Phosphoinositide 3-kinase modulators and uses thereof

Abstract

Described are PI3K modulators represented by the structural Formula I: (I); and pharmaceutically acceptable salts and compositions thereof, which are useful for treating a variety of conditions associated with modulation of PI3K.

Description

141039-00120PHOSPHOINOSITIDE 3-KINASE MODULATORS AND USES THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U. S. Provisional Application Serial No. 63 / 773,132, filed March 17, 2025, and U. S. Provisional Application Serial No. 63 / 922,823, filed November 21, 2025. The entire teachings of the aforementioned applications are incorporated herein by reference.BACKGROUND

[0002] According to the World Health Organization (WHO), cancer is a leading cause of death worldwide, accounting for nearly 10 million deaths in 2020, or nearly one is sixth deaths. The American Cancer Society project that by 2040, the number of new cancer cases is expected to increase to 29.9 million.

[0003] Phosphatidylinositol 3-kinase (PI3K) is a key regulator of many cellular processes and its hyperactivation promotes tumor cell growth and survival. Indeed, activation of the PI3K pathway is considered one of the most frequent and oncogenic events in human cancers, meaning it significantly contributes to the development and progression of tumors due to its role in regulating cell growth, survival, and proliferation when abnormally activated.

[0004] The frequency of cancers exhibiting PI3K malfunction has driven a widespread effort in the development of PI3K inhibitors. Despite recent advances, however, one of the primary concerns for PI3K-based drugs has been their toxicity profile. Given this, and the increasing cancer burden worldwide, the development of new small molecule modulators of PI3K, particularly those with high specificity and / or improved toxicity profiles is needed.SUMMARY

[0005] Provided herein are compounds having the Formula I:1ME1\60337174.v1141039-00120

[0071] and pharmaceutically acceptable salts thereof, wherein Ring A, Ring B, Ring C, L, R, R1, R2, R3, R4, R5, and R6are as described herein. In one aspect, the described compounds of Formula I and pharmaceutically acceptable salts thereof modulate PI3K (e.g disrupt, inhibit, or prevents and interaction between PI3K such as PI3Kα, and a GTPase such as Rac1, CDC42 or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1). In some aspects, the described compounds are useful in treating an indication associated with or characterized by the aberrant activity of PI3K. Such indications include, but are not limited to, one or more cancers.

[0006] Pharmaceutical compositions comprising the compounds and pharmaceutically acceptable salts of the described compounds, as well as methods for their preparation are also included.DETAILED DESCRIPTION

[0007] A. General Description of Compounds

[0008] In a first aspect, provided is a compound having the Formula I:or a pharmaceutically acceptable salt thereof, wherein:Ring A is phenyl, 5- to 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic carbocyclyl, 8- to 10-membered bicyclic heteroaryl, or 8- to 10-membered bicyclic heterocyclyl, wherein Ring A is attached to Ring B and Ring C via two adjacent atoms;Ring B is phenyl, 5- to 6-membered monocyclic heteroaryl, 3- to 10-membered monocyclic or bicyclic heterocyclyl, or (C3-C7)cycloalkyl, wherein Ring B is attached to Ring A and L via two adjacent atoms;Ring C is phenyl, 5- to 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl or 8- to 10-membered bicyclic heterocyclyl, wherein Ring C is attached to Ring A and L via two adjacent atoms;2ME1\60337174.v1141039-00120L is a (C3-C6)alkylene or halo(C3-C6)alkylene, each of which are optionally interrupted by 1 to 3 Rvand / or wherein two adjacent hydrogen atoms on said (C3-C6)alkylene or halo(C3-C6)alkylene may be taken together to form a (C3-C6)cycloalkyl;Rvis O, NH, N(Ci-C4)alkyl, S, C(O)NH, C(O)N(Ci-C4)alkyl, OC(O)NH, OC(O)N(Ci-C4)alkyl, S(O)2NH, S(O)2N(Ci-C4)alkyl, NHS(O)2NH, N(C1-C4)alkylS(O)2NH, NHS(O)2N(Ci-C4)alkyl, or N(Ci-C4)alkylS(O)2N(Ci-C4)alkyl;R is hydrogen, phenyl, naphthyl, 5- to 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, 5- to 8-membered bicyclic carbocyclyl, 4- to 8-membered monocyclic heterocyclyl, 7- to 10-membered bicyclic heterocyclyl, -C≡C-R7, -C(O)NR8R9, -OR8, -NR8R9, or -CR8a=CR8aR9a, wherein each of said phenyl, naphthyl, 5- to 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, 5- to 8-membered bicyclic carbocyclyl, 4- to 8-membered monocyclic heterocyclyl, and 7- to 10-membered bicyclic heterocyclyl are optionally substituted with 1 to 3 groups selected from Rx;R1is selected from hydrogen, halo, (C1-C6)alkyl, hydroxy(C1-C6)alkyl, cyano(C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkoxy, (C1-C6)alkyleneO(C1-C6)alkyl, (Ci-C6)alkyleneO(Ci-C6)alkyl, hydroxy, (C3-C6)cycloalkyl, (Ci-C6)alkyleneNH2, (Ci-C6)alkyleneNH(Ci-C6)alkyl, (Ci-C6)alkyleneN[(Ci-C6)alkyl]2, cyano, hydroxy, C(O)NH2, C(O)NH(Ci-C6)alkyl, C(O)N[(Ci-C6)alkyl]2, -NR8aR9a, 5- to 7-membered monocyclic heteroaryl, and 4- to 7-membered monocyclic heterocyclyl, wherein said 4- to 7-membered monocyclic heterocyclyl, (C3-C6)cycloalkyl, and 5- to 7-membered monocyclic heteroaryl are each optionally substituted with 1 to 3 groups selected from RY;R2is selected from hydrogen, halo, cyano, (C1-C6)alkyl, hydroxy(C1-C6)alkyl, cyano(C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy, and halo(C1-C6)alkoxy;R3is halo, cyano, hydroxy, (C1-C6)alkyl, hydroxy(C1-C6)alkyl, (Ci-C6)alkyleneO(Ci-C6)alkyl, (Ci-C6)alkyleneNH2, -Y-W, (Ci-C6)alkyleneNH(Ci-C6)alkyl, (Ci-C6)alkyleneN[(Ci-Ce)alkyl]2, cyano(C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkoxy, 5- to 7-membered monocyclic heteroaryl, 4- to 7-membered monocyclic heterocyclyl, (C3-C6)cycloalkyl, (C2-C6)alkynyl, and (C3-C6)cycloalkenyl, wherein said 5- to 7-membered monocyclic heteroaryl, 4- to 7-membered monocyclic heterocyclyl, (C3-C6)cycloalkenyl, and (C3-C6)cycloalkyl are each optionally substituted with 1 to 3 groups selected from RX1;R4is selected from hydrogen, halo, cyano, hydroxy, (C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C1-C6)alkyleneO(C1-C6)alkyl, (C1-C6)alkyleneNH2, -Y-W, (C1-C6)alkyleneNH(C1-C6)alkyl, (C1-C6)alkyleneN[(C1-C6)alkyl]2, cyano(C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkoxy, 5- to 7-membered monocyclic heteroaryl, 4- to 7-membered 3ME1\60337174.v1141039-00120monocyclic heterocyclyl, (C3-C6)cycloalkyl, (C2-C6)alkynyl, and (C3-C6)cycloalkenyl, wherein said 5- to 7-membered monocyclic heteroaryl, 4- to 7-membered monocyclic heterocyclyl, (C3-C6)cycloalkenyl, and (C3-C6)cycloalkyl are each optionally substituted with 1 to 3 groups selected from Rxl;R5and R6are independently selected from hydrogen, halo, cyano, hydroxy, NH2, (C1-C6)alkyl, halo(C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, halo(C1-C6)alkoxy, O(C3-C4)cycloalkyl, S(C1-C6)alkyl, NH(C1-C6)alkyl, N[(C1-C6)alkyl]2, NH(C3-C4)cycloalkyl, 5- to 7-membered monocyclic heteroaryl, and 4- to 7-membered monocyclic heterocyclyl, wherein said 5- to 7-membered monocyclic heteroaryl, 4- to 7-membered monocyclic heterocyclyl, and (C3-C6)cycloalkyl are each optionally substituted with 1 to 3 groups selected from RY1;R7is selected from (C1-C6)alkyl, (C3-C6)cycloalkyl, phenyl, 5- to 6-membered monocyclic heteroaryl, (C1-C6)alkylene[5- to 8-membered monocyclic heterocyclyl], 9- to 10-membered bicyclic fused aryl, and 9- to 10-membered bicyclic fused heteroaryl, wherein said (C3-C6)cycloalkyl, phenyl, 5- to 6-membered monocyclic heteroaryl, (C1-C6)alkylene[5-to 8-membered heterocyclyl], 9- to 10-membered bicyclic fused aryl, and 9- to 10-membered bicyclic fused heteroaryl are each optionally substituted with 1 to 3 groups selected from RZ;R8and R8aare each independently selected from hydrogen, CN, halogen, (C1-C6)alkyl, (C1-C3)alkylenecyano, and (C3-C6)cycloalkyl;R9and R9aare each independently selected from hydrogen, (C1-C6)alkyl, halo(C1-C6)alkyl, cyano(C1-C6)alkyl, hydroxy(C1-C6)alkyl, 3- to 6-membered monocyclic carbocyclyl, phenyl, naphthyl, 5- to 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl ring, 5- to 8-membered bicyclic carbocyclyl, 4- to 8-membered monocyclic heterocyclyl, and 7- to 10-membered spiro-fused heterocyclyl, wherein each of said 3- to 6-membered monocyclic carbocyclyl, phenyl, naphthyl, 5- to 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl ring, 5- to 8-membered bicyclic carbocyclyl, 4- to 8-membered monocyclic heterocyclyl, and 7- to 10-membered spiro-fused heterocyclyl is optionally substituted with 1 to 3 groups selected from (Ci-Ce)alkyl, (C3-C6)cycloalkyl, (Ci-C6)alkyleneNR8aR9a, halo, cyano, and hydroxy;Y, Ya, Yb, and Ycare each independently a bond, C(O), CH2, S(O), or S(O)2;W, Wa, Wb, and Wcare each independently selected from hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, 4- to 7-membered monocyclic heterocyclyl, phenyl, 5- to 6-membered monocyclic heteroaryl, -CR8=CR10R11, and -C≡C-R11;R10and R11are each independently selected from hydrogen, (C1-C6)alkyl, halo(C1-C6)alkyl, (C3-C6)cycloalkyl, halo, cyano, (C1-C6)alkoxy, (C1-C6)alkyleneNR8R9, (C1- 4ME1\60337174.v1141039-00120C3)alkylene 4- to 8-membered monocyclic heterocyclyl, 4- to 7-membered monocyclic heterocyclyl phenyl, C(O)NH(C1-3alkyl) and 5- to 6-membered monocyclic heteroaryl;RXand RX1are each independently halo, hydroxy, cyano, (C1-C6)alkyl, deuterated(C1-C6)alkyl halo(C1-C6)alkyl, hydroxy(Ci-C6)alkyl, cyano(Ci-C6)alkyl, (Ci-C6)alkoxy, halo(Ci-C6)alkoxy, (C3-C6)cycloalkyl, S(O)2NH2, NHS(O)2NH2, NHS(O)2(Ci-C6)alkyl, S(O)2NH(C1-C6)alkyl, NH(C1-C6)alkyl, 4- to 6-membered monocyclic heterocyclyl, 5- to 7-membered monocyclic heteroaryl, phenyl, (Ci-C6)alkyleneNR8R9, (Ci-C6)alkyleneO(Ci-C6)alkyl, hydroxy, O(C3-C4)cycloalkyl, -Ya-Wb, (Ci-C6)alkyleneO(C3-C4)cycloalkyl, (Ci-C6)alkylene[(C3-C4)cycloalkyl], (Ci-C6)alkylene[4- to 6-membered monocyclic heterocyclyl], (Ci-C6)alkylene[5- to 7-membered monocyclic heteroaryl], or -NR8aR9a, wherein said (C3-C6)cycloalkyl, 4- to 6-membered monocyclic heterocyclyl, 5- to 7-membered monocyclic heteroaryl, and phenyl are each optionally substituted with 1 to 3 groups selected from Rw;RWis halo, cyano, (C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C1-C6)alkyleneO(C1-C6)alkyl, (C1-C6)alkyleneNH2, (C1-C6)alkyleneNH(C1-C6)alkyl, (C1-C6)alkyleneN[(C1-C6)alkyl]2, cyano(C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkoxy, hydroxy, O(C3-C4)cycloalkyl, or 4- to 6-membered monocyclic heterocyclyl;RYand RY1are each independently -NR7a-Yc-Wc, -Yb-Wb, halo, cyano, (C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C1-C6)alkyleneO(C1-C6)alkyl, (C1-C6)alkyleneNH2, (C1-C6)alkyleneNH(C1-C6)alkyl, (C1-C6)alkyleneN[(C1-C6)alkyl]2, cyano(C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkoxy, hydroxy, O(C3-C4)cycloalkyl, or 4- to 6-membered monocyclic heterocyclyl; andRZis halo, hydroxy, hydroxy(C1-C6)alkyl, cyano, -NR8R9, S(O)2(C1-C6)alkyl, S(O)(C1-C6)alkyl, S(O)NR8R9, and S(O)2NR8R9; andq is 0, 1, 2, or 3.

[0009] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. The terminology used in the description is for describing particular aspects only and is not intended to be limiting of the disclosure.

[0010] The articles “a” and “an” as used herein and in the appended claims are used herein to refer to one or to more than one (e.g to at least one) of the grammatical object of the article unless the context clearly indicates otherwise. By way of example, “an element” means one element or more than one element.5ME1\60337174.v1141039-00120

[0011] When used in connection to describe a chemical group that may be construed as possibility having multiple points of attachment, a hyphen (-) designates the point of attachment of that group to the variable to which it is defined. For example, -Y-W means that the point of attachment for this group to the remainder of the molecule occurs on Y.

[0012] The number of carbon atoms in a group is specified herein by the prefix “Cx-Cxx”, wherein x and xx are integers. For example, "(Ci-C4)alkyl" is an alkyl group which has from 1 to 4 carbon atoms.

[0013] " Alkyl", when used alone or part of a larger moiety, refers to a fully saturated branched or unbranched hydrocarbon moiety. Unless otherwise specified, an alkyl comprises 1 to 6 carbon atoms, or 1 to 4 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec -butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or n-hexyl.

[0014] “Deuterated alkyl” as used by itself or as part of another group, refers to an alkyl group wherein on or more hydrogens are replace by deuterium.

[0015] When a range of carbon atoms is used herein, for example, Ci-6, all ranges, as well as individual numbers of carbon atoms are encompassed. For example, “C1-3” includes C1-3, C1-2, C2-3, Ci, C2, and C3.

[0016] The term “alkoxy” as used by itself or as part of another group refers to an oxygen radical attached to an alkyl group by a single bond. Examples of alkoxy include methoxy, ethoxy, isopropoxy, and the like.

[0017] The term “alkylene,” when used alone or as part of a substituent group, refers to an alkyl diradical, i.e a straight- or branched-chain hydrocarbon group that is attached to two other groups. For example, one aspect of a C2alkylene is the diradical -CH2CH2-.

[0018] The term “haloalkylene” refers to an alkylene group wherein one or more of the hydrogen atoms has been replaced with one or more halogen atoms which may be the same or different.

[0019] The terms “halo” and “halogen” refer to an atom selected from fluorine (fluoro, F), chlorine (chloro, Cl), bromine (bromo, Br), and iodine (iodo, I).

[0020] The term “haloalkyl” refers to an alkyl group wherein one or more of the hydrogen atoms has been replaced with one or more halogen atoms which may be the same or different.

[0021] The term “hydroxy alkyl” as used by itself or as part of another group refers to an alkyl group as defined herein wherein one or more of the hydrogen atoms has been replaced with one or more hydroxyl (i.e -OH).6ME1\60337174.v1141039-00120

[0022] The term “cyanoalkyl” as used by itself or as part of another group refers to an alkyl as defined herein that is substituted by one or more CN.

[0023] The term “haloalkoxy” as used by itself or as part of another group refers an oxygen radical attached to a haloalkyl group by a single bond, wherein haloalkyl is defined above. Examples of haloalkoxy groups include fluoromethoxy (OCH2F), 2-fluoroethoxy, difluoromethoxy (OCHF2), trifluoromethoxy (OCF3), pentafluoroethoxy, 1,1-difluoroethoxy (OC(CH3)F2), 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy (OCH2CF3), 3,3,3-trifluoropropoxy, 4.4.4-trifluorobutoxy, trichloromethoxy groups, and the like.

[0024] The term “aryl” when used alone or as part of a substituent group also refers to a mono- or bicyclic- aromatic hydrocarbon ring structure having 6 or 10 carbon atoms in the ring, wherein one or more of the carbon atoms in the ring is optionally substituted. The term “aryl” also includes a mono- or bicyclic- aromatic hydrocarbon ring structure having 6 or 10 carbon atoms in the ring, wherein two adjacent carbon atoms in the ring are optionally substituted such that said two adjacent carbon atoms and their respective substituents form a cycloalkyl or heterocyclyl ring. Examples of aryl groups include phenyl, indenyl, naphthyl, 1.2.3.4-tetrahydronaphthyl, and the like.

[0025] “Cycloalkyl” when used alone or as part of another group refers to a completely saturated monocyclic or bicyclic hydrocarbon group. Unless otherwise specified, a cycloalkyl has 3-10 ring carbon atoms, alternatively 3-6 ring carbon atoms. A cycloalkyl can be monocyclic, fused bicyclic and bridged bicyclic. The term “cycloalkyl” also includes groups where -CH2- is replaced by a -C(O)-. A monocyclic cycloalkyl has 3-6 ring carbon atoms (i.e, (C3-C6)cycloalkyl) and includes cyclopropyl, cyclobutyl, cyclpentyl, cyclohexyl, cyclopentyl, cyclopheptyl and cyclooctyl. Bicyclic cycloalkyl groups include fused bicyclic cycloalkyl groups, spiro bicyclic cycloalkyl groups, and bridged bicyclic cycloalkyl groups. In some aspects, cycloalkyl groups are selected from among spiro[2.2]pentyl, bicyclo [l.l.l]pentyl, bicyclo [3.3.0] octane, bicyclo[4.3.0]nonane, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo [3.3.2] decane, norbornyl, 3,4-dihydronaphthalen-l(2H)-one and decalinyl.

[0026] The term “carbocyclyl” when used alone or as part of a substituent group also refers to a saturated or partially unsaturated cyclic aliphatic monocyclic, bicyclic, or polycyclic ring systems, as described herein, having from 3 to 14 members, wherein the aliphatic ring system is optionally substituted as described herein. The term “carbocyclyl” also includes groups where -CH2- is replaced by a -C(O)-. A carbocycle may comprise fused ring systems, bridged ring systems, and / or spiro ring systems. Carbocyclic groups include,7ME1\60337174.v1141039-00120without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, norbornyl, adamantyl, and cyclooctadienyl.

[0027] " Heteroaryl" when used alone or as part of another group refers to an aromatic 5-to 10-membered mono or bicyclic cyclic ring system, having 1 to 4 heteroatoms independently selected from O, N and S, and wherein N can be oxidized (e.g N(O)) or quatemized, and S can be optionally oxidized to sulfoxide and sulfone. Monocyclic heteroaryls include e.g, pyrrolyl, furanyl, thiophenyl (or thienyl), imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dithiazolyl, triazolyl, tetrazolyl, pyridinyl, pyranyl, thiopyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazinyl, thiazinyl, dioxinyl, dithiinyl, oxathianyl, triazinyl, tetrazinyl, and the like. Examples of bicyclic heteroaryls include, but are not limited to indolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzofuranyl, benzothiofuranyl, pyrazolopyridinyl, quinolinyl, isoquinolinyl, thienopyridinyl, indazolyl and the like.

[0028] " Heterocyclyl" as used by itself or as part of another group refers to a nonaromatic saturated or partially unsaturated monocyclic or bicyclic (e.g, fused or bridged) ring system which has from 4- to 12-ring members, e.g, 4-10 ring members, at least one of which is a heteroatom, and up to 4 (e.g, 1, 2, 3, or 4) of which may be heteroatoms, wherein the heteroatoms are independently selected from O, S and N, and wherein N can be oxidized (e.g N(O)) or quatemized, and S can be optionally oxidized to sulfoxide and sulfone. The term “heterocyclyl” also includes groups where -CH2- is replaced by a -C(O)-. Examples of monocyclic heterocyclyls include, but are not limited to, oxetanyl, thietanyl, azetedinyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, trioxanyl, trithianyl, azepanyl, oxepanyl, thiepanyl, dihydrofuranyl, imidazolinyl, 1,1 -dioxide thietanyl, and dihydropyranyl. Examples of fused bicyclic heterocyclyls include cyclopropylpyrrolidinyl, cyclopentapyrrolidinyl, cyclopentapiperidinyl, cyclopentaazapanyl, cyclohexapyrrolidinyl, cyclohexapiperidinyl, cyclohexaazapanyl, cycloheptapyrrolidinyl, cycloheptapiperidinyl, cycloheptaazapanyl, pyranopyrrolidinyl, pyranopiperidinyl, pyranoazapanyl, 6,7 -dihydro-5H-pyrazolo [5, 1 -b] [ 1,3 ] oxazinyl, 2,3 -dihydropyrazolo [5,1-b]oxazolyl, tetrahydroisoquinolinyl, tetrahydropyrroloimidazolyl, tetrahydronaphthyridinyl, tetrahydroimidazopyridinyl, hexahydroimidazoazepinyl, iminohydrothieno[3,4-b]pyridine oxidyl, and the like. Examples of bridged bicyclic heterocyclyl groups include8ME1\60337174.v1141039-00120azabicyclo[2.2.1]hepantyl, azabicyclo[3.2.1]octanyl, azabicyclo [3.3.1]nonanyl, diazabicyclo[2.2.1]hepantyl, diazabicyclo[3.2.1]octanyl and diazabicyclo [3.3.1]nonanyl. Examples of oxygen containing bridged bicyclics include oxobicyclo[2.2.1]hepantyl, oxobicyclo[3.2.1]octanyl, oxobicyclo [3.3.1]nonanyl, oxa-azabicyclo[2.2.1]hepantyl, oxa-azabicyclo[3.2.1]octanyl and oxa-azabicyclo [3.3.1]nonanyl.

[0029] If a group is described as “optionally substituted”, the group can be either (1) not substituted or (2) substituted. For example, a substituent may be optionally substituted with one or more of: halo, cyano, -NO2, -N3, -OH, -SH, C1-6alkyl, C3-8cycloalkyl, C3-8cycloalkenyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6alkoxy(alkylene), C1-6haloalkoxy, C1-6haloalkoxy(alkylene), C1-6alkylcarbonyl, C1-6cyanoalkyl, C1-6hydoxyalkyl, C1-6alkylenethio, (CRvRx)pNRyRz(wherein Rvand Rxare, independently, H or Ci-6alkyl; Ryand Rz, are independently, H, C1-6alkyl, C3-6cycloalkyl, C1-6hydroxyalkyl, C1-6haloalkyl, C1-6alkoxy(alkylene), or C(O)OC1-6alkyl, and p is 0, 1, 2, or 3), -C(O)NH2, -C(O)NHCi-ealkyl, -C(O)N(Ci-6alkyl)2, -C(O)NHC3-6cycloalkyl, -C(O)N(C3-6cycloalkyl)2, -COOH, -C1-6alkyleneCOOH, -C3-6cycloalkylCOOH, -C1-6alkyleneCONH2, C3-6cycloalkylCONH2, -C1-6alkyleneCONHC1-6alkyl, -C1-6alkyleneCON(C1-6alkyl)2, -C(O)OCi-6alkyl, -NHCO(C1-6alkyl), -N(C1-6alkyl)C(O)(C1-6alkyl), -S(O)C1-6alkyl, -S(O)C3-6cycloalkyl, C1-6alkylsulfonyl, C3-8cycloalkylsulfonyl, C1-6alkylsulfonyl(alkylene), oxo (=0), 3-7-membered heterocyclyl, heterocyclyl(alkylene), aryl, aryl(alkylene), or heteroaryl groups.

[0030] Recitation of ranges of values herein are intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The use of any and all examples, or exemplary language (e.g “such as”) provided herein, is intended to better illustrate the disclosure and is not a limitation on the scope of the disclosure unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the disclosure.

[0031] Compounds having one or more chiral centers can exist in various stereoisomeric forms, i.e, each chiral center can have an R or S configuration or can be a mixture of both. Stereoisomers are compounds that differ only in their spatial arrangement. Stereoisomers include all diastereomeric and enantiomeric forms of a compound. Enantiomers are stereoisomers that are non-superimposable mirror images of each other. Diastereomers are stereoisomers having two or more chiral centers that are not identical and are not mirror images of each other. A “geometric isomer” refers to isomers that differ in the orientation of 9ME1\60337174.v1141039-00120substituent group in relationship to a carbon-carbon double bond, a cycloalkyl ring, or a bridged bicyclic system. Atoms (other than H) on each side of a carbon-carbon double bond may be in an E (substituents are on opposite sides of the carbon-carbon double bond) or Z (substituents are oriented on the same side) configuration. “Cis” refers to substituents oriented on the same side of the ring, whereas “trans” refers to substituents oriented on opposite sides of the ring.

[0032] When the stereochemical configuration at a chiral center in a compound having one or more chiral centers is depicted by its IUPAC Name (e.g, where the configuration is indicated in the IUPAC Name by “R” or “S”) or structure (e.g, the configuration is indicated by “wedge” bonds), the enrichment of the indicated configuration relative to the opposite configuration is greater than 50%, 60%, 70%, 80%, 90%, 99% or 99.9% “Enrichment of the indicated configuration relative to the opposite configuration” is a mole percent and is determined by dividing the number of compounds with the indicated stereochemical configuration at the chiral center(s) by the total number of all of the compounds with the same or opposite stereochemical configuration in a mixture.

[0033] When the stereochemistry of a disclosed compound is named or depicted by structure, and the named or depicted structure encompasses more than one stereoisomer (e.g as in a diastereomeric pair), it is to be understood that, unless otherwise indicated, one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers are included. It is to be further understood that the stereoisomeric purity of the named or depicted stereoisomers is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight. The stereoisomeric purity in this case is determined by dividing the total weight in the mixture of the stereoisomers encompassed by the name or structure by the total weight in the mixture of all of the stereoisomers.

[0034] When a geometric isomer is depicted by name or structure, the enrichment of the indicated isomer relative to the opposite isomer is greater than 50%, 60%, 70%, 80%, 90%, 99% or 99.9%. “Enrichment of the indicated isomer relative to the opposite isomer” is a mole percent and is determined by dividing the number of compounds with the indicated geometrical configuration by the total number of all of the compounds with the same or opposite geometrical configuration in a mixture.

[0035] When a disclosed compound is named or depicted by structure without indicating stereochemistry, it is understood that the name or the structure encompasses one of the possible stereoisomers or geometric isomers free of the others, or a mixture of the encompassed stereoisomers or geometric isomers.10ME1\60337174.v1141039-00120

[0036] In some aspects, the compounds described herein are isotopically enriched compound, e.g an isotopologue. The term “isotopically enriched” refers to an atom having an isotopic composition other than the naturally abundant isotopic composition of that atom. “Isotopically enriched” may also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of that atom. In an isotopologue, “isotopic enrichment” refers to the percentage of incorporation of an amount of a specific isotope of a given atom in a molecule in the place of that atom’s natural isotopic composition. For example, deuterium enrichment of 1% at a given position means that 1% of the molecules in a given sample contain deuterium at the specified position. Because the naturally occurring distribution of deuterium is about 0.0156%, deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is about 0.0156%. In one aspect, one or more hydrogen atoms on a described compound may be replaced by deuterium.

[0037] It will be understood that certain compounds disclosed herein may exist in tautomeric forms. Such forms are included as part of the present disclosure. Thus, when a compound herein is represented by a structural formula or designated by a IUPAC Name herein, all tautomeric forms which may exist for the compound are encompassed by the structural formula.

[0038] To the extent that a IUPAC Name is not consistent with the drawn structure, the structure takes priority.

[0039] The terms “subject” and “patient” may be used interchangeably, and means a mammal in need of treatment, e.g companion animals (e.g dogs, cats, and the like), farm animals (e.g cows, pigs, horses, sheep, goats and the like) and laboratory animals (e.g rats, mice, guinea pigs and the like). Typically, the subject is a human in need of treatment.

[0040] The term “inhibit,” “inhibition” or “inhibiting” includes a decrease in the baseline activity of a biological activity or process.

[0041] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some aspects, treatment may be administered after one or more symptoms have developed, i.e therapeutic treatment. In other aspects, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g in light of a history of symptoms and / or in light of exposure to a particular organism, or other11ME1\60337174.v1141039-00120susceptibility factors), i.e prophylactic treatment. Treatment may also be continued after symptoms have resolved, for example to delay their recurrence.

[0042] The terms “prevent,” “preventing,” and “prevention” refer to the prevention of the onset, recurrence, or spread of the disease in a subject resulting from the administration of a prophylactic or therapeutic agent.

[0043] The term “about” when used in combination with a numeric value or range of values means the value or range of values may deviate to an extent deemed reasonable to one of ordinary skill in the art.

[0044] “Pharmaceutically acceptable” means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in a country other than the United States, or that is listed in the U. S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, e.g in humans.

[0045] In cases where a compound provided herein is sufficiently basic or acidic to form stable nontoxic acid or base salts, preparation and administration of the compounds as pharmaceutically acceptable salts may be appropriate. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, a ketoglutarate, or a-glycerophosphate. Inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts.

[0046] Pharmaceutically-acceptable base addition salts can be prepared from inorganic and organic bases. Salts from inorganic bases, can include but are not limited to, sodium, potassium, lithium, ammonium, calcium or magnesium salts. Salts derived from organic bases can include, but are not limited to, salts of primary, secondary or tertiary amines, such as alkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines, di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenyl amines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines, di(substituted alkenyl) amines, tri(substituted alkenyl) amines, cycloalkyl amines, di(cycloalkyl) amines, tri(cycloalkyl) amines, substituted cycloalkyl amines, disubstituted cycloalkyl amine, trisubstituted cycloalkyl amines, cycloalkenyl amines, di(cycloalkenyl) amines, tri(cycloalkenyl) amines, substituted cycloalkenyl amines, disubstituted cycloalkenyl amine, trisubstituted cycloalkenyl amines, aryl amines, diaryl amines, triaryl amines, heteroaryl amines, diheteroaryl amines, triheteroaryl amines, heterocycloalkyl amines, diheterocycloalkyl amines, triheterocycloalkyl amines, or mixed di- and tri-amines where at least two of the substituents on the amine can be 12ME1\60337174.v1141039-00120different and can be alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, or heterocycloalkyl and the like. Also included are amines where the two or three substituents, together with the amino nitrogen, form a heterocycloalkyl or heteroaryl group. Non-limiting examples of amines can include, isopropylamine, trimethylamine, diethylamine, tri(iso-propyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethyl-aminoethanol, trimethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purines, piperazine, piperidine, morpholine, or N-ethylpiperidine, and the like. Other carboxylic acid derivatives can be useful, for example, carboxylic acid amides, including carboxamides, lower alkyl carboxamides, or dialkyl carboxamides, and the like.

[0047] The terms “administer”, “administering”, “administration”, and the like, as used herein, refer to methods that may be used to enable delivery of compositions to the desired site of biological action. These methods include, but are not limited to, intraarticular (in the joints), intravenous, intramuscular, intratumoral, intradermal, intraperitoneal, subcutaneous, orally, topically, intrathecally, inhalationally, transdermally, rectally, and the like.Administration techniques that can be employed with the agents and methods described herein are found in e.g Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co, Easton, Pa. In one aspect, the route of administration for the described compounds, salts, and compositions is oral administration.

[0048] The precise amount of compound or pharmaceutically acceptable salt thereof administered to provide an “effective amount” to the subject will depend on the mode of administration, the type, and severity of the disease or condition, and on the characteristics of the subject, such as general health, age, sex, body weight, and tolerance to drugs. The skilled artisan will be able to determine appropriate dosages depending on these and other factors. When administered in combination with other therapeutic agents, e.g when administered in combination with an anti-cancer or antiviral agent, an “effective amount” of any additional therapeutic agent(s) will depend on the type of drug used. Suitable dosages are known for approved therapeutic agents and can be adjusted by the skilled artisan according to the condition of the subject, the type of condition(s) being treated and the amount of a compound of the disclosure or a pharmaceutically acceptable salt thereof being used by following, for example, dosages reported in the literature and recommended in the Physician’s Desk Reference (57th ed, 2003).13ME1\60337174.v1141039-00120

[0049] The term “effective amount” means an amount when administered to the subject which results in beneficial or desired results, including clinical results, e.g, inhibits, suppresses or reduces the symptoms of the condition being treated in the subject as compared to a control. For example, a therapeutically effective amount can be given in unit dosage form (e.g 0.1 mg to about 50 g per day).

[0050] The particular mode of administration and the dosage regimen will be selected by the attending clinician, taking into account the particulars of the case (e.g. the subject, the disease, the disease state involved, the particular treatment, and whether the treatment is prophylactic). Treatment can involve daily or multi-daily or less than daily (such as weekly or monthly etc.) doses over a period of a few days to months, or even years.

[0051] “Pharmaceutically acceptable carrier” refers to a substance that aids the formulation and / or administration of an active agent to and / or absorption by a subject and can be included in the compositions of the disclosure without causing a significant adverse toxicological effect on the subject. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and / or aromatic substances and the like that do not deleteriously react with or interfere with the activity of the compounds provided herein. One of ordinary skill in the art will recognize that other pharmaceutical excipients are suitable for use with described compounds.

[0052] In an alternative first aspect, provided is the compound of Formula I, or a pharmaceutically acceptable salt thereof, whereinRing A is phenyl, 5- to 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, or 8- to 10-membered bicyclic heterocyclyl, wherein Ring A is attached to Ring B and Ring C via two adjacent atoms;R3is halo, cyano, hydroxy, (C1-C6)alkyl, hydroxy(C1-C6)alkyl, (Ci-C6)alkyleneO(Ci-C6)alkyl, (Ci-C6)alkyleneNH2, -Y-W, (Ci-C6)alkyleneNH(Ci-C6)alkyl, (Ci-C6)alkyleneN[(Ci-C6)alkyl]2, cyano(Ci-C6)alkyl, halo(Ci-C6)alkyl, (Ci-Cejalkoxy, halo(Ci-C6)alkoxy, 5- to 7-membered monocyclic heteroaryl, 4- to 7-membered monocyclic heterocyclyl, (C3-Cejcycloalkyl, and (Ci-Cejalkynyl, wherein said 5- to 7-membered monocyclic heteroaryl, 4- 14ME1\60337174.v1141039-00120to 7-membered monocyclic heterocyclyl, and (C3-C6)cycloalkyl are each optionally substituted with 1 to 3 groups selected from Rxl;R4is selected from hydrogen, halo, cyano, hydroxy, (Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, (Ci-C6)alkyleneO(Ci-C6)alkyl, (Ci-C6)alkyleneNH2, -Y-W, (Ci-C6)alkyleneNH(Ci-Ce)alkyl, (Ci-C6)alkyleneN[(Ci-C6)alkyl]2, cyano(Ci-C6)alkyl, halo(Ci-C6)alkyl, (Ci-Ce)alkoxy, halo(Ci-C6)alkoxy, 5- to 7-membered monocyclic heteroaryl, 4- to 7-membered monocyclic heterocyclyl, (C3-C6)cycloalkyl, and (C2-C6)alkynyl, wherein said 5- to 7-membered monocyclic heteroaryl, 4- to 7-membered monocyclic heterocyclyl, and (C3-C6)cycloalkyl are each optionally substituted with 1 to 3 groups selected from Rxl; and Y, Ya, Yb, and Ycare each independently a bond, C(O), S(O), or S(O)2;R10and R11are each independently selected from hydrogen, (Ci-C6)alkyl, (C3- C6)cycloalkyl, halo, cyano, (Ci-C6)alkoxy, (Ci-C6)alkyleneNR8R9, 4- to 7-membered monocyclic heterocyclyl phenyl, and 5- to 6-membered monocyclic heteroaryl, and wherein the variables are as described above for Formula I.

[0053] In a second aspect, R3in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is (Ci-C4)alkyl, and wherein the variables are as described above for Formula I.

[0054] In a third aspect, q in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is 0 or 2, and wherein the variables are as described above for Formula I, or the second aspect. Alternatively, as part of a third aspect, q in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is 0.

[0055] In a fourth aspect, L in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from:

[0072] IO I | JW 1 VH, and I, and wherein the variables are as described above for Formula I, the second or the third aspect. Alternatively, as part of a fourth aspect, L in the15ME1\60337174.v1141039-00120compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from:o, and, and wherein the variables are as described above for Formula I, the second or the third aspect.

[0073] In another alternative, as part of a fourth aspect, L in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from:described above for Formula I, the second or the third aspect. In another alternative, as part of a fourth aspect, L in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from:O, and H, and wherein the variables are as described above for Formula I, the second or the third aspect In another alternative, as part of a fourth aspect, L in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from::O', and and wherein the variables are as described above16ME1\60337174.v1141039-00120for Formula I, the second or the third aspect. In another alternative, as part of a fourth aspect, L in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selectedand wherein the variables are as described above for Formula I, the second or the third aspect. In another alternative, as part of a fourth aspect, L in the compound of Formula I, or apharmaceutically acceptable salt thereof, is selected from:and wherein the variables are as described above for Formula I, the second or the third aspect. In another alternative, as part of a fourth aspect, L in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selectedfrom:and, and wherein the variables are as described above for Formula I, the second or the third aspect. In another alternative, as part of a fourth aspect, L in the compound of Formula I, or apharmaceutically acceptable salt thereof, is selected from:, and wherein the variables are as described above for Formula I, the second or the third aspect. In another alternative, as part of a fourth aspect, L in the compound ofFormula I, or a pharmaceutically acceptable salt thereof, is selected from:O 0, and, wherein the squiggly line indicates the connection to Ring C and the dotted line indicates the connection to Ring B, and wherein the variables are as described above for Formula I, the second or the third aspect. In another alternative, as part of a fourth aspect, L in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from:O', and, wherein the squiggly line indicates the connection to Ring C and the dotted line indicates the connection to Ring B, and wherein the variables are as described above for Formula I, the second or the third aspect. In another alternative, as part of a second aspect, L in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from:17ME1\60337174.v1141039-00120, and, wherein the squiggly line indicates the connection to Ring C and the dotted line indicates the connection to Ring B, and wherein the variables are as described above for Formula I, the second or the third aspect. In another alternative, as part of a second aspect, L in the compound of Formula I, or apharmaceutically acceptable salt thereof, is selected from:O'dotted line indicates the connection to Ring B, and wherein the variables are as described above for Formula I, the second or the third aspect. In another alternative, as part of a second aspect, L in the compound of Formula I, or a pharmaceutically acceptable salt thereof, isselected from:and O' ', wherein the squiggly line indicates the connection to Ring C and the dotted line indicates the connection to Ring B, and wherein the variables are as described above for Formula I, the second or the third aspect.

[0056] In a fifth aspect, Ring B in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is phenyl, and wherein the variables are as described above for Formula I or any one of the second to fourth aspect.

[0057] In a sixth aspect, the compound of Formula I is of the Formula II:

[0076] (II);

[0077] or a pharmaceutically acceptable salt thereof, and wherein the variables are as described above for Formula I or any one of the second to fifth aspects.

[0058] In a seventh aspect, R1in the compound of Formula I or II, or a pharmaceutically acceptable salt thereof, is hydrogen or halo, and wherein the variables are as described above for Formula I or any one of the second to sixth aspects. Alternatively, as part of a seventh aspect, R1in the compound of Formula I or II, or a pharmaceutically acceptable salt thereof, is halo, and wherein the variables are as described above for Formula I or any one of the second to sixth aspects. In another alternative, as part of a seventh aspect, R1in the18ME1\60337174.v1141039-00120compound of Formula I or II, or a pharmaceutically acceptable salt thereof, is fluoro, and wherein the variables are as described above for Formula I or any one of the second to sixth aspects.

[0059] In an eighth aspect, R2in the compound of Formula I or II, or a pharmaceutically acceptable salt thereof, is hydrogen or halo, and wherein the variables are as described above for Formula I or any one of the second to seventh aspects. Alternatively, as part of an eighth aspect, R2in the compound of Formula I or II, or a pharmaceutically acceptable salt thereof, is halo, and wherein the variables are as described above for Formula I or any one of the second to seventh aspects. In another alternative, as part of an eighth aspect, R2in the compound of Formula I or II, or a pharmaceutically acceptable salt thereof, is hydrogen or fluoro, and wherein the variables are as described above for Formula I or any one of the second to seventh aspects. In another alternative, as part of an eighth aspect, R2in the compound of Formula I or II, or a pharmaceutically acceptable salt thereof, is fluoro, and wherein the variables are as described above for Formula I or any one of the second to seventh aspects.

[0060] In a ninth aspect, the compound of Formula I or II, is of the Formula III or IV:

[0079] or a pharmaceutically acceptable salt thereof, and wherein the variables are as described above for Formula I or any one of the second to eighth aspects.

[0061] In a tenth aspect, Ring A in the compound of Formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, is an 8- to 10-membered bicyclic heterocyclyl or an 8- to 10-membered bicyclic carbocyclyl, wherein Ring A is attached to Ring B and Ring C via two adjacent atoms, and wherein the variables are as described above for Formula I or any one of the third to ninth aspects. Alternatively, as part of a tenth aspect, Ring A in the compound of Formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, s a 9-membered bicyclic heterocyclyl or 9-membered bicyclic carbocyclyl, and wherein the variables are as described above for Formula I or any one of the third to ninth aspects. In another alternative, as part of a tenth aspect, Ring A in the compound of Formula I, II, III or19ME1\60337174.v1141039-00120IV, or a pharmaceutically acceptable salt thereof, is dihydrocyclopentapyridinyl or dihydroindenyl, and wherein the variables are as described above for Formula I or any one of the third to ninth aspects. In another alternative, as part of a tenth aspect, Ring A in the compound of Formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, is dihydrocyclopentapyridinyl, and wherein the variables are as described above for Formula I or any one of the second to ninth aspects. In another alternative, as part of a tenth aspect, Ring A in the compound of Formula I, II, III or IV, or a pharmaceutically acceptable saltthereof,is R or R, wherein the squiggly line indicates the connection to Ring C and the dotted line indicates the connection to Ring B, and wherein the variables are as described above for Formula I or any one of the third to ninth aspects. In another alternative, as part of a tenth aspect, Ring A in the compound of Formula I, II, III orIV, or a pharmaceutically acceptable salt thereof, isR wherein the squiggly line indicates the connection to Ring C and the dotted line indicates the connection to Ring B, and wherein the variables are as described above for Formula I or any one of the second to ninth aspects. In another alternative, as part of a tenth aspect, Ring A in the compound of Formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, is 8- to 10-membered bicyclic heteroaryl, and wherein the variables are as described above for Formula I or any one of the second to ninth aspects. In another alternative, as part of a tenth aspect, Ring A in the compound of Formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, is 8-to 10-membered thienopyridinyl, and wherein the variables are as described above for Formula I or any one of the second to ninth aspects. In another alternative, as part of a tenth aspect, Ring A in the compound of Formula I, II, III or IV, or a pharmaceutically acceptableI p5salt thereof,is R, and wherein the variables are as described above for Formula I or any one of the second to ninth aspects. In another alternative, as part of a tenth aspect, Ring A in the compound of Formula I, II, III or IV, or a pharmaceutically acceptable salt20ME1\60337174.v1141039-00120s.M ^XR6I R5thereof,is R, wherein the squiggly line indicates the connection to Ring C and the dotted line indicates the connection to Ring B, and wherein the variables are as described above for Formula I or any one of the second to ninth aspects.

[0062] In an eleventh aspect, R5in the compound of Formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, is hydrogen, and wherein the variables are as described above for Formula I or any one of the second to tenth aspects.

[0063] In a twelfth aspect, R6in the compound of Formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, is hydrogen, and wherein the variables are as described above for Formula I or any one of the second to eleventh aspects.

[0064] In a thirteenth aspect, R in the compound of Formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, is phenyl, 5- to 6-membered monocyclic heteroaryl, 7- to 10-membered bicyclic heterocyclyl, 8- to 10-membered bicyclic heteroaryl, or C≡C-R7, wherein each of said phenyl, 5- to 6-membered monocyclic heteroaryl, 7- to 10-membered bicyclic heterocyclyl, and 8- to 10-membered bicyclic heteroaryl are optionally substituted with 1 to 3 groups selected from Rx, and wherein the variables are as described above for Formula I or any one of the second to twelfth aspects. Alternatively, as part of a thirteenth aspect, R in the compound of Formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, is phenyl, 6-membered monocyclic heteroaryl, 9-membered bicyclic heteroaryl, 10-membered bicyclic heterocyclyl, or C≡C-R7, wherein each of said phenyl, 6-membered monocyclic heteroaryl, 9-membered bicyclic heteroaryl, and 10-membered bicyclic heterocyclyl are optionally substituted with 1 to 3 groups selected from Rx, and wherein the variables are as described above for Formula I or any one of the second to twelfth aspects. In another alternative, as part of a thirteenth aspect, R in the compound of Formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, is phenyl, pyridinyl, indazolyl, tetrahydroisoquinolinyl, tetrahydronaphthyridinyl, pyrazolopyridinyl or C≡C-R7, wherein each of said phenyl, indazolyl, and tetrahydroisoquinolinyl are optionally substituted with 1 to 3 groups selected from Rx, and wherein the variables are as described above for Formula I or any one of the second to twelfth aspects. In another alternative, as part of a thirteenth aspect, R in the compound of Formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, is 5- to 6-membered monocyclic heteroaryl, 7- to 10-membered bicyclic heterocyclyl, or 8- to 10-membered bicyclic heteroaryl, each of which are optionally substituted with 1 to 321ME1\60337174.v1141039-00120groups selected from Rx, and wherein the variables are as described above for Formula I or any one of the second to twelfth aspects. In another alternative, as part of a thirteenth aspect, R in the compound of Formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, is 6-membered monocyclic heteroaryl, 9-membered bicyclic heteroaryl, 9-membered bicyclic heterocyclyl, or 10-membered bicyclic heterocyclyl, each of which are optionally substituted with 1 to 3 groups selected from Rx, and wherein the variables are as described above for Formula I or any one of the second to twelfth aspects. In another alternative, as part of a thirteenth aspect, R in the compound of Formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, is phenyl, pyridinyl, indazolyl, tetrahydroisoquinolinyl, tetrahydronaphthyridinyl, pyrazolopyridinyl or C≡C-R7, wherein each of said phenyl, indazolyl, and tetrahydroisoquinolinyl are optionally substituted with 1 to 3 groups selected from Rx, and wherein the variables are as described above for Formula I or any one of the second to twelfth aspects. In another alternative, as part of a thirteenth aspect, R in the compound of Formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, is pyridinyl, dihydroimidazopyridin-2-onyl, tetrahydronaphthyridinyl, dihydropyrrolopyridin-7-onyl, dihydropyrrolopyridin-5-onyl, dihydropyrrolopyridinyl, pyrazolopyridinyl, imidazopyridinyl, each of which are optionally substituted with 1 to 3 groups selected from Rx, and wherein the variables are as described above for Formula I or any one of the second to twelfth aspects.

[0065] In a fourteenth aspect, Rxin the compound of Formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, is (C1-C4)alkyl halo(C1-C4)alkyl, halo(C1-C4)alkoxy, NHS(O)2NH2or (C1-C4)alkyleneNR8R9, and wherein the variables are as described above for Formula I or any one of the second to thirteenth aspects.

[0066] In a fifteenth aspect, R8in the compound of Formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, is (C1-C4)alkyl, and wherein the variables are as described above for Formula I or any one of the second to fourteenth aspects.

[0067] In a sixteenth aspect, R9in the compound of Formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, is (C1-C4)alkyl, and wherein the variables are as described above for Formula I or any one of the second to fifteenth aspects.

[0068] In a seventeenth aspect, R7in the compound of Formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, is 5- to 6-membered monocyclic heteroaryl optionally substituted with 1 to 3 groups selected from Rz, and wherein the variables are as described above for Formula I or any one of the second to thirteenth aspects. Alternatively, as part of a fifteenth aspect, R7in the compound of Formula I, II, III or IV, or a22ME1\60337174.v1141039-00120pharmaceutically acceptable salt thereof, is pyridinyl optionally substituted with 1 to 3 groups selected from Rz, and wherein the variables are as described above for Formula I or any one of the second to thirteenth aspects.

[0069] In an eighteenth aspect, Rzin the compound of Formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, is (C1-C4)alkyl, and wherein the variables are as described above for Formula I or any one of the second to thirteenth or seventeenth aspects.

[0070] In a nineteenth aspect,R in the compound of Formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, is23ME1\60337174.v1141039-0012024ME1\60337174.v1141039-00120 y y A " jy ° V A0*— O O / OH O VN\ H ~O\ '25ME1\60337174.v1141039-00120ME1\60337174.v1141039-0012027ME1\60337174.v1MEl\60337174.vl 28141039-0012029ME1\60337174.v1141039-0012030ME1\60337174.v1141039-0012031ME1\60337174.v1141039-00120line indicates the connection to Ring B, and wherein the variables are as described above for Formula I or any one of the second to ninth aspects. Alternatively, as part of a nineteenthaspect,R in the compound of Formula I, II, III or IV, or a pharmaceuticallyacceptable salt thereof, is:32ME1\60337174.v1141039-0012033ME1\60337174.v1141039-0012034ME1\60337174.v1141039-0012035ME1\60337174.v1141039-0012036ME1\60337174.v1141039-00120ME1\60337174.v1141039-0012038ME1\60337174.v1141039-0012039ME1\60337174.v1141039-00120squiggly line indicates the connection to Ring C and the dotted line indicates the connection to Ring B, and wherein the variables are as described above for Formula I or any one of thesecond to ninth aspects. In another aleternative, as part of a nineteenth aspect,R in the compound of Formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, is40ME1\60337174.v1141039-00120connection to Ring C and the dotted line indicates the connection to Ring B, and wherein the variables are as described above for Formula I or any one of the second to ninth aspects.Alternatively, as part of a nineteenth aspect,R in the compound of Formula I, II,C and the dotted line indicates the connection to Ring B, and wherein the variables are as described above for Formula I or any one of the second to ninth aspects.41ME1\60337174.v1141039-00120

[0071] In a twentieth aspect, Ring C in the compound of Formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, is 8- to 10-membered bicyclic heterocyclyl, and wherein the variables are as described above for Formula I or any one of the second to nineteenth aspects. Alternatively, as part of a twentieth aspect, Ring C in the compound of Formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, is tetrahydropyrroloimidazolyl, tetrahydroimidazopyridinyl, or -hexahydroimidazoazepinyl, and wherein the variables are as described above for Formula I or any one of the second to nineteenth aspects. In another alternative, as part of a twentieth aspect, Ring C in the compound of Formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, is tetrahydroimidazopyridinyl, and wherein the variables are as described above for Formula I or any one of the second to nineteenth aspects. In another alternative, as part of the twentieth aspect, Ring C in the compound of Formula I, II, III or IV, or a pharmaceutically acceptableline indicates the connection to L and the dotted line indicates the connection to Ring A, and wherein the variables are as described above for Formula I or any one of the second to nineteenth aspects. In another alternative, as part of a twentieth aspect, Ring C in the compound of Formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, isr3S,R\HNA^-R4, or R4, wherein the squiggly line indicates the connection to L and the dotted line indicates the connection to Ring A, and wherein the variables are as described above for Formula I or any one of the second to nineteenth aspects. In another alternative, as part of a twentieth aspect, Ring C in the compound of Formula I, II,42ME1\60337174.v1141039-00120Ill or IV, or a pharmaceutically acceptable salt thereof,iswherein the squiggly line indicates the connection to L and the dotted line indicates the connection to Ring A, and wherein the variables are as described above for Formula I or any one of the second to nineteenth aspects. In another alternative, as part of a twentieth aspect, Ring C in the compound of Formula I, II, III or IV,R3UN J| / >-R4, wherein the squiggly line indicates the connection to L and the dotted line indicates the connection to Ring A, and wherein the variables are as described above for Formula I or any one of the second to nineteenth aspects. In another alternative, as part of a twentieth aspect, Ring C in the compound of Formula I, II, III or IV, or a pharmaceutically R3R3SHN. Nacceptable salt thereof, is4R R4, wherein the squiggly line indicates the connection to L and the dotted line indicates the connection to Ring A, and wherein the variables are as described above for Formula I or any one of the second to nineteenth aspects. In another alternative, as part of a twentieth aspect, Ring C in the compound of Formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, isline indicates the connection to L and the dotted line indicates the connection to Ring A, and43ME1\60337174.v1141039-00120wherein the variables are as described above for Formula I or any one of the second to nineteenth aspects.

[0072] In a twenty-first aspect, R4in the compound of Formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, is -Yb-Wb, cyano, or (C3-C6)cycloalkenyl optionally subsitited with 1 to 3 groups selected from Rxl, and wherein the variables are as described above for Formula I or any one of the second to twentieth aspects. Alternatively, as part of a twenty-first aspect, R4in the compound of Formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, is -Yb-Wb, and wherein the variables are as described above for Formula I or any one of the second to twentieth aspects.

[0073] In a twenty-second aspect, Ybin the compound of Formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, is a bond, C(O), CFh, or SO2, and wherein the variables are as described above for Formula I or any one of the second to twenty-first aspects. Alternatively, as part of a twenty-second aspect, Ybin the compound of Formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, is C(O), and wherein the variables are as described above for Formula I or any one of the second to twenty-first aspects.

[0074] In a twenty-third aspect, Wbin the compound of Formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, is -CH2R8, -CR8=CR10Rn, (C3-C6)cycloalkenyl, or -C=CRn, and wherein the variables are as described above for Formula I or any one of the second to twenty-second aspects. Alternatively, as part of a twenty-third aspect, Wbin the compound of Formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, is -CR8=CR10Rn, and wherein the variables are as described above for Formula I or any one of the second to twenty-second aspects.

[0075] In a twenty-fourth aspect, R8in the compound of Formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, is CN, halogen, hydrogen, or (Ci-C3)alkylenecyano, and wherein the variables are as described above for Formula I or any one of the third to twenty-third aspects. Alternatively, as part of a twenty-fourth aspect, R8in the compound of Formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, is hydrogen or halo, and wherein the variables are as described above for Formula I or any one of the third to twenty-third aspects. In another alternative, as part of a twenty-fourth aspect, R8in the compound of Formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, is hydrogen or fluoro, and wherein the variables are as described above for Formula I or any one of the third to twenty-third aspects. In another alternative, as part of a twenty-fourth aspect, R8in the compound of Formula I, II, III or IV, or a pharmaceutically acceptable salt44ME1\60337174.v1141039-00120thereof, is hydrogen, and wherein the variables are as described above for Formula I or any one of the second to twenty-third aspects.

[0076] In a twenty-fifth aspect, R10and R11in the compound of Formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, are each hydrogen, halogen, C i-shaloalkyl, Ci-salkyl, (Ci-C3)alkyleneNR8R9, (Ci-C3)alkoxy, (Ci-C3)alkylene 4- to 8-membered monocyclic heterocyclyl, or C(O)NH(Ci-3alkyl), and wherein the variables are as described above for Formula I or any one of the third to twenty-fourth aspects. Alternatively, as part a twentyfirth aspect, R10and R11in the compound of Formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, are each hydrogen, and wherein the variables are as described above for Formula I or any one of the second to twenty-fourth aspects. In another alternative, as part of a twenty-fifth aspect, R10in the compound of Formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, is hydrogen or halo, and wherein the variables are as described above for Formula I or any one of the second to twenty-fourth aspects. In another alternative, as part of a twenty-fifth aspect, R10in the compound of Formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, is hydrogen or fluoro, and wherein the variables are as described above for Formula I or any one of the second to twenty-fourth aspects. In another alternative, as part of a twenty-fifth aspect, R11in the compound of Formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, is hydrogen or halo(Ci-C3)alkyl, and wherein the variables are as described above for Formula I or any one of the second to twenty-fourth aspects.

[0077] In a twenty-sixth aspect, RX1in the compound of Formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, is independently, oxo or Ci-3alkoxy, and wherein the variables are as described above for Formula I or any one of the second to twenty-fifth aspects.R3

[0078] In a twenty- seventh aspect,'~i~ in the compound of Formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, is45ME1\60337174.v1141039-0012046ME1\60337174.v1141039-0012047ME1\60337174.v1141039-00120connection to L and the dotted line indicates the connection to Ring A, and wherein the variables are as described above for Formula I or any one of the third to twenty- sixth aspects.48ME1\60337174.v1141039-00120indicates the connection to L and the dotted line indicates the connection to Ring A, and wherein the variables are as described above for Formula I or any one of the third to twentysixth aspects.49ME1\60337174.v1141039-00120

[0080] In another alternative, as part a twenty-seventh aspect,i in the compound of Formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, iswherein the squiggly line indicates the connection to L and the dotted line indicates the connection to Ring A, and wherein the variables are as described above for Formula I or any one of the second to twenty-sixth aspects. In another alternative, as part of a twenty-seventhR\ zR3aspect,'ATZin the compound of Formula I, II, III or IV, or a pharmaceuticallyindicates the connection to L and the dotted line indicates the connection to Ring A, and wherein the variables are as described above for Formula I or any one of the third to twentysixth aspects.

[0079] In a twenty-eighth aspect, the compound of Formula I, II, III or IV, is of the Formula IVA50ME1\60337174.v1141039-00120squiggly line indicates the connection to Ring C and the dotted line indicates the connectionconnection to L and the dotted line indicates the connection to Ring A.

[0080] Compounds having the Formula I, II, III and IV are further disclosed in the Exemplification and are included in the present disclosure. Pharmaceutically acceptable salts thereof as well as the neutral forms are included.

[0081] D. Uses, Formulation and Administration

[0082] In one aspect, the compounds described herein or pharmaceutically acceptable salts or compositions can be used for disrupting (e.g inhibiting and / or preventing and / or modulating) an interaction between a small GTPase (e.g Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) and a PI3Ka protein. In another51ME1\60337174.v1141039-00120aspect, the present disclosure provides methods of disrupting, interrupting, and / or preventing an interaction between a small GTPase (e.g Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HR AS, RRAS, RRAS2, MRAS, or RIT1) and a PI3Ka protein in a subject, comprising administering a provided compound or composition. In yet another aspect, the present disclosure provides methods of disrupting, interrupting, and / or preventing an interaction between a small GTPase (e.g Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) and a PI3Ka protein in a biological sample, comprising administering a provided compound or composition. In another aspect, the present disclosure provides methods comprising contacting a cell containing a small GTPase (e.g Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) and a PI3Ka protein with a provided compound or composition. In yet another aspect, a small GTPase is capable of binding a RAS -binding domain (RBD) of a PI3Ka protein. In another aspect, a small GTPase is selected from Rac1, CDC42, and RAS proteins. In yet another aspect, a RAS protein is selected from HRAS, NRAS, KRAS, RRAS, RRAS2, MRAS, and RIT1. In another aspect, a RAS protein is a wildtype RAS protein. In yet another aspect, a RAS protein is a mutant RAS protein. In another aspect, a RAS protein (e.g HRAS, NRAS, or KRAS) comprises a mutation in codon 12 (e.g G12), codon 13 (e.g G13), or codon 61 (e.g Q61). In yet another aspect, a KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In another aspect, a KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G13D, and / or Q61H mutation. In yet another aspect, an NRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In another aspect, an NRAS protein comprises a G12D, G12V, G13D, and / or Q61R mutation. In yet another aspect, an HRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In another aspect, an HRAS protein comprises a G12V, G13R, and / or Q61R mutation. In yet another aspect, a PI3Ka protein is a wild-type PI3Ka protein. In another aspect, a PI3Ka protein is a mutant PI3Ka protein. In yet another aspect, a PI3Ka protein comprises a R88Q, K11N, E545D, Q546E, Q546G, N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, M1043V, E81K, E545A, E545G, N1044K, Q546P, E542K, E545K, H1047Y, H1047R, and / or H1047L mutation. In another aspect, a PI3Ka protein comprises a E542K, E545K, H1047R, and / or H1047L mutation.52ME1\60337174.v1141039-00120

[0083] In one aspect, the compounds described herein or pharmaceutically acceptable salts or compositions can be administered to a subject in need thereof. In such aspect, a subject has a disease, disorder, or condition associated with an interaction between a small GTPase (e.g Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) and a PI3Ka protein. In another aspect, a subject has a disease, disorder, or condition ameliorated by disruption of an interaction between a small GTPase (e.g Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) and a PI3Ka protein. In yet another aspect, a small GTPase (e.g Rac1, CDC42, or a RAS protein such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) is capable of binding a RAS -binding domain (RBD) of a PI3Ka protein. In another aspect, a small GTPase is selected from Rac1, CDC42, and RAS proteins. In yet another aspect, a RAS protein is selected from HRAS, NRAS, KRAS, RRAS, RRAS2, MRAS, and RITE. In another aspect, a KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In another aspect, a KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G13D, and / or Q61H mutation. In yet another aspect, an NRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In another aspect, an NRAS protein comprises a G12D, G12V, G13D, and / or Q61R mutation. In yet another aspect, an HRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In another aspect, an HRAS protein comprises a G12V, G13R, and / or Q61R mutation. In yet another aspect, a RAS protein is a wild-type RAS protein. In another aspect, a PI3Ka protein is a wild-type PI3Ka protein. In yet another aspect, a PI3Ka protein is a mutant PI3Ka protein. In another aspect, a PI3Ka protein comprises a R88Q, K11N, E545D, Q546E, Q546G, N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, M1043V,, E81K, E545A, E545G, N1044K, Q546P, E542K, E545K, H1047Y, H1047R, and / or H1047L mutation. In yet another aspect, a PI3Ka protein comprises an E542K, E545K, H1047R, and / or H1047L mutation. In another aspect, a subject has a cancer or other indication described herein. In another aspect, a subject has previously undergone a treatment regimen for a cancer. In yet another aspect, a subject has previously entered remission from a cancer.

[0084] In one aspect, the present disclosure provides methods of treating a cancer, comprising administering to a subject a provided compound or composition. In one aspect, a cancer is associated with and / or characterized by aberrant activation of PI3Ka. In another 53ME1\60337174.v1141039-00120aspect, a cancer is characterized by a mutation in a RAS protein (e.g HRAS, NRAS, KRAS, RRAS, RRAS2, MRAS, and RIT1). In yet another aspect, a cancer is characterized by a mutation in a KRAS protein. In another aspect, a KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In another aspect, a KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G13D, and / or Q61H mutation. In yet another aspect, a cancer is characterized by a mutation in an NRAS protein. In another aspect, an NRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In yet another aspect, an NRAS protein comprises a G12D, G12V, G13D, and / or Q61R mutation. In another aspect, a cancer is characterized by a mutation in an HRAS protein. In yet another aspect, an HRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In another aspect, an HRAS protein comprises a G12V, G13R, and / or Q61R mutation. In yet another aspect, a cancer is characterized by a mutation in a PI3Ka protein. In another aspect, a PI3Ka protein comprises a R88Q, K11N, E545D, Q546E, Q546G, N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I,, M1043V,, E81K, E545A, E545G, N1044K, Q546P, E542K, E545K, H1047R, H1047Y, and / or H1047L mutation. In yet another aspect, a PI3Ka protein comprises a E542K, E545K, H1047R, and / or H1047L mutation.

[0085] In one aspect, provided are methods of re-activating mutated RAS-PI3K in a subject in need thereof, comprising administering to the subject an effective amount of the compound or pharmaceutically acceptable salt described herein, or a pharmaceutical composition comprising such. In another aspect, provided is an effective amount of the compound or pharmaceutically acceptable salt described herein, or a pharmaceutical composition comprising such for re-activating RAS-PI3K mutant e.g in a subject in need. In yet another aspect, provided is the use of an effective amount of the compound or pharmaceutically acceptable salt described herein, or a pharmaceutical composition comprising such for the manufacture of a medicament for re-activating RAS-PI3K mutant e.g, in a subject in need.

[0086] Also provided are methods for treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of the compound or pharmaceutically acceptable salt described herein, or a pharmaceutical composition comprising such. In another aspect, provided is an effective amount of the compound or pharmaceutically acceptable salt described herein, or a pharmaceutical composition54ME1\60337174.v1141039-00120comprising such for treating cancer e.g in a subject in need. In yet another aspect, provided is the use of an effective amount of the compound or pharmaceutically acceptable salt described herein, or a pharmaceutical composition comprising such for the manufacture of a medicament for treating cancer e.g in a subject in need.

[0087] Cancers which can be treated with the described compounds or pharmaceutically acceptable salts thereof or the described pharmaceutical compositions include acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, AIDS-related cancers, AIDS-related lymphoma, anal cancer, bladder cancer, bone cancers, brain tumors, such as cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumors, visual pathway and hypothalamic glioma, breast cancer, central nervous system lymphoma, cerebellar astrocytoma, cervical cancer, colon cancer, gallbladder cancer, gastric cancer, head and neck cancer, heart cancer, hepatocellular (liver) cancer, kidney cancer, liver cancer, lung cancers, such as non-small cell and small cell lung cancer, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, pancreatic cancer, pancreatic cancer islet cell, prostate cancer, rectal cancer, renal cell carcinoma, skin cancers, skin carcinoma merkel cell, small intestine cancer or throat cancer.

[0088] In one aspect, the described compounds or pharmaceutically acceptable salts thereof or described pharmaceutical compositions can be part of a combination therapies with one or more other therapeutic agents.

[0089] In some aspects, a cancer is characterized by one or more mutations. In some such aspects, a subject may be diagnosed with cancer and / or selected for therapy based on the detection of one or more mutations in a biological sample obtained from the subject. In some aspects, a cancer is characterized by a mutation in a RAS protein (e.g KRAS, HRAS, or NRAS). In some aspects, a cancer is characterized by a mutation in a KRAS protein. In some aspects, a KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In some aspects, a KRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G13D, and / or Q61H mutation. In some aspects, a cancer is characterized by a mutation in an NRAS protein. In some aspects, an NRAS protein comprises a G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In some aspects, an NRAS protein comprises a G12D, G12V, G13D, and / or Q61R mutation. In some aspects, a cancer is characterized by a mutation in an HRAS protein. In some aspects, an HRAS protein comprises a G12C, G12D, G12S, G12V, G12R,55ME1\60337174.v1141039-00120G12A, G13D, G13C, G13R, G13S, G13V, Q61K, Q61L, Q61P, Q61R, and / or Q61H mutation. In some aspects, an HRAS protein comprises a G12V, G13R, and / or Q61Rmutation. In some aspects, a cancer is characterized by a mutation in a PI3Ka protein. In someaspects, the PI3Ka protein comprises a R88Q, KI IN, E545D, Q546E, Q546G, N345K, E726K, C420R, Q546R, G118D, E453K, Q546K, G1049R, M1043I, K111E, K111N, E81K, E545A, E545G, N1044K, M1043V,, Q546P, E542K, E545K, H1047R, H1047Y, and / or H1047L mutation. In some aspects, a PI3Ka protein comprises a E542K, E545K, H1047Y, H1047R, and / or H1047L mutation. In some aspects, a cancer is characterized by mutated, overexpressed, and / or amplified receptor tyrosine kinases (e.g HER family (e.g HER2 and / or HER3), Met, FGFR, Aik, PDGF, EGFR, or ROS kinases). In some aspects, a cancer is characterized by a mutation in or a deletion of a PTEN protein. In some aspects, a cancer has demonstrable sensitivity to Avastin. For example, a cancer may be non-small cell lung cancer (NSCLC) or colorectal cancer. In some aspects, a cancer is ER positive (e.g having estrogen receptors). In some aspects, a cancer is PR positive (e.g having progesterone receptors).

[0090] In one aspect, the described compounds or pharmaceutically acceptable salts thereof or described pharmaceutical compositions can be part of a combination therapies with one or more other therapeutic agents.

[0091] In some aspects, one or more other therapeutic agents can be an immune checkpoint inhibitor. In some aspects, the checkpoint inhibitors include but are not limited to anti programed cell death receptor- 1 (aPD-1) monoclonal antibodies such as pembrolizumab, nivolumab, cemiplimab, or anti programed cell death receptor- 1 ligand (aPD-Ll) monoclonal antibodies such as atezolizumab, dostarlimab, durvalumab and avelumab, or anti cytotoxic T lymphocyte-associated antigen (anti-CTLA4) monoclonal antibodies such as ipilimumab and tremelimumab, or anti lymphocyte activated gene-3 (LAG-3) monoclonal antibodies such as relatlimab.

[0092] In some aspects, the one or more other therapeutic agent is an inhibitor of interaction between the two primary p53 suppressor proteins, MDMX and MDM2. Inhibitors of p53 suppression proteins being studied which may be used in the present invention include ALRN-6924 (Aileron), a stapled peptide that equipotently binds to and disrupts the interaction of MDMX and MDM2 with p53. ALRN-6924 is currently being evaluated in clinical trials for the treatment of AML, advanced myelodysplastic syndrome (MDS) and peripheral T-cell lymphoma (PTCL).56ME1\60337174.v1141039-00120

[0093] In some aspects, the one or more other therapeutic agent is an inhibitor of interaction between p53 and MDM2. Said MDM2 inhibitors include but are not limited to navtemadlin (AMG-232, KRG 232, Amgen), idasanutlin (RG7388, Hoffman-La Roche), milademetan (RAIN-32), MK-8242 (Merck), SAR405838, NVP-CGM097, RG7112, and DS-3032b.

[0094] In some aspects, the one or more other therapeutic agent is an MDM2 targeted protein degrader such as MD-224.

[0095] In some aspects, the one or more other therapeutic agent is a Poly ADP ribose polymerase (PARP) inhibitor. In some aspects, a PARP inhibitor is selected from olaparib (LYNPARZA®, AstraZeneca); rucaparib (RUBRACA®, Clovis Oncology); niraparib (ZEJULA®, Tesaro); talazoparib (MDV3800 / BMN 673 / LT00673, Medivation / Pfizer / Biomarin); veliparib (ABT-888, Abb Vie); and BGB-290 (BeiGene, Inc.).

[0096] In some aspects, the one or more other therapeutic agent is a CDK inhibitor such as a CDK4 / CDK6 inhibitor. In some aspects, a CDK 4 / 6 inhibitor is selected from Palbociclib (IB RANCE®, Pfizer); ribociclib (KISQALI®, Novartis); abemaciclib (Ly2835219, Eli Lilly); and trilaciclib (G1T28, G1 Therapeutics). In some aspects, a CDK inhibitor is a CDK9 selective inhibitor selected from dinaciclib, AT-7519, P276-00, AZD-4573, alvocidib / flavopiridol, CYC065, atuveciclib, BAY-1251152, voruciclib or GFH009.

[0097] In some aspects, the one or more other therapeutic agent is an inhibitor of antiapoptotic proteins, such as BCL-2. Approved anti-apoptotics which may be used in the present invention include venetoclax (VENCLEXTA®, AbbVie / Genentech); and blinatumomab (BLINCYTO®, Amgen). Other therapeutic agents targeting apoptotic proteins which have undergone clinical testing and may be used in the present invention include navitoclax (ABT-263, Abbott). Other therapeutic agents targeting BCL family proteins via E3 ligase-mediated target protein degradation may be used in the present invention.

[0098] In some aspects, the one or more other therapeutic agent is a platinum-based therapeutic, also referred to as platins. Platins cause cross-linking of DNA, such that they inhibit DNA repair and / or DNA synthesis, mostly in rapidly reproducing cells, such as cancer cells.

[0099] In some aspects, a platinum-based therapeutic is selected from cisplatin (PLATINOL®, Bristol-Myers Squibb); carboplatin (PARAPLATIN®, Bristol-Myers Squibb; also, Teva; Pfizer); oxaliplatin (ELOXITIN® Sanofi-Aventis); nedaplatin (AQUPLA®, Shionogi), picoplatin (Poniard Pharmaceuticals); and satraplatin (JM-216, Agennix).57ME1\60337174.v1141039-00120

[0100] In some aspects, the one or more other therapeutic agent is a taxane compound, which causes disruption of microtubules, which are essential for cell division. In some aspects, a taxane compound is selected from paclitaxel (TAXOL®, Bristol-Myers Squibb), docetaxel (TAXOTERE®, Sanofi- Aventis; DOCEFREZ®, Sun Pharmaceutical), albuminbound paclitaxel (ABRAXANE®; Abraxis / Celgene), cabazitaxel (JEVTANA®, Sanofi-Aventis), and SID530 (SK Chemicals, Co.).

[0101] In some aspects, the one or more other therapeutic agent is a nucleoside inhibitor, or a therapeutic agent that interferes with normal DNA synthesis, protein synthesis, cell replication, or will otherwise inhibit rapidly proliferating cells.

[0102] In some aspects, a nucleoside inhibitor is selected from trabectedin (guanidine alkylating agent, YONDELIS®, Janssen Oncology), mechlorethamine (alkylating agent, VALCHLOR®, Aktelion Pharmaceuticals); vincristine (ONCOVIN®, Eli Lilly;VINCASAR®, Teva Pharmaceuticals; MARQIBO®, Talon Therapeutics); temozolomide (prodrug to alkylating agent 5-(3-methyltriazen-l-yl)-imidazole-4-carboxamide (MTIC) TEMODAR®, Merck); cytarabine injection (ara-C, antimetabolic cytidine analog, Pfizer); lomustine (alkylating agent, CEENU®, Bristol-Myers Squibb; GLEOSTINE®, NextSource Biotechnology); azacytidine (pyrimidine nucleoside analog of cytidine, VID AZA®, Celgene); omacetaxine mepesuccinate. (cephalotaxine ester) (protein synthesis inhibitor, SYNRIBO®; Teva Pharmaceuticals); asparaginase Erwinia chrysanthemi (enzyme for depletion of asparagine, ELS PAR®, Lundbeck; ERWINAZE®, EEISA Pharma); eribulin mesylate (microtubule inhibitor, tubulin-based antimitotic, HALAVEN®, Eisai); cabazitaxel (microtubule inhibitor, tubulin-based antimitotic, JEVTANA®, Sanofi- Aventis); capacetrine (thymidylate synthase inhibitor, XELODA®, Genentech); bendamustine (bifunctional mechlorethamine derivative, believed to form interstrand DNA cross-links, TREANDA®, Cephalon / Teva); ixabepilone (semi-synthetic analog of epothilone B, microtubule inhibitor, tubulin-based antimitotic, IXEMPRA®, Bristol-Myers Squibb); nelarabine (prodrug of deoxyguanosine analog, nucleoside metabolic inhibitor, ARRANON®, Novartis); clorafabine (prodrug of ribonucleotide reductase inhibitor, competitive inhibitor of deoxycytidine, CLOLAR®, Sanofi- Aventis); and trifluridine and tipiracil (thymidinebased nucleoside analog and thymidine phosphorylase inhibitor, LONSEIRF®, Taiho Oncology).

[0103] In some aspects, the one or more other therapeutic agent is a phosphatidylinositol 3 kinase (PI3K) inhibitor. In some aspects, a PI3K inhibitor is selected from idelalisib (ZYDELIG®, Gilead), alpelisib (BYL719, Novartis), inavolisib (ITOVABI®, Genentech / Roche), taselisib (GDC-0032, Genentech / Roche); pictilisib (GDC-0941,58ME1\60337174.v1141039-00120Genentech / Roche); copanlisib (BAY806946, Bayer); duvelisib (formerly IPI-145, Infinity Pharmaceuticals); PQR309 (Piqur Therapeutics, Switzerland); and TGR1202(formerly RP5230, TG Therapeutics).

[0104] In some aspects, the one or more other therapeutic agent is a kinase inhibitor or VEGF-R antagonist. Approved VEGF inhibitors and kinase inhibitors useful in the present invention include: bevacizumab (AVASTIN®, Genentech / Roche) an anti- VEGF monoclonal antibody; ramucirumab (CYRAMZA®, Eli Lilly), an anti-VEGFR-2 antibody and ziv-aflibercept, also known as VEGF Trap (ZALTRAP®; Regeneron / Sanofi). VEGFR inhibitors, such as regorafenib (STIVARGA®, Bayer); vandetanib (CAPRELSA®, AstraZeneca); axitinib (INLYTA®, Pfizer); and lenvatinib (LENVIMA®, Eisai); Raf inhibitors, such as sorafenib (NEXAVAR®, Bayer AG and Onyx); dabrafenib (TAFINLAR®, Novartis); and vemurafenib (ZELBORAF®, Genentech / Roche); MEK inhibitors, such as cobimetanib (COTELLIC®, Exelexis / Genentech / Roche); trametinib (MEKINIST®, Novartis); Bcr-Abl tyrosine kinase inhibitors, such as imatinib (GLEEVEC®, Novartis); nilotinib (TASIGNA®, Novartis); dasatinib (SPRYCEL®, BristolMyersSquibb); bosutinib (BOSULIF®, Pfizer); and ponatinib (INCLUSIG®, Ariad Pharmaceuticals); Her2 and EGFR inhibitors, such as gefitinib (IRESSA®, AstraZeneca); erlotinib (TARCEVA®, Genentech / Roche / Astellas); lapatinib (TYKERB®, Novartis); afatinib (GILOTRIF®, Boehringer Ingelheim); osimertinib (targeting activated EGFR, TAGRISSO®, AstraZeneca); and brigatinib (ALUNBRIG®, Ariad Pharmaceuticals); c-Met and VEGFR2 inhibitors, such as cabozanitib (COMETRIQ®, Exelexis); and multikinase inhibitors, such as sunitinib (SUTENT®, Pfizer); pazopanib (VOTRIENT®, Novartis); ALK inhibitors, such as crizotinib (XALKORI®, Pfizer); ceritinib (ZYKADIA®, Novartis); and alectinib (ALECENZa®, Genentech / Roche); Bruton’s tyrosine kinase inhibitors, such as ibrutinib (IMBRErVICA®, Pharmacyclics / Janssen); and Flt3 receptor inhibitors, such as midostaurin (RYE)APT®, Novartis).

[0105] Other kinase inhibitors and VEGF-R antagonists that are in development and may be used in the present invention include tivozanib (Aveo Pharmaceuticals); vatalanib (Bayer / Novartis); lucitanib (Clovis Oncology); dovitinib (TKI258, Novartis); Chiauanib (Chipscreen Biosciences); CEP-11981 (Cephalon); linifanib (Abbott Laboratories); neratinib (HKL272, Puma Biotechnology); radotinib (SUPECT®, IY5511, Il-Yang Pharmaceuticals, S. Korea); ruxolitinib (JAKAFI®, Incyte Corporation); PTC299 (PTC Therapeutics); CP-547,632 (Pfizer); foretinib (Exelexis, GlaxoSmithKline); quizartinib (Daiichi Sankyo) and motesanib (Amgen / T akeda).59ME1\60337174.v1141039-00120

[0106] In some aspects, the one or more other therapeutic agent is an mTOR inhibitor, which inhibits cell proliferation, angiogenesis and glucose uptake. In some aspects, an mTOR inhibitor is everolimus (AFINITOR®, Novartis); temsirolimus (TORIS EL®, Pfizer); and sirolimus (RAPAMUNE®, Pfizer).

[0107] In some aspects, the one or more other therapeutic agent is a proteasome inhibitor. Approved proteasome inhibitors useful in the present invention include bortezomib (VELCADE®, Takeda); carfilzomib (KYPROLIS®, Amgen); and ixazomib (NINLARO®, Takeda).

[0108] In some aspects, the one or more other therapeutic agent is a growth factor antagonist, such as an antagonist of platelet-derived growth factor (PDGF), or epidermal growth factor (EGF) or its receptor (EGFR). Approved PDGF antagonists which may be used in the present invention include olaratumab (LARTRUVO®; Eli Lilly). Approved EGFR antagonists which may be used in the present invention include cetuximab (ERBITUX®, Eli Lilly); necitumumab (PORTRAZZA®, Eli Lilly), panitumumab (VECTIBIX®, Amgen); and Osimertinib (targeting activated EGFR, TAGRISSO®, AstraZeneca).

[0109] In some aspects, the one or more other therapeutic agent is an aromatase inhibitor. In some aspects, an aromatase inhibitor is selected from exemestane (AROMASIN®, Pfizer); anastazole (ARIMIDEX®, AstraZeneca) and letrozole (FEMARA®, Novartis).

[0110] In some aspects, the one or more other therapeutic agent is a folic acid inhibitor. Approved folic acid inhibitors useful in the present invention include pemetrexed (ALIMTA®, Eli Lilly).

[0111] In some aspects, the one or more other therapeutic agent is a topoisomerase inhibitor. Approved topoisomerase inhibitors useful in the present invention include irinotecan (ONIVYDE®, Merrimack Pharmaceuticals); topotecan (HYCAMTIN®, GlaxoSmithKline). Topoisomerase inhibitors being studied which may be used in the present invention include pixantrone (PIXUVRI®, CTI Biopharma). In some aspects, the second therapeutic is an agent for co-regulating MEK or RAF pathways. In some aspects, the second therapeutic agent is a MEK or RAF inhibitor. In some aspects, the RAF inhibitor is Vemurafenib (Zelboraf), Dabrafenib (Tafinlar), Encorafenib (Braftovi), Tovorafenib (Ojemda), XL-281, LGX-818, CEP-32496. ARQ-736, MEK-162, Sdumdinib, refametinib, E-620L pimasertib, WX-554, GDC-0973, naporafenib, or exarafenib. In some aspects, the MEK inhibitor is Trametinib (Mekinist), Cobimetinib (Cotellic), Selumetinib (Koselugo), Binimetinib (Mektovi). In some aspects, the second therapeutic agent is a MEK-RAF clamp60ME1\60337174.v1141039-00120such as avutometinib. In some aspects, the second therapeutic agent is a MEK-pan-RAF stabilizing molecular glue such as NST-628, IK-595 or IMM-1-104.

[0112] In some aspects, the second therapeutic is an agent for co-regulating MAPK pathway. In some aspects, the agent for co-regulating MAPK pathway is KRAS G12C mutant selective inhibitors including but not limited to Sotorasib (Lumakras), Adagrasib (Krazati), ARS-1620, ARS-3248, LY3499446, MK-1084, divarasib (GDC-6036), RMC-6291; KRAS G12D mutant selective inhibitors including but not limited to RMC-9805, MRTX1133, QTX3046, LY3962673; pan KRAS inhibitors including but not limited to PF-07934040, QTX3034, BI-2865, BI-1701963; RAS(multi) inhibitor RMC-6036, RMC-6235; Son of Sevenless 1 (SOS1) inhibitors (e.g BI1701963, BI-3406 and RMC-023);

[0113] Pharmaceutical compositions are described that include one or more compounds provided herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In some aspects, the described compounds or pharmaceutically acceptable salts thereof can be used in combination with other agents known to have beneficial activity targeting diseases or disorders listed above. For example, described compounds or pharmaceutically acceptable salts thereof can be administered alone or in combination with one or more anti-cancer or antiviral agent.

[0114] The pharmaceutical compositions of the disclosure are formulated to be compatible with its intended route of administration. In an aspect, the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous, subcutaneous, intramuscular, oral, intranasal, or topical administration to human beings. In some aspects, the pharmaceutical compositions are administered orally.EXEMPLIFICATION

[0115] The following examples are intended to be illustrative and are not meant in any way to be limiting.

[0116] Unless otherwise specified, abbreviations used herein will have the meaning as commonly used in the art, some of which are provided below:AbbreviatioName Abbreviation NamenAcOH acetic acid mM millimolarAq Aqueous MeOH MethanolACN Acetonitrile ACN Acetonitrile61ME1\60337174.v1141039-00120Atm Atmosphere mg Milligrams BOC tertButyloxycarbonyl min MinutesDi-tert-butylBoc2O MHz Mega Hertz (frequency) dicarbonateBr2 Benzyl mL MillitersBn n-Butyllithium mol Moles n-BuLi n-Butyllithium mmol Millimoles °C degree Celsius MS Mass spectroscopy CD3OD Deuterated methanol N2Nitrogen Cs2CO3Cesium carbonate NaH Sodium hydride Saturated sodium d doublet NaHCO3hydrogencarbonate dd Doublet of doublet NH3Ammonia dt Doublet of triplet NH4HCO3ammonium bicarbonate 8 delta Na2SO4Sodium sulfate DCE 1,2-Dichloroethane NH4CI Ammonium chloride Hydroxylamine DCM Dichloromethane NH2OH-HCIhydrochloride N, N- DIPEA Pd / C Palladium on carbon Diisopropylethylamine1,1’ B is(diphenylphosphino) N, N- DMF Pd(dppf)Ch ferrocene]dichloropalladium Dimethylformamide(II)T etrakis (tripheny Ipho sphine DMSO Dimethyl sulfoxide Pd(PPh3)4)palladium(0) de - DeuteratedDMSO-d6PE Petroleum ether dimethyl sulfoxideEA Ethyl acetate % percentage Preperative high Equiv Equivalents Prep-HPLC performance liquid chromatography Et3SiH Triethylsilane RT or rt room temperature62ME1\60337174.v1141039-00120EtOH Ethanol s singletg gram Sat. Saturated2- h or hr Hour SEMC1 (Trimethylsilyl)ethoxymeth yl chloride Proton nuclear magnetic’H NMR t Triplet resonanceH2Hydrogen tert Tertiary High performance liquidHPLC tt Triplet of triplet chromatographyH2O Water TEA Triethylamine Hz Hertz Tf TriflateJ Coupling constant TFA Trifluoroacetic acid K2CO3Potassium carbonate TFAA Trifluoroacetic anhydride Trifluoromethanesulfonic KOAc Potassium acetate Tf2Oanhydride Liquid chromatographyLCMS THF T etrahy drofuran mass spectrometryM+Molecular ion TLC Thin layer chromatography Preparative thin layer M Molar Prep TLCchromatography m multiplet br Broad singlet CBz benzyloxycarbonyl CD3CN Deuterated acetonitrile CDCI3 Deuterated chloroform CsF Cesium fluoride Disopropyl Diisobutylaluminium DIAD DIBALazodicarboxylate hydride DIEA Diisopropylethylamine DIPA N, N-diisopropylamine 4- DMAcDMAP N, N-Dimethylacetamide Dimethylaminopyridine or DMAESI Electrospray ionization HC1 Hydrochloric acid LithiumLiHMDS μL Microliters bis (trimethy Isily 1) amide63ME1\60337174.v1141039-00120μm Millimeters μmol Micromoles Mel Methyl iodide MeOD deuterated methanol methanesulfonylMsCl MTBE methyl tbutyl ether chlorideMS Mass spectroscopy NMP NMethyl2pyrrolidone Tris(dibenzylideneacetone)d NBS N-B romo succinimide Pdi(dba)3ipalladiumpH potential of Hydrogen PMB paramethoxybenzyl ppm Parts per million Py Pyridineq quartet Rt Retention time Supercritical fluid Supercritical fluid SFC SFCchromatography chromatographyTetrabutylammoniumTBAF TBSC1 tertB uty Idimethy Ichloro sila fluoridenePreparative thin layerPrep TLC TMEDA N, N, N', N'Tetramethylethan chromatographye 1,2 diamineIntermediate 1-1.2-(2-(benzyloxy)-4-fluorobenzyl)-V, V-diethylthiophene-3-carboxamideStep 1 Step 2

[0117] Step 1.2-((2-(benzyloxy)-4-fluorophenyl)(hydroxy)methyl)-2V,2V-diethylthiophene-3-carboxamide

[0118] To a solution of A,2V-diethylthiophene- 3 -carboxamide (1.5 g, 8.2 mmol, CAS NO: 73540-75-7) in THF (20 mL) was added n-BuLi (2.5 M in hexane) (4.0 mL, 9.8 mmol) at -60 °C under N2 atm. The reaction mixture was stirred for 30 min at this temperature. To the mixture was added 2-(benzyloxy)-4-fluorobenzaldehyde (2.1 g, 9.0 mmol, CAS NO: 202857-89-4). The resulting mixture was stirred for another 30 min. The reaction solution was quenched with MeOH (10 mL), concentrated to give residue which was purified by silica gel64ME1\60337174.v1141039-00120column chromatography, eluted with EA in PE (0%-30%) to give the title compound (3.0 g). LCMS (M + Na)+m / z: 436.0.

[0119] Step 2.2-(2-( benzyloxy )-4-fluorobenzyl)-A, A-diethylthiophene-3- carboxamide

[0120] To a solution of 2-((2-(benzyloxy)-4-fluorophenyl)(hydroxy)methyl)-A, A- diethylthiophene-3 -carboxamide (3.0 g, 7.2 mmol), Et3SiH (2.5 g, 21.8 mmol) in DCE (10 mL) was added TFA (8.3 g, 72.5 mmol). The reaction mixture was stirred for 1 h at 60 °C under N2 atm. The residue was poured into water (40 mL) and extracted with DCM (3 x 40 mL). The combined organic layer was washed with brine, dried over Na2SO4and concentrated. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-40%) to give the title compound (2.5 g). LCMS m / z [M+H]+398.5.

[0121] The intermediates in the table below were synthesized as described for Intermediate 1-1 from appropriate starting materials.Int. LCMS m / z Structure IUPAC NameNo. [M+H]+2-(2-(benzyloxy)-4-fluorobenzyl)-N, N- [M+H] 1-1diethylthiophene-3 -carboxamide 398.2 F] F 2-(2-(benzyloxy)-4,6-difluorobenzyl)-N, N- 1-2 [M+H]416.1 diethylthiophene-3 -carboxamideF

[0122] Intermediate 2-1. tert-butyl 2-cyano-l-((2-(trimethylsilyl)ethoxy)methyl)- 1,4,6,7- tetrahydro-5H-imidazo[4,5 -c ] pyridine-5-carboxylateSEM SEM

[0123] Step 1. tert-butyl l-((2-(trimethylsilyl)ethoxy)methyl)-l,4,6,7-tetrahydro-5H- imidazo[4,5-c]pyridine-5-carboxylate

[0124] To a solution of tert-butyl l,4,6,7-tetrahydro-5 / Z-imidazo[4,5-c]pyridine-5- carboxylate (3.0 g, 13.4 mmol, CAS NO: 1202800-68-7) in THF (100 mL) was added 60%65ME1\60337174.v1141039-00120NaH (699 mg, 17.5 mmol) at 0 °C under N2 atm. The reaction mixture was stirred at this temperature for 30 min. To the reaction mixture was added SEMC1 (2.7 g, 16.1 mmol). The reaction mixture was stirred at 0 °C for 2 h. The resulting mixture was poured into water (150 mL) and extracted with DCM (3 x 100 mL). The combined organic layer was washed with brine, dried over Na2SO4and concentrated. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-20%) to give the title compound (2.3 g) LCMS m / z [M+H]+354.2.

[0125] Step 2. tert-butyl 2-formyl-l-((2-(trimethylsilyl)ethoxy)methyl)-l, 4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate

[0126] To a solution of tert-butyl l-((2-(trimethylsilyl)ethoxy)methyl)-l,4,6,7-tetrahydro-5 / Z-imidazo[4,5-c]pyridine-5-carboxylate (2.3 g, 6.51 mmol) in THF (15 mL) was added 2.5 M n-BuLi (3.4 mL, 8.46 mmol) at -65 °C under N2 atm. The reaction mixture was stirred for 30 min at this temperature. To the reaction mixture was added DMF (714 mg, 9.77 mmol) dropwise. The resulting mixture was allowed to stir for 1 h at rt. The mixture was quenched with NH4CI (sat. aq 50 mL) and extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-30%) to give the title compound (1.6 g) LCMS m / z [M+H]+382.2.

[0127] Step 3. tert-butyl (Z)-2-((hydroxyimino)methyl)-l-((2- (trimethylsilyl)ethoxy)methyl)-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate

[0128] To a solution of tert-butyl 2-formyl-l-((2-(trimethylsilyl)ethoxy)methyl)-l,4,6,7-tetrahydro-5 / Z-imidazo[4,5-c]pyridine-5-carboxylate (1.6 g, 4.19 mmol), Pyridine (1.7 g, 20.95 mmol) in EtOH (20 mL) was added NH2OH-HCI (350 mg, 5.03mmol). The reaction mixture was stirred for 1.0 h at 70 °C under N2 atm. The mixture was concentrated in vacuo and the residue was diluted with water (20 mL). The aq layer was extracted with DCM (2 x 40 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-10%) to give the title compound (1.66 g) LCMS m / z [M+H]+397.0.

[0129] Step 3. tert-butyl 2-cyano-l-((2-(trimethylsilyl)ethoxy)methyl)-l, 4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate

[0130] To a solution of tert-butyl-2-((hydroxyimino)methyl)-l-((2- (trimethylsilyl)ethoxy)methyl)-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate 66ME1\60337174.v1141039-00120(1.66 g, 4.2 mmol), Pyridine (1.7 g, 20.9 mmol) in DCM (20 mL) was added TFAA (2.6 g, 12.6 mmol) at RT under N2. The reaction mixture was stirred for 1.5 h at this temperature. The mixture was quenched with water (40 mL) and extracted with DCM (2 x 50 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by silica gel column chromatography, eluted with EA in PE (0%-50%) to give the title compound (1.0 g) LCMS m / z [M+H]+379.5.

[0131] Intermediate 3. tert-butyl 2-cyano-l-((2-(trimethylsilyl)ethoxy)methyl)-4,5,7,8-tetrahydroimidazo[4,5-d]azepine-6(lH)-carboxylate

[0132] Step 1. l-benzyl-5-bromoazepan-4-one

[0133] 33% HBr in AcOH (11.4 mL) was added dropwise to l-benzylazepan-4-one (20 g, 98.38 mmol, 1 equiv, CAS NO: 1208-75-9) in AcOH (58 mL) at RT. Then Br2(15.7 g, 98.4 mmol, 1 equiv) was added at rt and the mixture was stirred for 1.5 h at RT. The mixture was diluted with NaHCOs aq (300 mL) and extracted with EA (3 x 300 mL). The organic layer was dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-12%) to afford l-benzyl-5-bromoazepan-4-one (21 g). LCMS m / z [M+H]+282.0.

[0134] Step 2.6-benzy 1-1,4, 5,6, 7,8-hexahydroimidazo[4,5-d]azepine

[0135] A solution of l-benzyl-5-bromoazepan-4-one (21 g, 74.4 mmol, 1 equiv), K2CCh (30.9 g, 223.3 mmol, 3 equiv) and formimidamide hydrochloride (17.9 g, 223.3 mmol, 3 equiv) in MeOH (200 mL) was stirred at 73 °C for 5 h. The reaction was concentrated to dyness and the residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-16%) to afford 6-benzyl-l,4,5,6,7,8-hexahydroimidazo[4,5-<7]azepine (6.2 g). LCMS m / z [M+H]+228.1.

[0136] Step 3.6-benzyl-l-((2-(trimethylsilyl)ethoxy)methyl)-l,4,5,6,7,8-hexahydroimidazo[4,5-d]azepine

[0137] SEMC1 (5.46 g, 32.73 mmol, 1.2 equiv) was added to a solution of 6-benzyl-l,4,5,6,7,8-hexahydroimidazo[4,5-<7]azepine (6.2 g, 27.28 mmol, 1 equiv) and 60% NaH (1.64 g, 40.9 mmol, 1.5 equiv) in THF (90 mL). The mixture was stirred at 0 °C for 1 h. The mixture was quenched with H2O (200 mL) and extracted with EA (3 x 200 mL). The organicME1\60337174.v1141039-00120layer was dried over Na2SO4and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-5%) to afford 6-benzyl-l-((2-(trimethylsilyl)ethoxy)methyl)-l,4,5,6,7,8-hexahydroimidazo[4,5-<7]azepine (9.26 g). LCMS m / z+[M+H] 358.3.

[0138] Step 4. tert-butyl l-((2-(trimethylsilyl)ethoxy)methyl)-4, 5,7,8-tetrahydroimidazo[4,5-d]azepine-6(lH)-carboxylate

[0139] A mixture of 6-benzyl-l-((2-(trimethylsilyl)ethoxy)methyl)-l,4,5,6,7,8-hexahydroimidazo[4,5-<7]azepine (9.26 g, 25.9 mmol, 1 equiv), Pd / C (2 g, 10% wt.) and (BOC)2O (14.1 g, 64.7 mmol, 2.5 equiv) in MeOH (150 mL) was stirred at 50 °C for 16 h under H2atm. The Pd / C was removed by filtration and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-4%) to afford the title compound (8.4 g). LCMS m / z+[M+H]368.3.

[0140] Step 5. tert-butyl 2-formyl-l-((2-(trimethylsilyl)ethoxy)methyl)-4, 5,7,8-tetrahydroimidazo[4,5-d]azepine-6(lH)-carboxylate

[0141] Tert-butyl l-((2-(trimethylsilyl)ethoxy)methyl)-4,5,7,8-tetrahydroimidazo[4,5-<7]azepine-6(l / T)-carboxylate (8.4 g, 22.8 mmol, 1 equiv) was dissolved in THF (90 mL) and chilled to -78°C. n-BuLi (2.5 M in hexanes, 18.3 mL, 45.7 mmol, 2 equiv) was added dropwise, the yellow solution was stirred at -78 °C for 0.5 h. DMF (8.35 g, 114.3 mmol, 5 equiv) was added slowly, and the reaction was stirred at -78 °C for 0.5 h. The reaction was quenched with 100 mL NH4CI aq extracted with EA (3 x 100 mL), washed with brine, dried over Na2SO4, filtered, and evaporated under reduced pressure to afford tert-butyl 2-formyl-l-((2-(trimethylsilyl)ethoxy)methyl)-4,5,7,8-tetrahydroimidazo[4,5-<7]azepine-6(l / f)-carboxylate (9.04 g, crude), which was used directly without further purification. LCMS m / z+[M+H] 396.1.

[0142] Step 6. tert-butyl (E)-2-((hydroxyimino)methyl)-l-((2-(trimethylsilyl)ethoxy)methyl)-4,5,7,8-tetrahydroimidazo[4,5-d]azepine-6(lH)-carboxylate

[0143] NH2OH. HC1 (1.91 g, 27.42 mmol, 1.2 equiv) was added to a solution of tert-butyl 2-formyl-l-((2-(trimethylsilyl)ethoxy)methyl)-4,5,7,8-tetrahydroimidazo[4,5-<7]azepine-6(l / f)-carboxylate (9.04 g, 22.8 mmol, 1 equiv) and pyridine (9.04 g, 114.25 mmol, 5 equiv) in EtOH (90 mL). The mixture was stirred at 70 °C for 5 h. After cooling to rt, the mixture was diluted with H2O (100 mL) and extracted with DCM (3 x 100 mL). The organic layer was dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by68ME1\60337174.v1141039-00120silica gel column chromatography, eluted with MeOH in DCM (0%-3%) to afford the title compound (6.9 g). LCMS m / z+[M+H]411.2.

[0144] Step 7. tert-butyl 2-cyano-l-((2-(trimethylsilyl)ethoxy)methyl)-4, 5,7,8-tetrahydroimidazo[4,5-d]azepine-6(lH)-carboxylate

[0145] TFAA (10.59 g, 50.4 mmol, 3 equiv) was added to a solution of tert-butyl (£)-2-((hydroxyimino)methyl)-l-((2-(trimethylsilyl)ethoxy)methyl)-4,5,7,8-tetrahydroimidazo[4,5-<7]azepine-6(l / f)-carboxylate (6.9 g, 16.8 mmol, 1 equiv) and pyridine (7.99 g, 100.8 mmol, 6 equiv) in DCM (70 mL). The mixture was stirred at RT for 1 h. The reaction was quenched with 100 mL aq NH4CI, extracted with EA (3 x 100 mL), washed with brine, dried over Na2SO4U, filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-23%) to afford the title compound (5.72 g). LCMS m / z+[M+H]393.1.

[0146] Intermediate 4. tert-butyl 2-cyano-l-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(lH)-carboxylate

[0147] Step 1.5-( tert -butyl) 2-ethyl 3a,4,6,6a-tetrahydropyrrolo[3,4-d]imidazole-2,5(1 / / ) -dicarboxylate

[0148] To a solution of tert-butyl 3, 4-diaminopyrrolidine- 1 -carboxylate (12.0 g, 0.06 mmol, 1.0 equiv, CAS NO: 945217-60-7) in EtOH (100 mL) was added ethyl 2-ethoxy-2-iminoacetate (9.52 g, 0.07 mmol, 1.1 equiv) in EtOH (20 mL). The reaction was stirred for 1.5 h at 0 °C under N2 atm. The reaction mixture was concentrated in vacuum. The residue was dissolved in DCM (200 mL), poured into water (200 mL), added TEA (3 g, 0.5 equiv), stirred evenly and separated the organic phase. The aq phase was extracted with DCM (200 mL). The combined organic layers were washed with brine (3 x 400 mL), dried over NaiSO4, filtered and the filtrate was concentrated in vacuum. The residue was purified by slurryring with PE to afford 5-(tert-butyl) 2-ethyl 3a,4,6,6a-tetrahydropyrrolo[3,4-< / ]imidazole-2,5(l / / )-dicarboxylate (14.00 g, crude. LCMS m / z+284.6.

[0149] Step 2.5-( / c / 7 -butyl) 2-ethyl 4,6-dihydropyrrolo[3,4-d]imidazole-2,5( 1H)-dicarboxylate69ME1\60337174.v1141039-00120

[0150] To a solution of (COC1)2 (12.54 g, 0.10 mmol, 2.0 equiv) in DCM (120 mL) was added DMSO (15.44 g, 0.20 mmol, 4.0 equiv) in DCM (100 mL) at -78 °C. The reaction mixture was stirred for 30 min at -78 °C, to the mixture was added (tert-butyl) 2-ethyl 3a,4,6,6a-tetrahydropyrrolo[3,4-<7]imidazole-2,5(l / / )-dicarboxylate (14.00 g, 0.05 mmol, 1.0 equiv) in DCM (180 mL) at -78 °C. The reaction mixture was stirred for 1 h at this temperature, then DIPEA (38.32 g, 0.30 mmol, 6.0 equiv) was added. The reaction mixture was allowed to RT then stirred for 16 h under N2 atm. The mixture was quenched with NH4CI (sat. aq 400 mL) and extracted with DCM (2 x 400 mL). combined with the organic layers, washed with H2O (2 x 400 mL), dried over Na2SO4, filtered and the filtrate was concentrated in vacuum, the residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-10%) to afford the title compound (2.8 g). LCMS m / z+[M+H]282.1.

[0151] Step 3. tert-butyl 2-carbamoyl-4,6-dihydropyrrolo[3,4-d]imidazole-5( 1H)-carboxylate

[0152] A solution of 5-(tert-butyl) 2-ethyl 4,6-dihydropyrrolo[3,4-d]imidazole-2,5(l / f)-dicarboxylate (2.8 g, 0.01 mmol, 1.0 equiv) in NH3 (7 M in MeOH, 60 mL) was stirred for 16 h at 100 °C under N2 atm. The mixture was concentrated in vacuo to afford the title compound (2.3 g, crude). LCMS m / z+[M+H]253.1.

[0153] Step 4. tert-butyl 2-cyano-4,6-dihydropyrrolo[3,4-d]imidazole-5( 1H)-carboxylate

[0154] To a solution of tert-butyl 2-carbamoyl-4,6-dihydropyrrolo[3,4-<7]imidazole-5(l / f)-carboxylate (1.7 g, 0.01 mol, 1 equiv) and Pyridine (5.33 g, 0.07 mol, 7 equiv) in DCM (20 mL) was added POCI3 (2.07 g, 0.02 mol, 2 equiv) at 0 °C. The reaction was stirred for 5 h at RT. To the reaction mixture was added water (30 mL) and extracted with DCM (3 x 50 mL). The combined organic phase was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography, eluted with EA in PE (0%-30%) to afford the title compound (842 mg). LCMS m / z+[M+H]235.0.

[0155] Step 5. tert-butyl 2-cyano-l-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(lH)-carboxylate

[0156] To a solution of tert-butyl 2-carbamoyl-4,6-dihydropyrrolo[3,4-<7]imidazole-5(l / f)-carboxylate (900 mg, 3.8 mmol, 1.0 equiv) in THF (90 mL) was added NaH (461 mg, 11.5 mmol, 60% purity, 3.0 equiv) at 0 °C. After stirring for 30 min a, SEMC1 (1281 mg, 7.7 mmol, 2.0 equiv) was added to the reaction mixture. The reaction was stirred for another 1 h at RT under N2 atm. The mixture was quenched with NH4CI (sat. aq 100 mL) and extracted 70ME1\60337174.v1141039-00120with EA (3 x 100 mL). The organic layers were combined, washed with brine (3 x 100 mL), dried over Na₂SO₄, filtered and the filtrate was concentrated in vacuum. The residue was purified by silica gel chromatography, eluted with EA in PE (0%-25%) to afford the title compound (910 mg). LCMS m / z+[M+H]365.2.

[0157] Intermediate 5-1. tert-butyl 2-(7-(2-(benzyloxy)-4-fluorophenyl)-4-(((trifluoromethyl)sulfonyl)oxy)thieno[3,2-c]pyridin-6-yl)-l-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(lH)-carboxylateOH OTf

[0158] Step 1. tert-butyl 2-(7-(2-(benzyloxy)-4-fluorophenyl)-4-hydroxythieno[3,2-c]pyridin-6-yl)-l-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H) -carboxylate

[0159] To a solution of 2-(2-(benzyloxy)-4-fluorobenzyl)-N, N-diethylthiophene-3-carboxamide (1191 mg, 3.0 mmol, 1.2 equiv) in THF (15 mL) was added n-BuLi (2.5 M in hexane, 1.2 mL, 3.0 mmol, 1.2 equiv) at -78 °C. The reaction mixture was stirred for 1 h at -78 °C. Then tert-butyl 2-cyano-l-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-<7]imidazole-5(l / Z)-carboxylate (910 mg, 2.5 mmol, 1.0 equiv) in THF (5 mL) was added to the mixture. The reaction was stirred for 1 h at -78 °C under N2 atm. The mixture was quenched with NH4CI (sat. aq 30 mL) and extracted with EA (3 x 30 mL). The organic layers were combined, washed with brine (3 x 30 mL), dried over Na₂SO₄, filtered and the filtrate was concentrated in vacuum. The residue was purified by silica gel chromatography, eluted with EA in PE (0%-80%) to afford the title compound (1.0 g). LCMS m / z+[M+H]689.1.

[0160] Step 2. tert-butyl 2-(7-(2-(benzyloxy)-4-fluorophenyl)-4-(((trifluoromethyl)sulfonyl)oxy)thieno[3,2-c]pyridin-6-yl)-l-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(lH)-carboxylate

[0161] To a solution of tert-butyl 2-(7-(2-(benzyloxy)-4-fluorophenyl)-4-hydroxythieno[3,2-c]pyridin-6-yl)-l-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-<7]imidazole-5(l / f)-carboxylate (150 mg, 0.22 mmol, 1.0 equiv) in DCM (5 mL) was added Pyridine (103 mg, 1.3 mmol, 6.0 equiv) and Tf₂O (123 mg, 0.4 mmol, 2.0 equiv) respectively at 0 °C. The reaction was stirred for 1 h. The mixture was quenched with ice water (10 mL) and extracted with DCM (3 x 10 mL). The combined organic layer was dried over Na₂SO₄, filtered and the filtrate was concentrated in vacuo. The residue was71ME1\60337174.v1141039-00120purified by silica gel chromatography, eluted with EA in PE (0%-30%) to afford the title compound (150 mg). LCMS m / z+[M+H]821.0.

[0162] The intermediates in the table below were synthesized as described for Intermediate 5-1 from appropriate starting materials.LCMSInt.Structure IUPAC Name m / z No.[M+H]+tert-butyl 2-(7-(2-(benzyloxy)-4-fluorophenyl)-4- (((trifluoromethyl)sulfonyl)oxy)thieno[3,2- A JABnO y N c]pyridin-6-yl)-l-((2- [M+H] 5-1SEM (trimethylsilyl)ethoxy)methyl)-4,6- 821.0 OTf dihydropyrrolo [3,4-d] imidazole-5( 1 H)- carboxylatetert-butyl 2-(7-(2-(benzyloxy)-4,6- difluorophenyl)-4- F1 o i (((trifluoromethyl)sulfonyl)oxy)thieno[3,2- [M+H] 83 5-2 BnO Y N-"\ J c]pyridin-6-yl)-l-((2- SNvSEM 9.2 OTf (trimethylsilyl)ethoxy)methyl)-4,6- dihydropyrrolo [3,4-d] imidazole-5( 1 H)- carboxylatetert-butyl 2-(7-(2-(benzyloxy)-4-fluorophenyl)-4- (((trifluoromethyl)sulfonyl)oxy)thieno[3,2- 1 o 1fS / •"^NAV c]pyridin-6-yl)-l-((2- [M+H] 84 5-3Bn0^ T> N~A )ZS'1| YXN.VL> N SEM (trimethylsilyl)ethoxy)methyl)-4, 5,7,8- 8.8 OTf tetrahydroimidazo [4,5 -d] azepine-6( 1 H)- carboxylatetert-butyl 2-(7-(2-(benzyloxy)-4-fluorophenyl)-4- F(((trifluoromethyl)sulfonyl)oxy)thieno[3,2- BnOX'y N-A N-BOC [M+H] 83 5-4 c]pyridin-6-yl)-3-((2- 4.7 SEM (trimethylsilyl)ethoxy)methyl)-3,4,6,7-tetrahydro- OTf5H-imidazo[4,5-c]pyridine-5-carboxylate72ME1\60337174.v1141039-00120F tert-butyl 2-(7-(2-(benzyloxy)-4-fluorophenyl)-4- Xx, Boc (((trifluoromethyl)sulfonyl)oxy)thieno[3,2- [M+H]83 5-5 c]pyridin-6-yl)-l-((2- 4.7 V\^N SEM (trimethylsilyl)ethoxy)methyl)- 1,4,6,7-tetrahydro- OTf5H-imidazo[4,5-c]pyridine-5-carboxylateF tert-butyl 2-(7-(2-(benzyloxy)-4-fluorophenyl)-4- BnCr X"'> J< N— A N-Boc (((trifluoromethyl)sulfonyl)oxy)thieno[3,2- [M+H]72 5-6 SXAX c]pyridin-6-yl)-6,7-dihydrothiazolo[5,4- 2.3OTf c]pyridine-5(4H)-carboxylatetert-butyl 2-(7-(2-(benzyloxy)-4,6- Fdifluorophenyl)-4- BOC(((trifluoromethyl)sulfonyl)oxy)thieno[3,2- [M+H]85 5-7c]pyridin-6-yl)-l-((2- 3.2 SEM OTf (trimethylsilyl)ethoxy)methyl)- 1,4,6,7-tetrahydro- 5H-imidazo[4,5-c]pyridine-5-carboxylatetert-butyl 2-(7-(2-(benzyloxy)-4,6- F difluorophenyl)-4- BnO J^T'"'rXFN— A / -\ N-Boc (((trifluoromethyl)sulfonyl)oxy)thieno[3,2- [M+H]85 5-8c]pyridin-6-yl)-3-((2- 3.2 SEM OTf (trimethylsilyl)ethoxy)methyl)-3,4,6,7-tetrahydro- 5H-imidazo[4,5-c]pyridine-5-carboxylate

[0163] Intermediate 6. tert-butyl l-(4-bromobutyl)-2-cyano-l,4,6,7-tetrahydro-5H- imidazo[4,5-c]pyridine-5-carboxylateME1\60337174.v1141039-00120

[0164] Step 1.4-((3-nitropyridin-4-yl)amino)butan-l-ol

[0165] To a solution of 4-methoxy-3 -nitropyridine (200 g, 1.30 mol, 1.0 equiv) in EtOH (1000 mL) was added 4-aminobutan-l-ol (139 g, 1.56 mol, 1.2 equiv). The reaction mixture was stirred at 80 °C for 12 h under N2 atmosphere. The reaction mixture was concentrated. To the residue was added EA (200 mL). The resulting mixture was stirred at RT for 30 min. Then the mixture was filtered to give product (260 g, 95%). LCMS m / z [M+H]+212.2.

[0166] Step 2.2-ethyl-6-(A^-(4-(l-(thiazol-2-ylamino)cyclopropyl)phenyl)sulfamoyl)benzofuran-3-carboxylic acid

[0167] To a solution of 4-((3-nitropyridin-4-yl)amino)butan-l-ol (130 g, 615.47 mmol, 1.0 equiv) in THF (500 mL) was added 10% Pd / C (13 g, 50% wt. H2O) at RT. The reaction mixture was stirred at RT for 72 h under H2 atmosphere. The reaction mixture was filtered and the filtrated was concentrated to give the title compound (106 g, 95%). LCMS m / z [M+H]+182.2.Step 3.4-(2-(ethoxycarbonyl)-lH-imidazo[4,5-c]pyridin-l-yl)butyl ethyl oxalateTo the mixture of 4-((3-aminopyridin-4-yl)amino)butan-l-ol (17.0 g, 93.92 mmol, 1 equiv) and TEA (47.43 g, 469.61 mmol, 5 equiv) in DMF (150 mL) was added ethyl 2-chloro-2-oxoacetate (in DCM) (28.10 g, 6.10 mmol, 2.2 equiv) dropwise to keep the temperature during 30 to 50 °C. The resulting mixture was stirred at RT for 3 h. The mixture was diluted with water (1500 mL) and extracted with EA (5 x 1500 mL). The combined organic phase was concentrated in vacuo to afford the title compound (19 g, crude). The crude was used for the next step directly. LCMS m / z+[M+H]364.3.

[0168] Step 4. ethyl l-(4-hydroxybutyl)-lH-imidazo[4,5-c]pyridine-2-carboxylate74ME1\60337174.v1141039-00120

[0169] The crude 4-(2-(ethoxycarbonyl)-l / Z-imidazo[4,5-c]pyridin-l-yl)butyl ethyl oxalate (19.0 g, crude) was dissolved in MeOH (100 mL). To the mixture was added K2CO3(1.30 g, 9.39 mmol, 0.1 equiv). The resulting mixture was stirred at RT for 3h. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-10%) to afford the title compound (8.3 g, 34% over 2 steps). LCMS m / z+[M+H]264.3.

[0170] Step 5.5-( / c / 7 -butyl) 2-ethyl l-(4-hydroxybutyl)-l, 3a, 4,6,7, 7a-hexahydro-5H-imidazo[4,5-c]pyridine-2,5-dicarboxylate

[0171] To the mixture of ethyl l-(4-hydroxybutyl)-l / Z-imidazo[4,5-c]pyridine-2-carboxylate (8.3 g, 31.56 mmol, 1 equiv) and Boc2O (13.76 g, 63.12 mmol, 2 equiv) in MeOH (50 mL) was added 10% Pd / C (1.67 g, 50% wt. H2O). The resulting mixture was stirred at RT for 16 h under H2 atmosphere. The mixture was filtered and the filter cake was washed with MeOH (3 x 50 mL). The combined filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-6%) to afford the title compound (7.5 g, 65%). LCMS m / z+[M+H]368.2.

[0172] Step 6.5-( / e / 7 -butyl) 2-ethyl l-(4-((tert-butyldimethylsilyl)oxy)butyl)-l, 4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-2,5-dicarboxylate

[0173] To the mixture of 5-(tert-butyl) 2-ethyl l-(4-((tert-butyldimethylsilyl)oxy)butyl)-l,4,6,7-tetrahydro-5 / Z-imidazo[4,5-c]pyridine-2,5-dicarboxylate (14.40 g, 39.2 mmol, 1.0 equiv) in DCM (200 mL) was added imidazole (7.90 g, 117.6 mmol, 3.0 equiv) and tert-butyldimethylsilyl chloride (8.82 g in DCM (150 mL), 58.8 mmol, 1.5 equiv) dropwise at 0 °C under N2 atmosphere. The mixture was stirred at RT overnight. The mixture was poured into water (200 mL) and extracted with DCM (3 x 100 mL). The combined organic layer was dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-60%) to afford the title compound (14.93 g, 80%). LCMS m / z+[M+H]482.9.

[0174] Step 7. tert-butyl l-(4-((tert-butyldimethylsilyl)oxy)butyl)-2-formyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate

[0175] To the mixture of 5-(tert-butyl) 2-ethyl l-(4-((tert-butyldimethylsilyl)oxy)butyl)-l,4,6,7-tetrahydro-5 / Z-imidazo[4,5-c]pyridine-2,5-dicarboxylate (14.93 g, 31.1 mmol, 1.0 equiv) in THF (150 mL) was added DIBAL-H (IM in hexanes, 37.3 mmol, 37.3 mL, 1.2 equiv) dropwise at -78 °C under N2 atmosphere. The mixture was stirred at -78 °C for 2 h. The mixture was poured into 150 mL water at 0 °C and extracted with DCM (3 x 100 mL). The combined organic layer was dried over Na2SO4, and concentrated under reduced75ME1\60337174.v1141039-00120pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-70%) to afford the title compound (12.73 g, 95%). LCMS m / z+[M+H]438.3.

[0176] Step 8. tert-butyl l-(4-((tert-butyldimethylsilyl)oxy)butyl)-2-cyano-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate

[0177] A mixture of l-amino-l,4-diazabicyclo[2.2.2]octane-l,4-diium (11.16 g, 29.13 mmol, 1.0 equiv) and t-BuOK (6.54 g, 58.26 mmol, 2.0 equiv) in THF (100 mL) was stirred at RT for 0.5 h. Then tert-butyl 1-(4-((tert-butyldimethylsilyl)oxy)butyl)-2-formyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate (12.73 g, 29.13 mmol, 1.0 equiv) in ACN (50 mL) was added into the mixture and stirred at RT for 16h. The mixture was poured into NH4CI (sat aq 150 mL) and extracted with DCM (3 x 100 mL). The combined organic layer was dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-70%) to afford the title compound (10.00 g, 72%). LCMS m / z+[M+H]435.4.

[0178] Step 9. tert-butyl 2-cyano- l-(4-hydroxybutyl)- 1,4,6, 7-tetrahydro-5H-imidazo[4,5 -c ] pyridine-5-carboxylate

[0179] To the mixture of tert-butyl l-(4-((tert-butyldimethylsilyl)oxy)butyl)-2-cyano-l,4,6,7-tetrahydro-5 / Z-imidazo[4,5-c]pyridine-5-carboxylate (10.0 g, 23.04 mmol, 1.0 equiv) in THF (100 mL) was added TBAF (IM in THF, 69.12 mmol, 69.12 mL, 3.0 equiv) and the resulting mixture was stirred at RT for 1 h. The solvent was concentrated in vacuo. The residue was diluted with water (100 mL) and extracted with DCM (3 x 100 mL). The combined organic layer was dried over Na₂SO₄, concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-10%) to afford the title compound (6.64 g, 90%). LCMS m / z+[M+H]321.3.

[0180] Step 10. tert-butyl l-(4-bromobutyl)-2-cyano-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate

[0181] To the mixture of tert-butyl 2-cyano- l-(4-hydroxybutyl)- 1,4,6, 7-tetrahy dro-5 / Z-imidazo[4,5-c]pyridine-5-carboxylate (6.64 g, 20.73 mmol, 1.0 equiv) in DCM (100 mL) was added PPI13 (8.16 g, 31.10 mmol, 1. 5 equiv) at RT under N2 atmosphere. Then CBr4 (10.29 g, 31.10 mmol, 1.5 equiv) was added into the mixture and stirred at 0 °C for 1 h. The reaction was washed with water (100 mL) and extracted with DCM (3 x 100 mL). The combined organic layer was dried over Na₂SO₄, concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-50%) to afford the title compound (5.97 g, 90%). LCMS m / z+[M+H]383.1.76ME1\60337174.v1141039-00120

[0182] Intermediate 7. l,3-dimethyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3-dihydro-2H-imidazo[4,5-&]pyridin-2-one

[0183] Step 1.6-bromo-l,3-dimethyl-l,3-dihydro-2H-imidazo[4,5-&]pyridin-2-one

[0184] To a solution of 6-bromo-l,3-dihydro-2H-imidazo[4,5-Z?]pyridin-2-one (5.0 g, 23.36 mmol, 1.00 equiv) in DMF (50 mL) was added NaH (2.34 g, 58.41 mmol, 2.5 equiv, 60% dispersion in mineral oil). The reaction mixture was stirred at 0 °C for 1 h. Then iodomethane (8.29 g, 58.41 mmol, 2.5 equiv) was added. The reaction mixture was stirred at RT for 16 h. The reaction mixture was quenched with water (100 mL) and extracted with EA (3 x 300 mL). The combined organic phase was washed with brine (30 mL) and dried over Na2SO4and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-5%) to afford the title compound (3.6 g, 66%). LCMS mJz [M+H]+242.0.

[0185] Step 2. l,3-dimethyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3-dihydro-2H-imidazo[4,5-&]pyridin-2-one

[0186] To a solution of 6-bromo-l,3-dimethyl-l,3-dihydro-2 / / -imidazo[4,5-Z?]pyridin-2-one (350 mg, 1.45 mmol, 1 equiv) in dioxane (15 mL) was added Bis(pinacolato)diboron (734 mg, 2.89 mmol, 2 equiv), Pd(dppf)Ch (53 mg, 0.07 mmol, 0.05 equiv) and KOAc (426 mg, 4.34 mmol, 3 equiv). The reaction mixture was stirred at 100 °C for 2 h under N2 atmosphere. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-50%) to afford the title compound (300 mg, 72%). LCMS m / z [M+H]+290.3.

[0187] Intermediate 8-1. (6-methyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)boronic acid

[0188] Step 1.3-bromo-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

[0189] To a solution of 3-bromo-6,7-dihydro-5H-pyrrolo[3,4-Z?]pyridin-5-one (760 mg, 3.57 mmol, 1 equiv) in DMF (8 mL) was added NaH (214 mg, 5.35 mmol, 1.5 equiv, 60%77ME1\60337174.v1141039-00120dispersion in mineral oil). The reaction mixture was stirred at 0 °C for 0.5 h. Then iodomethane (608 mg, 4.28 mmol, 1.2 equiv) was added. The reaction was stirred at RT for 0.5 h under N2 atmosphere. The mixture was added to water (30 mL) and extracted with EA (3 x 80 mL). The combined organic layers were washed with H2O (2 x 10 mL), dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-50%) to afford the title compound (325 mg, 35%). LCMS m / z [M+H]+226.4.

[0190] Step 2. (6-me 7thyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)boronic 1acid

[0191] To a mixture of 3-bromo-6-methyl-6,7-dihydro-577-pyrrolo[3,4-Z?]pyridin-5-one (80 mg, 0.35 mmol, 1 equiv) and Bis(pinacolato)diboron (179 mg, 0.71 mmol, 2 equiv) in dioxane (3 mL) was added Pd(dppf)Ch (52 mg, 0.07 mmol, 0.2 equiv) and KO Ac (104 mg, 1.06 mmol, 3 equiv). The reaction mixture was stirred at 90 °C for 1 h under N2 atmosphere. The solvent was removed in vacuo. The residue was purified by prep-HPLC(ACN / water / 10 mM NH4HCO3) to afford the title compound (25 mg, 26%). LCMS m / z [M+H]+193.1.

[0192] The intermediates in the table below were synthesized as described for Intermediate 8-1 from appropriate starting materials.LCMSInt. No. Structure IUPAC Name m / z.[M+H]+N,N-dimethyl-2-(3-(4,4,5,5- B tetramethyl- 1,3,2-dioxaborolan-2-yl)- 8-2 346.47,8-dihydro- 1,6-naphthyridin-6(577)- 1 yl)acetamide6-methyl-3-(4,4,5,5-tetramethyl- 8-3 l,3,2-dioxaborolan-2-yl)-6,7- 261.2 dihydro-577-pyrrolo[3,4-Z?]pyridinel-( l-methylazetidin-3-yl)-6-(4, 4,5,5- B8-4 tetramethyl- 1,3,2-dioxaborolan-2-yl)- 314.11 / 7- indazole^=N78ME1\60337174.v1141039-00120HO, OHB (5 - ((3 -hydroxy- 3 -methy lazetidin- 1 - 8-5 223.1IT’S r0OHy l)methy l)pyridin- 3 -y l)boronic acidHO, OHB(6-((3-hydroxy-3-methylazetidin-l- 8-6 223.2^ / °~~o ro- ■J5y l)methy l)pyridin- 3 -y l)boronic acid A?HO0 \A zx__7 0- / IHO (7-(2-hydroxy-2-methylpropyl)- 8-7 5,6,7,8-tetrahydro- 1,7-naphthyridin- 251.1W?3-yl)boronic acid2-(l-methylazetidin-3-yl)-6-(4, 4,5,5- O-B8-8 tetramethyl- 1,3,2-dioxaborolan-2-yl)- 314.10=12H-indazoleX2-(7-(4,4,5,5-tetramethyl-l,3,2- 8-9 X dioxaborolan-2-yl)imidazo [1,2- 303.1 a]pyridin-3-yl)propan-2-ol0Oco- 2-(5-(4,4,5,5-tetramethyl-l,3,2- 7\^>~8-10 dioxaborolan-2-yl)benzo[<7]oxazol-2- 304.2 yl)propan-2-olHO(7-methyl-5,6,7,8-tetrahydro-l,7- 8-11 --4Y-O 193.1 naphthyridin-3-yl)boronic acid(3 -hydroxy- 1 -methylazetidin-3 -y 1)(3 - \ N-^(4,4,5,5-tetramethyl-l,3,2- 8-12 374.4 dioxaborolan-2-yl)-7,8-dihydro-l,6- Nnaphthyridin-6(5 / / )-yl)methanone_u / =\ / 3-methoxy-l-methyl-5-(4, 4,5,5- 8-13 A 7^°BA_A tetramethyl- 1,3,2-dioxaborolan-2-yl)- 290.3 ox177-py razo Io [3,4- / ?] py ridi nc4-methyl-7-(4,4,5,5-tetramethyl- O-B 1,3,2-dioxaborolan-2-yl)-3,4- 8-14 \ _ O 305.0 dihydropyrido [3,2- / | [ 1,4] oxazepin- \=< rO-^ / 5(2 / f)-one79ME1\60337174.v1141039-001202-(3-methyl-6-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-3 / Z- 8-15 318.1 imidazo[4,5-b]pyridin-2-yl)propan-2- olN,3-dimethyl-6-(4,4,5,5-tetramethyl- 7-0z y ra—8-16 ^O' O Z=xBx_V!^YN\)--N / H l,3,2-dioxaborolan-2-yl)-3 / Z- 289.2Fa’ '° imidazo [4, 5 -b] pyridin-2- amineo / l-( l-methylazetidin-3-yl)-5-(4, 4,5,5- O-B8-17 tetramethyl- 1,3,2-dioxaborolan-2-yl)- 315.21H-pyrazolo[3,4-b]pyridineN V-N^O 3 -methyl- 1 - (4- (4,4, 5,5 - tetramethy 1- 8-18 To l,3,2-dioxaborolan-2-yl)pyridin-2- 291.2 N"-A yl)azetidin-3-olt-VOHom- 3 -methyl- 1 - (5 - (4,4, 5,5 - tetramethy 1- 8-19 l,3,2-dioxaborolan-2-yl)pyridin-2- 291.1 yl)azetidin-3-ol. OH (3-(2-hydroxypropan-2-yl)-l-methyl- HO \Z—8-20 HO'B'yJ>y^ 1 / Z-pyrazolo [3,4-Z?]pyridin-5- 236.1L L -Nyl)boronic acidHO iHO'B'Y^ (l-(2-methoxyethyl)-6-oxo-l,6- 8-21N199.1 dihydropyridazin-4-yl)boronic acid 06-methoxy-Af-(2-methoxyethyl)-5- ~V0' y=\-J>8-22 -~T'd / -N HN— \ (4,4,5,5-tetramethyl-l,3,2- 337.3 €Voxdioxaborolan-2-yl)picolinamide4-methoxy-l-methyl-5-(4, 4,5,5- 8-23 tetramethyl- 1,3,2-dioxaborolan-2-yl)- 290.11H-pyrazolo[3,4-b]pyridine80ME1\60337174.v1141039-00120HO,. OHB (6-((dimethyl(oxo)-l6- 8-24 245.0oX"' sulfanylidene)amino)-5- 01methoxypyridin-3-yl)boronic acid%((2-methoxy-5-(4,4,5,5-tetramethyl- o8-25 V / ° \A- J 327.1o e y to—— l,3,2-dioxaborolan-2-yl)pyridin-3- 1 ' z" °v \ \ " Wxyl)imino)dimethyl-16-sulfanone1 ° ” '° \ / z / z= X M7~o 2-(5-(4,4,5,5-tetramethyl-l,3,2- 8-26 dioxaborolan-2-yl)-l / Z-pyrazolo[3,4- 303.3 o^Z Zdpyridin- 1 -yl) acetamideNH2 / " O (S)-l-(5-(4,4,5,5-tetramethyl-l,3,2- 8-27 dioxaborolan-2-yl)-l / Z-pyrazolo[3,4- 304.1N N< onZ?]pyridin- 1 -yl)propan-2-ol / 'O (7?)-l-(5-(4,4,5,5-tetramethyl-l,3,2- 8-28Hdioxaborolan-2-yl)-l / Z-pyrazolo[3,4- 304.3Z?]pyridin- 1 -yl)propan-2-ol2-methoxy-5-(4,4,5,5-tetramethyl- 8-29 1,3,2-dioxaborolan-2-yl)pyridine-3 - 315.1 sulfonamideA'O AfJV-dimethyl-2-(5-(4, 4,5,5- tetramethyl- 1,3,2-dioxaborolan-2-yl)- 8-30 317.31 / Z-pyrazolo [3,4-Z?]pyridin- 1 - / yl)ethan-l -amineO(3-methyl-l-(oxetan-3-yl)-2-oxo-2,3- no y>8-31 dihydro-l / Z-imidazo[4,5-Z?]pyridin-6- 250.1LI >° yl)boronic acid81ME1\60337174.v1141039-00120l-methyl-3-(oxetan-3-yl)-6-(4, 4,5,5- tetramethyl- 1,3,2-dioxaborolan-2-yl)- 8-32 332.2 l,3-dihydro-2 / Z-imidazo[4,5- Z?]pyridin-2-oneI9 x 1 -methyl-3 -( 1 -methylazetidin-3 -yl)- ^y o oro--- O tD o- 00- 6-(4, 4,5, 5-tetramethyl- 1,3,2- 8-33 345.4 o dioxaborolan-2-yl)- 1,3-dihydro-2 / Z- 0\ z imidazo[4,5-Z?]pyridin-2-oneZI o ^o(3 -methoxy- 1 -methyl- 1H- 8-34 pyrazolo[4,3-Z?]pyridin-6-yl)boronic 208.0 acidOH(3-(2-hydroxypropan-2-yl)-l-methyl-. N. / 236.0 8-35 jf l / Z-pyrazolo[4,3-Z?]pyridin-6- HO,BAZN\ / \ / O OHO yl)boronic acidyx z°ZH (3-(2-hydroxypropan-2-yl)-2-methyl- 8-36 a 2 / Z-pyrazolo[4,3-Z?]pyridin-6- 236.0O tn-o rn-1do tn1- X X d X d1yl)boronic acid0 (l,2-dimethyl-3-oxo-2,3-dihydro-l / Z- _N. JJ8-37 jf N— 208.2H0'BA^<N' pyrazolo[4,3-Z?]pyridin-6-yl)boronicHO acid(3 -carbamoyl- 1 -methyl- 1 H- y NH2_N. J 221.2 8-38 pyrazolo[4,3-Z?]pyridin-6-yl)boronic jfHO.BA^N- acid H6 '( 1 -methyl-3 -(methylcarbamoyl)- 1H- 235.3 8-39 pyrazolo[4,3-Z?]pyridin-6-yl)boronic acid(6,6-dioxido-5,7 -dihydrothieno [3,4- 214.1 8-40Z?]pyridin-3-yl)boronic acid2-methoxy-l-methyl-6-(4, 4,5,5- A ° / 290.3 8-41 tetramethyl- 1,3,2-dioxaborolan-2-yl)- I X177-imidazo [4, 5 -Z?]pyridine82ME1\60337174.v1141039-00120l-methyl-6-(4,4,5,5-tetramethyl- 8-42 1,3,2-dioxaborolan-2-yl)oxazolo [5,4- 277.2Z?]pyridin-2(l / / )-one2-(l-methyl-6-(4,4,5,5-tetramethyl- V"? / 1,3,2-dioxaborolan-2-yl)- 1 H- 8-43 318.3O0 C0 05-- imidazo[4,5-Z?]pyridin-2-yl)propan-2- ol$8 V-' dimethyl((l-methyl-6-(4, 4,5,5- otetramethyl- 1,3,2-dioxaborolan-2-yl)- 8-44 351.3I JL / >-Nl / Z-imidazo[4,5-Z?]pyridin-2- yl)imino)-16-sulfanoneA^,l-dimethyl-6-(4,4,5,5-tetramethyl- 8-45 X"° ' 1,3,2-dioxaborolan-2-yl)- 1 H- 289.3N XO imidazo [4, 5 -b\ pyridin-2- amineAH° \ o ( 1 -methyl-2-oxo- 1,2,3,4- 8-46 tetrahy dropyrido [2,3- 223.0ftOoo-xb] [ 1,4]oxazepin-8-yl)boronic acid ^xo \HO 0 (6-methyl-5-oxo-5,6-1II8-47 HO'YYV dihy dropyrido [2,3 -ft] py ridazi n-3 - 206.0 yl)boronic acidHO 0 r-n (3-(oxetan-3-yl)-4-oxo-3,4- 8-48 247.2 dihydrophthalazin-6-yl)boronic acid l-methyl-7-(4,4,5,5-tetramethyl- 8-49 l,3,2-dioxaborolan-2-yl)-3,4- 289.2 dihydroquinazolin-2(l / / )-oneHO (6-(methylimino)-6-oxido-6,7- 7 '7’7 '7 8-50 dihydro-5 / Z-6X4-thieno[3,4-Z?]pyridin-H0' XXXN3-yl)boronic acidl,3,5-trimethyl-6-(4,4,5,5- tetramethyl- 1,3,2-dioxaborolan-2-yl)- 8-51 304.3 l,3-dihydro-2 / Z-imidazo[4,5- Z?]pyridin-2-one83ME1\60337174.v1141039-00120(2-(2-hydroxypropan-2- HO8-52 yl)imidazo [ 1,2-a]pyridin-6- 220.9 yl)boronic acidl,3-dimethyl-6-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-l,3- 8-53 V^ 326.^^ oY- 2 y °~~ °~~0 □3- O^\ZOo \ L BJo oo- oo00- 01- / —^ dihydro- [ 1,2,5] thiadiazolo [3,4- ^AA / cj oz / jjpyridinc 2,2-dioxide $Z z« _^A ° Y Y= Oz zZ ^^ ^-z.Y c / ) oy ooo^ l,3,7-trimethyl-6-(4,4,5,5- '> z o o o o ^zo tetramethyl- 1,3,2-dioxaborolan-2-yl)- 8-54 304.1 l,3-dihydro-2 / Z-imidazo[4,5- Z?]pyridin-2-oneHO 1 (l,4-dimethyl-2,3-dioxo-l,2,3,4- 8-55 HO'®Y^yNY° tetrahydropyrido [2,3 -b] py razi n-7 - 236.01 yl)boronic acidHO O (6-(2-hydroxy-2-methylpropyl)-5- 8-56 oxo-5,6-dihydropyrido[2,3- 264.0 k |Q»Toh<7]pyridazin-3-yl)boronic acid3-methyl-l-(oxetan-3-ylmethyl)-6- (4,4,5,5-tetramethyl-l,3,2- 8-57 346.0 dioxaborolan-2-yl)- 1,3-dihydro-2 / Z- imidazo[4,5-Z?]pyridin-2-one1,3-bis(methyl-d3)-6-(4,4,5,5- tetramethyl- 1,3,2-dioxaborolan-2-yl)- 8-58 296.21,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one2-(6-(4,4,5,5-tetramethyl-l,3,2- Yr- °8-59 dioxaborolan-2-yl)imidazo [1,2- 304.3Y UrIY N \ a]pyrimidin-2-yl)propan-2-ol3-(oxetan-3-yl)-6-(4, 4,5,5- 8-60 tetramethyl- 1,3,2-dioxaborolan-2- 319.2 yl)oxazolo[4,5-Z?]pyridin-2(3 / / )-one84ME1\60337174.v1141039-001207,8,8-trimethyl-3-(4,4,5,5- 8-61 tetramethyl- 1,3,2-dioxaborolan-2-yl)- 303.25,6,7,8-tetrahydro- 1,7-naphthyridineHO (6,7,7-trimethyl-6,7-dihydro-5 / Z- 8-62 pyrrolo [3,4-Z?]pyridin-3 -yl)boronic 207.2O tDO-N□J- acid( 1 -methyl-2-oxo-2, 3 -dihydro- 1 H- $8-63 Z Zx\^ ^ 193.2Y ' Z — pyrrolo [3,2-b]pyridin-6-yl)boronic / oacidH? / ( 1,2-dimethyl- 1 H-imidazo [4,5- 8-64 H0'BVV\ 191.9L IL 'Z — b]pyridin-6-yl)boronic acidOH (2-oxo-2, 3 -dihydro- 1 H-pyrrolo [3,2- 8-65 179.1 b]pyridin-6-yl)boronic acidHO'VX>°o3 -methyl- 1 -( 1 -methylazetidin-3 -yl)- 6-(4, 4, 5, 5-tetramethyl- 1,3, 2- 345.2 8-66dioxaborolan-2-yl)- 1,3-dihydro-2 / Z- OC0- OC0- b1imidazo[4,5-Z?]pyridin-2-one Xl-methyl-3-(methylamino)-5- B(4, 4, 5, 5-tetramethyl- 1,3, 2- 8-67 265.2 dioxaborolan-2-yl)pyridin-2( 1 H)-oneAHHOX. OHB(6-((dimethylamino)methyl)pyridin- 181.2 8-683-yl)boronic acid4 N13-methyl-6-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)quinazolin- 287.2 8-694(3H)-one

[0193] Intermediate 9. (6,7,7-trimethyl-6,7-dihydro-5H-pyrrolo[3,4-&]pyridin-3-yl)boronic acid85ME1\60337174.v1141039-00120

[0194] Step 1. N-methoxy-3-methylisothiazole-4-carboxamide

[0195] To a solution of ethyl 5-bromo-2-methylnicotinate (500 mg, 2.05 mmol, 1 equiv, CAS: 129477-21-0) and NBS (438 mg, 2.46 mmol, 1.2 equiv) in CCU (10 mL) was added AIBN (67 mg, 0.41 mmol, 0.2 equiv). The reaction mixtue was stirred at 80 °C for 0.5 h under N2 atmosphere. The reaction was quenched with water (20 mL) and extracted with EA (3 x 30 mL). The combined organic phases were washed with brine (30 mL) and dried over Na2SO4and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-10%) to afford ethyl 5-bromo-2-(bromomethyl)nicotinate (400 mg, 61%). LCMS m / z [M+H]+323.8.

[0196] Step 2.3-bromo-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-&]pyridin-5-one

[0197] To a solution of ethyl 5-bromo-2-(bromomethyl)nicotinate (400 mg, 8.20 mmol, 1 equiv) in MeOH (4 mL) was added MeNH2 (7 mL, 30% in ethanol). The reaction mixture was stirred at RT for 16 h. The reaction was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-10%) to afford the title compound (250 mg, 89%). LCMS m / z [M+H]+227.0.

[0198] Step 3.3-bromo-6,7,7-trimethyl-6,7-dihydro-5H-pyrrolo[3,4-&]pyridin-5-one

[0199] To a solution of 3-bromo-6-methyl-6,7-dihydro-5 / Z-pyrrolo[3,4-Z?]pyridin-5-one (250 mg, 1.10 mmol, 1 equiv) in DMF (15 mL) was added NaH (88 mg, 2.20 mmol, 2 equiv, 60% dispersion in mineral oil). The reaction mixture was stirred at 0 °C for 0.5 h under N2 atmosphere. Then iodomethane (391 mg, 2.75 mmol, 2.5 equiv) was added. The reaction mixture was stirred at RT for 2 h. The reaction was quenched with water (50 mL) and extracted with EA (3 x 150 mL). The combined organic phase was washed with brine (50 mL), dried over Na2SO4L and concentrate under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-30%) to afford the title compound (180 mg, 64%). LCMS m / z [M+H]+255.1.

[0200] Step 4.3-bromo-6,7,7-trimethyl-6,7-dihydro-5H-pyrrolo[3,4-&]pyridine

[0201] To a solution of 3-bromo-6,7,7-trimethyl-6,7-dihydro-5 / Z-pyrrolo[3,4-Z?]pyridin-5-one (150 mg, 0.59 mmol, 1 equiv) in DCM (30 mL) was added Tf2O (498 mg, 1.77 mmol, 3 equiv). The reaction mixture was stirred at RT for 1 h under N2 atmosphere. Then Hantzsch86ME1\60337174.v1141039-00120ester (cas no. 1149-23-1, 747 mg, 2.94 mmol, 5 equiv) was added. The reaction mixture was stirred at RT for 2 h under N2 atmosphere. The reaction was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-10%) to afford the title compound (50 mg, 35%). LCMS m / z [M+H]+241.0.

[0202] Step 5. (6,7,7-trimethyl-6,7-dihydro-5H-pyrrolo[3,4-&]pyridin-3-yl)boronic acid

[0203] To a solution of 3-bromo-6,7,7-trimethyl-6,7-dihydro-5 / Z-pyrrolo[3,4-Z?]pyridine (30 mg, 0.12 mmol, 1 equiv) in dioxane (2 mL) was added Bis(pinacolato)diboron (47 mg, 0.18 mmol, 1.5 equiv), KOAc (37 mg, 0.36 mmol, 3 equiv) and Pd(dppf)Ch (18 mg, 0.02 mmol, 0.2 equiv). The reaction mixture was stirred at 100 °C for 1 h under N2 atmosphere. The crude title compound (0.06M in dioxane, 2 mL) was obtained. LCMS m / z [M+H]+207.2.

[0204] Intermediate 10.7,8,8-trimethyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6,7,8-tetrahydro-l,7-naphthyridine

[0205] Step 1. tert-butyl 3-bromo-5,8-dihydro-l,7-naphthyridine-7(6H)-carboxylate

[0206] To a mixture of 3-bromo-5,6,7,8-tetrahydro-l,7-naphthyridine hydrochloride (500 mg, 1.75 mmol, 1 equiv, cas no. 2177267-75-1) in DCM (10 mL) was added Et3N (531 mg, 5.24 mmol, 3.0 equiv), (Boc)2O (572 mg, 2.62 mmol, 1.5 equiv). The mixture was stirred under N2 atmosphere at RT for 1 h. The reaction mixture was quenched with H2O (50 mL) and extracted with DCM (3 x 50 mL). The combined organic layer was washed with brine, dried over Na2SO4. After filtration, the organic layer was concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluted with EA in PE (0%-20%) to give the title compound (470 mg, 86%). LCMS m / z (M - t-Bu + H)+257.1.

[0207] Step 2. tert-butyl 3-bromo-8,8-dimethyl-5,8-dihydro-l,7-naphthyridine-7(6H)-carboxylate

[0208] To a mixture of tert-butyl 3-bromo-5,8-dihydro-l,7-naphthyridine-7(6 / f)-carboxylate (385 mg, 1.23 mmol, 1 equiv) in THF (5 mL) was cooled to -78 °C under N2 atmosphere and then added LDA (1.26 mL, 2.52 mmol, 2.05 equiv, 2.0 M in THF / n-heptane ethylbenzene). The mixture was stirred under N2 atmosphere at -78 °C for 0.5 h. To the87ME1\60337174.v1141039-00120resulting mixture was added Mel (358 mg, 2.52 mmol, 2.05 equiv) and the mixture was stirred under N2 atmosphere at -78 °C for 0.5 h. The reaction mixture was quenched with H2O (20 mL) and extracted with EA (3 x 30 mL). The combined organic layer was washed with brine, dried over Na2SO4. After filtration, the organic layer was concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluted with EA in PE (0%-10%) to give the title compound (140 mg, 33%). LCMS m / z [M+H]+341.2.

[0209] Step 3.3-bromo-8,8-dimethyl-5,6,7,8-tetrahydro-l,7-naphthyridine

[0210] To a solution of tert-butyl 3-bromo-8,8-dimethyl-5,8-dihydro-l,7-naphthyridine- 7(6 / / )-carboxylate (115 mg, 0.34 mmol, 1.0 equiv) in DCM (2 mL) was added TFA (1 mL). The reaction mixture was stirred at RT for 1 h. The reaction mixture was concentrated in vacuum to afford the title compound (110 mg, crude, TFA salt). LCMS m / z [M+H]+241.1.

[0211] Step 4.3-bromo-7,8,8-trimethyl-5,6,7,8-tetrahydro-l,7-naphthyridine

[0212] To a solution of 3-bromo-8,8-dimethyl-5,6,7,8-tetrahydro-l,7-naphthyridine (110 mg, 0.34 mmol, 1.0 equiv, crude TFA salt) in MeOH (5 mL) was added paraformaldehyde (103 mg, 3.44 mmol, 10.0 equiv) and NaBH(OAc)3 (730 mg, 3.44 mmol, 10.0 equiv). The reaction mixture was stirred at 60 °C for 16 h. The reaction mixture was quenched with NaHCO3(sat. aq50 mL) and extracted with DCM (3 x 50 mL). The combined organic layer was washed with brine, dried over Na2SO4. After filtration, the organic layer was concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluted with MeOH in DCM (0%-10%) to give the title compound (58 mg, 67% over two steps). LCMS m / z [M+H]+255.0.

[0213] Step 5.7,8,8-trimethyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6,7,8-tetrahydro- 1,7-naphthyridine

[0214] To a solution of 3-bromo-7,8,8-trimethyl-5,6,7,8-tetrahydro-l,7-naphthyridine (40 mg, 0.16 mmol, 1.0 equiv) in dioxane (2 mL) was added (BPin)2 (61 mg, 0.24 mmol, 1.5 equiv), KOAc (39 mg, 0.40 mmol, 2.5 equiv), Pd(dppf)Ch (22 mg, 0.03 mmol, 0.2 equiv). The mixture was stirred at 90°C for 2 h under N2 atmosphere. The crude title compound (0.08 M, 2 mL in dioxane) was obtained and used directly without further purification. LCMS m / z [M+H]+303.2.

[0215] Intermediate 11. (6-methyl-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-&]pyridin-3-yl)boronic acid88ME1\60337174.v1141039-00120o

[0216] Step 1. (6-methyl-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-&]pyridin-3-yl)boronic acid

[0217] To a solution of 3-bromo-6-methyl-5,6-dihydro-7 / Z-pyrrolo[3,4-Z?]pyridin-7-one (500 mg, 2.20 mmol, 1.0 equiv, cas no. 1254319-55-5) in dioxane (15 mL) was added (BPin)2 (838 mg, 3.30 mmol, 1.5 equiv), KOAc (540 mg, 5.50 mmol, 2.5 equiv), Pd(dppf)Ch (322 mg, 0.44mmol, 0.2 equiv). The mixture was stirred at 90°C for 2 h under N2 atmosphere. The mixture was diluted with brine (100 mL) and extracted with EA (3 x 120 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The reaction mixture purified by prep-HPLC (ACN / water / lOmM NH4HCO3) to give the title compound (150 mg, 36%). LCMS m / z [M+H]+193.3.

[0218] Intermediate 12. tert-butyl ( / ?)-3-bromo-8-methyl-5,8-dihydro-l,7-naphthyridine-7(6H)-carboxylate & tert-butyl (S)-3-bromo-8-methyl-5,8-dihydro-l,7-naphthyridine-7(6H)-carboxylateBr Br Br Br Br2HCI H Boc Boc Boc Boc

[0219] Step 1. tert-butyl 3-bromo-5,8-dihydro-l,7-naphthyridine-7(6H)-carboxylate

[0220] A mixture of 3-bromo-5,6,7,8-tetrahydro-l,7-naphthyridine dihydrochloride (1 g, 3.50 mmol, 1 equiv, cas no. 2177267-75-1), TEA (1.06 g, 10.49 mmol, 3 equiv) and (Boc O (1.15 g, 5.24 mmol, 1.5 equiv) in DCM (30 mL) was stirred at RT for 1 h. The mixture was diluted with H2O (50 mL) and extracted with DCM (3 x 50 mL). The organic layer was dried over Na2SO4and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-30%) to afford the title compound (1.07 g, 98%). LCMS m / z [M+H]+313.1.

[0221] Step 2. tert-butyl 3-bromo-8-methyl-5,8-dihydro-l,7-naphthyridine-7(6H)-carboxylate

[0222] Tert-butyl 3-bromo-5,8-dihydro-l,7-naphthyridine-7(67T)-carboxylate (1.30 g, 4.15 mmol, 1 equiv) was dissolved in THF (15 mL) and chilled to -78°C. Then Mel (619 mg, 4.36 mmol, 1.05 equiv), 2M LDA (2.7 mL, 5.40 mmol, 1.3 equiv) was added. The reaction89ME1\60337174.v1141039-00120mixture was stirred at -78 °C for 1 h. After completion of the reaction, the mixture was quenched with sat. aq NH4CI (80 mL) and extracted with EA (2 x 80 mL). The combined organic phase was washed with brine (80 mL), dried over Na2SO4and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-12%) to afford the title compound (1.035 g, 76%). LCMS m / z [M+H]+327.1.

[0223] Step 3. tert-butyl ( / ?)-3-bromo-8-methyl-5,8-dihydro-l,7-naphthyridine-7(6H) -carboxylate & tert-butyl (S)-3-bromo-8-methyl-5,8-dihydro-l,7-naphthyridine-7 (6H) -carboxylate

[0224] Tert-butyl 3-bromo-8-methyl-5,8-dihydro-l,7-naphthyridine-7(67T)-carboxylate (1.65 g) was purified by SFC (Daicel IC-3 (25*250mm,10um), CO2 / EtOH[0.5%NH3(7M in MeOH)]=85 / 15) to afford tert-butyl (R)-3-bromo-8-methyl-5,8-dihydro-l,7-naphthyridine-7(67f)-carboxylate (780 mg, 89% purity, e.e. 99.2%, peak 1) as a colorless oil and tert-butyl (S)-3-bromo-8-methyl-5,8-dihydro-l,7-naphthyridine-7(6 / / )-carboxylate (740 mg, 95% purity, e.e. 97.4%, peak 2). LCMS m / z [M+H]+327.1.

[0225] Intermediate 13-1. ( / ?)-7,8-dimethyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6,7,8-tetrahydro-l,7-naphthyridine

[0226] Step 1. ( / ?)-3-bromo-8-methyl-5,6,7,8-tetrahydro-l,7-naphthyridine

[0227] A mixture of tert-butyl (R)-3-bromo-8-methyl-5,8-dihydro-l,7-naphthyridine-7(67T)-carboxylate (200 mg, 0.61 mmol, 1 equiv) in TFA (1 mL) and DCM (1 mL) was stirred at RT for 1 h. The mixture was concentrated to afford the title compound (138 mg, crude, TFA salt). The crude product was used directly without further purification. LCMS m / z [M+H]+227.0.

[0228] Step 2. ( / ?)-3-bromo-7,8-dimethyl-5,6,7,8-tetrahydro-l,7-naphthyridine A solution of (R)-3-bromo-8-methyl-5,6,7,8-tetrahydro-l,7-naphthyridine (138 mg, 0.61 mmol, 1 equiv), paraformaldehyde (110 mg, 3.65 mmol, 6 equiv) and NaBH(OAc)3 (773 mg, 3.65 mmol, 6 equiv) in MeOH (3 mL) was stirred at 50 °C for 3 h. The mixture was purified90ME1\60337174.v1141039-00120by silica gel column chromatography, eluted with MeOH in DCM (0%-5%) to afford the title compound (130 mg, 89%). LCMS m / z [M+H]+241.0.

[0229] Step 3. ( / ?)-7,8-dimethyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 5,6,7,8-tetrahydro-l,7-naphthyridine

[0230] A mixture of (7?)-3-bromo-7,8-dimethyl-5,6,7,8-tetrahydro-l,7-naphthyridine (65 mg, 0.27 mmol, 1 equiv), (BPin)2 (103 mg, 0.40 mmol, 1.5 equiv), Pd(dppf)Ch (30 mg, 0.04 mmol, 0.15 equiv) and KOAc (79 mg, 0.81 mmol, 3 equiv) in dioxane (1 mL) was stirred at 100°C for 1.5 h in MW. The reaction mixture was used directly without further purification. LCMS m / z [M+H]+289.2.

[0231] The intermediates in the table below were synthesized as described for Intermediate 13-1 from appropriate starting materials.Int. LCMS m / z Structure IUPAC NameNo. [M+H]+B (S)-7,8-dimethyl-3-(4,4,5,5-tetramethyl- 289.1 13-2 l,3,2-dioxaborolan-2-yl)-5,6,7,8- tetrahydro- 1,7 -naphthyridine1

[0232] Intermediate 14-1.2-methylpropan-2-yl 5,7-difluoro-21,21-dimethyl-10,13- dioxa-16,20,23-triazatetracyclo[14.7.0.04’9.017’22]tricosa-l(23),4(5),6,8,17(22)-pentaen-2- yne-20-carboxylate2 HCIF

[0233] Step 1.4,4-dimethyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine91ME1\60337174.v1141039-00120

[0234] To a solution of NaOH (3.48 mg, 86.94 mmol, 2 equiv) in MeOH (64 mL) and H2O (16 mL) was added 2-(l / / -imidazol-4-yl)ethan-l-amine dihydrochloride (8.0 g, 43.47 mmol, 1 equiv) and acetone (25.21 g, 434.70 mmol, 10 equiv). The reaction mixture was stirred at 100 °C for 6 h. The reaction mixture was concentrated under reduced pressure to afford the title compound (6.60 g, crude) which was used for the next step without further purification. LCMS m / z [M+H]+152.2.

[0235] Step 2. tert-butyl 4,4-dimethyl-3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate

[0236] To the mixture of 4,4-dimethyl-4,5,6,7-tetrahydro-3 / Z-imidazo[4,5-c]pyridine (6.60 g, 43.42 mmol, 1 equiv) in MeOH (80 mL) was added Boc2O (37.86 g, 173.68 mmol, 4 equiv). The reaction mixture was stirred at RT for 6 h. The solvent was removed in vacuo. The residue was dissolved in MeOH (50 mL). Then NaOH (65 mL, 130.00 mmol, 3 equiv, 2M in H2O) was added. The reaction mixture was stirred at RT for 0.5 h. The solvent was removed in vacuo. The residue was diluted with water (100 mL) and extracted with DCM (3 x 200 mL). The combined organic layer was washed with brine, dried over Na2SO4and concentrated under reduced pressure. The residue was purified by prep-HPLC (ACN / water / 10 mM NH4HCO3) to afford the title compound (8.01 g, 73%). LCMS m / z [M+H]+252.1.

[0237] Step 3. tert-butyl 2-iodo-4,4-dimethyl-3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate

[0238] To the mixture of tert-butyl 4,4-dimethyl-3,4,6,7-tetrahydro-5 / Z-imidazo[4,5-c]pyridine-5 -carboxylate (5.0 g, 19.92 mmol, 1 equiv) in THF (50 mL) was added NIS (4.93 g, 21.91 mmol, 1.1 equiv). The reaction mixture was stirred at RT for 1 h. The reaction mixture was quenched with water (50 mL) and extracted with EA (3 x 80 mL). The combined organic layer was washed with brine (30 mL), dried over Na2SO4and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-30%) to afford the title compound (7.0 g, 93%). LCMS m / z [M+H]+378.1.

[0239] Step 4. tert-butyl l-(2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)ethyl)-2-iodo-4,4-dimethyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate

[0240] To the mixture of tert-butyl 2-iodo-4,4-dimethyl-3,4,6,7-tetrahydro-5 / Z-imidazo[4,5-c]pyridine-5-carboxylate (7.0 g, 18.57 mmol, 1 equiv) and (2-(2-bromoethoxy)ethoxy)(t rt-butyl)dimethylsilane (6.28 g, 22.28 mmol, 1.2 equiv) in DMF (3 mL) was added K2CO3(7.69 g, 55.70 mmol, 3 equiv). The reaction mixture was stirred at 80 °C for 6 h. The reaction mixture was quenched with water (50 mL) and extracted with EA 92ME1\60337174.v1141039-00120(3 x 80 mL). The combined organic layer was washed with brine (30 mL) and dried over Na2SO4and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-20%) to afford the title compound (8.50 g, 79%). LCMS m / z [M+H]+580.8.

[0241] Step 5. tert-butyl l-(2-(2-hydroxyethoxy)ethyl)-2-iodo-4,4-dimethyl-l, 4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate

[0242] To the mixture of tert-butyl l-(2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)ethyl)-2-iodo-4,4-dimethyl-l,4,6,7-tetrahydro-5 / Z-imidazo[4,5-c]pyridine-5-carboxylate (8.50 g, 14.68 mmol, 1 equiv) in THF (100 mL) was added TBAF (44 mL, 44.00 mmol, 3 equiv, IM in THF). The reaction mixture was stirred at RT for 1 h under N2 atmosphere. The reaction solution was quenched with water (50 mL) and extracted with DCM (3 x 100 mL). The combined organic layer was washed with H2O (2 x 50 mL), dried over Na2SO4and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-4%) to afford the title compound (6.50 g, 95%). LCMS m / z [M+H]+466.1.

[0243] Step 6. tert-butyl l-(2-(2-bromoethoxy)ethyl)-2-iodo-4,4-dimethyl-l, 4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate

[0244] To the mixture of tert-butyl l-(2-(2-hydroxyethoxy)ethyl)-2-iodo-4,4-dimethyl-l,4,6,7-tetrahydro-5 / Z-imidazo[4,5-c]pyridine-5-carboxylate (6.50 g, 13.98 mmol,l equiv) and PPhs (5.50 g, 20.97 mmol, 1.5 equiv) in DCM (70 mL) was added CBr4 (6.95 g, 20.97 mmol, 1.5 equiv) in DCM (30 mL) drop wise at 0 °C. The reaction mixture was stirred at RT for 2 h under N2 atmosphere. The reaction mixture was quenched with H2O (100 mL) and extracted with DCM (3 x 150 mL). The combined organic layer was washed with brine, dried over Na2SO4and concentrated under reduced pressure. The residue was purified by flash column chromatography, eluted with EA in PE (0%-36%) to afford the title compound (7.01 g, 96%). LCMS m / z [M+H]+528.1.

[0245] Step 7. tert-butyl l-(2-(2-(3,5-difluoro-2-formylphenoxy)ethoxy)ethyl)-2-iodo-4,4-dimethyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate

[0246] To the solution of tert-butyl l-(2-(2-bromoethoxy)ethyl)-2-iodo-4,4-dimethyl-l,4,6,7-tetrahydro-5 / Z-imidazo[4,5-c]pyridine-5-carboxylate (314 mg, 0.60 mmol, 1 equiv) and 2,4-difluoro-6-hydroxybenzaldehyde (94 mg, 0.60 mmol, 1 equiv) in DMF (4 mL) was added K2CO3(247 mg, 1.79 mmol, 3 equiv). The reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was quenched with water (20 mL) and extracted with EA (3 x 30 mL). The combined organic layer was washed with brine (30 mL) and dried over Na2SO4L and 93ME1\60337174.v1141039-00120concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-56%) to afford the title compound (334 mg, 92%). LCMS m / z [M+H]+606.8.

[0247] Step 8. tert-butyl l-(2-(2-(2-ethynyl-3,5-difluorophenoxy)ethoxy)ethyl)-2-iodo-4,4-dimethyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate

[0248] To the solution of tert-butyl l-(2-(2-(3,5-difluoro-2-formylphenoxy)ethoxy)ethyl)-2-iodo-4,4-dimethyl-l,4,6,7-tetrahydro-5 / Z-imidazo[4,5-c]pyridine-5-carboxylate (334 mg, 0.55 mmol, 1 equiv) and dimethyl (l-diazo-2-oxopropyl)phosphonate (127 mg, 0.66 mmol, 1.2 equiv) in MeOH (5 mL) was added K2CO3(229 mg, 1.66 mmol, 3 equiv). The reaction mixture was stirred at RT for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-20%) to afford the title compound (281 mg, 84%). LCMS m / z [M+H]+602.3.

[0249] Step 9.2-methylpropan-2-yl 5,7-difluoro-21,21-dimethyl-10,13-dioxa-16,20,23-triazatetracyclo[14.7.0.04’9.017’22]tricosa-l(23),4(5),6,8,17(22)-pentaen-2-yne-20-carboxylate

[0250] To the solution of tert-butyl l-(2-(2-(2-ethynyl-3,5-difluorophenoxy)ethoxy)ethyl)-2-iodo-4,4-dimethyl-l,4,6,7-tetrahydro-5 / Z-imidazo[4,5-c]pyridine-5 -carboxylate (90 mg, 0.15 mmol, 1 equiv), Brettphos (16 mg, 0.03 mmol, 0.2 equiv), Brettphos Pd G4 (14 mg, 0.01 mmol, 0.1 equiv) and Cui (3 mg, 0.01 mmol, 0.1 equiv) in DMF (50 mL) was added Et3N (5 mL). The reaction mixture was stirred at 90 °C for 16 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-20%) to afford the title compound (60 mg, 63%). LCMS m / z [M+H]+474.4.

[0251] The intermediates in the table below were synthesized as described for Intermediate 14-1 from appropriate starting materials.LCMSInt.Structure IUPAC Name m / z No.[M+H]+2-methylpropan-2-yl 5,7 -difluoro-21,21- dimethyl- 10,13 -dioxa- 16,20,23- 14-2 triazatetracyclo[14.7.0.04,9.017’22]tricosa- 474.4 CQl(23),4(5),6,8,17(22)-pentaen-2-yne-20- carboxylate94ME1\60337174.v1141039-001202-methylpropan-2-yl 5,7-difluoro-10,13- dioxa-16,20,23- 14-3 triazatetracyclo[14.7.0.04,9.017’22]tricosa- 446.3 c® — bl(23),4(5),6,8,17(22)-pentaen-2-yne-20- carboxylate2-methylpropan-2-yl (217?)-5,7-difluoro-21- methyl-10,13-dioxa-16,20,23- 14-4 triazatetracyclo[14.7.0.04,9.017’22]tricosa- 460.2^I b^>l(23),4(5),6,8,17(22)-pentaen-2-yne-20- carboxylate2-methylpropan-2-yl (21 S)-5,7 -difluoro-21 - methyl-10,13-dioxa-16,20,23- 14-5 triazatetracyclo[14.7.0.04,9.017,22]tricosa- 460.2 l(23),4(5),6,8,17(22)-pentaen-2-yne-20- carboxylate2-methylpropan-2-yl 5,7-difluoro-10-oxa- 16,20,23- 14-6 triazatetracyclo[14.7.0.04,9.017’22]tricosa- 444.243r£ bl(23),4(5),6,8,17(22)-pentaen-2-yne-20- carboxylate2-methylpropan-2-yl (21 S)-5-fluoro-21 - methyl-10,13-dioxa-16,20,23- 14-7 triazatetracyclo[14.7.0.04,9.017’22]tricosa- 442.6O — bi l(23),4(5),6,8,17(22)-pentaen-2-yne-20- carboxylate2-methylpropan-2-yl (217?)-5-fluoro-21- methyl-10,13-dioxa-16,20,23- 14-8 Q y=^H triazatetracyclo[14.7.0.04,9.017’22]tricosa- 442.2 l(23),4(5),6,8,17(22)-pentaen-2-yne-20- carboxylate95ME1\60337174.v1141039-00120

[0252] Intermediate 15.2-methylpropan-2-yl 5,7-difluoro-10,14-dioxa-17,20,23-triazatetracyclo[14.7.0.04’9.017’22]tricosa-l(16),4(5),6,8,22(23)-pentaen-2-yne-20-carboxylate

[0253] Step 1. ethyl 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxylate

[0254] To the mixture of ethyl imidazo[l,2-a]pyrazine-3-carboxylate (5.0 g, 26.18 mmol, 1 equiv) in MeOH (100 mL) was added PtCL (500 mg, 2.04 mmol, 10% wt.) at RT. The reaction mixture was stirred at RT for 16 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford the title compound (5.10 g, crude) which was used for the next step directly. LCMS m / z [M+H]+196.2.

[0255] Step 2.7-( / c / 7-butyl) 3-ethyl 5,6-dihydroimidazo[l,2-a]pyrazine-3,7(8H)-dicarboxylate

[0256] To the mixture of ethyl 5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine-3-carboxylate (5.10 g, 26.17 mmol, 1 equiv) in DCM (50 mL) was added Boc2O (8.56 g, 39.26 mmol, 1.5 equiv) and TEA (7.93 g, 78.51 mmol, 3 equiv) at RT. The reaction mixture was stirred at RT for 1 h. The reaction mixture was quenched with H2O (100 mL) and extracted with DCM (3 x 100 mL). The combined organic layer was washed with brine (100 mL) and dried over Na2SO4and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (40%-50%) to afford the title compound (6.0 g, 78%). LCMS m / z [M+H]+296.3.

[0257] Step 3. tert-butyl 3-( hydroxy met hy 1 )-5,6-dihyd roimidazo[ l,2-a]pyrazine-7(8H)-carboxylate

[0258] To the mixture of 7-(tert-butyl) 3-ethyl 5,6-dihydroimidazo[l,2-a]pyrazine-3,7(8 / f)-dicarboxylate (6.0 g, 20.34 mmol, 1 equiv) in EtOH (200 mL) was added CaCh (2.48 g, 22.37 mmol, 1.1 equiv) and NaBfL (2.26 g, 61.02 mmol, 3 equiv) at RT. The reaction mixture was stirred at RT for 16 h. The reaction mixture was filtered and the filtrate96ME1\60337174.v1141039-00120was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-10%) to afford the title compound (4.0 g, 78%). LCMS m / z [M+H]+254.3.

[0259] Step 4. tert-butyl 3-((3-((tert-butyldimethylsilyl)oxy)propoxy)methyl)-5,6-dihydroimidazo[ 1,2-a ] py razi ne-7 (8H) -carboxylate

[0260] To the mixture of tert-butyl 3-(hydroxymethyl)-5,6-dihydroimidazo[l,2-a]pyrazine-7(8 / / )-carboxylate (1 g, 3.95 mmol, 1 equiv) in DMF (20 mL) was added NaH (190 mg, 4.74 mmol, 1.2 equiv, 60% dispersion in mineral oil) portion wise at 0 °C under N2 atmosphere. The reaction mixture was stirred at RT for 1 h under N2 atmosphere. Then (3-bromopropoxy)(tert-butyl)dimethylsilane (1.2 g, 4.74 mmol, 1.2 equiv) was added into the mixture at 0 °C. The reaction mixture was stirred at RT for 1 h. The reaction mixture was quenched with H2O (60 mL) and extracted with DCM (3 x 60 mL). The combined organic layer was washed with brine, dried over Na2SO4and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-3%) to afford the title compound (804 mg, 48%). LCMS m / z [M+H]+426.3.

[0261] Step 5. tert-butyl 3-((3-hydroxypropoxy)methyl)-2-iodo-5,6-dihydroimidazo[ 1,2-a ] py razi ne-7 (8H) -carboxylate

[0262] To the mixture of tert-butyl 3-((3-((tert-butyldimethylsilyl)oxy)propoxy)methyl)-5,6-dihydroimidazo[l,2-a]pyrazine-7(8 / Z)-carboxylate (382 mg, 0.90 mmol, 1 equiv) in DMF (10 mL) was added NIS (1.20 g, 5.39 mmol, 6 equiv). The reaction mixture was stirred at 60 °C for 3 h. The solvent was removed in vacuo. The residue was purified by flash column chromatography, eluted with MeOH in DCM (0%-10%) to afford the crude desired compound which was repurified by prep-HPLC (ACN / water / 10 mM NH4HCO3) to afford the title compound (100 mg, 25%). LCMS m / z [M+H]+438.2.

[0263] Step 6. tert-butyl 3-((3-bromopropoxy)methyl)-2-iodo-5,6-dihydroimidazo[ 1,2-a ] py razi ne-7 (8H) -carboxylate

[0264] To the mixture of tert-butyl 3-((3-hydroxypropoxy)methyl)-2-iodo-5,6-dihydroimidazo[l,2-a]pyrazine-7(8 / f)-carboxylate (200 mg, 0.46 mmol, 1 equiv) and PPI13 (360 mg, 1.37 mmol, 3 equiv) in DCM (5 mL) was added CBr4 (758 mg, 1.37 mmol, 3 equiv) in DCM (5 mL) drop wise at 0 °C. The reaction mixture was stirred at RT for 2 h under N2 atmosphere. The reaction mixture was quenched with H2O (30 mL) and extracted with DCM (3 x 30 mL). The combined organic layer was washed with brine, dried over Na2SO4and concentrated under reduced pressure. The residue was purified by silica gel column97ME1\60337174.v1141039-00120chromatography, eluted with EA in PE (0%-50%) to afford the title compound (172 mg, 75%). LCMS m / z [M+H]+500.1.

[0265] Step 7. tert-butyl 3-((3-(3,5-difluoro-2-formylphenoxy)propoxy)methyl)-2-iodo-5,6-dihydroimidazo[l,2-a]pyrazine-7(8H)-carboxylate

[0266] To the mixture of tert-butyl 3-((3-bromopropoxy)methyl)-2-iodo-5,6-dihydroimidazo[l,2-a]pyrazine-7(8 / / )-carboxylate (172 mg, 0.34 mmol, 1 equiv) and 2,4-difluoro-6-hydroxybenzaldehyde (60 mg, 0.38 mmol, 1.1 equiv) in DMF (5 mL) was added K2CO3(143 mg, 1.03 mmol, 3 equiv). The reaction mixture was stirred at 80 °C for 4 h. The reaction mixture was quenched with H2O (30 mL) and extracted with DCM (3 x 30 mL). The combined organic layer was washed with brine, dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-50%) to afford the title compound (198 mg, 99 %). LCMS m / z [M+H]+578.6.

[0267] Step 8. tert-butyl 3-((3-(2-ethynyl-3,5-difluorophenoxy)propoxy)methyl)-2-iodo-5,6-dihydroimidazo[l,2-a]pyrazine-7(8H)-carboxylate

[0268] To the mixture of tert-butyl 3-((3-(3,5-difluoro-2-formylphenoxy)propoxy)methyl)-2-iodo-5,6-dihydroimidazo[l,2-a]pyrazine-7(8 / f)-carboxylate (198 mg, 0.34 mmol, 1 equiv) and K2CO3(158 mg, 0.69 mmol, 2 equiv) in MeOH (5 mL) was added dimethyl (l-diazo-2-oxopropyl)phosphonate (79 mg, 0.41 mmol, 1.2 equiv). The reaction mixture was stirred at RT for 2 h. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-5%) to afford the title compound (145 mg, 70%). LCMS m / z [M+H]+574.6.

[0269] Step 9.2-methylpropan-2-yl 5,7-difluoro-10,14-dioxa-17,20,23-triazatetracyclo[14.7.0.04’9.017’22]tricosa-l(16),4(5),6,8,22(23)-pentaen-2-yne-20-carboxylate

[0270] To the mixture of tert-butyl 3-((3-(2-ethynyl-3,5-difluorophenoxy)propoxy)methyl)-2-iodo-5,6-dihydroimidazo[l,2-a]pyrazine-7(8 / f)-carboxylate (95 mg, 0.17 mmol, 1 equiv) in DMF (48 mL) and TEA (5 mL) was added Brettphos (9 mg, 0.017 mmol, 0.1 equiv), Brettphos Pd G4 (8 mg, 0.008 mmol, 0.05 equiv) and Cui (2 mg, 0.008 mmol, 0.05 equiv). The reaction mixture was stirred at 90 °C for 48 h under N2 atmosphere. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-10%) to afford the crude desired compound which was repurified by prep-HPLC (ACN / water / 10 mM NH4HCO3) to afford the title compound (25 mg, 27%). LCMS m / z [M+H]+446.3.98ME1\60337174.v1141039-00120

[0271] Intermediate 16-1. tert-butyl 4,6-difluoro-21-(((trifluoromethyl)sulfonyl)oxy)- 2,3,9,10,12,13,15,18-octahydro-lH-benzo[A;]cyclopenta[4,5]pyrido[2,3-i]pyrido[3',4':4,5]imidazo[l,2-g][l,4]dioxa[7]azacyclododecine-17(16H)-carboxylate

[0272] Step 1. tert-butyl l-(2-(2-bromoethoxy)ethyl)-2-iodo-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate

[0273] To a solution of l-bromo-2-(2-bromoethoxy)ethane (39.85 g, 171.84 mmol, 3.0 equiv) in DMF (150 mL) was added K2CO3(31.67 g, 229.12 mmol, 4.0 equiv) and tert-butyl 2-iodo-l,4,6,7-tetrahydro-5 / Z-imidazo[4,5-c]pyridine-5-carboxylate (20.0 g, 57.3 mmol, 1.0 equiv) in DMF (150 mL). The mixture was stirred at 60 °C for 5 h. The mixture was concentrated under reduced pressure. The residue was diluted with brine (1500 mL) and extracted with EA (3 x 2000 mL). The combined organic layer was washed with brine, dried over Na2SO4U, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (10%-50%) to afford the title compound (19.1 g, 67%). LCMS m / z [M+H]+500.1.

[0274] Step 2. tert-butyl l-(2-(2-(3,5-difluoro-2-formylphenoxy)ethoxy)ethyl)-2-iodo-1,4,6,7- tetrahydro-5H-imidazo[4,5 -c ] pyridine-5-carboxylate

[0275] To a solution of tert-butyl l-(2-(2-bromoethoxy)ethyl)-2-iodo- 1,4,6, 7-tetrahydro-5 / Z-imidazo[4,5-c]pyridine-5-carboxylate (19.1 g, 38.2 mmol, 1.0 equiv) in DMF (250 mL) was added K2CO3(15.84 g, 114.57 mmol, 3.0 equiv) and 2,4-difluoro-6-hydroxybenzaldehyde (6.04 g, 38.19 mmol, 1.0 equiv). The mixture was stirred at 80 °C for 2 h. The mixture was distilled and concentrated under reduced pressure to get crude product. The residue was diluted with brine (500 mL) and extracted with EA (3 x 600 mL). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (10%-50%) to afford tert-butyl l-(2-(2-(3,5-difluoro-2-formylphenoxy)ethoxy)ethyl)-2-iodo- 1,4,6, 7-tetrahydro-5 / Z-imidazo[4,5-c]pyridine-5-carboxylate (17.5 g, 75%). LCMS m / z [M+H]+.l.99ME1\60337174.v1141039-00120

[0276] Step 3. tert-butyl l-(2-(2-(2-ethynyl-3,5-difluorophenoxy)ethoxy)ethyl)-2-iodo-1,4,6,7- tetrahydro-5H-imidazo[4,5 -c ] pyridine-5-carboxylate

[0277] To a solution of tert-butyl l-(2-(2-(3,5-difluoro-2-formylphenoxy)ethoxy)ethyl)-2-iodo-l,4,6,7-tetrahydro-5 / Z-imidazo[4,5-c]pyridine-5-carboxylate (17.50 g, 30.31 mmol, 1.0 equiv) in MeOH (300 mL) was added K2CO3(12.57 g, 90.93 mmol, 3.0 equiv) and dimethyl (l-diazo-2-oxopropyl)phosphonate (6.99 g, 36.37 mmol, 1.2 equiv). The mixture was stirred at RT for 2 h. The mixture was concentrated under reduced pressure. The residue was diluted with brine (500 mL) and extracted with DCM (3 x 600 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-50%) to afford tert-butyl l-(2-(2-(2-ethynyl-3,5-difluorophenoxy)ethoxy)ethyl)-2-iodo- 1,4,6, 7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate (13.01 g, 71%). LCMS m / z [M+H]+574.5.

[0278] Step 4.2-methylpropan-2-yl 5,7-difluoro-10,13-dioxa-16,20,23-triazatetracyclo[14.7.0.04,9.017,22]tricosa-1(23),4(5),6,8,17(22)-pentaen-2-yne-20-carboxylate

[0279] To a solution of Cui (99 mg, 0.52 mmol, 0.05 equiv), Brettphos (564 mg, 1.05 mmol, 0.1 equiv) and Brettphos Pd G4 (479 mg, 0.52 mmol, 0.05 equiv) in DMF (500 mL) was added tert-butyl l-(2-(2-(2-ethynyl-3,5-difluorophenoxy)ethoxy)ethyl)-2-iodo-l, 4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate (6.0 g, 10.46 mmol, 1.0 equiv) in DMF (400 mL) and Et3N (90 mL). The mixture was stirred at 90 °C for 48 h under N2 atmosphere. The mixture was concentrated under reduced pressure. The residue was diluted with brine (1000 mL) and extracted with EA (3 x 1000 mL). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-70%) to afford the title compound (2.57 g, 55%). LCMS m / z [M+H]+446.3.

[0280] Step 5. tert-butyl 4,6-difluoro-21-hydroxy-2,3,9,10,12,13,15,18-octahydro-lH-benzo[£]cyclopenta[4,5]pyrido[2,3-i]pyrido[3',4':4,5]imidazo[l,2-g][l,4]dioxa[7]azacyclododecine-17(16H)-carboxylate

[0281] To a solution of 2-methylpropan-2-yl 5,7-difluoro- 10, 13-dioxa- 16,20,23-triazatetracyclo[14.7.0.04, 9.017, 22] tricosa-l(23),4(5),6,8,17(22)-pentaen-2-yne-20-carboxylate (5.13 g, 11.513mmol), [Cp*RhCl2]2(356 mg, 0.576 mmol) and CsOAc (4.42 g, 23.03 mmol) in EtOH (500 mL) was added N-methoxycyclopent-l-ene-1 -carboxamide (2.11 g, 14.97 mmol). The mixture was stirred for 16 h at 80 °C in the air. The reaction mixture 100ME1\60337174.v1141039-00120was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluted with MeOH in DCM (0%-10%) to afford the crude product (4.65 g) which was repurified by prep-HPLC (ACN / water / 0.1% FAC) to afford the title compound (2.47 g, 40%). LCMS m / z [M+H]+555.6.

[0282] Step 6. tert-butyl 4,6-difluoro-21-(((trifluoromethyl)sulfonyl)oxy)- 2,3,9,10,12,13,15,18-octahydro-lH-benzo[A;]cyclopenta[4,5]pyrido[2,3- i]pyrido[3',4':4,5]imidazo[l,2-g][l,4]dioxa[7]azacyclododecine-17(16H)-carboxylate

[0283] To a solution of tert-butyl 4,6-difluoro-21-hydroxy-2,3,9,10,12,13,15,18- octahydro-lH-benzo[L|cyclopenta[4,5]pyrido[2,3-z]pyrido[3',4':4,5]imidazo[l,2- g][l, 4] dioxa[7] azacydododecine- 17(16 / f)-carboxylate (1.8 g, 3.25 mmol, 1.0 equiv) and pyridine (1.28 g, 16.23 mmol, 5.0 equiv) in DCM (40 mL) was added Tf2O (1.37 g, 4.87 mmol, 1.5 equiv) at 0 °C. The reaction was stirred for 1 h at RT under N2 atmosphere. The mixture was diluted with H2O (100 mL) and extracted with DCM (3 x 100 mL). The combined organic layer was dried over Na2SO4and the solvent was removed in vacuo. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-30%) to afford TM as racemate (2100 mg, 94%) which was separated by SFC (Column: Daicel IC-3 (25*250 mm, 10 um), Mobile phase: CO2 / MeOH=75 / 25) to afford the chiral title compound (1.0 g, peak 2, e.e. 97.1%). LCMS m / z [M+H]+687.3. The compounds in the table below were synthesized as described forlntermediate 16-1 from appropriate starting materials.LCMS m / z Int. No. Structure Name[M+H]+tert-butyl 4,6-difluoro-21- (((trifluoromethyl)sulfonyl)oxy)- 2,3,9,10,12,13,15,18-octahydro-lH- 16-1benzo[k]cyclopenta[4,5]pyrido[2,3- 687.3 racemic C9^NYi]pyrido[3',4':4,5]imidazo[l,2- g][l,4]dioxa[7]azacyclododecine-17(16H)- carboxylate(S)-tert-butyl 4,6-difluoro-21- (((trifluoromethyl)sulfonyl)oxy)- 16-22,3,9,10,12,13,15,18-octahydro-lH- 687.3 Peak 1benzo[k]cyclopenta[4,5]pyrido[2,3- i]pyrido[3',4':4,5]imidazo[l,2-101ME1\60337174.v1141039-00120g][l,4]dioxa[7]azacyclododecine-17(16H)- carboxylatetert-butyl 4,6-difluoro-21- (((trifluoromethyl)sulfonyl)oxy)- 2,3,9,10,12,13,15,18-octahydro-lH- 16-3 bVbenzo[k]cyclopenta[4,5]pyrido[2,3- 687.3 Peak 2i]pyrido[3',4':4,5]imidazo[l,2- g][l,4]dioxa[7]azacyclododecine-17(16H)- carboxylatetert-butyl 4,6-difluoro-20- (((trifluoromethyl)sulfonyl)oxy)- 2,3,9,10,11,12,14,17-octahydro-lH- XA-A16-4 benzo[j]cyclopenta[4,5]pyrido[2,3- 671.8VLNh]pyrido[3',4':4,5]imidazo[l,2- f][l]oxa[6]azacycloundecine-16(15H)- carboxylatetert-butyl 4,6-difluoro-21- (((trifluoromethyl)sulfonyl)oxy)- 2,3,10,ll,13,15,16,18-octahydro-9H- 16-5 benzo[ll',12']cyclopenta[4",5"]pyrido[2", 687.3VL3":9',10'][l,5]dioxacyclododecino[8',7':4,5 ]imidazo[l,2-a]pyrazine-17(lH)- carboxylatetert-butyl 4,6-difluoro-18,18-dimethyl-21- (((trifluoromethyl)sulfonyl)oxy)- 2,3,9,10,12,13,15,18-octahydro-lH- 16-6 FH benzo[k]cyclopenta[4,5]pyrido[2,3- 728.5 cxp A ii]pyrido[3',4':4,5]imidazo[l,2- g][l,4]dioxa[7]azacyclododecine-17(16H)- carboxylatey tert-butyl (R)-4,6-difluoro-18-methyl-21- 16-7 A, N^O^Z (((trifluoromethyl)sulfonyl)oxy)- 701.3 cxp A I2,3,9,10,12,13,15,18-octahydro-lH-102ME1\60337174.v1141039-00120benzo[k]cyclopenta[4,5]pyrido[2,3- i]pyrido[3',4':4,5]imidazo[l,2- g][l,4]dioxa[7]azacyclododecine-17(16H)- carboxylatetert-butyl (S)-4,6-difluoro-18-methyl-21- (((trifluoromethyl)sulfonyl)oxy)- V r'o 2,3,9,10,12,13,15,18-octahydro-lH- Z”Vo16-8 benzo[k]cyclopenta[4,5]pyrido[2,3- 701.3 v r- i]pyrido[3',4':4,5]imidazo[l,2- g][l,4]dioxa[7]azacyclododecine-17(16H)- carboxylatetert-butyl 4,6-difluoro-21- (((trifluoromethyl)sulfonyl)oxy)- 2,3,10,ll,12,13,15,18-octahydro-lH,9H- HQ16-9< Q IMXXO'-K benzo[b]cyclopenta[4,5]pyrido[3,2- 685.3 VyN F N'^- / V « P 1 - d]pyrido[3',4':4,5]imidazo[2,l- f][l]oxa[7]azacyclododecine-17(16H)- carboxylatetert-butyl (R)-4,6-difluoro-18-methyl-21- (((trifluoromethyl)sulfonyl)oxy)- 2,3,10,ll,13,15,16,18-octahydro-9H- c" V° -016-10 7 4. / ZN1 benzo[ll',12']cyclopenta[4",5"]pyrido[2",< T T \i^^NB°c3":9',10'][l,5]dioxacyclododecino[8',7':4,5 ]imidazo[l,2-a]pyrazine-17(lH)- carboxylatetert-butyl (S)-4,6-difluoro-18-methyl-21- (((trifluoromethyl)sulfonyl)oxy)- 2,3,10,ll,13,15,16,18-octahydro-9H- V-"0^o16-11 benzo[ll',12']cyclopenta[4",5"]pyrido[2",< J T^N^k / NBoc3":9',10'][l,5]dioxacyclododecino[8',7':4,5 ]imidazo[l,2-a]pyrazine-17(lH)- carboxylate103ME1\60337174.v1141039-00120tert-butyl 4,6,10,10-tetrafluoro-21- (((trifluoromethyl)sulfonyl)oxy)- v S 2,3,10,ll,13,15,16,18-octahydro-9H- 16-12 benzo[ir,12']cyclopenta[4",5"]pyrido[2",^N'BOC3":9',10'][l,5]dioxacyclododecino[8',7':4,5 ]imidazo[l,2-a]pyrazine-17(lH)- carboxylate

[0284] Intermediate 17. l-(4-ethynyl-lH-pyrazol-l-yl)-2-methylpropan-2-olHO

[0285] Step 1. l-(4-ethynyl-lH-pyrazol-l-yl)-2-methylpropan-2-ol

[0286] To a solution of 4-ethynyl-l / Z-pyrazole (940 mg, 10.21 mmol, 1 equiv, CAS: 57121-49-0) in DMF (20 mL) was added Cs2CO3(6.64 g, 20.41 mmol, 2 equiv) and 2,2- dimethyloxirane (1.10 g, 15.31 mmol, 1.5 equiv). The reaction mixture was stirred at 80 °C for 16 h under N2 atmosphere. The reaction mixture was quenched with H2O (100 mL) and extracted with EA (3 x 100 mL). The combined organic layer was washed with brine, dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (10%-35%) to afford the title compound (1.32 g, 79%). LCMS m / z [M+H]+165.1.

[0287] Intermediate 18.6-bromo-l-(l-methylazetidin-3-yl)-lH-indazolestep 2 step 3

[0288] Step 1. tert-butyl 3-(6-bromo- IH-indazol- l-yl)azetidine- 1-carboxylate and tert-butyl 3-(6-bromo-2H-indazol-2-yl)azetidine- 1-carboxylate

[0289] To a mixture of 6-bromo-l / Z-indazole (1.0 g, 5.08 mmol, 1 equiv) in DMF (20 mL) was added K2CO3(1.40 g, 10.15 mmol, 2 equiv) and tert-butyl 3 -iodoazetidine- 1- 104ME1\60337174.v1141039-00120carboxylate (2.87 g, 10.15 mmol, 2 equiv). The reaction mixture was stirred at 100 °C for 5 h under N2 atmosphere. The reaction mixture was quenched with H2O (100 mL) and extracted with EA (3 x 100 mL). The combined organic layer was washed with brine, dried over Na2SO4. After filtration, the organic layer was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluted with EA in PE (0%-30%) to afford the title compound (880 mg, 49%) and the isomer of the title compound (450 mg, 25%). LCMS (M- / Bu+H)+m / z: 296.1. The LCMS of the isomer: LCMS m / z (M-tBu+H)+296.1.

[0290] Step 2. l-(azetidin-3-yl)-6-bromo-lH-indazole

[0291] To a mixture of tert-butyl 3-(6-bromo-lH-indazol-l-yl)azetidine-l-carboxylate (210 mg, 0.59 mmol, 1 equiv) in DCM (2 mL) was added TFA (2 mL). The reaction mixture was stirred at RT for 1 h. The reaction mixture was concentrated under reduced pressure to afford the title compound (150 mg, crude, TFA salt). LCMS m / z [M+H]+252.1.

[0292] Step 3.6-bromo-l-(l-methylazetidin-3-yl)-lH-indazole

[0293] To a mixture of l-(azetidin-3-yl)-6-bromo-l / Z-indazole (150 mg, crude, TFA salt, 0.59 mmol, 1 equiv) in MeOH (4 mL) was added paraformaldehyde (89 mg, 2.97 mmol, 5 equiv) and NaBH3CN (112 mg, 1.78 mmol, 3 equiv). The reaction mixture was stirred at RT for 16 h under N2 atmosphere. The reaction mixture was quenched with H2O (50 mL) and extracted with DCM (3 x 50 mL). The combined organic layer was washed with brine, dried over Na2SO4. After filtration, the organic layer was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluted with MeOH in DCM (0%-10%) to afford the title compound (80 mg, 51%). LCMS m / z [M+H]+266.0.

[0294] Intermediate 19. l-((5-bromopyridin-3-yl)methyl)-3-methylazetidin-3-olStep 1

[0295] Step 1. l-((5-bromopyridin-3-yl)methyl)-3-methylazetidin-3-ol

[0296] To a solution of 3-methylazetidin-3-ol hydrochloride (199 mg, 1.61 mmol, 1 equiv, CAS: 113118-81-3) in MeOH (5 mL) was added 5-bromonicotinaldehyde (300 mg, 1.61 mmol, 1 equiv). The reaction mixture was stirred at RT for 1 h. Then NaBH3CN (152 mg, 2.42 mmol, 1.5 equiv) was added. The reaction mixture was stirred at RT for 16 h. The reaction mixture was quenched with H2O (50 mL) and extracted with EA (3 x 30 mL). The105ME1\60337174.v1141039-00120combined organic layer was washed with H2O (2 x 20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-15%) to afford the title compound (150 mg, 36%). LCMS m / z [M+H]+257.1.

[0297] Intermediate 20. l-(3-bromo-5,8-dihydro-l,7-naphthyridin-7(6H)-yl)-2-methylpropan-2-ol

[0298] Step 1. l-(3-bromo-5,8-dihydro-l,7-naphthyridin-7(6H)-yl)-2-methylpropan-2-ol

[0299] To a solution of 3-bromo-5,6,7,8-tetrahydro-l,7-naphthyridine (220 mg, 0.77 mmol, 1 equiv, CAS: 1196156-01-0) in EtOH (6 mL) was added K2CO3(319 mg, 2.31 mmol, 3 equiv) and 2,2-dimethyloxirane (277 mg, 3.85 mmol, 5 equiv). The reaction mixture was stirred at 110 °C for 3 h under microwave condition. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-5%) to afford the title compound (202 mg, 92%). LCMS m / z [M+H]+285.1.

[0300] Intermediate 21.2-(7-bromoimidazo[l,2-a]pyridin-3-yl)propan-2-ol

[0301] Step 1.2-(7-bromoimidazo[l,2-a]pyridin-3-yl)propan-2-ol

[0302] To a solution of ethyl 7 -bromoimidazo[l,2-a]pyridine-3 -carboxylate (150 mg, 0.56 mmol, 1 equiv, CAS: 1134327-98-2) in THF (5 mL) was added MeMgBr (1.67 mL, 1.67 mmol, 3 equiv) at -78 °C under N2 atmosphere. The reaction mixture was stirred at -78 °C for 10 min. The reaction mixture was stirred at RT for 16 h. The reaction mixture was quenched with H2O (10 mL) and extracted with EA (3 x 30 mL). The combined organic layer was washed with H2O (2 x 10 mL), dried over Na2SO4, filtered and concentrated under reduced presssure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-90%) to afford the title compound (125 mg, 88%). LCMS m / z [M+H]+254.9.

[0303] Intermediate 22.2-(5-bromobenzo[d]oxazol-2-yl)propan-2-ol106ME1\60337174.v1141039-00120Step 1

[0304] Step 1.2-(5-bromobenzo[d]oxazol-2-yl)propan-2-ol

[0305] Prepared from methyl 5-bromobenzo[<f|oxazole-2-carboxylate using the method described for intermediate 21 (169 mg, 68%). LCMS m / z [M+H]+256.0.

[0306] Intermediate 23.2-(5-bromo-l-methyl-lH-pyrazolo[3,4-&]pyridin-3-yl)propan-2-ol

[0307] Step 1. methyl 5-bromo-l-methyl-lH-pyrazolo[3,4-&]pyridine-3-carboxylate

[0308] Prepared from methyl 5-bromo- 1 -methyl- l / Z-pyrazolo[3,4-Z?]pyridine-3-carboxylate using the method described for intermediate 21 LCMS m / z [M+H]+270.1

[0309] Intermediate 24.2-(6-bromoimidazo[l,2-a]pyridin-2-yl)propan-2-olStep 1.2-(6-bromoimidazo[l,2-a]pyridin-2-yl)propan-2-ol

[0310] Prepared from methyl 6-bromoimidazo[l,2-a]pyridine-2-carboxylate using the method described for intermediate 21. LCMS m / z [M+H]+255.0.

[0311] Intermediate 25.2-(6-bromo-2-methyl-2H-pyrazolo[4,3-b]pyridin-3-yl)propan-2-ol

[0312] Step 1.2-(6-bromo-2-methyl-2H-pyrazolo [4,3-&]pyridin-3-yl)propan-2-ol

[0313] Prepared from methyl 6-bromo-2-methyl-2 / Z-pyrazolo[4,3-Z?]pyridine-3-carboxylate using the method described for intermediate 21. LCMS m / z [M+H]+270.0.

[0314] Intermediate 26.3-bromo-7-methyl-5,6,7,8-tetrahydro-l,7-naphthyridine

[0315] Step 1.3-bromo-7-methyl-5,6,7,8-tetrahydro-l,7-naphthyridine

[0316] To a solution of 3-bromo-5,6,7,8-tetrahydro-l,7-naphthyridine dihydrochloride (900 mg, 3.15 mmol, 1 equiv, CAS: 2177267-75-1) in MeOH (15 mL) was added NaBH3CN 107ME1\60337174.v1141039-00120(1.98 g, 31.47 mmol, 10 equiv) and paraformaldehyde (1.89 g, 31.47 mmol, 10 equiv) at RT. The reaction mixture was stirred at 40 °C for 1 h. The reaction mixture was added to H2O (30 mL) and extracted with DCM (3 x 30 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-5%) to afford the title compound (325 mg, 34%). LCMS m / z [M+H]+227.1.

[0317] Intermediate 27. (3-bromo-7,8-dihydro-l,6-naphthyridin-6(5H)-yl)(3-hydroxy-l-methylazetidin-3-yl)methanone

[0318] Step 1. tert-butyl 3-(3-bromo-5,6,7,8-tetrahydro-l,6-naphthyridine-6-carbonyl)-3-hydroxyazetidine-l-carboxylate

[0319] To a solution of 3-bromo-5,6,7,8-tetrahydro-l,6-naphthyridine dihydrochloride (80 mg, 0.28 mmol, 1 equiv, CAS: 1187932-53-1) and TEA (170 mg, 1.68 mmol, 6 equiv) in DMF (1 mL) was added l-(tert-butoxycarbonyl)-3-hydroxyazetidine-3-carboxylic acid (61 mg, 0.28 mmol, 1 equiv, CAS: 1035351-06-4). The reaction mixture was stirred at RT for 1 h. Then HATU (117 mg, 0.31 mmol, 1.1 equiv) was added. The reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EA (3 x 20 mL). The organic layer was dried over Na2SO4and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-4%) to afford the title compound (90 mg, 78%). LCMS m / z (M-tBu+H)+356.0.

[0320] Step 2. (3-bromo-7,8-dihydro-l,6-naphthyridin-6(5H)-yl)(3-hydroxyazetidin-3-yl)methanone

[0321] To a mixture of tert-butyl 3-(3-bromo-5,6,7,8-tetrahydro-l,6-naphthyridine-6-carbonyl)-3-hydroxyazetidine-l -carboxylate (90 mg, 0.22 mmol, 1 equiv) in DCM (0.5 mL) was added TFA (0.5 mL). The reaction mixture was stirred at RT for 1 h. The reaction mixture was concentrated under reduced pressure to afford the title compound (68 mg, crude, TFA salt). LCMS m / z [M+H]+312.1.

[0322] Step 3. (3-bromo-7,8-dihydro-l,6-naphthyridin-6(5H)-yl)(3-hydroxy-l-methylazetidin-3-yl)methanone

[0323] To a solution of (3-bromo-7,8-dihydro-l,6-naphthyridin-6(5 / f)-yl)(3-hydroxyazetidin-3-yl)methanone (68 mg, 0.22 mmol, 1 equiv) and paraformaldehyde (65 mg, 2.18 mmol, 10 equiv) in MeOH (2 mL) was added NaBH3CN (27 mg, 0.44 mmol, 2 equiv).108ME1\60337174.v1141039-00120The reaction mixture was stirred at 50 °C for 3 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%- 18%) to afford the title compound (65 mg, 92%). LCMS m / z [M+H]+326.1.

[0324] Intermediate 28.5-bromo-3-methoxy-l-methyl-lH-pyrazolo[3,4-&]pyridine

[0325] Step 1.5-bromo-3-methoxy-l-methyl-lH-pyrazolo[3,4-&]pyridine

[0326] To a solution of 5-bromo-3-methoxy-l / / -pyrazolo[3,4-Z?]pyridine (50 mg, 0.22 mmol, 1 equiv, CAS: 1363381-82-1) in DMF (2 mL) was added NaH (11 mg, 0.26 mmol, 1.2 equiv, 60% dispersion in mineral oil) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. Then CH3I (37 mg, 0.26 mmol, 1.2 equiv) was added. The reaction mixture was stirred at RT for 1 h under N2 atmosphere. The reaction mixture was quenched with H2O (5 mL) and extracted with EA (2 x 5 mL). The organic layer was dried over Na2SO4and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-10%) to afford the title compound (35 mg, 66%). LCMS m / z [M+H]+242.0.

[0327] Intermediate 29.7-bromo-4-methyl-3,4-dihydropyrido[3,2- / ][l,4]oxazepin-5(2H)-one

[0328] Step 1.7-bromo-4-methyl-3,4-dihydropyrido[3,2- ][l,4]oxazepin-5(2H)-one To a solution of 7-bromo-3,4-dihydropyrido[3,2- / |[l,4]oxazepin-5(2 / Z)-one (100 mg, 0.41 mmol, 1 equiv, CAS: 1823339-95-2) in DMF (5 mL) was added NaH (49 mg, 2.04 mmol, 3 equiv, 60% dispersion in mineral oil). The reaction mixture was stirred at 0 °C for 1 h under N2 atmosphere. Then CH3I (70 mg, 0.49 mmol 1.2 equiv) was added. The reaction mixture was stirred at RT for 1 h. The reaction mixture was quenched with H2O (30 mL) and extracted with EA (3 x 50 mL). The combined organic layer was washed with brine (3 x 50 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-20%) to afford the title compound (60 mg, 57%). LCMS m / z [M+H]+256.9.109ME1\60337174.v1141039-00120

[0329] Intermediate 30.2-(6-bromo-3-methyl-3H-imidazo[4,5-&]pyridin-2-yl)propan-2-olBr

[0330] Step 1.5-bromo-2V-methyl-3-nitropyridin-2-amine

[0331] To a solution of 5-bromo-2-chloro-3 -nitropyridine (2.0 g, 8.4 mmol, 1 equiv, CAS: 67443-38-3) in THF (60 mL) was added DIPEA (16.29 g, 126.0 mmol, 15 equiv) and methylamine hydrochloride (2.84 g, 42.0 mmol, 5 equiv). The reaction mixture was stirred at 80 °C for 48 h. The reaction mixture was diluted with brine (500 mL) and extracted with EA (3 x 600 mL). The combined organic layer was washed with brine, dried over Na2SO4U, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-30%) to afford the title compound (1.70 g, 87%). LCMS m / z [M+H]+231.9.

[0332] Step 2.5-bromo- V2-methylpyridine-2,3-diamine

[0333] To a solution of 5-bromo-A-methyl-3-nitropyridin-2-amine (1.70 g, 7.33 mmol, 1 equiv) in MeOH (30 mL) and H2O (5 mL) was added Fe (4.09 g, 73.30 mmol, 10 equiv) and NH4CI (3.92 mg, 73.30 mmol, 10 equiv). The reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with EA in PE (0%-30%) to afford the title compound (940 mg, 57%). LCMS m / z [M+H]+202.0.

[0334] Step 3.2-(6-bromo-3-methyl-3H-imidazo[4,5-&]pyridin-2-yl)propan-2-ol

[0335] To a solution of 5-bromo-A2-methylpyridine-2,3-diamine (330 mg, 1.6 mmol, 1 equiv) in pyridine (10 mL) was added 2-hydroxy-2-methylpropanoic acid (250 mg, 2.4 mmol, 1.5 equiv), HOBT (253 mg, 1.9 mmol, 1.2 equiv) and EDCI (369 mg, 1.9 mmol, 1.2 equiv). The reaction mixture was stirred at 80 °C for 8 h. The reaction mixture was diluted with brine (100 mL) and extracted with EA (3 x 120 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was dissolved in AcOH (10 mL). Then the reaction mixture was stirred at 120 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with NaHCCL (sat aq 50 mL) and extracted with EA (3 x 50 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced110ME1\60337174.v1141039-00120pressure. The residue was purified by silica gel chromatography eluted with EA in PE (0%-30%) to afford the title compound (120 mg, 27%). LCMS m / z [M+H]+270.1.

[0336] Intermediate 31.6-bromo-A^,3-dimethyl-3H-imidazo[4,5-&]pyridin-2-amine Br Br Br

[0337] Step 1.6-bromo-3-methyl-3H-imidazo[4,5-&]pyridin-2-amine

[0338] To a solution of 5-bromo-A2-methylpyridine-2,3-diamine (250 mg, 1.24 mmol, 1 equiv, CAS: 89415-54-3) in H2O (3 mL) and THF (0.3 mL) was added cyanic bromide (655 mg, 6.19 mmol, 5 equiv). The reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was quenched with NaHCOs (sat aq 100 mL) and extracted with EA (3 x 100 mL). The combined organic layer was washed with H2O (2 x 100 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-l 1%) to afford the title compound (120 mg, 42%). LCMS m / z [M+H]+227.0.

[0339] Step 2.6-bromo-2-chloro-3-methyl-3H-imidazo[4,5-&]pyridine

[0340] To a solution of 6-bromo-3-methyl-3 / Z-imidazo[4,5-Z?]pyridin-2-amine (30 mg, 0.13 mmol, 1 equiv) and CuCh (71 mg, 0.52 mmol, 4 equiv) in ACN (1 mL) was added amyl nitrite (31 mg, 0.26 mmol, 2 equiv). The reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was quenched with NH4CI (sat aq 10 mL) and extracted with EA (3 x 10 mL). The combined organic layer was washed with H2O (2 x 10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-10%) to afford the title compound (15 mg, 46%). LCMS m / z [M+H]+245.9.

[0341] Step 3.6-bromo-A^,3-dimethyl-3H-imidazo[4,5-&]pyridin-2-amine

[0342] To a solution of 6-bromo-2-chloro-3-methyl-3 / Z-imidazo[4,5-Z?]pyridine (15 mg, 0.06 mmol, 1 equiv) and TEA (27 mg, 0.26 mmol, 4 equiv) in ACN (1 mL) was added methylamine hydrochloride (9 mg, 0.13 mmol, 2 equiv). The reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was quenched with H2O (10 mL) and extracted with EA (3 x 10 mL). The combined organic layer was washed with H2O (2 x 10 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-15%) to afford the title compound (9 mg, 61%). LCMS m / z [M+H]+241.0.111ME1\60337174.v1141039-00120

[0343] Intermediate 32.5-bromo-l-(l-methylazetidin-3-yl)-lH-pyrazolo[3,4- / ?]pyridine

[0344] Step 1. tert-butyl 3-(5-bromo-lH-pyrazolo[3,4-&]pyridin-l-yl)azetidine-l-carboxylate

[0345] To a solution of 5-bromo-l / Z-pyrazolo[3,4-Z?]pyridine (1.0 g, 5.08 mmol, 1 equiv, CAS: 875781-17-2) and tert-butyl 3 -iodoazetidine- 1 -carboxylate (2.15 g, 7.61 mmol, 1.5 equiv) in DMF (15 mL) was added K2CO3(2.10 g, 15.24 mmol, 3 equiv). The reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was poured into H2O (200 mL) and extracted with EA (3 x 50 mL). The organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-100%) to afford the title compound (800 mg, 45%). LCMS m / z (M-tBu+H)+297.1.

[0346] Step 2. l-(azetidin-3-yl)-5-bromo-lH-pyrazolo[3,4-&]pyridine

[0347] To a solution of tert-butyl 3-(5-bromo-l / Z-pyrazolo[3,4-Z?]pyridin-l-yl)azetidine- 1-carboxylate (200 mg, 0.57 mmol, 1 equiv) in DCM (2 mL) was added TFA (2 mL). The reaction mixture was stirred at RT for 2 h. The reaction mixture was concentrated under reduced pressure to afford the title compound (200 mg, crude, TFA salt). LCMS m / z [M+H]+253.0.

[0348] Step 3.5-bromo-l-(l-methylazetidin-3-yl)-lH-pyrazolo[3,4-&]pyridine

[0349] A solution of l-(azetidin-3-yl)-5-bromo-l / Z-pyrazolo[3,4-Z?]pyridine (200 mg, 0.79 mmol, 1 equiv) and paraformaldehyde (119 mg, 3.97 mmol, 5 equiv) in MeOH (5 mL) was stirred at RT for 1 h. Then NaBH3CN (100 mg, 1.59 mmol, 2 equiv) was added. The reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was diluted with H2O (100 mL) and adjusted to pH = 11 with LiOH (IM in H2O). The reaction mixture was extracted with EA (3 x 50 mL). The combined organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-15%) to afford the title compound (140 mg, 93%). LCMS m / z [M+H]+267.1.

[0350] Intermediate 33. l-(4-bromopyridin-2-yl)-3-methylazetidin-3-ol112ME1\60337174.v1141039-00120Br

[0351] Step 1. l-(4-bromopyridin-2-yl)-3-methylazetidin-3-ol

[0352] To a mixture of 4-bromo-2-fluoropyridine (100 mg, 0.57 mmol, 1 equiv, CAS: 128071-98-7) and 3-methylazetidin-3-ol hydrochloride (84 mg, 0.68 mmol, 1.2 equiv) in DMF (3 mL) was added Cs2CO3(555 mg, 1.71 mmol, 3 equiv). The reaction mixture was stirred at 90 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-50%) to afford the title compound (55 mg, 40%). LCMS m / z [M+H]+243.0.

[0353] Intermediate 34.5-chloro-2-(2-methoxyethyl)pyridazin-3(2H)-oneci

[0354] Step 1.5-chloro-2-(2-methoxyethyl)pyridazin-3(2H)-one

[0355] To a solution of 5-chloropyridazin-3(2 / f)-one (500 mg, 3.83 mmol, 1 equiv, CAS: 660425-07-0) in DMF (10 mL) was added l-bromo-2-methoxy ethane (1.07 g, 7.66 mmol, 2 equiv) and Cs2CO3(2.50 g, 7.66 mmol, 2 equiv) at RT. The reaction mixture was stirred at RT for 2 h. The reaction mixture was added H2O (30 mL) and extracted with EA (2 x 30 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-15%) to afford the title compound (450 mg, 62%). LCMS m / z [M+H]+189.0.

[0356] Intermediate 35.5-bromo-6-methoxy-A-(2-methoxyethyl)picolinamideo | o.0.. N. ASteP1O. _N A o'Y OH - ► Y N \II J II J H

[0357] Step 1.5-bromo-6-methoxy-A-(2-methoxyethyl)picolinamide

[0358] To a solution of 5-bromo-6-methoxypicolinic acid (550 mg, 2.37 mmol, 1 equiv, CAS: 1214334-70-9) in pyridine (10 mL) was added 2-methoxyethan- 1 -amine (267 mg, 3.55 mmol, 1.5 equiv) and POCI3 (545 mg, 3.55 mmol, 1.5 equiv) at 0 °C. The reaction mixture was stirred at RT for 1 h under N2 atmosphere. The reaction mixture was diluted with brine (100 mL) and extracted with EA (3 x 120 mL). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was113ME1\60337174.v1141039-00120purified by silica gel chromatography eluted with EA in PE (0%-30%) to afford the title compound (530 mg, 77%). LCMS m / z [M+H]+289.1.

[0359] Intermediate 36.5-bromo-4-methoxy-l-methyl-lH-pyrazolo[3,4-&]pyridine Step 1 Step 3Br.

[0360] Step 1.4-methoxy-lH-pyrazolo|3.4- / j Ipyridine

[0361] To a solution of 4-chloro-l / Z-pyrazolo[3,4-Z?]pyridine (2.0 g, 13.02 mmol, 1 equiv, CAS: 29274-28-0) in DMSO (20 mL) was added NaOMe (3.52 g, 65.12 mmol, 5 equiv). The reaction mixture was stirred at 120 °C for 16 h. The reaction mixture was quenched with NH4CI (sat aq 80 mL) and extracted with EA (2 x 80 mL). The combined organic layer was washed with H2O (80 mL), dried over Na2SO4U, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-60%) to afford the title compound (927 mg, 48%). LCMS m / z [M+H]+150.1.

[0362] Step 2.4-methoxy-l -methyl- lH-pyrazolo| 3,4- / ?] pyridine

[0363] To a solution of 4-methoxy-l / Z-pyrazolo[3,4-Z?]pyridine (100 mg, 0.67 mmol, 1 equiv) in DMSO (2 mL) was added NaHMDS (1 mL, 1.01 mmol, 1.5 equiv, IM in THF) at 0 °C. The reaction mixture was stirred at RT for 30 min. Then CH3I (285 mg, 2.01 mmol, 3 equiv) was added. The reaction mixture was stirred at RT for 2 h. The reaction mixture was quenched with NH4CI (sat aq 20 mL) and extracted with EA (2 x 20 mL). The combined organic layer was washed with H2O (20 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-50%) to afford the title compound (75 mg, 69%). LCMS m / z [M+H]+164.1.

[0364] Step 3.5-bromo-4-methoxy-l-methyl-lH-pyrazolo[3,4-&]pyridine

[0365] To a solution of 4-methoxy-l-methyl-l / Z-pyrazolo[3,4-Z?]pyridine (75 mg, 0.46 mmol, 1 equiv) in HO Ac (1 mL) was added Bn (66 mg, 0.41 mmol, 0.9 equiv) at RT. The reaction mixture was stirred at RT for 16 h. The reaction mixture was quenched with NaHCOs (sat aq 15 mL) and extracted with EA (2 x 15 mL). The combined organic layer was washed with H2O (15 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-50%) to afford the title compound (105 mg, 94%). LCMS m / z [M+H]+242.0.

[0366] Intermediate 37. ((5-bromo-3-methoxypyridin-2-yl)imino)dimethyl-k6-sulfanone114ME1\60337174.v1141039-00120Br

[0367] Step 1.5-bromo-2-iodo-3-methoxypyridine

[0368] To a mixture of 5-bromo-2-iodopyridin-3-ol (300 mg, 1.00 mmol, 1 equiv, CAS: 188057-49-0) in DMF (10 mL) was added NaH (120 mg, 5.00 mmol, 3 equiv, 60% dispersion in mineral oil). The reaction mixture was stirred at 0 °C for 1 h under N2 atmosphere. Then CH3I (170 mg, 1.20 mmol 1.2 equiv) was added and stirred at RT for 5 h. The reaction was quenched with H2O (80 mL) and extracted with EA (3 x 100 mL). The combined organic layer was washed with brine (3 x 100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-20%) to afford the title compound (150 mg, 48%). LCMS m / z [M+H]+313.9.

[0369] Step 2. ((5-bromo-3-methoxypyridin-2-yl)imino)dimethyl-k6-sulfanone

[0370] To a mixture of BINAP (208 mg, 0.33 mmol, 0.7 equiv) in toluene (10 mL) was added Pd(OAc)2 (54 mg, 0.24 mmol 0.5 equiv). The reaction mixture was stirred at RT for 20 min under N2 atmosphere. Then 5-bromo-2-iodo-3-methoxypyridine (150 mg, 0.48 mmol, 1 equiv), iminodimethyl-l6-sulfanone (53 mg, 0.57 mmol 1.2 equiv) and Cs2CO3(233 mg, 0.72 mmol, 1.5 equiv) was added. The reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-20%) to afford the title compound (80 mg, 60%). LCMS m / z [M+H]+279.0.

[0371] Intermediate 38. ((5-bromo-2-methoxypyridin-3-yl)imino)dimethyl-k6-sulfanoneBr Br

[0372] Step 1. ((5-bromo-2-methoxypyridin-3-yl)imino)dimethyl-k6-sulfanone

[0373] Prepared from 5-bromo-3-iodo-2-methoxypyridine uisng the method described for intermediate 37. LCMS m / z [M+H]+279.0.

[0374] Intermediate 39.2-(5-bromo-lH-pyrazolo[3,4-&]pyridin-l-yl)acetamide115ME1\60337174.v1141039-00120NH2

[0375] Step 1.2-(5-bromo-lH-pyrazolo[3,4-&]pyridin-l-yl)acetamide

[0376] To a solution of 5-bromo-l / Z-pyrazolo[3,4-Z?]pyridine (1.0 g, 5.05 mmol, 1 equiv, CAS: 875781-17-2) in DMF (10 mL) was added 2-bromoacetamide (697 mg, 5.05 mmol, 1 equiv) and K2CO3(2.09 g, 15.15 mmol, 3 equiv). The reaction mixture was stirred at 80 °C for 16 h under N2 atmosphere. The reaction mixture was quenched with H2O (10 mL) and extracted with EA (2 x 10 mL). The combined organic layer was washed with H2O (2 x 10 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-10%) to afford the title compound (340 mg, 26%). LCMS m / z [M+H]+255.0.

[0377] Intermediate 40. (S)-l-(5-bromo-lH-pyrazolo[3,4-Z>]pyridin-l-yl)propan-2-ol

[0378] Step 1. (S)-l-(5-bromo-lH-pyrazolo[3,4-&]pyridin-l-yl)propan-2-ol

[0379] To a mixture of 5-bromo-l / Z-pyrazolo[3,4-Z?]pyridine (1.0 g, 5.05 mmol, 1 equiv, CAS: 875781-17-2) in DMF (10 mL) was added NaH (242 mg, 6.06 mmol, 1.2 equiv, 60% dispersion in mineral oil) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 h. Then (S)-2-methyloxirane (352 mg, 6.06 mmol, 1.2 equiv) was added. The reaction mixture was stirred at 60 °C for 16 h under N2 atmosphere. The reaction mixture was quenched with H2O (100 mL) and extracted with EA (3 x 100 mL). The combined organic layer was washed with brine, dried over Na2SO4. After filtration, the organic layer was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluted with EA in PE (10%-70%) to afford the title compound (610 mg, 47%). LCMS m / z [M+H]+256.0.

[0380] Intermediate 41. ( / ?)-l-(5-bromo-lH-pyrazolo[3,4-&]pyridin-l-yl)propan-2-ol

[0381] Step 1. ( / ?)-l-(5-bromo-lH-pyrazolo[3,4-&]pyridin-l-yl)propan-2-ol

[0382] Prepared from 5-bromo-l / Z-pyrazolo[3,4-Z?]pyridine and (7?)-2-methyloxirane using the method described for intermediate 40. LCMS m / z [M+H]+256.1.116ME1\60337174.v1141039-00120

[0383] Intermediate 42.2-(5-bromo-lH-pyrazolo[3,4-&]pyridin-l-yl)-V, V-dimethylethan- 1 -amine

[0384] Step 1.2-(5-bromo-lH-pyrazolo[3,4-Z>]pyridin-l-yl)-V, V-dimethylethan-l-amine

[0385] Prepared from 5-bromo-l / Z-pyrazolo[3,4-Z?]pyridine using the method described for intermediate 40. LCMS m / z [M+H]+269.1.

[0386] Intermediate 43.6-bromo-3-methyl-l-(oxetan-3-yl)-l,3-dihydro-2H-imidazo[4,5-&]pyridin-2-one

[0387] Step 1.5-bromo-2-nitro-2V-(oxetan-3-yl)pyridin-3-amine

[0388] To a solution of 5-bromo-3-fluoro-2-nitropyridine (600 mg, 2.71 mmol, 1 equiv, CAS: 1532517-95-5) in ACN (6 mL) was added oxetan-3-amine (238 mg, 3.25 mmol, 1.2 equiv) and TEA (823 mg, 4.07 mmol, 3 equiv). The reaction mixture was stirred at 80 °C for 1 h. The reaction mixture was added to H2O (150 mL) and extracted with EA (3 x 30 mL). The combined organic layer was washed with brine, dried over Na2SO4and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-30%) to afford the title compound (690 mg, 92%). LCMS m / z [M+H]+274.1.

[0389] Step 2.5-bromo-2V3-(oxetan-3-yl)pyridine-2,3-diamine

[0390] To a solution of 5-bromo-2-nitro-A-(oxetan-3-yl)pyridin-3-amine (690 mg, 2.51 mmol, 1 equiv) in EtOH (10 mL) and H2O (2 mL) was added Fe (1.4 g, 25.1 mmol, 10 equiv) and NH4CI (1.3 g, 25.1 mmol, 10 equiv). The reaction mixture was stirred at 80 °C for 1 h. The reaction mixture was filtered and the filterate was added to H2O (150 mL). The mixture was adjusted to pH = 10 and extracted with EA (3 x 30 mL). The combined organic layer was117ME1\60337174.v1141039-00120washed with brine, dried over Na2SO4and concentrated under reduced pressure to afford the title compound (640 mg, crude). LCMS m / z [M+H]+244.1.

[0391] Step 3.6-bromo-l-(oxetan-3-yl)-l,3-dihydro-2H-imidazo[4,5-&]pyridin-2-one

[0392] To a solution of 5-bromo-A3-(oxetan-3-yl)pyridine-2,3-diamine (320 mg, 1.30 mmol, 1 equiv) in THF (8 mL) was added CDI (2.12 g, 13.0 mmol, 10 equiv). The reaction mixture was stirred at 60 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-5%) to afford the title compound (288 mg, 82%). LCMS m / z [M+H]+270.0.

[0393] Step 4.6-bromo-3-methyl-l-(oxetan-3-yl)-l,3-dihydro-2H-imidazo[4,5-&]pyridin-2-one

[0394] To a solution of 6-bromo-l-(oxetan-3-yl)-l,3-dihydro-2 / Z-imidazo[4,5-Z?]pyridin-2-one (100 mg, 0.37 mmol, 1 equiv) in dry DMF (4 mL) was added NaH (22 mg, 0.56 mmol, 1.5 equiv, 60% dispersion in mineral oil) and CH3I (63 mg, 0.44 mmol, 1.2 equiv). The reaction mixture was stirred at RT for 16 h. The reaction mixture was added to H2O (80 mL) and extracted with EA (3 x 20 mL). The combined organic layer was washed with brine, dried over Na2SO4and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-30%) to afford the title compound (99 mg, 94%). LCMS m / z [M+H]+284.0.

[0395] Intermediate 44.6-bromo-l-methyl-3-(oxetan-3-yl)-l,3-dihydro-2H-imidazo[4,5-Z>]pyridin-2-one

[0396] Step 1.5-bromo-3-nitro-2V-(oxetan-3-yl)pyridin-2-amine

[0397] To a mixture of 5-bromo-2-chloro-3-nitropyridine (900 mg, 3.79 mmol, 1 equiv, CAS: 67443-38-3) in THF (15 mL) was added oxetan-3- amine (416 mg, 5.69 mmol, 1.5 equiv) and DIPEA (980 mg, 7.58 mmol, 2 equiv). The reaction mixture was stirred at 80 °C for 2 h under N2 atmosphere. The reaction mixture was quenched with H2O (50 mL) and extracted with DCM (3 x 50 mL). The combined organic layer was washed with brine, dried over Na2SO4. After filtration, the organic layer was concentrated under reduced pressure. The118ME1\60337174.v1141039-00120residue was purified by silica gel chromatography, eluted with EA in PE (0%-20%) to afford the title compound (870 mg, 84%). LCMS m / z [M+H]+274.0.

[0398] Step 2.5-bromo- V2-(oxetan-3-yl)pyridine-2,3-diamine

[0399] To a mixture of 5-bromo-3-nitro-A-(oxetan-3-yl)pyridin-2-amine (940 mg, 3.43 mmol, 1 equiv) in EtOH (15 mL) and H2O (3 mL) was added Fe (1.92 g, 34.30 mmol, 10 equiv) and NH4CI (1.84 g, 34.30 mmol, 10 equiv). The reaction mixture was stirred at 80 °C for 1 h under N2 atmosphere. The reaction mixture was filtered and the filter cake was washed with EtOH (2 x 20 mL). The combined filtrate and concentrated under reduced pressure. The residue was added to H2O (50 mL) and extracted with DCM (3 x 50 mL). The combined organic layer was washed with brine, dried over Na2SO4and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluted with MeOH in DCM (0%-5%) to afford the title compound (290 mg, 35%). LCMS m / z [M+H]+244.0.

[0400] Step 3.6-bromo-3-(oxetan-3-yl)-l,3-dihydro-2H-imidazo[4,5-&]pyridin-2-one

[0401] To a mixture of 5-bromo-A2-(oxetan-3-yl)pyridine-2,3-diamine (270 mg, 1.11 mmol, 1 equiv) in THF (5 mL) was added CDI (269 mg, 1.66 mmol, 1.5 equiv) and Et3N (336 mg, 3.32 mmol, 3 equiv). The reaction mixture was stirred at 80 °C for 3 h under N2 atmosphere. The reaction mixture was quenched with H2O (50 mL) and extracted with DCM (3 x 50 mL). The combined organic layer was washed with brine, dried over Na2SO4. After filtration the organic layer was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluted with MeOH in DCM (0%-10%) to afford the title compound (180 mg, 60%). LCMS m / z [M+H]+270.0.

[0402] Step 4.6-bromo-l-methyl-3-(oxetan-3-yl)-l,3-dihydro-2H-imidazo[4,5-&]pyridin-2-one

[0403] To a mixture of 6-bromo-3-(oxetan-3-yl)-l,3-dihydro-2 / Z-imidazo[4,5-Z?]pyridin-2-one (150 mg, 0.56 mmol, 1 equiv) in DMF (5 mL) was added NaH (33 mg, 0.83 mmol, 1.5 equiv, 60% dispersion in mineral oil) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 h under N2 atmosphere. Then CH3I (95 mg, 0.67 mmol, 1.2 equiv) was added. The reaction mixture was stirred at RT for 2 h under N2 atmosphere. The reaction mixture was quenched with H2O (50 mL) and extracted with EA (3 x 50 mL). The combined organic layer was washed with brine, dried over Na2SO4. After filtration, the organic layer was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluted with MeOH in DCM (0%-3%) to afford the title compound (150 mg, 95%). LCMS m / z [M+H]+284.0.119ME1\60337174.v1141039-00120

[0404] Intermediate 45.6-bromo-3-methyl-l-(l-methylazetidin-3-yl)-l,3-dihydro-2H-imidazo[4,5-&]pyridin-2-one

[0405] Step 1. tert-butyl 3-((5-bromo-2-nitropyridin-3-yl)amino)azetidine-l-carboxylate

[0406] To a mixture of 5-bromo-3-fluoro-2-nitropyridine (600 mg, 2.72 mmol, 1 equiv, CAS: 1532517-95-5) and tert-butyl 3-aminoazetidine-l-carboxylate (468 mg, 2.72 mmol, 1 equiv) in ACN (5 mL) was added DIPEA (1.05 g, 6.79 mmol, 3 equiv). The reaction mixture was stirred at 80 °C foe 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-10%) to afford the title compound (1.01 g, 99.7%). LCMS m / z (M-tBu+H)+317.0.

[0407] Step 2. tert-butyl 3-((2-amino-5-bromopyridin-3-yl)amino)azetidine-l-carboxylate

[0408] To a mixture of tert-butyl 3-((5-bromo-2-nitropyridin-3-yl)amino)azetidine-l-carboxylate (1.01 g, 2.71 mmol, 1 equiv) in EtOH (50 mL) and H2O (10 mL) was added Fe (1.52 g, 27.06 mmol, 10 equiv) and NH4CI (1.45 g, 27.06 mmol, 10 equiv). The reaction mixture was stirred at 80 °C for 1 h. The reaction mixture was filtered. The filtrate was diluted with H2O (100 mL) and extracted with DCM (3 x 100 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title compound (980 mg, crude). LCMS m / z [M+H]+343.0.

[0409] Step 3. tert-butyl 3-(6-bromo-2-oxo-2,3-dihydro-lH-imidazo[4,5-&]pyridin-l-yl)azetidine- 1 -carboxylate

[0410] To a mixture of tert-butyl 3-((2-amino-5-bromopyridin-3-yl)amino)azetidine-l-carboxylate (500 mg, 1.46 mmol, 1 equiv) and CDI (473 mg, 2.92 mmol, 2 equiv) in THF (10 mL) was added TEA (441 mg, 4.37 mmol, 3 equiv). The reaction mixture was stirred at 60 °C for 16 h. The reaction mixture was diluted with H2O (80 mL) and extracted with DCM (3 x 80 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced120ME1\60337174.v1141039-00120pressure. The residue was purified by silica gel chromatography, eluted with EA in PE (0%-80%) to afford the title compound (376 mg, 70%). LCMS m / z (M - / Bu + H)+m / z 313.1.

[0411] Step 4. tert-butyl 3-(6-bromo-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-b ] pyridin- 1 -yl) azetidine- 1 -carboxylate

[0412] To a mixture of tert-butyl 3-(6-bromo-2-oxo-2,3-dihydro-l / Z-imidazo[4,5-Z?]pyridin-l-yl)azetidine-l -carboxylate (376 mg, 1.02 mmol, 1 equiv) in DMF (3 mL) was added NaH (49 mg, 1.22 mmol, 1.2 equiv, 60% dispersion in mineral oil) at 0 °C under N2 atmosphere. The reaction mixture was stirred at 0 °C for 1 h. Then CH3I (174 mg, 1.23 mmol, 1.2 equiv) in DMF (2 mL) was added. The reaction mixture was stirred at RT for 1 h under N2 atmosphere. The reaction mixture was diluted with NH4CI (sat aq 60 mL) and extracted with DCM (3 x 60 mL). The organic layer was dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluted with EA in PE (0%-80%) to afford the title compound (350 mg, 90%). LCMS m / z (M -tBu + H)+327.1.

[0413] Step 5. l-(azetidin-3-yl)-6-bromo-3-methyl-l,3-dihydro-2H-imidazo[4,5-&]pyridin-2-one

[0414] Tert-butyl 3-(6-bromo-3-methyl-2-oxo-2,3-dihydro-l / Z-imidazo[4,5-Z?]pyridin-l-yl)azetidine- 1 -carboxylate (100 mg, 0.26 mmol, 1 equiv) was dissolved in TFA (5 mL). The reaction mixture was stirred at RT for 0.5 h. The reaction mixture was concentrated under reduced pressure to afford the title compound (74 mg, crude, TFA salt). LCMS m / z [M+H]+283.0.

[0415] Step 6.6-bromo-3-methyl-l-(l-methylazetidin-3-yl)-l,3-dihydro-2H-imidazo[4,5-&]pyridin-2-one

[0416] To a mixture of l-(azetidin-3-yl)-6-bromo-3-methyl-l,3-dihydro-2 / Z-imidazo[4,5-Z?]pyridin-2-one (74 mg, crude, TFA salt, 0.26 mmol, 1 equiv) in MeOH (5 mL) was added paraformaldehyde (65 mg, 1.31 mmol, 5 equiv) and NaBH₃CN (82 mg, 1.31 mmol, 5 equiv). The reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was diluted with H2O (20 mL) and extracted with DCM (3 x 20 mL). The organic layer was dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluted with MeOH in DCM (0%-10%) to afford the title compound (75 mg, 97%). LCMS m / z [M+H]+297.0.

[0417] Intermediate 46.6-bromo-l-methyl-3-(l-methylazetidin-3-yl)-l,3-dihydro-2H-imidazo[4,5-Z>]pyridin-2-one121ME1\60337174.v1141039-00120Step 1 Step 2 Step 3Step 4 Step 6

[0418] Step 1. tert-butyl 3-((5-bromo-3-nitropyridin-2-yl)amino)azetidine-l-carboxylate

[0419] To the solution of 5-bromo-2-chloro-3 -nitropyridine (900 mg, 3.79 mmol, 1 equiv) in THF (20 mL) was added DIPEA (1.47 g, 11.37 mmol, 3 equiv) and tert-butyl 3-aminoazetidine-1 -carboxylate (980 mg, 5.69 mmol, 1.5 equiv). The reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluted with EA in PE (0%-30%) to afford the title compound (1.35 g, 96%). LCMS m / z [M+H]+373.2.

[0420] Step 2. tert-butyl 3-((3-amino-5-bromopyridin-2-yl)amino)azetidine-l-carboxylate

[0421] To the solution of tert-butyl 3-((5-bromo-3-nitropyridin-2-yl)amino)azetidine-l-carboxylate (1.50 g, 4.02 mmol, 1 equiv) in EtOH (10 mL) and H2O (2 mL) was added Fe (2.20 g, 40.20 mmol, 10 equiv) and NH4CI (2.11 g, 40.20 mmol, 10 equiv). The reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluted with EA in PE (0%-30%) to afford the title compound (1.25 g, 86%). LCMS m / z [M+H]+343.2.

[0422] Step 3. tert-butyl 3-(6-bromo-2-oxo-l,2-dihydro-3H-imidazo[4,5-&]pyridin-3-yl)azetidine- 1 -carboxylate

[0423] To the solution of tert-butyl 3-((3-amino-5-bromopyridin-2-yl)amino)azetidine-l-carboxylate (1.25 g, 3.64 mmol, 1 equiv) in THF (20 mL) was added TEA (1.10 g, 10.92 mmol, 3 equiv) and CDI (1.18 g, 7.28 mmol, 2 equiv). The reaction mixture was stirred at 60 °C for 2 h. The reaction mixture was diluted with brine (120 mL) and extracted with EA (3 x 200 mL). The combined organic layer was washed with brine, dried over Na2SO4U, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with EA in PE (0%-15%) to afford the title compound (1.34 g, 99%). LCMS m / z [M+H]+369.2.122ME1\60337174.v1141039-00120

[0424] Step 4. tert-butyl 3-(6-bromo-l-methyl-2-oxo-l,2-dihydro-3H-imidazo[4,5- / ?] py rid in-3-yl)azet id i ne- 1 -carboxy late

[0425] To the solution of tert-butyl 3-(6-bromo-2-oxo-l,2-dihydro-3 / Z-imidazo[4,5-Z?]pyridin-3-yl)azetidine-l -carboxylate (1.04 g, 2.83 mmol, 1 equiv) in DMF (15 mL) was added NaH (136 mg, 3.40 mmol, 1.2 equiv, 60% dispersion in mineral oil). The reaction mixture was stirred at 0 °C for 0.5 h under N2 atmosphere. Then CH3I (483 mg, 3.40 mmol 1.2 equiv) was added. The reaction mixture was stirred at RT for 2 h. The reaction mixture was quenched with H2O (200 mL) and extracted with EA (3 x 100 mL). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue purified by silica gel chromatography eluted with EA in PE (0%-15%) to afford the title compound (1.2 g, crude, contain DMF). LCMS m / z [M+H]+383.2.

[0426] Step 5.3-(azetidin-3-yl)-6-bromo-l-methyl-l,3-dihydro-2H-imidazo[4,5-&]pyridin-2-one

[0427] Tert-butyl 3-(6-bromo-l-methyl-2-oxo-l,2-dihydro-3 / / -imidazo[4,5-Z?]pyridin-3-yl)azetidine- 1 -carboxylate (200 mg, 0.52 mmol, 1 equiv) was dissolved in HFIP (5 mL). The reaction mixture was stirred at 110 °C for 2 h in microwave reactor. The reaction mixture was concentrated under reduced pressure to afford the title compound (160 mg, crude). LCMS m / z [M+H]+283.2.

[0428] Step 6.6-bromo-l-methyl-3-(l-methylazetidin-3-yl)-l,3-dihydro-2H-imidazo[4,5-&]pyridin-2-one

[0429] To the solution of 3-(azetidin-3-yl)-6-bromo-l -methyl- l,3-dihydro-27T-imidazo[4,5-Z?]pyridin-2-one (160 mg, crude, 0.56 mmol, 1 equiv) in MeOH (5 mL) were added paraformaldehyde (76 mg, 0.85 mmol, 1.5 equiv) and NaBH3CN (71 mg, 1.13 mmol, 2 equiv). The reaction mixture was stirred at RT for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-6%) to afford the title compound (70 mg, 42%). LCMS m / z [M+H]+297.1.

[0430] Intermediate 47.6-bromo-3-methoxy-l-methyl-lH-pyrazolo[4,3-&]pyridine and 6-bromo-l,2-dimethyl-l,2-dihydro-3H-pyrazolo[4,3-&]pyridin-3-one123ME1\60337174.v1141039-00120Step 1 Step 2 Step 3OHStep 4

[0431] Step 1. tert-butyl 2-(5-bromo-3-fluoropicolinoyl)-l-methylhydrazine-l-carboxylate

[0432] To a solution of 5-bromo-3-fluoropicolinic acid (1.80 g, 8.18 mmol, 1 equiv, CAS: 669066-91-5) and HATU (3.73 g, 9.82 mmol, 1.2 equiv) in DMF (20 mL) was added DIPEA (3.17 g, 24.40 mmol, 3 equiv) and tert-butyl 1 -methylhydrazine- 1 -carboxylate (1.40 g, 9.82 mmol, 1.2 equiv). The reaction mixture was stirred at RT for 1 h. The reaction mixture was poured into NH4CI (sat aq 50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layer was washed with brine, dried over Na2SO4U, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-40%) to afford the title compound (2.80 g, 98%). LCMS m / z (M-tBu+H)+292.0.

[0433] Step 2.5-bromo-3-fluoro-N'-methylpicolinohydrazide

[0434] Tert-butyl 2-(5-bromo-3-fluoropicolinoyl)- 1 -methylhydrazine- 1 -carboxylate (2.80 g, 8.04 mmol, 1 equiv) was dissolved in HC1 (4M in dioxane, 15 mL). The reaction mixture was stirred at RT for 1 h. The reaction mixture was poured into NaHCOs (sat aq 50 mL) at 0 °C and extracted with EA (3 x 50 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title compound (1.95 g, 97%). LCMS m / z [M+H]+248.0.

[0435] Step 3.6-bromo-l-methyl-lH-pyrazolo[4,3-&]pyridin-3-ol and 6-bromo-l-methyl- L2-dihydro-3H-pyrazolo|4,3- / ?]pyridin-3-one

[0436] To a solution of 5-bromo-3-fluoro-N'-methylpicolinohydrazide (225 mg, 0.91 mmol, 1 equiv) in DMF (4 mL) was added K2CO3(376 mg, 1.20 mmol, 3 equiv). The reaction mixture was stirred at 90 °C for 1 h. The reaction mixture was purified by prep-HPLC (ACN / water / 10 mM NH4HCO3) to afford the compound (200 mg, 24%) and the isomer (70 mg, 8%). LCMS [M+H]+m / z 228.2. The LCMS of the isomer: LCMS m / z [M+H]+228.2.

[0437] Step 4.6-bromo-3-methoxy-l-methyl- lH-pyrazolo| 4,3- / ?] pyridine and 6-bromo-l,2-dimethyl-l,2-dihydro-3H-pyrazolo[4,3-&]pyridin-3-one124ME1\60337174.v1141039-00120

[0438] To a solution of 6-bromo-3-methoxy-l-methyl-l / Z-pyrazolo[4,3-Z?]pyridine (200 mg, 0.88 mmol, 1 equiv) and CH3I (371 mg, 2.63 mmol, 3 equiv) in DMF (3 mL) was added K2CO3(363 mg, 2.63 mmol, 3 equiv). The reaction mixture was stirred at 90 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (ACN / water / 10 mM NH4HCO3) to afford the title compound (45 mg, 16%) and the isomer of the title compound (45 mg, 16%). LCMS [M+H]+m / z. 242.0. The LCMS of the isomer: LCMS m / z [M+H]+242.0

[0439] Intermediate 48.2-(6-bromo-l-methyl-lH-pyrazolo[4,3-Z>]pyridin-3-yl)propan-2-ol

[0440] Step 1. methyl 6-bromo-l-methyl-lH-pyrazolo[4,3-&]pyridine-3-carboxylate and methyl 6-bromo-2-methyl-2H-pyrazolo[4,3-&]pyridine-3-carboxylate

[0441] To a solution of methyl 6-bromo-l / Z-pyrazolo[4,3-Z?]pyridine-3-carboxylate (750 mg, 2.93 mmol, 1 equiv, CAS: 1363380-66-8) in DMF (20 mL) was added NaH (176 mg, 4.39 mmol, 1.5 equiv, 60% dispersion in mineral oil) at 0 °C. The reaction mixture was stirred for 0.5 h at 0°C. Then CH3I (1.24 g, 8.79 mmol, 3 equiv) was added at 0°C. The reation mixture was stirred at RT for 16 h. The reaction mixture was poured into H2O (100 mL) and extracted with EA (3 x 50 mL). The organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (ACN / water / 10 mM NH4HCO3) to afford the title compound (310 mg, 39%) and the isomer (270 mg, 34%). LCMS [M+H]+m / z 270.0. LCMS of the isomer: LCMS m / z [M+H]+270.0.

[0442] Step 2.2-(6-bromo-l-methyl-lH-pyrazolo[4,3-&]pyridin-3-yl)propan-2-ol

[0443] To a solution of methyl 6-bromo-l-methyl-l / Z-pyrazolo[4,3-Z?]pyridine-3-carboxylate (100 mg, 0.37 mmol, 3 equiv) in THF (2 mL) was added CH₃MgBr (3.70 mL, 3.70 mmol, 10 equiv, IM in THF) at 0 °C under N2 atmosphere. The reaction mixture stirred at 0 °C for 1 h. The reaction mixture was quenched with NH4CI (sat aq 10 mL) and extracted with EA (3 x 20 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (EA: PE = 1:2) to afford the title compound (39 mg, 39%). LCMS m / z [M+H]+270.0.

[0444] Intermediate 49.6-bromo-1-methyl-1H-pyrazolo[4,3-b]pyridine-3-carboxamide125ME1\60337174.v1141039-00120

[0445] Step 1.6-bromo-l-methyl-lH-pyrazolo[4,3-&]pyridine-3-carboxamide

[0446] To a solution of methyl 6-bromo-l-methyl-l / Z-pyrazolo[4,3-Z?]pyridine-3-carboxylate (90 mg, 0.33 mmol, 1 equiv) was dissolved in NH3 (3 mL, 7M in MeOH). The reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-5%) to afford the title compound (85 mg, 90%). LCMS m / z [M+H]+255.2.

[0447] Intermediate 50.6-bromo-N,1-dimethyl-1H-pyrazolo[4,3-b]pyridine-3-carboxamide

[0448] Step 1.6-bromo-N,1-dimethyl-1H-pyrazolo[4,3-b]pyridine-3-carboxamide

[0449] To a solution of methyl 6-bromo-l-methyl-l / / -pyrazolo[4,3-Z?]pyridine-3-carboxylate (90 mg, 0.33 mmol, 1 equiv) was dissolved in methylamine (3 mL, 33% wt. in EtOH). The reaction mixture was stirred at RT for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-5%) to afford the title compound (95 mg, 95%). LCMS m / z [M+H]+269.2.

[0450] Intermediate 51.5-bromo-l-methyl-3-(methylamino)pyridin-2(lH)-one Br Br Br

[0451] Step 1.5-bromo-l-methyl-3-(methyleneamino)pyridin-2(lH)-one

[0452] To a mixture of 3-amino-5-bromo-l-methylpyridin-2(l / f)-one (200 mg, 0.99 mmol, 1 equiv, CAS: 910543-72-5) in DCM (5 mL) was added MeOH (1 drop) and AcOH (1 drop). The reaction mixture was stirred at RT for 10 min. Then 37% formaldehyde solution (0.5 mL) was added into the mixture. The reaction mixture was stirred at RT for 1 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EA (3 x 20 mL). The126ME1\60337174.v1141039-00120combined organic layer was dried over Na2SO4. filtered and concentrated under reduced pressure to afford the title compound (300 mg, crude). LCMS m / z [M+H]+215.0.

[0453] Step 2.5-bromo-l-methyl-3-(methylamino)pyridin-2(lH)-one

[0454] To a mixture of 5-bromo-l -methyl-3-(methyleneamino)pyridin-2(l 7f)-one (280 mg, crude, 1.30 mmol, 1 equiv) in EtOH (10 mL) was added NaBH₄ (99 mg, 2.62 mmol, 2 equiv) at RT. The reaction mixture was stirred at RT for 1 h. The reaction mixture was quenched with H2O (50 mL) and extracted with EA (3 x 50 mL). The combined organic layer was washed with brine, dried over Na2SO4, and concentrate under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-5%) to afford the title compound (64 mg, 30%). LCMS m / z [M+H]+216.9.

[0455] Intermediate 52.3-bromo-5,7-dihydrothieno[3,4-Z>]pyridine 6,6-dioxide

[0456] Step 1.3-bromo-5,7-dihydrothieno[3,4-&]pyridineTo a solution of 5-bromo-2,3-bis(chloromethyl)pyridine (200 mg, 0.78 mmol, 1 equiv) in EtOH (4 mL) was added Na₂S·9H₂O (188 mg, 0.78 mmol, 1 equiv). The reaction mixture was stirred at 80 °C for 5 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-10%) to afford the title compound (62 mg, 37%). LCMS m / z [M+H]+216.0.

[0457] Step 2.3-bromo-5,7-dihydrothieno[3,4-&]pyridine 6,6-dioxide

[0458] To a solution of 3-bromo-5,7-dihydrothieno[3,4-Z?]pyridine (62 mg, 0.28 mmol, 1 equiv) in DCM (4 mL) was added m-CPBA (171 mg, 0.84 mmol, 3 equiv, purity: 85%). The reaction mixture was stirred at RT for 16 h. The reaction mixture was added NaHCO3(sat aq 30 mL) and extracted with DCM (3 x 5 mL). The combined organic layer was washed with brine, dried over Na2SO4and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-80%) to afford the title compound (48 mg, 67%). LCMS m / z (M+2+H)+249.9.

[0459] Intermediate 53.6-bromo-2-methoxy-l-methyl-lH-imidazo[4,5-&]pyridine

[0460] Step 1.6-bromo-l-methyl-l,3-dihydro-2H-imidazo[4,5-&]pyridin-2-one

[0461] To the solution of 5-bromo-A3-methylpyridine-2,3-diamine (70 mg, 0.35 mmol, 1 equiv, CAS: 166047-15-0) and DIPEA (135 mg, 1.05 mmol, 3 equiv) in THF (1 mL) was127ME1\60337174.v1141039-00120added CDI (115 mg, 0.70 mmol, 2 equiv). The reaction mixture was stirred at 60 °C for 5 h. The reaction mixture was quenched with H2O (30 mL) and extracted with EA (3 x 30 mL). The combined organic layer was washed with H2O (2 x 10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-5%) to afford the title compound (60 mg, 76%). LCMS m / z [M+H]+228.1.

[0462] Step 2.6-bromo-2-chloro-l-methyl-lH-imidazo[4,5-&]pyridine

[0463] A solution of 6-bromo-l-methyl-l,3-dihydro-2 / Z-imidazo[4,5-Z?]pyridin-2-one (60 mg, 0.26 mmol, 1 equiv) in POCI3 (2 mL) was stirred at 110 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was adjusted pH = 7-8 with NaHCO3(sat aq) and extracted with DCM (3 x 30 mL). The combined rganic layer was washed with H2O (2 x 10 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-8%) to afford the title compound (45 mg, 69%). LCMS m / z [M+H]+246.0.

[0464] Step 3.6-bromo-2-methoxy-l-methyl-lH-imidazo[4,5-&]pyridine

[0465] To the solution of 6-bromo-2-chloro-l -methyl- l / Z-imidazo[4,5-Z?]pyridine (45 mg, 0.18 mmol, 1 equiv) in DMF (1 mL) was added NaOMe (30 mg, 0.54 mmol, 3 equiv). The reaction mixture was stirred at RT for 16 h. The reaction mixture was quenched with H2O (30 mL) and extracted with EA (3 x 30 mL). The combined organic layer was washed with H2O (2 x 10 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-5%) to afford the title compound (30 mg, 67%). LCMS m / z [M+H]+242.0.

[0466] Intermediate 54.6-bromo-l-methyloxazolo[5,4-&]pyridin-2(lH)-one

[0467] Step 1.6-bromooxazolo[5,4-Z>]pyridin-2(lH)-one

[0468] To a solution of 3-amino-5-bromopyridin-2-ol (500 mg, 2.65 mmol, 1 equiv, CAS: 98786-86-3) in THF (10 mL) was added CDI (515 mg, 3.18 mmol, 1.2 equiv). The reaction mixture was stirred at 50 °C for 2 h. The reaction mixture was diluted with brine (30 mL) and extracted with EA (3 x 50 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title compound (190 mg, crude). LCMS m / z [M+H]+215.0.

[0469] Step 2.6-bromo-l-methyloxazolo[5,4-&]pyridin-2(lH)-one128ME1\60337174.v1141039-00120

[0470] To a solution of 6-bromooxazolo[5,4-Z?]pyridin-2(l / f)-one (190 mg, 0.88 mmol, 1 equiv) in DMF (5 mL) was added Cs2CO3(430 mg, 1.32 mmol, 1.5 equiv) and CH3I (188 mg, 1.32 mmol, 1.5 equiv). The reaction mixture was stirred at RT for 2 h. The reaction mixture was concentrated under reduced pressure. Then the residue was diluted with brine (50 mL) and extracted with EA (3 x 60 mL). The combined organic layer was washed with brine, dried over Na2SO4U, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-35%) to afford the title compound (50 mg, 25%). LCMS m / z [M+H]+229.0.

[0471] Intermediate 55.2-(6-bromo-l-methyl-lH-imidazo[4,5-&]pyridin-2-yl)propan-2-ol

[0472] Step 1.5-bromo-N-methyl-2-nitropyridin-3-amine

[0473] To a solution of 5-bromo-3-fluoro-2-nitropyridine (1.0 g, 4.53 mmol, 1 equiv, CAS: 1532517-95-5) and DIPEA (2.92 g, 22.62 mmol, 5 equiv) in THF (14 mL) was added methylamine hydrochloride (917 mg, 13.58 mmol, 3 equiv). The reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was diluted with H2O (40 mL) and extracted with EA (3 x 40 mL). The combined organic layer was washed with brine (30 mL) and dried over Na2SO4and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-30%) to afford the title compound (1.0 g, 95%). LCMS m / z [M+H]+232.0.

[0474] Step 2.5-bromo-N³-methylpyridine-2,3-diamine

[0475] To a solution of 5-bromo-N-methyl-2-nitropyridin-3-amine (1.0 g, 4.31 mmol, 1 equiv) and Fe (2.41 g, 43.10 mmol, 10 equiv) in EtOH (10 mL) and H2O (2 mL) was added NH4CI (2.31 g, 43.10 mmol, 10 equiv). The reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was diluted with H2O (30 mL) and extracted with EA (3 x 30 mL). The combined organic layer was washed with brine (30 mL), dried over Na2SO4and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-60%) to afford the title compound (700 mg, 80%). LCMS m / z [M+H]+202.0.

[0476] Step 3.6-bromo-l -met hyl-lH-imidazo| 4, 5- / >] pyridine129ME1\60337174.v1141039-00120

[0477] 5-bromo-A3-methylpyridine-2,3-diamine (200 mg, 0.99 mmol, 1 equiv) was dissolved in HCOOH (3 mL). The reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was diluted with ice H2O (50 mL) and extracted with DCM (2 x 50 mL). The combined organic layer was washed with brine (50 mL) and dried over Na2SO4and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-6%) to afford the title compound (200 mg, 95%). LCMS m / z [M+H]+212.1.

[0478] Step 4. 2-(6-bromo-l-methyl-lH-imidazo[4,5-&]pyridin-2-yl)propan-2-ol

[0479] To a solution of 6-bromo-l-methyl-l / / -imidazo[4,5-Z?]pyridine (90 mg, 0.42 mmol, 1 equiv) in THF (2 mL) was added LiTMP (1.27 mL, 1.27 mmol, 3 equiv, IM in THF) at -78 °C. The reaction mixture was stirred at -78 °C for 1 h. Then acetone (123 mg, 2.12 mmol, 5 equiv) was added. The reaction mixture was stirred at -78 °C for 1 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EA (2 x 20 mL). The combined organic layer was washed with brine (20 mL) and dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-75%) to afford the title compound (90 mg, 79%). LCMS m / z [M+H]+270.1.

[0480] Intermediate 56. ((6-bromo-l-methyl-lH-imidazo[4,5-&]pyridin-2-yl)imino)dimethyl-k6-sulfanoneStep 1

[0481] Step 1. ((6-bromo-l-methyl-lH-imidazo[4,5-&]pyridin-2-yl)imino)dimethyl-λ6-sulfanone

[0482] To a solution of 6-bromo-2-chloro-l -methyl- 1 / Z-imidazo [4, 5 -Z?] pyridine (60 mg, 0.24 mmol, 1 equiv) and Cs2CO3(238 mg, 0.73 mmol, 3 equiv) in DMSO (2 mL) was added iminodimethyl-X6-sulfanone (114 mg, 1.22 mmol, 5 equiv). The reaction mixture was stirred at 100 °C for 5 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EA (2 x 20 mL). The combined organic layer was washed with brine (20 mL) and dried over Na2SO4and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-6%) to afford the title compound (60 mg, 81%). LCMS m / z [M+H]+303.1.

[0483] Intermediate 57. 6-bromo-N,1-dimethyl-1H-imidazo[4,5-b]pyridin-2-amine130ME1\60337174.v1141039-00120step 1

[0484] Step 1.6-bromo-\.1 -di methyl -LH-imidazo[ 4,5- / ? ] py rid in -2-amine

[0485] To the solution of 6-bromo-2-chloro-l -methyl- 17 / -imidazo[4,5-Z?]pyridine (50 mg, 0.20 mmol, 1 equiv) and DIPEA (131 mg, 1.01 mmol, 5 equiv) in ACN (1 mL) was added methylamine hydrochloride (41 mg, 0.61 mmol, 3 equiv). The reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was quenched with H2O (30 mL) and extracted with EA (3 x 30 mL). The combined organic layer was washed with H2O (2 x 10 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-l 1%) to afford the title compound (40 mg, 81%). LCMS m / z [M+H]+241.0.

[0486] Intermediate 58.8-bromo-l-methyl-3,4-dihydropyrido[2,3-&][l,4]oxazepin-2(lH)-oneTN' T) Step 3O'^O

[0487] Step 1. methyl 3-((5-bromo-3-nitropyridin-2-yl)oxy)propanoate

[0488] To a solution of methyl 5-bromo-3-nitropyridin-2-ol (900 mg, 4.11 mmol, 1 equiv, CAS: 15862-34-7) in 1,4-dioxane (10 mL) was added methyl 3-hydroxypropanoate (855 mg, 8.22 mmol, 2 equiv) and triphenylphosphine (1.62 g, 6.16 mmol, 1.5 equiv) at RT. Then diethyl azodicarboxylate (1.07 g, 6.17 mmol, 1.5 equiv) was added at 0 °C under N2 atmosphere. The reaction mixture was stirred at 0 °C for 1 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-10%) to afford the title compound (850 mg, 61%). LCMS m / z [M+H]+305.0.

[0489] Step 2. methyl 3-((3-amino-5-bromopyridin-2-yl)oxy)propanoate

[0490] To a solution of methyl 3-((5-bromo-3-nitropyridin-2-yl)oxy)propanoate (850 mg, 2.79 mmol, 1 equiv) in HO Ac (10 mL) was added Fe (1.56 g, 27.88 mmol, 10 equiv) at RT. The reaction mixture was stirred at 60 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was adjusted to pH = 8-9 with NaHCOs (sat aq 40 mL)131ME1\60337174.v1141039-00120and extracted with EA (100 mL). The combined organic layer was washed with brine, dried over Na2SO4U, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in DCM (0%-15%) to afford the title compound (670 mg, 87%). LCMS m / z [M+H]+275.0.

[0491] Step 3.8-bromo-3,4-dihydropyrido[2,3-&][l,4]oxazepin-2(lH)-one

[0492] To a mixture of methyl 3-((3-amino-5-bromopyridin-2-yl)oxy)propanoate (670 mg, 2.44 mmol, 1 equiv) in toluene (15 mL) was added trimethylaluminium (2.44 mL, 4.88 mmol, 2 equiv, 2M in toluene) at 0 °C under N2 atmosphere. The reaction mixture was stirred for 3 h at RT. The reaction mixture was added to MeOH (5 mL) at 0 °C. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-3%) to afford the title compound (400 mg, 75%). LCMS m / z [M+H]+243.0.

[0493] Step 4.8-bromo-l-methyl-3,4-dihydropyrido[2,3-&][l,4]oxazepin-2(lH)-one

[0494] To a solution of methyl 8-bromo-3,4-dihydropyrido[2,3-Z?][l,4]oxazepin-2(l / f)-one (200 mg, 0.82 mmol, 1 equiv) in DMF (10 mL) was added NaH (40 mg, 0.98 mmol, 1.2 equiv, 60% dispersion in mineral oil) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 h. Then CH3I (116 mg, 0.11 mmol, 1 equiv) was added at 0 °C. The reaction mixture was stirred at RT for 1 h. The reaction mixture was poured into H2O (50 mL) and extracted with EA (3 x 50 mL). The organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (ACN / water / 10 mM NH4HCO3) to afford the title compound (110 mg, 52%). LCMS m / z [M+H]+257.0.

[0495] Intermediate 59.3-bromo-6-methylpyrido[2,3-d]pyridazin-5(6H)-one

[0496] Step 1. ethyl 5-bromo-2-formylnicotinate

[0497] To a solution of ethyl 5-bromo-2-methylnicotinate (500 mg, 2.06 mmol, 1 equiv, CAS: 129477-21-0) in dioxane (5 mL) was added SeC (457 mg, 4.12 mmol, 2 equiv). The reaction mixture was stirred at 130 °C for 4 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EA (3 x 30 mL). The combined organic layer was washed with brine (30 mL), dried over Na2SO4and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-50%) to afford the title compound (320 mg, 61%). LCMS m / z [M+H]+257.9.132ME1\60337174.v1141039-00120

[0498] Step 2.3-bromo-6-methylpyrido[2,3-d]pyridazin-5(6H)-one

[0499] To a solution of ethyl 5-bromo-2-formylnicotinate (270 mg, 1.05 mmol, 1 equiv) in EtOH (5 mL) was added methylhydrazine sulfate (303 mg, 2.10 mmol, 2 equiv). The reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was added H2O (20 mL) and extracted with EA (3 x 30 mL). The combined organic layer was washed with brine (30 mL), dried over Na2SO4and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-50%) to afford the title compound (260 mg, 87%). LCMS m / z [M+H]+240.0.

[0500] Intermediate 60.7-bromo-2-(oxetan-3-yl)phthalazin-l(2H)-one

[0501] Step 1.7-bromo-2-(oxetan-3-yl)phthalazin-l(2H)-one

[0502] To a solution of 7-bromophthalazin-l(2 / / )-one (100 mg, 0.44 mmol, 1 equiv, CAS: 152265-57-1) in DMF (3 mL) was added NaH (36 mg, 0.88 mmol, 2 equiv, 60% dispersion in mineral oil) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 h under N2 atmosphere. Then 3-iodooxetane (123 mg, 0.66 mmol, 1.5 equiv) was added. The reaction mixture was stirred at 80 °C for 6 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EA (3 x 30 mL). The combined organic layer was washed with brine (30 mL), dried over Na2SO4and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-50%) to afford the title compound (45 mg, 36%). LCMS m / z [M+H]+281.0.

[0503] Intermediate 61.6-bromo-l-methyl-l,3-dihydro-2H-pyrrolo[3,2-&]pyridin-2-oneH / Step 1T jT " Y X Y°

[0504] Step 1.6-bromo-l-methyl-l,3-dihydro-2H-pyrrolo[3,2-&]pyridin-2-one

[0505] To a mixture of 6-bromo-l,3-dihydro-2 / Z-pyrrolo[3,2-Z?]pyridin-2-one (200 mg, 0.94 mmol, 1 equiv, CAS: 1190319-62-0), PPI13 (296 mg, 1.13 mmol, 1.2 equiv) and MeOH (36 mg, 1.13 mmol, 1.2 equiv) in DCM (4 mL) was added DIAD (228 mg, 1.13 mmol, 1.2 equiv) drop wise at 0 °C under N2 atmosphere. The reaction mixture was stirred at RT for 1 h. The reaction mixture was quenched with H2O (30 mL) and extracted with EA (3 x 30 mL).133ME1\60337174.v1141039-00120The combined organic layer was washed with brine, dried over Na2SO4and concentrated under reduced pressure. The residue was purified by prep-HPLC (ACN / water / 10 mM NH4HCO3) to afford the title compound (21 mg, 10%). LCMS m / z [M+H]+226.9.

[0506] Intermediate 62.7-bromo-l-methyl-3,4-dihydroquinazolin-2(lH)-oneStep 1.4-bromo-2-(methylamino)benzonitrile

[0507] To a solution of 4-bromo-2-fluorobenzonitrile (1.0 g, 5.0 mmol, 1 equiv, CAS: 105942-08-3) in THF (20 mL) was added DIPEA (6.46 g, 50.0 mmol, 10 equiv) and methylamine hydrochloride (3.38 g, 50.0 mmol, 10 equiv). The reaction mixture was stirred at RT for 8 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with brine (500 mL) and extracted with EA (3 x 600 mL). The combined organic layer was washed with brine, dried over Na2SO4U, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-35%) to afford the title compound (930 mg, 79%). LCMS m / z [M+H]+210.9.

[0508] Step 2.2-(aminomethyl)-5-bromo- V-methylaniline

[0509] To a solution of 4-bromo-2-(methylamino)benzonitrile (500 mg, 2.37 mmol, 1 equiv) in dry THF (5 mL) was added BH3 (11.85 mL, 11.85 mmol, 5 equiv, IM in THF) drop wise at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched with HC1 (6M in H2O, 25 mL) at 0 °C. The mixture was adjusted to pH = 8 with NaOH (IM in H2O) and extracted with EA (3 x 120 mL). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-20%) to afford the title compound (390 mg, 72%). LCMS m / z [M+H]+198.0.

[0510] Step 3.7-bromo-l-methyl-3,4-dihydroquinazolin-2(lH)-one

[0511] To a solution of 2-(aminomethyl)-5-bromo-A-methylaniline (470 mg, 2.19 mmol, 1 equiv) in THF (20 mL) was added DIPEA (849 mg, 6.57 mmol, 3 equiv) and CDI (710 mg, 4.38 mmol, 2 equiv). The reaction mixture was stirred at 50 °C for 2 h. The reaction mixture was diluted with brine (200 mL) and extracted with EA (3 x 250 mL). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue purified by silica gel chromatography eluted with MeOH in DCM (0-10%) to afford the title compound (400 mg, 68%). LCMS m / z [M+H]+241.1.134ME1\60337174.v1141039-00120

[0512] Intermediate 63.3-bromo-6-(methylimino)-6,7-dihydro-5H-6k4-thieno[3,4- / ?]pyridine 6-oxide

[0513] Step 1.3-bromo-5,7-dihydrothieno[3,4-Z>]pyridine 6-oxide

[0514] To a solution of 3-bromo-5,7-dihydrothieno[3,4-Z?]pyridine (200 mg, 0.93 mmol, 1 equiv) in DCM (6 mL) was added m-CPBA (188 mg, 0.93 mmol, 1 equiv, purity: 85%). The reaction mixture was stirred at RT for 16 h. The reaction mixture was added to NaHCOs (sat. aq 80 mL) and extracted with DCM (3 x 15 mL). The combined organic layer was washed with brine, dried over Na2SO4and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-10%) to afford the title compound (184 mg, 72%). LCMS m / z [M+H]+232.0.

[0515] Step 2.3-bromo-6-imino-6,7-dihydro-5H-6k4-thieno[3,4-&]pyridine 6-oxide

[0516] To a solution of 3-bromo-5,7-dihydrothieno[3,4-Z?]pyridine 6-oxide (124 mg, 0.53 mmol, 1 equiv) and DPH (319 mg, 1.60 mmol, 3 equiv) in TFE (4 mL) was added Rh(esp)2 (20 mg, 0.03 mmol. 0.05 equiv) at 0 °C. The reaction mixture was stirred RT for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-5%) to afford the title compound (28 mg, 21%). LCMS m / z [M+H]+247.1.

[0517] Step 3.3-bromo-6-(methylimino)-6,7-dihydro-5H-6k4-thieno[3,4-&]pyridine 6-oxide

[0518] To a solution of 3-bromo-6-imino-6,7-dihydro-5H-6X4-thieno[3,4-Z?]pyridine 6-oxide (18 mg, 0.07 mmol, 1 equiv) and DIPEA (151 mg, 0.98 mmol, 16 equiv) in DCM (8 mL) was added trimethoxonium tetrafluoroborate (87 mg, 0.59 mmol, 8 equiv) drop wise. The reaction mixture was stirred at RT for 6 h under N2 atmosphere. The reaction mixture was diluted with H2O (20 mL) and extracted with DCM (3 x 30 mL). The combined organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-5%) to afford the title compound (6 mg, 32%). LCMS m / z [M+H]+261.0.

[0519] Intermediate 64.6-bromo-l,3,5-trimethyl-l,3-dihydro-2H-imidazo[4,5-&]pyridin-2-one135ME1\60337174.v1141039-00120

[0520] Step 1.6-bromo-l,3,5-trimethyl-l,3-dihydro-2H-imidazo[4,5-&]pyridin-2-one

[0521] To a solution of 6-bromo-5-methyl-l,3-dihydro-2 / Z-imidazo[4,5-Z?]pyridin-2-one (480 mg, 2.10 mmol, 1 equiv, CAS: 116035-73-5) in DMF (10 mL) was added NaH (210 mg, 5.25 mmol, 2.5 equiv, 60% dispersion in mineral oil) at 0 °C. After 10 min, CH3I (717 mg, 5.05mmol, 2.4 equiv) was added at 0 °C. The reaction mixture was stirred at RT for 1 h. The reaction mixture was added to H2O (80 mL) and extracted with EA (3 x 10 mL). The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-50%) to afford the title compound (439 mg, 82%). LCMS m / z [M+H]+256.1.

[0522] Intermediate 65.6-bromo-l,3-dimethyl-l,3-dihydro-[l,2,5]thiadiazolo[3,4- / dpyridine 2,2-dioxide

[0523] Step 1.6-bromo- L3-dihydro-| 1.2,5 ]thiadiazolo| 3.4- / ? Ipyridine 2,2-dioxide

[0524] To a solution of 5-bromopyridine-2,3-diamine (100 mg, 0.54 mmol, 1 equiv, CAS: 38875-53-5) in pyridine (5 mL) was added sulfamide (103 mg, 1.07 mmol, 2 equiv) at RT. The reaction mixture was stirred at 125 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-50%) to afford the crude desired compound which was repurified by slurried with 5% MeOH in DCM (5 mL) to afford the title compound (50 mg, crude). LCMS m / z [M+H]+250.0.

[0525] Step 2.6-bromo-l,3-dimethyl-l,3-dihydro-[l,2,5]thiadiazolo[3,4-&]pyridine 2,2-dioxide

[0526] To a solution of 6-bromo-l,3-dihydro-[l,2,5]thiadiazolo[3,4-Z?]pyridine 2,2-dioxide (550 mg, 2.20 mmol, 1 equiv) in DMF (10 mL) was added NaH (264 mg, 6.60 mmol, 3 equiv, 60% dispersion in mineral oil) at 0 °C. The reaction mixture was sitrred at 0 °C for 0.5 h. Then CH3I (931 mg, 6.60 mmol, 3 equiv) was added at 0 °C. The reaction mixture was sitrred at RT for 3 h. The reaction mixture was added to H2O (100 mL) and extracted with EA (3 x 50 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-l%) to afford the title compound (120 mg, 20%). LCMS m / z [M+H]+278.0.

[0527] Intermediate 66.6-bromo-l,3,7-trimethyl-l,3-dihydro-2H-imidazo[4,5- / ?]pyridin-2-one136ME1\60337174.v1141039-00120

[0528] Step 1.6-bromo-7-methyl-l,3-dihydro-2H-imidazo[4,5-&]pyridin-2-one

[0529] To a solution of 5-bromo-4-methylpyridine-2,3-diamine (300 mg, 1.48 mmol, 1 equiv, CAS: 41230-93-7) and CDI (482 mg, 2.97 mmol, 2 equiv) in THF (5 mL) was added TEA (451 mg, 4.45 mmol, 3 equiv) at RT. The reaction mixture was stirred at 60 °C for 2 h under N2 atmosphere. The reaction mixture was filtered and the filter cake was washed with THF (10 mL). The filter cake was concentrated under reduced pressure to afford the title compound (311 mg, 92%). LCMS m / z [M+H]+228.0.

[0530] Step 2.6-bromo-l,3,7-trimethyl-l,3-dihydro-2H-imidazo[4,5-&]pyridin-2-one

[0531] The 6-bromo-7 -methyl- l,3-dihydro-2 / Z-imidazo[4,5-Z?]pyridin-2-one (250 mg, 1.10 mmol, 1 equiv) and NaH (132 mg, 3.30 mmol, 3 equiv, 60% dispersion in mineral oil) was dissolved in DMF (5 mL). The reaction mixture was stirred at 0 °C for 0. 5 h. Then CH3I (469 mg, 3.30 mmol, 3 equiv) was added. The reaction mixture was stirred at RT for 16 h under N2 atmosphere. The reaction mixture was added to H2O (60 mL) and extracted with EA (3 x 15 mL). The combined organic layer was dried over Na2SO4and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-30%) to afford the title compound (88 mg, 31%). LCMS m / z [M+H]+256.0.

[0532] Intermediate 67.7-br<mio- L4-dimethy 1- L4-dihyd ropy rido| 2,3- / ? Ipyrazine- 2, 3-dione

[0533] Step 1.7-bromo-l,4-dimethyl-l,4-dihydropyrido[2,3-&]pyrazine-2, 3-dione

[0534] To a solution of 7-bromo-l,4-dihydropyrido[2,3-Z?]pyrazine-2, 3-dione (600 mg, 2.48 mmol, 1 equiv, CAS: 168123-82-8) in DMF (8 mL) was added NaH (298 mg, 7.44 mmol, 3 equiv, 60% dispersion in mineral oil) at 0 °C. The reaction mixture was stirred at 0 °C for 0. 5 h. Then CH3I (880 mg, 6.20 mmol, 2.5 equiv) was added. The reaction mixture was stirred at RT for 6 h under N2 atmosphere. The reaction mixture was added to H2O (30 mL) and extracted with EA (3 x 80 mL). The combined organic layer was washed with H2O (2 x 10 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-50%) to afford the title compound (569 mg, 85%). LCMS m / z [M+H]+271.8.137ME1\60337174.v1141039-00120

[0535] Intermediate 68.3-bromo-6-(2-hydroxy-2-methylpropyl)pyrido[2,3-d]pyridazin-5(6H)-one

[0536] Step 1.3-bromo-6-(2-hydroxy-2-methylpropyl)pyrido[2,3-d]pyridazin-5(6H)-one

[0537] To a solution of 3-bromopyrido[2,3-<7]pyridazin-5(6 / f)-one (180 mg, 0.80 mmol, 1 equiv, CAS: 152265-57-1) in DMF (4 mL) was added NaH (48 mg, 1.19 mmol, 1.5 equiv, 60% dispersion in mineral oil) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 h. Then 2,2-dimethyloxirane (172 mg, 2.39 mmol, 3 equiv) was added. The reaction mixture was stirred at 80 °C for 3 h under N2 atmosphere. The reaction mixture was quenched with H2O (30 mL) and extracted with DCM (3 x 10 mL). The combined organic layer was washed with brine (2 x 10 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-50%) to afford the title compound (24 mg, 10%). LCMS m / z [M+H]+298.0.

[0538] Intermediate 69.6-bromo-3-methyl-l-(oxetan-3-ylmethyl)-l,3-dihydro-2H-imidazo[4,5 -b ] pyridin-2-one

[0539] Step 1.5-bromo-2-nitro-2V-(oxetan-3-ylmethyl)pyridin-3-amine

[0540] To a mixture of 5-bromo-3-fluoro-2-nitropyridine (800 mg, 3.62 mmol, 1 equiv, CAS: 1532517-95-5) in THF (30 mL) was added oxetan-3-ylmethanamine (472 mg, 5.43 mmol, 1.5 equiv) and DIPEA (1.40 g, 10.86 mmol, 3 equiv). The reaction mixture was stirred at RT for 2 h. The reaction mixture was concentrated under redued pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-5%) to afford the title compound (950 mg, 91%). LCMS m / z [M+H]+288.0.

[0541] Step 2.5-bromo-2V3-(oxetan-3-ylmethyl)pyridine-2,3-diamine

[0542] To a mixture of 5-bromo-2-nitro-A-(oxetan-3-ylmethyl)pyridin-3-amine (950 mg, 3.30 mmol, 1 equiv) in EtOH (50 mL) and H2O (10 mL) was added Fe (921 mg, 16.50 mmol,138ME1\60337174.v1141039-001205 equiv) and NH4CI (882 mg, 16.50 mmol, 5 equiv). The reaction mixture was stirred at 60 °C for 2 h. The reaction mixture was concentrated under redued pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-5%) to afford the title compound (720 mg, 85%). LCMS m / z [M+H]+258.0.

[0543] Step 3.6-bromo-l-(oxetan-3-ylmethyl)-l,3-dihydro-2H-imidazo[4,5-&]pyridin-2-one

[0544] To a mixture of 5-bromo-A3-(oxetan-3-ylmethyl)pyridine-2,3-diamine (200 mg, 0.78 mmol, 1 equiv) in THF (10 mL) was added CDI (188 mg, 1.17 mmol, 1.5 equiv) and TEA (235 mg, 2.34 mmol, 3 equiv). The reaction mixture was stirred at 50 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-5%) to afford the title compound (200 mg, 92%). LCMS m / z [M+H]+284.1.

[0545] Step 4.6-bromo-3-methyl-l-(oxetan-3-ylmethyl)-l,3-dihydro-2H-imidazo[4,5-&]pyridin-2-one

[0546] To a mixture of 6-bromo-l-(oxetan-3-ylmethyl)-l,3-dihydro-2 / Z-imidazo[4,5-Z?]pyridin-2-one (180 mg, 0.63 mmol, 1 equiv) in DMF (8 mL) was added NaH (76 mg, 1.89 mmol, 3 equiv, 60% dispersion in mineral oil). The reaction mixture was stirred at 0 °C for 0.5 h under N2 atmosphere. Then CH3I (99 mg, 0.69 mmol, 1.1 equiv) was added. The reaction mixture was stirred at RT for 2 h under N2 atmosphere. The reaction mixture was quenched with NH4CI (sat aq) and extracted with EA (3 x 50 mL). The combined organic layer was washed with NaCl (sat aq 150 mL), dried over Na2SO4and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-30%) to afford the title compound (180 mg, 95%). LCMS m / z [M+H]+298.0.

[0547] Intermediate 70.6-bromo-l,3-bis(methyl-d3)-l,3-dihydro-2H-imidazo[4,5-&]pyridin-2-one

[0548] Step 1.6-bromo-l,3-bis(methyl-d3)-l,3-dihydro-2H-imidazo[4,5-&]pyridin-2-one

[0549] To a solution of 6-bromo-l,3-dihydro-2 / Z-imidazo[4,5-Z?]pyridin-2-one (3.0 g, 14.02 mmol, 1 equiv) and NaH (1.40 g, 58.41 mmol, 2.5 equiv, 60% dispersion in mineral139ME1\60337174.v1141039-00120oil) in DMF (30 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. Then CHsLdb (5.08 g, 35.04 mmol, 2.5 equiv) was added. The reaction mixture was stirred at RT for 16 h. The reaction mixture was quenched with H2O (100 mL) and extracted with EA (3 x 300 mL). The combined organic layer was washed with brine (30 mL) and dried over Na2SO4and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-5%) to afford the title compound (2.4 g, 71%). LCMS m / z [M+H]+248.0.

[0550] Intermediate 71.2-(6-bromoimidazo[l,2-a]pyrimidin-2-yl)propan-2-ol

[0551] Step 1. l-bromo-3-hydroxy-3-methylbutan-2-one

[0552] To a solution of 3 -hydroxy-3 -methylbutan-2-one (200 mg, 1.96 mmol, 1 equiv, CAS: 115-22-0) in dioxane (3 mL) was added Bn (376 mg, 2.35 mmol, 1.2 equiv). The reaction mixture was stirred at RT for 2 h. The reaction mixture concentrated under reduced pressure to afford the title compound (250 mg, crude).1H NMR (400 MHz, DMSO-^fc): 5 4.70 (s, 2H), 3.90 - 3.69 (m, 1H), 1.24 (s, 6H).

[0553] Step 2.2-(6-bromoimidazo[l,2-a]pyrimidin-2-yl)propan-2-ol

[0554] To a solution of 5-bromopyrimidin-2-amine (120 mg, 0.69 mmol, 1 equiv) in dioxane (4 mL) was added NaHCCL (145 mg, 1.73 mmol, 2.5 equiv) and l-bromo-3-hydroxy-3-methylbutan-2-one (250 mg, 1.38mmol, 2 equiv). The reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was diluted with brine (50 mL) and extracted with EA (3 x 60 mL). The combined organic layer was washed with brine, dried over Na2SO4U, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with EA in PE (0%-20%) to afford the title compound (50 mg, 28%). LCMS m / z [M+H]+256.0.

[0555] Intermediate 72.6-bromo-3-(oxetan-3-yl)oxazolo[4,5-Z>]pyridin-2(3H)-oneStep 1.5-bromo-2-(oxetan-3-ylamino)pyridin-3-ol

[0556] To a solution of 5-bromo-2-fluoropyridin-3-ol (500 mg, 2.60 mmol, 1 equiv, CAS: 1012084-53-5) in oxetan-3-amine (1 mL) was added DIPEA (1.01 g, 0.78 mmol, 3 equiv). The reaction mixture was stirred at 120 °C for 48 h. The reaction mixture was added140ME1\60337174.v1141039-00120to H2O (30 mL) and extracted with EA (3 x 80 mL). The combined organic layer was washed with H2O (2 x 10 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-50%) to afford the title compound (150 mg, 21%). LCMS m / z [M+H]+245.0.

[0557] Step 2.6-bromo-3-(oxetan-3-yl)oxazolo[4,5-Z>]pyridin-2(3H)-one

[0558] To a solution of 5-bromo-2-(oxetan-3-ylamino)pyridin-3-ol (130 mg, 0.53 mmol, 1 equiv) and CDI (173 mg, 1.07 mmol, 2 equiv) in THF (4 mL) was added TEA (162 mg, 1.60 mmol, 3 equiv) at RT. The reaction mixture was stirred at 60 °C for 16 h. The reaction mixture was added to H2O (30 mL) and extracted with EA (3 x 80 mL). The combined organic layer was washed with H2O (2 x 10 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-50%) to afford the title compound (136 mg, 82%). LCMS m / z [M+H]+270.4

[0559] Intermediate 73.3-bromo-7,8,8-trimethyl-5,6,7,8-tetrahydro-l,7-naphthyridine

[0560] Step 1. tert-butyl 3-bromo-5,8-dihydro-l,7-naphthyridine-7(6H)-carboxylate

[0561] To a mixture of 3-bromo-5,6,7,8-tetrahydro-l,7-naphthyridine dihydrochloride (500 mg, 1.75 mmol, 1 equiv, CAS: 2177267-75-1) in DCM (10 mL) was added Et3N (531 mg, 5.24 mmol, 3 equiv) and (Boc)2O (572 mg, 2.62 mmol, 1.5 equiv). The reaction mixture was stirred at RT for 1 h under N2 atmosphere. The reaction mixture was quenched with H2O (50 mL) and extracted with DCM (3 x 50 mL). The combined organic layer was washed with brine, dried over Na2SO4. After filtration, the organic layer was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluted with EA in PE (0%-20%) to affor the title compound (470 mg, 86%). LCMS m / z (M - tBu + H)+257.1.

[0562] Step 2. tert-butyl 3-bromo-8,8-dimethyl-5,8-dihydro-l,7-naphthyridine-7(6H)-carboxylate

[0563] To a mixture of tert-butyl 3-bromo-5,8-dihydro-l,7-naphthyridine-7(6 / f)-carboxylate (385 mg, 1.23 mmol, 1 equiv) in THF (5 mL) was added LDA (1.26 mL, 2.52 mmol, 2.05 equiv, 2M in THF) at -78 °C under reduced pressure. The reaction mixture was141ME1\60337174.v1141039-00120stirred at -78 °C for 0.5 h under N2 atmosphere. Then CH3I (358 mg, 2.52 mmol, 2.05 equiv) was added. The reaction mixture was stirred at -78 °C for 0.5 h under N2 atmosphere. The reaction mixture was quenched with H2O (20 mL) and extracted with EA (3 x 30 mL). The combined organic layer was washed with brine, dried over Na2SO4. After filtration, the organic layer was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluted with EA in PE (0%-10%) to afford the title compound (140 mg, 33%). LCMS m / z [M+H]+341.2.

[0564] Step 3.3-bromo-8,8-dimethyl-5,6,7,8-tetrahydro-l,7-naphthyridine

[0565] To a solution of tert-butyl 3-bromo-8,8-dimethyl-5,8-dihydro-l,7-naphthyridine- 7(6 / / )-carboxylate (115 mg, 0.34 mmol, 1 equiv) in DCM (2 mL) was added TFA (1 mL). The reaction mixture was stirred at RT for 1 h. The reaction mixture was concentrated under reduced pressure to afford the title compound (110 mg, crude, TFA salt). LCMS m / z [M+H]+241.1.

[0566] Step 4.3-bromo-7,8,8-trimethyl-5,6,7,8-tetrahydro-l,7-naphthyridine To a solution of 3-bromo-8,8-dimethyl-5,6,7,8-tetrahydro-l,7-naphthyridine (110 mg, crude, TFA salt, 0.34 mmol, 1 equiv) in MeOH (5 mL) was added paraformaldehyde (103 mg, 3.44 mmol, 10 equiv) and NaBH(OAc)3 (730 mg, 3.44 mmol, 10 equiv). The reaction mixture was stirred at 60 °C for 16 h. The reaction mixture was quenched with NaHCO3(sat. aq 50 mL) and extracted with DCM (3 x 50 mL). The combined organic layer was washed with brine, dried over Na2SO4. After filtration, the organic layer was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluted with MeOH in DCM (0%-10%) to afford the title compound (58 mg, 67% over two steps). LCMS m / z [M+H]+255.0.

[0567] Intermediate 74. (6,7,7-trimethyl-6,7-dihydro-5H-pyrrolo[3,4-&]pyridin-3-yl)boronic acid

[0568] Step 1. V-methoxy-3-methylisothiazole-4-carboxamide

[0569] To a solution of ethyl 5-bromo-2-methylnicotinate (500 mg, 2.05 mmol, 1 equiv, CAS: 129477-21-0) and NBS (438 mg, 2.46 mmol, 1.2 equiv) in CCI4 (10 mL) was added AIBN (67 mg, 0.41 mmol, 0.2 equiv). The reaction mixtue was stirred at 80 °C for 0.5 h142ME1\60337174.v1141039-00120under N2 atmosphere. The reaction mixture was quenched with H2O (20 mL) and extracted with EA (3 x 30 mL). The combined organic layer was washed with brine (30 mL) and dried over Na2SO4and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-10%) to afford the title compoound (400 mg, 61%). LCMS m / z [M+H]+323.8.

[0570] Step 2.3-bromo-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-&]pyridin-5-one

[0571] To a solution of ethyl 5-bromo-2-(bromomethyl)nicotinate (400 mg, 8.20 mmol, 1 equiv) in MeOH (4 mL) was added MeNH2(7 mL, 30% in ethanol). The reaction mixture was stirred at RT for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-10%) to afford the title compound (250 mg, 89%). LCMS m / z [M+H]+227.0.

[0572] Step 3.3-bromo-6,7,7-trimethyl-6,7-dihydro-5H-pyrrolo[3,4-&]pyridin-5-one

[0573] To a solution of 3-bromo-6-methyl-6,7-dihydro-5 / Z-pyrrolo[3,4-Z?]pyridin-5-one (250 mg, 1.10 mmol, 1 equiv) in DMF (15 mL) was added NaH (88 mg, 2.20 mmol, 2 equiv, 60% dispersion in mineral oil). The reaction mixture was stirred at 0 °C for 0.5 h under N2 atmosphere. Then CH3I (391 mg, 2.75 mmol, 2.5 equiv) was added. The reaction mixture was stirred at RT for 2 h. The reaction mixture was quenched with H2O (50 mL) and extracted with EA (3 x 150 mL). The combined organic layer was washed with brine (50 mL), dried over Na2SO4and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0%-30%) to afford the title compound (180 mg, 64%). LCMS m / z [M+H]+255.1.

[0574] Step 4.3-bromo-6,7,7-trimethyl-6,7-dihydro-5H-pyrrolo[3,4-&]pyridine

[0575] To a solution of 3-bromo-6,7,7-trimethyl-6,7-dihydro-5 / Z-pyrrolo[3,4-Z?]pyridin-5-one (150 mg, 0.59 mmol, 1 equiv) in DCM (30 mL) was added Tf2O (498 mg, 1.77 mmol, 3 equiv). The reaction mixture was stirred at RT for 1 h under N2 atmosphere. Then hantzschester (747 mg, 2.94 mmol, 5 equiv) was added. The reaction mixture was stirred at RT for 2 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-10%) to afford the title compound (50 mg, 35%). LCMS m / z [M+H]+241.1.

[0576] Intermediate 75. Tert-butyl (S)-l-(2-(2-hydroxyethoxy)ethyl)-2-iodo-4-methyl-l,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate143ME1\60337174.v1141039-00120

[0577] Step 1. tert-butyl (2S)-3-cyano-4-hydroxy-2-methylpiperidine- 1 -carboxy late

[0578] To a solution of tert-butyl (2S)-3-cyano-2-methyl-4-oxopiperidine-l-carboxylate (50 g, 209.83 mmol, 1 equiv CAS: 2212021-56-0) in EtOH (500 mL) was added NaBH4(7.94 g, 209.83 mmol, 1 equiv) at 0 °C. The resulting mixture was stirred at RT for 16 h. The reaction mixture was quenched with H2O (300 mL). The reaction mixture was concentrated under reduced pressure to remove EtOH. The resulting mixture was extracted with DCM (5 x 500 mL). The combined organic layers were dried over Na2SO4and concentrated under reduced pressure to afford the crude title compound (50 g). LCMS m / z (M-t-Bu+H)+185.1.

[0579] Step 2. tert-butyl (2S)-3-carbamoyl-4-hydroxy-2-methylpiperidine-l-carboxylate

[0580] To a solution of tert-butyl (2S)-3-cyano-4-hydroxy-2-methylpiperidine-l-carboxylate (48.60 g, crude, 202.28 mmol, 1 equiv) in EtOH (500 mL) was added K2CO3(27.95 g, 202.28 mmol, 1 equiv), DMSO (79.01 g, 1.01 mol, 5 equiv) and H2O2(57.32 g, 505.62 mmol, 2.5 equiv 30 wt. %) dropwise at 0 °C. The reaction mixture was stirred at RT for 16 h, and then was quenched with Na2SO3(sat aq 500 mL) and diluted with H2O (1 L). The mixture was extracted with EA (6 x 500 mL). The combined organic layers were dried over Na2SO4and concentrated under reduced pressure to afford the title compound (52 g, crude). LCMS m / z (M-t-Bu+H)+203.1.

[0581] Step 3. tert-butyl (4S)-4-methyl-2-oxohexahydrooxazolo[4,5-c ]pyridine-5(4H)-carboxylate

[0582] To a solution of tert-butyl (2S)-3-carbamoyl-4-hydroxy-2-methylpiperidine-l-carboxylate (50.0 g, 193.56 mmol, 1 equiv) in ACN (500 mL) was added PhI(OAc)2 (74.81 g, 232.27 mmol, 1.2 equiv) at RT. The reaction mixture was stirred at 50 °C for 3 h. The reaction mixture was concentrated under reduced pressure to afford the title compound (117 g, crude, about 40% purity). LCMS m / z (M-t-Bu+H)+201.1.144ME1\60337174.v1141039-00120

[0583] Step 4. tert-butyl (2S)-3-amino-4-hydroxy-2-methylpiperidine-l -carboxy late

[0584] To a solution of tert-butyl (4S)-4-methyl-2-oxohexahydrooxazolo[4,5-c]pyridine-5(4 / f)-carboxylate (20 g, crude, 78.03 mmol, 1 equiv) in EtOH (200 mL) and H2O (100 mL) was added NaOH (7.80 g, 195.08 mmol, 2.5 equiv) at RT. The reaction mixture was stirred at 80 °C for 10 h. The reaction mixture was concentrated under reduced pressure. The residue was adjusted to pH = 2 with HCl (1M in H2O). The mixture was extracted with DCM (3 x 200 mL). The crude desired compound was in the aqueous phase and impurities in the DCM phase. Then the aqeous phase was adjusted to pH = 14 with NaOH (sat aq) and extracted with DCM (5 x 200 mL). The combined organic layer was dried over Na2SO4and concentrated under reduced pressure to afford the title compound (7.43 g, 89% for three steps). LCMS m / z [M+H]+231.2.

[0585] Step 5. tert-butyl (2S)-3-formamido-4-hydroxy-2-methylpiperidine-l-carboxylateTo a solution of tert-butyl (2S)-3-amino-4-hydroxy-2-methylpiperidine-l-carboxylate (9.40 g, 40.81 mmol, 1 equiv) in MeOH (100 mL) was added methyl formate (12.25 g, 204.07 mmol, 5 equiv) and NaOMe (1.76 g, 32.65 mmol, 0.8 equiv). The reaction mixture was stirred at 50 °C for 4 h under N2 atmosphere. The reaction mixture was added to H2O (100 mL) and extracted with DCM (3 x 100 mL). The combined organic layer was washed with brine (100 mL), dried over Na2SO4and filtered. The filtrate was concentrated under reduced pressure to afford the title compound (10.50 g, crude). LCMS m / z (M-t-Bu+H)+203.1.

[0586] Step 6. tert-butyl (2S)-3-formamido-2-methyl-4-oxopiperidine- 1 -carboxy late

[0587] To a solution of tert-butyl (2S)-3-formamido-4-hydroxy-2-methylpiperidine-l-carboxylate (10.50 g, crude, 40.65 mmol, 1 equiv) in DCM (100 mL) was added Dess-Martin periodinane (25.86 g, 60.97 mmol, 1.5 equiv, CAS : 87413-09-0) at 0 °C. The reaction mixture was stirred at RT for 4 h under N2 atmosphere. The reaction mixture was filtered and the filter cake was washed with DCM (3 x 100 mL). The combined filtrate was washed with NaOH (IM in H2O) (3 x 200 mL), dried over Na2SO4and concentrated under reduced pressure to afford the title compound (6.3 g, crude). LCMS m / z (M–t-Bu + H)+201.1.

[0588] Step 7. tert-butyl (S)-l-(2-(2-hydroxyethoxy)ethyl)-4-methyl-l, 4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate

[0589] To a solution of tert-butyl (2S)-3-formamido-2-methyl-4-oxopiperidine-l-carboxylate (5.30 g, 20.68 mmol, 1 equiv) in xylene (50 mL) was added 2-(2-aminoethoxy)ethan-l-ol (3.26 g, 31.01 mmol, 1.5 equiv) and HOAc (621 mg, 10.34 mmol, 0.5 equiv). The reaction mixture was stirred at 150 °C for 1 h under N2 atmosphere. The 145ME1\60337174.v1141039-00120reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-5%) to afford the title compound (6.6 g, 98%). LCMS m / z [M+H]+326.3.

[0590] Step 8. tert-butyl (S)-l-(2-(2-hydroxyethoxy)ethyl)-2-iodo-4-methyl-l, 4,6,7- tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate

[0591] To a solution of tert-butyl (S)-l-(2-(2-hydroxyethoxy)ethyl)-4-methyl-l,4,6,7- tetrahydro-5 / Z-imidazo[4,5-c]pyridine-5-carboxylate (1.12 g, 3.44 mmol, 1 equiv) in DMF (20 mL) was added NIS (2.32 g, 10.32 mmol, 3 equiv). The reaction mixture was stirred at 80 °C for 2 h under N2 atmosphere. The reaction mixture was poured into Na2CO3(sat aq 50 mL) and extracted with EA (3 x 50 mL). The combined organic layer was washed with brine (50 mL), dried over Na2SO4and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0%-6%) to afford the title compound (980 mg, 63%). LCMS m / z [M+H]+452.2.

[0592] Intermediate 76-1. (14-2) (6-(3-hydroxy-3-methylazetidin-l-yl)pyridin-3- yl)boronic acid

[0593] Step 1. (6-(3-hydroxy-3-methylazetidin-l-yl)pyridin-3-yl)boronic acid

[0594] To a solution of 2-fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (50 mg, 0.22 mmol, 1 equiv, CAS: 444120-95-0) and 3-methylazetidin-3-ol hydrochloride (42 mg, 0.34 mmol, 1.5 equiv) in DMSO (2 mL) was added DIPEA (145 mg, 1.12 mmol, 5 equiv). The reaction mixture was stirred at 100 °C for 1 h under N2 atmosphere. The reaction mixture was purified by prep-HPLC (ACN / water / 10 mM NH4HCO3) to afford the title compound (54 mg, crude). LCMS m / z [M+H]+209.0.

[0595] The examples in the table below were synthesized as described for Intermediate 76 from appropriate starting materials.Int. LCMS m / z Structure IUPAC NameNo. [M+H]+146ME1\60337174.v1141039-00120HOXJDHB(S)-(6-(3-hydroxy-3-methylpyrrolidin-l- 76-2 223.1 yl)pyridin-3-yl)boronic acid.0HO' JHOXOHB(7?)-(6-(3-hydroxy-3-methylpyrrolidin-l- 76-3 222.7$ yl)pyridin-3-yl)boronic acidHO<7OxxoB2-(3-methoxyazetidin-l-yl)-5-(4, 4,5,5- 76-4 291.1 tetramethyl- 1,3,2-dioxaborolan-2-yl)pyridineO\7OxxoB2-(azetidin-l-yl)-5-(4, 4,5, 5-tetramethyl- 1,3,2- 76-5 260.8 dioxaborolan-2-yl)pyridineNHOX. OHB(6-(3-fluoroazetidin-l-yl)pyridin-3-yl)boronic76-6 197.1 acidF147ME1\60337174.v1141039-00120148 ME1\60337174.v1141039-00120(17?,5S)-8-(5-(4,4,5,5-tetramethyl-l,3,2- 76-12 dioxaborolan-2-yl)pyridin-2-yl)-3-oxa-8- 235.1azabicyclo[3.2. l]octaneHOXOHB(6-(4-hydroxy-4-methylpiperidin- 1 -yl)pyridin- 76-13 237.13-yl)boronic acidQOs xOB(S)-3-methyl-l-(3-methyl-5-(4, 4,5,5- 76-14 tetramethyl- 1,3,2-dioxaborolan-2-yl)pyridin-2- 319.1Ayl)pyrrolidin-3 -olpHO' | AS / X / °'"1 v o m v z— —z o X-2 / \=Z"X

[0596] Example 1. l-(6-fluoro-17-((2-(2-hydroxypropan-2-yl)pyridin-4-yl)ethynyl)- 9,10,12,14-tetrahydro-13H-benzo[^]pyrrolo[3',4':4,5]imidazo[l,2- d]thieno[2',3':4,5]pyrido[2,3- / ][l,4]oxazonin-13-yl)prop-2-en-l-one149ME1\60337174.v1141039-00120

[0597] Step 1. tert-butyl 2-(7-(2-(benzyloxy)-4-fluorophenyl)-4-((2-(2-hydroxypropan-2-yl)pyridin-4-yl)ethynyl)thieno[3,2-c]pyridin-6-yl)-l-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(lH)-carboxylate

[0598] To a solution of tert-butyl 2-(7-(2-(benzyloxy)-4-fluorophenyl)-4-((2-(2-hydroxypropan-2-yl)pyridin-4-yl)ethynyl)thieno[3,2-c]pyridin-6-yl)-4,6-dihydropyrrolo[3,4-<7]imidazole-5(l / f)-carboxylate (150 mg, 0.18 mmol) and 2-(4-ethynylpyridin-2-yl)propan-2-ol (45 mg, 0.27 mmol, 1.5 eq.) in DMF (5 mL) was added Pd(dppf)Ch (27 mg, 0.04 mmol, 0.2 eq.) and Cui (7.0 mg, 0.04 mmol, 0.2 eq.) and Cs2CO3(178 mg, 0.54 mmol, 3.0 eq.). The tube was capped and purged with N2 three times. The resulting mixture was heated to 100 °C for 2 h. The reaction mixture was poured into water (20 mL) and extracted with DCM (3 x 60 mL). The combined organic phase was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography, eluted with MeOH in DCM (0%-30%) to afford the title compound (55 mg). LCMS m / z [M+H]+832.2.

[0599] Step 2.5-fluoro-2-(4-((2-(2-hydroxypropan-2-yl)pyridin-4-yl)ethynyl)-6-(l,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)thieno[3,2-c]pyridin-7-yl)phenol

[0600] The solution of tert-butyl 2-(7-(2-(benzyloxy)-4-fluorophenyl)-4-((2-(2-hydroxypropan-2-yl)pyridin-4-yl)ethynyl)thieno[3,2-c]pyridin-6-yl)-l-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(l / f)-carboxylate (55 mg, 0.07 mmol) in TFA (2 mL) was stirred for 3 h at 80 °C. The solvent was removed in vacuo to afford the title compound (60 mg, crude, TFA salt). LCMS m / z+[M+H]512.1.

[0601] Step 3. tert-butyl 2-(7-(4-fluoro-2-hydroxyphenyl)-4-((2-(2-hydroxypropan-2-yl)pyridin-4-yl)ethynyl)thieno[3,2-c]pyridin-6-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(lH)-carboxylate

[0602] To a solution of 5-fluoro-2-(4-((2-(2-hydroxypropan-2-yl)pyridin-4-yl)ethynyl)-6-(l,4,5,6-tetrahydropyrrolo[3,4-<7]imidazol-2-yl)thieno[3,2-c7pyridin-7-yl)phenol (60 mg, 0.12 mmol) and TEA (119 mg, 1.2 mmol, 10.0 eq.) in DCM (2 mL) was added BOC2O (13 mg, 0.06 mmol, 0.5 eq.). The reaction was stirred for 1 h at RT. The reaction was poured into water (10 mL) and extracted with DCM (3 x 30 mL). The combined organic phase was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-TLC to afford the title compound (36 mg). LCMS m / z+[M+H]612.0.150ME1\60337174.v1141039-00120

[0603] Step 4. tert-butyl 6-fluoro-17-((2-(2-hydroxypropan-2-yl)pyridin-4-yl)ethynyl)-9,10,12,14-tetrahydro-13H-benzo[ / i]pyrrolo[3',4':4,5]imidazo[l,2-d]thieno[2',3':4,5]pyrido[2,3- / ][l,4]oxazonine-13-carboxylate

[0604] To a solution of tert-butyl 2-(7-(4-fluoro-2-hydroxyphenyl)-4-((2-(2-hydroxypropan-2-yl)pyridin-4-yl)ethynyl)thieno[3,2-c]pyridin-6-yl)-4,6-dihydropyrrolo[3,4-<7]imidazole-5(l / f)-carboxylate (40 mg, 0.07 mmol) and K2CO3(27 mg, 0.20 mmol) in DMF (2 mL) was added 1,2-dibromoethane (14 mg, 0.07 mmol). The reaction was stirred for 2 h at 80 °C. The reaction was diluted with water (10 mL) and extracted with EA (3 x 30 mL). The combined organic phase was washed with brine (50 mL), dried over Na2SO4E, filtered and concentrated in vacuo. The residue was purified by prep-TLC (5% MeOH in DCM) to afford the title compound (22 mg). LCMS m / z+[M+H]638.7.

[0605] Step 5.2-(4-((6-fluoro-9,10,13,14-tetrahydro-12H-benzo[^]pyrrolo[3',4':4,5]imidazo[l,2-d]thieno[2',3':4,5]pyrido[2,3- / ][l,4]oxazonin-17-yl)ethynyl)pyridin-2-yl)propan-2-ol

[0606] To a solution of tert-butyl 6-fluoro-17-((2-(2-hydroxypropan-2-yl)pyridin-4-yl)ethynyl)-9,10,12,14-tetrahydro-13 / Z-benzo[ / z]pyrrolo[3',4':4,5]imidazo[l,2-<7]thieno[2',3':4,5]pyrido[2,3- / |[l,4]oxazonine-13-carboxylate (20 mg, 0.03 mmol) in DCM (1 mL) was added TFA (1 mL). The reaction was stirred for 1 h at RT. The solvent was removed in vacuo to afford the title compound (16 mg, crude, TFA salt). LCMS m / z+[M+H]538.5.

[0607] Step 6. l-(6-fluoro-17-((2-(2-hydroxypropan-2-yl)pyridin-4-yl)ethynyl)-9,10,12,14-tetrahydro-13H-benzo[ / i]pyrrolo[3',4':4,5]imidazo[l,2-d]thieno[2',3':4,5]pyrido[2,3- / ][l,4]oxazonin-13-yl)prop-2-en-l-one

[0608] To a solution of 2-(4-((6-fluoro-9,10,13,14-tetrahydro-12 / Z-benzo[A]pyrrolo[3',4':4,5]imidazo[l,2-<7]thieno[2',3':4,5]pyrido[2,3- / |[l,4]oxazonin-17-yl)ethynyl)pyridin-2-yl)propan-2-ol (20 mg, 0.04 mmol) and DIPEA (48 mg, 0.40 mmol) in ACN (2 mL) was added acrylic anhydride (5 mg, 0.04 mmol). The reaction was stirred for 10 min at RT. The mixture was purified by prep-HPLC (ACN / water / 10 mM NH4HCO3) to afford the title compound (7.65 mg). LCMS m / z+[M+H]592.0.

[0609] The compounds in the table below were synthesized as described for Example 1 from appropriate starting materials.151ME1\60337174.v1141039-00120

[0610] Ex. Structure IUPAC Name,1H NMR, MSl-(6-fluoro-19-((2-(2-hydroxypropan-2-yl)pyridin-4-yl)ethynyl)- 9,10,ll,12,14,16-hexahydro-15H- (Racemic mixturebenzo[j]pyrrolo[3',4':4,5]imidazo[l,2- of atropisomersf]thieno[2',3':4,5]pyrido[2,3-h][l]oxa[6]azacycloundecin-15- shown below)yl)prop-2-en-l-one’H NMR (400 MHz, DMSO-6) δ 8.63 (d, J = 5.0 Hz, 1H), 8.19 (d, J = 5.6 Hz, 1H), 7.94 (d, J = 5.6 Hz, 2H), 7.66 (dd, J = 8.2, 6.7 Hz, 1H), 7.58 (dd, J = 5.0, 1.4 Hz, 1H), 6.93 (t, J = 8.2 Hz, 1H), 6.85 (d, J = 11.2 Hz, 1H), 6.72-6.57 (m, 1H), 6.26 - 6.19 (m, 1H), 5.78-5.71 (m, 1H), 5.37 (s, 1H), 4.94 (dd, J = 46.6, 12.0 Hz, 1H), 4.68 (s, 1H), 4.46 (s, 1H), 4.18 (t, J = 13.2 Hz, 2H), 4.02 (d, J = 4.8 Hz, 2H), 3.46 (d, J = 24.4 Hz, 1H), 1.92 (s, 2H), 1.64 (s, 2H), 1.48 (s, 6H), LCMS m / z+[M+H] 620.0.l-(6-fluoro-20-((2-(2-hydroxypropan-2-yl)pyridin-4-yl)ethynyl)- 9,10,ll,12,16,17-hexahydrobenzo[j]pyrido[4',3':4,5]imidazo[l,2- f]thieno[2',3':4,5]pyrido[2,3-h][l]oxa[6]azacycloundecin- 1-2 15(14H)-yl)prop-2-en-l-one’H NMR (400 MHz, DMSO-6) 88.64-8.62 (m, 1H), 8.17 - 8.15 (m, 1H), 7.92 - 7.91 (m, 2H), 7.71 - 7.66 (m, 1H), 7.58 - 7.56 (m, 1H), 7.05 - 6.81 (m, 3H), 6.20 - 5.94 (m, 1H), 5.73 - 5.64 (m, 1H),152ME1\60337174.v1141039-00120(inseparable 5.37 (s, 1H), 4.89 - 4.63 (m, 1H), 4.45 - 4.30 (m, 1H), 4.22 - 4.17 mixture of four (m, 1H), 4.15 - 4.11 (m, 1H), 4.10 – 4.01 (m, 2H), 3.84 - 3.84-3.67 compounds - (m, 1H), 3.55 - 3.40 (m, 1H), 3.12 - 3.04 (m, 1H), 2.90 - 2.71 (m, 7X / — °Z=zregiois / ^^2omz z- — ers and 1H), 1.85 - 1.77 (m, 2H), 1.69 - 1.55 (m, 2H), 1.48 (s, 6H), LCMS atropisomers) m / z+[M+H]633.7.A l-(6-fluoro-17-((2-(2-hydroxypropan-2-yl)pyridin-4-yl)ethynyl)- 9,10,12,14-tetrahydro-13H- benzo[h]pyrrolo[3',4':4,5]imidazo[l,2- d]thieno[2',3':4,5]pyrido[2,3-f][l,4]oxazonin-13-yl)prop-2-en-l- F.one / ?IL N—1H NMR (400 MHz, DMSO-6) 88.64 (d, J = 5.0 Hz, 1H), 8.23 (d, J VU \=-3 = 5.6 Hz, 1H), 7.99 (d, J = 5.6 Hz, 1H), 7.94 (s, 1H), 7.59 (dd, J =II5.0, 1.6 Hz, 1H), 7.51 - 7.45 (m, 1H), 7.10 (d, J = 10.0 Hz, 1H), uu 7.06 - 6.98 (m, 1H), 6.59 (dt, J = 16.8, 10.2 Hz, 1H), 6.22 (dd, J =N16.8, 2.4 Hz, 1H), 5.80 - 5.71 (m, 1H), 5.39 (s, 1H), 4.92 - 4.75 (m, 1H), 4.59 (d, J = 10.6 Hz, 1H), 4.54 (s, 1H), 4.49 - 4.40 (m, 1H), 4.35 -4.14 (m, 3H), 4.10 - 4.02 (m, 1H), 1.48 (s, 6H), LCMS m / z+[M+H]592.0.l-(6-fluoro-18-((2-(2-hydroxypropan-2-yl)pyridin-4-yl)ethynyl)- 10,ll,13,15-tetrahydro-9H,14H- benzo[i]pyrrolo[3',4':4,5]imidazo[l,2- e]thieno[2',3':4,5]pyrido[2,3-g][l,5]oxazecin-14-yl)prop-2-en-l- one1H NMR (400 MHz, DMSO-6) δ 8.63 (d, J = 5.2 Hz, 1H), 8.22 (d, J -4 = 5.6 Hz, 1H), 7.97 - 7.92 (m, 2H), 7.74 - 7.68 (m, 1H), 7.58 (d, J =5.0 Hz, 1H), 7.03 (dd, J = 10.8, 6.2 Hz, 2H), 6.68 - 6.58 (m, 1H), 6.26 - 6.20 (m, 1H), 5.81 - 5.70 (m, 1H), 5.37 (s, 1H), 4.92 (dd, J = 36.2, 12.2 Hz, 1H), 4.67 (s, 1H), 4.54 (s, 1H), 4.48 (d, J = 5.6 Hz, 1H), 4.33 -4.11 (m, 2H), 3.92 (dd, J = 20.6, 10.8 Hz, 1H), 2.78 (dd, J = 16.8, 7.2 Hz, 1H), 2.13 (s, 2H), 1.48 (s, 6H), LCMS m / z+[M+H] 606.2.153ME1\60337174.v1141039-00120l-(4,6-difluoro-20-((2-(2-hydroxypropan-2-yl)pyridin-4- yl)ethynyl)-9,10,ll,12,14,17- hexahydrobenzo[j]pyrido[3',4':4,5]imidazo[l,2- f]thieno[2',3':4,5]pyrido[2,3-h][l]oxa[6]azacycloundecin- 16(15H)-yl)prop-2-en-l-one’H NMR (400 MHz, DMSO-6) 88.64 (d, J = 5.0 Hz, 1H), 8.18 (d, J -5= 5.2 Hz, 1H), 7.95 - 7.90 (m, 2H), 7.59 (dd, J = 5.0, 1.4 Hz, 1H), 7.06 (t, J = 9.4 Hz, 1H), 6.96 - 6.75 (m, 2H), 6.18 - 6.06 (m, 1H), 5.76 - 5.63 (m, 1H), 5.39 (s, 1H), 4.49 - 4.14 (m, 3H), 4.12 - 4.00 (m, 3H), 3.56 - 3.40 (m, 1H), 3.26 - 3.14 (m, 1H), 2.84 - 2.71 (m, 2H), 1.80 - 1.70 (m, 2H), 1.69 - 1.50 (m, 2H), 1.48 (s, 6H), LCMS m / z+[M+H]652.4.l-(4,6-difluoro-20-((l-methyl-lH-pyrazol-3-yl)ethynyl)- 9,10,ll,12,14,17-hexahydrobenzo[j]pyrido[3',4':4,5]imidazo[l,2- f]thieno[2',3':4,5]pyrido[2,3-h][l]oxa[6]azacycloundecin- 16(15H)-yl)prop-2-en-l-one’H NMR (400 MHz, DMSO-6) 88.13 (d, J = 5.6 Hz, 1H), 7.87 (d, J -6 = 2.2 Hz, 1H), 7.76 (d, J = 5.6 Hz, 1H), 7.04 (t, J = 9.6 Hz, 1H), 6.95II - 6.76 (m, 2H), 6.75 (d, J = 2.4 Hz, 1H), 6.17 - 6.05 (m, 1H), 5.76 - 5.60 (m, 1H), 4.48 - 4.13 (m, 3H), 4.12 - 3.98 (m, 3H), 3.93 (s, 3H), 3.55 - 3.43 (m, 1H), 3.22 - 3.10 (m, 1H), 2.83 - 2.69 (m, 2H), 1.84 - 1.68 (m, 2H), 1.67 - 1.56 (m, 1H), 1.54 - 1.42 (m, 1H), LCMS m / z+[M+H]597.3.l-(4,6-difluoro-20-((l-(2-hydroxy-2-methylpropyl)-lH-pyrazol- 4-yl)ethynyl)-9,10,ll,12,14,17- hexahydrobenzo[j]pyrido[3',4':4,5]imidazo[l,2- f]thieno[2',3':4,5]pyrido[2,3-h][l]oxa[6]azacycloundecin--7 16(15H)-yl)prop-2-en-l-one1H NMR (400 MHz, DMSO-6) 88.22 (s, 1H), 8.09 (d, J = 5.6 Hz, 1H), 7.90 (s, 1H), 7.83 (d, J = 5.6 Hz, 1H), 7.03 (t, J = 9.6 Hz, 1H), 6.94 - 6.74 (m, 2H), 6.20 - 6.04 (m, 1H), 5.79 - 5.61 (m, 1H), 4.79 (s, 1H), 4.45 - 4.20 (m, 2H), 4.18 - 4.00 (m, 6H), 3.53 - 3.44 (m,154ME1\60337174.v1141039-001201H), 3.23 - 3.09 (m, 1H), 2.79 - 2.70 (d, J = 16.6 Hz, 2H), 1.78 - 1.44 (m, 4H), 1.09 (d, J = 1.6 Hz, 6H), LCMS m / z+[M+H]655.5. l-(4,6-difluoro-20-(3-(4-methylpiperazin-l-yl)prop-l-yn-l-yl)- 9,10,ll,12,14,l’7-hexahydrobenzo[j]pyrido[3',4':4,5]imidazo[l,2- f]thieno[2',3':4,5]pyrido[2,3-h][l]oxa[6]azacycloundecin- 16(15H)-yl)prop-2-en-l-one’H NMR (400 MHz, DMSO-6) 88.10 (d, J = 5.4 Hz, 1H), 7.67 (d, J -8= 5.4 Hz, 1H), 7.02 (t, J = 9.6 Hz, 1H), 6.94 - 6.73 (m, 2H), 6.16 - 6.05 (m, 1H), 5.76 - 5.59 (m, 1H), 4.48 - 4.11 (m, 3H), 4.09 - 3.99 (m, 3H), 3.72 (s, 2H), 3.53 - 3.43 (m, 1H), 3.22 - 3.12 (m, 1H), 2.80 - 2.71 (m, 2H), 2.66 - 2.53 (m, 5H), 2.44 - 2.35 (m, 3H), 2.17 (s, 3H), 1.74 - 1.44 (m, 4H), LCMS m / z+[M+H]629.4.l-(4,6-difluoro-20-((6-(2-hydroxypropan-2-yl)pyridin-2- yl)ethynyl)-9,10, H,12,14,17- hexahydrobenzo[j]pyrido[3',4':4,5]imidazo[l,2- f]thieno[2',3':4,5]pyrido[2,3-h][l]oxa[6]azacycloundecin- 16(15H)-yl)prop-2-en-l-one-9 ’H NMR (400 MHz, DMSO-6) 88.17 (d, J = 5.6 Hz, 1H), 7.95 - 7.87 (m, 2H), 7.80 - 7.75 (m, 2H), 7.05 (t, J = 9.6 Hz, 1H), 6.95 - 6.74 (m, 2H), 6.17 - 6.06 (m, 1H), 5.75 - 5.63 (m, 1H), 5.35 (s, 1H), 4.48 - 4.01 (m, 6H), 3.57 - 3.39 (m, 1H), 3.24 - 3.12 (m, 1H), 2.86 - 2.69 (m, 2H), 1.86 - 1.50 (m, 4H), 1.48 (s, 6H), LCMS m / z+[M+H] 652.4.l-(4,6-difluoro-20-(3-(3-hydroxy-3-methylazetidin-l-yl)prop-l- yn-l-yl)-9,10,ll,12,14,17- hexahydrobenzo[j]pyrido[3',4':4,5]imidazo[l,2- f]thieno[2',3':4,5]pyrido[2,3-h][l]oxa[6]azacycloundecin- 16(15H)-yl)prop-2-en-l-one1H NMR (400 MHz, DMSO-6) 88.08 (d, J = 5.6 Hz, 1H), 7.78 (d, J = 5.6 Hz, 1H), 7.02 (t, J = 9.6 Hz, 1H), 6.93 - 6.73 (m, 2H), 6.18 - 6.05 (m, 1H), 5.74 - 5.65 (m, 1H), 5.45 - 5.19 (m, 1H), 4.51 - 4.24 (m, 2H), 4.20 - 4.09 (m, 2H), 4.08 - 4.05 (m, 1H), 4.00 - 3.92 (m, 2H), 3.67 (s, 2H), 3.26 - 3.24 (m, 2H), 3.22 - 3.20 (m, 2H), 3.18 -155ME1\60337174.v1141039-001203.08 (m, 1H), 2.80 - 2.69 (m, 2H), 1.80 - 1.67 (m, 2H), 1.64 - 1.55 (m, 1H), 1.49 - 1.44 (m, 1H), 1.40 (s, 3H), LCMS m / z+[M+H]616.0.

[0611] Example 2. l-(6-fluoro-17-(l-methyl-LH-indazol-5-yl)-9,10,12,14-tetrahydro- 13H-benzo[7i]pyrrolo[3',4':4,5]imidazo[l,2-d]thieno[2',3':4,5]pyrido[2,3- l[l,4]oxazonin- 13-yl)prop-2-en-l-one

[0612] Step 1. tert-butyl 2-(7-(2-(benzyloxy)-4-fluorophenyl)-4-(l-methyl-lH-indazol- 5-yl)thieno[3,2-c]pyridin-6-yl)-l-((2-(trimethylsilyl)ethoxy)methyl)-4,6- dihydropyrrolo[3,4-d]imidazole-5(lH)-carboxylate

[0613] To a solution of tert-butyl 2-(7-(2-(benzyloxy)-4-fluorophenyl)-4- (((trifluoromethyl)sulfonyl)oxy)thieno[3,2-c]pyridin-6-yl)-l-((2- (trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-<7]imidazole-5(l / f)-carboxylate (130 mg, 0.16 mmol, 1.0 eq.), (l-methyl-l / Z-indazol-5-yl)boronic acid (42 mg, 0.24 mmol, 1.5 eq.) and K2CO3(66 mg, 0.48 mmol, 3.0 eq.) in toluene (4 mL) and H2O (1 mL) was added Pd(PPh3)4(18 mg, 0.02 mmol, 0.1 eq.). The reaction was stirred for 2 h at 90 °C under N2 atm. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography, eluted with EA in PE (0%-60%) to afford the title compound (139 mg).LCMS m / z+[M+H] 803.9.

[0614] Step 2.5-fluoro-2-(4-(l-methyl-lH-indazol-5-yl)-6-(l, 4,5,6- tetrahydropyrrolo[3,4-d]imidazol-2-yl)thieno[3,2-c]pyridin-7-yl)phenol

[0615] tert-butyl 2-(7-(2-(benzyloxy)-4-fluorophenyl)-4-(l-methyl-l / Z-indazol-5- yl)thieno[3,2-c]pyridin-6-yl)-l-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4- <7]imidazole-5(l / Z)-carboxylate (130 mg, 0.16 mmol) was dissolved in TFA (10 mL). The156ME1\60337174.v1141039-00120reaction was stirred for 12 h at 80 °C. The solvent was removed in vacuo and co-evaporated with DCM (3 x 20 mL) to afford the title compound (78 mg, TFA salt, crude). LCMS m / z+[M+H]482.7.

[0616] Step 3. tert-butyl 2-(7-(4-fluoro-2-hydroxyphenyl)-4-(l-methyl-lH-indazol-5- yl)thieno[3,2-c]pyridin-6-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(lH)-carboxylate

[0617] To a solution of 5-fluoro-2-(4-(l-methyl-l / Z-indazol-5-yl)-6-(l, 4,5,6- tetrahydropyrrolo[3,4-<7]imidazol-2-yl)thieno[3,2-c]pyridin-7-yl)phenol (78 mg, 0.16 mmol, 1.0 eq.) and Et3N (164 mg, 1.6 mmol, 10.0 eq.) in DCM (10 mL) was added Boc2O (18 mg, 0.08 mmol, 0.5 eq.). The reaction was stirred for 1 h at RT. The mixture was diluted with H2O (20 mL) and extracted with DCM (3 x 20 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-TLC (5% MeOH in DCM) to afford the title compound (30 mg). LCMS m / z+[M+H]583.6.

[0618] Step 4. tert-butyl 6-fluoro-17-(l-methyl-lH-indazol-5-yl)-9,10,12,14- tetrahydro-13H-benzo[ / i]pyrrolo[3',4':4,5]imidazo[l,2-d]thieno[2',3':4,5]pyrido[2,3- / ]| L4]oxazonine-13-carboxylate

[0619] To a solution of tert-butyl 2-(7-(4-fluoro-2-hydroxyphenyl)-4-(l-methyl-l / Z- indazol-5-yl)thieno[3,2-c]pyridin-6-yl)-4,6-dihydropyrrolo[3,4-<7]imidazole-5(l / f)- carboxylate (30 mg, 0.05 mmol, 1.0 eq.) and K2CO3(43 mg, 0.31 mmol, 6.0 eq.) in DMF (3 mL) was added 1,2-dibromoethane (17 mg, 0.09 mmol, 2.0 eq.). The reaction was stirred for 3 h at 80 °C. The solvent was removed in vacuo and the residue was purified by prep-TLC (5% MeOH in DCM) to afford the title compound (21 mg). LCMS m / z+[M+H]609.5.

[0620] Step 5.6-fluoro-17-(l-methyl-lH-indazol-5-yl)-9,10,13,14-tetrahydro-12H- benzo[^]pyrrolo[3',4':4,5]imidazo[l,2-d]thieno[2',3':4,5]pyrido[2,3- / ][l,4]oxazonine

[0621] To a solution of tert-butyl 6-fluoro-17-(l-methyl-l / Z-indazol-5-yl)-9,10,12,14- tetrahydro-13H-benzo[ / t]pyrrolo[3',4':4,5]imidazo[l,2- ]thieno[2',3':4,5]pyrido[2,3-f [ 1, 4] oxazonine- 13 -carboxylate (28 mg, 0.05 mmol) in DCM (1 mL) was added TFA (2 mL). The reaction was stirred for 1 h at RT. The solvent was removed in vacuo and the residue was co-evaporated with DCM (3 x 10 mL) to afford the title compound (23 mg, crude, TFA salt). LCMS m / z+[M+H] 509.2.

[0622] Step 6. l-(6-fluoro-17-(l-methyl-lH-indazol-5-yl)-9,10,12,14-tetrahydro-13H- benzo[^]pyrrolo[3',4':4,5]imidazo[l,2-d]thieno[2',3':4,5]pyrido[2,3- / ][l,4]oxazonin-13- yl)prop-2-en-l-one

[0623] To a solution of 6-fluoro-17-(l-methyl-l / Z-indazol-5-yl)-9,10,13,14-tetrahydro- 12 / Z-benzo[ / z]pyrrolo[3',4':4,5]imidazo[l,2-<7]thieno[2',3':4,5]pyrido[2,3- |[l,4]oxazonine (23157ME1\60337174.v1141039-00120mg, 0.05 mmol, TFA salt, 1.0 eq.) and DIPEA (58 mg, 0.45 mmol, 10.0 eq.) in DMF (1 mL) was added acrylic anhydride (6 mg, 0.05 mmol). The reaction was stirred for 1 h at RT under N2 atm. The mixture was purified by prep-HPLC (ACN / water / 10 mM NH4HCO3) to afford the title compound (7.45 mg). LCMS m / z+[M+H]563.5.

[0624] The compounds in the table below were synthesized following the methods described for Example 2 using the appropriate starting materials.Ex. Structure IUPAC Name,1H NMR, MSl-(6-fluoro-17-(l-methyl-lH-indazol-5-yl)-9,10,12,14- tetrahydro-13H-benzo[h]pyrrolo[3',4':4,5]imidazo[l,2- d]thieno[2',3':4,5]pyrido[2,3-f][l,4]oxazonin-13-yl)prop-2- Fen-l-one'A 0 1H NMR (400 MHz, DMSO-6) δ 8.35 (s, 1H), 8.21 (s, 1H), 2-1 VC N \= 8.09 (d, J = 5.6 Hz, 1H), 7.98 (dd, J = 8.8, 1.4 Hz, 1H), 7.88 (d,J = 5.6 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.50 - 7.45 (m, 1H), \ / )ZN-N 7.11 - 7.08 (m, 1H), 7.02 (tt, J = 8.4, 2.6 Hz, 1H), 6.64 - 6.55(m, 1H), 6.25 - 6.19 (m, 1H), 5.79 - 5.71 (m, 1H), 4.90 - 4.42 (m, 4H), 4.33 - 4.15 (m, 3H), 4.14 - 4.01 (m, 4H) LCMS m / z+[M+H]563.5.l-(19-(4-((dimethylamino)methyl)phenyl)-6-fluoro- 10,ll,15,16-tetrahydro-9H- benzo[i]pyrido[4',3':4,5]imidazo[l,2- e]thieno[2',3':4,5]pyrido[2,3-g][l,5]oxazecin-14(13H)- F / \ yl)prop-2-en-l-oneJUyN N-\j 1H NMR (400 MHz, DMSO-6) 88.04 (d, J = 5.6 Hz, 1H), 2-27.84 - 7.77 (m, 3H), 7.72 - 7.68 (m, 1H), 7.49 (d, J = 8.0 Hz, 02H), 7.05 - 6.99 (m, 2H), 6.94 - 6.76 (m, 1H), 6.19 - 6.08 (m, 11H), 5.73 - 5.64 (m, 1H), 5.00 - 4.56 (m, 1H), 4.59 - 4.56 (m, 1H), 4.36 - 3.91 (m, 4H), 3.80 - 3.68 (m, 1H), 3.50 (s, 2H), 2.86 - 2.68 (m, 2H), 2.47 - 2.37 (m, 1H), 2.21 (s, 6H), 2.14 - 1.99 (m, 2H), LCMS m / z+[M+H]594.3.158ME1\60337174.v1141039-00120l-(18-(4-((dimethylamino)methyl)phenyl)-6-fluoro- 9,10,14,15-tetrahydrobenzo[h]pyrido[4',3':4,5]imidazo[l,2- -n d]thieno[2',3':4,5]pyrido[2,3-f][l,4]oxazonin-13(12H)- F>^p / ;z==yl)prop-2-en-l-one< \r=y / °A | os A Ji 1H NMR (400 MHz, DMSO-d6) 58.01 (d, J = 5.6 Hz, 1H), < V Yk r N U N-AA2-3 B 7.90 - 7.83 (m, 2H), 7.78 (d, J = 5.6 Hz, 1H), 7.68 (dd, J =A. 14.8, 6.4 Hz, 1H), 7.49 (d, J = 8.0 Hz, 2H), 7.01 - 6.71 (m, 03H), 6.21 - 6.05 (m, 1H), 5.73 - 5.64 (m, 1H), 4.89 - 4.59 (m, 11H), 4.46 - 3.89 (m, 5H), 3.81 - 3.56 (m, 1H), 3.51 (s, 2H), 3.10 - 2.94 (m, 1H), 2.78 - 2.74 (m, 1H), 2.41 - 2.33 (m, 1H), 2.21 (s, 6H), 1.88 - 1.54 (m, 4H), LCMS m / z+[M+H]607.9.l-(20-(4-((dimethylamino)methyl)phenyl)-6-fluoro- 9,10,11,12,16,17- hexahydrobenzolj ]pyrido[4',3 ': 4,5]imidazo[l,2- F f]thieno[2',3':4,5]pyrido[2,3-h][l]oxa[6]azacycloundecin- 15(14H)-yl)prop-2-en-l-one / SYMI J 1H NMR (400 MHz, DMSO-d6) 58.32 (s, 1H), 8.20 (s, 1H), 2-4 v£ IT8.02 (d, J = 5.6 Hz, 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.84 - 7.80 0 (m, 2H), 7.68 (t, J = 7.6 Hz, 1H), 7.02 - 6.84 (m, 3H), 6.18 - 1 6.13 (m, 1H), 5.72 (d, J = 10.4 Hz, 1H), 4.90 - 4.61 (m, 2H),4.37 - 4.29 (m, 1H), 4.13 (s, 3H), 4.09 - 4.04 (m, 2H), 3.98 - 3.47 (m, 2H), 3.11 - 2.95 (m, 1H), 2.44 - 2.78 (m, 2H), 1.92 - 1.77 (m, 1H), 1.71 - 1.58 (m, 3H), LCMS m / z+[M+H]604.8. l-(6-fluoro-20-(l-methyl-lH-indazol-5-yl)-9,10,ll,12,16,17- hexahydrobenzolj ]pyrido[4',3 ': 4,5]imidazo[l,2- f]thieno[2',3':4,5]pyrido[2,3-h][l]oxa[6]azacycloundecin- 15(14H)-yl)prop-2-en-l-one2-5 1H NMR (400 MHz, DMSO-d6) 58.31 (s, 1H), 8.20 (s, 1H),8.01 (d, J = 5.6 Hz, 1H), 7.95 (dd, J = 8.8, 1.6 Hz, 1H), 7.85 - 7.79 (m, 2H), 7.72 - 7.64 (m, 1H), 7.00 - 6.93 (m, 1H), 6.92 - 6.73 (m, 2H), 6.17 - 6.05 (m, 1H), 5.75 - 5.62 (m, 1H), 4.47 - 4.15 (m, 3H), 4.12 (s, 3H), 4.10 - 4.00 (m, 3H), 3.61 - 3.41159ME1\60337174.v1141039-00120(m, 1H), 3.12 - 2.97 (m, 1H), 2.86 - 2.70 (m, 2H), 1.83 - 1.71 (m, 2H), 1.70 - 1.53 (m, 2H), LCMS m / z+[M+H]605.7. l-(6-fluoro-20-(l-methyl-lH-indazol-5-yl)-9,10,ll,12,16,17- 4JJXY \hexahydrobenzolj ]pyrido[4',3 ': 4,5]imidazo[l,2- 5f]thieno[2',3':4,5]pyrido[2,3-h][l]oxa[6]azacycloundecin- F r15(14H)-yl)prop-2-en-l-one0So o1H NMR (400 MHz, DMSO-6) 88.31 (s, 1H), 8.20 (s, 1H), 2-6 tU 8.01 (d, J = 5.6 Hz, 1H), 7.95 (dd, J = 8.8, 1.6 Hz, 1H), 7.85 - 7.79 (m, 2H), 7.72 - 7.64 (m, 1H), 7.00 - 6.93 (m, 1H), 6.92 - O Yk / N-N 6.73 (m, 2H), 6.17 - 6.05 (m, 1H), 5.75 - 5.62 (m, 1H), 4.47 - 4.15 (m, 3H), 4.12 (s, 3H), 4.10 - 4.00 (m, 3H), 3.61 - 3.41 (m, 1H), 3.12 - 2.97 (m, 1H), 2.86 - 2.70 (m, 2H), 1.83 - 1.71 (m, 2H), 1.70 - 1.53 (m, 2H) LCMS m / z+[M+H]605.7. l-(6-fluoro-19-(l-methyl-lH-indazol-5-yl)-9,10,12,13,15,16- hexahydro-14H-azepino[4',5':4,5]imidazo[l,2- d]benzo[h]thieno[2',3':4,5]pyrido[2,3-f][l,4]oxazonin-14- E yl)prop-2-en-l-oneX\ / — 1H NMR (400 MHz, DMSO-6) 88.27 (s, 1H), 8.19 (d, J = 0.6 zs^r il — JI N— / 2-7 Vk^NNA_ / xb Hz, 1H), 8.03 (d, J = 5.6 Hz, 1H), 7.90 (dd, J = 8.8, 1.6 Hz,1H), 7.81 - 7.79 (m, 2H), 7.70 (dd, J = 8.2, 6.6 Hz, 1H), 7.05 - O ' kN-N V6.97 (m, 2H), 6.92 - 6.78 (m, 1H), 6.20 - 6.13 (m, 1H), 5.73 - 5.66 (m, 1H), 4.44 - 4.39 (m, 1H), 4.16 - 3.88 (m, 7H), 3.63 - 3.36 (m, 1H), 3.30 - 3.20 (m, 2H), 2.93 - 2.69 (m, 2H), 2.64 - 2.52 (m, 2H), 2.10 - 1.97 (m, 2H), LCMS m / z+[M+H]605.3.l-(6-fluoro-20-(l-methyl-lH-indazol-5-yl)- 10,ll,13,14,16,17-hexahydro-9H,15H- azepino[4',5':4,5]imidazo[l,2- e]benzo[i]thieno[2',3':4,5]pyrido[2,3-g][l,5]oxazecin-15- 2-8 yl)prop-2-en-l-one1H NMR (400 MHz, DMSO-6) δ 8.30 (s, 1H), 8.20 (s, 1H), 7.99 (d, J = 5.6 Hz, 1H), 7.93 (dd, J = 8.8, 1.6 Hz, 1H), 7.82 - 7.80 (m, 2H), 7.69 (dd, J = 8.2, 6.8 Hz, 1H), 6.98 - 6.76 (m, 3H), 6.19 - 6.13 (m, 1H), 5.73 - 5.66 (m, 1H), 4.33 - 4.28 (m,160ME1\60337174.v1141039-001201H), 4.17 - 4.05 (m, 5H), 4.01 - 3.84 (m, 2H), 3.61 - 3.37 (m, 1H), 3.28 - 3.15 (m, 1H), 3.09 - 3.01 (m, 1H), 2.93 - 2.80 (m, T 2H), 2.60 - 2.54 (m, 1H), 2.45 - 2.42 (m, 1H), 1.90 - 1.81 (m, >^fXz= * 1H), 1.66 - 1.54 (m, 3H), LCMS m / z+[M+H]619.2.£ l-(6-fluoro-21-(l-methyl-lH-indazol-5-yl)- 9,10,ll,12,14,15,17,18-octahydro-16H- A azepino[4',5':4,5]imidazo[l,2- f]benzo[j ]thieno[2',3 ':4,5]pyrido[2,3- h][l]oxa[6]azacycloundecin-16-yl)prop-2-en-l-one1H NMR (400 MHz, DMSO-6) δ 8.33 (s, 1H), 8.20 (s, 1H), 2-9 8.04 (d, J = 5.6 Hz, 1H), 7.96 (dd, J = 8.8, 1.4 Hz, 1H), 7.84 (d,J = 5.6 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.66 (dd, J = 8.0, 7.0 Hz, 1H), 6.97 - 6.82 (m, 2H), 6.72 - 6.56 (m, 1H), 6.22 (dt, J = 16.8, 2.4 Hz, 1H), 5.78 - 5.71 (m, 1H), 5.08 - 4.80 (m, 1H), 4.68 (s, 1H), 4.51 - 4.41 (m, 1H), 4.31 - 4.07 (m, 6H), 4.07 - 4.01 (m, 1H), 3.56 - 3.38 (m, 1H), 1.97 - 1.82 (m, 2H), 1.70 - 1.59 (m, 2H), LCMS m / z+[M+H]591.6.l-(6-fluoro-19-(l-methyl-lH-indazol-5-yl)-9,10,ll,12,14,16- hexahydro-15H-benzo[j]pyrrolo[3',4':4,5]imidazo[l,2- f]thieno[2',3':4,5]pyrido[2,3-h][l]oxa[6]azacycloundecin- 15-yl)prop-2-en-l-one1H NMR (400 MHz, DMSO-6) δ 8.30 (s, 1H), 8.20 (s, 1H), 8.07 (d, J = 5.6 Hz, 1H), 7.93 (dd, J = 8.8, 1.4 Hz, 1H), 7.84 (d, 2-10J = 5.6 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.71 (dd, J = 8.4, 6.6 Hz, 1H), 7.07 - 6.98 (m, 2H), 6.68 - 6.58 (m, 1H), 6.26 - 6.20 (m, 1H), 5.81 - 5.68 (m, 1H), 4.97 - 4.86 (m, 1H), 4.72 - 4.61 (m, 1H), 4.58 - 4.51 (m, 1H), 4.51 - 4.44 (m, 1H), 4.33 - 4.21 (m, 1H), 4.21 - 4.08 (m, 4H), 4.05 - 3.93 (m, 1H), 2.88 - 2.72 (m, 1H), 2.18 - 2.06 (m, 2H), LCMS m / z+[M+H]577.5.161ME1\60337174.v1141039-00120l-(6-fluoro-18-(l-methyl-lH-indazol-5-yl)-10,ll,13,15- tetrahydro-9H,14H-benzo[i]pyrrolo[3',4':4,5]imidazo[l,2- e]thieno[2',3':4,5]pyrido[2,3-g][l,5]oxazecin-14-yl)prop-2- en-l-oneKj )1H NMR (400 MHz, DMSO-6) δ 8.07 (d, J = 5.6 Hz, 1H), z <^® Tk^ N^ NX-^DzN' ~Y^2-11o===7.87 (d, J = 8.0 Hz, 2H), 7.83 (d, J = 5.6 Hz, 1H), 7.51 - 7.45 Ok (m, 3H), 7.16 - 7.06 (m, 1H), 7.02 - 6.98 (m, 1H), 6.95 - 6.75 / N-N (m, 1H), 6.19 -6.05 (m, 1H), 5.78 - 5.62 (m, 1H), 4.77 - 4.51(m, 1H), 4.49 - 4.28 (m, 2H), 4.22 - 4.08 (m, 2H), 4.01 - 3.61 (m, 3H), 3.50 (s, 2H), 2.66 - 2.54 (m, 1H), 2.44 - 2.36 (m, 1H), 2.21 (s, 6H), LCMS m / z+[M+H]580.1.(R)-l-(4,6-difluoro-20-(l-methyl-lH-indazol-5-yl)- 9,10,11,12,16,17- hexahydrobenzolj ]pyrido[4',3 ': 4,5]imidazo[l,2- F f]thieno[2',3':4,5]pyrido[2,3-h][l]oxa[6]azacycloundecin- £V°Q 2 15(14H)-yl)prop-2-en-l-one’H NMR (400 MHz, DMSO-6) δ 8.35 (s, 1H), 8.21 (s, 1H), 2-12 4 V. IGI N 1 8.03 (d, J = 5.6 Hz, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.86 - 7.79O 1k (m, 2H), 7.09 - 7.01 (m, 1H), 7.00 - 6.86 (m, 1H), 6.83 (d, J =ZN- N 10.6 Hz, 1H), 6.25 - 6.04 (m, 1H), 5.72 (d, J = 10.8 Hz, 1H),4.94 - 4.70 (m, 1H), 4.65 (t, J = 16.0 Hz, 1H), 4.39 - 4.26 (m, 1H), 4.13 (s, 3H), 4.08 - 3.94 (m, 2H), 3.89 - 3.38 (m, 2H), 3.21 - 3.06 (m, 1H), 2.45 - 2.22 (m, 2H), 1.86 - 1.64 (m, 3H), 1.57 - 1.43 (m, 1H) LCMS m / z+[M+H]623.4.(S)-l-(4,6-difluoro-20-(l-methyl-lH-indazol-5-yl)- 9,10,11,12,16,17- hexahydrobenzolj ]pyrido[4',3 ': 4,5]imidazo[l,2- f]thieno[2',3':4,5]pyrido[2,3-h][l]oxa[6]azacycloundecin- )2-13 / V |G| N 1 15(14H)-yl)prop-2-en-l-oneOk ’H NMR (400 MHz, DMSO-6) δ 8.35 (s, 1H), 8.21 (s, 1H), 8.03 (d, J = 5.6 Hz, 1H), 7.97 (dd, J = 8.8, 1.4 Hz, 1H), 7.83(dd, J = 7.2, 3.6 Hz, 2H), 7.04 (td, J = 9.6, 2.2 Hz, 1H), 7.01 - 6.86 (m, 1H), 6.83 (d, J = 10.6 Hz, 1H), 6.21 - 6.08 (m, 1H),162ME1\60337174.v1141039-001205.77 - 5.66 (m, 1H), 4.92 - 4.70 (m, 1H), 4.65 (t, J = 15.8 Hz, 1H), 4.38 - 4.27 (m, 1H), 4.13 (s, 3H), 4.09 - 3.94 (m, 2H), 3.90 - 3.41 (m, 2H), 3.21 - 3.06 (m, 1H), 2.45 - 2.23 (m, 2H), 1.78 - 1.61 (m, 3H), 1.55 - 1.45 (m, 1H) LCMS m / z+[M+H] 623.4.(R)-l-(4,6-difluoro-20-(l-methyl-lH-indazol-5-yl)- 9,10,11,12,14,17- hexahydrobenzolj ]pyrido[3 ’,4 ': 4,5]imidazo[l,2- f]thieno[2',3':4,5]pyrido[2,3-h][l]oxa[6]azacycloundecin- 16(15H)-yl)prop-2-en-l-one’H NMR (400 MHz, DMSO-6) δ 8.34 (s, 1H), 8.21 (s, 1H),2-14 L 8.03 (d, J = 5.6 Hz, 1H), 7.97 (dd, J = 8.8, 1.4 Hz, 1H), 7.86 - 7.80 (m, 2H), 7.04 (t, J = 9.6 Hz, 1H), 6.95 - 6.73 (m, 2H), 0\N— N 6.11 (t, J = 15.2 Hz, 1H), 5.70 (dd, J = 20.6, 11.6 Hz, 1H), 4.47- 4.33 (m, 1H), 4.33 - 4.14 (m, 2H), 4.13 (s, 3H), 4.11 - 3.98 (m, 3H), 3.59 - 3.55 (m, 1H), 3.19 - 3.09 (m, 1H), 2.82 - 2.71 V(m, 2H), 1.80 - 1.70 (m, 2H), 1.68 - 1.57 (m, 1H), 1.53 - 1.43 a (m, 1H) LCMS m / z+[M+H] 623.4.\, (, _ A J / \\ / 'Z--~ (S)-l-(4,6-difluoro-20-(l-methyl-lH-indazol-5-yl)- 9, 10,11,12, 14, 17- hexahydrobenzolj ]pyrido[3 ',4': 4,5]imidazo[l,2- f]thieno[2',3':4,5]pyrido[2,3-h][l]oxa[6]azacycloundecin- 16(15H)-yl)prop-2-en-l-one’H NMR (400 MHz, DMSO-6) δ 8.34 (s, 1H), 8.21 (s, 1H), 2-15 8.03 (d, J = 5.6 Hz, 1H), 7.97 (dd, J = 8.8, 1.4 Hz, 1H), 7.86 - 7.80 (m, 2H), 7.04 (t, J = 9.6 Hz, 1H), 6.95 - 6.73 (m, 2H), 6.11 (t, J = 15.2 Hz, 1H), 5.70 (dd, J = 20.6, 11.6 Hz, 1H), 4.47 - 4.33 (m, 1H), 4.33 - 4.14 (m, 2H), 4.13 (s, 3H), 4.11 - 3.98 (m, 3H), 3.59 - 3.55 (m, 1H), 3.19 - 3.09 (m, 1H), 2.82 - 2.71 (m, 2H), 1.80 - 1.70 (m, 2H), 1.68 - 1.57 (m, 1H), 1.53 - 1.43(m, 1H) LCMS m / z+[M+H] 623.4.163ME1\60337174.v1141039-00120(R)-l-(4, 6-difluoro-20-(2-methyl-l, 2,3,4- tetrahydroisoquinolin-6-yl)-9,10,ll,12,14,17- >T1 / \Mji > / =\ hexahydrobenzolj ]pyrido[3 ',4': 4,5]imidazo[l,2- ^nrYz_ f]thieno[2',3':4,5]pyrido[2,3-h][l]oxa[6]azacycloundecin- 16(15H)-yl)prop-2-en-l-oneB1H NMR (400 MHz, DMSO-6) δ 8.01 (d, J = 5.6 Hz, 1H), 7.78 (d, J = 5.6 Hz, 1H), 7.66 - 7.64 (m, 2H), 7.25 (d, J = 7.8 2-16Hz, 1H), 7.02 (d, J = 9.4 Hz, 1H), 6.96 - 6.72 (m, 2H), 6.11 (t, J = 15.2 Hz, 1H), 5.68 (dd, J = 21.0, 10.8 Hz, 1H), 4.51 - 4.37 (m, 1H), 4.37 - 4.31 (m, 1H), 4.23 - 4.13 (m, 1H), 4.10 - 4.03 (m, 3H), 3.57 - 3.45 (m, 2H), 3.55 - 3.46 (m, 1H), 3.20 - 3.10 (m, 1H), 2.96 (t, J = 12.8 Hz, 2H), 2.77 - 2.66 (m, 4H), 2.38 (s, 3H), 1.75 - 1.65 (m, 2H), 1.63 - 1.56 (m, 1H), 1.51 - 1.43 (m,1H), LCMS+m / z: [M+H] 638.4.(S)-l-(4, 6-difluoro-20-(2-methyl-l, 2,3,4- V tetrahydroisoquinolin-6-yl)-9,10,ll,12,14,17- hexahydrobenzolj ]pyrido[3 ',4': 4,5]imidazo[l,2- a f]thieno[2',3':4,5]pyrido[2,3-h][l]oxa[6]azacycloundecin- 16(15H)-yl)prop-2-en-l-onen £Tw1H NMR (400 MHz, DMSO-6) 88.01 (d, J = 5.6 Hz, 1H),7.78 (d, J = 5.6 Hz, 1H), 7.65 (d, J = 7.8 Hz, 2H), 7.25 (d, J = 2-177.8 Hz, 1H), 7.02 (d, J = 9.4 Hz, 1H), 6.96 - 6.72 (m, 2H), 6.11 (t, J = 15.2 Hz, 1H), 5.68 (dd, J = 21.0, 10.8 Hz, 1H), 4.45 - 4.40 (m, 1H), 4.33 - 4.31 (m, 1H), 4.23 - 4.13 (m, 1H), 4.10 - 4.02 (m, 3H), 3.61 (s, 2H), 3.55 - 3.46 (m, 1H), 3.20 - 3.10 (m, 1H), 2.96 (t, J = 12.8 Hz, 2H), 2.77 - 2.73 (m, 4H), 2.38 (s, 3H), 1.75 - 1.65 (m, 2H), 1.63 - 1.56 (m, 1H), 1.51 - 1.43 (m,1H), LCMS+m / z: [M+H] 638.5.164ME1\60337174.v1141039-00120(S)-l-(4,6-difluoro-20-(2-methyl-l,2,3,4- tetrahydroisoquinolin-6-yl)-9,10,ll,12,16,17- hexahydrobenzolj ]pyrido[4',3 ': 4,5]imidazo[l,2- f]thieno[2',3':4,5]pyrido[2,3-h][l]oxa[6]azacycloundecin- 15(14H)-yl)prop-2-en-l-one1H NMR (400 MHz, DMSO-6) δ 8.01 (d, J = 5.6 Hz, 1H), 7.78 (d, J = 5.6 Hz, 1H), 7.67 - 7.65 (m, 2H), 7.26 (d, J = 7.6 2-18 vurnHz, 1H), 7.04 (td, J = 9.6, 2.0 Hz, 1H), 7.0 - 6.86 (m, 1H),6.83 (d, J = 10.6 Hz, 1H), 6.21 - 6.10 (m, 1H), 5.73 (d, J = Ok10.4 Hz, 1H), 4.90 - 4.73 (m, 1H), 4.71 - 4.56 (m, 1H), 4.33 - 14.18 (m, 1H), 4.14 - 3.93 (m, 2H), 3.83 - 3.67 (m, 1H), 3.59 (s, 2H), 3.57 - 3.36 (m, 1H), 3.19 - 3.06 (m, 1H), 2.96 (t, J = 5.2 Hz, 2H), 2.67 - 2.63 (d, J = 5.8 Hz, 2H), 2.48 - 2.41 (m, 1H), 2.38 (s, 3H), 2.37 - 2.26 (m, 1H), 1.75 - 1.60 (m, 3H), 1.55 - 1.42 (m, 1H), LCMS+m / z. [M+H] 638.5.(R)-l-(4,6-difluoro-20-(2-methyl-l,2,3,4- tetrahydroisoquinolin-6-yl)-9,10,ll,12,16,17- hexahydrobenzolj ]pyrido[4',3 ': 4,5]imidazo[l,2- f]thieno[2',3':4,5]pyrido[2,3-h][l]oxa[6]azacycloundecin- 15(14H)-yl)prop-2-en-l-oneF1H NMR (400 MHz, DMSO-6) δ 8.01 (d, J = 5.6 Hz, 1H),F^ \ N-~z'''^NZ^'X7.79 (d, J = 5.6 Hz, 1H), 7.67 - 7.65 (m, 2H), 7.26 (d, J = 7.8 2-19 vLJNHz, 1H), 7.08 - 7.01 (m, 1H), 7.00 - 6.85 (m, 1H), 6.85 - 6.79(m, 1H), 6.20 - 6.09 (m, 1H), 5.73 (d, J = 10.6 Hz, 1H), 4.88 - Ok4.75 (m, 1H), 4.71 - 4.56 (m, 1H), 4.34 - 4.19 (m, 1H), 4.08 - 13.97 (m, 2H), 3.83 - 3.68 (m, 1H), 3.64 - 3.55 (m, 2H), 3.55 - 3.36 (m, 1H), 3.20 - 3.06 (m, 1H), 2.96 (t, J = 5.4 Hz, 2H), 2.68 - 2.65 (m, 2H), 2.47 - 2.42 (m, 1H), 2.39 (s, 3H), 2.32 - 2.17 (m, 1H), 1.77 - 1.58 (m, 3H), 1.54 - 1.42 (m, 1H),LCMS+m / z [M+H] 638.5.165ME1\60337174.v1141039-00120l-(4,6-difluoro-20-(6-methyl-5,6,7,8-tetrahydro-l,6- naphthyridin-3-yl)-9, 10, 11,12, 14,17- hexahydrobenzolj ]pyrido[3 ',4': 4,5]imidazo[l,2- f]thieno[2',3':4,5]pyrido[2,3-h][l]oxa[6]azacycloundecin- 16(15H)-yl)prop-2-en-l-one1H NMR (400 MHz, DMSO-6) δ 8.86 (d, J = 2.0 Hz, 1H), 8.06 (d, J = 5.6 Hz, 1H), 8.00 (d, J = 2.0 Hz, 1H), 7.83 (d, J = 2-205.6 Hz, 1H), 7.04 (t, J = 9.2 Hz, 1H), 6.95 - 6.73 (m, 2H), 6.11 (t, J = 15.0 Hz, 1H), 5.69 (dd, J = 22.4, 12.2 Hz, 1H), 4.47 - 4.25 (m, 2H), 4.24 - 4.12 (m, 1H), 4.10 - 3.97 (m, 3H), 3.67 (s, 2H), 3.55 - 3.50 (m, 1H), 3.18 - 3.10 (m, 1H), 3.02 (t, J = 5.8 Hz, 2H), 2.80 - 2.72 (m, 4H), 2.41 (s, 3H), 1.77 - 1.67 (m, 2H), 1.65 - 1.54 (m, 1H), 1.53 - 1.41 (m, 1H), LCMS+m / z:[M+H] 639.1.l-(4,6-difluoro-20-(l-methyl-lH-pyrazolo[3,4-b]pyridin-5- yl)-9,10,ll,12,16,17- hexahydrobenzolj ]pyrido[4',3 ': 4,5]imidazo[l,2- f]thieno[2',3':4,5]pyrido[2,3-h][l]oxa[6]azacycloundecin- 15(14H)-yl)prop-2-en-l-one1H NMR (400 MHz, DMSO-6) δ 9.09 (d, J = 2.2 Hz, 1H), 8.81 (d, J = 2.0 Hz, 1H), 8.30 (s, 1H), 8.07 (d, J = 5.6 Hz, 1H),7.85 (d, J = 5.6 Hz, 1H), 7.05 (td, J = 9.6, 2.2 Hz, 1H), 7.01 - 6.86 (m, 1H), 6.85 - 6.82 (m, 1H), 6.20 - 6.11 (m, 1H), 5.74 - 5.71 (m, 1H), 4.88 - 4.59 (m, 2H), 4.41 - 4.29 (m, 1H), 4.15 (s, 3H), 4.12 - 4.01 (m, 2H), 4.01 - 3.49 (m, 2H), 3.18 - 3.04 (m, 1H), 2.47 - 2.35 (m, 2H), 1.82 - 1.42 (m, 4H), LCMS+m / z: [M+H] 624.1.l-(4,6-difluoro-20-(l-methyl-lH-pyrazolo[3,4-b]pyridin-5- yl)-9,10,ll,12,14,17- 2-22 hexahydrobenzolj ]pyrido[3 ',4': 4,5]imidazo[l,2- f]thieno[2',3':4,5]pyrido[2,3-h][l]oxa[6]azacycloundecin- 16(15H)-yl)prop-2-en-l-one166ME1\60337174.v1141039-001201H NMR (400 MHz, DMSO-6) δ 9.09 (d, J = 2.4 Hz, 1H), 8.81 (d, J = 2.4 Hz, 1H), 8.30 (s, 1H), 8.07 (d, J = 5.6 Hz, 1H), 7.85 (d, J = 5.6 Hz, 1H), 7.05 (t, J = 9.6 Hz, 1H), 6.94 - 6.75 (m, 2H), 6.17 - 6.03 (m, 1H), 5.73 - 5.64 (m, 1H), 4.45 - 4.19 (m, 3H), 4.15 (s, 3H), 4.11 - 4.00 (m, 3H), 3.57 - 3.47 (m, 1H), 3.19 - 3.07 (m, 1H), 2.82 - 2.70 (m, 2H), 1.78 - 1.68 (m, 2H), 1.67 - 1.61 (m, 1H), 1.53 - 1.46 (m, 1H), LCMS+m / z:[M+H] 624.3.l-(20-(6-(difluoromethoxy)pyridin-3-yl)-4,6-difluoro- 9,10,11,12,16,17- hexahydrobenzolj ]pyrido[4',3 ': 4,5]imidazo[l,2- f]thieno[2',3':4,5]pyrido[2,3-h][l]oxa[6]azacycloundecin- F 15(14H)-yl)prop-2-en-l-onervQ X / 1H NMR (400 MHz, DMSO-6) δ 8.82 (d, J = 2.4 Hz, 1H), SvMx l )<< II 1VGN 8.46 (dd, J = 8.6, 2.4 Hz, 1H), 8.07 (d, J = 5.6 Hz, 1H), 8.02 - 2-237.63 (m, 2H), 7.31 (d, J = 8.6 Hz, 1H), 7.05 (td, J = 9.6, 2.2 N (1. J1Hz, 1H), 7.00 - 6.85 (m, 1H), 6.83 (d, J = 10.8 Hz, 1H), 6.19 - O^FF 6.10 (m, 1H), 5.72 (d, J = 10.4 Hz, 1H), 4.89 - 4.71 (m, 1H),4.71 - 4.57 (m, 1H), 4.36 - 4.24 (m, 1H), 4.13 - 4.00 (m, 2H), 3.99 – 3.44 (m, 2H), 3.17 - 3.01 (m, 1H), 2.46 - 2.22 (m, 2H), 1.76 - 1.60 (m, 3H), 1.56 - 1.45 (m, 1H), LCMS+m / z:[M+H] 636.5.l-(20-(6-(difluoromethoxy)pyridin-3-yl)-4,6-difluoro- 9,10,11,12,14,17- hexahydrobenzolj ]pyrido[3 ',4': 4,5]imidazo[l,2- TycQ f]thieno[2',3':4,5]pyrido[2,3-h][l]oxa[6]azacycloundecin- 16(15H)-yl)prop-2-en-l-one2-24 ’H NMR (400 MHz, DMSO-6) δ 8.81 (d, J = 2.4 Hz, 1H),11 1 8.46 (dd, J = 8.6, 2.4 Hz, 1H), 8.08 (d, J = 5.6 Hz, 1H), 8.01 - °y-F7.65 (m, 2H), 7.31 (d, J = 8.6 Hz, 1H), 7.05 (t, J = 9.4 Hz, 1H), F6.94 - 6.75 (m, 2H), 6.15 - 6.06 (m, 1H), 5.69 (ddd, J = 11.8, 9.8, 1.6 Hz, 1H), 4.44 - 4.11 (m, 3H), 4.10 – 4.01 (m, 3H), 3.58 - 3.46 (m, 1H), 3.18 - 3.05 (m, 1H), 2.75 (dt, J = 18.2,167ME1\60337174.v1141039-001205.8 Hz, 2H), 1.83 - 1.68 (m, 2H), 1.66 - 1.54 (m, 1H), 1.52 - 1.42 (m, 1H), LCMS+m / z: [M+H] 636.1.l-(20-(l-(difluoromethyl)-lH-indazol-5-yl)-4,6-difluoro- 9,10,11,12,16,17- hexahydrobenzolj ]pyrido[4',3 ': 4,5]imidazo[l,2- f]thieno[2',3':4,5]pyrido[2,3-h][l]oxa[6]azacycloundecin- 15(14H)-yl)prop-2-en-l-one1H NMR (400 MHz, DMSO-6) δ 9.03 (s, 1H), 8.42 (s, 1H), 8.38 - 8.03 (m, 2H), 7.96 - 7.94 (m, 1H), 7.91 - 7.89 (m, 1H),7.87 (d, J = 5.6 Hz, 1H), 7.09 - 7.01 (m, 1H), 7.01 - 6.86 (m, 1H), 6.86 - 6.81 (m, 1H), 6.20 - 6.10 (m, 1H), 5.76 - 5.69 (m, 1H), 4.88 - 4.61 (m, 2H), 4.40 - 4.26 (m, 1H), 4.19 - 4.04 (m, 2H), 4.02 - 3.47 (m, 2H), 3.19 - 3.01 (m, 1H), 2.45 - 2.36 (m, 2H), 1.79 - 1.68 (m, 2H), 1.66 - 1.42 (m, 2H), LCMS+m / z:[M+H] 659.4.l-(20-(l-(difluoromethyl)-lH-indazol-5-yl)-4,6-difluoro- 9,10,11,12,14,17- hexahydrobenzolj ]pyrido[3 ',4': 4,5]imidazo[l,2- f]thieno[2',3':4,5]pyrido[2,3-h][l]oxa[6]azacycloundecin- 16(15H)-yl)prop-2-en-l-one1H NMR (400 MHz, DMSO-6) δ 9.03 (s, 1H), 8.42 (s, 1H), 8.22 (t, J = 58.8 Hz, 1H), 8.06 (d, J = 5.6 Hz, 1H), 7.97 - 7.92(m, 2H), 7.87 (d, J = 5.6 Hz, 1H), 7.05 (t, J = 9.6 Hz, 1H), 6.94 - 6.75 (m, 2H), 6.11 (t, J = 14.8 Hz, 1H), 5.75 - 5.61 (m, 1H), 4.52 - 4.13 (m, 3H), 4.10 - 4.03 (m, 3H), 3.56 - 3.47 (m, 1H), 3.21 - 3.09 (m, 1H), 2.83 - 2.70 (m, 2H), 1.85 - 1.69 (m, 2H), 1.68 - 1.58 (m, 1H), 1.53 - 1.42 (m, 1H), LCMS+m / z:[M+H] 659.4.168ME1\60337174.v1141039-00120(4-(16-acryloyl-4,6-difluoro-9,10,ll,12,14,15,16,17- octahydrobenzo[j]pyrido[3',4':4,5]imidazo[l,2- f]thie...

Claims

141039-00120CLAIMSListing of Claims:

1. A compound having the structural Formula I:or a pharmaceutically acceptable salt thereof, wherein:Ring A is phenyl, 5- to 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic carbocyclyl, 8- to 10-membered bicyclic heteroaryl, or 8- to 10-membered bicyclic heterocyclyl, wherein Ring A is attached to Ring B and Ring C via two adjacent atoms;Ring B is phenyl, 5- to 6-membered monocyclic heteroaryl, 3- to 10-membered monocyclic or bicyclic heterocyclyl, or (C3-C7)cycloalkyl, wherein Ring B is attached to Ring A and L via two adjacent atoms;Ring C is phenyl, 5- to 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl or 8- to 10-membered bicyclic heterocyclyl, wherein Ring C is attached to Ring A and L via two adjacent atoms;L is a (Cs-Cejalkylene or halo(C3-C6)alkylene, each of which are optionally interrupted by 1 to 3 Rvand / or wherein two adjacent hydrogen atoms on said (Cs-Cejalkylene or halo(C3-Ce)alkylene may be taken together to form a (C3-C6)cycloalkyl;Rvis O, NH, N(Ci-C4)alkyl, S, C(O)NH, C(O)N(Ci-C4)alkyl, OC(O)NH, OC(O)N(Ci-C4)alkyl, S(O)2NH, S(O)2N(Ci-C4)alkyl, NHS(O)2NH, N(C1-C4)alkylS(O)2NH, NHS(O)2N(Ci-C4)alkyl, or N(Ci-C4)alkylS(O)2N(Ci-C4)alkyl;R is hydrogen, phenyl, naphthyl, 5- to 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, 5- to 8-membered bicyclic carbocyclyl, 4- to 8-membered monocyclic heterocyclyl, 7- to 10-membered bicyclic heterocyclyl, -C≡C-R7, -C(O)NR8R9, -OR8, -NR8R9, or -CR8a=CR8aR9a, wherein each of said phenyl, naphthyl, 5- to 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, 5- to 8-membered bicyclic423ME1\60337174.v1141039-00120carbocyclyl, 4- to 8-membered monocyclic heterocyclyl, and 7- to 10-membered bicyclic heterocyclyl are optionally substituted with 1 to 3 groups selected from Rx;R1is selected from hydrogen, halo, (Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, cyano(Ci-Ce)alkyl, halo(Ci-C6)alkyl, (Ci-C6)alkoxy, halo(Ci-C6)alkoxy, (Ci-C6)alkyleneO(Ci-C6)alkyl, (Ci-C6)alkyleneO(Ci-C6)alkyl, hydroxy, (C3-C6)cycloalkyl, (Ci-C6)alkyleneNH2, (Ci-C6)alkyleneNH(Ci-C6)alkyl, (Ci-C6)alkyleneN[(Ci-C6)alkyl]2, cyano, hydroxy, C(0)NH2, C(O)NH(Ci-C6)alkyl, C(O)N[(Ci-C6)alkyl]2, -NR8aR9a, 5- to 7-membered monocyclic heteroaryl, and 4- to 7-membered monocyclic heterocyclyl, wherein said 4- to 7-membered monocyclic heterocyclyl, (C3-C6)cycloalkyl, and 5- to 7-membered monocyclic heteroaryl are each optionally substituted with 1 to 3 groups selected from RY;R2is selected from hydrogen, halo, cyano, (Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, cyano(Ci-C6)alkyl, halo(Ci-C6)alkyl, (Ci-C6)alkoxy, and halo(Ci-C6)alkoxy;R3is halo, cyano, hydroxy, (Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, (Ci-C6)alkyleneO(Ci-C6)alkyl, (Ci-C6)alkyleneNH2, -Y-W, (Ci-C6)alkyleneNH(Ci-C6)alkyl, (Ci-C6)alkyleneN[(Ci-Ce)alkyl]2, cyano(Ci-C6)alkyl, halo(Ci-C6)alkyl, (Ci-C6)alkoxy, halo(Ci-C6)alkoxy, 5- to 7-membered monocyclic heteroaryl, 4- to 7-membered monocyclic heterocyclyl, (C3-C6)cycloalkyl, (C2-C6)alkynyl, and (C3-C6)cycloalkenyl, wherein said 5- to 7-membered monocyclic heteroaryl, 4- to 7-membered monocyclic heterocyclyl, (C3-C6)cycloalkenyl, and (C3-C6)cycloalkyl are each optionally substituted with 1 to 3 groups selected from Rxl;R4is selected from hydrogen, halo, cyano, hydroxy, (Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, (Ci-C6)alkyleneO(Ci-C6)alkyl, (Ci-C6)alkyleneNH2, -Y-W, (Ci-C6)alkyleneNH(Ci-Ce)alkyl, (Ci-C6)alkyleneN[(Ci-C6)alkyl]2, cyano(Ci-C6)alkyl, halo(Ci-C6)alkyl, (Ci-Ce)alkoxy, halo(Ci-C6)alkoxy, 5- to 7-membered monocyclic heteroaryl, 4- to 7-membered monocyclic heterocyclyl, (C3-C6)cycloalkyl, (C2-C6)alkynyl, and (C3-C6)cycloalkenyl, wherein said 5- to 7-membered monocyclic heteroaryl, 4- to 7-membered monocyclic heterocyclyl, (C3-C6)cycloalkenyl, and (C3-C6)cycloalkyl are each optionally substituted with 1 to 3 groups selected from Rxl;R5and R6are independently selected from hydrogen, halo, cyano, hydroxy, NH2, (C1-C6)alkyl, halo(C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, halo(C1-C6)alkoxy, O(C3-C4)cycloalkyl, S(C1-C6)alkyl, NH(C1-C6)alkyl, N[(C1-C6)alkyl]2, NH(C3-C4)cycloalkyl, 5- to 7-membered monocyclic heteroaryl, and 4- to 7-membered monocyclic heterocyclyl, wherein said 5- to 7-membered monocyclic heteroaryl, 4- to 7-membered monocyclic heterocyclyl, and (C3-C6)cycloalkyl are each optionally substituted with 1 to 3 groups selected from RY1;424ME1\60337174.v1141039-00120R7is selected from (C1-C6)alkyl, (C3-C6)cycloalkyl, phenyl, 5- to 6-membered monocyclic heteroaryl, (C1-C6)alkylene[5- to 8-membered monocyclic heterocyclyl], 9- to 10-membered bicyclic fused aryl, and 9- to 10-membered bicyclic fused heteroaryl, wherein said (C3-C6)cycloalkyl, phenyl, 5- to 6-membered monocyclic heteroaryl, (C1-C6)alkylene[5-to 8-membered heterocyclyl], 9- to 10-membered bicyclic fused aryl, and 9- to 10-membered bicyclic fused heteroaryl are each optionally substituted with 1 to 3 groups selected from RZ;R8and R8aare each independently selected from hydrogen, CN, halogen, (C1-C6)alkyl, (C1-C3)alkylenecyano, and (C3-C6)cycloalkyl;R9and R9aare each independently selected from hydrogen, (C1-C6)alkyl, halo(C1-C6)alkyl, cyano(C1-C6)alkyl, hydroxy(C1-C6)alkyl, 3- to 6-membered monocyclic carbocyclyl, phenyl, naphthyl, 5- to 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl ring, 5- to 8-membered bicyclic carbocyclyl, 4- to 8-membered monocyclic heterocyclyl, and 7- to 10-membered spiro-fused heterocyclyl, wherein each of said 3- to 6-membered monocyclic carbocyclyl, phenyl, naphthyl, 5- to 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl ring, 5- to 8-membered bicyclic carbocyclyl, 4- to 8-membered monocyclic heterocyclyl, and 7- to 10-membered spiro-fused heterocyclyl is optionally substituted with 1 to 3 groups selected from (Ci-Ce)alkyl, (C3-C6)cycloalkyl, (Ci-C6)alkyleneNR8aR9a, halo, cyano, and hydroxy;Y, Ya, Yb, and Ycare each independently a bond, C(O), CH2, S(O), or S(O)2;W, Wa, Wb, and Wcare each independently selected from hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, 4- to 7-membered monocyclic heterocyclyl, phenyl, 5- to 6-membered monocyclic heteroaryl, -CR8=CR10R11, and -C≡C-R11;R10and R11are each independently selected from hydrogen, (C1-C6)alkyl, halo(C1-C6)alkyl, (C3-C6)cycloalkyl, halo, cyano, (C1-C6)alkoxy, (C1-C6)alkyleneNR8R9, (C1-C3)alkylene 4- to 8-membered monocyclic heterocyclyl, 4- to 7-membered monocyclic heterocyclyl phenyl, C(O)NH(Ci-3alkyl) and 5- to 6-membered monocyclic heteroaryl;Rxand RX1are each independently halo, hydroxy, cyano, (Ci-C6)alkyl, deuterated(Ci-Ce)alkyl, halo(Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, cyano(Ci-C6)alkyl, (Ci-C6)alkoxy, halo(Ci-C6)alkoxy, (C3-C6)cycloalkyl, S(O)2NH2, NHS(O)2NH2, NHS(O)2(Ci-C6)alkyl, S(O)2NH(C1-C6)alkyl, NH(C1-C6)alkyl, 4- to 6-membered monocyclic heterocyclyl, 5- to 7-membered monocyclic heteroaryl, phenyl, (Ci-C6)alkyleneNR8R9, (Ci-C6)alkyleneO(Ci-C6)alkyl, hydroxy, O(C3-C4)cycloalkyl, -Ya-Wb, (Ci-C6)alkyleneO(C3-C4)cycloalkyl, (Ci-C6)alkylene[(C3-C4)cycloalkyl], (Ci-C6)alkylene[4- to 6-membered monocyclic heterocyclyl], (Ci-C6)alkylene[5- to 7-membered monocyclic heteroaryl], or -NR8aR9a,425ME1\60337174.v1141039-00120wherein said (C3-C6)cycloalkyl, 4- to 6-membered monocyclic heterocyclyl, 5- to 7-membered monocyclic heteroaryl, and phenyl are each optionally substituted with 1 to 3 groups selected from Rw;Rwis halo, cyano, (Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, (Ci-C6)alkyleneO(Ci-C6)alkyl, (Ci-C6)alkyleneNH2, (Ci-C6)alkyleneNH(Ci-C6)alkyl, (Ci-C6)alkyleneN[(Ci-C6)alkyl]2, cyano(Ci-C6)alkyl, halo(Ci-C6)alkyl, (Ci-Cejalkoxy, halo(Ci-C6)alkoxy, hydroxy, O(Cs-C4)cycloalkyl, or 4- to 6-membered monocyclic heterocyclyl;RYand RY1are each independently -NR7a-Yc-Wc, -Yb-Wb, halo, cyano, (Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, (Ci-C6)alkyleneO(Ci-C6)alkyl, (Ci-C6)alkyleneNH2, (Ci-C6)alkyleneNH(Ci-C6)alkyl, (Ci-C6)alkyleneN[(Ci-C6)alkyl]2, cyano(Ci-C6)alkyl, halo(Ci-Ce)alkyl, (Ci-C6)alkoxy, halo(Ci-C6)alkoxy, hydroxy, O(C3-C4)cycloalkyl, or 4- to 6-membered monocyclic heterocyclyl; andRzis halo, hydroxy, hydroxy(Ci-C6)alkyl, cyano, -NR8R9, S(O)2(Ci-C6)alkyl, S(O)(Ci-C6)alkyl, S(O)NR8R9, and S(O)2NR8R9; andq is 0, 1, 2, or 3.

2. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl, 5- to 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, or 8- to 10-membered bicyclic heterocyclyl, wherein Ring A is attached to Ring B and Ring C via two adjacent atoms;R3is halo, cyano, hydroxy, (C1-C6)alkyl, hydroxy(C1-C6)alkyl, (Ci-C6)alkyleneO(Ci-C6)alkyl, (Ci-C6)alkyleneNH2, -Y-W, (Ci-C6)alkyleneNH(Ci-C6)alkyl, (Ci-C6)alkyleneN[(Ci-Ce)alkyl]2, cyano(Ci-C6)alkyl, halo(Ci-C6)alkyl, (Ci-Cejalkoxy, halo(Ci-C6)alkoxy, 5- to 7-membered monocyclic heteroaryl, 4- to 7-membered monocyclic heterocyclyl, (C3-Cejcycloalkyl, and (Ci-Cejalkynyl, wherein said 5- to 7-membered monocyclic heteroaryl, 4-to 7-membered monocyclic heterocyclyl, and (C3-C6)cycloalkyl are each optionally substituted with 1 to 3 groups selected from Rxl;R4is selected from hydrogen, halo, cyano, hydroxy, (Ci-Cejalkyl, hydroxy(Ci-C6)alkyl, (Ci-C6)alkyleneO(Ci-C6)alkyl, (Ci-C6)alkyleneNH2, -Y-W, (Ci-C6)alkyleneNH(Ci-Cejalkyl, (Ci-C6)alkyleneN[(Ci-C6)alkyl]2, cyano(Ci-C6)alkyl, halo(Ci-C6)alkyl, (Ci-Cejalkoxy, halo(Ci-C6)alkoxy, 5- to 7-membered monocyclic heteroaryl, 4- to 7-membered monocyclic heterocyclyl, (C3-C6)cycloalkyl, and (Ci-Cejalkynyl, wherein said 5- to 7-membered monocyclic heteroaryl, 4- to 7-membered monocyclic heterocyclyl, and (C3-Cejcycloalkyl are each optionally substituted with 1 to 3 groups selected from Rxl; and426ME1\60337174.v1141039-00120Y, Ya, Yb, and Ycare each independently a bond, C(O), S(O), or S(O)2;R10and R11are each independently selected from hydrogen, (Ci-C6)alkyl, (C3-C6)cycloalkyl, halo, cyano, (Ci-C6)alkoxy, (Ci-C6)alkyleneNR8R9, 4- to 7-membered monocyclic heterocyclyl phenyl, and 5- to 6-membered monocyclic heteroaryl.

3. The compound of Claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R3is (Ci-C4)alkyl.

4. The compound of any one of Claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein q is 0 or 2.

5. The compound of any one of Claims 1 to 4, wherein q is 0.

6. The compound of any one of Claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein L is selected from:

7. The compound of any one of Claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein L is selected from:427ME1\60337174.v1141039-001208. The compound of any one of Claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein L is selected from:

09. The compound of any one of Claims 1 to 6 or 8, or a pharmaceutically acceptable salt thereof, wherein L is selected from:428ME1\60337174.v1141039-0012010. The compound of any one of Claims 1 to 9, or a pharmaceutically acceptable saltthereof, wherein L is selected from:

11. The compound of Claims 1 to 10, or a pharmaceutically acceptable salt thereof,wherein L is selected from:, and12. The compound of Claims 1 to 11, or a pharmaceutically acceptable salt thereof,wherein L is selected from:

13. The compound of any one of Claims 1 to 11, or a pharmaceutically acceptable saltthereof, wherein L is selected fromO'14. The compound of any one of Claims 1 to 3, or a pharmaceutically acceptable saltthereof, whereinL is15. The compound of any one of Claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein L is selected from:andr 0 ", wherein the squiggly line indicates the connection to Ring C and the dotted line indicates the connection to Ring B.429ME1\60337174.v1141039-0012016. The compound of any one of Claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein L is selected from:, wherein the squiggly line indicates the connection to Ring C and the dotted line indicates the connection to Ring B.

17. The compound of any one of Claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein L is selected from:indicates the connection to Ring C and the dotted line indicates the connection to Ring B.

18. The compound of any one of Claims 1 to 17, or a pharmaceutically acceptable saltthereof, wherein Lis', wherein the squiggly line indicates the connection to Ring C and the dotted line indicates the connection to Ring B.

19. The compound of any one of Claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein Ring B is phenyl.

20. The compound of any one of Claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein the compound is of the structural Formula II:

21. The compound of any one of Claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein R1is hydrogen or halo.430ME1\60337174.v1141039-0012022. The compound of any one of Claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein R1is halo.

23. The compound of any one of Claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein R1is fluoro.

24. The compound of any one of Claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein R2is hydrogen or halo.

25. The compound of any one of Claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein R2is halo.

26. The compound of any one of Claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein R2is hydrogen or fluoro.

27. The compound of any one of Claims 1 to 26, or a pharmaceutically acceptable salt thereof, wherein R2is fluoro.

28. The compound of any one of Claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein the compound is of the structural Formula III or IV:

29. The compound of any one of Claims 1 and 3 to 28, or a pharmaceutically acceptable salt thereof, wherein Ring A is an 8- to 10-membered bicyclic heterocyclyl or an 8- to 10-membered bicyclic carbocyclyl, wherein Ring A is attached to Ring B and Ring C via two adjacent atoms.431ME1\60337174.v1141039-0012030. The compound of any one of Claims 1 and 3 to 29, or a pharmaceutically acceptable salt thereof, wherein Ring A is a 9-membered bicyclic heterocyclyl or 9-membered bicyclic carbocyclyl.

31. The compound of any one of Claims 1 and 3 to 30, or a pharmaceutically acceptable salt thereof, wherein Ring A is dihydrocyclopentapyridinyl or dihydroindenyl.

32. The compound of any one of Claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein Ring A is dihydrocyclopentapyridinyl.

33. The compound of any one of Claims 1 and 3 to 32, or a pharmaceutically acceptable salt thereof, wherein Ring A isR or R, wherein the squiggly line indicates the connection to Ring C and the dotted line indicates the connection to Ring B.

34. The compound of any one of Claims 1 to 33, or a pharmaceutically acceptable salt thereof, wherein Ring A isR wherein the squiggly line indicates the connection to Ring C and the dotted line indicates the connection to Ring B.

35. The compound of any one of Claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein Ring A is 8- to 10-membered bicyclic heteroaryl.

36. The compound of any one of Claims 1 to 28 and 35, or a pharmaceutically acceptable salt thereof, wherein Ring A is thienopyridinyl.

37. The compound of any one of Claims 1 to 36, or a pharmaceutically acceptable salt thereof, wherein Ring A is432ME1\60337174.v1141039-00120JV IWVPR'IR538. The compound of any one of Claims 1 to 37, or a pharmaceutically acceptable salt thereof, wherein Ring A isN^P''R6I R5R wherein the squiggly line indicates the connection to Ring C and the dotted line indicates the connection to Ring B.

39. The compound of any one of Claims 1 to 38, or a pharmaceutically acceptable salt thereof, wherein R5is hydrogen.

40. The compound of any one of Claims 1 to 39, or a pharmaceutically acceptable salt thereof, wherein R6is hydrogen.

41. The compound of any one of Claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein Ris phenyl, 5- to 6-membered monocyclic heteroaryl, 7- to 10-membered bicyclic heterocyclyl, 8- to 10-membered bicyclic heteroaryl, or C≡C-R7, wherein each of said phenyl, 5- to 6-membered monocyclic heteroaryl, 7- to 10-membered bicyclic heterocyclyl, and 8- to 10-membered bicyclic heteroaryl are optionally substituted with 1 to 3 groups selected from Rx.

42. The compound of any one of Claims 1 to 41, or a pharmaceutically acceptable salt thereof, wherein R is phenyl, 6-membered monocyclic heteroaryl, 9-membered bicyclic heteroaryl, 10-membered bicyclic heterocyclyl, or C≡C-R7, wherein each of said phenyl, 6-membered monocyclic heteroaryl, 9-membered bicyclic heteroaryl, and 10-membered bicyclic heterocyclyl are optionally substituted with 1 to 3 groups selected from Rx.

43. The compound of any one of Claims 1 to 42, or a pharmaceutically acceptable salt thereof, wherein R is phenyl, pyridinyl, indazolyl, tetrahydroisoquinolinyl,433ME1\60337174.v1141039-00120tetrahydronaphthyridinyl, pyrazolopyridinyl, or C≡C-R7, wherein each of said phenyl, indazolyl, and tetrahydroisoquinolinyl are optionally substituted with 1 to 3 groups selected from Rx.

44. The compound of any one of Claims 1 to 43, or a pharmaceutically acceptable salt thereof, wherein R is 5- to 6-membered monocyclic heteroaryl, 7- to 10-membered bicyclic heterocyclyl, or 8- to 10-membered bicyclic heteroaryl, each of which are optionally substituted with 1 to 3 groups selected from Rx.

45. The compound of any one of Claims 1 to 44, or a pharmaceutically acceptable salt thereof, wherein R is 6-membered monocyclic heteroaryl, 9-membered bicyclic heteroaryl, 9-membered bicyclic heterocyclyl, or 10-membered bicyclic heterocyclyl, each of which are optionally substituted with 1 to 3 groups selected from Rx.

46. The compound of any one of Claims 1 to 45, or a pharmaceutically acceptable salt thereof, wherein R is pyridinyl, dihydroimidazopyridin-2-onyl, tetrahydronaphthyridinyl, dihydropyrrolopyridin-7-onyl, dihydropyrrolopyridin-5-onyl, dihydropyrrolopyridinyl, pyrazolopyridinyl, or imidazopyridinyl, each of which are optionally substituted with 1 to 3 groups selected from Rx.

47. The compound of any one of Claims 1 to 46, or a pharmaceutically acceptable salt thereof, wherein Rxis (C1-C4)alkyl, halo(C1-C4)alkyl, halo(C1-C4)alkoxy, NHS(O)2NH2or (C1-C4)alkyleneNR8R9.

48. The compound of any one of Claims 1 to 47, or a pharmaceutically acceptable salt thereof, wherein R8is (C1-C4)alkyl.

49. The compound of any one of Claims 1 to 48, or a pharmaceutically acceptable salt thereof, wherein R9is (C1-C4)alkyl.

50. The compound of any one of Claims 1 to 43 and 47 to 49, or a pharmaceutically acceptable salt thereof, wherein R7is 5- to 6-membered monocyclic heteroaryl optionally substituted with 1 to 3 groups selected from Rz.434ME1\60337174.v1141039-0012051. The compound of any one of Claims 1 to 43 and 47 to 50, or a pharmaceutically acceptable salt thereof, wherein R7is pyridinyl optionally substituted with 1 to 3 groups selected from Rz.

52. The compound of any one of Claims 1 to 43 and 47 to 51, or a pharmaceutically acceptable salt thereof, wherein Rzis hydroxy(C1-C4)alkyl.

53. The compound of any one of Claims 1 and 3 to 28, or a pharmaceutically acceptable435ME1\60337174.v1141039-00120436ME1\60337174.v1141039-00120437ME1\60337174.v1141039-00120438ME1\60337174.v1141039-00120439ME1\60337174.v1141039-00120440ME1\60337174.v1141039-00120 w -tb °T?;v " 'N 0-J 0-J O441ME1\60337174.v1141039-00120442ME1\60337174.v1141039-00120443ME1\60337174.v1141039-00120, wherein the squiggly line indicates the connection to Ring C and the dotted line indicates the connection to Ring B.

54. The compound of any one of Claims 1 and 3 to 28, or a pharmaceutically acceptable444ME1\60337174.v1141039-00120445ME1\60337174.v1141039-00120446ME1\60337174.v1141039-00120447ME1\60337174.v1141039-00120448ME1\60337174.v1141039-00120449ME1\60337174.v1141039-00120450ME1\60337174.v1141039-00120451ME1\60337174.v1141039-00120line indicates the connection to Ring C and the dotted line indicates the connection to Ring B.

55. The compound of any one of Claims 1 to 28 and 54, or a pharmaceutically acceptable452ME1\60337174.v1141039-00120 56. The compound of any one of Claims 1, 3 to 28, 54 and 55, or a pharmaceuticallyC and the dotted line indicates the connection to Ring B.453ME1\60337174.v1141039-0012057. The compound of any one of Claims 1, 3 to 28, 54 and 55, or a pharmaceuticallyO, wherein the squiggly line indicates the connection to Ring C and the dotted line indicates the connection to Ring B.

58. The compound of any one of Claims 1 to 57, or a pharmaceutically acceptable salt thereof, wherein Ring C is 8- to 10-membered bicyclic heterocyclyl.454ME1\60337174.v1141039-0012059. The compound of any one of Claims 1 to 58, or a pharmaceutically acceptable salt thereof, wherein Ring C is tetrahydropyrroloimidazolyl, tetrahydroimidazopyridinyl, or -hexahydroimidazoazepinyl.

60. The compound of any one of Claims 1 to 59, or a pharmaceutically acceptable salt thereof, wherein Ring C is tetrahydroimidazopyridinyl.

61. The compound of any one of Claims 1 to 60, or a pharmaceutically acceptable saltline indicates the connection to L and the dotted line indicates the connection to Ring A.

62. The compound of any one of Claims 1 to 61, or a pharmaceutically acceptable salt thereof, wherein Ring C is63. The compound of any one of Claims 1 to 62, or a pharmaceutically acceptable salt thereof, wherein Ring C is455ME1\60337174.v1141039-00120squiggly line indicates the connection to L and the dotted line indicates the connection to Ring A.

64. The compound of any one of Claims 1 to 63, or a pharmaceutically acceptable salt thereof, wherein Ring C isR3R3AVN HN l| HNt1| / )--- V\-< NR4, or R4, wherein the squiggly line indicates the connection to L and the dotted line indicates the connection to Ring A.

65. The compound of any one of Claims 1 to 64, or a pharmaceutically acceptable salt thereof, wherein Ring C is, wherein the squiggly line indicates the connection to L and the dotted line indicates the connection to Ring A.

66. The compound of any one of Claims 1 to 65, or a pharmaceutically acceptable salt thereof, wherein R3is hydrogen or methyl.

67. The compound of any one of Claims 1 to 66, or a pharmaceutically acceptable salt thereof, wherein R3is hydrogen.

68. The compound of any one of Claims 1 to 67, or a pharmaceutically acceptable salt thereof, wherein R4is -Yb-Wb, cyano, or (C3-C6)cycloalkenyl optionally subsitited with 1 to 3 groups selected from Rxl.

69. The compound of any one of Claims 1 to 68, or a pharmaceutically acceptable salt thereof, wherein R4is -Yb-Wb.456ME1\60337174.v1141039-0012070. The compound of any one of Claims 1 and 3 to 69, or a pharmaceutically acceptable salt thereof, wherein Ybis a bond, C(O), CH2, or SO2.

71. The compound of any one of Claims 1 to 70, or a pharmaceutically acceptable salt thereof, wherein Ybis C(O).

72. The compound of any one of Claims 1 to 71, or a pharmaceutically acceptable salt thereof, wherein Wbis -CH2R8, -CR8=CR10R11, (C3-C6)cycloalkenyl, or -C≡CR11.

73. The compound of any one of Claims 1 to 72, or a pharmaceutically acceptable salt thereof, wherein Wbis -CR8=CR10R11.

74. The compound of any one of Claims 1 and 3 to 73, or a pharmaceutically acceptable salt thereof, wherein R8is CN, halogen, hydrogen, or (C1-C3)alkylenecyano.

75. The compound of any one of Claims 1 and 3 to 74, or a pharmaceutically acceptable salt thereof, wherein R8is hydrogen or halo.

76. The compound of any one of Claims 1 and 3 to 75, or a pharmaceutically acceptable salt thereof, wherein R8is hydrogen or fluoro.

77. The compound of any one of Claims 1 to 76, or a pharmaceutically acceptable salt thereof, wherein R8is hydrogen.

78. The compound of any one of Claims 1 and 3 to 77, or a pharmaceutically acceptable salt thereof, wherein R10and R11are each hydrogen, halogen, C1-3haloalkyl, C1-3alkyl, (C1-C3)alkyleneNR8R9, (C1-C3)alkoxy, (C1-C3)alkylene 4- to 8-membered monocyclic heterocyclyl, or C(O)NH(C1-3alkyl).

79. The compound of any one of Claims 1 to 78, or a pharmaceutically acceptable salt thereof, wherein R10and R11are each hydrogen.457ME1\60337174.v1141039-0012080. The compound of any one of Claims 1 to 78, or a pharmaceutically acceptable salt thereof, wherein R10is hydrogen or halo.

81. The compound of any one of Claims 1 to 78 and 80, or a pharmaceutically acceptable salt thereof, wherein R10is hydrogen or fluoro.

82. The compound of any one of Claims 1 to 81, or a pharmaceutically acceptable salt thereof, wherein R11is hydrogen or halo(C1-C3)alkyl.

83. The compound of any one of Claims 1 to 82, or a pharmaceutically acceptable salt thereof, wherein each RX1is independently, oxo or C1-3alkoxy.

84. The compound of any one of Claims 1 and 3 to 83, or a pharmaceutically acceptable458ME1\60337174.v1141039-00120459ME1\60337174.v1141039-00120connection to L and the dotted line indicates the connection to Ring A460ME1\60337174.v1141039-00120 85. The compound of any one of Claims 1 and 3 to 84, or a pharmaceutically acceptable461ME1\60337174.v1141039-00120indicates the connection to Ring A.

86. The compound of any one of Claims 1 to 85, or a pharmaceutically acceptable saltindicates the connection to L and the dotted line indicates the connection to Ring A.

87. The compound of any one of Claims 1 and 3 to 86, or a pharmaceutically acceptable, wherein the squiggly line indicates the connection to L and the dotted line indicates the connection to Ring A.

88. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the following formula (IVA):462ME1\60337174.v1141039-00120wherein L is selected fromwherein the squiggly line indicates the connection to Ring C and the dotted line indicates the connection to phenyl ring;connection to L and the dotted line indicates the connection to Ring A.

89. The compound selected from Examples 1-1 to 1-10, 2-1 to 2-31, 3-1 to 3-173, 4-1 to 4-9, 5-1 to 5-17, 6-1, 7-1 to 7-11, 8-1 to 8-92, 9-1 to 9-17, 10, 11, 12-1 to 12-6, 13-1 to 13-44 or a pharmaceutically acceptable salt thereof.

90. A pharmaceutical composition comprising a compound of any one of Claims 1 to 89, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.463ME1\60337174.v1141039-0012091. A method of treating a disease or disorder responsive to the modulation of PI3K comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of Claims 1 to 89, or a pharmaceutically acceptable salt thereof.

92. The method of Claim 91, wherein the disease or disorder is responsive to the modulation of RAS-PI3K.

93. The method of Claim 91 or 92, wherein the disease or disorder is cancer.

94. The method of Claim 93, wherein the cancer is selected from bladdercancer, uterine cancer, head and neck cancer, esophageal cancer, ovarian cancer, liver cancer, cervical cancer, lung cancer, colorectal cancer, cholangiocarcinoma, gastric cancer, kidney cancer, and pancreatic cancer.464ME1\60337174.v1

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