acetonitrile in water and 0.225% formic acid) to afford the title compound (4.1 mg, 2%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) 10.91 (s, 1H), 8.90 (s, 1H), 8.54 (s, 1H), 8.48-8.37 (m, 2H), 7.96 (s, 1H), 7.76 (s, 1H), 7.63-7.56 (m, 2H), 7.51-7.43 (m, 1H), 7.37 (d, J= 9.6 Hz, 1H), 5.51 (s, 2H), 3.62 (s, 3H), 2.33 (s, 3H). LCMS RT = 0.475 min, m/z = 520.1 [M + H]+.
[89717] Example 70. Synthesis of COMPOUND-367
[88718] Scheme 44.
Figure imgf000228_0002
[88719] Step 1: 2-bromo-5-((5-methylpyridin-3-yl)methoxy)pyridine
[88728] To a solution of (5-methyl-3-pyridyl)methanol (70 mg, 0.568 mmol) in toluene (3 mL) was added 6-bromopyridin-3-ol (89 mg, 0.511 mmol), (E)-N1,N1,N2,N2-tetramethyldiazene-l,2- dicarboxamide (147 mg, 0.852 mmol) and tributylphosphane (230 mg, 1.14 mmol). The mixture was stirred at 100 °C for 1 hour. The mixture was filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 - 10% methanol in dichloromethane) to afford the title compound (140 mg, 75%) as a yellow solid. LCMS RT = 0.391 min, m/z = 278.9 [M + H]+.
[80721 [ Step 2: 6-(2,6-dichlorophenyl)-8-methyl-2-((5-((5-methylpyridin-3-yl)methoxy)pyridin-2- yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one
W722] To a solution of 2-amino-6-(2,6-dichlorophenyl)-8-methyl-pyrido[2,3-d]pyrimidin-7-one (76 mg, 0.232 mmol) in dioxane (2 mL) was added 2-bromo-5-[(5-methyl-3-pyridyl)methoxy]pyridine (90 mg, 0.257 mmol), sodium tert-butoxide (62 mg, 0.644 mmol), 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (29 mg, 0.051 mmol) and tris(dibenzylideneacetone)dipalladium (0) (24 mg, 0.025 mmol). The mixture was stirred at 95 °C for 4 hours. The mixture was filtered and the filtrate was purified by RP-HPLC (20 to 50% acetonitrile in water and 0.225% formic acid) to afford the title compound (5.5 mg, 4%) as a yellow solid. ‘H NMR (400 MHz, DMSO-d6) b 10.37 (s, 1H), 8.87 (s, 1H), 8.52-8.38 (m, 2H), 8.27-8.14 (m, 2H), 7.93 (s, 1H), 7.72 (s, 1H), 7.64-7.56 (m, 3H), 7.51-7.43 (m, 1H), 5.20 (s, 2H), 3.66 (s, 3H), 2.33 (s, 3H). LCMS RT = 1.385 min, m/z = 519.3 [M + H]+
IC 733] Example 71. Synthesis of COMPOUND-364 [88724] Scheme 45.
Figure imgf000229_0001
[88725] Step 1: tert-butyl 2-(((6-chloropyridazin-3-yl)oxy)methyl)-6-azaspiro[3.4]octane-6- carboxylate
[88726] To a solution of sodium hydride (5 mg, 0.13 mmol) in tetrahydrofuran (1.5 ml) was added tert-butyl 2-(hydroxymethyl)-6-azaspiro[3.4]octane-6-carboxylate (30 mg, 0.13 mmol) at 0 °C. The mixture was stirred at 20 °C for 20 minutes and added 3,6-dichloropyridazine (17 mg, 0.11 mmol) at 0 °C. The mixture was stirred at 20 °C for 2 hours. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with brine (15 mL), dried over sodium sulphate and concentrated. The residue was purified by prep-TLC to afford the title compound (15 mg, 37%) as a light yellow solid. LCMS RT = 0.590 min, m/z = 354.1 [M + H]+. [88727] Step 2: tert-butyl 2-(((6-((6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-2-yl)amino)pyridazin-3-yl)oxy)methyl)-6-azaspiro[3.4]octane-6-carboxylate
[08728] To a solution of tert-butyl 2-(((6-chloropyridazin-3-yl)oxy)methyl)-6-azaspiro[3.4]octane-6- carboxylate (15 mg, 0.04 mmol) and 2-amino-6-(2,6-dichlorophenyl)-8-methylpyrido[2,3-d]pyrimidin- 7(8H)-one (14 mg, 0.04 mmol) in dioxane (2.0 mL) was added sodium tert-butoxide (10 mg, 0. 10 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (5 mg, 0.008 mmol) and tris(dibenzylideneacetone)dipalladium (0) (4 mg, 0.005 mmol). The mixture was stirred at 130 °C for 2.5 hours under microwave. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC to afford the title compound (18 mg, 67%) as a light yellow solid. LCMS RT = 1.553 min, m/z = 638.2 [M + H]+.
[08729] Step 3: 2-((6-(6-azaspiro[3.4]octan-2-ylmethoxy)pyridazin-3-yl)amino)-6-(2,6- dichlorophenyl)-8-methylpyrido[2,3-d]pyrimidin-7( 8H)-one f < '738j A solution of tert-butyl 2-(((6-((6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-2-yl)amino)pyridazin-3-yl)oxy)methyl)-6-azaspiro[3.4]octane-6-carboxylate (18 mg, 0.028 mmol) in hydrochloric acid (4M in dioxane, 4.5 mL) was stirred at 20 °C for 0.5 hour. The mixture was concentrated under reduced pressure. The residue was purified by RP-HPLC (0 to 50% acetonitrile in water and 0.225% formic acid) to afford the title compound (8.8 mg, 53%) as a light yellow solid. rH NMR (400 MHz, DMSO- 6) b 1.15-10.45 (m, 1H), 8.89 (s, 1H), 8.41 (s, 1H), 8.39 (s, 1H), 7.96 (s, 1H), 7.63-7.55 (m, 2H), 7.51-7.44 (m, 1H), 7.29 (d, J= 9.6 Hz, 1H), 4.40 (m, J= 6.4 Hz, 2H), 3.61 (s, 6H), 3.13-3.01 (m, 4H), 2.77-2.68 (m, 1H), 2.20-2.03 (m, 2H), 2.00-1.81 (m, 4H). LCMS RT = 1.370 min, m/z = 538.4 [M + H]+.
[88731 ] Example 72. Synthesis of COMPOUND-366
[88732] Scheme 46.
Figure imgf000230_0001
[88733] Step 1: tert-butyl 2-(((6-bromopyridin-3-yl)oxy)methyl)-6-azaspiro[3.4]octane-6-carboxylate [88734] To a solution of tert-butyl 2-(hydroxymethyl)-6-azaspiro[3.4]octane-6-carboxylate (20 mg, 0.08 mmol) in toluene (1.5 mL) was added 6-bromopyridin-3-ol (14 mg, 0.08 mmol), (E^N^N^N^N2- tetramethyldiazene-l,2-dicarboxamide (21 mg, 0.12 mmol) and tributylphosphine (34 mg, 0.17 mmol). The mixture was stirred at 100 °C for 1 hour. The mixture was diluted with ethyl acetate (20 mL), washed with water (15 mL) and concentrated. The residue was purified by prep-TLC to afford the title compound (27 mg, 82%) as a light yellow solid. LCMS RT = 1.843 min, m/z = 399.0 [M +H]+.
[88735] Step 2: tert-butyl 2-(((6-((6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-2-yl)amino)pyridin-3-yl)oxy)methyl)-6-azaspiro[3.4]octane-6-carboxylate [88736] To a solution of tert-butyl 2-(((6-bromopyridin-3-yl)oxy)methyl)-6-azaspiro[3 ,4]octane-6- carboxylate (27 mg, 0.068 mmol) and 2-amino-6-(2,6-dichlorophenyl)-8-methylpyrido[2,3-d]pyrimidin- 7(8H)-one (22 mg, 0.068 mmol) in dioxane (2.0 mb) was added sodium tert-butoxide (16 mg, 0.17 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (8 mg, 0.014 mmol) and tris(dibenzylideneacetone)dipalladium (6 mg, 0.007 mmol). The mixture was stirred at 95 °C for 4.5 hours. The mixture was fdtered and the filtrate was purified by prep-TLC to afford the title compound (40 mg, 92%) as a light yellow solid. LCMS RT = 1.520 min, m/z = 637.2 [M + H]+.
[88737] Step 3: 2-((5-(6-azaspiro[3.4]octan-2-ylmethoxy)pyridin-2-yl)amino)-6-(2,6-dichlorophenyl)- 8-methylpyrido[2,3-d]pyrimidin- 7( 8H)-on e
[88738] A solution of tert-butyl 2-(((6-((6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-2-yl)amino)pyridin-3-yl)oxy)methyl)-6-azaspiro[3.4]octane-6-carboxylate (40 mg, 0.063 mmol) in hydrochloric acid (4 M in dioxane, 2.67 mb) was stirred at 20 °C for 0.5 hour. The mixture was concentrated under reduced pressure. The residue was purified by RP-HPLC (0 to 50% acetonitrile in water and 0.225% formic acid) to afford the title compound (15.8 mg, 43%) as a light yellow solid. rH NMR (400 MHz, DMSO- 6) d 10.33 (m, 1H), 8.86 (s, 1H), 8.40 (s, 1H), 8.21 (d, J= 8.8 Hz, 1H), 8.08 (d, J= 2.8 Hz, 1H), 7.93 (s, 1H), 7.64-7.55 (m, 2H), 7.54-7.43 (m, 2H), 4.04 (d, J= 2.8, 6.4 Hz, 2H), 3.66 (s, 3H), 3.13-2.99 (m, 4H), 2.74-2.64 (m, 1H), 2.21-2.02 (m, 2H), 2.00-1.78 (m, 4H). LCMS RT = 1.347 min, m/z = 537.4 [M + H]+.
[08739] Example 73. Synthesis of COMPOUND-262
[88748] Scheme 47.
Figure imgf000231_0001
[1817 1] Step 1: 3-methyl-2-(((6-nitropyridin-3-yl)oxy)methyl)pyridine
[181742] To a solution of (3-methyl-2-pyridyl)methanol (100 mg, 0.8 mmol), 5 -fluoro-2 -nitro-pyridine (115 mg, 0.8 mmol) in N,N-dimethylformamide (3 mb) was added cesium carbonate (795 mg, 2.44 mmol). The mixture was stirred at 60 °C for 1 hour. The mixture was quenched by addition of water (5 mL) and extracted with ethyl acetate (10 mb x 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 - 2% ethyl acetate in petroleum ether) to afford the title compound (170 mg, 68%) as white oil. LCMS RT = 0.826 min, m/z = 245.9 [M + H]+
[181743] Step 2: 5-((3-methylpyridin-2-yl)methoxy)pyridin-2-amine
[88744] To a solution of 3-methyl-2-[(6-nitro-3-pyridyl)oxymethyl]pyridine (160 mg, 0.65 mmol) in tetrahydrofuran (4.5 mL) and water (1.5 mL) was added ammonium chloride (175 mg, 3.26 mmol) and iron (182 mg, 3.26 mmol). The mixture was stirred at 60 °C for 3 hours. The mixture was quenched by addition of water (5 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, fdtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 - 100% ethyl acetate in petroleum ether) to afford the title compound (150 mg, 85%) as a yellow oil.
LCMS RT = 0. 115 min, m/z = 216.0 [M + H]+
Step 3: 6-(2,6-dichlorophenyl)-8-methyl-2-((5-((3-methylpyridin-2-yl)methoxy)pyridin-2- yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one
[88746] To a solution of 2-chloro-6-(2,6-dichlorophenyl)-8-methyl-pyrido[2,3-d]pyrimidin-7-one (152 mg, 0.44 mmol) in l-methylpyrrolidin-2-one (5 mL) was added 5-[(3-methyl-2-pyridyl)methoxy]pyridin- 2-amine (120 mg, 0.44 mmol) and cesium fluoride (203 mg, 1.34 mmol). The mixture was stirred at 100 °C for 4 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by RP-HPLC (10 to 50% acetonitrile in water and 0.225% hydrogen chloride) to afford the title compound (2.2 mg, 1%) as a white solid. rH NMR (400 MHz, DMSO-t/g) <5 10.93 (s, 1H), 8.95 (s, 1H), 8.68 (s, 1H), 8.40-8.10 (m, 3H), 8.03-7.80 (m, 3H), 7.68-7.39 (m, 3H), 5.57 (s, 2H), 3.68 (s, 3H), 2.59-2.51 (m, 3H). LCMS RT = 1.426 min, m/z = 519.3 [M + H]+.
[88747] Example 74. Synthesis of COMPOUND-311
[88748] Scheme 48.
Figure imgf000232_0001
[08749] Step 1: (2R,4R)-tert-butyl 2-methyl-4-((6-nitropyridin-3-yl)oxy)pyrrolidine-l-carboxylate [08758] To a solution of tert-butyl (2R, 4R)-4-hydroxy-2 -methyl -pyrrolidine- 1 -carboxylate (100 mg, 0.49 mmol) in N,N-dimethylformamide (5 mL) was added cesium carbonate (485 mg, 1.49 mmol) and 5- fluoro-2-nitro-pyridine (70 mg, 0.49 mmol). The mixture was stirred at 60 °C for 1 hour. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to remove solvent. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 - 25% ethyl acetate in petroleum ether) to afford the title compound (130 mg, 81%) as a white solid. LCMS RT = 0.542 min, m/z = 268.1 [M + H]+
[08751 ] Step 2: (2R,4R)-tert-butyl 4-((6-aminopyridin-3-yl)oxy)-2-methylpyrrolidine-l-carboxylate (80752] To a solution of tert-butyl (2R,4R)-2-methyl-4-[(6-nitro-3-pyridyl)oxy]pyrrolidine-l- carboxylate (130 mg, 0.40 mmol) in tetrahydrofuran (4 mb) and water (1 mL) was added iron (179 mg, 3.22 mmol) and ammonium chloride (107 mg, 2.01 mmol). The mixture was stirred at 60 °C for 3 hours. The reaction mixture was fdtered and the fdtrate was concentrated under reduced pressure to remove solvent. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 - 100% ethyl acetate in petroleum ether) to afford the title compound (130 mg, 66%) as a white solid. LCMS RT = 0.443 min, m/z = 294.1 [M + H]+
(88753] Step 3: (2R,4R)-tert-butyl 4-((6-((6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)oxy)-2-methylpyrrolidine-l-carboxylate (88754] To a solution of 2-chloro-6-(2,6-dichlorophenyl)-8-methyl-pyrido[2,3-d]pyrimidin-7-one (90 mg, 0.26 mmol) in l-methylpyrrolidin-2-one (4 mL) was added cesium fluoride (121 mg, 0.79 mmol) and tert-butyl (2R,4R)-4-[(6-amino-3-pyridyl)oxy]-2-methyl-pyrrolidine-l-carboxylate (130 mg, 0.26 mmol). The mixture was stirred at 100 °C for 4 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 - 40% ethyl acetate in petroleum ether) to afford the title compound (50 mg, 9%) as a white solid. LCMS RT = 0.545 min, m/z = 597.2 [M + H]+
(80755] Step 4: 6-(2,6-dichlorophenyl)-8-methyl-2-((5-(((3R,5R)-5-methylpyrrolidin-3- yl)oxy)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one
(88758] To a solution of tert-butyl (2R, 4R)-4-[[6-[[6-(2,6-dichlorophenyl)-8-methyl-7-oxo-pyrido[2,3- d]pyrimidin-2-yl]amino]-3-pyridyl]oxy]-2-methyl-pyrrolidine-l-carboxylate (50 mg, 0.083 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL). The mixture was stirred at 20 °C for 0.5 hour. The mixture was concentrated under reduced pressure. The residue was purified by RP-HPLC (0 to 40% acetonitrile in water and 0.225% formic acid) to afford the title compound (7 mg, 17%) as a white solid. ‘H NMR (400 MHz, DMSO- 6) b 10.32 (s, 1H), 8.87 (s, 1H), 8.21 (d, J= 9.2 Hz, 1H), 8.03 (d, J = 3.2 Hz, 1H), 7.92 (s, 1H), 7.62-7.55 (m, 2H), 7.50-7.41 (m, 2H), 4.95-4.92 (m, 1H), 3.66 (s, 3H), 3.19- 3.03 (m, 4H), 2.44-2.40 (m, 1H), 1.46-1.30 (m, 1H), 1.18 (d, J= 6.4 Hz, 3H). LCMS RT = 1.333 min, m/z = 497.1 [M + H]+.
HW7S7] Example 75. Synthesis of COMPOUND-351
(88788] Scheme 49.
Figure imgf000233_0001
COMPOUND 351
(8875 ] Step 1: (2S,5S)-5-((6-nitropyridin-3-yl)oxy)hexan-2-ol
(00768] To a solution of (2S, 5S)-hexane-2,5-diol (100 mg, 0.85 mmol), 5-fluoro-2-nitro-pyridine (108 mg, 0.76 mmol) in N,N-dimethylformamide (2 mL) was added cesium carbonate (551 mg, 1.69 mmol).
The mixture was stirred at 60 °C for 1 hour. The mixture was quenched by addition of water (10 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (5 mb), dried over anhydrous sodium sulfate, fdtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 - 50% ethyl acetate in petroleum ether) to afford the title compound (150 mg, 74%) as a yellow oil. LCMS RT = 0.845 min, m/z = 241.1 [M + H]+
| (M1761] Step 2: (2S,5S)-5-((6-aminopyridin-3-yl)oxy)hexan-2-ol
[88762] To a solution of (2S,5S)-5-((6-nitropyridin-3-yl)oxy)hexan-2-ol (150 mg, 0.62 mmol) in tetrahydrofuran (1.5 mL) and water (0.5 mL) was added ammonium chloride (167 mg, 3.12 mmol) and iron (174 mg, 3.12 mmol). The mixture was stirred at 60 °C for 2 hours. The mixture was quenched by addition of water (5 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 - 70% methanol in dichloromethane) to afford the title compound (100 mg, 76%) as a yellow oil. LCMS RT = 0.665 min, m/z = 211.1 [M + H]+
[88783] Step 3: 6-(2,6-dichlorophenyl)-2-((5-(((2S,5S)-5-hydroxyhexan-2-yl)oxy)pyridin-2- yl)amino)-8-methylpyrido[2,3-d]pyrimidin-7( 8H)-one
[88764] To a solution of 2-chloro-6-(2,6-dichlorophenyl)-8-methyl-pyrido[2,3-d]pyrimidin-7-one (89 mg, 0.26 mmol) in dioxane (1 mL) was added (2S,5S)-5-((6-aminopyridin-3-yl)oxy)hexan-2-ol (50 mg, 0.24 mmol), tris(dibenzylideneacetone)dipalladinm(0) (22 mg, 0.024 mmol), (9,9-dimethyl-9H-xanthene- 4,5-diyl)bis(diphenylphosphine) (28 mg, 0.048 mmol) and cesium carbonate (232 mg, 0.71 mmol). The mixture was stirred at 120 °C for 2 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by RP-HPLC (34% to 74% acetonitrile in water and 0.05% ammonium hydrate and 10 mM ammonium bicarbonate) to afford the title compound (5.0 mg, 4%) as a white solid. 1H NMR (400 MHz, DMSO- 6) d 10.32 (s, 1H), 8.86 (s, 1H), 8.41 (s, 1H), 8.31- 8.16 (m, 1H), 8.07 (s, 1H), 7.93 (s, 1H), 7.59-7.48 (m, 4H), 4.41-4.30 (m, 1H), 3.66 (s, 3H), 3.21-3.08 (m, 2H), 2.72-2.65 (m, 2H), 1.95-1.61 (m, 3H), 1.48-1.25 (m, 5H). LCMS RT = 0.870 min, m/z = 525.1 [M + H]+.
HW765] Example 76. Synthesis of COMPOUND-313 [88766] Scheme 50.
Figure imgf000235_0001
(88787) Step 1: tert-butyl 4-(l-((6-nitropyridin-3-yl)oxy)ethyl)piperidine-l-carboxylate
(88788) To a solution of tert-butyl 4-(l-hydroxyethyl)piperidine-l -carboxylate (100 mg, 0.44 mmol) in N,N-dimethylformamide (1 mL) was added cesium carbonate (426 mg, 1.31 mmol) and 5 -fluoro-2 -nitropyridine (62 mg, 0.44 mmol). The mixture was stirred at 60 °C for 1 hour. The mixture was quenched by addition of water (10 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, fdtered and concentrated under reduced pressure to afford the title compound (165 mg, 100%) as a yellow oil. LCMS RT = 1.032 min, m/z = 296.0 [M + H]+
(88769) Step 2: tert-butyl 4-(l-((6-aminopyridin-3-yl)oxy)ethyl)piperidine-l-carboxylate
(88778) To a solution of tert-butyl 4-(l-((6-nitropyridin-3-yl)oxy)ethyl)piperidine-l -carboxylate (150 mg, 0.43 mmol) in tetrahydrofuran (1.5 mL)and water (0.5 mL) was added iron (119 mg, 2.13 mmol) and ammonium chloride (114 mg, 2.13 mmol). The mixture was stirred at 60 °C for 3 hours. The mixture was quenched by addition of water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, fdtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 - 10% methanol in dichloromethane) to afford the title compound (120 mg, 87%) as a yellow oil. LCMS RT = 0.838 min, m/z = 322.1 [M + H]+
(88771) Step 3: tert-butyl 4-(l-((6-((6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-2-yl)amino)pyridin-3-yl)oxy)ethyl)piperidine-l-carboxylate
(88772) To a solution of 2-chloro-6-(2,6-dichlorophenyl)-8-methyl-pyrido[2,3-d]pyrimidin-7-one (64 mg, 0.19 mmol) in dioxane (2 mL) was added tert-butyl 4-(l-((6-aminopyridin-3-yl)oxy)ethyl)piperidine- 1-carboxylate (60 mg, 0.19 mmol), tris(dibenzylideneacetone)dipalladium (0) (17 mg, 0.018 mmol), (9,9- dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (22 mg, 0.037 mmol) and cesium carbonate (182 mg, 0.56 mmol). The mixture was stirred at 120 °C for 2 hours. The mixture was fdtered and the fdtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 - 8% methanol in dichloromethane) to afford the title compound (60 mg, 51%) as a yellow oil. LCMS RT = 1.680 min, m/z = 625.2 [M + H]+
[90773 [ Step 4: 6-(2,6-dichlorophenyl)-8-methyl-2-((5-(l-(piperidin-4-yl)ethoxy)pyridin-2- yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one
[(.8)774} To a solution of tert-butyl 4-(l-((6-((6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8- dihydropyrido [2, 3 -d]pyrimidin-2-yl)amino)pyridin-3-yl)oxy)ethyl)piperidine-l -carboxylate (10 mg, 0.016 mmol) in methane (0.5 mL) was added hydrochloric acid (4 M in dioxane, 4 mb). The mixture was stirred at 20 °C for 1 hour. The mixture was concentrated under reduced pressure. The residue was purified by RP-HPLC (19% to 39% acetonitrile in water and 0.225% formic acid) to afford the title compound (2.2 mg, 26%) as a white solid. ’H NMR (400 MHz, DMSO- 6) 5 10.32 (s, 1H), 8.87 (s, 1H), 8.21 (d, J= 9.2 Hz, 1H), 8.05 (s, 1H), 7.93 (s, 1H), 7.63-7.55 (m, 2H), 7.55-7.43 (m, 2H), 4.53-4.40 (m, 2H), 3.67 (s, 3H), 3.65-3.55 (m, 1H), 1.88-1.73 (m, 1H), 1.58-1.36 (m, 3H), 1.26 (d, J= 6.0 Hz, 3H), 1.06 (d, J = 6.4 Hz, 3H).
(66775} LCMS RT = 0.940 min, m/z = 514.1 [M + H]+
(66776} Example 77. Synthesis of COMPOUND-386
(06777} Scheme 51.
Figure imgf000236_0001
[00778 [ Step 1: 3-(3-((tert-butyldimethylsilyl)oxy)propoxy)-6-chloropyridazine
[(8)779} To a solution of sodium hydride (23 mg, 0.58 mmol) in tetrahydrofuran (1.5 mL) was added 3- ((tert-butyldimethylsilyl)oxy)propan-l-ol (100 mg, 0.53 mmol) at 0 °C. The mixture was stirred at 25 °C for 15 minutes and added 3,6-dichloropyridazine (78 mg, 0.53 mmol) at 0 °C. The mixture was stirred at 25 °C for 2 hours. The mixture was diluted with ethyl acetate (30 mL) and washed with water (20 mL x 3). The organic layer was dried over sodium sulphate and concentrated to afford the title compound (120 mg, 75%) as a yellow oil. LCMS RT = 1.728 min, m/z = 303.2 [M + H]+.
[90780} Step 2: 2-((6-(3-((tert-butyldimethylsilyl)oxy)propoxy)pyridazin-3-yl)amino)-6-(2,6- dichlorophenyl)-8-methylpyrido[2,3-d]pyrimidin-7( 8H)-one
[90781 [ To a solution of 3-(3-((tert-butyldimethylsilyl)oxy)propoxy)-6-chloropyridazine (120 mg, 0.4 mmol) and 2-amino-6-(2,6-dichlorophenyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (127 mg, 0.4 mmol) in dioxane (2 mL) was added sodium tert-butoxide (114 mg, 1.19 mmol), 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (46 mg, 0.08 mmol) and tris(dibenzylideneacetone)dipalladium (0) (36 mg, 0.04 mmol). The mixture was stirred at 140 °C for 16 hours. The mixture was fdtered and the fdtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 - 30% ethyl acetate in petroleum ether) to afford the title compound (110 mg, 47%) as a yellow solid. LCMS RT = 1.795 min, m/z = 587.2 [M + H]+. [88782] Step 3: 6-(2,6-dichlorophenyl)-2-((6-(3-hydroxypropoxy)pyridazin-3-yl)amino)-8- methylpyrido[2,3-d]pyrimidin- 7( 8H)-on e
[00783] To a solution of 2-((6-(3-((tert-butyldimethylsilyl)oxy)propoxy)pyridazin-3-yl)amino)-6-(2,6- dichlorophenyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (110 mg, 0.19 mmol) in tetrahydrofuran (2 mL) was added tetrabutylammonium fluoride (1 M in tetrahydrofuran, 0.37 mL). The mixture was stirred at 25 °C for 2 hours. The mixture was concentrated under reduced pressure. The residue was purified by RP-HPLC (25% to 55% acetonitrile in water and 0.225% formic acid) to afford the title compound (10.7 mg, 11%) as a light yellow solid. 1 H NMR (400 MHz, DMSO-d6) b 10.86 (s, 1H), 8.89 (s, 1H), 8.40 (d, J = 9.6 Hz, 1H), 7.96 (s, 1H), 7.64-7.55 (m, 2H), 7.54-7.40 (m, 1H), 7.32-7.25 (m, 1H), 4.59 (t, J= 2.8 Hz, 1H), 4.47 (t, J= 6.4 Hz, 2H), 3.65-3.49 (m, 5H), 1.99-1.86 (m, 2H). LCMS RT = 1.933 min, m/z = 473.3 [M + H]+
[80784] Example 78. Synthesis of COMPOUND-304
[8878S] Scheme 52.
Figure imgf000237_0001
1 0'786 Step 1: 2-bromo-5-(3-((tert-butyldimethylsilyl)oxy)propoxy)pyridine
[8^78'7] To a solution of 3-((tert-butyldimethylsilyl)oxy)propan-l-ol (100 mg, 0.53 mmol) in toluene (2 mL) was added 6-bromopyridin-3-ol (91 mg, 0.53 mmol), (E)-N1,N1,N2,N2-tetramethyldiazene-l,2- dicarboxamide (131 mg, 0.79 mmol) and tributylphosphine (213 mg, 1.05 mmol). The mixture was stirred at 100 °C for 1 hour. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 - 15% ethyl acetate in petroleum ether) to afford the title compound (100 mg, 55%) as a colorless oil. LCMS RT = 1.967 min, m/z = 346.1 [M + H]+.
] 88788 ] Step 2: 2-((5-( 3-((tert-butyldimethylsilyl)oxy)propoxy)pyridin-2-yl)amin o)-6-( 2, 6- dichlorophenyl)-8-methylpyrido[2,3-d]pyrimidin-7( 8H)-one
[88788] To a solution of 2-bromo-5-(3-((tert-butyldimethylsilyl)oxy)propoxy)pyridine (100 mg, 0.29 mmol) and 2-amino-6-(2,6-dichlorophenyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (93 mg, 0.29 mmol) in dioxane (3 mL) was added sodium tert-butoxide (83 mg, 0.87 mmol), 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (33 mg, 0.058 mmol) and tris(dibenzylideneacetone)dipalladium (0) (26 mg, 0.029 mmol). The mixture was stirred at 140 °C for 16 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 - 75% ethyl acetate in petroleum ether) to afford the title compound (40 mg, 24%) as a yellow solid. LCMS RT = 1.793 min, m/z = 586.2 [M + H]+.
[88798] Step 3: 6-(2,6-dichlorophenyl)-2-((5-(3-hydroxypropoxy)pyridin-2-yl)amino)-8- methylpyrido[2,3-d]pyrimidin- 7( 8H)-on e [68791] To a solution of 2-((5-(3-((tert-butyldimethylsilyl)oxy)propoxy)pyridin-2-yl)amino)-6-(2,6- dichlorophenyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (40 mg, 0.068 mmol) in tetrahydrofiiran (2 mL) was added tetrabutylammonium fluoride (1 M in tetrahydrofiiran, 0.14 mL). The mixture was stirred at 25 °C for 2 hours. The mixture was concentrated under reduced pressure. The residue was purified by RP-HPLC (25% to 45% acetonitrile in water and 0.225% formic acid) to afford the title compound (0.9 mg, 3%) as a white solid. 1H NMR (400 MHz, DMSO-d6) S 10.31 (s, 1H), 8.87 (s, 1H), 8.21 (d, J= 6.4 Hz, 1H), 8.08 (d, J= 3.2 Hz, 1H), 7.93 (s, 1H), 7.62-7.55 (m, 2H), 7.54-7.43 (m, 2H), 4.59 (s, 1H), 4.12
(t, J= 6.4 Hz, 2H), 3.67 (s, 3H), 3.62-3.53 (m, 2H), 1.93-1.83 (m, 2H). LCMS RT = 1.900 min, m/z
=472.3 [M + H]+
[60792] Example 79. Synthesis of COMPOUND-387
[90793] Scheme 53.
Figure imgf000238_0001
[66794] Step 1: 3-chloro-6-((2,2-dimethyl-l,3-dioxan-5-yl)methoxy)pyridaz/ine
[00795] To a solution of sodium hydride (30 mg, 0.75 mmol) in tetrahydrofuran (1.5 mL) was added (2,2-dimethyl-l,3-dioxan-5-yl)methanol (100 mg, 0.68 mmol) at 0 °C. After stirred at 25 °C for 15 minutes, the mixture was added 3,6-dichloropyridazine (102 mg, 0.68 mmol) at 0 °C. The mixture was stirred at 25 °C for 2 hours. The mixture was diluted with ethyl acetate (30 mL) and washed with water (20 mL x 3). The organic layer was dried over sodium sulphate and concentrated to afford the title compound (120 mg, 68%) as a yellow solid which was used in next step without further purification. LCMS RT = 1.208 min, m/z = 259. 1 [M + H]+.
[66796] Step 2: 6-(2,6-dichlorophenyl)-2-((6-((2,2-dimethyl-l,3-dioxan-5-yl)methoxy)pyridazin-3- yl)amino)-8-methylpyrido[2,3-d]pyrimidin-7( 8H)-one
[66797] To a solution of 3-chloro-6-((2,2-dimethyl-l,3-dioxan-5-yl)methoxy)pyridazine (120 mg, 0.46 mmol) and 2-amino-6-(2,6-dichlorophenyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (149 mg, 0.46 mmol) in dioxane (2 mL) was added sodium tert-butoxide (134 mg, 1.39 mmol), 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (54 mg, 0.093 mmol) and tris(dibenzylideneacetone)dipalladium (0) (42 mg, 0.046 mmol). The mixture was stirred at 140 °C for 16 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 - 52% ethyl acetate in petroleum ether) to afford the title compound (HO mg, 44%) as a yellow solid. LCMS RT = 1.390 min, m/z = 543.1 [M + H]+.
[66798] Step 3: 6-(2,6-dichlorophenyl)-2-((6-(3-hydroxy-2-(hydroxymethyl)propoxy)pyridazin-3- yl)amino)-8-methylpyrido[2,3-d]pyrimidin-7( 8H)-one
[90799] To a solution of 6-(2,6-dichlorophenyl)-2-((6-((2,2-dimethyl-l,3-dioxan-5- yl)methoxy)pyridazin-3-yl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (110 mg, 0.2 mmol) in tetrahydrofiiran (2 mL) was added hydrochloric acid (4 M, 1 mL). The mixture was stirred at 25 °C for 2 hours. The mixture was concentrated under reduced pressure. The residue was purified by RP-HPLC (10% to 50% acetonitrile in water and 1% hydrochloric acid) to afford the title compound (31.7 mg, 31%) as a white solid. 1H NMR (400 MHz, DMSO- 6) d 11.65-11.54 (m, 1H), 9.00 (s, 1H), 8.33 (d, J = 9.6 Hz, 1H), 8.07 (s, 1H), 7.64-7.57 (m, 2H), 7.56-7.45 (m, 2H), 5.60-5.51 (m, 2H), 4.41 (d, J = 6.0 Hz, 2H), 3.66 (s, 3H), 3.62-3.49 (m, 4H), 2.14-1.99 (m, 1H). LCMS RT = 1.817 min, m/z = 503.3 [M + H]+ )888] Example 80. Synthesis of COMPOUND-297 [86881] Scheme 54.
Figure imgf000239_0001
[88882] Step 1: 2-bromo-5-((2,2-dimethyl-l,3-dioxan-5-yl)methoxy)pyridine
[86803] To a solution of (2,2-dimethyl-l,3-dioxan-5-yl)methanol (100 mg, 0.68 mmol) in toluene (2 mL) was added 6-bromopyridin-3-ol (119 mg, 0.68 mmol), (E)-N1,N1,N2,N2-tetramethyldiazene-l,2- dicarboxamide (177 mg, 1.03 mmol) and tributylphosphine (277 mg, 1.37 mmol). The mixture was stirred at 100 °C for 1 hour. The mixture was diluted with ethyl acetate (30 mL) and washed with water (20 mL x 3). The organic layers were dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 - 21% ethyl acetate in petroleum ether) to afford the title compound (140 mg, 68%) as a colorless oil. LCMS RT = 1.328 min, m/z = 302.1 [M + H]+.
[888 4] Step 2: 6-(2,6-dichlorophenyl)-2-((5-((2,2-dimethyl-l,3-dioxan-5-yl)methoxy)pyridin-2- yl)amino)-8-methylpyrido[2,3-d]pyrimidin-7( 8H)-one
[08885] To a solution of 2-bromo-5-((2,2-dimethyl-l,3-dioxan-5-yl)methoxy)pyridine (140 mg, 0.46 mmol) and 2-amino-6-(2,6-dichlorophenyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (149 mg, 0.46 mmol) in dioxane (2 mL) was added sodium tert-butoxide (134 mg, 1.39 mmol), 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (54 mg, 0.093 mmol) and tris(dibenzylideneacetone)dipalladium (0) (42 mg, 0.046 mmol). The mixture was stirred at 140 °C for 16 hours. The mixture was filtered and the filtrate was concentrated. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 - 56% ethyl acetate in petroleum ether) to afford the title compound (70 mg, 28%) as a yellow solid. LCMS RT = 1.440 min, m/z = 542. 1 [M + H]+.
[86888 [ Step 3: 6-(2,6-dichlorophenyl)-2-((5-(3-hydroxy-2-(hydroxymethyl)propoxy)pyridin-2- yl)amino)-8-methylpyrido[2,3-d]pyrimidin-7( 8H)-one
[68887] To a solution of 6-(2,6-dichlorophenyl)-2-((5-((2,2-dimethyl-l,3-dioxan-5-yl)methoxy)pyridin- 2-yl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (50 mg, 0.092 mmol) in tetrahydrofuran (2 mL) was added hydrochloric acid (4 M, 0.5 mL). The mixture was stirred at 25 °C for 2 hours. The mixture was concentrated under reduced pressure. The residue was purified by RP-HPLC (15% to 50% acetonitrile in water and 1% hydrochloric acid) to afford the title compound (6.3 mg, 14%) as a white solid. 1H NMR (400 MHz, DMSO- 6) d 11.79-11.54 (m, 1H), 9.05 (s, 1H), 8.20 (s, 1H), 8.12 (s, 1H), 7.98 (s, 2H), 7.65-7.58 (m, 2H), 7.52-7.45 (m, 1H), 4.11 (d, J= 5.6 Hz, 2H), 3.70 (s, 3H), 3.67-3.42 (m, 4H), 2.09-1.95 (m, 1H). LCMS RT = 1.798 min, m/z =502.3 [M + H]+
[88888) Example 81. Synthesis of COMPOUND-308
Scheme 55.
Figure imgf000240_0001
[88811 [ To a solution of benzyl 6-hydroxy-2-azabicyclo[2.2. l]heptane-2-carboxylate (100 mg, 0.4 mmol) in toluene (5 mL) was added 6-bromopyridin-3-ol (77 mg, 0.44 mmol), (E)-N1,N1,N2,N2- tetramethyldiazene-l,2-dicarboxamide (104 mg, 0.6 mmol) and tributylphosphine (164 mg, 0.81 mmol). The mixture was stirred at 100 °C for 1 hour. The mixture was diluted with ethyl acetate (20 mL). The organic layer was washed with water (15 mL) and concentrated. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 - 30% ethyl acetate in petroleum ether) to afford the title compound (110 mg, 67%) as a light yellow solid. LCMS RT = 0.575 min, m/z = 405.0 [M + H]+.
Step 2: benzyl 6-((6-((6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-2-yl)amino)pyridin-3-yl)oxy)-2-azabicyclo[2.2.1]heptane-2-carboxylate W81.3) To a solution of benzyl 6-((6-bromopyridin-3-yl)oxy)-2-azabicyclo[2.2.1]heptane-2- carboxylate (100 mg, 0.25 mmol) and 2-amino-6-(2,6-dichlorophenyl)-8-methylpyrido[2,3-d]pyrimidin- 7(8H)-one (80 mg, 0.25 mmol) in dioxane (5 mL) was added sodium tert-butoxide (60 mg, 0.62 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (29 mg, 0.05 mmol) and tris(dibenzylideneacetone)dipalladium (0) (23 mg, 0.025 mmol). The mixture was stirred at 95 °C for 12 hours. The mixture was filtered and the filtrate was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 - 100% ethyl acetate in petroleum ether) to afford the title compound (90 mg, 56%) as a light yellow solid. LCMS RT = 1.538 min, m/z = 643.2 [M + H]+. 814) Step 3: 2-((5-(2-azabicyclo[2.2.1]heptan-6-yloxy)pyridin-2-yl)amino)-6-(2,6-dichlorophenyl)- 8-methylpyrido[2,3-d]pyrimidin- 7( 8H)-on e
[8081 ) A solution of benzyl 6-((6-((6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-2-yl)amino)pyridin-3-yl)oxy)-2-azabicyclo[2.2.1]heptane-2-carboxylate (90 mg, 0.14 mmol) in hydrochloric acid (12 M, 15 mL) was stirred at 20 °C for 3 hours. The mixture was concentrated under reduced pressure. The residue was purified by RP-HPLC (0 to 40% acetonitrile in water and 0.225% formic acid) to afford the title compound (36.7 mg, 51%) as a light yellow solid. 1 H NMR (400 MHz, DMSO-d6) b 10.36 (s, 1H), 8.87 (s, 1H), 8.29-8.20 (m, 2H), 8.06 (d, J= 2.8 Hz, 1H), 7.93 (s, 1H), 7.63- 7.56 (m, 2H), 7.53-7.44 (m, 2H), 4.53-4.56 (m, 1H), 3.70 (s, 1H), 3.67 (s, 3H), 2.88-2.80 (m, 1H), 2.64- 2.53 (m, 2H), 2.07-1.99 (m, 1H), 1.79-1.64 (m, 1H), 1.61-1.48 (m, 2H). LCMS RT = 1.297 min, m/z = 509.3 [M + H]+ [88816] Example 82. Synthesis of COMPOUND-517
[88817] Scheme 56.
Figure imgf000241_0001
[88818[ Step 1: 4-(2-((6-nitropyridin-3-yl)oxy)ethyl)morpholine
[88819^ A mixture of 5 -fluoro-2 -nitro-pyridine (500 mg, 3.52 mmol), 2-morpholinoethanol (461 mg, 3.52 mmol) and cesium carbonate (3.44 g, 10.56 mmol) in N,N-dimethylformamide (2 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 60 °C for 1 hour under nitrogen atmosphere. The reaction mixture extracted with ethyl acetate (20 mL x 3). The organic phases were washed with brine (100 mL). The organic extracts were combined and dried over sodium sulphate and filtered. The filtrate was concentrated under reduced pressure to give the title compound (670 mg, 75%) as a yellow solid. LCMS RT = 0.250 min, m/z = 254.0 [M + H]+
^88S28[ Step 2: 5-(2-morpholinoethoxy)pyridin-2-amine
[8882^ A mixture of 4-[2-[(6-nitro-3-pyridyl)oxy]ethyl]morpholine (660 mg, 2.61 mmol), iron (727 mg, 13.03 mmol) and ammonium chloride (697 mg, 13.03 mmol) in water (1 mL) and ethyl alcohol (3 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 60 °C for 1 hour under nitrogen atmosphere. The reaction mixture extracted with ethyl acetate (20 mL x 3). The organic phases were washed with brine (100 mL). The organic extracts were combined and dried over sodium sulphate and filtered. The filtrate was concentrated under reduced pressure to give the title compound 5-(2-morpholinoethoxy)pyridin-2-amine (350 mg, 60%) as a yellow solid. LCMS RT = 0.350 min, m/z = 224.0 [M + H]+
[88822^ Step 3: 6-(2,6-dichlorophenyl)-8-methyl-2-((5-(2-morpholinoethoxy)pyridin-2- yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one
[00823 [ A mixture of 5-(2-morpholinoethoxy)pyridin-2-amine (200 mg, 0.89 mmol), 2-chloro-6-(2,6- dichlorophenyl)-8-methyl-pyrido[2,3-d]pyrimidin-7-one (305 mg, 0.89 mmol) and potassium fluoride (156 mg, 2.69 mmol) in N-methylpyrrolidone (2 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 100 °C for 12 hour under nitrogen atmosphere. The mixture was fdtered. The residue was purified by RP-HPLC (37 to 62% acetonitrile in water and 10 mM ammonium bicarbonate) to give the title compound (2 mg, 1%) as a white solid. rH NMR (400 MHz, DMSO-t/g) 8 10.31 (s, 1H), 8.87 (s, 1H), 8.22-8.20 (m, 1H), 8.10-8.09 (m, 1H), 7.93 (s, 1H), 7.61-7.59 (m, 2H), 7.55- 7.52 (m, 1H), 7.49-7.45 (m, 1H), 4.20-4.15 (m, 2H), 4.18 (s, 3H), 3.65-3.50 (m, 4H), 3.48-3.31 (m, 4H), 2.34-2.33 (m, 2H). LCMS RT = 2.076 min, m/z = 527.2[M + H]+
[< )824| Example 83. Synthesis of COMPOUND-518 Scheme 57.
Figure imgf000242_0001
COMPOUND-518
[88828] Step 1: tert-butyl N-[4-[(6-bromo-3-pyridyl)oxy]cyclohexyl]carbamate
[88827] A mixture of tert-butyl N-(4-hydroxycyclohexyl)carbamate (100 mg, 0.46 mmol), 6- bromopyridin-3-ol (81 mg, 0.46 mmol), TMAD (80 mg, 0.46 mmol) and /-BtnP (94 mg, 0.46 mmol) in toluene (5.0 mb) was degassed and purged with nitrogen for three times, then the reaction was stirred at 100 °C for 3 hours under nitrogen atmosphere. The mixture was concentrated under reduced pressure to remove toluene. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of gradient 0-50% ethyl acetate in petroleum ether; Flow rare: 50 mL/min) to afford tert-butyl N-[4-[(6-bromo-3-pyridyl)oxy]cyclohexyl]carbamate (100 mg, 37% yield) as light yellow oil. LCMS RT = 0.580 min, m/z = 372.8 [M + H]+.
[88828] Step 2: 2-[[5-(4-aminocyclohexoxy)-2-pyridyl]amino]-6-(2,6-dichlorophenyl)-8-methyl- pyrido[2,3-d]pyrimidin-7-one
[88829] A mixture of tert-butyl N-[4-[(6-bromo-3-pyridyl)oxy]cyclohexyl]carbamate (100 mg, 0.27 mmol), 2-amino-6-(2,6-dichlorophenyl)-8-methyl-pyrido[2,3-d]pyrimidin-7-one (87 mg, 0.27 mmol), Pd2(dba)3 (25 mg, 0.03 mmol), Xantphos (31 mg, 0.05 mmol) and sodium tert-butoxide (78 mg, 0.81 mmol) in dioxane (5.0 m ) was degassed and purged with nitrogen for three times, then the reaction was stirred at 130 °C for 3 hours under nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of gradient 0-100% ethyl acetate in petroleum ether; Flow rate: 50 mL/min) and RP-HPLC {FA condition; Column: Xtimate C18 100*30mm* lOum; Mobile phase: [water (FA)-MeCN]; B%: 15 - 45; Gradient time: 10 min} to afford 2-[[5-(4-aminocyclohexoxy)-2-pyridyl]amino]-6-(2,6- dichlorophenyl)-8-methyl-pyrido[2,3-d]pyrimidin-7-one (5.7 mg) as white solid. ’H NMR (400 MHz, DMSO- tf) d 10.32 (brs, 1H), 8.87 (s, 1H), 8.40 (s, 1H), 8.22 (d, J= 8.8 Hz, 1H), 8.08 (s, 1H), 7.93 (s, 1H), 7.60 (d, J= 8.0 Hz, 2H), 7.58-7.54 (m, 1H), 7.53-7.46 (m, 1H), 4.59 (s, 1H), 3.66 (s, 3H), 3.00 (s, 1H), 1.98-1.93 (m, 2H), 1.71-1.60 (m, 6H). LCMS RT = 1.813 min, m/z = 511.2 [M + H]+.
[ 88838] Example 84. Synthesis of COMPOUND-519
[88831] Scheme 58.
Figure imgf000243_0001
[80832] Step 1: tert-butyl N-[l-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-hydroxy-ethyl]carbamate [80833] To a solution of tert-butyl N-[2-hydroxy-l-(hydroxymethyl)ethyl]carbamate (500 mg, 2.61 mmol) in tetrahydrofuran (5.0 mL) was added sodium hydride (105 mg, 2.61 mmol, 60% purity) at 0°C. After stirring at 0 °C for 0.5 hour, TBSC1 (394 mg, 2.61 mmol) was added and the reaction was stirred at 0~20 °C for 1 hour. The mixture was quenched by water (10 mL) at 0 °C and extracted with ethyl acetate (20 mL * 3). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl N-[l-[[tert-butyl(dimethyl)silyl]oxymethyl]-2- hydroxy-ethyl] carbamate (760 mg, 86% yield) as a colorless oil, which would be used directly in the next step without purification. rH NMR (400 MHz, DMSO- c) 5 = 6.30 (d, J= 7.6 Hz, 1H), 4.56-4.50 (m, 1H), 3.58-3.52 (m, 1H), 3.50-3.40 (m, 2H), 3.38-3.35 (m, 2H), 1.37 (s, 9H), 0.85 (s, 9H), 0.02 (s, 6H).
[88834] Step 2: tert-butyl N-[l-[(6-bromo-3-pyridyl)oxymethyl]-2-[tert-butyl(dimethyl)silyl]oxy- ethyl]carbamate
[88835] To a solution of tert-butyl N-[l-[[tert-butyl(dimethyl)silyl]oxymethyl]-2 -hydroxy- ethyl] carbamate (200 mg, 0.65 mmol) and 6-bromopyridin-3-ol (68 mg, 0.39 mmol) in toluene (5 mL) were added TMAD (169 mg, 0.98 mmol) and /-Bu-P (265 mg, 1.31 mmol). The reaction was stirred at 100 °C for 3 hours. After cooling, the mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of gradient 0-50% ethyl acetate in petroleum ether; Flow rate: 50 mL/min) to afford tert-butyl N-[l-[(6- bromo-3-pyridyl)oxymethyl]-2-[tert-butyl(dimethyl)silyl]oxy-ethyl]carbamate (280 mg, 57% yield) as a light yellow oil. LCMS RT = 0.679 min, m/z = 462.7 [M + H]+.
[88836] Step 3: tert-butyl N-[l-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-[[6-[[6-(2,6-dichlorophenyl)- 8-methyl-7-oxopyrido[2,3-d]pyrimidin-2-yl]amino]-3-pyridyl]oxy]ethyl]carbamate
[88837] A mixture of tert-butyl N-[ l-[(6-bromo-3-pyridyl)oxymethyl]-2-[tert-butyl(dimethyl)silyl]oxy- ethyl] carbamate (280 mg, 0.38 mmol), 2-amino-6-(2,6-dichlorophenyl)-8-methyl-pyrido[2,3- d]pyrimidin-7-one (121 mg, 0.38 mmol), Pd2(dba)i (34 mg, 0.04 mmol), Xantphos (44 mg, 0.08 mmol) and sodium tert-butoxide (108 mg, 1.13 mmol) in dioxane (5.0 mL) was degassed and purged with nitrogen for three times, then the reaction was stirred at 130 °C for 3 hours under nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of gradient 0-100% ethyl acetate in petroleum ether gradient; Flow rate: 50 mL/min) to afford tert-butyl N-[ 1 -[[tert- butyl(dimethyl)silyl]oxymethyl]-2-[[6-[[6-(2,6-dichlorophenyl)-8-methyl-7-oxopyrido[2,3-d]pyrimidin- 2-yl]amino]-3-pyridyl]oxy]ethyl]carbamate (140 mg, 18% yield) as a light yellow solid. LCMS RT = 0.622 min, m/z = 701.3 [M + H]+.
Figure imgf000244_0001
[88839] A solution of tert-butyl N-[l-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-[[6-[[6-(2,6- dichlorophenyl)-8-methyl-7-oxopyrido[2,3-d]pyrimidin-2-yl]amino]-3-pyridyl]oxy] ethyl] carbamate (140 mg, 0.20 mmol) in 4M HCl/EtOAc (5.0 mL) was stirred at 20 °C for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by RP-HPLC {HC1 condition; Column: Welch Xtimate C18 150*30mm*5um; Mobile phase: [water (HCl)-MeCN]; B%: 5 - 30;
Gradient time: 10 min} to afford 2-[[5-(2-amino-3-hydroxy-propoxy)-2-pyridyl]amino]-6-(2,6- dichlorophenyl)-8-methyl-pyrido[2,3-d]pyrimidin-7-one (21 mg, 20% yield) as a white solid. ’H NMR (400 MHz, DMSO- tf) 5 = 10.50 (s, 1H), 8.89 (s, 1H), 8.23-8.10 (m, 5H), 7.96 (s, 1H), 7.62-7.55 (m, 3H), 7.50-7.45 (m, 1H), 4.30-4.25 (m, 1H), 4.21-4.15 (m, 1H), 3.69-3.65 (m, 2H), 3.65-3.63 (m, 4H). LCMS RT = 1.626 min, m/z = 487.2 [M + H]+.
[88848] Example 85. Synthesis of COMPOUND-520 ] (8)841] Scheme 59.
Figure imgf000244_0002
A mixture of tert-butyl N-[(lR,3S)-3-hydroxycyclopentyl]carbamate (100 mg, 0.50 mmol), 6- bromopyridin-3-ol (86 mg, 0.50 mmol), TMAD (128 mg, 0.75 mmol), /-Bt P (201 mg, 0.99 mmol) in toluene (5.0 mL) was degassed and purged with nitrogen for 3 times, then the reaction was stirred at 100 °C for 3 hours under nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of gradient 0-50% ethyl acetate in petroleum ether; Gradient time: 50 mL/min) to afford the title compound (170 mg, 43%) as a yellow oil. LCMS RT = 0.555 min, m/z = 359.0 [M + H]+.
[80844] Step 2: tert-butyl N-[(lR,3R)-3-[[6-[[6-(2,6-dichlorophenyl)-8-methyl-7-oxo-pyrido[2,3- d]pyrimidin-2-yl]amino]- 3-pyridyl]oxy]cyclopentyl]carbamate
[80845] A mixture of tert-butyl N-[(lR,3R)-3-[(6-bromo-3-pyridyl)oxy]cyclopentyl]carbamate (170 mg, 0.21 mmol), 2-amino-6-(2.6-dichlorophcnyl)-8-mcthyl-pyrido|2.3-t/|pyrimidin-7-onc (69 mg, 0.21 mmol), Pd2(dba)3 (20 mg, 0.02 mmol), Xantphos (25 mg, 0.04 mmol) and sodium tert-butoxide (62 mg, 0.64 mmol) in dioxane (5.0 mL) was degassed and purged with nitrogen for 3 times, then the reaction was stirred at 130 °C for 3 hours under microwave under nitrogen atmosphere. The mixture was filtered to remove insoluble solid and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of gradient 0-50% ethyl acetate in petroleum ether; Flow rate: 50 mL/min) to afford the title compound (90 mg, 23%) as a light brown solid. LCMS RT = 0.537 min, m/z =597.2.0 [M + H]+.
Figure imgf000245_0001
[00847[ A solution of tert-butyl N-[(lR,3R)-3-[[6-[[6-(2,6-dichlorophenyl)-8-methyl-7-oxo-pyrido[2,3- d]pyrimidin-2-yl]amino]-3-pyridyl]oxy]cyclopentyl]carbamate (90 mg, 0.15 mmol) in 4M HCl/EtOAc (3.0 mL) was stirred at 20 °C for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by RP-HPLC {HC1 condition; Column: Welch Xtimate C18 150*30mm*5um;
Mobile phase: [water (HCl)-MeCN]; B%: 0 ~ 50; Gradient time: lOrnin} to afford the title compound (39.60 mg) as a white solid. LCMS RT = 1.773 min, m/z = 497.2 [M + H]+. ’H NMR (400 MHz, DMSO- d6) 5 = 10.50 (s, 1H), 8.89 (s, 1H), 8.18 (d, J= 9.2 Hz, 1H), 8.11-7.90 (m, 4H), 7.65-7.40 (m, 4H),5.00 (s, 1H), 3.75-3.61 (m, 4H), 2.26-2.13 (m, 3H), 2.12-2.00 (m, 1H), 1.99-1.64 (m, 2H).
[ 00848 [ Example 86. Synthesis of COMPOUND-521
[80849] Scheme 60.
Figure imgf000245_0002
[80858] Step 1: tert-butyl N-[(3S,4R)-4-[(6-bromo-3-pyridyl)oxy]tetrahydrofuran-3-yl]carbamate [80831] A mixture of tert-butyl N-[(3S,4R)-4-hydroxytetrahydrofuran-3-yl]carbamate (100 mg, 0.49 mmol), 6-bromopyridin-3-ol (86 mg, 0.49 mmol), TMAD (127 mg, 0.74 mmol) , /-Bii,P (199 mg, 0.98 mmol) in toluene (5.0 mL) was degassed and purged with nitrogen for 3 times, then the reaction was stirred at 100 °C for 3 hours under nitrogen atmosphere. The mixture was concentrated under reduced pressure to remove toluene. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of gradient 0-50% ethyl acetate in petroleum ether; Flow rate: 50 mL/min) to afford the title compound (160 mg, 54%) as a light yellow oil. LCMS RT = 0.508 min, m/z = 359.0 [M + H]+.
[88832] Step 2: tert-butyl N-[(3S,4S)-4-[[6-[[6-(2,6-dichlorophenyl)-8-methyl-7-oxo-pyri do[2,3- d]pyrimidin-2-yl]amino]-3-pyridyl]oxy]tetrahydrofuran-3-yl]carbamate
[88853] A mixture of tert-butyl N-[(3S,4S)-4-[(6-bromo-3-pyridyl)oxy]tetrahydrofuran-3-yl]carbamate (160 mg, 0.27 mmol), 2-amino-6-(2,6-dichlorophenyl)-8-methyl-pyrido[2,3-d]pyrimidin-7-one (86 mg, 0.27mmol), Pd2(dba)3 (24 mg, 0.03 mmol), Xantphos (31 mg, 0.05 mmol) and sodium tert-butoxide (77 mg, 0.80 mmol) in dioxane (5 mL) was degassed and purged with nitrogen for 3 times, then the reaction was stirred at 130 °C for 3 hours under microwave under nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of gradient 0-50% ethyl acetate in petroleum ether; Flow rate: 50 mL/min) to afford the title compound (80 mg, 26.97%) as a light brown solid. LCMS RT = 0.512 min, m/z =599.2 [M + H]+.
[86834] Step 3: 2-[[5-[(3S,4S)-4-aminotetrahydrofuran-3-yl]oxy-2-pyridyl]amino]-6-(2,6- dichlorophenyl)-8-methyl pyrido[2,3-d]pyrimidin-7-one
[88855] A solution of tert-butyl N-[(3S,4S)-4-[[6-[[6-(2,6-dichlorophenyl)-8-methyl-7-oxo-pyrido[2,3- d]pyrimidin-2-yl]amino]-3-pyridyl]oxy]tetrahydrofuran-3-yl]carbamate (80 mg, 0.13 mmol) in 4M HCl/EtOAc (3.0 mL) was stirred at 20 °C for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by RP-HPLC {HC1 condition; Column: Welch Xtimate C18 150*30mm*5um; Mobile phase: [water (HCl)-MeCN]; B%: 5 - 38; Gradient time: lOrnin} to afford the title compound (15.7 mg) as a white solid. LCMS RT = 1.703 min, m/z =499.2 [M + H]+. 1H NMR (400 MHz, DMSO- tf) 5 = 10.60 (brs, 1H), 8.91 (s, 1H), 8.48 (d, J = 0.8 Hz, 3H), 8.51-8.15 (m, 2H), 7.97 (s, 1H), 7.75-7.62 (m, 1H), 7.60 (d, J= 8.0 Hz, 2H), 7.53-7.42 (m, 1H), 5.10 (s, 1H), 4.12-3.82 (m, 5H), 3.68 (s, 3H).
[88856] Example 87. Synthesis of COMPOUND-523
[80857] Scheme 61.
Figure imgf000246_0001
[88858] Step 1: tert-butyl N-[(lR,2S)-2-[(6-bromo-3-pyridyl)oxy]cyclopentyl]carbamate
[80859] To a solution of tert-butyl N-[(lR,2R)-2-hydroxycyclopentyl]carbamate (200 mg, 0.99 mmol) and 6-bromopyridin-3-ol (86 mg, 0.50 mmol) in toluene (5.0 mL) were added TMAD (257 mg, 1.49 mmol) and /-BtnP (402 mg, 1.99 mmol). The reaction mixture was stirred at 100 °C for 3 hours, cooled and diluted with water (10 mL), then extracted with ether ethyl acetate (10 mL * 2). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, gradient 0 - 100% ethyl acetate in petroleum) to afford the title compound (180 mg, 62%) as a yellow oil. LCMS RT = 0.575 min, m/z =358.6 [M + H]+.
[80868] Step 2: tert-butyl N-[(lR,2S)-2-[[6-[[6-(2,6-dichlorophenyl)-8-methyl-7-oxo-pyrido[2,3- d]pyrimidin-2-yl]amino]-3-pyridyl]oxy]cyclopentyl]carbamate
[88861] A mixture of tert-butyl N-[(lR,2S)-2-[(6-bromo-3-pyridyl)oxy]cyclopentyl]carbamate (180 mg, 0.31 mmol), 2-amino-6-(2,6-dichlorophenyl)-8-methyl-pyrido[2,3-d]pyrimidin-7-one (100 mg, 0.31 mmol), Pd2(dba)3 (29 mg, 0.03 mmol), Xantphos (36 mg, 0.06 mmol) and sodium tert-butoxide (90 mg, 0.94 mmol) in dioxane (5.0 mL) was degassed and purged with nitrogen for 3 times, then the reaction was stirred at 130 °C for 3 hours under microwave under nitrogen atmosphere. After cooling, the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, gradient 0 ~ 50% ethyl acetate in petroleum ether) to afford the title compound (120 mg, 80%) as a brown solid. LCMS RT = 0.551 min, m/z =598.8 [M + H]+.
[00802] Step 3: 2-[[5-[(lS,2R)-2-aminocyclopentoxy]-2-pyridyl]amino]-6-(2,6-dichlorophenyl)-8- methyl-pyrido[2,3-d]pyrimidin-7-one
[88863] A solution of tert-butyl N-[(lR,2S)-2-[[6-[[6-(2,6-dichlorophenyl)-8-methyl-7-oxo-pyrido[2,3- d]pyrimidin-2-yl]amino]-3-pyridyl]oxy]cyclopentyl]carbamate (120 mg, 0.16 mmol) in 4M HCl/EtOAc (3.0 mL) was stirred at 20 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to remove dioxane. The residue was purified by RP-HPLC {HC1 condition; Column: Welch Xtimate C18 150*30mm*5um; Mobile phase: [water (HCl)-MeCN]; B%: 0 ~ 50%; Gradient time: 10 min) to afford the title compound (55.6 mg, 64%) as a white solid. LCMS RT = 1.591 min, m/z = 497.3 [M + H]+. rH NMR (400 MHz, DMSO-tL) 5 = 10.92 (brs, 1H), 8.95 (s, 1H), 8.34 (d, J= 3.6 Hz, 3H), 8.19 (d, J= 3.2 Hz, 1H), 8.12 (d, J = 9.2 Hz, 1H), 8.01 (s, 1H), 7.85-7.65 (m, 1H), 7.60 (d, J= 7.6 Hz, 2H), 7.55-7.42 (m, 1H), 4.84 (s, 1H), 3.68 (s, 4H), 2.11-1.95 (m, 2H), 1.91-1.60 (m, 4H).
[00864] Example 88. Synthesis of COMPOUND-524
[00865] Scheme 62.
Figure imgf000247_0001
[08866] Step 1: tert-butyl 4-[(6-bromo-3-pyridyl)oxy]-3-fluoro-piperidine-l-carboxylate
[88867] To a solution of tert-butyl 3 -fluoro-4-hydroxy-piperidine-l -carboxylate (100 mg, 0.46 mmol) in toluene (7.0 mL) were added 6-bromopyridin-3-ol (79 mg, 0.46 mmol), TMAD (118 mg, 0.68 mmol) and /-Bii.P (92 mg, 0.46 mmol). The reaction was stirred at 100 °C for 1 hour. After cooling, the mixture was diluted with water (4.0 mL) and extracted with ethyl acetate (4.0 mL * 3). The combined extracts were washed with brine (5.0 mL), dried over sodium sulfate and concentrated. The residue was purified by column chromatography (silica gel, 100-200 mesh, gradient 0-30% ethyl acetate in petroleum ether gradient) to afford the title compound (117 mg, 68% yield) as a colorless oil. LCMS RT = 1.610 min, m/z = 377.0 [M + H]+.
[88868] Step 2: tert-butyl 4-[[6-[[6-(2,6-dichlorophenyl)-8-methyl-7-oxo-pyrido[2,3-d]pyrimidin-2- yl]amino]-3-pyridyl]oxy]-3-fluoro-piperidine-l-carboxylate
[00869] To a solution of tert-butyl 4-[(6-bromo-3-pyridyl)oxy]-3-fluoro-piperidine-l-carboxylate (117 mg, 0.31 mmol) in dioxane (5.0 mL) were added 2-amino-6-(2,6-dichlorophenyl)-8-methyl-pyrido[2,3- d]pyrimidin-7-one (100 mg, 0.31 mmol), sodium tert-butoxide (75 mg, 0.78 mmol), Xantphos (36 mg, 0.06 mmol) and Pd2(dba)3 (29 mg, 0.03 mmol). The reaction was stirred at 95 °C for 6 hours under nitrogen atmosphere. After cooling, the mixture was diluted with water (4.0 mL) and extracted with ethyl acetate (4.0 mL * 3). The combined extracts were washed with brine (5.0 mb), dried over sodium sulfate, fdtered and concentrated. The residue was purified by column chromatography (silica gel, 100-200 mesh, gradient 0-8% methanol in dichloromethane) to afford the title compound (175 mg, 91% yield) as a white solid. LCMS RT = 0.548 min, m/z = 615.3 [M + H]+.
[88878] Step 3: 6-(2,6-dichlorophenyl)-2-[[5-[(3-fluoro-4-piperidyl)oxy]-2-pyridyl]amino]-8-methyl- pyrido[2,3-d]pyrimidin-7-one
[0 871] To a solution of tert-butyl 4-[[6-[[6-(2,6-dichlorophenyl)-8-methyl-7-oxo-pyrido[2,3- d]pyrimidin-2-yl]amino]-3-pyridyl]oxy]-3-fluoro-piperidine-l-carboxylate (175 mg, 0.28 mmol) in dioxane (3.0 mL) was added 4M HCl/dioxane (3.0 mL). The mixture was stirred at 20 °C for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by RP-HPLC [gradient 12-42% of MeCN in water (0.225% FA)] to afford the title compound (39 mg, 25% yield) as a white solid. ’H NMR (400 MHz, DMSO-t/tf) 5 = 10.35 (s, 1H), 8.87 (s, 1H), 8.27-8.17 (m, 2H), 8.13 (d, J = 2.8 Hz, 1H), 7.93 (s, 1H), 7.59 (d, J= 7.6 Hz, 3H), 7.51-7.42 (m, 1H), 4.61-4.43 (m, 2H), 3.67 (s, 3H), 3.24-3.20 (m, 1H), 2.90-2.83 (m, 1H), 2.66-2.53 (m, 3H), 2.15-2.06 (m, 1H), 1.46 (d, J= 10.4 Hz, 1H). LCMS RT = 1.153 min, m/z = 515.3 [M + H]+.
[88872] Example 89. Synthesis of COMPOUND-525 [88873] Scheme 63.
Figure imgf000248_0001
[88874] Step 1: tert-butyl 4-[(6-bromo-3-pyridyl)oxy]-3-fluoro-piperidine-l-carboxylate
[08875] To a solution of tert-butyl /ram-3-fluoro-4-hydroxy-pipcridinc- 1 -carboxylate (100 mg, 0.46 mmol) in toluene (7.0 mL) were added 6-bromopyridin-3-ol (79 mg, 0.46 mmol), TMAD (118 mg, 0.68 mmol) and /-BtnP (92 mg, 0.46 mmol). The reaction was stirred at 100 °C for 1 hour. After cooling, the mixture was diluted with water (4.0 mL) and extracted with ethyl acetate (4.0 mL * 3). The combined extracts were washed with brine (5.0 mL), dried over sodium sulfate and concentrated. The residue was purified by column chromatography (silica gel, 100-200 mesh, gradient 0-29% ethyl acetate in petroleum ether) to afford the title compound (109 mg, 63% yield) as a colorless oil. LCMS RT = 1.607 min, m/z = 374.9 [M + H]+
[88876] Step 2: tert-butyl 4-[[6-[[6-(2,6-dichlorophenyl)-8-methyl-7-oxo-pyrido[2,3-d]pyrimidin-2- yl]amino]-3-pyridyl]oxy]-3-fluoro-piperidine-l-carboxylate
|00877] To a solution of tert-butyl traws-4-[(6-bromo-3-pyridyl)oxy]-3-fluoro-piperidine-l-carboxylate (117 mg, 0.31 mmol) in dioxane (5.0 mL) were added 2-amino-6-(2,6-dichlorophenyl)-8-methyl- pyrido[2,3-d]pyrimidin-7-one (100 mg, 0.31 mmol), sodium tert-butanol (75 mg, 0.78 mmol), Xantphos (36 mg, 0.06 mmol) and Pd2(dba)i (29 mg, 0.03 mmol). The reaction was stirred at 95 °C for 6 hours under nitrogen atmosphere. After cooling, the mixture was diluted with water (4.0 mL) and extracted with ethyl acetate (4.0 mL * 3). The combined extracts were washed with brine (5.0 mL), dried over sodium sulfate, fdtered and concentrated. The residue was purified by column chromatography (silica gel, 100-200 mesh, gradient 0-7% methanol in dichloromethane) to afford the title compound (162 mg, 90% yield) as a white solid. LCMS RT = 0.552 min, m/z = 615.3 [M + H]+.
[ 0878] Step 3: 6-(2,6-dichlorophenyl)-2-[[5-[(3-fluoro-4-piperidyl)oxy]-2-pyridyl]amino]-8-methyl- pyrido[2,3-d]pyrimidin-7-one
[C 879] To a solution of tert-butyl /ram-4-| |6-| |6-(2.6-dichlorophcnyl)-8-mcthyl-7-oxo-pyrido|2.3- d]pyrimidin-2-yl]amino]-3-pyridyl]oxy]-3-fluoro-piperidine-l-carboxylate (175 mg, 0.28 mmol) in dioxane (3.0 mL) was added 4M HCl/dioxane (3.0 mL). The reaction mixture was stirred at 20 °C for 1 hour, and then concentrated under reduced pressure. The residue was and purified by RP-HPLC [gradient 12-42% MeCN in water (0.225% FA)] to afford the title compound (37 mg, 23% yield) as a white solid.
1 H NMR (400 MHz, DMSO-t/tf) 5 = 10.35 (brs, 1H), 8.87 (s, 1H), 8.27-8. 10 (m, 3H), 7.93 (s, 1H), 7.59 (d, J= 7.6 Hz, 3H), 7.52-7.43 (m, 1H), 4.61-4.44 (m, 2H), 3.67 (s, 3H), 3.21 (d, J= 5.6 Hz, 1H), 2.87 (d, J= 2.8 Hz, 1H), 2.67-2.53 (m, 3H), 2.15-2.07 (m, 1H), 1.52-1.40 (m, 1H). LCMS RT = 1.153 min, m/z = 515.4 [M + H]+.
[ 80] Example 90. Synthesis of COMPOUND-528
[00881] Scheme 64.
Figure imgf000249_0001
[00882] Step 1: (3-methoxy-2,6-dimethylphenyl)boronic acid
[00883] To a solution of 3 -bromo- 1 -methoxy -2, 4-dimethyl-benzene (1.0 g, 4.18 mmol) in tetrahydrofuran (10 mL) was added dropwise n-BuLi (2.5 M, 1.84 mL) at -65 °C. After 30 minutes’ stirring, trimethyl borate (610 mg, 5.86 mmol) was added at -65 °C, and the mixture was allowed to warm to 20 °C gradually within 2 hours. The reaction mixture is quenched by 3M hydrochloric acid and adjusted to pH = 4, then partitioned between ethyl acetate (5.0 mL) and water (5.0 mL). The organic phase was washed with saturated brine (2.0 mL), dried with anhydrous sodium sulfate, filtered and concentrated to afford the title compound (800 mg, 85%) as a colorless oil, which would be used directly in the next step. ’H NMR (400 MHz, CDCh) d = 6.98 (d, 1H), 6.75 (d, 1H), 4.64 (brs, 2H), 3.80 (s, 3 H), 2.27 (s, 3H), 2.22 (s, 3H).
[80884] Step 2: 6-(3-methoxy-2,6-dimethylphenyl)-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin- 7(8H)-one [8888S] To a mixture of 3-methoxy-2,6-dimethyl-phenyl)boronic acid (740 mg, 4.11 mmol) in dioxane (10 mL) and water (1.0 mL) were added 6-bromo-8-methyl-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7- one (470 mg, 1.64 mmol), potassium phosphate (680 mg, 4.93 mmol), Sphos (135 mg, 0.33 mmol) and Pd2(dba)3 (1 0 mg, 0.16 mmol). The mixture was stirred at 95 °C under nitrogen atmosphere for 4 hours. After cooling, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, gradient 0-10% ethyl acetate in petroleum ether) to afford the title compound (350 mg, 56%) as a yellow solid. LCMS RT = 0.578 min, m/z = 342.0 [M+H]+.
[88886] Step 3: 6-(3-methoxy-2,6-dimethylphenyl)-8-methyl-2-(methylsulfonyl)pyrido[2,3- djpyrimidin- 7(8H)-one
[80887] To a solution of 6-(3-methoxy-2,6-dimethyl-phenyl)-8-methyl-2-methylsulfanyl-pyrido[2,3- d]pyrimidin-7-one (250 mg, 0.73 mmol) in dichloromethane (3.0 mL) was added 3- chlorobenzenecarboperoxoic acid (380 mg, 1.54 mmol) in portions. The reaction mixture was stirred at 0-20 °C for 2 hours, and then filtered to remove the insoluble solid. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, gradient 0-40% ethyl acetate in petroleum ether) to afford the title compound (150 mg, 52%) as a yellow solid. LCMS RT = 0.500 min, m/z = 374. 1 [M+H]+.
[00888 [ Step 4: 6-(3-methoxy-2,6-dimethylphenyl)-8-methyl-2-(pyridin-2-ylamino)pyrido[2,3- djpyrimidin- 7(8H)-one
[00889] To a solution of 6-(3-methoxy-2,6-dimethyl-phenyl)-8-methyl-2-methylsulfonyl-pyrido[2,3- d]pyrimidin-7-one (110 mg, 0.3 mmol) in dimethyl sulfoxide (1.0 mL) were added pyridin-2 -amine (55 mg, 0.59 mmol) and potassium tert-butoxide (70 mg, 0.59 mmol). The reaction mixture was stirred at 20 °C for 2 hours, quenched by water (30 mL) and extracted withed ethyl acetate (15 mL * 2). The combined extracts was washed with brine (20 mL * 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, gradient 0-40% ethyl acetate in petroleum ether) to afford the title compound (100 mg, 80%) as a yellow solid. LCMS RT = 0.459 min, m/z = 388.2 [M+H]+.
[00898] Step 5: 6-(3-hydroxy-2,6-dimethylphenyl)-8-methyl-2-(pyridin-2-ylamino)pyrido[2,3- djpyrimidin- 7(8H)-one
[09891] To a solution of 6-(3-methoxy-2,6-dimethyl-phenyl)-8-methyl-2-(2-pyridylamino)pyrido[2,3- d]pyrimidin-7-one (80 mg, 0.2 mmol) in dichloromethane (3.0 mL) was added dropwise tribromoborane (520 mg, 2.06 mmol) at 0 °C. The reaction mixture was stirred at 0-20 °C for 16 hours, quenched by IM hydrochloric acid (0.50 mL) and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by RP-HPLC [gradient 10 - 24% acetonitrile in water (0.225% formic acid)] to give the title compound (3.7 mg) as a colorless solid. rH NMR (400 MHz, DMS0-< ) 5 = 10.29 (brs, 1H), 9.14 (s, 1H), 8.84 (s, 1H), 8.38-8.31 (m, 2H), 7.88-7.81 (m, 1H), 7.68 (s, 1H), 7.07 (s, 1H), 6.89 (s, 1H), 6.74-6.71 (d, J= 8.0 Hz, 1H), 3.68 (s, 3H), 1.93 (s, 3H), 1.86 (s, 3H). LCMS RT = 0.864 min, m/z = 333.3 [M + H]+. Example 91. Synthesis of COMPOUND-529
Figure imgf000251_0001
](8)894] Step 1: tert-butyl 4-(2-(3-bromophenoxy)ethyl)piperazine-l-carboxylate
[80895] To a solution of 3 -bromophenol (300 mg, 1.73 mmol) in toluene (8.0 ml) were added tertbutyl 4-(2-hydroxyethyl)piperazine- 1 -carboxylate (400 mg, 1.73 mmol), TMAD (450 mg, 2.60 mmol) and /-Bu.P (700 mg, 3.47 mmol). The reaction was stirred at 100 °C for 1 hour. After cooling, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, gradient 0-30% ethyl acetate in petroleum ether) to afford the title compound (380 mg, 51%) as a yellow oil. LCMS RT = 0.472 min, m/z = 387. 1 [M+H]+.
[88896] Step 2: tert-butyl 4-(2-(3-((6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydro pyrido[2,3- d]pyrimidin-2-yl)amino)phenoxy)ethyl)piperazine-l-carboxylate
[88897] To a solution of 2-amino-6-(2,6-dichlorophenyl)-8-methyl-pyrido[2,3-d]pyrimidin-7-one (60 mg, 0.19 mmol) in dioxane (4.0 mL) were added tert-butyl 4-[2-(3-bromophenoxy)ethyl]piperazine-l- carboxylate (80 mg, 0.2 mmol), sodium t-butoxide (50 mg, 0.52 mmol), Xantphos (25 mg, 0.04 mmol) and Pdildbafi (20 mg, 0.02 mmol). The reaction was stirred at 95 °C for 3 hours under reduced pressure. After cooling, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, gradient 0-5% methanol in dichloromethane) to afford the title compound (120 mg, 65%) as a yellow solid. LCMS RT = 1.338 min, m/z = 625.4 [M+H]+.
[88898] Step 3: 6-(2,6-dichlorophenyl)-8-methyl-2-((3-(2-(piperazin-l- yl)ethoxy)phenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one
[88899] A solution of tert-butyl 4-[2-[4-[[6-(2,6-dichlorophenyl)-8-methyl-7-oxo-pyrido[2,3- d]pyrimidin-2-yl]amino]phenoxy]ethyl]piperazine-l-carboxylate (120 mg, 0.19 mmol) in 4M HCl/dioxane (4.0 mL) was stirred at 20 °C for 1 hour, and then concentrated under reduced pressure. The residue was purified by RP-HPLC [gradient 10 - 40% acetonitrile in water (0.225% formic acid)] to give the title compound (33.5 mg) as a yellow solid. rH NMR (400 MHz, DMSO- c) 5 = 10.24 (brs, 1H), 8.86 (s, 1H), 8.33 (s, 1H), 7.92 (s, 1H), 7.63-7.58 (m, 3H), 7.49-7.45 (m, 1H), 7.36 (d, J= 8.0 Hz, 1H), 7.24 (t, J= 8.0 Hz, 1H), 6.56 (d, J= 8.0 Hz, 1H), 4.11 (t, J= 5.6 Hz, 2H), 3.68 (s, 3H), 2.83 (s, 4H), 2.72 (t, J = 5.6 Hz, 2H), 2.53 (s, 4H). LCMS RT = 1.213 min, m/z = 525.4 [M + H]+.
[00999] Example 92. Synthesis of COMPOUND-530
Figure imgf000252_0001
[90902] Step 1: tert-butyl 4-[2-[(2-bromo-4-pyridyl)oxy]ethyl]piperazine-l-carboxylate
[99903] To a solution of tert-butyl 4-(2-hydroxyethyl)piperazine-l -carboxylate (654 mg, 2.84 mmol) in tetrahydrofuran (5.0 m ) was added sodium hydride (227 mg, 5.68 mmol, 60% dispersion in mineral oil) at 0 °C, and the resulting mixture was stirred at 0 °C for 30 minutes, followed by the addition of 2- bromo-4-fluoro-pyridine (500 mg, 2.84 mmol) at 0 °C. The reaction stirred at 60 °C for 1.5 hour, cooled and quenched by saturated ammonium chloride solution (20 m ), then extracted with ethyl acetate (10 mb * 3). The combined extracts were washed with brine (10 mb), dried over anhydrous sodium sulfate, fdtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Biotage®; 12 g Sepaflash® silica flash column, eluent of gradient 0-95% ethyl acetate in petroleum ether; Flow rate: 40 mL/min). LCMS RT = 0.418 min, m/z = 387.9 [M + H]+.
[90904] Step 2: tert-butyl 4-[2-[[2-[[6-(2,6-dichlorophenyl)-8-methyl-7-oxo-pyrido[2,3-d]pyrimidin-2- yl]amino]-4-pyridyl]oxy]ethyl]piperazine-l -carboxylate
[00995] To a solution of 2-amino-6-(2,6-dichlorophenyl)-8-methyl-pyrido[2,3-d]pyrimidin-7-one (166 mg, 0.52 mmol) in dioxane (1.0 mL) were added tert-butyl 4-[2-[(2-bromo-4- pyridyl)oxy]ethyl]piperazine-l -carboxylate (200 mg, 518 mmol), Pd2(dba)i (47 mg, 0.05 mmol), Xantphos (60 mg, 0.10 mmol) and cesium carbonate (506 mg, 1.55 mmol) at 20 °C, then the mixture was stirred at 100 °C for 2 hours under nitrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Biotage®; 4 g Sepaflash® silica flash column, eluent of gradient 0-20% ethyl acetate in petroleum ether; Flow rate: 20 mL/min) to afford the title compound (300 mg) as a yellow solid. LCMS RT = 1.068 min, m/z = 626.1 [M + H]+.
[00995] Step 3: -(2,6-dichlorophenyl)-8-methyl-2-[[4-(2-piperazin-l-ylethoxy)-2- pyridyl]amino]pyrido[2,3-d]pyrimidin-7-one
[99907] A mixture of tert-butyl 4-[2-[[2-[[6-(2,6-dichlorophenyl)-8-methyl-7-oxo-pyrido[2,3- d]pyrimidin-2-yl]amino]-4-pyridyl]oxy]ethyl]piperazine-l-carboxylate (200 mg, 0.32 mmol) in 4M HCl/dioxane (40 mL) was stirred at 15 °C for 1 hour, and then concentrated under reduced pressure. The residue was purified by RP-HPLC [gradient 12 - 42% MeCN in water (0.225% FA)] to afford the title compound (39 mg, 25% yield) as a white solid. rH NMR (400 MHz, CD3OD) 5 = 9.11 (s, 1H), 8.38 (d, J = 7.2 Hz, 1H), 8.05 (s, 1H), 7.59 (d, J= 7.6 Hz, 2H), 7.51-7.42 (m, 1H), 7.35-7.26 (m, 1H), 7.08 (d, J= 2.4 Hz, 1H), 4.75 (s, 2H), 3.85 (s, 3H), 3.76 (s, 2H), 3.68 (s, 8H). LCMS RT = 0.897 min, m/z = 526.4 [M + H]+. Example 93. Synthesis of COMPOUND-534
Figure imgf000253_0004
Scheme 67.
Figure imgf000253_0001
Step 1: 3-bromo-l-methoxy-2,4-dimethyl-benzene To a mixture of hydrogen bromide (48% aqueous, 100 mL) and tetrahydrofuran (200 mL) were
Figure imgf000253_0002
added lithium bromide (37.3 g, 429.88 mmol) and cuprous bromide (75.9 g, 529.08 mmol), followed by a solution of sodium nitrite (33.1 g, 479.48 mmol) in water (80 mL) dropwise and 3-methoxy-2,6- dimethyl-aniline (10.0 g, 66.14 mmol) in portions at 0 °C. The reaction mixture was stirred at 20°C for 1 hour under nitrogen atmosphere, then diluted with water (200 mL) and extracted with ethyl acetate (200 mL * 3). The combined extracts were washed with brine (200 * 2 mL), dried over sodium sulfate, fdtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, gradient 0 ~ 5% ethyl acetate in petroleum) to afford the title compound (7.0 g, 49%) as a colorless oil. ’H NMR (400 MHz, DMSO-tL) b 7.14 (t, J= 8.0 Hz, 1H), 6.88 (t, J= 8.0 Hz, 1H), 3.76 (s, 3H), 2.28 (s, 3H), 2.24 (s, 3H).
(G8912] Step 2: 3-bromo-2,4-dimethyl-phenol
Figure imgf000253_0003
[ ] To a solution of 3 -bromo- 1 -methoxy -2, 4-dimethyl-benzene (1.0 g, 4.65 mmol) in dichloromethane (10 mL) was added boron tribromide (1 M solution, 11.62 mL) dropwise at 0°C. The reaction mixture was stirred at 20 °C for 1 hour, then quenched by water (30 mL) and extracted with ethyl acetate (30 mL * 3). The combined extracts were washed with brine (30 mL * 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound (570 mg) as a white solid, which would be used directly in the next step. ’H NMR (400 MHz, DMSO-t/r,) b 9.55 (s, 1H), 6.97 (d, J= 8.4 Hz, 1H), 6.72 (d, J= 8.4 Hz, 1H), 2.24 (s, 3H), 2.21 (s, 3H). Step 3: (3-bromo-2,4-dimethyl-phenoxy)-tert-butyl-dimethyl-silane
Figure imgf000253_0005
[88935] To a solution of 3 -bromo-2,4-dimethyl -phenol (500 mg, 2.49 mmol) in dichloromethane (10 mL) were added tert-butyl-dimethylsilyl chloride (750 mg, 4.97 mmol) and imidazole (508 mg, 7.46 mmol). The mixture was stirred at 20 °C for 1 hour under nitrogen atmosphere, then quenched by water (30 mL) and extracted with ethyl acetate (30 mL * 3). The combined extracts were washed with brine (30 mL * 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, gradient 0 ~ 5% ethyl acetate in petroleum) to afford the title compound (755 mg, 96%) as a colorless oil. rH NMR (400 MHz, DMSO- tf) 3 6.89 (d, J= 8.0 Hz, 1H), 6.57 (d, J= 8.4 Hz, 1H), 2.09 (s, 3H), 2.06 (s, 3H), 0.79 (s, 9H), 0.00 (s, 6H).
Figure imgf000254_0001
[88917] To a solution of (3-bromo-2,4-dimethyl-phenoxy)-tert-butyl-dimethyl-silane (1.5 g, 4.76 mmol) in tetrahydrofuran (10 mL) was added w-BuLi (IM solution, 5.71 mL) dropwise at -78 °C under nitrogen atmosphere. After stirring at -78 °C for 30 minutes, trimethyl borate (741 mg, 7.14 mmol) was added. The reaction mixture was warmed to 20 °C gradually and continued stirring for 2 hours under nitrogen atmosphere. After quenching by water (30 mL), the resultant suspension was extracted with ethyl acetate (30 mL * 3). The combined extracts were washed with brine (30 mL * 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound (1.75 g, crude) as a colorless oil, which would be used directly in the next step.
[88918] Step 5: 6-[3-[tert-butyl(dimethyl)silyl]oxy-2,6-dimethyl-phenyl]-8-methyl-2-methylsulfanyl- pyrido[2,3-d]pyrimidin-7-one
]88919] To a suspension of 6-bromo-8-methyl-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7-one (460 mg, 1.61 mmol) in dioxane (1.0 mL) and water (0.10 mL) were added [3-[tert-butyl(dimethyl)silyl]oxy- 2,6-dimethyl-phenyl]boronic acid (991 mg, 3.54 mmol), Pd2(dba)3 (147 mg, 0.16 mmol), SPhos (132 mg, 322 mmol) and potassium carbonate (667 mg, 4.82 mmol). The reaction was stirred at 100 °C for 2 hours under nitrogen atmosphere. After cooling, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, gradient 0 ~ 15% ethyl acetate in petroleum ether) to afford the title compound (250 mg, 35%) as a yellow solid. LCMS RT = 0.668 min, m/z = 442.6 [M + H]+.
[88928] Step 6: 6-[3-[tert-butyl(dimethyl)silyl]oxy-2,6-dimethyl-phenyl]-8-methyl-2-methylsulfonyl- pyrido[2,3-d]pyrimidin-7-one
[88921] To a solution of 6-[3-[tert-butyl(dimethyl)silyl]oxy-2,6-dimethyl-phenyl]-8-methyl-2- methylsulfanyl-pyrido[2,3-d]pyrimidin-7-one (230 mg, 0.52 mmol) in dichloromethane (15 mL) was added 3-chlorobenzenecarboperoxoic acid (423 mg, 85% purity, 2.08 mmol). The reaction mixture was stirred at 20 °C for 2 hours, then diluted with water (30 mL) and extracted with ethyl acetate (30 mL * 3). The combined extracts were washed with brine (30 mL * 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (silica gel, petroleum ether/ethyl acetate = 1/1, v/v) to afford the title compound (170 mg, 69%) as a white solid. LCMS RT = 0.633 min, m/z = 474.4 [M + H]+. ’H NMR (400 MHz, DMSO-t/tf) 3 9.25 (s, 1H), 8.00 (s, 1H), 7.01 (d, J= 8.0 Hz, 1H), 6.89 (d, J= 8.4 Hz, 1H), 3.72 (s, 3H), 3.50 (s, 3H), 1.97 (s, 3H), 1.90 (s, 3H), 0.99 (s, 9H), 0.23 (s, 6H).
[00922 [ Step 7: 6-[3-[tert-butyl(dimethyl)silyl]oxy-2,6-dimethyl-phenyl]-2-[(5-methoxy-2- pyridyl)amino]-8-methylpyrido[2,3-d]pyrimidin-7-one
100923) A mixture of 6-[3-[tert-butyl(dimethyl)silyl]oxy-2,6-dimethyl-phenyl]-8-methyl-2- methylsulfonyl-pyrido[2,3-d]pyrimidin-7-one (50 mg, 0.11 mmol), 5-methoxypyridin-2-amine (26 mg, 0.21 mmol) and tert-butoxide (I M solution in THF, 317 pL) was stirred at 20 °C for 1 hour under nitrogen atmosphere. The resultant mixture was then fdtered and the fdtrate was concentrated under reduced pressure to afford the crude title compound (50 mg) as a yellow solid.
[00924 [ Step 8: 6-(3-hydroxy-2,6-dimethyl-phenyl)-2-[(5-methoxy-2-pyridyl)amino]-8-methyl- pyrido[2,3-d]pyrimidin-7-one
[00926) 6-[3-[tert-butyl(dimethyl)silyl]oxy-2,6-dimethyl-phenyl]-2-[(5-methoxy-2-pyridyl)amino]-8- methylpyrido[2,3-d]pyrimidin-7-one (15 mg, 0.03 mmol) was treated with 4M HCl/dioxane (72 pL). The reaction mixture was stirred at 20 °C for 1 hour and then concentrated under reduced pressure. The residue was purified by RP-HPLC {Column: Welch Xtimate C18 150*30mm*5um; Mobile phase: [water (HCl)-MeCN]; B%: 0 ~ 40; Gradient time: 12min} to afford the title compound (3.4 mg) as a yellow solid. LCMS RT = 1.536 min, m/z = 404.3 [M + H]+. 1 H NMR (400 MHz, DMSO-t/tf) <5 11.40 (brs, 1H), 8.93 (s, 1H), 8.13 (d, J= 3.2 Hz, 1H), 8.01-7.89 (m, 1H), 7.86-7.84 (m, 1H), 7.80 (s, 1H), 6.90 (d, J= 8.4 Hz, 1H), 6.75 (d, J= 8.0 Hz, 1H), 3.88 (s, 3H), 3.68 (s, 3H), 1.94 (s, 3H), 1.86 (s, 3H).
[ 0926 ) Example 94. Synthesis of COMPOUND-536
[00927) Scheme 68.
Figure imgf000255_0001
536-3 COMPOUND-536
[00926) Step 1: tert-butyl (lR,5S)-6-[(6-bromo-3-pyridyl)oxymethyl]-3-azabicyclo[3.1.0]hexane-3- carboxylate
[00929) To a solution of 6-bromopyridin-3-ol (160 mg, 0.92 mmol) and tert-butyl (lR,5S)-6- (hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (196 mg, 0.92 mmol) in toluene (2.0 mL) were added TMAD (475 mg, 2.76 mmol) and /-Bt P (372 mg, 1.84 mmol). The reaction was stirred at 100°C for 1 hour under nitrogen, the cooled and quenched by water (30 mL). The resultant mixture was extracted with ethyl acetate (30 mL * 3). The combined extracts were washed with brine (20 mL * 2), dried over anhydrous sodium sulfate, fdtered and concentrated under reduced pressure. The residue was purified by prep-TLC (silica gel, petroleum ether/ethyl acetate = 1/1, v/v) to afford tert-butyl (lR,5S)-6- [(6-bromo-3-pyridyl)oxymethyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (170 mg, 41% yield) as a white solid. LCMS RT = 1.592 min, m/z = 369.25 [M + H]+.
[88938] Step 2: tert-butyl (lR,5S)-6-[[6-[[6-(2,6-dichlorophenyl)-8-methyl-7-oxo-pyrido[2,3- d]pyrimidin-2-yl]amino]-3-pyridyl]oxymethyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate [889 1 ] To a solution of tert-butyl ( 1 R,5 S)-6- [(6-bromo-3 -pyridyl)oxymethyl] -3 - azabicyclo[3.1.0]hexane-3-carboxylate (50 mg, 0.14 mmol) and 2-amino-6-(2,6-dichlorophenyl)-8- methyl-pyrido[2,3-d]pyrimidin-7-one (43 mg, 0.14 mmol) in dioxane (1.0 mL) were added Xantphos (16 mg, 27 mmol), Pd2(dba)3 (12 mg, 0.01 mmol) and potassium tert-butoxide (46 mg, 0.41 mmol). The reaction was stirred at 100 °C for 2 hours under nitrogen. After cooling, the reaction solution was concentrated under reduced pressure. The residue was purified by RP-HPLC {Column: C18-6 100*30mm*5um;mobile phase: [water (FA)-MeCN]; B%: 55 ~ 85; Gradient time: 15 min) to afford tertbutyl (lR,5S)-6-[[6-[[6-(2,6-dichlorophenyl)-8-methyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl]amino]-3- pyridyl]oxymethyl]-3-azabicyclo[3. 1.0]hexane -3 -carboxylate (20 mg, 24% yield) as a white solid.
LCMS RT = 1.725 min, m/z = 609.50 [M + H]+.
[08932] Step 3: 2-[[5-[[(lR,5S)-3-azabicyclo[3.1.0]hexan-6-yl]methoxy]-2-pyridyl]amino]-6-(2,6- dichlorophenyl)-8- methyl-pyrido[2,3-d]pyrimidin-7-one
[00933] Tert-butyl (lR,5S)-6-[[6-[[6-(2,6-dichlorophenyl)-8-methyl-7-oxo-pyrido[2,3-d]pyri midin-2 - yl]amino]-3-pyridyl]oxymethyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (15 mg, 0.02 mmol) was treated with 4M HCl/dioxane (1.0 mL). The reaction mixture was stirred at 20 °C for 1 hour and then concentrated under reduced pressure. The residue was purified by RP-HPLC {Column: Welch Xtimate C18 150*30mm*5um; Mobile phase: [water (HCl)-MeCN]; B%: 0 ~ 50; Gradient time: 10 min} to afford 2-[[5-[[(lR,5S)-3-azabicyclo[3.1.0]hexan-6-yl]methoxy]-2-pyridyl]amino]-6-(2,6- dichlorophenyl)-8- methyl -pyrido [2,3 -d]pyrimidin-7-one (2.6 mg, 20.74% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-t/6) b 11.25 (brs, 1H), 9.63 (s, 1H), 9.42 (s, 1H), 8.98 (s, 1H), 8.17-8.06 (m, 1H), 8.06 (s, 1H), 8.07-7.95 (m, 1H), 7.86-7.75 (m, 1H), 7.60-7.55 (m, 2H),7.50 (t, J= 7.6 Hz, 1H), 4.05- 3.93 (m, 2H), 3.68 (s, 3H), 3.33 (t, J = 5.2 Hz, 4H), 1.84 (s, 1 H), 1.63 (t, J = 3.2 Hz, 1H). LCMS RT = 1.070 min, m/z = 509.39 [M + H]+.
[88934] Compounds of the disclosure can be made by the representative methods described herein in Examples 1-94.
BIOLOGICAL EXAMPLES
[00935] Example B- l : //? vitro assay
[1W938] Compound-s that bind the kinase active site and directly (sterically) or indirectly (allosterically) prevent kinase binding to an immobilized ligand, will reduce the amount of kinase captured on the solid support. Screening "hits" are identified by measuring the amount of kinase captured in test versus control samples by using a quantitative, precise and ultra-sensitive qPCR method that detects the associated DNA label. In a similar manner, dissociation constants (I s) for test compound— kinase interactions are calculated by measuring the amount of kinase captured on the solid support as a function of the test compound- concentration.
Representative biochemical data is presented in Table 2, where A is <10 nM, B >10<100, C >100<500, and D >500 .
Table 2. Representative in vitro data
Figure imgf000257_0001
Figure imgf000258_0001
Figure imgf000259_0001
^00938^ It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

Claims

CLAIMS WHAT IS CLAIMED IS:
1. A compound having the structure of Formula (I), or a pharmaceutically acceptable salt thereof:
Figure imgf000260_0001
wherein,
A, B, and C, are each independently N or CR4;
D is N, CR4, or CR5;
E is N, CR4, or CR5; wherein one of D or E is CR5;
R1 is hydrogen, Ci-Cg alkyl, Ci-Cg heteroalkyl, C3-C6 cycloalkyl, or 4 to 6 membered heterocycloalkyl;
W is O or NH; or W and R1 combine with the atoms to which they are attached to form a 5 to 6-membered heterocycloalkyl or 5 to 6-membered heteroaryl;
R2 is Cg-Cio aryl or 6 to 10 membered heteroaryl; each of which is optionally substituted with one, two, three, or four R7; each R7 is independently selected from halogen, -CN, -OH, -ORa, -SH, -SRa, -N(Rb)2, -C(=O)Ra, - C(=O)ORb, -C(=O)N(Rb)2, Ci-C6 alkyl, Ci-C6 aminoalkyl, Ci-C6 haloalkyl, or Ci-C6 hydroxyalkyl; or two R7 together with the atoms to which they are attached form a 5 to 6-membered heterocycloalkyl;
R3A is hydrogen or C1-C3 alkyl; each R4 is independently hydrogen, halogen, -CN, -OH, -ORa, -SH, -SRa, -S(=O)Ra, -NO2, -N(Rb)2, - S(=O)2Ra, -NHS(=O)2Ra, -S(=O)2N(Rb)2, -C(=O)Ra, -OC(=O)Ra, -C(=O)ORb, -OC(=O)ORb, - C(O)N(Rb)2, -OC(=O)N(Rb)2, -NRbC(=O)N(Rb)2, -NRbC(=O)Ra, -NRbC(=O)ORb, -C1-C3 alkylene-NHS(=O)2Ra, -C1-C3 alkylene-NRbC(=O)Ra, -C1-C3 alkylene-OC(=O)Ra, -C1-C3 alkylene-NRbC(=O)N(Rb)2, -C1-C3 alkylene-NRbC(=O)ORb, -C1-C3 alkylene-OC(=O)N(Rb)2, Ci- Cg alkyl, Ci-Cg aminoalkyl, Ci-Cg haloalkyl, Ci-Cg hydroxyalkyl, Ci-Cg heteroalkyl, 5-membered heteroaryl, C3-C8 cycloalkyl, or 4 to 8 membered heterocycloalkyl, each of which is optionally substituted with one, two, three, or four halogen, -OH, C1-C3 alkyl, C1-C3 haloalkyl, or a 4 to 5- membered heterocycloalkyl; or two R4 on adjacent carbon atoms together with the atoms to which they are attached form a 5 to 6- membered heteroaryl;
Figure imgf000261_0001
L is absent or Z-L1, wherein
Z is -0- or -NR3B-; wherein R3B is hydrogen or C1-C3 alkyl;
L1 is absent or Ci-Cg alkylene which is optionally substituted with one, two, or three R8;
L2 is Ci-Cg alkylene which is optionally substituted with one, two, or three R8; each R8 is independently halogen, -OH, oxo, Ci-Cg alkyl, Ci-Cg haloalky 1, Ci-Cg hydroxyalkyl, or C3-C6 cycloalkyl; ring A is 5 to 10-membered heteroaryl, Cg-Cw cycloalkyl, or 5 to 10 membered heterocycloalkyl; each R6 is independently hydrogen, halogen, -CN, -OH, -ORa, -N(Rb)2, -S(=O)2Ra, -NHS(=O)2Ra, -S(=O)2N(Rb)2, -C(=O)Ra, -OC(=O)Ra, -C(=O)ORb, -C(=O)N(Rb)2, -NRbC(=O)Ra, oxo, Ci- Cg alkyl, Ci-Cg alkylamino, Ci-Cg haloalkyl, Ci-Cg hydroxyalkyl, Ci-Cg heteroalkyl, C3-C8 cycloalkyl, or 4 to 8 membered heterocycloalkyl; or two R6 together with the intervening atoms to which they are attached form a 5 to 8 membered heteroaryl, C’s-Cx cycloalkyl, or 5 to 8 membered heterocycloalkyl;
Q is -OR11 or -N(Rn)2; each R11 is independently hydrogen, Ci-Cg alkyl, Ci-Cg alkylamino, Ci-Cg haloalkyl, or Ci-Cg hydroxyalkyl, each of which is optionally substituted with one, two, or three halogen or Ci- C3 hydroxy alkyl; m is 0, 1, 2, 3, or 4;
R10 is hydrogen, halogen, -CN, -OH, -NH2, Ci-Cg alkyl, or Ci-Cg haloalkyl; each Ra is independently Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, Ci-Cg heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Ci-Cg alkyl(aryl), -Ci-Cg alkyl(heteroaryl), -Ci-Cg alkyl(cycloalkyl), or -Ci-Cg alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-Cg alkyl, or Ci-Cg haloalkyl; and each Rb is independently hydrogen, Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, Ci-Cg heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-Cg alkyl, or Ci-Cg haloalkyl. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R3A is hydrogen; and R1 is CH3.. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Z is absent; and R2 is phenyl or 6 membered heteroaryl. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein R2 is phenyl, pyridinyl, pyrazinyl, or pyrimidinyl. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I), has the structure of Formula (II), or a pharmaceutically acceptable salt thereof:
Figure imgf000262_0001
Formula (II), wherein,
X1 is CH or N; and
R7A and R7B are each independently selected from hydrogen, halogen, -CN, -OH, -ORa, -SH, -SRa, - N(Rb)2, -C(=0)N(Rb)2, Ci-Cg alkyl, Ci-Cg aminoalkyl, Ci-Cg haloalky 1, or Ci-Cg hydroxy alkyl. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein D is CR5 and E is N or CR4. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein D is N or CR4; and E is CR5. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein C is A is N or CH; B is N or CH; and C is CH. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein , .
Figure imgf000262_0002
, wherein
L is absent or Z-L1,
Z is -O- or -NR3B-; wherein R3B is hydrogen or C1-C3 alkyl;
L1 is absent or C1-C3 alkylene which is optionally substituted with one, two, or three R8; each R8 is independently halogen, -OH, oxo, Ci-Cg alkyl, Ci-Cg haloalky 1, Ci-Cg hydroxyalkyl, or C3-Cg cycloalkyl; ring A is 5 to 10-membered heteroaryl, Cg-Cio cycloalkyl, or 5 to 10 membered heterocycloalkyl; each R6 is independently hydrogen, halogen, -CN, -OH, -ORa, -N(Rb)2, -S(=O)2Ra, - NHS(=O)2Ra, -S(=O)2N(Rb)2, -C(=O)Ra, -OC(=O)Ra, -C(=O)ORb, -C(=O)N(Rb)2, - NRbC(=O)Ra, oxo (=0), Ci-C6 alkyl, Ci-C6 alkylamino, Ci-C6haloalkyl, Ci-C6 hydroxyalkyl, Ci-Cg heteroalkyl, C3-C8 cycloalkyl, or 4 to 8 membered heterocycloalkyl; or two R6 together with the intervening atoms to which they are attached form a 5 to 8 membered heteroaryl, Cs-Cx cycloalkyl, or 5 to 8 membered heterocycloalkyl; and m is 0, 1, 2, 3, or 4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula (III), or a pharmaceutically acceptable salt thereof:
Figure imgf000263_0001
Formula (III), wherein,
A and B are each independently N or CH;
X1 is N or CH;
W is O;
Ring A is ring A is 5 to 10-membered heteroaryl, Cg-Cio cycloalkyl, or 5 to 10 membered heterocycloalkyl; each R4 is independently hydrogen, halogen, -CN, -OH, -ORa, -SH, -SRa, -S(=O)Ra, -NO2, -N(Rb)2, - S(=O)2Ra, -NHS(=O)2Ra, -S(=O)2N(Rb)2, -C(=O)Ra, -OC(=O)Ra, -C(=O)ORb, -OC(=O)ORb, - C(O)N(Rb)2, -OC(=O)N(Rb)2, -NRbC(=O)N(Rb)2, -NRbC(=O)Ra, -NRbC(=O)ORb, -Ci-C3 alkylene-NHS(=O)2Ra, -Ci-C3 alkylene-NRbC(=O)Ra, -Ci-C3 alkylene-OC(=O)Ra, -Ci-C3 alkylene-NRbC(=O)N(Rb)2, -Ci-C3 alkylene-NRbC(=O)ORb, -Ci-C3 alkylene-OC(=O)N(Rb)2, Ci- Cg alkyl, Ci-Cg aminoalkyl, Ci-Cg haloalky 1, Ci-Cg hydroxyalkyl, Ci-Cg heteroalkyl, 5-membered heteroaryl, C3-Cx cycloalkyl, or 4 to 8 membered heterocycloalkyl, each of which is optionally substituted with one, two, three, or four halogen, -OH, Ci-C3 alkyl, Ci-C3 haloalkyl, or a 4 to 5- membered heterocycloalkyl; each R6 is independently hydrogen, halogen, -CN, -OH, -ORa, -N(Rb)2, -S(=O)2Ra, -NHS(=O)2Ra, - S(=O)2N(Rb)2, -C(=O)Ra, -OC(=O)Ra, -C(=O)ORb, -C(=O)N(Rb)2, -NRbC(=O)Ra, oxo, Ci-C6 alkyl, Ci-Cg alkylamino, Ci-Cg haloalkyl, Ci-Cg hydroxyalkyl, Ci-Cg heteroalkyl, C3-Cx cycloalkyl, or 4 to 8 membered heterocycloalkyl; or two R6 together with the intervening atoms to which they are attached form a 5 to 8 membered heteroaryl, Cs-Cx cycloalkyl, or 5 to 8 membered heterocycloalkyl;
R7A and R7B are each independently selected from hydrogen, halogen, -CN, -OH, -ORa, -SH, -SRa, - N(Rb)2, Ci-Cg alkyl, Ci-Cg aminoalkyl, Ci-Cg haloalkyl, or Ci-Cghydroxyalkyl;
L is absent or Z-L1, wherein
Z is -O- or -NR3B-; wherein R3B is hydrogen or Ci-C3 alkyl;
L1 is absent or Ci-C3 alkylene which is optionally substituted with one, two, or three R8; each R8 is independently halogen, -OH, oxo, Ci-Cg alkyl, Ci-Cg haloalkyl, Ci-Cghydroxyalkyl, or C3-Cg cycloalkyl; each Ra is independently Ci-Cg alkyl, C -Cg alkenyl, CS-Cg alkynyl, Ci-Cg heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Ci-Cg alkyl(aryl), -Ci-Cg alkyl(heteroaryl), -Ci-Cg alkyl(cycloalkyl), or -Ci-Cg alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-Cg alkyl, or Ci-Cg haloalkyl; each Rb is independently hydrogen, Ci-Cg alkyl, C -Cg alkenyl, C -Cg alkynyl, Ci-Cg heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-C3 alkyl, or Ci-C3 haloalkyl; and m is 0, 1, 2, 3, or 4. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein ring A is a Cg-Cio cycloalkyl or 5 to 10 membered heterocycloalkyl. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein ring A is a 5 to 10 membered heterocycloalkyl, wherein the heterocycloalkyl is a monocyclic, bicyclic, or spirocyclic heterocycloalkyl. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein ring A is piperidine, piperazine, or morpholine. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula (IV), or a pharmaceutically acceptable salt thereof:
Figure imgf000264_0001
Formula (IV), wherein,
W is O;
X1 is CH or N;
X2 is CH or N;
X3 and X5 are each independently CR6R6, O or NRX;
X4 is CR6R6, O, NRX, S, S(=O), S(=O)2, S(=O)=NRY, or S(=O)ORY;
Rx is hydrogen, -S(=O)2OH, -S(=O)2NH2, Ci-Cg alkyl, Ci-Cg haloalkyl, or Ci-Cg hydroxyalkyl; each RY is independently hydrogen or C1-C3 alkyl;
A and B are each independently N or CH; each R4 is independently hydrogen, halogen, -CN, -OH, -ORa, -SH, -SRa, -S(=O)Ra, -NO2, -N(Rb)2, - S(=O)2Ra, -NHS(=O)2Ra, -S(=O)2N(Rb)2, -C(=O)Ra, -OC(=O)Ra, -C(=O)ORb, -OC(=O)ORb, - C(O)N(Rb)2, -OC(=O)N(Rb)2, -NRbC(=O)N(Rb)2, -NRbC(=O)Ra, -NRbC(=O)ORb, -Ci-C3 alkylene-NHS(=O)2Ra, -Ci-C3 alkylene-NRbC(=O)Ra, -Ci-C3 alkylene-OC(=O)Ra, -Ci-C3 alkylene-NRbC(=O)N(Rb)2, -C C3 alkylene-NRbC(=O)ORb, -C C3 alkylene-OC(=O)N(Rb)2, C Cg alkyl, Ci-Cg aminoalkyl, Ci-Cg haloalkyl, Ci-Cg hydroxyalkyl, Ci-Cg heteroalkyl, 5-membered heteroaryl, C3-Cx cycloalkyl, or 4 to 8 membered heterocycloalkyl, each of which is optionally substituted with one, two, three, or four halogen, -OH, C1-C3 alkyl, C1-C3 haloalkyl, or a 4 to 5- membered heterocycloalkyl; each R6 is independently hydrogen, halogen, -CN, -OH, -ORa, -N(Rb)2, -S(=O)2Ra, -NHS(=0)2Ra, - S(=O)2N(Rb)2, -C(=O)Ra, -OC(=O)Ra, -C(=O)ORb, -C(=O)N(Rb)2, -NRbC(=O)Ra, oxo (=0), Ci- Cg alkyl, Ci-Cg alkylamino, Ci-Cg haloalkyl, Ci-Cghydroxyalkyl, Ci-Cg heteroalkyl, C3-C8 cycloalkyl, or 4 to 8 membered heterocycloalkyl; or two R6 together with the intervening atoms to which they are attached form a 5 to 8 membered heteroaryl, C’s-Cx cycloalkyl, or 5 to 8 membered heterocycloalkyl;
R7A and R7B are each independently selected from hydrogen, halogen, -CN, -OH, -0Ra, -SH, -SRa, - N(Rb)2, Ci-Cg alkyl, Ci-Cg aminoalkyl, Ci-Cg haloalkyl, or Ci-Cghydroxyalkyl;
L is absent or Z-L1, wherein
Z is -O- or -NR3B-; wherein R3B is hydrogen or C1-C3 alkyl;
L1 is absent or C1-C3 alkylene which is optionally substituted with one, two, or three R8; each R8 is independently halogen, -OH, oxo, Ci-Cg alkyl, Ci-Cg haloalkyl, Ci-Cghydroxyalkyl, or C3-Cg cycloalkyl; each Ra is independently Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, Ci-Cg heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Ci-Cg alkyl(aryl), -Ci-Cg alkyl(heteroaryl), -Ci-Cg alkyl(cycloalkyl), or -Ci-Cg alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-Cg alkyl, or Ci-Cg haloalkyl; each Rb is independently hydrogen, Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, Ci-Cg heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-Cg alkyl, or Ci-Cg haloalkyl; and m is 0, 1, 2, 3, or 4. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein X2 is CH; X3 and X5 are each independently CR6R6, O, or NRX; and X4 is CR6R6. The compound of claim 14 or 15, or a pharmaceutically acceptable salt thereof, wherein X3 and X5 are each independently O or NRX. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein X3 and X5 are each independently CR6R6. The compound of claims 14, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (IV) has the structure of Formula (IVa), or a pharmaceutically acceptable salt thereof:
Figure imgf000266_0001
Formula (IVa). The compound of clam 18, or a pharmaceutically acceptable salt thereof, wherein X4 is S, S(=O), or S(=O)2. The compound of clam 18, or a pharmaceutically acceptable salt thereof, wherein X4 is S(=O)2. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein X4 is O or NRX. The compound of any one of claims 18-21 or a pharmaceutically acceptable salt thereof, wherein X2 is CH. The compound of any one of claims 18-21 or a pharmaceutically acceptable salt thereof, wherein X2 is N. The compound of any one of claims 14-23, or a pharmaceutically acceptable salt thereof, wherein each R6 is independently hydrogen, halogen, -N(Rb)2, oxo (=0), Ci-Cg alkyl, Ci-Cg alkylamino, Ci-Cg haloalky 1, or Ci-Cghydroxyalkyl. The compound of any one of claims 14-23, or a pharmaceutically acceptable salt thereof, wherein two R6 together with the intervening atoms to which they are attached form a 5 to 8 membered heteroaryl, C -Cx cycloalkyl, or 5 to 8 membered heterocycloalkyl. The compound of any one of claims 14-25, or a pharmaceutically acceptable salt thereof, wherein m is 1 or 2. The compound of any one of claims 14-23, or a pharmaceutically acceptable salt thereof, wherein m is 0. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein ring A is 5 to 10-membered heteroaryl having one, two, or three heteroatoms selected from N, O, and S and wherein the heteroaryl is monocyclic or bicyclic. The compound of claim 28, or a pharmaceutically acceptable salt thereof, wherein ring A is a 5 or 6 membered heteroaryl having one, two, or three heteroatoms selected from N, O, and S. The compound of claim 29, or a pharmaceutically acceptable salt thereof, wherein ring A is pyridyl or pyrimidyl. The compound of claim 29, or a pharmaceutically acceptable salt thereof, wherein ring A is triazinyl, pyrrolyl, furanyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, or tetrazolyl. The compound of claim 31, or a pharmaceutically acceptable salt thereof, wherein ring A is pyrrolyl, imidazolyl, or pyrazolyl. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula (V), or a pharmaceutically acceptable salt thereof:
Figure imgf000267_0001
Formula (V), wherein,
X1 is CH or N;
Y1 is C or N and Y2 is CH or N, provided that at least one of Y1 or Y2 is N;
W is O;
A and B are each independently N or CH; each R4 is independently hydrogen, halogen, -CN, -OH, -ORa, -SH, -SRa, -S(=O)Ra, -NO2, -N(Rb)2, - S(=O)2Ra, -NHS(=O)2Ra, -S(=O)2N(Rb)2, -C(=O)Ra, -OC(=O)Ra, -C(=O)ORb, -OC(=O)ORb, - C(O)N(Rb)2, -OC(=O)N(Rb)2, -NRbC(=O)N(Rb)2, -NRbC(=O)Ra, -NRbC(=O)ORb, -Ci-C3 alkylene-NHS(=O)2Ra, -Ci-C3 alkylene-NRbC(=O)Ra, -Ci-C3 alkylene-OC(=O)Ra, -Ci-C3 alkylene-NRbC(=O)N(Rb)2, -Ci-C3 alkylene-NRbC(=O)ORb, -Ci-C3 alkylene-OC(=O)N(Rb)2, Ci- Cg alkyl, Ci-Cg aminoalkyl, Ci-Cg haloalky 1, Ci-Cg hydroxyalkyl, Ci-Cg heteroalkyl, 5-membered heteroaryl, C3-Cx cycloalkyl, or 4 to 8 membered heterocycloalkyl, each of which is optionally substituted with one, two, three, or four halogen, -OH, Ci-C3 alkyl, Ci-C3 haloalkyl, or a 4 to 5- membered heterocycloalkyl;
R6A is hydrogen, halogen, Ci-Cg alkyl, Ci-Cg haloalkyl, or Ci-Cghydroxyalkyl;
R9 is hydrogen, Ci-Cg alkyl, Ci-Cg haloalkyl, Ci-Cghydroxyalkyl, -Ci-C3 alkylene(cycloalkyl), -Ci-C3 alkylene(heterocycloalkyl), C3-Cg cycloalkyl, or 4 to 6 membered heterocycloalkyl; or R6A and R9 together with the intervening atoms to which they are attached form a 6 to 8 membered heteroaryl or 6 to 8 membered heterocycloalkyl;
R7A and R7B are each independently selected from hydrogen, halogen, -CN, -OH, -ORa, -SH, -SRa, - N(Rb)2, Ci-Cg alkyl, Ci-Cg aminoalkyl, Ci-Cg haloalkyl, or Ci-Cghydroxyalkyl;
L is absent or Z-L1, wherein
Z is -O- or -NR3B-; wherein R3B is hydrogen or Ci-C3 alkyl;
L1 is absent or Ci-C3 alkylene which is optionally substituted with one, two, or three R8; each R8 is independently halogen, -OH, oxo, Ci-Cg alkyl, Ci-Cg haloalkyl, Ci-Cghydroxyalkyl, or C3-Cg cycloalkyl; each Ra is independently Ci-Cg alkyl, C -Cg alkenyl, CS-Cg alkynyl, Ci-Cg heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Ci-Cg alkyl(aryl), -Ci-Cg alkyl(heteroaryl), -Ci-Cg alkyl(cycloalkyl), or -Ci-Cg alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-Cg alkyl, or Ci-Cg haloalkyl; and each Rb is independently hydrogen, Ci-Cg alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Cg heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-Cg alkyl, or Ci-Cg haloalkyl. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein Y1 is N and Y2 is N. The compound of claim 33 or 34, or a pharmaceutically acceptable salt thereof, wherein: R6 is hydrogen; and
R9 is Ci-Cg alkyl, Ci-Cg haloalkyl, Ci-Cg hydroxyalkyl, -C1-C3 alkylene(C3-Cgcycloalkyl), -C1-C3 alkylene(4 to 6 membered heterocycloalkyl), C3-Cg cycloalkyl, or 4 to 6 membered heterocycloalkyl. The compound of claim 35, or a pharmaceutically acceptable salt thereof, wherein R9 is methyl, ethyl, -CH2-(C3-Cgcycloalkyl), -CH2-(4 to 6 membered heterocycloalkyl), C3-Cg cycloalkyl, or 4 to 6 membered heterocycloalkyl. The compound of claim 35, or a pharmaceutically acceptable salt thereof, wherein R9 is methyl or ethyl. The compound of claim 33 or 34, or a pharmaceutically acceptable salt thereof, wherein R6A and R9 together with the intervening atoms to which they are attached form a 6 to 8 membered heteroaryl or 6 to 8 membered heterocycloalkyl. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (V) has the structure of Formula (Va) or Formula (Vb), or a pharmaceutically acceptable salt thereof:
Figure imgf000268_0001
Formula (Vb). The compound of any one of claims 1-39, or a pharmaceutically acceptable salt thereof, wherein Z is -O- or -NR3B-; and
L1 is Ci-Cg alkylene which is optionally substituted with one, two, or three R8. The compound of claim 40, or a pharmaceutically acceptable salt thereof, wherein L1 is -CH2- or -CH2CH2- The compound of claim 40 or 41, or a pharmaceutically acceptable salt thereof, wherein Z is -O-. The compound of claim 40 or 41, or a pharmaceutically acceptable salt thereof, wherein Z is - NR3B-. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt thereof, wherein Z is -O-; and
L1 is absent. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein: R5 is -Z-l -Q; wherein
Z is -O- or -NR3B-; wherein R3B is hydrogen or C1-C3 alkyl;
L2 is Ci-Cg alkylene which is optionally substituted with one, two, or three R8; each R8 is independently halogen, -OH, oxo, Ci-Cg alkyl, Ci-Cg haloalky 1, Ci-Cg hydroxyalkyl, or C3-C6 cycloalkyl;
Q is -OR11 or -N(Rn)2; and each R11 is independently hydrogen, Ci-Cg alkyl, Ci-Cg alkylamino, Ci-Cg haloalkyl, or Ci- Cg hydroxyalkyl, each of which is optionally substituted with one, two, or three halogen. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula (VI), or a pharmaceutically acceptable salt thereof:
Figure imgf000269_0001
Formula (VI), wherein,
X1 is CH or N;
W is O;
A and B are each independently N or CH; each R4 is independently hydrogen, halogen, -CN, -OH, -ORa, -SH, -SRa, -S(=O)Ra, -NO2, -N(Rb)2, - S(=O)2Ra, -NHS(=O)2Ra, -S(=O)2N(Rb)2, -C(=O)Ra, -OC(=O)Ra, -C(=O)ORb, -OC(=O)ORb, - C(O)N(Rb)2, -OC(=O)N(Rb)2, -NRbC(=O)N(Rb)2, -NRbC(=O)Ra, -NRbC(=O)ORb, -C1-C3 alkylene-NHS(=O)2Ra, -C1-C3 alkylene-NRbC(=O)Ra, -C1-C3 alkylene-OC(=O)Ra, -C1-C3 alkylene-NRbC(=O)N(Rb)2, -C1-C3 alkylene-NRbC(=O)ORb, -C1-C3 alkylene-OC(=O)N(Rb)2, Ci- Cg alkyl, Ci-Cg aminoalkyl, Ci-Cg haloalkyl, Ci-Cg hydroxyalkyl, Ci-Cg heteroalkyl, 5-membered heteroaryl, C3-C8 cycloalkyl, or 4 to 8 membered heterocycloalkyl, each of which is optionally substituted with one, two, three, or four halogen, -OH, C1-C3 alkyl, C1-C3 haloalkyl, or a 4 to 5- membered heterocycloalkyl;
R7A and R7B are each independently selected from hydrogen, halogen, -CN, -OH, -ORa, -SH, -SRa, - N(Rb)2, Ci-Cg alkyl, Ci-Cg aminoalkyl, Ci-Cg haloalkyl, or Ci-Cghydroxyalkyl;
Z is -O- or -NR3B-; wherein R3B is hydrogen or C1-C3 alkyl; L2 is C1-C3 alkylene which is optionally substituted with one, two, or three R8; each R8 is independently halogen, -OH, oxo, Ci-Cg alkyl, Ci-Cg haloalky 1, Ci-Cghydroxyalkyl, or C3- Cg cycloalkyl;
Q is -OR11 or -NCR1 ^2; each R11 is independently hydrogen, Ci-Cg alkyl, Ci-Cg alkylamino, Ci-Cg haloalkyl, or Ci-Cg hydroxyalkyl, each of which is optionally substituted with one, two, or three halogen or C1-C3 hydroxyalkyl; each Ra is independently Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, Ci-Cg heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -Ci-Cg alkyl(aryl), -Ci-Cg alkyl(heteroaryl), -Ci-Cg alkyl(cycloalkyl), or -Ci-Cg alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-Cg alkyl, or Ci-Cg haloalkyl; and each Rb is independently hydrogen, Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, Ci-Cg heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-Cg alkyl, or Ci-Cg haloalkyl. The compound of claim 46, or a pharmaceutically acceptable salt thereof, wherein Q is -OR11. The compound of claim 46, or a pharmaceutically acceptable salt thereof, wherein Q is -N(Rn)2. The compound of any one of claims 46-48, or a pharmaceutically acceptable salt thereof, wherein Z is -O-. The compound of any one of claims 46-48, or a pharmaceutically acceptable salt thereof, wherein Z is -NR3B-. The compound of any one of claims 1-50, or a pharmaceutically acceptable salt thereof, wherein A is CH and B is CH. The compound of any one of claims 1-50, or a pharmaceutically acceptable salt thereof, wherein A is CH and B is N. The compound of any one of claims 1-50, or a pharmaceutically acceptable salt thereof, wherein A is N and B is CH. The compound of any one of claims 1-50, or a pharmaceutically acceptable salt thereof, wherein A is N and B is N. The compound of any one of claims 10-54, or a pharmaceutically acceptable salt thereof, wherein R4 is hydrogen, halogen, -CN, -S(=O)Ra, -N(Rb)2, -S(=O)2Ra, -NHS(=O)2Ra, - S(=O)2N(Rb)2, -C(=O)Ra, -C(=O)ORb, -C(O)N(Rb)2, -OC(=O)N(Rb)2, -NRbC(=O)N(Rb)2, - NRbC(=O)Ra, -NRbC(=O)ORb, -Ci-C3 alkylene-NHS(=O)2Ra, -C1-C3 alkylene-NRbC(=O)Ra, -Ci- C3 alkylene-OC(=O)Ra, -C1-C3 alkylene-NRbC(=O)N(Rb)2, -C1-C3 alkylene-NRbC(=O)ORb, -Ci- C3 alkylene-OC(=O)N(Rb)2, Ci-Cg alkyl, Ci-Cg aminoalkyl, Ci-Cg haloalkyl, Ci-Cg hydroxyalkyl, Ci-Cg heteroalkyl, 5-membered heteroaryl, C3-C8 cycloalkyl, or 4 to 8 membered heterocycloalkyl, each of which is optionally substituted with one, two, three, or four halogen, - OH, C1-C3 alkyl, C1-C3 haloalkyl, or a 4 to 5-membered heterocycloalkyl. The compound of any one of claims 10-54, or a pharmaceutically acceptable salt thereof, wherein R4 is hydrogen, halogen, -CN, -C(=O)Ra, -C(=O)ORb, -C(O)N(Rb)2, -CH2-NHS(=O)2Ra, -CH2-NRbC(=O)Ra, -CH2-NRbC(=O)N(Rb)2, -CH2-NRbC(=O)ORb, -CH2-OC(=O)N(Rb)2, Ci-C6 alkyl, Ci-Cg haloalkyl, Ci-Cg hydroxyalkyl, Ci-Cg heteroalkyl, 5-membered heteroaryl, C3-C8 cycloalkyl, or 4 to 6 membered heterocycloalkyl. The compound of any one of claims 5-56, or a pharmaceutically acceptable salt thereof, wherein X1 is N. The compound of any one of claims 5-56, or a pharmaceutically acceptable salt thereof, wherein X1 is CH. The compound of any one of claims 5-58, or a pharmaceutically acceptable salt thereof, wherein R7A and R7B are each independently halogen. The compound of claim 59, or a pharmaceutically acceptable salt thereof, wherein R7A and R7B are each independently chloro or fluoro. A compound selected from Table 1 or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising a compound of any one of claims 1-61, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient. A method of treating a disease or condition associated with inhibiting protein kinase, membrane associated tyrosine/threonine 1 (PKMYT1) in a patient in need thereof, comprising administering to the patient a compound of any one of claims 1-61 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 62. The method of claim 63, wherein the condition associated with inhibition of PKMYT1 is a cancer. A method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of any one of claims 1-61, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 62. The method of claim 64, wherein the cancer is leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia, acute lymphoblastic leukemia (ALL), non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), or multiple myeloma (MM). The method of claim 65, wherein the cancer is a solid cancer. The method of claim 65, the cancer is a skin cancer, ocular cancer, gastrointestinal cancer, thyroid cancer, breast cancer, ovarian cancer, central nervous system cancer, laryngeal cancer, cervical cancer, lymphatic system cancer, genitourinary tract cancer, bone cancer, biliary tract cancer, endometrial cancer, liver cancer, lung cancer, prostate cancer, or colon cancer.
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