Compounds and pharmaceutical compositions that degrade swi / snf-related matrix-associated actin-dependent regulator of chromatin subfamily a

Abstract

Disclosed are compounds that are useful for modulating or degrading protein which is expressed from one or more SWI / SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A (SMARCA) (e.g., SMARCA2 and / or SMARCA4).

Description

COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS THAT DEGRADE SWI / SNF- RELATED MATRIX-ASSOCIATED ACTIN-DEPENDENT REGULATOR OF CHROMATIN SUBFAMILY A CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit under 35 U.S.C. § 119(e) of United States ProvisionalApplication Numbers 63 / 598,019, filed November 10, 2023, and 63 / 673,138, filed July 18, 2024, the contents of which are hereby incorporated by reference in their entireties. Field

[0001] This disclosure provides for compounds, including pharmaceutically acceptable salts thereof, thatare useful as modulators of targeted ubiquitination. The compounds disclosed herein bind to and degrade protein which is expressed from one or more SWI / SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A (“SMARCA”). Also disclosed are pharmaceutical compositions comprising the compounds, and methods of using such compounds in the treatment of various SMARCA-mediated diseases or disorders. State of the Art

[0002] Ubiquitin-Proteasome Pathway (UPP) is a critical pathway that regulates key regulator proteinsand degrades misfolded or abnormal proteins. UPP is central to multiple cellular processes, and ifdefective or imbalanced, it leads to pathogenesis of a variety of diseases. The covalent attachment ofubiquitin to specific protein substrates is achieved through the action of E3 ubiquitin ligases.

[0003] There are over 600 E3 ubiquitin ligases which facilitate the ubiquitination of different proteins invivo, which can be divided into four families: HECT-domain E3s, U-box E3s, monomeric RING E3s and multi-subunit E3s. See e.g., Li et al. “Genome-wide and functional annotation of human E3 ubiquitin ligases identifies MULAN, a mitochondrial E3 that regulates the organelle’s dynamics and signaling.” PLOS One 2008, (3) 1487; Berndsen et al. “New insights into ubiquitin E3 ligase mechanism” Nat. Struct. Mol. Biol.2014, 21:301; Deshaies et al. “RING domain E3 ubiquitin ligases” Ann. Rev. Biochem.2009, 78:399; Sprattetal. “RBRE3 ubiquitin ligases: new structures, new insights, new questions” Biochem.2014, 458:421; and Wang et al., “Roles of F-box proteins in cancer” Nat. Rev. Cancer.2014, 14:233.

[0004] UPP plays a key role in the degradation of short-lived and regulatory proteins important in avariety of basic cellular processes, including regulation of the cell cycle, modulation of cell surface receptors and ion channels, and antigen presentation. The pathway has been implicated in several forms of malignancy, in the pathogenesis of several genetic diseases (including cystic fibrosis, Angelman’s syndrome, and Liddle syndrome), in immune surveillance / viral pathogenesis, and in the pathology of muscle wasting. Many diseases are associated with an abnormal UPP and negatively affect cell cycle and division, the cellular response to stress and to extracellular modulators, morphogenesis of neuronal networks, modulation of cell surface receptors, ion channels, the secretory pathway, DNA repair, and biogenesis of organelles.

[0005] Aberrations in the process have recently been implicated in the pathogenesis of several diseases,both inherited and acquired. These diseases fall into two major groups: (a) those that result from loss of function with the resultant stabilization of certain proteins, and (b) those that result from gain of function, i.e. abnormal or accelerated degradation of the protein target.

[0006] The UPP is used to induce selective protein degradation, including use of fusion proteins toartificially ubiquitinate target proteins and synthetic small-molecule probes to induce proteasome-dependent degradation. Compounds that act as molecular glues can induce or stabilize protein-proteininteractions between a target protein and an E3 ubiquitin ligase ligand, leading to protein ubiquitination and subsequent proteasome-mediated degradation via the recruitment to E3 ubiquitin ligase and subsequent ubiquitination. These drug-like molecules offer the possibility of temporal control over protein expression. Such compounds are capable of inducing the inactivation of a protein of interest uponaddition to cells or administration to an animal or human, and could be useful as biochemical reagentsand lead to a new paradigm for the treatment of diseases by removing pathogenic or oncogenic proteins. See e.g., Crews, Chem. & Biol.2010, 17 (6): 551; Schneekloth and Crews, Chem Bio Chem., 2005, 6 (1): 40.

[0007] An ongoing need exists in the art for effective treatments for disease, especially hyperplasias andcancers. However, non-specific effects, and the inability to target and modulate certain classes of proteins altogether, such as transcription factors, remain as obstacles to the development of effective anti-cancer agents. As such, small molecule therapeutic agents that leverage E3 ligase mediated protein degradation to target cancer-associated proteins, such as one or more SWESNF-related matrix-associated actin- dependent regulator of chromatin subfamily A (“SMARCA”) and / or polybromo-1 (“PB1”) protein, hold promise as therapeutic agents. Accordingly, there remains a need to find compounds that are degraders of protein which is expressed from the SMARCA gene useful as therapeutic agents. Summary

[0008] Disclosed are compounds and pharmaceutically acceptable salts thereof, pharmaceuticalcompositions comprising said compounds or pharmaceutically acceptable salts thereof, and methods foruse of said compounds, pharmaceutically acceptable salts thereof, and pharmaceutical compositionsthereof, which find utility as inducers of targeted ubiquitination of protein which is expressed from the SMARCA gene, which are then degraded and / or inhibited by the monovalent compounds as described herein. An advantage of the compounds provided herein is that a broad range of pharmacological activities are possible, consistent with the degradation / inhibition of protein which is expressed from the SMARCA gene. In addition, the disclosure provides methods of using an effective amount of the compounds as described herein for the treatment or amelioration of a disease condition, such as cancer, e.g., lung cancer, in a subject in need thereof.

[0009] Provided herein is a compound of Formula I:or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopically enriched analog, or tautomer thereof, wherein: n is 0, 1, or 2; R1 is OR12, halo, cyano, C1-4 alkoxy, N(R2)2, or C(O)CH(C1-4 alkyl)N(R2)2;each R2is independently hydrogen, C1-4alkyl, or C3-6cycloalkyl, wherein each alkyl or cycloalkyl is unsubstituted or substituted with one to three Z1; each R3is independently halo, cyano, C1-6 alkyl, or C1-3 haloalkyl; L1is a bond, C1-4 alkylene, -C1-4 alkylene-heteroaryl-, C2-3 alkenylene, C2-3 alkynylene, or -C(O)-; X is selected from:andRing A is a monocyclic, spirocyclic, fused bicyclic, or bridged bicyclic 4-10 membered heterocyclyl or a monocyclic or fused bicyclic 5-10 membered heteroaryl; Ring B is a monocyclic, spirocyclic, fused bicyclic, or bridged bicyclic 3-10 membered cycloalkyl, a monocyclic, spirocyclic, fused bicyclic, or bridged bicyclic 4-10 membered heterocyclyl, ora monocyclic or fused bicyclic 5-10 membered heteroaryl; wherein the nitrogen atom and L1 may beattached via any atom on Ring B, including on the same carbon atom; each R4is independently oxo, halo, cyano, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -C(O)R11, -C(O)OR11, -S(O)0-2R11, -NR11S(O)0-2R11, -S(O)0-2N(R11)2, -NR11S(O)0-2N(R11)2, -NR11C(O)N(R11)2, -C(O)N(R11)2, -NR11C(O)R11, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to eight Z1; R5is hydrogen, halo, cyano, or C1-6alkyl optionally substituted with one to three Z1; R6is hydrogen, halo, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -C(O)R11, -C(O)OR11, -S(O)0-2R11, -NR11S(O)0-2R11, -S(O)0-2N(R11)2, -NR11S(O)0-2N(R11)2, -NR11C(O)N(R11)2, -C(O)N(R11)2, -NR11C(O)R11, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to eight Z1;R7is hydrogen, halo, cyano, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -C(O)R11, -C(O)OR11, -S(O)0-2R11, -NR11S(O)0-2R11, -S(O)0-2N(R11)2, -NR11S(O)0-2N(R11)2, -NR11C(O)N(R11)2, -C(O)N(R11)2, -NR11C(O)R11, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to eight Z1; R8is hydrogen or C1-6alkyl optionally substituted with one to three Z1; R9 is hydrogen, -C(O)R13, -C(R13)2OC(O)R15, -C(O)OCH2OC(O)R15,-C(O)OCH(CH3)OC(O)R15, -C(O)OCH2OC(O)R15, -C(O)OCH(CH3)OC(O)R15, -(CH2)mOP(O)(OR14)2,-CH(CH3)OP(O)(OR14)2, -(CH2)mOP(O)(R14)(OR14), -CH(CH3)OP(O)(R14)(OR14),-(CH2)mOP(O)(N(R14)2)(OR14), -CH(CH3)OP(O)(N(R14)2)(OR14), -(CH2)mOP(O)(R14)(N(R14)2),-(CH2)mOP(O)(N(R14)2)2, or -C(CH3)OP(O)(N(R14)2)2;m is 1 or 2; each Z1is independently halo, cyano, -NO2, -SF5, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -P(O)(OR11)2, -C(O)R11, -C(O)OR11, -S(O)0-2R11, -NR11S(O)0-2R11, -S(O)0-2N(R11)2, -NR11S(O)0-2N(R11)2, -NR11C(O)N(R11)2, -C(O)N(R11)2, -NR11C(O)R11, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a; each R11is independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a; each Z1ais independently hydroxy, halo, cyano, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R13)2, -OR13, -P(O)(OR13)2, -C(O)R13, -C(O)OR13, -S(O)0-2R13, -NR13S(O)0-2R13, -S(O)0-2N(R13)2, -NR13S(O)0-2N(R13)2, -NR13C(O)N(R13)2, -C(O)N(R13)2, -NR13C(O)R13, -OC(O)N(R13)2, or -NR13C(O)OR13; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1b; R12 is hydrogen, -C(O)R13, -C(O)N(R14)2, -P(O)(OR14)2, -CH2OP(O)(OR14)2,-CH(CH3)OP(O)(OR14)2, -P(O)(R14)(OR14), -CH2OP(O)(R14)(OR14), -CH(CH3)OP(O)(R14)(OR14),-P(O)(N(R14)2)(OR14), -CH2OP(O)(N(R14)2)(OR14), -CH(CH3)OP(O)(N(R14)2)(OR14), -P(O)(R14)(N(R14)2), -CH2OP(O)(R14)(N(R14)2), -CH(CH3)OP(O)(R14)(N(R14)2), -P(O)(N(R14)2)2,-CH2OP(O)(N(R14)2)2, or -CH(CH3)OP(O)(N(R14)2)2; each R13is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1b;each R14is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, aryl, heteroaryl, or heterocyclyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is independently optionally substituted with one to five Z1b; or two R14together with the atom to which they are attached form a heterocyclyl; wherein said heterocyclyl is independently optionally substituted one to five Z1b; R15is independently R16, -OR16, -SR16, or -N(R16)2; each R16is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, aryl, heteroaryl, or heterocyclyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is independently optionally substituted with one to five Z1b; each Z1b is independently halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, -P(O)(OH)2, C1-6 alkyl,C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-C1-6 alkyl, -L- C2-6alkenyl, -L-C2-6alkynyl, -L-C1-6haloalkyl, -L-C3-10cycloalkyl, -L-heterocyclyl, -L-aryl, or -L- heteroaryl; and each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6alkyl)-, -N(C2-6alkenyl)-, -N(C2-6alkynyl)-, -N(C1-6haloalkyl)-, -N(C3-10cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-6 alkyl)-, -C(O)N(C2-6 alkenyl)-, -C(O)N(C2-6 alkynyl)-, -C(O)N(C1-6 haloalkyl)-, -C(O)N(C3-10 cycloalkyl)-, -C(O)N(heterocyclyl)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)-, -S(O)2NH-, -P(O)(OH)O-, -P(O)(O-C1-6alkyl)O-, -P(O)(O-C2-6alkenyl)-O, -P(O)(O-C2-6alkynyl)O-, -P(O)(OC1-6haloalkyl)O-, -P(O)(OC3-10cycloalkyl)O-, -P(O)(O-heterocyclyl)O-, -P(O)(O-aryl)O-, or -P(O)(O-heteroaryl)O-; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, and heteroaryl of Z1band L is further independently optionally substituted with one to five hydroxy, halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0010] In some embodiments, the compound is not 1-[3-[3-(2-hydroxyphenyl)-7H-pyrrolo[2,3-c]pyridazin-6-yl]-1-azetidinyl]-2-propen-1-one.

[0011] In some embodiments, the compounds as described herein modulate protein which is expressedfrom the SMARCA gene. In some embodiments, the compounds as described herein degrade protein which is expressed from the SMARCA gene. In some embodiments, the protein which is modulated or degraded is expressed from the SMARCA gene member 2 (SMARCA2). In some embodiments, the protein which is modulated or degraded is expressed by the SMARCA gene member 4 (SMARCA4).

[0012] In some embodiments, this disclosure provides a pharmaceutical composition comprising apharmaceutically acceptable excipient and an effective amount of a compound of Formula I or any subformula thereof, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopically enriched analog, tautomer thereof.

[0013] In some embodiments, this disclosure provides a method for modulating or degrading proteinwhich is expressed from the SMARCA gene, which method comprises contacting the protein with aneffective amount of a compound of Formula I or any subformula thereof under conditions wherein the protein which is expressed from the SMARCA gene is bound to said compound and modulated or degraded. In some embodiments, the protein which is modulated or degraded is the protein which is expressed from the SMARCA2 gene. In some embodiments, the protein which is modulated or degraded is the protein which is expressed from the SMARCA4 gene.

[0014] In some embodiments, this disclosure provides a method for modulating or degrading proteinwhich is expressed from the SMARCA gene in a subject, which method comprises administering to said subject an effective amount of a compound of Formula I or any subformula thereof, or a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of Formula I or any subformula thereof under conditions wherein the protein which is expressed from the SMARCA gene is bound to said compound and modulated or degraded. In some embodiments, the protein which is modulated or degraded in a subject is the protein which is expressed from the SMARCA2 gene. In some embodiments, the protein which is modulated or degraded in a subject is the protein which is expressed from the SMARCA4 gene.

[0015] In some embodiments, this disclosure provides a method for treating hyperplasia in a subject inneed thereof, which method comprises administering to said subject an effective amount of a compoundof Formula I or any subformula thereof, or a pharmaceutical composition comprising a pharmaceuticallyacceptable excipient and an effective amount of a compound of Formula I or any subformula thereof.

[0016] In some embodiments, this disclosure provides a method for treating cancer in a subject in needthereof, which method comprises administering to said subject an effective amount of a compound of Formula I or any subformula thereof, or a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of Formula I or any subformula thereof. Detailed Description

[0017] This disclosure provides for compounds, pharmaceutical compositions comprising suchcompounds, and methods of using such compounds and compositions to treat diseases, disorders, or conditions mediated, at least in part, by SMARCA2 or SMARCA4 transcription factors. However, prior to providing a detailed description of the disclosure, the following terms will first be defined. If not defined, terms used herein have their generally accepted scientific meaning.

[0018] The terminology used herein is for the purpose of describing particular embodiments only and isnot intended to be limiting of the disclosure. As used herein, the singular forms “a”, “an,” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise.

[0019] A dash (“that is not between two letters or symbols is used to indicate a point of attachmentfor a substituent. For example, -C(O)NH2 is attached through the carbon atom. A dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. A wavy line or a dashed line drawn through a line in a structure indicates a specified point of attachment of a group. Unless chemically or structurally required, no directionality or stereochemistry is indicated or implied by the order in which a chemical group is written or named.

[0020] The prefix Cu-v indicates that the following group has from u to v carbon atoms. For example,“C1-6 alkyl” indicates that the alkyl group has from 1 to 6 carbon atoms.

[0021] The term “about” when used before a numerical designation, e.g., temperature, time, amount,concentration, and such other, including a range, indicates approximations which may vary by ( + ) or( - ) 10%, 5%, 1%, or any subrange or subvalue there between. In one embodiment, the term “about”when used with regard to a dose amount means that the dose may vary by + / - 10%.

[0022] “Comprising” or “comprises” is intended to mean that the compositions and methods include therecited elements, but not excluding others.

[0023] “Consisting essentially of” when used to define compositions and methods, shall mean excludingother elements of any essential significance to the combination for the stated purpose. Thus, a composition consisting essentially of the elements as defined herein would not exclude other materials or steps that do not materially affect the basic and novel characteristic(s) of the claimed disclosure.

[0024] “Consisting of” shall mean excluding more than trace elements of other ingredients andsubstantial method steps. Embodiments defined by each of these transition terms are within the scope of this disclosure.

[0025] “Alkyl” refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkylhas 1 to 20 carbon atoms (i.e., C1-20 alkyl), 1 to 12 carbon atoms (i.e., C1-12 alkyl), 1 to 8 carbon atoms (i.e., C1-8 alkyl), 1 to 6 carbon atoms (i.e., C1-6 alkyl), or 1 to 4 carbon atoms (i.e., C1-4 alkyl). Examples of alkyl groups include, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl,pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkylresidue having a specific number of carbons is named by chemical name or identified by molecular formula, all positional isomers having that number of carbons may be encompassed; thus, for example, “butyl” includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3); and “propyl” includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0026] Certain commonly used alternative chemical names may be used. For example, a divalent groupsuch as a divalent “alkyl” group, a divalent “aryl” group, a divalent heteroaryl group, etc., may also be referred to as an “alkylene” group or an “alkylenyl” group (for example, methylenyl, ethylenyl, and propylenyl), an “arylene” group or an “arylenyl” group (for example, phenylenyl or napthylenyl, or quinolinyl for heteroarylene), respectively. Also, unless indicated explicitly otherwise, where combinations of groups are referred to herein as one moiety, e.g., arylalkyl or aralkyl, the last mentioned group contains the atom by which the moiety is attached to the rest of the molecule.

[0027] “Alkenyl” refers to an alkyl group containing at least one (e.g., 1-3, or 1) carbon-carbon doublebond and having from 2 to 20 carbon atoms (i.e., C2-20 alkenyl), 2 to 12 carbon atoms (i.e., C2-12alkenyl), 2 to 8 carbon atoms (i.e., C2-8alkenyl), 2 to 6 carbon atoms (i.e., C2-6alkenyl), or 2 to 4 carbon atoms (i.e., C2-4alkenyl). Examples of alkenyl groups include, e.g., ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0028] Alkynyl refers to an alkyl group containing at least one (e.g., 1-3, or 1) carbon-carbon triplebond and having from 2 to 20 carbon atoms (i.e., C2-20 alkynyl), 2 to 12 carbon atoms (i.e., C2-12 alkynyl), 2 to 8 carbon atoms (i.e., C2-8 alkynyl), 2 to 6 carbon atoms (i.e., C2-6 alkynyl), or 2 to 4 carbon atoms (i.e., C2-4alkynyl). The term “alkynyl” also includes those groups having one triple bond and one double bond.

[0029] “Alkoxy” refers to the group “alkyl-O-”. Examples of alkoxy groups include, e.g., methoxy,ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0030] “Alkylthio” refers to the group “alkyl-S-”. “Alkylsulfinyl” refers to the group “alkyl-S(O)-”.“Alkylsulfonyl” refers to the group “alkyl-S(O)2-”. “Alkylsulfonylalkyl” refers to -alkyl-S(O)2-alkyl.

[0031] “Acyl” refers to a group -C(O)Ry, wherein Ry is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be unsubstituted or substituted, as defined herein. Examples of acyl include, e.g., formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl- carbonyl, and benzoyl.

[0032] “Amido” refers to both a “C-amido” group which refers to the group -C(O)NRyRz and an“N-amido” group which refers to the group -NRyC(O)Rz, wherein Ryand Rzare independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be unsubstituted or substituted, as defined herein, or Ryand Rzare taken together to form a cycloalkyl or heterocyclyl; each of which may be unsubstituted or substituted, as defined herein.

[0033] “Amino” refers to the group -NRyRz wherein Ry and Rz are independently hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be unsubstituted or substituted, as defined herein.

[0034] “Amidino” refers to -C(NRy)(NRz2), wherein Ry and Rz are independently hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be unsubstituted or substituted, as defined herein.

[0035] “Aryl” refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiplerings (e.g., bicyclic or tricyclic) including fused systems. As used herein, aryl has 6 to 20 ring carbon atoms (i.e., C6-20aryl), 6 to 12 carbon ring atoms (i.e., C6-12aryl), or 6 to 10 carbon ring atoms (i.e., C6-10aryl). Examples of aryl groups include, e.g., phenyl, naphthyl, fluorenyl, and anthryl. Aryl, however, does not encompass or overlap in any way with heteroaryl defined below. If one or more aryl groups are fused with a heteroaryl, the resulting ring system is heteroaryl regardless of point of attachment. If one or more aryl groups are fused with a heterocyclyl, the resulting ring system is heterocyclyl regardless of point of attachment. If one or more aryl groups are fused with a cycloalkyl, the resulting ring system is cycloalkyl regardless of point of attachment.

[0036] “Carbamoyl” refers to both an “O-carbamoyl” group which refers to the group -O-C(O)NRyRzand an “N-carbamoyl” group which refers to the group -NRyC(O)ORz, wherein Ryand Rzare independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be unsubstituted or substituted, as defined herein.

[0037] Carboxyl ester or ester refer to both -OC(O)R and -C(O)OR , wherein R is alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be unsubstituted or substituted, as defined herein.

[0038] “Cycloalkyl” refers to a saturated or partially unsaturated cyclic alkyl group having a single ringor multiple rings including fused, bridged, and spiro ring systems. The term “cycloalkyl” includes cycloalkenyl groups (i.e., the cyclic group having at least one double bond) and carbocyclic fused ring systems having at least one sp3carbon atom (i.e., at least one non-aromatic ring). As used herein, cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C3-20 cycloalkyl), 3 to 14 ring carbon atoms (i.e., C3-14 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C3-6 cycloalkyl). Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic groups include, for example, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Further, the term cycloalkyl is intended to encompass any non-aromatic ring which may be fused to an aryl ring, regardless of the attachment to the remainder of the molecule. Still further, cycloalkyl also includes “spirocycloalkyl” when there are two positions for substitution on the same carbon atom, for example spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro[5.5]undecanyl.

[0039] “Imino” refers to a group -C(NRy)Rz, wherein Ry and Rz are each independently hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be unsubstituted or substituted, as defined herein.

[0040] “Imido” refers to a group -C(O)NRyC(O)Rz, wherein Ry and Rz are each independently hydrogen,alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be unsubstituted or substituted, as defined herein.

[0041] “Halogen” or “halo” refers to atoms occupying group VIIA of the periodic table, such as fluoro,chloro, bromo, or iodo.

[0042] “Haloalkyl” refers to an unbranched or branched alkyl group as defined above, wherein one ormore (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by a halogen. For example, where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be, but are not necessarily, the same halogen. Examples of haloalkyl include, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0043] “Haloalkoxy” refers to an alkoxy group as defined above, wherein one or more (e.g., 1 to 6 or1 to 3) hydrogen atoms are replaced by a halogen.

[0044] “Hydroxyalkyl” refers to an alkyl group as defined above, wherein one or more (e.g., 1 to 6 or1 to 3) hydrogen atoms are replaced by a hydroxy group.

[0045] “Heteroalkyl” refers to an alkyl group in which one or more of the carbon atoms (and anyassociated hydrogen atoms), excluding any terminal carbon atom(s), are each independently replacedwith the same or different heteroatomic group, provided the point of attachment to the remainder of the molecule is through a carbon atom. The term “heteroalkyl” includes unbranched or branched saturated chain having carbon and heteroatoms. By way of example, 1, 2 or 3 carbon atoms may be independently replaced with the same or different heteroatomic group. Heteroatomic groups include, but are not limited to, -NRy-, -O-, -S-, -S(O)-, -S(O)2-, and the like, wherein Ryis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be unsubstituted or substituted, as defined herein. Examples of heteroalkyl groups include, e.g., ethers (e.g., -CH2OCH3, -CH(CH3)OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, etc.), thioethers (e.g., -CH2SCH3, -CH(CH3)SCH3, -CH2CH2SCH3,-CH2CH2SCH2CH2SCH3, etc.), sulfones (e.g., -CH2S(O)2CH3, -CH(CH3)S(O)2CH3, -CH2CH2S(O)2CH3, -CH2CH2S(O)2CH2CH2OCH3, etc.), and amines (e.g., -CH2NRyCH3, -CH(CH3)NRyCH3, -CH2CH2NRyCH3, -CH2CH2NRyCH2CH2NRyCH3, etc., where Ryis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be unsubstituted or substituted, as defined herein). As used herein, heteroalkyl includes 2 to 10 carbon atoms, 2 to 8 carbon atoms, or 2 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

[0046] “Heteroaryl” refers to an aromatic group having a single ring, multiple rings or multiple fusedrings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. Asused herein, heteroaryl includes 1 to 20 ring carbon atoms (i.e., C1-20 heteroaryl), 3 to 12 ring carbonatoms (i.e., C3-12heteroaryl), or 3 to 8 carbon ring atoms (i.e., C3-8heteroaryl), and 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ringheteroatom independently selected from nitrogen, oxygen, and sulfur. In certain instances, heteroarylincludes 5-10 membered ring systems, 5-7 membered ring systems, or 5-6 membered ring systems, each independently having 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, e.g., acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl,isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoquinolyl, isoxazolyl, naphthyridinyl,oxadiazolyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl,pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl,thiophenyl (i.e., thienyl), triazolyl, tetrazolyl, and triazinyl. Examples of the fused-heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, where theheteroaryl can be bound via either ring of the fused system. Any aromatic ring, having a single ormultiple fused rings, containing at least one heteroatom, is considered a heteroaryl regardless of the attachment to the remainder of the molecule (i.e., through any one of the fused rings). Heteroaryl does not encompass or overlap with aryl as defined above.

[0047] Heterocyclyl – used interchangeably with heterocycloalkyl - refers to a saturated or partiallyunsaturated cyclic alkyl group, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. The term “heterocyclyl” includes heterocycloalkenyl groups (i.e., the heterocyclyl group having at least one double bond), bridged-heterocyclyl groups, fused-heterocyclyl groups, and spiro-heterocyclyl groups. A heterocyclyl may be a single ring or multiple rings wherein the multiple rings may be fused, bridged, or spiro, and may comprise one or more (e.g., 1 to 3) oxo (=O) or N-oxide (-O-) moieties. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclyl, regardless of the attachment (i.e., can be bound through a carbon atom or a heteroatom). Further, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, which ring may be fused to a cycloalkyl, an aryl, or heteroaryl ring, regardless of the attachment to theremainder of the molecule. As used herein, heterocyclyl has 2 to 20 ring carbon atoms (i.e., C2-20heterocyclyl), 2 to 12 ring carbon atoms (i.e., C2-12heterocyclyl), 2 to 10 ring carbon atoms (i.e., C2-10heterocyclyl), 2 to 8 ring carbon atoms (i.e., C2-8heterocyclyl), 3 to 12 ring carbon atoms (i.e., C3-12heterocyclyl), 3 to 8 ring carbon atoms (i.e., C3-8heterocyclyl), or 3 to 6 ring carbon atoms (i.e., C3-6heterocyclyl); having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur, or oxygen. Examples of heterocyclyl groups include, e.g., azetidinyl, azepinyl, benzodioxolyl, benzo[b][1,4]dioxepinyl, 1,4- benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyranonyl, benzofuranonyl, dioxolanyl,dihydropyranyl, hydropyranyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl,imidazolidinyl, indolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, oxetanyl, phenothiazinyl, phenoxazinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, tetrahydropyranyl, trithianyl, tetrahydroquinolinyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. The term “heterocyclyl” also includes “spiroheterocyclyl” when there are two positions for substitution on the same carbon atom. Examples of the spiro-heterocyclyl rings include, e.g., bicyclic and tricyclic ring systems, such as oxabicyclo[2.2.2]octanyl, 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl. Examples of the fused-heterocyclyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl, where the heterocyclyl can be bound via either ring of the fusedsystem. In some embodiments, the heterocycloalkyl may be substituted with oxo group(s) on aheteroatom (e.g., S=O, S(=O)2).

[0048] “Oxime” refers to the group -CRy(=NOH) wherein Ry is hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be unsubstituted or substituted, as defined herein.

[0049] “Oxo” refers to the moiety =O.

[0050] “Sulfonyl” refers to the group -S(O)2Ry, where Ry is hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be unsubstituted orsubstituted, as defined herein. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

[0051] “Sulfinyl” refers to the group -S(O)Ry, where Ry is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be unsubstituted or substituted, as defined herein. Examples of sulfinyl are methylsulfinyl, ethylsulfinyl, phenylsulfinyl, and toluenesulfinyl.

[0052] “Sulfonamido” refers to the groups -SO2NRyRz and -NRySO2Rz, where Ry and Rz are eachindependently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be unsubstituted or substituted, as defined herein.

[0053] The terms “optional” or “optionally” means that the subsequently described event orcircumstance may or may not occur and that the description includes instances where said event or circumstance occurs and instances in which it does not. Also, the term “unsubstituted or substituted” refers to any one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms on the designated atom or group may or may not be replaced by a moiety other than hydrogen.

[0054] The term “substituted” used herein means any of the above groups (i.e., alkyl, alkenyl, alkynyl,alkylene, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, and / or heteroalkyl) wherein at least one (e.g., 1 to 5 or 1 to 3) hydrogen atom is replaced by a bond to a non-hydrogen atom such as, but not limited to alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amido, amino, amidino, aryl, aralkyl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkylalkyl, guanadino, halo, haloalkyl, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -NHNH2, =NNH2, imino, imido, hydroxy, oxo, oxime, nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl, thiocyanate, -S(O)OH, -S(O)2OH, sulfonamido, thiol, thioxo, N-oxide, or -Si(Ry)3, wherein each Ryis independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl.

[0055] In certain embodiments, “substituted” includes any of the above alkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, or heteroaryl groups in which one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are independently replaced with deuterium, halo, cyano, nitro, azido, oxo, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NRgRh, -NRgC(O)Rh, -NRgC(O)NRgRh, -NRgC(O)ORh, -NRgS(O)1-2Rh, -C(O)Rg, -C(O)ORg, -OC(O)ORg, -OC(O)Rg, -C(O)NRgRh, -OC(O)NRgRh, -ORg, -SRg, -S(O)Rg, -S(O)2Rg, -OS(O)1-2Rg, -S(O)1-2ORg, -NRgS(O)1-2NRgRh, =NSO2Rg, =NORg, -S(O)1-2NRgRh, -SF5, -SCF3, or -OCF3. In certain embodiments, “substituted” also means any of the above groups in which one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are replaced with -C(O)Rg, -C(O)ORg, -C(O)NRgRh, -CH2SO2Rg, or -CH2SO2NRgRh. In the foregoing, Rgand Rhare the same or different and independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and / or heteroarylalkyl. In certain embodiments, “substituted” also means any of the above groups in which one or more (e.g., 1 to 5 or 1 to3) hydrogen atoms are replaced by a bond to an amino, cyano, hydroxy, imino, nitro, oxo, thioxo, halo,alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl,N-heterocyclyl, heterocyclylalkyl, heteroaryl, and / or heteroarylalkyl, or two of Rgand Rhare taken together with the atoms to which they are attached to form a heterocyclyl ring unsubstituted or substituted with oxo, halo, or alkyl unsubstituted or substituted with oxo, halo, amino, hydroxy, or alkoxy.

[0056] Polymers or similar indefinite structures arrived at by defining substituents with furthersubstituents appended ad infinitum (e.g., a substituted aryl having a substituted alkyl which is itself substituted with a substituted aryl group, which is further substituted by a substituted heteroalkyl group, etc.) are not intended for inclusion herein. Unless otherwise noted, the maximum number of serial substitutions in compounds described herein is three. For example, serial substitutions of substituted aryl groups with two other substituted aryl groups are limited to ((substituted aryl)substituted aryl) substituted aryl. Similarly, the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluorines or heteroaryl groups having two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to the skilled artisan. When used to modify a chemical group, the term “substituted” may describe other chemical groups defined herein.

[0057] In certain embodiments, as used herein, the phrase “one or more” refers to one to five. In certainembodiments, as used herein, the phrase “one or more” refers to one to three.

[0058] Any compound or structure given herein, is also intended to represent unlabeled forms as well asisotopically labeled forms of the compounds. These forms of compounds may also be referred to as “isotopically enriched analogs.” Isotopically labeled compounds have structures depicted herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2H, 3H, 11C, 13C,14C, 13N, 15N, 15O, 17O, 18O, 31P, 32P, 35S, 18F, 36Cl, 123I, and 125I, respectively. Various isotopically labeledcompounds of the present disclosure, for example those into which radioactive isotopes such as3H and14C are incorporated. Such isotopically labelled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single- photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients.

[0059] The term “isotopically enriched analogs” includes “deuterated analogs” of compounds describedherein in which one or more hydrogens is / are replaced by deuterium, such as a hydrogen on a carbonatom. Such compounds exhibit increased resistance to metabolism and are thus useful for increasing thehalf-life of any compound when administered to a mammal, particularly a human. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci.5(12): 524-527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium.

[0060] Accordingly, in some embodiments, the terms C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl,C3-10 cycloalkyl, heterocyclyl, aryl, and heteroaryl comprise isotopically enriched analogs thereof, suchas, but not limited to, deuterated versions thereof.

[0061] Deuterium labelled or substituted therapeutic compounds of the disclosure may have improvedDMPK (drug metabolism and pharmacokinetics) properties, relating to absorption, distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements, and / or an improvement in therapeutic index. An18F,3H, or11Clabeled compound may be useful for PET or SPECT or other imaging studies. Isotopically labeledcompounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. It is understood that deuterium in this context is regarded as a substituent in a compound described herein.

[0062] The concentration of such a heavier isotope, specifically deuterium, may be defined by anisotopic enrichment factor. In the compounds of this disclosure any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as “H” or “hydrogen,” the position is understood to have hydrogen at its natural abundance isotopic composition. Accordingly, in the compounds of this disclosure any atom specifically designated as a deuterium (D) is meant to represent deuterium.

[0063] In many cases, the compounds of this disclosure are capable of forming acid and / or base salts byvirtue of the presence of amino, and / or carboxyl groups, or groups similar thereto.

[0064] Provided are also or a pharmaceutically acceptable salt, isotopically enriched analog, deuteratedanalog, stereoisomer, mixture of stereoisomers, and prodrugs of the compounds described herein. “Pharmaceutically acceptable” or “physiologically acceptable” refer to compounds, salts, compositions, dosage forms, and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.

[0065] The term “pharmaceutically acceptable salt” of a given compound refers to salts that retain thebiological effectiveness and properties of the given compound and which are not biologically or otherwise undesirable. “Pharmaceutically acceptable salts” or “physiologically acceptable salts” include, for example, salts with inorganic acids, and salts with an organic acid. In addition, if the compounds described herein are obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare nontoxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts may be prepared from inorganic or organic acids. Salts derived from inorganic acids include, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include, e.g., acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonicacid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like. Likewise, pharmaceutically acceptable base addition salts can be prepared from inorganic or organic bases. Salts derived frominorganic bases include, by way of example only, sodium, potassium, lithium, aluminum, ammonium,calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, such as alkyl amines (i.e., NH2(alkyl)), dialkyl amines (i.e., HN(alkyl)2), trialkyl amines (i.e., N(alkyl)3), substituted alkyl amines (i.e., NH2(substituted alkyl)), di(substituted alkyl) amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl) amines (i.e., N(substituted alkyl)3), alkenyl amines (i.e., NH2(alkenyl)), dialkenyl amines (i.e., HN(alkenyl)2), trialkenyl amines (i.e., N(alkenyl)3), substituted alkenyl amines (i.e., NH2(substituted alkenyl)), di(substituted alkenyl) amines(i.e., HN(substituted alkenyl)2), tri(substituted alkenyl) amines (i.e., N(substituted alkenyl)3, mono-, di- ortri- cycloalkyl amines (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), mono-, di- ortri- arylamines (i.e., NH2(aryl), HN(aryl)2, N(aryl)3), or mixed amines, etc. Specific examples of suitableamines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0066] A “solvate” is formed by the interaction of a solvent and a compound. Solvates of salts of thecompounds described herein are also provided. A hydrate is an example of a solvate, where the solvent is water.

[0067] Some of the compounds exist as tautomers. Tautomers are in equilibrium with one another. Forexample, amide containing compounds may exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown and regardless of the nature of the equilibrium among tautomers, the compounds are understood by one of ordinary skill in the art to comprise both amide and imidic acid tautomers. Thus, the amide containing compounds are understood to include their imidic acid tautomers.Likewise, the imidic acid containing compounds are understood to include their amide tautomers.

[0068] The compounds, or their pharmaceutically acceptable salts include an asymmetric center andmay thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, interms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids. The presentdisclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms.Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthonsor chiral reagents, or resolved using conventional techniques, for example, chromatography and / or fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.

[0069] A “stereoisomer” refers to a compound made up of the same atoms bonded by the same bondsbut having different three-dimensional structures, which are not interchangeable. The present disclosurecontemplates various stereoisomers, or mixtures thereof, and includes enantiomers, which refers to two stereoisomers whose molecules are nonsuperimposeable mirror images of one another.

[0070] “Diastereomers” are stereoisomers that have at least two asymmetric atoms, but which are notmirror-images of each other.

[0071] Relative centers of the compounds as depicted herein are indicated graphically using the “thickbond” style (bold or parallel lines) and absolute stereochemistry is depicted using wedge bonds (bold or parallel lines).

[0072] “Prodrug” means any compound which releases an active parent drug according to a structuredescribed herein in vivo when such prodrug is administered to a mammalian subject. Prodrugs of acompound described herein are prepared by modifying functional groups present in the compounddescribed herein in such a way that the modifications may be cleaved in vivo to release the parentcompound. Prodrugs may be prepared by modifying functional groups present in the compounds in sucha way that the modifications are cleaved, either in routine manipulation or in vivo, to the parentcompounds. Prodrugs include compounds described herein wherein a hydroxy, amino, carboxyl, orsulfhydryl group in a compound described herein is bonded to any group that may be cleaved in vivo toregenerate the free hydroxy, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), amides, guanidines, carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy functional groups in compounds described herein, and the like. Preparation, selection, and use of prodrugs is discussed in T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol.14 of the A.C.S. Symposium Series; “Design of Prodrugs,” ed. H. Bundgaard, Elsevier, 1985; and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, each of which are hereby incorporated by reference in their entirety.

[0073] “Subject” refers to a mammal. The mammal can be a human or non-human mammalianorganism. A “patient” refers to a human subject.

[0074] “Treating” or “treatment” of a disease or disorder in a subject refers to 1) preventing the diseaseor disorder from occurring in a subject that is predisposed or does not yet display symptoms of the disease or disorder; 2) inhibiting the disease or disorder or arresting its development; or 3) ameliorating or causing regression of the disease or disorder.

[0075] “Effective amount” refers to the amount of a compound described herein that is sufficient to treatthe disease or disorder afflicting a subject or to prevent such a disease or disorder from arising in said subject or patient.

[0076] “Administration” refers to any art recognized form of administration to a subject including oral(including oral gavage), pulmonary, transdermal, sublingual, injection (e.g., intravenous, intramuscular), transmucosal (e.g., vaginal, nasal, etc.), and the like. The route of administration is selected by the attending clinician and is based on factors such as the age, weight and general health of the patient as well as the severity of the condition. In one embodiment, the compounds and pharmaceutical compositions described herein are administered orally.

[0077] The term ubiquitin ligase refers to a family of proteins that facilitate the transfer of ubiquitin toa specific substrate protein, targeting the substrate protein for degradation. For example, an E3 ubiquitin ligase protein that alone or in combination with an E2 ubiquitin-conjugating enzyme causes the attachment of ubiquitin to a lysine on a target protein, and subsequently targets the specific protein substrates for degradation by the proteasome. Thus, E3 ubiquitin ligase alone or in complex with an E2 ubiquitin conjugating enzyme is responsible for the transfer of ubiquitin to targeted proteins. In general, the ubiquitin ligase is involved in polyubiquitination such that a second ubiquitin is attached to the first; a third is attached to the second, and so forth. Polyubiquitination marks proteins for degradation by the proteasome. However, there are some ubiquitination events that are limited to mono-ubiquitination, in which only a single ubiquitin is added by the ubiquitin ligase to a substrate molecule. Mono-ubiquitinated proteins are not targeted to the proteasome for degradation, but may instead be altered in their cellular location or function, for example, via binding other proteins that have domains capable of binding ubiquitin. Further complicating matters, different lysines on ubiquitin can be targeted by an E3 to make chains. The most common lysine is Lys48 on the ubiquitin chain. This is the lysine used to make polyubiquitin, which is recognized by the proteasome. Compounds

[0078] In one embodiment, this disclosure provides a compound of Formula I:or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopically enriched analog, or tautomer thereof, wherein: n is 0, 1, or 2; R1 is OR12, halo, cyano, C1-4 alkoxy, N(R2)2, or C(O)CH(C1-4 alkyl)N(R2)2;each R2is independently hydrogen, C1-4 alkyl, or C3-6 cycloalkyl, wherein each alkyl or cycloalkyl is unsubstituted or substituted with one to three Z1; each R3is independently halo, cyano, C1-6 alkyl, or C1-3 haloalkyl; L1is a bond, C1-4 alkylene, -C1-4 alkylene-heteroaryl-, C2-3 alkenylene, C2-3 alkynylene, or -C(O)-; X is selected from:andp is 0, 1, or 2; Ring A is a monocyclic, spirocyclic, fused bicyclic, or bridged bicyclic 4-10 membered heterocyclyl or a monocyclic or fused bicyclic 5-10 membered heteroaryl;Ring B is a monocyclic, spirocyclic, fused bicyclic, or bridged bicyclic 3-10 membered cycloalkyl, a monocyclic, spirocyclic, fused bicyclic, or bridged bicyclic 4-10 membered heterocyclyl, or a monocyclic or fused bicyclic 5-10 membered heteroaryl; wherein the nitrogen atom and L1may be attached via any atom on Ring B, including on the same carbon atom; each R4is independently oxo, halo, cyano, -NO2, -SF5, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -C(O)R11, -C(O)OR11, -S(O)0-2R11, -NR11S(O)0-2R11, -S(O)0-2N(R11)2, -NR11S(O)0-2N(R11)2, -NR11C(O)N(R11)2, -C(O)N(R11)2, -NR11C(O)R11, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to eight Z1; R5is hydrogen, halo, cyano, or C1-6 alkyl optionally substituted with one to three Z1; R6is hydrogen, halo, cyano, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -C(O)R11, -C(O)OR11, -S(O)0-2R11, -NR11S(O)0-2R11, -S(O)0-2N(R11)2, -NR11S(O)0-2N(R11)2, -NR11C(O)N(R11)2, -C(O)N(R11)2, -NR11C(O)R11, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to eight Z1; R7is hydrogen, halo, cyano, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -C(O)R11, -C(O)OR11, -S(O)0-2R11, -NR11S(O)0-2R11, -S(O)0-2N(R11)2, -NR11S(O)0-2N(R11)2, -NR11C(O)N(R11)2, -C(O)N(R11)2, -NR11C(O)R11, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to eight Z1; R8is hydrogen or C1-6 alkyl optionally substituted with one to three Z1; R9 is hydrogen, -C(O)R13, -C(R13)2OC(O)R15, -C(O)OCH2OC(O)R15, -C(O)OCH(CH3)OC(O)R15, -C(O)OCH2OC(O)R15, -C(O)OCH(CH3)OC(O)R15, -(CH2)mOP(O)(OR14)2, -CH(CH3)OP(O)(OR14)2, -(CH2)mOP(O)(R14)(OR14), -CH(CH3)OP(O)(R14)(OR14), -(CH2)mOP(O)(N(R14)2)(OR14),-CH(CH3)OP(O)(N(R14)2)(OR14), -(CH2)mOP(O)(R14)(N(R14)2), -(CH2)mOP(O)(N(R14)2)2, or-C(CH3)OP(O)(N(R14)2)2; m is 1 or 2; each Z1is independently halo, cyano, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -P(O)(OR11)2, -C(O)R11, -C(O)OR11, -S(O)0-2R11, -NR11S(O)0-2R11, -S(O)0-2N(R11)2, -NR11S(O)0-2N(R11)2, -NR11C(O)N(R11)2, -C(O)N(R11)2, -NR11C(O)R11, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a; each R11is independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl,C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a; each Z1ais independently hydroxy, halo, cyano, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R13)2, -OR13, -P(O)(OR13)2, -C(O)R13, -C(O)OR13, -S(O)0-2R13, -NR13S(O)0-2R13, -S(O)0-2N(R13)2, -NR13S(O)0-2N(R13)2, -NR13C(O)N(R13)2, -C(O)N(R13)2, -NR13C(O)R13, -OC(O)N(R13)2, or -NR13C(O)OR13; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1b; R12 is hydrogen, -C(O)R13, -C(O)N(R14)2, -P(O)(OR14)2, -CH2OP(O)(OR14)2,-CH(CH3)OP(O)(OR14)2, -P(O)(R14)(OR14), -CH2OP(O)(R14)(OR14), -CH(CH3)OP(O)(R14)(OR14),-P(O)(N(R14)2)(OR14), -CH2OP(O)(N(R14)2)(OR14), -CH(CH3)OP(O)(N(R14)2)(OR14),-P(O)(R14)(N(R14)2), -CH2OP(O)(R14)(N(R14)2), -CH(CH3)OP(O)(R14)(N(R14)2), -P(O)(N(R14)2)2,-CH2OP(O)(N(R14)2)2, or -CH(CH3)OP(O)(N(R14)2)2; each R13is independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1b; each R14is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, aryl, heteroaryl, or heterocyclyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is independently optionally substituted with one to five Z1b; or two R14together with the atom to which they are attached form a heterocyclyl; wherein said heterocyclyl is independently optionally substituted one to five Z1b; R15is independently R16, -OR16, -SR16, or -N(R16)2; each R16is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, aryl, heteroaryl, or heterocyclyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is independently optionally substituted with one to five Z1b; each Z1bis independently halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, -P(O)(OH)2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-C1-6alkyl, -L-C2-6alkenyl, -L-C2-6alkynyl, -L-C1-6haloalkyl, -L-C3-10cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; and each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6 alkyl)-, -N(C2-6 alkenyl)-, -N(C2-6 alkynyl)-, -N(C1-6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-6 alkyl)-, -C(O)N(C2-6 alkenyl)-, -C(O)N(C2-6 alkynyl)-, -C(O)N(C1-6 haloalkyl)-, -C(O)N(C3-10 cycloalkyl)-, -C(O)N(heterocyclyl)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)-, -S(O)2NH-, -P(O)(OH)O-, -P(O)(O-C1-6alkyl)O-, -P(O)(O-C2-6alkenyl)-O, -P(O)(O-C2-6alkynyl)O-, -P(O)(OC1-6haloalkyl)O-, -P(O)(OC3-10cycloalkyl)O-, -P(O)(O-heterocyclyl)O-, -P(O)(O-aryl)O-, or -P(O)(O-heteroaryl)O-;wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, and heteroaryl of Z1band L is further independently optionally substituted with one to five hydroxy, halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0079] In one embodiment, this disclosure provides a compound of Formula I:or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopically enriched analog, or tautomer thereof, wherein: n is 0, 1, or 2; R1is -OR12, halo, cyano, C1-4 alkoxy, or -N(R2)2; each R2is independently hydrogen, C1-4 alkyl, or C3-6 cycloalkyl, wherein each alkyl or cycloalkyl is unsubstituted or substituted with one to three Z1; each R3is independently halo, cyano, C1-6alkyl, or C1-3haloalkyl; L1is a bond, C1-4alkylene, -C1-4alkylene-heteroaryl-, C2-3alkenylene, C2-3alkynylene, or -C(O)-; X is selected from:and; p is 0, 1, or 2; Ring A is a monocyclic, spirocyclic, fused bicyclic, or bridged bicyclic 4-10 membered heterocyclyl or a monocyclic or fused bicyclic 5-10 membered heteroaryl; Ring B is a monocyclic, spirocyclic, fused bicyclic, or bridged bicyclic 3-10 membered cycloalkyl, a monocyclic, spirocyclic, fused bicyclic, or bridged bicyclic 4-10 membered heterocyclyl, ora monocyclic or fused bicyclic 5-10 membered heteroaryl; wherein the nitrogen atom and L1 may beattached via any atom on Ring B, including on the same carbon atom; each R4is independently oxo, halo, cyano, -NO2, -SF5, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -C(O)R11, -C(O)OR11, -S(O)0-2R11, -NR11S(O)0-2R11, -S(O)0-2N(R11)2, -NR11S(O)0-2N(R11)2, -NR11C(O)N(R11)2, -C(O)N(R11)2, -NR11C(O)R11, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to eight Z1; R5is hydrogen, halo, cyano, or C1-6 alkyl optionally substituted with one to three Z1; R6is hydrogen, halo, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -C(O)R11, -C(O)OR11, -S(O)0-2R11, -NR11S(O)0-2R11, -S(O)0-2N(R11)2,-NR11S(O)0-2N(R11)2, -NR11C(O)N(R11)2, -C(O)N(R11)2, -NR11C(O)R11, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to eight Z1; R7is hydrogen, halo, cyano, -NO2, -SF5, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -C(O)R11, -C(O)OR11, -S(O)0-2R11, -NR11S(O)0-2R11, -S(O)0-2N(R11)2, -NR11S(O)0-2N(R11)2, -NR11C(O)N(R11)2, -C(O)N(R11)2, -NR11C(O)R11, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to eight Z1; R8is hydrogen or C1-6 alkyl optionally substituted with one to three Z1; R9 is hydrogen, -C(O)R13, -C(R13)2OC(O)R15, -C(O)OCH2OC(O)R15,-C(O)OCH(CH3)OC(O)R15, -C(O)OCH2OC(O)R15, -C(O)OCH(CH3)OC(O)R15, -(CH2)mOP(O)(OR14)2,-CH(CH3)OP(O)(OR14)2, -(CH2)mOP(O)(R14)(OR14), -CH(CH3)OP(O)(R14)(OR14),-(CH2)mOP(O)(N(R14)2)(OR14), -CH(CH3)OP(O)(N(R14)2)(OR14), -(CH2)mOP(O)(R14)(N(R14)2),-(CH2)mOP(O)(N(R14)2)2, or -C(CH3)OP(O)(N(R14)2)2;m is 1 or 2; each Z1is independently halo, cyano, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -P(O)(OR11)2, -C(O)R11, -C(O)OR11, -S(O)0-2R11, -NR11S(O)0-2R11, -S(O)0-2N(R11)2, -NR11S(O)0-2N(R11)2, -NR11C(O)N(R11)2, -C(O)N(R11)2, -NR11C(O)R11, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a; each R11is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a; each Z1ais independently hydroxy, halo, cyano, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R13)2, -OR13, -P(O)(OR13)2, -C(O)R13, -C(O)OR13, -S(O)0-2R13, -NR13S(O)0-2R13, -S(O)0-2N(R13)2, -NR13S(O)0-2N(R13)2, -NR13C(O)N(R13)2, -C(O)N(R13)2, -NR13C(O)R13, -OC(O)N(R13)2, or -NR13C(O)OR13; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1b; R12 is hydrogen, -C(O)R13, -C(O)N(R14)2, -P(O)(OR14)2, -CH2OP(O)(OR14)2,-CH(CH3)OP(O)(OR14)2, -P(O)(R14)(OR14), -CH2OP(O)(R14)(OR14), -CH(CH3)OP(O)(R14)(OR14),-P(O)(N(R14)2)(OR14), -CH2OP(O)(N(R14)2)(OR14), -CH(CH3)OP(O)(N(R14)2)(OR14), -P(O)(R14)(N(R14)2), -CH2OP(O)(R14)(N(R14)2), -CH(CH3)OP(O)(R14)(N(R14)2), -P(O)(N(R14)2)2,-CH2OP(O)(N(R14)2)2, or -CH(CH3)OP(O)(N(R14)2)2; each R13is independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl,C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1b; each R14is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, aryl, heteroaryl, or heterocyclyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is independently optionally substituted with one to five Z1b; or two R14together with the atom to which they are attached form a heterocyclyl; wherein said heterocyclyl is independently optionally substituted one to five Z1b; R15 is independently R16, -OR16, -SR16, or -N(R16)2;each R16is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, aryl, heteroaryl, or heterocyclyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is independently optionally substituted with one to five Z1b; each Z1bis independently halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, -P(O)(OH)2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-C1-6alkyl, -L-C2-6alkenyl, -L-C2-6alkynyl, -L-C1-6haloalkyl, -L-C3-10cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; and each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6 alkyl)-, -N(C2-6 alkenyl)-, -N(C2-6 alkynyl)-, -N(C1-6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-6 alkyl)-, -C(O)N(C2-6 alkenyl)-, -C(O)N(C2-6 alkynyl)-, -C(O)N(C1-6haloalkyl)-, -C(O)N(C3-10cycloalkyl)-, -C(O)N(heterocyclyl)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)-, -S(O)2NH-, -P(O)(OH)O-, -P(O)(O-C1-6alkyl)O-, -P(O)(O-C2-6alkenyl)-O, -P(O)(O-C2-6alkynyl)O-, -P(O)(OC1-6 haloalkyl)O-, -P(O)(OC3-10 cycloalkyl)O-, -P(O)(O-heterocyclyl)O-, -P(O)(O-aryl)O-, or -P(O)(O-heteroaryl)O-; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, and heteroaryl of Z1band L is further independently optionally substituted with one to five hydroxy, halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0080] In some embodiments, the compound is not 1-[3-[3-(2-hydroxyphenyl)-7H-pyrrolo[2,3-c]pyridazin-6-yl]-1-azetidinyl]-2-propen-1-one.

[0081] In some embodiments, provided is a compound of Formula I:or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopically enriched analog, or tautomer thereof, wherein:n is 0, 1, or 2; R1is hydroxy, halo, cyano, C1-4 alkoxy, or N(R2)2; each R2is independently hydrogen, C1-4 alkyl, or C3-6 cycloalkyl; each R3is independently halo, cyano, C1-6alkyl, or C1-3haloalkyl; L1is a bond, C1-4alkylene, -C1-4alkylene-heteroaryl-, C2-3alkenylene, C2-3alkynylene, or -C(O)-; X is selected from:and ;p is 0, 1, or 2; Ring A is a monocyclic, spirocyclic, fused bicyclic, or bridged bicyclic 4-10 membered heterocyclyl; Ring B is a monocyclic, spirocyclic, fused bicyclic, or bridged bicyclic 3-10 membered cycloalkyl; wherein the nitrogen atom and L1may be attached via any atom on Ring B, including on the same carbon atom; each R4 is independently halo, cyano, C1-6 alkyl, -OR11, -C(O)N(R11)2, heterocyclyl, or heteroaryl,wherein each C1-6alkyl is independently optionally substituted with one to eight Z1; R5is hydrogen, halo, cyano, or C1-6alkyl optionally substituted with one to three Z1; R6is hydrogen, halo, cyano, or C1-6alkyl optionally substituted with one to three Z1; R7is hydrogen, halo, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, or -C(O)R11, wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3- 10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to eight Z1; R8is hydrogen or C1-6 alkyl; R9is hydrogen; each Z1is independently halo, cyano, -NO2, -SF5, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -C(O)R11, -C(O)OR11, -S(O)0-2R11, -NR11S(O)0-2R11, -S(O)0-2N(R11)2, -NR11S(O)0-2N(R11)2, -NR11C(O)N(R11)2, -C(O)N(R11)2, -NR11C(O)R11, -OC(O)N(R11)2, or -NR11C(O)OR11; and each R11is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0082] In some embodiments, provided is a compound of Formula I:or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopically enriched analog, or tautomer thereof, wherein: n is 0, 1, or 2; R1is hydroxy, halo, cyano, C1-4alkoxy, or N(R2)2; each R2is independently hydrogen, C1-4alkyl, or C3-6cycloalkyl; each R3is independently halo, cyano, C1-6alkyl, or C1-3haloalkyl; L1is a bond, C1-4 alkylene, -C1-4 alkylene-heteroaryl-, C2-3 alkenylene, C2-3 alkynylene, or -C(O)-; X is selected from:andp is 0, 1, or 2; Ring A is a monocyclic, spirocyclic, fused bicyclic, or bridged bicyclic 4-10 membered heterocyclyl; Ring B is a monocyclic, spirocyclic, fused bicyclic, or bridged bicyclic 3-10 membered cycloalkyl; wherein the nitrogen atom and L1may be attached via any atom on Ring B, including on the same carbon atom; each R4is independently halo, cyano, C1-6alkyl, -OR11, or -C(O)N(R11)2, wherein each C1-6alkyl is independently optionally substituted with one to eight Z1; R5is hydrogen, halo, cyano, or C1-6 alkyl optionally substituted with one to three Z1; R6is hydrogen, halo, cyano, or C1-6 alkyl optionally substituted with one to three Z1; R7is hydrogen, halo, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, or -C(O)R11, wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3- 10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to eight Z1; R8is hydrogen or C1-6alkyl; R9is hydrogen; each Z1is independently halo, cyano, -NO2, -SF5, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -C(O)R11, -C(O)OR11, -S(O)0-2R11, -NR11S(O)0-2R11, -S(O)0-2N(R11)2, -NR11S(O)0-2N(R11)2, -NR11C(O)N(R11)2, -C(O)N(R11)2, -NR11C(O)R11, -OC(O)N(R11)2, or -NR11C(O)OR11; and each R11is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0083] In some embodiments, provided is a compound of Formula I:or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopically enriched analog, or tautomer thereof, wherein: n is 0, 1, or 2; R1is hydroxy; each R3is independently halo or C1-3haloalkyl; L1is -CH2-, -C(O)-, -CH2-heteroaryl, or ethynyl; X is selected from:and; p is 0, 1, or 2; Ring A is a monocyclic, spirocyclic, fused bicyclic, or bridged bicyclic 4-10 membered heterocyclyl; Ring B is a monocyclic, spirocyclic, fused bicyclic, or bridged bicyclic 3-10 membered cycloalkyl; wherein the nitrogen atom and L1may be attached via any atom on Ring B, including on the same carbon atom; each R4 is independently halo, cyano, -OCH3, azetidinyl, morpholino, pyridyl, or C1-6 alkyloptionally substituted with cyano, -OH, -OCH3, or -C(O)N(CH3)2; R5is hydrogen, halo, cyano, or C1-6alkyl; R6is hydrogen, halo, cyano, or C1-6 alkyl; R7is halo, -C(O)CH3, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with halo, cyano, C1-6 alkyl, -OH, -OCH3, -OCH2CH3,-C(O)NH2, -C(O)CH3, -N(CH3)2, cyclopropyl, morpholino, or phenyl; R8is hydrogen or C1-6alkyl; and R9is hydrogen.

[0084] In some embodiments, provided is a compound of Formula I:or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopically enriched analog, or tautomer thereof, wherein: nis 0 or 1;R1is hydroxy; each R3 is independently halo or C1-3 haloalkyl;L1is -CH2-, -C(O)-, -CH2-heteroaryl, or ethynyl; X is selected from:and; p is 0, 1, or 2; Ring A is a monocyclic, spirocyclic, fused bicyclic, or bridged bicyclic 4-10 membered heterocyclyl; Ring B is a monocyclic, spirocyclic, fused bicyclic, or bridged bicyclic 3-10 membered cycloalkyl; wherein the nitrogen atom and L1may be attached via any atom on Ring B, including on the same carbon atom; each R4is independently halo, cyano, or C1-6alkyl optionally substituted with cyano, -OH, - OCH3, or -C(O)N(CH3)2; R5is hydrogen, halo, cyano, or C1-6alkyl; R6is hydrogen, halo, cyano, or C1-6 alkyl; R7is halo, -C(O)CH3, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with halo, cyano, C1-6 alkyl, -OH, -OCH3, -OCH2CH3,-C(O)NH2, -C(O)CH3, -N(CH3)2, cyclopropyl, morpholino, or phenyl; R8is hydrogen or C1-6alkyl; and R9is hydrogen.

[0085] In some embodiments, provided herein is a compound of Formula II:or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopically enriched analog, or tautomer thereof.

[0086] In some embodiments, provided herein is a compound of Formula III:III or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopically enriched analog, or tautomer thereof.

[0087] In some embodiments, R1 is -OR12, halo, cyano, C1-4 alkoxy, or -N(R2)2.

[0088] In some embodiments, R2 is hydrogen.

[0089] In some embodiments, R1 is -OR12.

[0090] In some embodiments, R12 is hydrogen, -C(O)R13, C(O)N(R14)2, -P(O)(OR14)2, or-CH2OP(O)(OR14)2, or -CH(CH3)OP(O)(OR14)2.

[0091] In some embodiments, R12 is hydrogen.

[0092] In some embodiments, R12 is -C(O)R13. In some embodiments, R12 is -C(O)-C1-6 alkyl,-C(O)-C3-10cycloalkyl, -C(O)-aryl, or -C(O)-heteroaryl.

[0093] In some embodiments, R12 is -C(O)R13 wherein R13 is C1-6 alkyl optionally substituted with oneto five Z1b. In some embodiments, R12 is -C(O)R13 wherein R13 is unsubstituted C1-6 alkyl. In someembodiments, R12is -C(O)R13wherein R13is C1-6 alkyl optionally substituted with one to three halo,cyano, hydroxy, or -NH2. In some embodiments, R12 is -C(O)R13 wherein R13 is C1-6 alkyl substitutedwith -NH2.

[0094] In some embodiments, R12 is -CH2OP(O)(OR14)2. In some embodiments, R12 is -CH2P(O)(OH)2,-CH2P(O)(O-C1-6 alkyl)2, or -CH2P(O)(O-aryl)2. R12 is -CH(CH3)OP(O)(OR14)2. In some embodiments,R12is -CH(CH3)OP(O)(OH)2, -CH(CH3)OP(O)(O-C1-6alkyl)2, or -CH(CH3)OP(O)(O-aryl)2.

[0095] In some embodiments, R12 is selected from:,, , , or.

[0096] In some embodiments, R12 is selected from:, , , ,, or.

[0097] In some embodiments, R12 is selected from, , , and.

[0098] In some embodiments, R1 is hydroxy.

[0099] In some embodiments, R9 is hydrogen, -C(O)R13, -(CH2)mP(O)(OR14)2, -CH(CH3)P(O)(OR14)2, or-(CH2)mP(O)(R14)(OR14).

[0100] In some embodiments, R9 is -C(O)-C1-6 alkyl, -C(O)-C3-10 cycloalkyl, -C(O)-aryl, or-C(O)-heteroaryl.

[0101] In some embodiments, R9 is -CH2P(O)(OR14)2. In some embodiments, R9 is -CH2P(O)(OH)2,-CH2P(O)(O-C1-6 alkyl)2, or -CH2P(O)(O-aryl)2.

[0102] In some embodiments, R9 or R13 is selected from:, ,, or.

[0103] In some embodiments, n is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1.

[0104] In some embodiments, R3 is halo or cyano. In some embodiments, R3 is halo. In someembodiments, R3 is fluoro, chloro, or cyano. In some embodiments, R3 is fluoro.

[0105] In some embodiments, n is 1 and R3 is halo or cyano. In some embodiments, n is 1 and R3 ishalo. In some embodiments, n is 1 and R3 is fluoro.

[0106] In some embodiments, R9 is hydrogen.

[0107] In some embodiments, provided herein is a compound of Formula IIA:or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopically enriched analog, or tautomer thereof.

[0108] In some embodiments, provided herein is a compound of Formula IIB:

[0109] In some embodiments, Ring A is a monocyclic, spirocyclic, fused bicyclic, or bridged bicyclic 4-10 membered heterocyclyl or a monocyclic or fused bicyclic 5-10 membered heteroaryl, wherein each Ring A is optionally substituted with one or two R4.

[0110] In some embodiments, Ring A is a monocyclic 5-10 membered heteroaryl optionally substitutedwith one or two R4. In some embodiments, Ring A is a fused bicyclic 5-10 membered heteroaryloptionally substituted with one or two R4.

[0111] In some embodiments, Ring A is a monocyclic, spirocyclic, fused bicyclic, or bridged bicyclic 4-10 membered heterocyclyl optionally substituted with one or two R4. In some embodiments, Ring A is amonocyclic 4-10 membered heterocyclyl optionally substituted with one or two R4. In someembodiments, Ring A is a spirocyclic 4-10 membered heterocyclyl optionally substituted with one or twoR4. In some embodiments, Ring A is a fused bicyclic 5-10 membered heterocyclyl optionally substitutedwith one or two R4. In some embodiments, Ring A is a bridged bicyclic 5-10 membered heterocyclyl optionally substituted with one or two R4. In some embodiments, Ring A is a monocyclic 4-10membered heterocyclyl optionally substituted with one or two R4.

[0112] In some embodiments, Ring A is a monocyclic 4-7 membered heterocyclic optionally substitutedwith one or two R4. In some embodiments, Ring A is azetidinyl, pyrrolidinyl, piperidinyl, or azepanyl,wherein each Ring A is optionally substituted with one or two R4.

[0113] In some embodiments, Ring A is morpholinyl or piperazinyl, wherein each Ring A is optionallysubstituted with one or two R4.

[0114] In some embodiments, Ring A is selected from:,, , , , , , , ,and; wherein each Ring A is optionally substituted with one or two R4; ( ) representsthe point of attachment to L1or the 7H-pyrrolo[2,3-c]pyridazine moiety; and (*) represents the point of attachment to the carbonyl moiety.

[0115] In some embodiments, Ring A is selected from:,, , , , , , , and; wherein each Ring A is optionally substituted with one or two R4; ( ) represents thepoint of attachment to L1or the 7H-pyrrolo[2,3-c]pyridazine moiety; and (*) represents the point of attachment to the carbonyl moiety.

[0116] In some embodiments, Ring A is a spirocyclic 4-10 membered heterocyclyl optionallysubstituted with one or two R4.

[0117] In some embodiments, Ring A is selected from:, , ,, and; wherein each Ring A is optionally substituted with one or two R4; ( ) representsthe point of attachment to L1or the 7H-pyrrolo[2,3-c]pyridazine moiety; and (*) represents the point of attachment to the carbonyl moiety.

[0118] In some embodiments, Ring A is selected from:, , ,and; whereineach Ring A is optionally substituted with one or two R4; 1represents the point of attachment to Lor the 7H-pyrrolo[2,3-c]pyridazine moiety; and (*) represents the point of attachment to the carbonyl moiety.

[0119] In some embodiments, Ring A is selected from:, , , , and; wherein each Ring A is optionally substituted with one or two R4;) represents the point ofattachment to L1or the 7H-pyrrolo[2,3-c]pyridazine moiety; and (*) represents the point of attachment to the carbonyl moiety.

[0120] In some embodiments, Ring A is a bridged bicyclic 4-10 membered heterocyclyl optionallysubstituted with one or two R4.

[0121] In some embodiments, Ring A is selected from:, , ,, , , , , , and; wherein each Ring A is optionally substituted with one or two R4;) representsthe point of attachment to L1or the 7H-pyrrolo[2,3-c]pyridazine moiety; and (*) represents the point of attachment to the carbonyl moiety.

[0122] In some embodiments, Ring A is selected from:, , , and; wherein each Ring A isoptionally substituted with one or two R4; ( ) represents the point of attachment to L1 or the 7H-pyrrolo[2,3-c]pyridazine moiety; and (*) represents the point of attachment to the carbonyl moiety.

[0123] In some embodiments, Ring A is selected from:and; wherein each Ring A is optionally substituted with one or two R4; ( ) represents the point of attachment to L1 or the 7H-pyrrolo[2,3-c]pyridazine moiety; and (*) represents the point of attachment to the carbonyl moiety.

[0124] In some embodiments, Ring A is a fused bicyclic 4-10 membered heterocyclyl optionallysubstituted with one or two R4.

[0125] In some embodiments, Ring A is selected from:, , and; wherein each Ring A is optionally substituted with one or two R4; ( ) represents the point of attachment to L1 or the 7H-pyrrolo[2,3-c]pyridazine moiety; and (*) represents the point of attachment to the carbonyl moiety.

[0126] In some embodiments, Ring A is selected from:, , , , ,, , , , and; wherein each Ring A is optionally substituted with one or two R4; ( ) represents the point ofattachment to L1or the 7H-pyrrolo[2,3-c]pyridazine moiety; and (*) represents the point of attachment to the carbonyl moiety.

[0127] In some embodiments, Ring A is selected from:, , ,, and; wherein each Ring A is optionally substitutedwith one or two R ; ( ) represents the point of attachment to L or the 7H-pyrrolo[2,3-c]pyridazinemoiety; and (*) represents the point of attachment to the carbonyl moiety.

[0128] In some embodiments, provided herein is a compound of Formula IIIA:or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopically enriched analog, or tautomer thereof.

[0129] In some embodiments, provided herein is a compound of Formula IIIB:or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopically enriched analog, or tautomer thereof.

[0130] In some embodiments, L1 is a bond, C1-4 alkylene, -C1-4 alkylene-heteroaryl-, C2-3 alkenylene, C2-3alkynylene, or -C(O)-.

[0131] In some embodiments, L1 is a bond.

[0132] In some embodiments, L1 is C1-4 alkylene. In some embodiments, L1 is -CH2-.

[0133] In some embodiments, L1 is C1-4 alkylene-heteroaryl. In some embodiments, L1 is -CH2-heteroaryl. In some embodiments, L1 is -CH2-pyrazolyl-.

[0134] In some embodiments, L1 is C2-3 alkynylene. In some embodiments, L1 is ethynyl.

[0135] In some embodiments, L1 is -C(O)-.

[0136] In some embodiments, L1 is a bond, -CH2-, -C(O)-, -CH2-heteroaryl, or ethynyl.

[0137] In some embodiments, L1 is -CH2-, -C(O)-, -CH2-heteroaryl, or ethynyl.

[0138] In some embodiments, Ring B is a monocyclic, spirocyclic, fused bicyclic, or bridged bicyclic 3-10 membered cycloalkyl, a monocyclic, spirocyclic, fused bicyclic, or bridged bicyclic 4-10 memberedheterocyclyl, or a monocyclic or fused bicyclic 5-10 membered heteroaryl, wherein each Ring B isoptionally substituted with one or two R4.

[0139] In some embodiments, Ring B is a monocyclic 3-10 membered cycloalkyl optionally substitutedwith one or two R4. In some embodiments, Ring B is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,or cycloheptyl, wherein each Ring B is optionally substituted with one or two R4.

[0140] In some embodiments, Ring B is a bridged bicyclic 3-10 membered cycloalkyl optionallysubstituted with one or two R4. In some embodiments, Ring B is bicyclo[1.1.1]pentyl optionallysubstituted with one or two R4. In some embodiments, Ring B is bicyclo[2.2.2]octyl optionallysubstituted with one or two R4.

[0141] In some embodiments, Ring B is a monocyclic 4-10 membered heterocyclyl optionallysubstituted with one or two R4.

[0142] In some embodiments, Ring B is selected from:, , , ,and; wherein each Ring B is optionally substituted with oneor two R4; ( ) represents the point of attachment to L1 or the 7H-pyrrolo[2,3-c]pyridazine moiety;and (*) represents the point of attachment to the nitrogen atom.

[0143] In some embodiments, p is 0, 1, or 2. In some embodiments, p is 1 or 2. In some embodiments,p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

[0144] In some embodiments, p is 1 or 2 and each R4 is independently oxo, halo, cyano, -NO2, -SF5,C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -C(O)R11, -C(O)OR11, -S(O)0-2R11, -NR11S(O)0-2R11, -S(O)0-2N(R11)2, -NR11S(O)0-2N(R11)2, -NR11C(O)N(R11)2, -C(O)N(R11)2, -NR11C(O)R11, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to eight Z1.

[0145] In some embodiments, each R4 is independently halo, cyano, C1-6 alkyl, -OR11, or -C(O)N(R11)2,wherein each C1-6alkyl is independently optionally substituted with one to eight Z1.

[0146] In some embodiments, each R4 is independently halo. In some embodiments, R4 is fluoro.

[0147] In some embodiments, p is 1 and R4 is halo. In some embodiments, p is 1 and R4 is fluoro. Insome embodiments, p is 2 and each R4 is independently halo. In some embodiments, p is 2 and R4 isfluoro.

[0148] In some embodiments, R4 is cyano. In some embodiments, p is 1 and R4 is cyano.

[0149] In some embodiments, each R4 is independently C1-6 alkyl optionally substituted with one to threeZ1.

[0150] In some embodiments, each R4 is independently C1-6 alkyl substituted with cyano or methoxy. Insome embodiments, R4 is -CH2CN. In some embodiments, R4 is -CH2OCH3. In some embodiments, p is1 and R4is -CH2CN or -CH2OCH3.

[0151] In some embodiments, R4 is C1-6 alkyl substituted with cyano.

[0152] In some embodiments, R4 is unsubstituted C1-6 alkyl. In some embodiments, R4 is methyl, ethyl,or propyl. In some embodiments, R4 is methyl.

[0153] In some embodiments, p is 1 and R4 is methyl. In some embodiments, p is 2 and R4 is methyl.

[0154] In some embodiments, R is -OR . In some embodiments, R is -OH. In some embodiments, Ris -OCH3. In some embodiments, p is 1 and R4 is -OH. In some embodiments, p is 1 and R4 is -OCH3.

[0155] In some embodiments, R4 is -C(O)N(R11)2. In some embodiments, R4 is -C(O)N(CH3)2. In someembodiments, p is 1 and R4is -C(O)N(CH3)2.

[0156] In some embodiments, R4 is C3-10 cycloalkyl, aryl, heteroaryl, or heterocyclyl.

[0157] In some embodiments, R4 is aryl. In some embodiments, R4 is a C6-10 aryl. In someembodiments, p is 1 and R4 is phenyl or naphthenyl. In some embodiments, p is 1 and R4 is phenyl.

[0158] In some embodiments, R4 is heteroaryl. In some embodiments, R4 is a 5-6 membered heteroarylcontaining 1-3 heteroatoms selected from N, O, and S. In some embodiments, p is 1 and R4 is pyrrolyl,pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, or triazolyl.

[0159] In some embodiments, R4 is heterocyclyl. In some embodiments, R4 is a 4-6 memberedheterocyclyl containing 1-2 heteroatoms selected from N, O, and S. In some embodiments, p is 1 and R4is azetidinyl, pyrrolidinyl, piperidinyl, or morpholino. In some embodiments, p is 1 and R4 ismorpholino.

[0160] In some embodiments, p is 1 and R4 is phenyl, pyrazolyl, triazolyl, azetidinyl, or morpholino.

[0161] In some embodiments, R4 is fluoro, cyano, methyl, ethyl, propyl, -CH2CN, -CH2OCH3, -OH,-OCH3, -C(O)N(CH3)2, phenyl, pyrazolyl, triazolyl, azetidinyl, or morpholino. In some embodiments, pis 1 or 2 and R4is fluoro, cyano, methyl, ethyl, propyl, -CH2CN, -CH2OCH3, -OH, -OCH3,-C(O)N(CH3)2, phenyl, pyrazolyl, triazolyl, azetidinyl, or morpholino. In some embodiments, p is 1 andR4is fluoro, cyano, methyl, ethyl, propyl, -CH2CN, -CH2OCH3, -OH, -OCH3, -C(O)N(CH3)2, phenyl,pyrazolyl, triazolyl, azetidinyl, or morpholino. In some embodiments, p is 2 and R4 is fluoro or methyl.

[0162] In some embodiments, R4 is fluoro, cyano, methyl, ethyl, propyl, -CH2CN, -OH, -OCH3, or-C(O)N(CH3)2. In some embodiments, p is 1 or 2 and R4 is fluoro, cyano, methyl, ethyl, propyl,-CH2CN, -OH, -OCH3, or -C(O)N(CH3)2. In some embodiments, p is 1 and R4 is fluoro, cyano, methyl,ethyl, propyl-CH2CN, -OH, -OCH3, or -C(O)N(CH3)2. In some embodiments, p is 2 and R4 is fluoro ormethyl.

[0163] In some embodiments, R5 I s hydrogen, halo, cyano, or C1-6 alkyl optionally substituted with oneto three Z1.

[0164] In some embodiments, R5 is hydrogen. In some embodiments, R5 is halo. In some embodiments,R5 is fluoro. In some embodiments, R5 is cyano.

[0165] In some embodiments, R6 is hydrogen, halo, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl,C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -C(O)R11, -C(O)OR11, -S(O)0-2R11, -NR11S(O)0-2R11, -S(O)0-2N(R11)2, -NR11S(O)0-2N(R11)2, -NR11C(O)N(R11)2, -C(O)N(R11)2, -NR11C(O)R11, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to eight Z1.

[0166] In some embodiments, R6 is hydrogen, halo, cyano, C3-10 cycloalkyl, or C1-6 alkyl optionallysubstituted with one to eight Z1.

[0167] In some embodiments, R6 is hydrogen, halo, cyano, or C1-6 alkyl optionally substituted with oneto eight Z1. In some embodiments, R6 is hydrogen, halo, or cyano.

[0168] In some embodiments, R6 is hydrogen.

[0169] In some embodiments, R6 is C3-10 cycloalkyl. In some embodiments, R6 is cyclopropyl.

[0170] In some embodiments, R6 is C1-6 alkyl optionally substituted with one to eight Z1. In someembodiments, R6 is C1-6 alkyl substituted with halo, -N(R11)2, or heterocyclyl optionally substituted withone to five Z1a.

[0171] In some embodiments, R6 is C1-6 alkyl substituted with one to three halo. In some embodiments,R6is C1-3 alkyl substituted with one to three fluoro.

[0172] In some embodiments, R6 is C1-6 alkyl substituted with heterocyclyl optionally substituted withone to five Z1a. In some embodiments, R6 is C1-3 alkyl substituted with heterocyclyl substituted with oneor two C1-6alkyl.

[0173] In some embodiments, R6 is C1-3 alkyl substituted with a 4-10 membered heterocyclyl, whereinthe heterocyclyl is optionally substituted with one or two methyl or fluoro.

[0174] In some embodiments, R6 is C1-6 alkyl substituted with -N(R11)2. In some embodiments, R6 is C1-3 alkyl substituted with -N(CH3)2 or -N(CH2CH3)2.

[0175] In some embodiments, R5 is hydrogen and R6 is hydrogen. In some embodiments, R5 is halo andR6 is hydrogen. In some embodiments, R5 is fluoro and R6 is hydrogen. In some embodiments, R5 ishydrogen and R6 is cyano. In some embodiments, R5 is hydrogen and R6 is halo, cyano, or C1-6 alkyloptionally substituted with one to eight Z1.

[0176] In some embodiments, R5 is hydrogen or cyano and R6 is halo, cyano, cyclopropyl, or C1-6 alkyloptionally substituted with one to three groups selected from fluoro, cyano, -N(CH3)2, -N(CH2CH3)2, andheterocyclyl substituted with one to three Z1a. In some embodiments, R5 is hydrogen and R6 is C1-3 alkylsubstituted with a 4-10 membered heterocyclyl optionally substituted with one or two Z1a.

[0177] In some embodiments, R5 is hydrogen and R6 is halo, cyano, or C1-6 alkyl optionally substitutedwith one to three fluoro, cyano, -N(CH3)2, -N(CH2CH3)2, or heterocyclyl substituted with one or two methyl.

[0178] In some embodiments, the moietyis selected from:, ,, , , ,, and

[0179] In some embodiments, the moietyis selected from:, , , , and

[0180] In some embodiments, the moietyis selected from:, , , , ,, , , and

[0181] In some embodiments, R8 is hydrogen. In some embodiments, R8 is C1-6 alkyl. In someembodiments, R8is methyl.

[0182] In some embodiments, R, R6, and R8 are hydrogen. In some embodiments, R5 and R6 arehydrogen and R8is methyl.

[0183] In some embodiments, R7 is hydrogen, halo, cyano, -NO2, -SF5, -CD3, C1-6 alkyl, C2-6 alkenyl,C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -C(O)R11, -C(O)OR11, -S(O)0-2R11, -NR11S(O)0-2R11, -S(O)0-2N(R11)2, -NR11S(O)0-2N(R11)2, -NR11C(O)N(R11)2, -C(O)N(R11)2, -NR11C(O)R11, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl,C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to eight Z1.

[0184] In some embodiments, R7 is hydrogen, halo, cyano, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl,C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -C(O)R11, -C(O)OR11, -NR11C(O)N(R11)2, -C(O)N(R11)2, -NR11C(O)R11, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to eight Z1;

[0185] In some embodiments, R7 is hydrogen, halo, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl,C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -C(O)R11, or -C(O)N(R11)2, wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to eight Z1.

[0186] In some embodiments, R7 is hydrogen, halo, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl,C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, or -C(O)R11, wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to eight Z1.

[0187] In some embodiments, R7 is hydrogen.

[0188] In some embodiments, R7 is halo. In some embodiments, R7 is fluoro. In some embodiments, R7is chloro. In some embodiments, R7 is bromo. In some embodiments, R7 is iodo.

[0189] In some embodiments, R7 is -C(O)R11. In some embodiments, R7 is -C(O)CH3.

[0190] In some embodiments, R7 is hydrogen, fluoro, chloro, bromo, iodo, or -C(O)CH3.

[0191] In some embodiments, R7 is C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, wherein each C1-6 alkyl,C2-6 alkenyl, or C2-6 alkynyl is independently optionally substituted with one to three Z1.

[0192] In some embodiments, R7 is C1-6 alkyl. In some embodiments, R7 is methyl, ethyl, n-propyl, orisopropyl. In some embodiments, R7 is methyl. In some embodiments, R7 is ethyl. In someembodiments, R7is isopropyl. In some embodiments, R7is linear or branched butyl.

[0193] In some embodiments, R7 is C1-6 alkyl optionally substituted with one to three Z1. In someembodiments, R7is C1-6alkyl substituted with one to three cyano, -OR11, -N(R11)2, C3-10cycloalkyl, heterocyclyl, or aryl.

[0194] In some embodiments, R7 is C1-6 alkyl substituted with cyano. In some embodiments, R7 is C1-6alkyl substituted with -OCH3. In some embodiments, R7 is C1-6 alkyl substituted with -OCH2CH3. Insome embodiments, R7 is C1-6 alkyl substituted with -OH and -OCH2CH3. In some embodiments, R7 isC1-6 alkyl substituted with -N(CH3)2. In some embodiments, R7 is C1-6 alkyl substituted with cyclopropyl.In some embodiments, R7 is C1-6 alkyl substituted with a 6-membered heterocyclyl. In someembodiments, R7is C1-6 alkyl substituted with phenyl.

[0195] In some embodiments, R7 is selected from hydrogen, halo, C1-4 alkyl, -CD3, cyclopropyl, phenyl,, , , , ,, , , and.

[0196] In some embodiments, R7 is selected from:and .

[0197] In some embodiments, R7 is selected from:and.

[0198] In some embodiments, R7 is C2-6 alkenyl optionally substituted with one to three Z1. In someembodiments, R7 is C2-6 alkenyl. In some embodiments, R7 is propenyl.

[0199] In some embodiments, R7 is C2-6 alkynyl optionally substituted with one to three Z . In someembodiments, R7 is C2-6 alkynyl substituted with -OR11 or C3-10 cycloalkyl. In some embodiments, R7 isC2-6 alkynyl substituted with -OH. In some embodiments, R7 is C2-6 alkynyl substituted with cyclopropyl.

[0200] In some embodiments, R7 is selected from:, , ,and

[0201] In some embodiments, R7 is C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, wherein each C1-6 alkyl, C2-6alkenyl, or C2-6 alkynyl is independently optionally substituted with one to three cyano, -OH, -OCH3, -OCH2CH3, -N(CH3)2, cyclopropyl, phenyl, or morpholino.

[0202] In some embodiments, R7 is C3-10 cycloalkyl or heterocyclyl, wherein each C3-10 cycloalkyl orheterocyclyl is independently optionally substituted with one to three Z1.

[0203] In some embodiments, R7 is C3-10 cycloalkyl or heterocyclyl, wherein each C3-10 cycloalkyl orheterocyclyl is independently optionally substituted with C1-6alkyl, -C(O)N(R11)2, or -C(O)R11.

[0204] In some embodiments, R7 is C3-10 cycloalkyl optionally substituted with one to three Z1. In someembodiments, R7 is C3-6 cycloalkyl substituted with -C(O)N(R11)2. In some embodiments, R7 is C3-6cycloalkyl substituted with -C(O)NH2. In some embodiments, R7 is C3-6 cycloalkyl substituted withmethoxy.

[0205] In some embodiments, R7 is C3-6 cycloalkyl substituted with heterocyclyl. In some embodiments,R7is C3-6cycloalkyl substituted with morpholinyl, piperidinyl, or pyrrolidinyl.

[0206] In some embodiments, R7 is heterocyclyl optionally substituted with one to three Z1. In someembodiments, R7 is a 5-6 membered heterocyclyl optionally substituted with C1-6 alkyl or -C(O)R11. Insome embodiments, R7 is a 5-6 membered heterocyclyl substituted with methyl. In some embodiments,R7is a 5-6 membered heterocyclyl substituted with -C(O)CH3.

[0207] In some embodiments, R7 is a spirocyclic heterocyclyl optionally substituted with one to three Z1.In some embodiments, R7 is unsubstituted spirocyclic heterocyclyl.

[0208] In some embodiments, R7 is cyclopropyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl,tetrahydropyranyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, pyrrolidinyl, piperidinyl, or morpholino, wherein each R7is optionally substituted with one to three Z1.

[0209] In some embodiments, R7 is cyclopropyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl,tetrahydropyranyl, pyrrolidinyl, piperidinyl, or morpholino, wherein each R7 is optionally substituted with methyl, -C(O)CH3, or -C(O)NH2.

[0210] In some embodiments, R7 is selected from:, and

[0211] In some embodiments, R7 is selected from:, , , and

[0212] In some embodiments, R7 is phenyl or 5-6 membered heteroaryl, wherein each phenyl or 5-6membered heteroaryl is independently optionally substituted with one to three Z1.

[0213] In some embodiments, R7 is phenyl optionally substituted with one to three Z1. In someembodiments, R7 is phenyl optionally substituted with halo, C1-6 alkyl, or -OR11. In some embodiments,R7is phenyl optionally substituted with fluoro. In some embodiments, R7is phenyl optionally substituted with chloro. In some embodiments, R7 is phenyl optionally substituted with bromo. In someembodiments, R7 is phenyl optionally substituted with cyano. In some embodiments, R7 is phenyloptionally substituted with -OCH3. In some embodiments, R7 is phenyl optionally substituted with C1-3alkyl. In some embodiments, R7 is phenyl optionally substituted with tert-butyl.

[0214] In some embodiments, R7 is a 5-6 membered heteroaryl optionally substituted with one to threeZ1. In some embodiments, R7 is a 5-membered heteroaryl optionally substituted with C1-6 alkyl. In someembodiments, R7is a 5-membered heteroaryl containing one or two nitrogen atoms and optionally substituted with methyl. In some embodiments, R7 is pyrazolyl. In some embodiments, R7 is1-methylpyrazolyl. In some embodiments, R7 is 3-methylpyrazolyl. In some embodiments, R7 is a6-membered heteroaryl optionally substituted with one to three Z1. In some embodiments, R7 is a6-membered unsubstituted heteroaryl containing one or two nitrogen atoms. In some embodiments, R7 ispyridinyl. In some embodiments, R7 is pyrimidinyl.

[0215] In some embodiments, R7 is phenyl or 5-6 membered heteroaryl, wherein each phenyl or 5-6membered heteroaryl is independently optionally substituted with halo, C1-6 alkyl, or -OR11.

[0216] In some embodiments, R7 is phenyl, pyridinyl, pyrazolyl, or pyrimidinyl, wherein each R7 isoptionally substituted with chloro, methyl, tert-butyl, or -OCH3.

[0217] In some embodiments, R7 is selected from:, , , , , , ,, and.

[0218] In some embodiments, R7 is selected from:and.

[0219] In some embodiments, R7 is halo, -C(O)CH3, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to three Z1.

[0220] In some embodiments, R7 is halo, -C(O)CH3, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, or heteroaryl is optionally substituted with halo, cyano, C1-6 alkyl, -OH, -OCH3,-OCH2CH3,-C(O)NH2, -C(O)CH3, -N(CH3)2, cyclopropyl, morpholino, or phenyl.

[0221] In some embodiments, each Z1 is independently deuterium, halo, cyano, -NO2, -SF5, C1-6 alkyl,C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -P(O)(OR11)2, -C(O)R11, -C(O)OR11, -S(O)0-2R11, -NR11S(O)0-2R11, -S(O)0-2N(R11)2, -NR11S(O)0-2N(R11)2, -NR11C(O)N(R11)2, -C(O)N(R11)2, -NR11C(O)R11, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a;

[0222] In some embodiments, provided herein is a compound of Formula IIC:or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopically enriched analog, or tautomer thereof, wherein q and r are each independently 0, 1, 2, 3, or 4; provided that the sum of q and r is at least 2.

[0223] In some embodiments, provided herein is a compound of Formula IIC:or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopically enriched analog, or tautomer thereof, wherein: p is 0, 1, or 2; q and r are each independently 0, 1, 2, 3, or 4; provided that the sum of q and r is at least 2; each R4is independently oxo, halo, cyano, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -C(O)R11, -C(O)OR11, -S(O)0-2R11, -NR11S(O)0-2R11, -S(O)0-2N(R11)2, -NR11S(O)0-2N(R11)2, -NR11C(O)N(R11)2, -C(O)N(R11)2, -NR11C(O)R11, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to eight Z1; R5is hydrogen, halo, cyano, or C1-6alkyl optionally substituted with one to three Z1; R6is hydrogen, halo, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -C(O)R11, -C(O)OR11, -S(O)0-2R11, -NR11S(O)0-2R11, -S(O)0-2N(R11)2, -NR11S(O)0-2N(R11)2, -NR11C(O)N(R11)2, -C(O)N(R11)2, -NR11C(O)R11, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to eight Z1; R7is hydrogen, halo, cyano, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -C(O)R11, -C(O)OR11, -S(O)0-2R11, -NR11S(O)0-2R11, -S(O)0-2N(R11)2, -NR11S(O)0-2N(R11)2, -NR11C(O)N(R11)2, -C(O)N(R11)2, -NR11C(O)R11, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to eight Z1;each Z1is independently halo, cyano, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -P(O)(OR11)2, -C(O)R11, -C(O)OR11, -S(O)0-2R11, -NR11S(O)0-2R11, -S(O)0-2N(R11)2, -NR11S(O)0-2N(R11)2, -NR11C(O)N(R11)2, -C(O)N(R11)2, -NR11C(O)R11, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a; each R11is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a; each Z1ais independently hydroxy, halo, cyano, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R13)2, -OR13, -P(O)(OR13)2, -C(O)R13, -C(O)OR13, -S(O)0-2R13, -NR13S(O)0-2R13, -S(O)0-2N(R13)2, -NR13S(O)0-2N(R13)2, -NR13C(O)N(R13)2, -C(O)N(R13)2, -NR13C(O)R13, -OC(O)N(R13)2, or -NR13C(O)OR13; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1b; each R13is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1b; each Z1bis independently halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, -P(O)(OH)2, C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 alkynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; and each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6 alkyl)-, -N(C2-6 alkenyl)-, -N(C2-6 alkynyl)-, -N(C1-6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-6alkyl)-, -C(O)N(C2-6alkenyl)-, -C(O)N(C2-6alkynyl)-, -C(O)N(C1-6haloalkyl)-, -C(O)N(C3-10cycloalkyl)-, -C(O)N(heterocyclyl)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)-, -S(O)2NH-, -P(O)(OH)O-, -P(O)(O-C1-6 alkyl)O-, -P(O)(O-C2-6 alkenyl)-O, -P(O)(O-C2-6 alkynyl)O-, -P(O)(OC1-6 haloalkyl)O-, -P(O)(OC3-10 cycloalkyl)O-, -P(O)(O-heterocyclyl)O-, -P(O)(O-aryl)O-, or -P(O)(O-heteroaryl)O-; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, and heteroaryl of Z1band L is further independently optionally substituted with one to five hydroxy, halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0224] In some embodiments, provided herein is a compound of Formula IID:IID or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopically enriched analog, ortautomer thereof, wherein Y is O or N; s and t are each independently 0, 1, 2, or 3; and u is 1, 2, 3, or 4;provided that the sum of s, t, and u is not greater than 7.

[0225] In some embodiments, provided herein is a compound of Formula IID:or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopically enriched analog, or tautomer thereof, wherein: Y is O or N; s and t are each independently 0, 1, 2, or 3; u is 1, 2, 3, or 4; provided that the sum of s, t, and u is not greater than 7; R5is hydrogen, halo, cyano, or C1-6alkyl optionally substituted with one to three Z1; R6is hydrogen, halo, cyano, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -C(O)R11, -C(O)OR11, -S(O)0-2R11, -NR11S(O)0-2R11, -S(O)0-2N(R11)2, -NR11S(O)0-2N(R11)2, -NR11C(O)N(R11)2, -C(O)N(R11)2, -NR11C(O)R11, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to eight Z1; R7is hydrogen, halo, cyano, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -C(O)R11, -C(O)OR11, -S(O)0-2R11, -NR11S(O)0-2R11, -S(O)0-2N(R11)2, -NR11S(O)0-2N(R11)2, -NR11C(O)N(R11)2, -C(O)N(R11)2, -NR11C(O)R11, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to eight Z1; each Z1is independently halo, cyano, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -P(O)(OR11)2, -C(O)R11, -C(O)OR11, -S(O)0-2R11, -NR11S(O)0-2R11, -S(O)0-2N(R11)2, -NR11S(O)0-2N(R11)2, -NR11C(O)N(R11)2, -C(O)N(R11)2, -NR11C(O)R11, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a;each R11is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a; each Z1ais independently hydroxy, halo, cyano, -NO2, -SF5, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R13)2, -OR13, -P(O)(OR13)2, -C(O)R13, -C(O)OR13, -S(O)0-2R13, -NR13S(O)0-2R13, -S(O)0-2N(R13)2, -NR13S(O)0-2N(R13)2, -NR13C(O)N(R13)2, -C(O)N(R13)2, -NR13C(O)R13, -OC(O)N(R13)2, or -NR13C(O)OR13; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1b; each R13is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1b; each Z1bis independently halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, -P(O)(OH)2, C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 alkynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; and each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6alkyl)-, -N(C2-6alkenyl)-, -N(C2-6alkynyl)-, -N(C1-6haloalkyl)-, -N(C3-10cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-6alkyl)-, -C(O)N(C2-6alkenyl)-, -C(O)N(C2-6alkynyl)-, -C(O)N(C1-6 haloalkyl)-, -C(O)N(C3-10 cycloalkyl)-, -C(O)N(heterocyclyl)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)-, -S(O)2NH-, -P(O)(OH)O-, -P(O)(O-C1-6 alkyl)O-, -P(O)(O-C2-6 alkenyl)-O, -P(O)(O-C2-6 alkynyl)O-, -P(O)(OC1-6 haloalkyl)O-, -P(O)(OC3-10 cycloalkyl)O-, -P(O)(O-heterocyclyl)O-, -P(O)(O-aryl)O-, or -P(O)(O-heteroaryl)O-; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, and heteroaryl of Z1band L is further independently optionally substituted with one to five hydroxy, halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0226] In some embodiments, provided herein is a compound of Formula IIIC:or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopically enriched analog, ortautomer thereof, wherein v and w are each independently 0, 1, 2, 3, or 4; provided that the sum of v andw is at least 1.

[0227] In some embodiments, provided herein is a compound of Formula IIIC:or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopically enriched analog, or tautomer thereof, wherein: p is 0, 1, or 2; v and w are each independently 0, 1, 2, 3, or 4; provided that the sum of v and w is at least 1; each R4is independently oxo, halo, cyano, -NO2, -SF5, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -C(O)R11, -C(O)OR11, -S(O)0-2R11, -NR11S(O)0-2R11, -S(O)0-2N(R11)2, -NR11S(O)0-2N(R11)2, -NR11C(O)N(R11)2, -C(O)N(R11)2, -NR11C(O)R11, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to eight Z1; R5is hydrogen, halo, cyano, or C1-6 alkyl optionally substituted with one to three Z1; R6is hydrogen, halo, cyano, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -C(O)R11, -C(O)OR11, -S(O)0-2R11, -NR11S(O)0-2R11, -S(O)0-2N(R11)2, -NR11S(O)0-2N(R11)2, -NR11C(O)N(R11)2, -C(O)N(R11)2, -NR11C(O)R11, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to eight Z1; R7is hydrogen, halo, cyano, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -C(O)R11, -C(O)OR11, -S(O)0-2R11, -NR11S(O)0-2R11, -S(O)0-2N(R11)2, -NR11S(O)0-2N(R11)2, -NR11C(O)N(R11)2, -C(O)N(R11)2, -NR11C(O)R11, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to eight Z1; R8is hydrogen or C1-6alkyl optionally substituted with one to three Z1; each Z1is independently halo, cyano, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -P(O)(OR11)2, -C(O)R11, -C(O)OR11, -S(O)0-2R11, -NR11S(O)0-2R11, -S(O)0-2N(R11)2, -NR11S(O)0-2N(R11)2, -NR11C(O)N(R11)2, -C(O)N(R11)2, -NR11C(O)R11, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a;each R11is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a; each Z1ais independently hydroxy, halo, cyano, -NO2, -SF5, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R13)2, -OR13, -P(O)(OR13)2, -C(O)R13, -C(O)OR13,-S(O)0-2R13, -NR13S(O)0-2R13, -S(O)0-2N(R13)2, -NR13S(O)0-2N(R13)2, -NR13C(O)N(R13)2, -C(O)N(R13)2,-NR13C(O)R13, -OC(O)N(R13)2, or -NR13C(O)OR13; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1b; each R13is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1b; each Z1bis independently halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, -P(O)(OH)2, C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 alkynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; and each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6alkyl)-, -N(C2-6alkenyl)-, -N(C2-6alkynyl)-, -N(C1-6haloalkyl)-, -N(C3-10cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-6alkyl)-, -C(O)N(C2-6alkenyl)-, -C(O)N(C2-6alkynyl)-, -C(O)N(C1-6 haloalkyl)-, -C(O)N(C3-10 cycloalkyl)-, -C(O)N(heterocyclyl)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)-, -S(O)2NH-, -P(O)(OH)O-, -P(O)(O-C1-6 alkyl)O-, -P(O)(O-C2-6 alkenyl)-O, -P(O)(O-C2-6 alkynyl)O-, -P(O)(OC1-6 haloalkyl)O-, -P(O)(OC3-10 cycloalkyl)O-, -P(O)(O-heterocyclyl)O-, -P(O)(O-aryl)O-, or -P(O)(O-heteroaryl)O-; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, and heteroaryl of Z1band L is further independently optionally substituted with one to five hydroxy, halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0228] In some embodiments, provided herein is a compound of Formula IIIC’:or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopically enriched analog, or tautomer thereof, wherein v and w are each independently 0, 1, 2, 3, or 4; provided that the sum of v and w is at least 1.

[0229] In some embodiments, provided herein is a compound of Formula IIIC’:or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopically enriched analog, or tautomer thereof, wherein: v and w are each independently 0, 1, 2, 3, or 4; provided that the sum of v and w is at least 1; p is 0, 1, or 2; each R4is independently oxo, halo, cyano, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -C(O)R11, -C(O)OR11, -S(O)0-2R11, -NR11S(O)0-2R11, -S(O)0-2N(R11)2, -NR11S(O)0-2N(R11)2, -NR11C(O)N(R11)2, -C(O)N(R11)2, -NR11C(O)R11, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to eight Z1; R7is hydrogen, halo, cyano, -NO2, -SF5, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -C(O)R11, -C(O)OR11, -S(O)0-2R11, -NR11S(O)0-2R11, -S(O)0-2N(R11)2, -NR11S(O)0-2N(R11)2, -NR11C(O)N(R11)2, -C(O)N(R11)2, -NR11C(O)R11, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to eight Z1; each Z1is independently halo, cyano, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -P(O)(OR11)2, -C(O)R11, -C(O)OR11, -S(O)0-2R11, -NR11S(O)0-2R11, -S(O)0-2N(R11)2, -NR11S(O)0-2N(R11)2, -NR11C(O)N(R11)2, -C(O)N(R11)2, -NR11C(O)R11, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a; each R11is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a; each Z1ais independently hydroxy, halo, cyano, -NO2, -SF5, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R13)2, -OR13, -P(O)(OR13)2, -C(O)R13, -C(O)OR13, -S(O)0-2R13, -NR13S(O)0-2R13, -S(O)0-2N(R13)2, -NR13S(O)0-2N(R13)2, -NR13C(O)N(R13)2, -C(O)N(R13)2,-NR13C(O)R13, -OC(O)N(R13)2, or -NR13C(O)OR13; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1b; each R13is independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1b; each Z1bis independently halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, -P(O)(OH)2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 alkynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; and each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6alkyl)-, -N(C2-6alkenyl)-, -N(C2-6alkynyl)-, -N(C1-6haloalkyl)-, -N(C3-10cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-6alkyl)-, -C(O)N(C2-6alkenyl)-, -C(O)N(C2-6alkynyl)-, -C(O)N(C1-6haloalkyl)-, -C(O)N(C3-10cycloalkyl)-, -C(O)N(heterocyclyl)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)-, -S(O)2NH-, -P(O)(OH)O-, -P(O)(O-C1-6 alkyl)O-, -P(O)(O-C2-6 alkenyl)-O, -P(O)(O-C2-6 alkynyl)O-, -P(O)(OC1-6 haloalkyl)O-, -P(O)(OC3-10 cycloalkyl)O-, -P(O)(O-heterocyclyl)O-, -P(O)(O-aryl)O-, or -P(O)(O-heteroaryl)O-; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, and heteroaryl of Z1band L is further independently optionally substituted with one to five hydroxy, halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0230] In some embodiments, provided herein is a compound of Formula IVA:or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopically enriched analog, or tautomer thereof.

[0231] In some embodiments, provided herein is a compound of Formula IVA:or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopically enriched analog, or tautomer thereof; wherein: p is 0, 1, or 2; each R4is independently oxo, halo, cyano, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -C(O)R11, -C(O)OR11, -S(O)0-2R11, -NR11S(O)0-2R11, -S(O)0-2N(R11)2, -NR11S(O)0-2N(R11)2, -NR11C(O)N(R11)2, -C(O)N(R11)2, -NR11C(O)R11, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to eight Z1; R5is hydrogen, halo, cyano, or C1-6alkyl optionally substituted with one to three Z1; R6is hydrogen, halo, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -C(O)R11, -C(O)OR11, -S(O)0-2R11, -NR11S(O)0-2R11, -S(O)0-2N(R11)2, -NR11S(O)0-2N(R11)2, -NR11C(O)N(R11)2, -C(O)N(R11)2, -NR11C(O)R11, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to eight Z1; R7is hydrogen, halo, cyano, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -C(O)R11, -C(O)OR11, -S(O)0-2R11, -NR11S(O)0-2R11, -S(O)0-2N(R11)2, -NR11S(O)0-2N(R11)2, -NR11C(O)N(R11)2, -C(O)N(R11)2, -NR11C(O)R11, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to eight Z1; each Z1is independently halo, cyano, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -P(O)(OR11)2, -C(O)R11, -C(O)OR11, -S(O)0-2R11, -NR11S(O)0-2R11, -S(O)0-2N(R11)2, -NR11S(O)0-2N(R11)2, -NR11C(O)N(R11)2, -C(O)N(R11)2, -NR11C(O)R11, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a; each R11is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a; each Z1ais independently hydroxy, halo, cyano, -NO2, -SF5, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R13)2, -OR13, -P(O)(OR13)2, -C(O)R13, -C(O)OR13,-S(O)0-2R13, -NR13S(O)0-2R13, -S(O)0-2N(R13)2, -NR13S(O)0-2N(R13)2, -NR13C(O)N(R13)2, -C(O)N(R13)2, -NR13C(O)R13, -OC(O)N(R13)2, or -NR13C(O)OR13; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1b; each R13is independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1b; each Z1bis independently halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, -P(O)(OH)2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 alkynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; and each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6alkyl)-, -N(C2-6alkenyl)-, -N(C2-6alkynyl)-, -N(C1-6haloalkyl)-, -N(C3-10cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-6alkyl)-, -C(O)N(C2-6alkenyl)-, -C(O)N(C2-6alkynyl)-, -C(O)N(C1-6 haloalkyl)-, -C(O)N(C3-10 cycloalkyl)-, -C(O)N(heterocyclyl)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)-, -S(O)2NH-, -P(O)(OH)O-, -P(O)(O-C1-6 alkyl)O-, -P(O)(O-C2-6 alkenyl)-O, -P(O)(O-C2-6 alkynyl)O-, -P(O)(OC1-6haloalkyl)O-, -P(O)(OC3-10cycloalkyl)O-, -P(O)(O-heterocyclyl)O-, -P(O)(O-aryl)O-, or -P(O)(O-heteroaryl)O-; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, and heteroaryl of Z1band L is further independently optionally substituted with one to five hydroxy, halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0232] In some embodiments, the compound of Formula IVA is represented by Formula IVA-a:or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopically enriched analog, or tautomer thereof.

[0233] In some embodiments, the compound of Formula IVA is represented by Formula IVA-b:or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopically enriched analog, or tautomer thereof.

[0234] In some embodiments, provided herein is a compound of Formula IVA’:or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopically enriched analog, or tautomer thereof.

[0235] In some embodiments, provided herein is a compound of Formula IVA’:or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopically enriched analog, or tautomer thereof; wherein: p is 0, 1, or 2; each R4is independently oxo, halo, cyano, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -C(O)R11, -C(O)OR11, -S(O)0-2R11, -NR11S(O)0-2R11, -S(O)0-2N(R11)2, -NR11S(O)0-2N(R11)2, -NR11C(O)N(R11)2, -C(O)N(R11)2, -NR11C(O)R11, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to eight Z1; R7is hydrogen, halo, cyano, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -C(O)R11, -C(O)OR11, -S(O)0-2R11, -NR11S(O)0-2R11, -S(O)0-2N(R11)2, -NR11S(O)0-2N(R11)2, -NR11C(O)N(R11)2, -C(O)N(R11)2, -NR11C(O)R11, -OC(O)N(R11)2,or -NR11C(O)OR11; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to eight Z1; each Z1is independently halo, cyano, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -P(O)(OR11)2, -C(O)R11, -C(O)OR11, -S(O)0-2R11, -NR11S(O)0-2R11, -S(O)0-2N(R11)2, -NR11S(O)0-2N(R11)2, -NR11C(O)N(R11)2, -C(O)N(R11)2, -NR11C(O)R11, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a; each R11is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a; each Z1ais independently hydroxy, halo, cyano, -NO2, -SF5, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R13)2, -OR13, -P(O)(OR13)2, -C(O)R13, -C(O)OR13, -S(O)0-2R13, -NR13S(O)0-2R13, -S(O)0-2N(R13)2, -NR13S(O)0-2N(R13)2, -NR13C(O)N(R13)2, -C(O)N(R13)2, -NR13C(O)R13, -OC(O)N(R13)2, or -NR13C(O)OR13; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1b; each R13is independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1b; each Z1bis independently halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, -P(O)(OH)2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 alkynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; and each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6alkyl)-, -N(C2-6alkenyl)-, -N(C2-6alkynyl)-, -N(C1-6haloalkyl)-, -N(C3-10cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-6alkyl)-, -C(O)N(C2-6alkenyl)-, -C(O)N(C2-6alkynyl)-, -C(O)N(C1-6 haloalkyl)-, -C(O)N(C3-10 cycloalkyl)-, -C(O)N(heterocyclyl)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)-, -S(O)2NH-, -P(O)(OH)O-, -P(O)(O-C1-6 alkyl)O-, -P(O)(O-C2-6 alkenyl)-O, -P(O)(O-C2-6 alkynyl)O-, -P(O)(OC1-6 haloalkyl)O-, -P(O)(OC3-10 cycloalkyl)O-, -P(O)(O-heterocyclyl)O-, -P(O)(O-aryl)O-, or -P(O)(O-heteroaryl)O-; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, and heteroaryl of Z1band L is further independently optionally substituted with one to five hydroxy, halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0236] In some embodiments, the compound of Formula IVA is represented by Formula IVA -a:or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopically enriched analog, or tautomer thereof.

[0237] In some embodiments, the compound of Formula IVA’ is represented by Formula IVA’-b:or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopically enriched analog, or tautomer thereof.

[0238] In some embodiments, provided herein is a compound of Formula IVA’:or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopically enriched analog, or tautomer thereof.

[0239] In some embodiments, provided herein is a compound of Formula IVB:or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopically enriched analog, or tautomer thereof.

[0240] In some embodiments, provided herein is a compound of Formula IVB’:or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopically enriched analog, or tautomer thereof.

[0241] In some embodiments, provided herein is a compound of Formula IVC:or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopically enriched analog, or tautomer thereof; wherein X1is O or CH2.

[0242] In some embodiments, provided herein is a compound of Formula IVC’:or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopically enriched analog, or tautomer thereof; wherein X1is O or CH2.

[0243] In one embodiment, provided is a compound, or a pharmaceutically acceptable salt, solvate,stereoisomer, isotopically enriched analog, or tautomer thereof, selected from Table 1.

[0244] Each compound denoted as “1st eluting isomer,” “2nd eluting isomer,”, etc. is a single unknownstereoisomer whose stereochemistry is unknown at the stereocenter depicted as racemic. Where the orderof elution is not specified, the compound is a mixture of stereoisomers with respect to the stereocenter depicted as racemic.Table 111

[0245] In one embodiment, provided is a compound, or a pharmaceutically acceptable salt, solvate,isotopically enriched analog, or tautomer thereof, selected from Table 2. Table 2ıIJıĶĸ

[0246] For the compounds having a meso substituent, e.g., a 3-oxa-9-azabicyclo[3.3.1]nonane, thediastereomers may be depicted in Table 2 with straight or wedged bonds to show the relativestereochemistry. Methods

[0247] In one embodiment, the compounds and compositions described herein are useful in methods fortreating a SMARCA2 dependent disease or disorder or a disease or disorder that is mediated, at least in part by, SMARCA2. The methods comprise administering to a subject suffering from a SMARCA2 dependent disease or disorder an effective amount of a compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopically enriched analog, or tautomer thereof or a pharmaceutical compositioncomprising said compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopicallyenriched analog, or tautomer thereof as described herein.

[0248] In one embodiment, there is provided a compound, or a pharmaceutically acceptable salt, solvate,stereoisomer, isotopically enriched analog, or tautomer thereof or a pharmaceutical composition comprising said compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopically enriched analog, or tautomer thereof as described herein for use in treating an SMARCA2 dependent disease or disorder.

[0249] In one embodiment, provided are methods of treating a SMARCA2 dependent disease ordisorder or a disease or disorder that is mediated, at least in part by, SMARCA2, comprising administering to a subject suffering from a SMARCA2 dependent disease or disorder an effective amount of a compound of Formula I:or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopically enriched analog, or tautomer thereof, wherein: n is 0, 1, or 2; R1is hydroxy, halo, cyano, C1-4 alkoxy, or N(R2)2; R2is independently hydrogen, C1-4alkyl, or C3-6cycloalkyl, wherein each alkyl or cycloalkyl is unsubstituted or substituted with one to three Z1; each R3is independently halo, cyano, C1-6alkyl, or C1-3haloalkyl; L1is a bond, C1-4 alkylene, -C1-4 alkylene-heteroaryl-, C2-3 alkenylene, C2-3 alkynylene, or -C(O)-; X is selected from:andp is 0, 1, or 2; Ring A is a monocyclic, spirocyclic, fused bicyclic, or bridged bicyclic 4-10 membered heterocyclyl or a monocyclic or fused bicyclic 5-10 membered heteroaryl; Ring B is a monocyclic, spirocyclic, fused bicyclic, or bridged bicyclic 3-10 membered cycloalkyl, a monocyclic, spirocyclic, fused bicyclic, or bridged bicyclic 4-10 membered heterocyclyl, ora monocyclic or fused bicyclic 5-10 membered heteroaryl; wherein the nitrogen atom and L1 may beattached anywhere on Ring B, including on the same carbon; each R4is independently oxo, halo, cyano, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -C(O)R11, -C(O)OR11, -S(O)0-2R11, -NR11S(O)0-2R11, -S(O)0-2N(R11)2, -NR11S(O)0-2N(R11)2, -NR11C(O)N(R11)2, -C(O)N(R11)2, -NR11C(O)R11, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to eight Z1; R5is hydrogen, halo, cyano, or C1-6alkyl optionally substituted with one to three Z1; R6is hydrogen, halo, cyano, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -C(O)R11, -C(O)OR11, -S(O)0-2R11, -NR11S(O)0-2R11, -S(O)0-2N(R11)2, -NR11S(O)0-2N(R11)2, -NR11C(O)N(R11)2, -C(O)N(R11)2, -NR11C(O)R11, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to eight Z1; R7is hydrogen, halo, cyano, -NO2, -SF5, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -C(O)R11, -C(O)OR11, -S(O)0-2R11, -NR11S(O)0-2R11, -S(O)0-2N(R11)2, -NR11S(O)0-2N(R11)2, -NR11C(O)N(R11)2, -C(O)N(R11)2, -NR11C(O)R11, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to eight Z1; R8is hydrogen or C1-6 alkyl optionally substituted with one to three Z1; each Z1is independently halo, cyano, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -C(O)R11, -C(O)OR11, -S(O)0-2R11, -NR11S(O)0-2R11, -S(O)0-2N(R11)2, -NR11S(O)0-2N(R11)2, -NR11C(O)N(R11)2, -C(O)N(R11)2, -NR11C(O)R11, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a; each R11is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a; each Z1ais independently hydroxy, halo, cyano, -NO2, -SF5, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R13)2, -OR13, -C(O)R13, -C(O)OR13, -S(O)0-2R13, -NR13S(O)0-2R13, -S(O)0-2N(R13)2, -NR13S(O)0-2N(R13)2, -NR13C(O)N(R13)2, -C(O)N(R13)2, -NR13C(O)R13,-OC(O)N(R13)2, or -NR13C(O)OR13; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1b; each R13is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1b; each Z1bis independently halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 alkynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; and each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6 alkyl)-, -N(C2-6 alkenyl)-, -N(C2-6 alkynyl)-, -N(C1-6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-6alkyl)-, -C(O)N(C2-6alkenyl)-, -C(O)N(C2-6alkynyl)-, -C(O)N(C1-6haloalkyl)-, -C(O)N(C3-10cycloalkyl)-, -C(O)N(heterocyclyl)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)-, or -S(O)2NH-; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, and heteroaryl of Z1band L is further independently optionally substituted with one to five hydroxy, halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0250] In some embodiments, this disclosure provides for a method for modulating or degrading proteinwhich is expressed from the SMARCA2 gene, which method comprises contacting the protein with an effective amount of a compound of Formula I, II, III, IV, or any subformula thereof, under conditions wherein the protein which is expressed from the SMARCA2 gene is modulated or degraded.

[0251] In some embodiments, this disclosure provides for a method for modulating or degrading proteinwhich is expressed from the SMARCA4 gene, which method comprises contacting the protein with an effective amount of a compound of Formula I, II, III, IV, or any subformula thereof, under conditions wherein the protein which is expressed from the SMARCA4 gene is modulated or degraded.

[0252] In some embodiments, there is provided a method to modulate or degrade protein which isexpressed from the SMARCA2 gene in a subject, which method comprises administering to said subjectan effective amount of a compound of Formula I, II, III, IV, or any subformula thereof, or apharmaceutical composition comprising an effective amount of a compound of Formula I, or any subformula thereof, and a pharmaceutically acceptable excipient.

[0253] In some embodiments, there is provided a method to modulate or degrade protein which isexpressed from the SMARCA4 gene in a subject, which method comprises administering to said subject an effective amount of a compound of Formula I, II, III, IV, or any subformula thereof, or a pharmaceutical composition comprising an effective amount of a compound of Formula I, II, III, IV, or any subformula thereof, and a pharmaceutically acceptable excipient.

[0254] In some embodiments, there is provided a method for treating cancer in a subject in need thereof,which method comprises selecting a subject whose cancer is mediated at least in part by SMARCA2 andadministering to said subject an effective amount of a compound of Formula I, II, III, IV, or any subformula thereof, or an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of Formula I, II, III, IV, or any subformula thereof.

[0255] In some embodiments, there is provided a method for treating cancer in a subject in need thereof,which method comprises selecting a subject whose cancer is mediated at least in part by SMARCA4 and administering to said subject an effective amount of a compound of Formula I, II, III, IV, or any subformula thereof, or an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of Formula I, II, III, IV, or any subformula thereof.

[0256] In some embodiments, there is provided a method for treating hyperplasia in a subject in needthereof, which method comprises administering to said subject an effective amount of a compound of Formula I, II, III, IV, or any subformula thereof, or an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of Formula I, II, III, IV, or any subformula thereof.

[0257] In one embodiment, the method relates to a compound, or a pharmaceutically acceptable salt,solvate, stereoisomer, isotopically enriched analog, or tautomer thereof or a pharmaceutical composition comprising said compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopically enriched analog, or tautomer thereof as described herein for use in manufacture of a medicament for reducing levels of protein which is expressed from the SMARCA2 gene, where reduction of such proteinlevels treats or ameliorates the diseases or disorder.

[0258] In one embodiment, the methods described herein comprise use of a prodrug of the compoundsdescribed herein. Prodrugs may be prepared by modifying functional groups present in the compounds insuch a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Prodrugs include compounds described herein wherein a hydroxy, amino, carboxyl, orsulfhydryl group in a compound described herein is bonded to any group that may be cleaved in vivo toregenerate the free hydroxy, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), amides, guanidines, carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy functional groups in compounds described herein, and the like.

[0259] In one embodiment, the method relates to a compound, or a pharmaceutically acceptable salt,solvate, stereoisomer, isotopically enriched analog, or tautomer thereof or a pharmaceutical composition comprising said compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopically enriched analog, or tautomer thereof as described herein for use as described herein, wherein the degradation of protein which is expressed from the SMARCA2 gene at 1 µM concentration of the compounds described herein is in the range of about 25%-99%. The degradation of the protein which is expressed from the SMARCA2 gene is measured by the assay described in the biological example. In some embodiments, the degradation of the protein which is expressed from the SMARCA2 gene is fromabout 25% to about 50%, from about 45% to about 70%, from about 65% to about 90% or from about 75% to about 99%. In some embodiments, the degradation of the protein which is expressed from the SMARCA2 gene is from about 25% to about 35%, from about 35% to about 45%, from about 45% to about 55%, from about 55% to about 65%, from about 65% to about 75%, from about 75% to about 85%, from about 85% to about 99%. In some embodiments, the degradation of the protein which is expressedfrom the SMARCA2 gene is more than 60%. In some embodiments, the degradation of the protein whichis expressed from the SMARCA2 gene is more than 70%. In some embodiments, the degradation of the protein which is expressed from the SMARCA2 gene is more than 80%. In some embodiments, the degradation of the protein which is expressed from the SMARCA2 gene is more than 90%.

[0260] The compounds and compositions described herein are useful in treating SMARCA2 dependentdiseases or disorders such as, e.g., liposarcoma, glioblastoma, bladder cancer, adrenocortical cancer,multiple myeloma, colorectal cancer, non-small cell lung cancer, Human Papilloma Virus-associated cervical, oropharyngeal, penis, anal, thyroid, or vaginal cancer or Epstein-Barr Virus-associated nasopharyngeal carcinoma, gastric cancer, rectal cancer, thyroid cancer, Hodgkin lymphoma or diffuselarge B-cell lymphoma. The cancer also may be selected from prostate cancer, breast carcinoma,lymphomas, leukemia, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, renal cancer, glioblastoma multiform, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, cholangiocarcinoma, gastric cancer, soft tissue sarcomas, rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancers, cancer for which the immune response is deficient, an immunogenic cancer, and Ewing’s sarcoma. In one embodiment, the SMARCA2-dependent disease or disorder is a disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, and gastrointestinal stromal tumor (GIST). In another embodiment, the cancer is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myelogenous leukemia, and gastrointestinal stromal tumor (GIST). In another embodiment, the SMARCA2-dependent disease or disorder is a disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple- negative breast cancer (TNBC), nasopharyngealcancer (NPC), and microsatellite stable colorectal cancer (mssCRC).

[0261] The compounds of the disclosure can be administered in effective amounts to treat or prevent adisorder and / or prevent the development thereof in subjects.

[0262] In certain embodiments, compounds as described herein are useful in the treatment ofproliferative disorders (e.g., cancer, benign neoplasms, inflammatory disease, and autoimmune diseases). In certain embodiments, according to the methods of treatment of the present application, levels of cell proteins of interest, e.g., pathogenic and oncogenic proteins are modulated, or their growth is inhibited or the proteins are degraded by contacting said cells with an compound or composition, as described herein. In other embodiments, the compounds are useful in treating cancer.

[0263] Thus, in another aspect of the application, methods for the treatment of cancer are providedcomprising administering a therapeutically effective amount of compound or composition, as described herein, to a subject in need thereof. In certain embodiments, a method for the treatment of cancer is provided comprising administering a therapeutically effective amount of a compound, or a pharmaceutical composition comprising a compound as described herein to a subject in need thereof, insuch amounts and for such time as is necessary to achieve the desired result. In some embodiments, thecompounds of present application are administered orally or intravenously. In certain embodiments of the present application a “therapeutically effective amount” of the compound or pharmaceutical composition is that amount effective for killing or inhibiting the growth of tumor cells. The compounds and compositions, according to the method of the present application, may be administered using any amount and any route of administration effective for killing or inhibiting the growth of tumor cells. Thus, the expression “amount effective to kill or inhibit the growth of tumor cells,” as used herein, refers to a sufficient amount of agent to kill or inhibit the growth of tumor cells. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the disease, the particular anticancer agent, its mode of administration, and the like. In certainembodiments of the present application a “therapeutically effective amount” of the compound orpharmaceutical composition described herein is that amount effective for reducing the levels of target proteins. In certain embodiments of the present application a “therapeutically effective amount” of the compound or pharmaceutical composition is that amount effective to kill or inhibit the growth of skin cells.

[0264] In certain embodiments, the method involves the administration of a therapeutically effectiveamount of the compound or a pharmaceutically acceptable derivative thereof to a subject (including, but not limited to a human or other mammal in need of it. In certain embodiments, the compounds or compositions described herein are useful for the treatment of cancer (including, but not limited to, glioblastoma, retinoblastoma, breast cancer, cervical cancer, colon and rectal cancer, leukemia,lymphoma, lung cancer (including, but not limited to small cell lung cancer), melanoma and / or skincancer, multiple myeloma, non-Hodgkin's lymphoma, ovarian cancer, pancreatic cancer, prostate cancerand gastric cancer, bladder cancer, uterine cancer, kidney cancer, testicular cancer, stomach cancer, braincancer, liver cancer, or esophageal cancer).

[0265] In certain embodiments, the compounds or compositions described herein are useful in thetreatment of cancers and other proliferative disorders, including, but not limited to breast cancer, cervical cancer, colon and rectal cancer, leukemia, lung cancer, melanoma, multiple myeloma, non-Hodgkin's lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, and gastric cancer. In certain embodiments, compounds or compositions described herein are active against solid tumors.

[0266] Another aspect of the application relates to a method of treating or lessening the severity of adisease or condition associated with a proliferation disorder in a patient, said method comprising a step of administering to said patient, a compound of Formula I or a composition comprising said compound.

[0267] It will be appreciated that the compounds and compositions, according to the method of thepresent application, may be administered using any amount and any route of administration effective forthe treatment of cancer and / or disorders associated with cell hyperproliferation. For example, when usingthe compounds for the treatment of cancer, the expression “effective amount” as used herein, refers to a sufficient amount of agent to inhibit proliferation, or refers to a sufficient amount to reduce the effects of cancer. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the diseases, the particular anticancer agent, its mode of administration, and the like.

[0268] The present application provides methods for the treatment of a proliferative disorder in a subjectin need thereof by administering to a subject in need of such treatment, a therapeutically effective amount of a compound of the present application, or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopically enriched analog, or tautomer thereof. The proliferative disorder can be cancer or a precancerous condition. The present application further provides the use of a compound of the present application, or a pharmaceutically acceptable salt, salt, solvate, stereoisomer, or tautomer thereof, for the preparation of a medicament useful for the treatment of a proliferative disorder.

[0269] The present application also provides methods of protecting against a proliferative disorder in asubject in need thereof by administering a therapeutically effective amount of compound of the present application, or a pharmaceutically acceptable salt, salt, solvate, stereoisomer, or tautomer thereof, to a subject in need of such treatment. The proliferative disorder can be cancer or a precancerous condition. The present application also provides the use of compound of the present application, or a pharmaceutically acceptable salt, salt, solvate, stereoisomer, or tautomer thereof, for the preparation of a medicament useful for the prevention of a proliferative disorder.

[0270] As used herein, the term “proliferative disorder” refers to conditions in which unregulated orabnormal growth, or both, of cells can lead to the development of an unwanted condition or disease, which may or may not be cancerous. Exemplary proliferative disorders of the application encompass a variety of conditions wherein cell division is deregulated. Exemplary proliferative disorder include, but are not limited to, neoplasms, benign tumors, malignant tumors, pre-cancerous conditions, in situ tumors, encapsulated tumors, metastatic tumors, liquid tumors, solid tumors, immunological tumors, hematological tumors, cancers, carcinomas, leukemias, lymphomas, sarcomas, and rapidly dividing cells. The term “rapidly dividing cell” as used herein is defined as any cell that divides at a rate that exceeds or is greater than what is expected or observed among neighboring or juxtaposed cells within the same tissue. A proliferative disorder includes a precancer or a precancerous condition. A proliferative disorder includes cancer. The methods provided herein are used to treat or alleviate a symptom of cancer. The term “cancer” includes solid tumors, as well as, hematologic tumors and / or malignancies. A “precancer cell” or “precancerous cell” is a cell manifesting a proliferative disorder that is a precancer or a precancerous condition. A “cancer cell” or “cancerous cell” is a cell manifesting a proliferative disorder that is a cancer. Any reproducible means of measurement may be used to identify cancer cells or precancerous cells. Cancer cells or precancerous cells can be identified by histological typing or gradingof a tissue sample (e.g., a biopsy sample). Cancer cells or precancerous cells can be identified through the use of appropriate molecular markers.

[0271] Exemplary non-cancerous conditions or disorders which may be treatable by the compoundsdescribed herein include, but are not limited to, rheumatoid arthritis; inflammation; autoimmune disease; lymphoproliferative conditions; acromegaly; rheumatoid spondylitis; osteoarthritis; gout, other arthritic conditions; sepsis; septic shock; endotoxic shock; gram-negative sepsis; toxic shock syndrome; asthma; adult respiratory distress syndrome; chronic obstructive pulmonary disease; chronic pulmonary inflammation; inflammatory bowel disease; Crohn's disease; psoriasis; eczema; ulcerative colitis; pancreatic fibrosis; hepatic fibrosis; acute and chronic renal disease; irritable bowel syndrome; pyresis; restenosis; cerebral malaria; stroke and ischemic injury; neural trauma; Alzheimer's disease; Huntington's disease; Parkinson's disease; acute and chronic pain; allergic rhinitis; allergic conjunctivitis; chronic heart failure; acute coronary syndrome; cachexia; malaria; leprosy; leishmaniasis; Lyme disease; Reiter's syndrome; acute synovitis; muscle degeneration, bursitis; tendonitis; tenosynovitis; herniated, ruptures, or prolapsed intervertebral disk syndrome; osteopetrosis; thrombosis; restenosis; silicosis; pulmonary sarcoidosis; bone resorption diseases, such as osteoporosis; graft-versus-host reaction; Multiple Sclerosis; lupus; fibromyalgia; AIDS and other viral diseases such as Herpes Zoster, Herpes Simplex I or II, influenza virus and cytomegalovirus; and diabetes mellitus.

[0272] Exemplary cancers include, but are not limited to, adrenocortical carcinoma, AIDS-relatedcancers, AIDS-related lymphoma, anal cancer, anorectal cancer, cancer of the anal canal, appendix cancer, childhood cerebellar astrocytoma, childhood cerebral astrocytoma, basal cell carcinoma, skin cancer (non-melanoma), biliary cancer, extrahepatic bile duct cancer, intrahepatic bile duct cancer, bladder cancer, urinary bladder cancer, bone and joint cancer, osteosarcoma and malignant fibrous histiocytoma, brain cancer, brain tumor, brain stem glioma, cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumors, visual pathway and hypothalamic glioma, breast cancer, bronchial adenomas / carcinoids, carcinoid tumor, gastrointestinal, nervous system cancer, nervous system lymphoma, central nervous system cancer, central nervous system lymphoma, cervical cancer, childhood cancers, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myeloproliferative disorders, colon cancer, colorectal cancer, cutaneous T-cell lymphoma, lymphoid neoplasm, mycosis fungoides, Sezary Syndrome, endometrial cancer, esophageal cancer, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, eye cancer, intraocular melanoma, retinoblastoma, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, ovarian germ cell tumor, gestational trophoblastic tumor glioma, head and neck cancer, hepatocellular (liver) cancer, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, ocular cancer, islet cell tumors (endocrine pancreas), Kaposi Sarcoma, kidney cancer, renal cancer, kidneycancer, laryngeal cancer, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocyticleukemia, chronic myelogenous leukemia, hairy cell leukemia, lip and oral cavity cancer, liver cancer, lung cancer, non-small cell lung cancer, small cell lung cancer, AIDS-related lymphoma, non-Hodgkinlymphoma, primary central nervous system lymphoma, Waldenstrom macroglobulinemia,medulloblastoma, melanoma, intraocular (eye) melanoma, Merkel cell carcinoma, mesotheliomamalignant, mesothelioma, metastatic squamous neck cancer, mouth cancer, cancer of the tongue, multiple endocrine neoplasia syndrome, mycosis fungoides, myelodysplastic syndromes, myelodysplastic / myeloproliferative diseases, chronic myelogenous leukemia, acute myeloid leukemia, multiple myeloma, chronic myeloproliferative disorders, nasopharyngeal cancer, neuroblastoma, oral cancer, oral cavity cancer, oropharyngeal cancer, ovarian cancer, ovarian epithelial cancer, ovarian low malignant potential tumor, pancreatic cancer, islet cell pancreatic cancer, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineoblastoma and supratentorial primitive neuroectodermal tumors, pituitary tumor, plasma cell neoplasm / multiplemyeloma, pleuropulmonary blastoma, prostate cancer, rectal cancer, renal pelvis and ureter, transitionalcell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, Ewing family of sarcoma tumors, Kaposi Sarcoma, soft tissue sarcoma, uterine cancer, uterine sarcoma, skin cancer (non-melanoma), skincancer (melanoma), Merkel cell skin carcinoma, small intestine cancer, soft tissue sarcoma, squamouscell carcinoma, stomach (gastric) cancer, supratentorial primitive neuroectodermal tumors, testicular cancer, throat cancer, thymoma, thymoma and thymic carcinoma, thyroid cancer, transitional cell cancer of the renal pelvis and ureter and other urinary organs, gestational trophoblastic tumor, urethral cancer, endometrial uterine cancer, uterine sarcoma, uterine corpus cancer, vaginal cancer, vulvar cancer, and Wilms’ Tumor.

[0273] A “proliferative disorder of the hematologic system” is a proliferative disorder involving cells ofthe hematologic system. A proliferative disorder of the hematologic system can include lymphoma, leukemia, myeloid neoplasms, mast cell neoplasms, myelodysplasia, benign monoclonal gammopathy, lymphomatoid granulomatosis, lymphomatoid papulosis, polycythemia vera, chronic myelocytic leukemia, agnogenic myeloid metaplasia, and essential thrombocythemia. A proliferative disorder of the hematologic system can include hyperplasia, dysplasia, and metaplasia of cells of the hematologic system. The compositions of the present application may be used to treat a cancer selected from the group consisting of a hematologic cancer of the present application or a hematologic proliferative disorder of the present application. A hematologic cancer of the present application can include multiple myeloma, lymphoma (including Hodgkin's lymphoma, non-Hodgkin's lymphoma, childhood lymphomas, and lymphomas of lymphocytic and cutaneous origin), leukemia (including childhood leukemia, hairy- cell leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, chronic myelogenous leukemia, and mast cell leukemia), myeloid neoplasms and mast cell neoplasms.

[0274] A “proliferative disorder of the lung” is a proliferative disorder involving cells of the lung.Proliferative disorders of the lung can include all forms of proliferative disorders affecting lung cells. Proliferative disorders of the lung can include lung cancer, a precancer or precancerous condition of the lung, benign growths or lesions of the lung, and malignant growths or lesions of the lung, and metastatic lesions in tissue and organs in the body other than the lung. Compositions of the present application maybe used to treat lung cancer or proliferative disorders of the lung. Lung cancer can include all forms of cancer of the lung. Lung cancer can include malignant lung neoplasms, carcinoma in situ, typicalcarcinoid tumors, and atypical carcinoid tumors. Lung cancer can include small cell lung cancer(“SCLC”), non-small cell lung cancer (“NSCLC”), squamous cell carcinoma, adenocarcinoma, small cell carcinoma, large cell carcinoma, adenosquamous cell carcinoma, and mesothelioma. Lung cancer can include “scar carcinoma”, bronchioalveolar carcinoma, giant cell carcinoma, spindle cell carcinoma, and large cell neuroendocrine carcinoma. Lung cancer can include lung neoplasms having histologic and ultrastructural heterogeneity (e.g., mixed cell types).

[0275] Proliferative disorders of the lung can include all forms of proliferative disorders affecting lungcells. Proliferative disorders of the lung can include lung cancer, precancerous conditions of the lung. Proliferative disorders of the lung can include hyperplasia, metaplasia, and dysplasia of the lung. Proliferative disorders of the lung can include asbestos-induced hyperplasia, squamous metaplasia, and benign reactive mesothelial metaplasia. Proliferative disorders of the lung can include replacement of columnar epithelium with stratified squamous epithelium, and mucosal dysplasia. Individuals exposed to inhaled injurious environmental agents such as cigarette smoke and asbestos may be at increased risk for developing proliferative disorders of the lung. Prior lung diseases that may predispose individuals to development of proliferative disorders of the lung can include chronic interstitial lung disease, necrotizing pulmonary disease, scleroderma, rheumatoid disease, sarcoidosis, interstitial pneumonitis, tuberculosis, repeated pneumonias, idiopathic pulmonary fibrosis, granulomata, asbestosis, fibrosing alveolitis, and Hodgkin's disease.

[0276] A “proliferative disorder of the colon” is a proliferative disorder involving cells of the colon. Inone embodiment, the proliferative disorder of the colon is colon cancer. In one embodiment, compositions of the present application may be used to treat colon cancer or proliferative disorders of the colon. Colon cancer can include all forms of cancer of the colon. Colon cancer can include sporadic and hereditary colon cancers. Colon cancer can include malignant colon neoplasms, carcinoma in situ, typical carcinoid tumors, and atypical carcinoid tumors. Colon cancer can include adenocarcinoma, squamous cell carcinoma, and adenosquamous cell carcinoma. Colon cancer can be associated with a hereditary syndrome selected from the group consisting of hereditary nonpolyposis colorectal cancer, familial adenomatous polyposis, Gardner's syndrome, Peutz-Jeghers syndrome, Turcot's syndrome and juvenile polyposis. Colon cancer can be caused by a hereditary syndrome selected from the group consisting of hereditary nonpolyposis colorectal cancer, familial adenomatous polyposis, Gardner's syndrome, Peutz- Jeghers syndrome, Turcot's syndrome and juvenile polyposis.

[0277] Proliferative disorders of the colon can include all forms of proliferative disorders affecting coloncells. Proliferative disorders of the colon can include colon cancer, precancerous conditions of the colon, adenomatous polyps of the colon and metachronous lesions of the colon. A proliferative disorder of the colon can include adenoma. Proliferative disorders of the colon can be characterized by hyperplasia, metaplasia, and dysplasia of the colon. Prior colon diseases that may predispose individuals to development of proliferative disorders of the colon can include prior colon cancer. Current disease thatmay predispose individuals to development of proliferative disorders of the colon can include Crohn's disease and ulcerative colitis. A proliferative disorder of the colon can be associated with a mutation in a gene selected from the group consisting of p53, ras, FAP and DCC. An individual can have an elevated risk of developing a proliferative disorder of the colon due to the presence of a mutation in a gene selected from the group consisting of p53, ras, FAP and DCC.

[0278] A “proliferative disorder of the pancreas” is a proliferative disorder involving cells of thepancreas. Proliferative disorders of the pancreas can include all forms of proliferative disorders affecting pancreatic cells. Proliferative disorders of the pancreas can include pancreas cancer, a precancer or precancerous condition of the pancreas, hyperplasia of the pancreas, and dysplasia of the pancreas, benign growths or lesions of the pancreas, and malignant growths or lesions of the pancreas, andmetastatic lesions in tissue and organs in the body other than the pancreas. Pancreatic cancer includes allforms of cancer of the pancreas. Pancreatic cancer can include ductal adenocarcinoma, adenosquamous carcinoma, pleomorphic giant cell carcinoma, mucinous adenocarcinoma, osteoclast-like giant cell carcinoma, mucinous cystadenocarcinoma, acinar carcinoma, unclassified large cell carcinoma, small cell carcinoma, pancreatoblastoma, papillary neoplasm, mucinous cystadenoma, papillary cystic neoplasm, and serous cystadenoma. Pancreatic cancer can also include pancreatic neoplasms having histologic and ultrastructural heterogeneity (e.g., mixed cell types).

[0279] A “proliferative disorder of the prostate” is a proliferative disorder involving cells of the prostate.Proliferative disorders of the prostate can include all forms of proliferative disorders affecting prostate cells. Proliferative disorders of the prostate can include prostate cancer, a precancer or precancerous condition of the prostate, benign growths or lesions of the prostate, and malignant growths or lesions of the prostate, and metastatic lesions in tissue and organs in the body other than the prostate. Proliferative disorders of the prostate can include hyperplasia, metaplasia, and dysplasia of the prostate.

[0280] A “proliferative disorder of the skin” is a proliferative disorder involving cells of the skin.Proliferative disorders of the skin can include all forms of proliferative disorders affecting skin cells. Proliferative disorders of the skin can include a precancer or precancerous condition of the skin, benign growths or lesions of the skin, melanoma, malignant melanoma and other malignant growths or lesions of the skin, and metastatic lesions in tissue and organs in the body other than the skin. Proliferative disorders of the skin can include hyperplasia, metaplasia, and dysplasia of the skin.

[0281] A “proliferative disorder of the ovary” is a proliferative disorder involving cells of the ovary.Proliferative disorders of the ovary can include all forms of proliferative disorders affecting cells of the ovary. Proliferative disorders of the ovary can include a precancer or precancerous condition of the ovary, benign growths or lesions of the ovary, ovarian cancer, malignant growths or lesions of the ovary, and metastatic lesions in tissue and organs in the body other than the ovary. Proliferative disorders of the skin can include hyperplasia, metaplasia, and dysplasia of cells of the ovary.

[0282] A “proliferative disorder of the breast” is a proliferative disorder involving cells of the breast.Proliferative disorders of the breast can include all forms of proliferative disorders affecting breast cells. Proliferative disorders of the breast can include breast cancer, a precancer or precancerous condition ofthe breast, benign growths or lesions of the breast, and malignant growths or lesions of the breast, and metastatic lesions in tissue and organs in the body other than the breast. Proliferative disorders of the breast can include hyperplasia, metaplasia, and dysplasia of the breast.

[0283] A cancer that is to be treated can be staged according to the American Joint Committee onCancer (AJCC) TNM classification system, where the tumor (T) has been assigned a stage of TX, T1, T1mic, T1a, T1b, T1c, T2, T3, T4, T4a, T4b, T4c, or T4d; and where the regional lymph nodes (N) have been assigned a stage of NX, N0, N1, N2, N2a, N2b, N3, N3a, N3b, or N3c; and where distant metastasis (M) can be assigned a stage of MX, M0, or M1. A cancer that is to be treated can be staged according toan American Joint Committee on Cancer (AJCC) classification as Stage I, Stage IIA, Stage IIB, StageIIIA, Stage IIIB, Stage IIIC, or Stage IV. A cancer that is to be treated can be assigned a grade according to an AJCC classification as Grade GX (e.g., grade cannot be assessed), Grade 1, Grade 2, Grade 3 or Grade 4. A cancer that is to be treated can be staged according to an AJCC pathologic classification (pN) of pNX, pN0, PN0 (I-), PN0 (I+), PN0 (mol-), PN0 (mol+), PN1, PN1(mi), PN1a, PN1b, PN1c, pN2, pN2a, pN2b, pN3, pN3a, pN3b, or pN3c.

[0284] A cancer that is to be treated can include a tumor that has been determined to be less than orequal to about 2 centimeters in diameter. A cancer that is to be treated can include a tumor that has beendetermined to be from about 2 to about 5 centimeters in diameter. A cancer that is to be treated caninclude a tumor that has been determined to be greater than or equal to about 3 centimeters in diameter. A cancer that is to be treated can include a tumor that has been determined to be greater than 5 centimeters in diameter. A cancer that is to be treated can be classified by microscopic appearance as well differentiated, moderately differentiated, poorly differentiated, or undifferentiated. A cancer that is to be treated can be classified by microscopic appearance with respect to mitosis count (e.g., amount of cell division) or nuclear pleiomorphism (e.g., change in cells). A cancer that is to be treated can be classified by microscopic appearance as being associated with areas of necrosis (e.g., areas of dying or degenerating cells). A cancer that is to be treated can be classified as having an abnormal karyotype, having an abnormal number of chromosomes, or having one or more chromosomes that are abnormal in appearance. A cancer that is to be treated can be classified as being aneuploid, triploid, tetraploid, or as having an altered ploidy. A cancer that is to be treated can be classified as having a chromosomal translocation, or a deletion or duplication of an entire chromosome, or a region of deletion, duplication or amplification of a portion of a chromosome.

[0285] A cancer that is to be treated can be evaluated by DNA cytometry, flow cytometry, or imagecytometry. A cancer that is to be treated can be typed as having 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of cells in the synthesis stage of cell division (e.g., in S phase of cell division). A cancer that is to be treated can be typed as having a low S-phase fraction or a high S-phase fraction.

[0286] As used herein, a “normal cell” is a cell that cannot be classified as part of a “proliferativedisorder”. A normal cell lacks unregulated or abnormal growth, or both, that can lead to the developmentof an unwanted condition or disease. In one embodiment, a normal cell possesses normally functioningcell cycle checkpoint control mechanisms.

[0287] One skilled in the art may refer to general reference texts for detailed descriptions of knowntechniques discussed herein or equivalent techniques. These texts include Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3rd edition), Cold Spring Harbor Press, Cold Spring Harbor, N.Y. (2000); Coligan et al., Current Protocols in Immunology, John Wiley & Sons, N.Y.; Erma et al., Current Protocols in Pharmacology, John Wiley & Sons, N.Y.; Fingl et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 18th edition (1990).These texts can, of course, also be referred to in making or using an aspect of the application.

[0288] In certain embodiments, compounds of the application are useful in the treatment of proliferativedisorders (e.g., cancer, benign neoplasms, inflammatory disease, and autoimmune diseases). In certain embodiments, according to the methods of treatment of the present application, levels of cell proteins of interest, e.g., pathogenic and oncogenic proteins are modulated, or their growth is inhibited by contacting said cells with an compound or composition, as described herein. In other embodiments, the compounds are useful in treating cancer.

[0289] In certain embodiments, the method involves the administration of a therapeutically effectiveamount of the compound or a pharmaceutically acceptable derivative thereof to a subject (including, but not limited to a human or animal) in need of it. In certain embodiments, the compounds are useful for the treatment of cancer (including, but not limited to, glioblastoma, retinoblastoma, breast cancer, cervical cancer, colon and rectal cancer, leukemia, lymphoma, lung cancer (including, but not limited to small cell lung cancer), melanoma and / or skin cancer, multiple myeloma, non-Hodgkin's lymphoma, ovarian cancer, pancreatic cancer, prostate cancer and gastric cancer, bladder cancer, uterine cancer, kidneycancer, testicular cancer, stomach cancer, brain cancer, liver cancer, or esophageal cancer).

[0290] In certain embodiments, the anticancer agents are useful in the treatment of cancers and otherproliferative disorders, including, but not limited to breast cancer, cervical cancer, colon and rectal cancer, leukemia, lung cancer, melanoma, multiple myeloma, non-Hodgkin's lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, and gastric cancer. In certain embodiments, the anticancer agents are active against solid tumors.

[0291] Additionally, the present application provides pharmaceutically acceptable derivatives of thecompounds, and methods of treating a subject using these compounds, pharmaceutical compositions thereof, or either of these in combination with one or more additional therapeutic agents.

[0292] For example, other therapies or anticancer agents that may be used in combination with thecompounds disclosed herein including surgery, radiotherapy, endocrine therapy, biologic response modifiers (interferons, interleukins, and tumor necrosis factor (TNF), to name a few), hyperthermia and cryotherapy, agents to attenuate any adverse effects (e.g., antiemetics), and other approved chemotherapeutic drugs, including, but not limited to, alkylating drugs (mechlorethamine, chlorambucil, cyclophosphamide, melphalan, ifosfamide), antimetabolites (methotrexate), purine antagonists and pyrimidine antagonists (6-mercaptopurine, 5-fluorouracil, cytarabine, gemcitabine), spindle poisons (vinblastine, vincristine, vinorelbine, paclitaxel), podophyllotoxins (etoposide, irinotecan, topotecan),antibiotics (doxorubicin, bleomycin, mitomycin), nitrosoureas (carmustine, lomustine), inorganic ions (cisplatin, carboplatin), enzymes (asparaginase), and hormones (tamoxifen, leuprolide, flutamide, and megestrol), to name a few. For a more comprehensive discussion of overview of cancer therapy see The Merck Manual, Twentieth Ed.2020, the entire contents of which are hereby incorporated by reference. See also the National Cancer Institute (NCI) website (www.nci.nih.gov) and the Food and Drug Administration (FDA) website for a list of the FDA approved oncology drugs (www.fda.gov / cder / cancer / druglistframe).

[0293] In certain embodiments, the pharmaceutical compositions comprising the compounds disclosedherein further comprise one or more additional therapeutically active ingredients (e.g., chemotherapeutic and / or palliative). For purposes of the application, the term “palliative” refers to treatment that is focused on the relief of symptoms of a disease and / or side effects of a therapeutic regimen, but is not curative. For example, palliative treatment encompasses painkillers, antinausea medications and anti-sickness drugs. In addition, chemotherapy, radiotherapy and surgery can all be used palliatively (that is, to reduce symptoms without going for cure; e.g., for shrinking tumors and reducing pressure, bleeding, pain and other symptoms of cancer). Administration, Pharmaceutical Compositions

[0294] Administration of the disclosed compounds and pharmaceutical compositions can beaccomplished via any mode of administration for therapeutic agents. These modes include systemic or local administration such as oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal or topical administration modes.

[0295] Depending on the intended mode of administration, the disclosed compositions can be in solid,semi-solid or liquid dosage form, such as, for example, injectables, tablets, suppositories, pills, time- release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or the like, sometimes in unit dosages and consistent with conventional pharmaceutical practices. Likewise, they can also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous or intramuscular form, and all using forms well known to those skilled in the pharmaceutical arts.

[0296] Illustrative pharmaceutical compositions are tablets and gelatin capsules comprising a compoundof the disclosure and a pharmaceutically acceptable carrier, such as a) a diluent, e.g., purified water, triglyceride oils, such as hydrogenated or partially hydrogenated vegetable oil, or mixtures thereof, com oil, olive oil, sunflower oil, safflower oil, fish oils, such as EPA or DHA, or their esters or triglycerides or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and / or glycine; b) a lubricant, e.g., silica, talcum, stearic acid, its magnesium or calcium salt, sodium oleate, sodium stearate, magnesium stearate, sodiumbenzoate, sodium acetate, sodium chloride, and / or polyethylene glycol; for tablets also; c) a binder, e.g.,magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, waxes, and / or polyvinylpyrrolidone, if desired; d) a disintegrant, e.g., starches, agar, methyl cellulose, bentonite,xanthan gum, algic acid or its sodium salt, or effervescent mixtures; e) absorbent, colorant, flavorant and sweetener; f) an emulsifier or dispersing agent, such as Tween 80, Labrasol, HPMC, DOSS, caproyl 909,labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex 355, gelucire, vitamin E TGPSor other acceptable emulsifier; and / or g) an agent that enhances absorption of the compound such as cyclodextrin, hydroxypropyl-cyclodextrin, PEG400, PEG200.

[0297] Liquid, particularly injectable, compositions can, for example, be prepared by dissolution,dispersion, etc. For example, the disclosed compound is dissolved in or mixed with a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form an injectable isotonic solution or suspension. Proteins such as albumin, chylomicron particles, or serum proteins can be used to solubilize the disclosed compounds.

[0298] The disclosed compounds can be also formulated as a suppository that can be prepared from fattyemulsions or suspensions; using polyalkylene glycols such as propylene glycol, as the carrier.

[0299] The disclosed compounds can also be administered in the form of liposome delivery systems,such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, containing cholesterol, stearylamine or phosphatidylcholines.

[0300] In some embodiments, a film of lipid components is hydrated with an aqueous solution of drug toa form lipid layer encapsulating the drug, as described in U.S. Pat. No.5,262,564, which is hereby incorporated by reference in its entirety.

[0301] Disclosed compounds can also be delivered by the use of monoclonal antibodies as individualcarriers to which the disclosed compounds are coupled. The disclosed compounds can also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspanamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, the disclosed compounds can be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels. In one embodiment, disclosed compounds are not covalently bound to a polymer, e.g., a polycarboxylic acid polymer, or a polyacrylate.

[0302] Parental injectable administration is generally used for subcutaneous, intramuscular orintravenous injections and infusions. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions or solid forms suitable for dissolving in liquid prior to injection.

[0303] Another aspect of the disclosure is directed to pharmaceutical compositions comprising acompound of Formula I, and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may further include an excipient, diluent, or surfactant.

[0304] Compositions can be prepared according to conventional mixing, granulating or coating methods,respectively, and the present pharmaceutical compositions can contain from about 0.1% to about 99%, from about 5% to about 90%, or from about 1% to about 20% of the disclosed compound by weight or volume.

[0305] In one embodiment, the disclosure provides a kit comprising two or more separatepharmaceutical compositions, at least one of which contains a compound of the present disclosure. In one embodiment, the kit comprises means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is a blister pack, as typically used for the packaging of tablets, capsules and the like.

[0306] The kit of the disclosure may be used for administering different dosage forms, for example, oraland parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit of the disclosure typically comprises directions for administration.

[0307] Pharmaceutical dosage forms of a compound of this disclosure may be manufactured by any ofthe methods well-known in the art, such as, for example, by conventional mixing, sieving, dissolving, melting, granulating, dragee-making, tableting, suspending, extruding, spray-drying, levigating, emulsifying, (nano- / micro-) encapsulating, entrapping, or lyophilization processes. As noted above, the compositions of this disclosure can include one or more physiologically acceptable inactive ingredients that facilitate processing of active molecules into preparations for pharmaceutical use.

[0308] As noted above, the compositions are comprised of, in general, a compound of this disclosure incombination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non- toxic, aid administration, and do not adversely affect the therapeutic benefit of the claimed compounds. Such excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.

[0309] Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin,malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodiumchloride, dried skim milk and the like. Liquid and semi-solid excipients may be selected from glycerol,propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. In some embodiments, liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.

[0310] Compressed gases may be used to disperse a compound of this disclosure in an aerosol form.Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc. Other suitable pharmaceuticalexcipients and their formulations are described in Remington’s Pharmaceutical Sciences, edited by E. W.Martin (Mack Publishing Company, 18th ed., 1990).

[0311] The compositions of this disclosure may, if desired, be presented in a pack or dispenser devicecontaining one or more unit dosage forms containing the active ingredient. Such a pack or device may, for example, comprise metal or plastic foil, such as a blister pack, or glass, and rubber stoppers such as in vials. The pack or dispenser device may be accompanied by instructions for administration. Compositions comprising a compound of this disclosure that can be formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0312] The amount of the compound in a formulation can vary within the full range employed by thoseskilled in the art. Typically, the formulation will contain, on a weight percent (wt %) basis, from about0.01-99.99 wt % of a compound of this disclosure based on the total formulation, with the balance beingone or more suitable pharmaceutical excipients. In one embodiment, the compound is present at a level of about 1-80 wt %. Representative pharmaceutical formulations are described below. Dosing

[0313] The dosage regimen utilizing the disclosed compound is selected in accordance with a variety offactors including type, species, age, weight, sex, and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal or hepatic function of the patient; and the particular disclosed compound employed. A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.

[0314] Effective dosage amounts of the compounds, when used for the indicated effects, range fromabout 0.5 mg to about 5000 mg of the disclosed compound as needed to treat the condition. Formulation Examples

[0315] The following are representative pharmaceutical formulations containing a compound of thisdisclosure.Formulation Example 1 -- Tablet formulation

[0316] The following ingredients are mixed intimately and pressed into single scored tablets.I ccFormulation Example 2 -- Capsule formulation

[0317] The following ingredients are mixed intimately and loaded into a hard-shell gelatin capsule.I clFormulation Example 3 -- Suspension formulation

[0318] The following ingredients are mixed to form a suspension for oral administration.IcfssFormulation Example 4 -- Injectable formulation

[0319] The following ingredients are mixed to form an injectable formulation.IcsFormulation Example 5 -- Suppository Formulation

[0320] A suppository of total weight 2.5 g is prepared by mixing the compound of this disclosure withWitepsol® H-15 (triglycerides of saturated vegetable fatty acid; Riches-Nelson, Inc., New York), and has the following composition: IGeneral Synthetic Methods

[0321] The compounds described herein can be prepared from readily available starting materials usingthe following general methods and procedures. It will be appreciated that where typical process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

[0322] Additionally, as will be apparent to those skilled in the art, conventional protecting groups maybe necessary to prevent certain functional groups from undergoing undesired reactions. Suitableprotecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, and references cited therein.

[0323] The starting materials for the following reactions are generally known compounds or can beprepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Sigma Aldrich (St. Louis, Missouri, USA), Bachem (Torrance, California, USA), Emka-Chemce (St. Louis, Missouri, USA). Others may be prepared by procedures, or obvious modifications thereof, described in standard reference texts such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 2016),Rodd’s Chemistry of Carbon Compounds, Volumes 1-5, and Supplementals (Elsevier Science Publishers,2001), Organic Reactions, Volumes 1-40 (John Wiley, and Sons, 2019), March’s Advanced Organic Chemistry, (John Wiley, and Sons, 8thEdition, 2019), and Larock’s Comprehensive OrganicTransformations (VCH Publishers Inc., 1989).Synthesis of Representative Compounds

[0324] The general synthesis of the compounds described herein is set forth in the reaction schemesbelow. Schemes 1-8 illustrate general methods for preparing compounds of Formula I. In Schemes 1-8,substituents L1, R1, R3, R5, R6, R7, R9, and n are each independently as defined throughout thespecification, where X is depicted with the -C(O)CR5=R6 moiety. PG is a protecting group (including,but not limited to, Boc and the like). The -Cl in 1A, 3A, and 4A may be replaced by a suitable leavinggroup (such as halo, mesylate, tosylate, or -OH).Scheme 1

[0325] In some embodiments, compounds of Formula I and sub-formulae thereof are prepared as shownin Scheme 1. In Scheme 1, the first step is a conventional Sonogashira coupling reaction wherein at leasta stoichiometric amount of a suitable alkyne, compound 2A, is combined with compound 1A underconventional reaction conditions well known in the art including the use of palladium (II) bis(triphenylphosphine) dichloride and copper (I) iodide as catalysts typically in the presence of asuitable base such as diisopropylethylamine, triethylamine, pyridine, cesium carbonate and the like. Thereaction is typically conducted in an inert solvent such as toluene, N,N-dimethylformamide, and the like. The reaction is typically conducted at from about 25 ºC to about 110 ºC for a period of time sufficient for substantial completion of the reaction as evidenced by e.g., thin layer chromatography. Upon reaction completion, conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 3A.

[0326] In the next step, a cyclization reaction is performed, wherein at least a stoichiometric amount ofcompound 3A in an inert diluent, such as tetrahydrofuran, dioxane, toluene, dimethoxyethane, and thelike, typically in the presence of a suitable base such as TBAF, DeShong’s salt, or the like. The reactionis typically maintained at from 80 ^C to 100 ^C until it is substantially complete. Conventional workupof the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 4A.

[0327] In the next step, a conventional Suzuki coupling reaction wherein at least a stoichiometricequivalent of a suitable boronic acid, compound 5A, or an ester thereof, is combined with compound 4A,in an inert diluent such as tetrahydrofuran, dioxane, toluene, dimethoxyethane, and the like, typically inthe presence of a palladium catalyst (e.g., palladium diacetate) and a suitable base such asdiisopropylethylamine, triethylamine, pyridine, potassium carbonate, and the like. The reaction istypically maintained at from 10 °C to 65 °C until it is substantially complete. Conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 6A.

[0328] In the next step, the t-butoxycarbonyl (t-BOC) protecting group is removed by conventionalconditions. The t-BOC group is illustrative only and other conventional amino blocking groups such asbenzyl, 9-fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), p-nitrobenzyloxycarbonyl andthe like. Upon reaction completion, conventional workup of the reaction solution can be followed byisolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like.

[0329] In the final step, at least a stoichiometric amount of a suitable acid chloride, compound 7A, iscombined with compound from the previous step in an inert diluent such as DMF, DCM, MeCN and the like in the presence of a suitable base such as potassium carbonate, pyridine, triethylamine and the like. The reaction is typically maintained at from 0 °C to 50 °C until it is substantially complete. Conventionalworkup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 8A.

[0330] Additionally, compound 8A may be further reacted to functionalize the amine. Suitablealkylating reagents such as dibenzyl(chloromethyl) phosphate or di(tert-butyl)chloromethyl phosphate may be used in the presence of a base to alkylate the amine, followed by acidic or reductive deprotection.Scheme 2

[0331] As to the reaction in Scheme 2, the first step is an aryl bromination reaction, wherein at least astoichiometric equivalent of a suitable 7H-pyrrolo[2,3-c]pyridazine, compound 6A, is combined withNBS, in an inert diluent such as tetrahydrofuran, DMF and the like. The reaction is typically maintainedat from 0 °C to 40 °C until it is substantially complete. Conventional workup of the reaction solution can be followed by isolation / purification processes, such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 9A.

[0332] In the next step, a conventional Suzuki coupling reaction wherein at least a stoichiometricequivalent of a suitable boronic acid, compound 9A, is combined with compound 10A, in an inert diluentsuch as tetrahydrofuran, dioxane, toluene, dimethoxyethane, and the like, typically in the presence of a palladium catalyst (e.g., palladium diacetate) and a suitable base such as diisopropylethylamine,triethylamine, pyridine, potassium carbonate, and the like. The reaction is typically maintained at from10 °C to 65 °C until it is substantially complete. Conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 11A.

[0333] In the next step, the t-butoxycarbonyl (t-BOC) protecting group is removed by conventionalconditions. The t-BOC group is illustrative only and other conventional amino blocking groups such asbenzyl, 9-fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), p-nitrobenzyloxycarbonyl andthe like. Upon reaction completion, conventional workup of the reaction solution can be followed byisolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like.

[0334] In the final step, at least a stoichiometric amount of a suitable acid chloride, compound 7A, iscombined with compound from the previous step in an inert diluent such as DMF, DCM, MeCN and the like in the presence of a suitable base such as potassium carbonate, pyridine, triethylamine and the like. The reaction is typically maintained at from 0 °C to 50 °C until it is substantially complete.

[0335] Conventional workup of the reaction solution can be followed by isolation / purification processessuch as crystallization, chromatography, high performance liquid chromatography (HPLC), and the liketo provide for compound 12A. Compound 12A may additional further undergo reaction to provide anamine-functionalized compound 12A-1 via a similar protocol as shown above for compound 8A-1.Scheme 3

[0336] In Scheme 3, the first step is a metallaphotoredox-enabled deoxygenative arylation of an alcohol(Nature volume 598, pages 451–456 (2021)) wherein alcohol 14A is first activated by reacting with abenzoxazolium salt (NHC-1) to form an NHC–alcohol adduct. Excitation of an Iridium-basedphotocatalyst in a presence of a base (quincludine) will then produce a deoxygenated alkyl radical whichcan further react with an aryl Ni(ii) species generated from the reaction of a nickel catalyst and an arylbromide derivative 13A. The reaction is typically maintained between 20 ^C and 40 ^C until it issubstantially complete. Conventional workup of the reaction solution can be followed by isolation / purification processes, such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 15A.

[0337] In the next step, the t-butoxycarbonyl (t-BOC) protecting group is removed by conventionalconditions. The t-BOC group is illustrative only and other conventional amino blocking groups such asbenzyl, 9-fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), p-nitrobenzyloxycarbonyl andthe like. Upon reaction completion, conventional workup of the reaction solution can be followed byisolation / purification processes such as crystallization, chromatography, high performance liquidchromatography (HPLC), and the like.

[0338] In the final step, at least a stoichiometric amount of a suitable acid chloride, compound 16A, iscombined with compound from the previous step in an inert diluent such as DMF, DCM, MeCN and thelike in the presence of a suitable base such as potassium carbonate, pyridine, triethylamine and the like. The reaction is typically maintained at from 0 °C to 50 °C until it is substantially complete.

[0339] Conventional workup of the reaction solution can be followed by isolation / purification processessuch as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 17A.Scheme 4

[0340] In Scheme 4, the first step is a metallaphotoredox-enabled deoxygenative arylation of an alcohol(Nature volume 598, pages 451–456 (2021)) wherein alcohol 19A is first activated by reacting with abenzoxazolium salt (NHC-1) to form an NHC–alcohol adduct. Excitation of an Iridium-based photocatalyst in a presence of a base (quinuclidine) will then produce a deoxygenated alkyl radical whichcan further react with an aryl Ni(ii) species generated from the reaction of a nickel catalyst and an arylbromide derivative 18A. The reaction is typically maintained between 20 °C and 40 °C until it is substantially complete. Conventional workup of the reaction solution can be followed by isolation / purification processes, such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 20A.

[0341] The second step is an aryl bromination reaction, wherein at least a stoichiometric equivalent of asuitable 7H-pyrrolo[2,3-c]pyridazine, compound 20A, is combined with NBS, in an inert diluent such as tetrahydrofuran, DMF and the like. The reaction is typically maintained at from 0 °C to 40 °C until it is substantially complete. Conventional workup of the reaction solution can be followed by isolation / purification processes, such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 21A.

[0342] In the next step, a conventional Suzuki coupling reaction wherein at least a stoichiometricequivalent of a suitable boronic acid, compound 22A, or an ester thereof, is combined with compound21A, in an inert diluent such as tetrahydrofuran, dioxane, toluene, dimethoxyethane, and the like, typically in the presence of a palladium catalyst (e.g., palladium diacetate) and a suitable base such asdiisopropylethylamine, triethylamine, pyridine, potassium carbonate, and the like. The reaction istypically maintained at from 10 °C to 65 °C until it is substantially complete. Conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization,chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 23A.

[0343] In the next step, the t-butoxycarbonyl (t-BOC) protecting group is removed by conventionalconditions. The t-BOC group is illustrative only and other conventional amino blocking groups such asbenzyl, 9-fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), p-nitrobenzyloxycarbonyl andthe like. Upon reaction completion, conventional workup of the reaction solution can be followed byisolation / purification processes such as crystallization, chromatography, high performance liquidchromatography (HPLC), and the like.

[0344] In the final step, at least a stoichiometric amount of a suitable acid chloride, compound 24A, iscombined with compound from the previous step in an inert diluent such as DMF, DCM, MeCN and the like in the presence of a suitable base such as potassium carbonate, pyridine, triethylamine and the like. The reaction is typically maintained at from 0 °C to 50 °C until it is substantially complete.

[0345] Conventional workup of the reaction solution can be followed by isolation / purification processessuch as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 25A.Scheme 5

[0346] In Scheme 5, the first step is a metallaphotoredox-enabled deoxygenative arylation of an alcohol(Nature volume 598, pages 451–456 (2021)) wherein alcohol 27A is first activated by reacting with abenzoxazolium salt (NHC-1) to form an NHC–alcohol adduct. Excitation of an Iridium-based photocatalyst in a presence of a base (quinuclidine) will then produce a deoxygenated alkyl radical whichcan further react with an aryl Ni(ii) species generated from the reaction of a nickel catalyst and an arylbromide derivative 26A. The reaction is typically maintained between 20 °C and 40 °C until it is substantially complete. Conventional workup of the reaction solution can be followed by isolation / purification processes, such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 28A.

[0347] The second step is an aryl bromination reaction, wherein at least a stoichiometric equivalent of asuitable 7H-pyrrolo[2,3-c]pyridazine, compound 28A, is combined with NBS, in an inert diluent such as tetrahydrofuran, DMF and the like. The reaction is typically maintained at from 0 °C to 40 °C until it issubstantially complete. Conventional workup of the reaction solution can be followed by isolation / purification processes, such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 29A.

[0348] In the next step, a conventional Suzuki coupling reaction wherein at least a stoichiometricequivalent of a suitable boronic acid, compound 30A, or an ester thereof, is combined with compound29A, in an inert diluent such as tetrahydrofuran, dioxane, toluene, dimethoxyethane, and the like, typically in the presence of a palladium catalyst (e.g., palladium diacetate) and a suitable base such asdiisopropylethylamine, triethylamine, pyridine, potassium carbonate, and the like. The reaction istypically maintained at from 10 °C to 65 °C until it is substantially complete. Conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 31A.

[0349] The Suzuki step is generally followed by an hydrogenation reaction to reduce the alkene groupfrom the molecule. The reaction is carried out in the presence of hydrogen, palladium on carbon and thecompound from the previous step dissolved in various solvents such as ethyl acetate, tetrahydrofuran,methanol and ethanol. Upon reaction completion, conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performanceliquid chromatography (HPLC), and the like to provide for compound 31A.

[0350] In the next step, the t-butoxycarbonyl (t-BOC) protecting group is removed by conventionalconditions. The t-BOC group is illustrative only and other conventional amino blocking groups such as benzyl, 9-fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), p-nitrobenzyloxycarbonyl andthe like. Upon reaction completion, conventional workup of the reaction solution can be followed byisolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like.

[0351] In the final step, at least a stoichiometric amount of a suitable acid chloride, compound 32A, iscombined with compound from the previous step in an inert diluent such as DMF, DCM, MeCN and the like in the presence of a suitable base such as potassium carbonate, pyridine, triethylamine and the like. The reaction is typically maintained at from 0 °C to 50 °C until it is substantially complete.

[0352] Conventional workup of the reaction solution can be followed by isolation / purification processessuch as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 33A.Scheme 6

[0353] In the first step, a conventional Suzuki coupling reaction wherein at least a stoichiometricequivalent of a suitable boronic acid, compound 35A, or an ester thereof, is combined with compound34A, in an inert diluent such as tetrahydrofuran, dioxane, toluene, dimethoxyethane, and the like,typically in the presence of a palladium catalyst (e.g., palladium diacetate) and a suitable base such asdiisopropylethylamine, triethylamine, pyridine, potassium carbonate, and the like. The reaction is typically maintained at from 10 °C to 65 °C until it is substantially complete. Conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide the desired product.

[0354] The Suzuki reaction above is followed by an hydrogenation reaction to reduce the alkene groupfrom the molecule. The reaction is carried out in the presence of hydrogen, palladium on carbon and thecompound from the previous step dissolved in various solvents such as ethyl acetate, tetrahydrofuran, methanol and ethanol. Upon reaction completion, conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performanceliquid chromatography (HPLC), and the like to provide for compound 36A.

[0355] In the next step, the t-butoxycarbonyl (t-BOC) protecting group is removed by conventionalconditions. The t-BOC group is illustrative only and other conventional amino blocking groups such as benzyl, 9-fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), p-nitrobenzyloxycarbonyl and the like. Upon reaction completion, conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquidchromatography (HPLC), and the like.

[0356] In the final step, at least a stoichiometric amount of a suitable acid chloride, compound 37A, iscombined with compound from the previous step in an inert diluent such as DMF, DCM, MeCN and the like in the presence of a suitable base such as potassium carbonate, pyridine, triethylamine and the like. The reaction is typically maintained at from 0 °C to 50 °C until it is substantially complete.

[0357] Conventional workup of the reaction solution can be followed by isolation / purification processessuch as crystallization, chromatography, high performance liquid chromatography (HPLC), and the liketo provide for compound 38A.Scheme 7

[0358] In the first step, a conventional Suzuki coupling reaction wherein at least a stoichiometricequivalent of a suitable boronic acid, compound 40A, or an ester thereof, is combined with compound39A, in an inert diluent such as tetrahydrofuran, dioxane, toluene, dimethoxyethane, and the like,typically in the presence of a palladium catalyst (e.g., palladium diacetate) and a suitable base such asdiisopropylethylamine, triethylamine, pyridine, potassium carbonate, and the like. The reaction istypically maintained at from 10 °C to 65 °C until it is substantially complete. Conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide compound 41A.

[0359] The second step is an aryl bromination reaction, wherein at least a stoichiometric equivalent of asuitable 7H-pyrrolo[2,3-c]pyridazine, compound 41A, is combined with NBS, in an inert diluent such as tetrahydrofuran, DMF and the like. The reaction is typically maintained at from 0 °C to 40 °C until it is substantially complete. Conventional workup of the reaction solution can be followed by isolation / purification processes, such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 42A.

[0360] In the next step, a conventional Suzuki coupling reaction wherein at least a stoichiometricequivalent of a suitable boronic acid, compound 43A, is combined with compound 42A, in an inertdiluent such as tetrahydrofuran, dioxane, toluene, dimethoxyethane, and the like, typically in the presenceof a palladium catalyst (e.g., palladium diacetate) and a suitable base such as diisopropylethylamine,triethylamine, pyridine, potassium carbonate, and the like. The reaction is typically maintained at from 10°C to 65 °C until it is substantially complete. Conventional workup of the reaction solution can befollowed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for the desired compound.

[0361] The Suzuki reaction above is followed by an hydrogenation reaction to reduce alkene groupsfrom the molecule. The reaction is carried out in the presence of hydrogen, palladium on carbon and thecompound from the previous step dissolved in various solvents such as ethyl acetate, tetrahydrofuran,methanol and ethanol. Upon reaction completion, conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 44A.

[0362] In the next step, the t-butoxycarbonyl (t-BOC) protecting group is removed by conventionalconditions. The t-BOC group is illustrative only and other conventional amino blocking groups such as benzyl, 9-fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), p-nitrobenzyloxycarbonyl and the like. Upon reaction completion, conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquidchromatography (HPLC), and the like.

[0363] The Suzuki reaction above is followed by an hydrogenation reaction to reduce the alkene groupfrom. The reaction is carried out in the presence hydrogen, palladium on carbon and the compound fromthe previous step dissolved in various solvents such as ethyl acetate, tetrahydrofuran, methanol and ethanol. Upon reaction completion, conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like.

[0364] In the final step, at least a stoichiometric amount of a suitable acid chloride, compound 45A, iscombined with compound from the previous step in an inert diluent such as DMF, DCM, MeCN and the like in the presence of a suitable base such as potassium carbonate, pyridine, triethylamine and the like. The reaction is typically maintained at from 0 °C to 50 °C until it is substantially complete.

[0365] Conventional workup of the reaction solution can be followed by isolation / purification processessuch as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 46A.

[0366] The first step is an aryl bromination reaction, wherein at least a stoichiometric equivalent of 3-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-c]pyridazine, compound 47A, is combined with NBS, in an inert diluent such as tetrahydrofuran, DMF and the like. The reaction is typically maintained at from 0 °C to 40 °C until it is substantially complete. Conventional workup of the reaction solution can be followed by isolation / purification processes, such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 48A.

[0367] The second step is a conventional Suzuki coupling reaction wherein at least a stoichiometricequivalent of a suitable boronic acid, compound 49A, or an ester thereof, is combined with compound48A, in an inert diluent such as tetrahydrofuran, dioxane, toluene, dimethoxyethane, and the like, typically in the presence of a palladium catalyst (e.g, palladium diacetate) and a suitable base such asdiisopropylethylamine, triethylamine, pyridine, potassium carbonate, and the like. The reaction is typically maintained at from 10 °C to 65 °C until it is substantially complete. Conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide compound 50A.

[0368] The next step is a formylation reaction wherein at least a stoichiometric equivalent of compound50A dissolved in an inert diluent such as tetrahydrofuran, is sequentially reacted with a strong base (e.g.n-BuLi, s-BuLi, or t-BuLi, LDA), and then dimethylformamide. The reaction is typically maintained at - 78 °C until it is substantially complete. Conventional workup of the reaction solution can be followed by isolation / purification processes, such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 51A.

[0369] In the next step, a conventional reductive amination is conducted wherein at least astoichiometric equivalent of compound 51A is combined with a primary or secondary amine 52A, in aninert diluent such as tetrahydrofuran, dioxane, dimethylformamide and the like, in the presence of a reducing agent (e.g. sodium cyanoborohydride, Sodium triacetoxyborohydride). The reaction is typically maintained at from 20°C to 40 °C until it is substantially complete. Conventional workup of the reaction solution can be followed by isolation / purification processes, such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 53A.

[0370] The fifth step is a conventional Suzuki coupling reaction wherein at least a stoichiometricequivalent of a suitable boronic acid, compound 54A, or an ester thereof, is combined with compound53A, in an inert diluent such as tetrahydrofuran, dioxane, toluene, dimethoxyethane, and the like, typically in the presence of a palladium catalyst (e.g, palladium diacetate) and a suitable base such as diisopropylethylamine, triethylamine, pyridine, potassium carbonate, and the like. The reaction is typically maintained at from 10 °C to 65 °C until it is substantially complete. Conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide compound 55A.

[0371] In the next step, the t-butoxycarbonyl (t-BOC) protecting group is removed by conventionalconditions. The t-BOC group is illustrative only and other conventional amino blocking groups such as benzyl, 9-fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), p-nitrobenzyloxycarbonyl and the like. Upon reaction completion, conventional workup of the reaction solution can be followed by isolation / purification processes such as crystallization, chromatography, high performance liquidchromatography (HPLC), and the like.

[0372] In the final step, at least a stoichiometric amount of a suitable acid chloride, compound 56A, iscombined with compound from the previous step in an inert diluent such as DMF, DCM, MeCN and the like in the presence of a suitable base such as potassium carbonate, pyridine, triethylamine and the like. The reaction is typically maintained at from 0 °C to 50 °C until it is substantially complete.

[0373] Conventional workup of the reaction solution can be followed by isolation / purification processessuch as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide for compound 57A.

[0374] Other starting materials used herein are either well known in the art, commercially available, orcan be prepared by conventional synthetic methods. EXAMPLES

[0375] This disclosure is further understood by reference to the following examples, which are intendedto be purely exemplary of this disclosure. This disclosure is not limited in scope by the exemplified embodiments, which are intended as illustrations of single aspects of this disclosure only. Any methods that are functionally equivalent are within the scope of this disclosure. Various modifications of this disclosure in addition to those described herein will become apparent to those skilled in the art from the foregoing description and accompanying figures. Such modifications fall within the scope of the appended claims.

[0376] In the specification and in the examples below, all temperatures are in degrees Celsius. Inaddition, the following abbreviations have the following meanings. If not defined, these abbreviations have their art recognized meaning. Abbreviation Meaningδ chemical shift (ppm)ACN or MeCN Acetonitrile Ar Argon Boc tert -butoxycarbonylBOP benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate BRET Bioluminescence Resonance Energy TransfercataCXiumA-Pd-G2 chloro[(di(1-adamantyl)-N-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) Cbz benzyloxycarbonylCbzCl benzyloxycarbonyl chlorideDC50corresponding to half maximal degradation DCM dichloromethaneDIEA or DIPEA diisopropylethylamineDMA dimethylacetamideDMAP 4-dimethylaminopyridineDMF N,N-dimethylformamideDMSO Dimethylsulfoxide DMP Dess–Martin periodinane d6-DMSO deuterated dimethylsulfoxideDSC N,N′-disuccinimidyl carbonated4-MeOH deuterated methanoldtbbpy 4,4'-di-tert-butyl-2,2'-dipyridylEDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimideeq. equivalent(s)ESI electrospray ionizationEtOAc or EA ethyl acetateEtOH EthanolFBS Fetal Bovine SerumFITC fluorescein isothiocyanateFmoc fluorenylmethyloxycarbonyl1H NMR proton nuclear magnetic resonance spectroscopyHPLC high performance liquid chromatographyIPA isopropyl alcoholLC liquid chromatographyLC-MS liquid chromatography – mass spectrometryM MolarMeOH Methanol MTBE Methyl tert-butyl etherm / z mass-to-charge ratioMsOH methanesulfonic acidN Normal NBS N-BromosuccinimideNHC-1 5,7-di-tert-butyl-3-phenylbenzo[d]oxazol-3-ium tetrafluoroboratePBS phosphate-buffered salinePd2(dba)3 tris(dibenzylideneacetone)dipalladium(0) Pd(OAc)2 palladium (II) acetate PE Petroleum Ether pM Picomolarq.s. amount which is sufficientrt room temperatureSEM trimethylsilylethoxymethylSFC supercritical fluid chromatographyt-Bu tert-butylTEA TriethylamineTFA trifluoroacetic acidTFP tri(2-furyl)phosphineTHF tetrahydrofuranTMP 2,2,6,6-tetramethylpiperidineT3P propanephosphonic acid anhydrideTRITC tetramethylrhodamineTsCl 4-toluenesulfonyl chlorideTsOH 4-toluenesulfonic acidUV Ultravioletv / v volume / volume ratiowt % weight percentNMR abbreviations br = broadd = doublet dd = doublet of doublets m = multiplet q = quartet quin = quintet s = singlet t = triplet Synthesis of intermediate 1Step 1:To a solution of 3-chloro-7H-pyrrolo[2,3-c]pyridazine (100 g, 651.17 mmol, 1 eq) in DMF (1100 mL)was added NaH (39.07 g, 976.76 mmol, 60% purity, 1.5 eq) in portions at 0 °C under N2. After addition,the mixture was stirred at this temperature for 30 min, then 2-(trimethylsilyl)ethoxymethyl chloride(162.85 g, 976.76 mmol, 172.87 mL, 1.5 eq) was added dropwise over 40 min at 0 °C. The resultingmixture was stirred at 0 °C for 5 min. The reaction mixture was quenched by addition of H2O (100 mL)at 0 °C, then diluted with brine (1 L) and extracted with EtOAc (1 L × 3). The combined organic layerswere washed with brine (500 mL × 2), dried over Na2SO4, filtered, and concentrated under reducedpressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to give 3-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-c]pyridazine (130 g,448.86 mmol, 68.93% yield) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.69 (s, 1H),7.66 (d, J=3.50 Hz, 1H), 6.52 (d, J=3.63 Hz, 1H), 5.81 (s, 2H), 3.51-3.63 (m, 2H), 0.83-0.96 (m, 2H), -0.07 (s, 9H),Step 2To a solution of 3-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-c]pyridazine (130 g,458.02 mmol, 1 eq) and [2-(methoxymethoxy)phenyl]boronic acid (100.02 g, 549.63 mmol, 1.2 eq) in dioxane (1300 mL) and H2O (650 mL) was added Pd(dppf)Cl2 (33.51 g, 45.80 mmol, 0.1 eq) and Cs2CO3(447.70 g, 1.37 mol, 3 eq) under N2. The mixture was stirred at 80 °C for 2 h. The reaction mixture wasdiluted with water (1000 mL) and extracted with EtOAc (1500 mL × 2). The combined organic layerswere washed with brine (2000 mL), dried over Na2SO4, filtered, and concentrated under reducedpressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate =10 / 1 to 5 / 1) to give 3-(2-(methoxymethoxy)phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-c]pyridazine (120 g, 298.81 mmol, 65.24% yield) as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.14 (s, 1H), 7.91 (dd, J=7.67, 1.36 Hz, 1H), 7.60 (d, J=3.46 Hz, 1H), 7.34-7.43 (m, 1H), 7.25 (s, 1H), 7.17 (t, J=7.48 Hz, 1H), 6.57 (d, J=3.46 Hz, 1H), 5.87 (s, 2H), 5.19 (s, 2H), 3.57-3.71 (m, 2H), 3.41 (s, 3H), 0.84-1.01 (m, 2H), -0.08 (s, 10H) Step 3In a flow chemistry setup, LDA (2M in THF, 1.26 L, 2.5 eq) was added to a solution of 3-(2- (methoxymethoxy)phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-c]pyridazine (390 g,1.01 mol, 1 eq) in THF (7800 mL) at -40 °C to which was subsequently added a solution of 1,2-dibromoethane (665.14 g, 3.54 mol, 267.12 mL, 3.5 eq) in THF (3900 mL). The reaction was thenquenched by addition of saturated NH4Cl (1 L) at 10 °C, then diluted with H2O (300 mL) and extractedwith EtOAc (500 mL × 3). The combined organic layers were washed with brine (500 mL × 2), driedover Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified bycolumn chromatography (SiO2, petroleum ether / ethyl acetate=1 / 0 to 10 / 1) to give 6-bromo-3-(2-(methoxymethoxy)phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-c]pyridazine (570 g,1.20 mol, 59.39% yield,) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.14 (s, 1H), 7.71 (dd, 1H,J=1.8, 7.6 Hz), 7.4-7.5 (m, 1H), 7.29 (d, 1H, J=8.3 Hz), 7.1-7.2 (m, 1H), 6.98 (s, 1H), 5.85 (s, 2H), 5.22(s, 2H), 3.64 (t, 2H, J=7.9 Hz), 3.27 (s, 3H), 0.86 (t, 2H, J=7.9 Hz), -0.10 (s, 8H); LCMS (ESI+): m / z 466 (M+H)+.Example 1: Synthesis of 1-{3-[5-(o-hydroxyphenyl)-1H-1,6,7-triazainden-2-yl]-1-azetidinyl}-2- propen-1-one (Compound 216): Step 1:

[0377] A mixture of 4-bromo-6-chloropyridazin-3-amine (10 g, 47.98 mmol, 1 eq), tert-butyl 3-ethynylazetidine-1-carboxylate (10 g, 55.18 mmol, 1.15 eq), Pd(PPh3)2Cl2(3.37 g, 4.80 mmol, 0.1 eq),CuI (913.80 mg, 4.80 mmol, 0.1 eq), and TEA (4.86 g, 47.98 mmol, 6.68 mL, 1 eq) in DMF (300 mL)was degassed and purged with N2. The mixture was stirred at 120 °C for 2 h under a N2 atmosphere.The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (2 × 200 mL). Thecombined organic layers were washed with brine (200 mL), dried over Na2SO4, and filtered. The filtratewas concentrated under reduced pressure, and the residue was purified by column chromatography (SiO2,50% petroleum ether in ethyl acetate) to give tert-butyl 3-((3-amino-6-chloropyridazin-4-yl)ethynyl)azetidine-1-carboxylate. 1H NMR (400 MHz, CHLOROFORM-d) δ =8.06 (s, 1H), 5.84 (s,2H), 4.30 (t, J = 8.4 Hz, 2H), 4.07 (dd, J = 6.4, 8.4 Hz, 2H), 3.70 - 3.60 (m, 1H), 1.50 (s, 9H).Step 2:

[0378] To a solution of tert-butyl 3-((3-amino-6-chloropyridazin-4-yl)ethynyl)azetidine-1-carboxylate(4.3 g, 13.93 mmol, 1 eq) in THF (43 mL) was added TBAF (1M, 55.71 mL, 4 eq) at 25 °C. The mixturewas stirred at 80 °C for 1 h. The reaction mixture was diluted with water (50 mL) and extracted withEtOAc (2 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4,filtered, and concentrated under reduced pressure to give tert-butyl 3-(3-chloro-7H-pyrrolo[2,3-c]pyridazin-6-yl)azetidine-1-carboxylate, which was used in the next step without further purification.1H NMR (400 MHz, CHLOROFORM-d) δ 11.32 - 10.84 (m, 1H), 7.78 - 7.65 (m, 1H), 6.48 (s, 1H), 4.47(t, J = 8.0 Hz, 2H), 4.18 - 4.07 (m, 3H), 1.48 (s, 9H).Step 3:

[0379] A mixture of tert-butyl 3-(3-chloro-7H-pyrrolo[2,3-c]pyridazin-6-yl)azetidine-1-carboxylate,(4.2 g, 13.60 mmol, 1 eq), (2-(methoxymethoxy)phenyl)boronic acid (3.71 g, 20.40 mmol, 1.5 eq),Cs2CO3 (13.30 g, 40.81 mmol, 3 eq), and XPhos-Pd-G3 (1.73 g, 2.04 mmol, 0.15 eq) in dioxane (42 mL)and water (21 mL) was degassed and purged with N2. The mixture was stirred at 80 ℃ for 1 h under aN2 atmosphere. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 × 50mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and filtered.The filtrate was concentrated under reduced pressure, and the residue was purified by columnchromatography (SiO2, 35% petroleum ether in ethyl acetate) to give tert-butyl 3-(3-(2-(methoxymethoxy)phenyl)-7H-pyrrolo[2,3-c]pyridazin-6-yl)azetidine-1-carboxylate. 1H NMR (400MHz, CHLOROFORM-d) δ 12.08 (br s, 1H), 8.12 (s, 1H), 7.88 (dd, J = 1.6, 7.6 Hz, 1H), 7.44 - 7.38 (m,1H), 7.29 (d, J = 8.4 Hz, 1H), 7.24 - 7.18 (m, 1H), 6.49 (s, 1H), 5.21 (s, 2H), 4.54 - 4.42 (m, 2H), 4.21 -4.10 (m, 3H), 3.43 (s, 3H), 1.47 (s, 9H). S

[0380] A solution of tert-butyl 3-(3-(2-(methoxymethoxy)phenyl)-7H-pyrrolo[2,3-c]pyridazin-6-yl)azetidine-1-carboxylate (3 g, 7.31 mmol, 1 eq) in DMF (50 mL) was cooled to 0 ℃. NBS (1.30 g,7.31 mmol, 1 eq) in DMF (10 mL) was added dropwise to the solution. The mixture was stirred at 0 ℃for 0.5 h. The reaction mixture was poured into ice water (100 mL) and filtered. The filter cake wasdried to give tert-butyl 3-(5-bromo-3-(2-(methoxymethoxy)phenyl)-7H-pyrrolo[2,3-c]pyridazin-6-yl)azetidine-1-carboxylate, which was used in the next step without further purification. 1H NMR (400MHz, DMSO-d6) δ 13.25 (s, 1H), 7.95 (d, J = 5.2 Hz, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.49 - 7.39 (m, 1H),7.28 (d, J = 8.0 Hz, 1H), 7.17 (t, J = 7.2 Hz, 1H), 5.25 (s, 2H), 4.25 (s, 5H), 3.33 (s, 3H), 1.49 - 1.39 (m,9H) Step 5:

[0381] To a solution of tert-butyl 3-(5-bromo-3-(2-(methoxymethoxy)phenyl)-7H-pyrrolo[2,3-c]pyridazin-6-yl)azetidine-1-carboxylate (3 g, 6.13 mmol, 1 eq) and TEA (2.48 g, 24.52 mmol, 3.41 mL,4 eq) in DMF (30 mL) was added SEM-Cl (2.04 g, 12.26 mmol, 2.17 mL, 2 eq) dropwise at 0 ℃ under aN2 atmosphere. The mixture was stirred at 0 ℃ for 1 h. The reaction mixture was quenched by additionof ice water (10 mL) at 0 °C and extracted with EtOAc (2 × 30 mL). The combined organic layers werewashed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. Theresidue was purified by column chromatography (SiO2, 25% ethyl acetate in petroleum ether) to give tert-butyl 3-(5-bromo-3-(2-(methoxymethoxy)phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-c]pyridazin-6-yl)azetidine-1-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1H),7.63 (dd, J = 1.6, 7.6 Hz, 1H), 7.48 (dt, J = 1.6, 8.0 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.17 (dt, J = 0.8,7.6 Hz, 1H), 6.21 (s, 2H), 5.27 (s, 2H), 4.34 - 4.10 (m, 5H), 3.84 (t, J = 8.0 Hz, 2H), 3.34 - 3.34 (m, 3H),1.42 (s, 9H), 0.96 - 0.86 (m, 2H), 0.11 (s, 9H).Step 6:

[0382] A mixture of tert-butyl 3-(5-bromo-3-(2-(methoxymethoxy)phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-c]pyridazin-6-yl)azetidine-1-carboxylate (250.0 mg, 403.5 μmol, 1.0 eq), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (202.6 mg, 806.9 μmol, 225.6 μL, 2.0 eq),K3PO4 (171.3 mg, 806.9 μmol, 2.0 eq), and bis(4-(di-tert-butylphosphanyl)-N,N-dimethylaniline)-palladium chloride (42.8 mg, 60.5 μmol, 42.8 μL, 0.15 eq) in dioxane (5 mL) and H2O (2.5 mL) wasdegassed and purged with N2. The mixture was stirred at 60 °C for 4 h under N2. The reaction mixturewas partitioned between ethyl acetate (5 mL) and H2O (5 mL). The organic phase was separated, washedwith brine (5 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure,and the residue was purified by column chromatography (SiO2, 10 to 15% ethyl acetate in petroleumether) to give tert-butyl 3-(3-(2-(methoxymethoxy)phenyl)-5-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-c]pyridazin-6-yl)azetidine-1-carboxylate. 1H NMR (400MHz, METHANOL-d4) δ 8.23 (s, 1H), 7.64 (dd, J = 1.6, 7.6 Hz, 1H), 7.47 - 7.39 (m, 1H), 7.31 (d, J =8.0 Hz, 1H), 7.15 (dt, J = 0.8, 7.6 Hz, 1H), 6.23 (s, 2H), 5.24 (s, 2H), 4.36 - 4.23 (m, 5H), 3.87 (t, J = 8.0Hz, 2H), 3.39 (s, 3H), 2.31 (s, 3H), 1.49 (s, 9H), 0.96 - 0.91 (m, 2H), -0.10 (s, 9H).Step 7:

[0383] A solution of tert-butyl 3-(3-(2-(methoxymethoxy)phenyl)-5-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-c]pyridazin-6-yl)azetidine-1-carboxylate (160.0 mg, 288.4μmol, 1.0 eq) in DCM (2 mL) and TFA (1 mL) was stirred at 25 °C for 1 h. The reaction mixture wasconcentrated under reduced pressure. The residue was triturated with tert-butyl methyl ether (5 mL) togive 2-(6-(azetidin-3-yl)-5-methyl-7H-pyrrolo[2,3-c]pyridazin-3-yl)phenol (TFA salt), which was used inthe subsequent step without purification. 1H NMR (400 MHz, METHANOL-d4) δ 8.58 (s, 1H), 7.76 -7.70 (m, 1H), 7.44 (dt, J = 1.6, 7.6 Hz, 1H), 7.12 - 7.04 (m, 2H), 4.65 - 4.56 (m, 2H), 4.54 - 4.47 (m, 2H),4.43 - 4.39 (m, 1H), 2.42 - 2.37 (m, 3H).Step 8:

[0384] To a solution of 2-(6-(azetidin-3-yl)-5-methyl-7H-pyrrolo[2,3-c]pyridazin-3-yl)phenol (TFA salt)(100.0 mg, 253.6 μmol, 1.0 eq, TFA) and DIEA (98.3 mg, 760.7 μmol, 132.5 μL, 3.0 eq) in DMA (2 mL) was added prop-2-enoyl chloride (16.1 mg, 177.5 μmol, 14.4 μL, 0.7 eq) in DCM (0.2 mL) dropwise at 0°C. The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reducedpressure, and the residue was purified by prep-HPLC (Instrument: Gilson 281 semi-preparative HPLCsystem; Mobile phase: A: H2O (10 mM NH4HCO3); B: ACN; Column: Waters Xbridge BEH C18100 mm × 30 mm × 10 µm; Flow rate: 25.00 ml / min) to give 1-{3-[5-(o-hydroxyphenyl)-1H-1,6,7-triazainden-2-yl]-1-azetidinyl}-2-propen-1-one. 1H NMR (400 MHz, METHANOL-d4) δ 8.56 (s, 1H),7.64 (dd, J = 1.6, 7.6 Hz, 1H), 7.49 (dt, J = 1.6, 8.0 Hz, 1H), 7.15 - 7.07 (m, 2H), 6.49 - 6.39 (m, 1H),6.36 - 6.28 (m, 1H), 5.82 (dd, J = 2.4, 10.4 Hz, 1H), 4.66 - 4.57 (m, 3H), 4.57 - 4.52 (m, 1H), 4.40 - 4.33(m, 1H), 2.42 (s, 3H). Example 2: Synthesis of 1-{(2S)-3-[5-(o-hydroxyphenyl)-1H-1,6,7-triazainden-2-yl]-2-methyl-4- morpholinyl}-2-propen-1-one (Compound 11):Step 1:

[0385] To a solution of (2S,3R)-4-(tert-butoxycarbonyl)-2-methylmorpholine-3-carboxylic acid (900.0mg, 3.7 mmol, 1.0 eq) in THF (18 mL) was added BH3·THF (1M, 11.0 mL, 3.0 eq) dropwise undernitrogen at 0 °C. After the addition was completed, the reaction mixture was warmed to 25 °C andstirred at the same temperature for 2 h. The reaction mixture was quenched by addition of MeOH (10mL) at 0 °C, then stirred at 25 °C for 2 h. The mixture was concentrated under reduced pressure to givetert-butyl (2S,3S)-3-(hydroxymethyl)-2-methylmorpholine-4-carboxylate, which was used in the nextstep without further purification.NMR (400 MHz, CHLOROFORM-d) δ 3.97 - 3.91 (m, 1H), 3.91 -3.84 (m, 2H), 3.84 - 3.79 (m, 1H), 3.79 - 3.74 (m, 1H), 3.73 - 3.66 (m, 1H), 3.60 - 3.51 (m, 1H), 3.32 -3.21 (m, 1H), 1.48 (s, 9H), 1.34 (d, J = 6.4 Hz, 3H).Step 2:

[0386] To a solution of tert-butyl (2S,3S)-3-(hydroxymethyl)-2-methylmorpholine-4-carboxylate (0.6 g,2.6 mmol, 1.0 eq) in DCM (14 mL) was added DMP (1.7 g, 3.9 mmol, 1.2 mL, 1.5 eq) at 0 °C. Themixture was warmed up to 25 °C and stirred for 2 h. The reaction mixture was quenched by addition ofNaHCO3 (10 mL) at 0 °C, then diluted with H2O (10 mL) and extracted with EtOAc (3 × 10 mL). Thecombined organic layers were washed with brine (10 mL), dried over Na2SO4, and filtered. The filtratewas concentrated under reduced pressure to give tert-butyl (2S,3R)-3-formyl-2-methylmorpholine-4-carboxylate, which was used in the next step without further purification. 1H NMR (400 MHz,CHLOROFORM-d) δ 10.04 - 9.44 (m, 1H), 4.10 - 3.98 (m, 1H), 3.95 - 3.86 (m, 1H), 3.77 (dd, J = 2.0,6.0 Hz, 1H), 3.57 (td, J = 5.2, 11.2 Hz, 1H), 3.45 (s, 2H), 1.48 (s, 9H), 1.34 (d, J = 6.4 Hz, 3H).Step 3:

[0387] To a solution of tert-butyl (2S,3R)-3-formyl-2-methylmorpholine-4-carboxylate (440 mg, 1.9mmol, 1.0 eq) in MeOH (5 mL) was added K2CO3(795.7 mg, 5.8 mmol, 3.0 eq) and 1-diazo-1-dimethoxyphosphoryl-propan-2-one (442.4 mg, 2.3 mmol, 1.2 eq) at 0 °C. The mixture was warmed upto 25 °C and stirred for 2 h. The reaction mixture was quenched by addition of H2O (5 mL) and extractedwith EtOAc (2 × 5 mL). The combined organic layers were washed with brine (5 mL), dried overNa2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (SiO2, 2 to 10% EtOAc in petroleum ether) to give tert-butyl (2S,3S)-3-ethynyl-2-methylmorpholine-4-carboxylate. 1H NMR (400 MHz, CHLOROFORM-d) δ 4.56 (s, 1H),4.08 (dq, J = 1.6, 6.8 Hz, 1H), 3.84 (dt, J = 3.6, 12.0 Hz, 1H), 3.73 (dd, J = 3.6, 13.6 Hz, 1H), 3.63 (ddd,J = 1.2, 4.0, 11.6 Hz, 1H), 3.37 (ddd, J = 4.0, 12.0, 13.6 Hz, 1H), 2.36 - 2.31 (m, 1H), 1.49 (s, 9H), 1.33(d, J = 6.8 Hz, 3H).Step 4:

[0388] A mixture of 4-bromo-6-chloropyridazin-3-amine (291.5 mg, 1.4 mmol, 1.1 eq), tert-butyl(2S,3S)-3-ethynyl-2-methylmorpholine-4-carboxylate (300.0 mg, 1.3 mmol, 1.0 eq), CuI (38.0 mg, 199.8μmol, 0.15 eq), Pd(PPh3)2Cl2 (93.5 mg, 133.2 μmol, 0.1 eq), and TEA (673.8 mg, 6.7 mmol, 926.8 μL,5.0 eq) in DMF (3 mL) was degassed and purged with N2. The mixture was then stirred at 40 °C for 2 hunder a N2 atmosphere. The reaction mixture was diluted with H2O (5 mL) and extracted with EtOAc(2 × 5 mL). The combined organic layers were washed with brine (2 × 5 mL), dried over Na2SO4, andfiltered. The filtrate was concentrated under reduced , and the residue was purified by column chromatography (SiO2, 15 to 25% EtOAc in petroleum ether) to give tert-butyl (2S,3S)-3-((3-amino-6-chloropyridazin-4-yl)ethynyl)-2-methylmorpholine-4-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ7.60 (s, 1H), 6.92 - 6.62 (m, 2H), 4.20 - 4.10 (m, 1H), 3.81 - 3.68 (m, 1H), 3.63 (d, J = 13.6 Hz, 1H), 3.55(dd, J = 2.4, 11.6 Hz, 1H), 3.50 - 3.37 (m, 1H), 3.30 - 3.24 (m, 1H), 1.43 (s, 9H), 1.28 - 1.20 (m, 3H).Step 5:

[0389] To a solution of tert-butyl (2S,3S)-3-((3-amino-6-chloropyridazin-4-yl)ethynyl)-2-methylmorpholine-4-carboxylate (300 mg, 850.3 μmol, 1.0 eq) in THF (9 mL) was added potassium tert-butoxide (1M, 1.7 mL, 2.0 eq) at 25 °C. The mixture was stirred at the same temperature for 2 h. Thereaction mixture was quenched with H2O (5 mL) and extracted with EtOAc (2 × 5 mL). The combinedorganic layers were washed with brine (5 mL), dried over Na2SO4, and filtered. The filtrate wasconcentrated under reduced pressure, and the residue was purified by column chromatography (SiO2, 20 to 50% EtOAc in petroleum ether) to give tert-butyl (2S)-3-(3-chloro-7H-pyrrolo[2,3-c]pyridazin-6-yl)-2-methylmorpholine-4-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 12.72 - 12.42 (m, 1H), 8.09 -7.81 (m, 1H), 6.60 - 6.32 (m, 1H), 5.17 - 4.81 (m, 1H), 4.43 - 3.95 (m, 1H), 3.93 - 3.78 (m, 1H), 3.70 -3.54 (m, 3H), 1.45 - 1.28 (m, 9H), 1.22 - 0.88 (m, 3H).Step 6:

[0390] A mixture of tert-butyl (2S)-3-(3-chloro-7H-pyrrolo[2,3-c]pyridazin-6-yl)-2-methylmorpholine-4-carboxylate (130 mg, 368.5 μmol, 1.0 eq), (2-hydroxyphenyl)boronic acid (152.5 mg, 1.1 mmol, 3.0eq), Cs2CO3 (720.3 mg, 2.2 mmol, 6.0 eq), and Xphos-Pd-G3 (46.8 mg, 55.3 μmol, 0.15 eq) in dioxane(1.4 mL) and H2O (0.7 mL) was degassed and purged with N2. The resulting mixture was stirred at 100°C for 2 h under a N2 atmosphere. The reaction mixture was partitioned between EtOAc (5 mL) and H2O(5 mL). The organic phase was separated, washed with brine (5 mL), dried over Na2SO4, and filtered.The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (SiO2, 15 to 25% EtOAc in petroleum ether) to give tert-butyl (2S)-3-(3-(2-hydroxyphenyl)-7H-pyrrolo[2,3-c]pyridazin-6-yl)-2-methylmorpholine-4-carboxylate. 1H NMR (400MHz, METHANOL-d4) δ 8.87 - 8.46 (m, 1H), 8.15 - 7.90 (m, 1H), 7.51 - 7.24 (m, 1H), 7.17 - 7.03 (m,1H), 6.88 - 6.73 (m, 1H), 6.72 - 6.50 (m, 1H), 5.28 - 5.05 (m, 1H), 5.01 - 4.92 (m, 1H), 4.02 - 3.92 (m,1H), 3.84 - 3.66 (m, 2H), 3.47 - 3.35 (m, 1H), 1.42 - 1.38 (m, 9H), 1.17 - 1.00 (m, 3H).Step 7:

[0391] To a solution of tert-butyl (2S)-3-(3-(2-hydroxyphenyl)-7H-pyrrolo[2,3-c]pyridazin-6-yl)-2-methylmorpholine-4-carboxylate (100 mg, 243.6 μmol, 1.0 eq) in DCM (2 mL) was added TFA (1.5 g,13.5 mmol, 1.0 mL, 55.3 eq) at 25 °C. The mixture was stirred at the same temperature for 2 h. Themixture was concentrated under reduced pressure to remove DCM, and the residue was triturated with methyl tert-butyl ether (3 mL) at 25 °C for 30 min to give 2-(6-((2S)-2-methylmorpholin-3-yl)-7H-pyrrolo[2,3-c]pyridazin-3-yl)phenol, which was used in the subsequent step without purification. m / z(ESI+): 311.1 (M+H)+. Step 8:

[0392] To a solution of 2-(6-((2S)-2-methylmorpholin-3-yl)-7H-pyrrolo[2,3-c]pyridazin-3-yl)phenol (70mg, 165.0 μmol, 1.0 eq, TFA salt) and DIEA (213.2 mg, 1.7 mmol, 287.3 μL, 10.0 eq) in DCM (0.4 mL) was added prop-2-enoyl chloride (11.9 mg, 132.0 μmol, 10.7 μL, 0.8 eq) in DCM (0.1 mL) dropwise at 0°C. The resulting mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched by additionof MeOH (0.5 mL) at 25 °C, and the mixture was concentrated under reduced pressure. The residue waspurified by prep-TLC (SiO2, 20% THF in DCM) to give 1-((2S)-3-(3-(2-hydroxyphenyl)-7H-pyrrolo[2,3-c]pyridazin-6-yl)-2-methylmorpholino)prop-2-en-1-one. 1H NMR (400 MHz, DMSO-d6) δ 14.09 - 13.57(m, 1H), 12.77 - 12.38 (m, 1H), 8.73 - 8.45 (m, 1H), 8.00 (d, J = 7.6 Hz, 1H), 7.40 - 7.20 (m, 1H), 7.12 -6.66 (m, 4H), 6.28 - 6.08 (m, 1H), 5.82 - 5.67 (m, 1H), 5.66 - 5.28 (m, 1H), 4.74 - 4.10 (m, 1H), 4.10 -3.96 (m, 1H), 3.93 - 3.75 (m, 1H), 3.73 - 3.56 (m, 2H), 1.37 - 1.32 (m, 1H), 1.23 (s, 1H), 1.04 - 0.98 (m,2H). Step 9:

[0393] 1-((2S)-3-(3-(2-hydroxyphenyl)-7H-pyrrolo[2,3-c]pyridazin-6-yl)-2-methylmorpholino)prop-2-en-1-one (24 mg, 65.9 μmol) was separated by SFC (Column: DAICEL CHIRALCEL OJ 250mm×30mm10µm; mobile phase: [CO2-MeOH ]; B%: 46%, isocratic elution mode) to give 1-{(2S)-3-[5-(o-hydroxyphenyl)-1H-1,6,7-triazainden-2-yl]-2-methyl-4-morpholinyl}-2-propen-1-one (1st elutingisomer). 1H NMR (400 MHz, METHANOL-d4) δ 8.49 (s, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.34 - 7.22 (m,1H), 7.04 - 6.93 (m, 2H), 6.86 (dd, J = 10.4, 16.8 Hz, 1H), 6.72 (s, 1H), 6.35 (dd, J = 1.6, 16.8 Hz, 1H),5.85 (dd, J = 2.0, 10.4 Hz, 1H), 5.54 (s, 1H), 4.67 (dq, J = 2.0, 6.4 Hz, 1H), 4.14 - 4.05 (m, 1H), 4.04 -3.95 (m, 1H), 3.71 (dd, J = 2.8, 11.6 Hz, 1H), 3.52 - 3.39 (m, 1H), 1.45 (d, J = 6.4 Hz, 3H).Example 3: Synthesis of 1-{(2S)-3-[5-(o-hydroxyphenyl)-1H-1,6,7-triazainden-2-yl]-2-methyl-4- morpholinyl}-2-propen-1-one (Compound 10):Step 1:

[0394] 1-((2S)-3-(3-(2-hydroxyphenyl)-7H-pyrrolo[2,3-c]pyridazin-6-yl)-2-methylmorpholino)prop-2-en-1-one (24 mg, 65.9 μmol) was separated by SFC (Column: DAICEL CHIRALCEL OJ 250mm×30mm10µm; mobile phase: [CO2-MeOH ]; B%: 46%, isocratic elution mode) to give 1-{(2S)-3-[5-(o-hydroxyphenyl)-1H-1,6,7-triazainden-2-yl]-2-methyl-4-morpholinyl}-2-propen-1-one (2nd elutingisomer). 1H NMR (400 MHz, METHANOL-d4) δ 8.51 (s, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.34 - 7.23 (m,1H), 7.01 - 6.93 (m, 2H), 6.87 - 6.79 (m, 1H), 6.72 (dd, J = 10.8, 16.8 Hz, 1H), 6.32 - 6.18 (m, 1H), 5.91- 5.77 (m, 1H), 5.75 (s, 1H), 4.40 - 4.13 (m, 1H), 4.08 - 3.87 (m, 2H), 3.85 - 3.73 (m, 1H), 3.71 - 3.60 (m,1H), 1.23 - 1.07 (m, 3H).Example 4: Synthesis of 1-{3-[3-cyclopropyl-5-(o-hydroxyphenyl)-1H-1,6,7-triazainden-2-yl]-3- methyl-1-pyrrolidinyl}-2-propen-1-one (Compound 31):Step 1:

[0395] To a solution of tert-butyl 3-(hydroxymethyl)-3-methylpyrrolidine-1-carboxylate (3.9 g, 18.1mmol, 1.0 eq) in DCM (50 mL) was added DMP (11.5 g, 27.2 mmol, 8.4 mL, 1.5 eq) at 0 °C and themixture was warmed up to 25 °C and stirred for 1 h. The reaction mixture was filtered, and the filtratewas concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 5to 15% EtOAc in petroleum ether) to give tert-butyl 3-formyl-3-methylpyrrolidine-1-carboxylate. 1HNMR (400 MHz, CHLOROFORM-d) δ 9.55 (s, 1H), 3.83 - 3.70 (m, 1H), 3.50 - 3.35 (m, 2H), 3.18 -3.05 (m, 1H), 2.25 (s, 1H), 1.76 - 1.66 (m, 1H), 1.47 (s, 9H), 1.24 (s, 3H).Step 2:

[0396] To a solution of tert-butyl 3-formyl-3-methylpyrrolidine-1-carboxylate (3.2 g, 15.0 mmol, 1.0eq) and K2CO3 (6.2 g, 45.0 mmol, 3.0 eq) in MeOH (40 mL) was added 1-diazo-1-dimethoxyphosphoryl-propan-2-one (3.5 g, 18.0 mmol, 1.2 eq) at 0 °C. The mixture was warmed up to 25 °C and stirred for 2hours. The reaction mixture was partitioned between ethyl acetate (30 mL) and H2O (20 mL). Theorganic phase was separated, washed with brine (20 mL), dried over Na2SO4, and filtered. The filtratewas concentrated under reduced pressure to give tert-butyl 3-ethynyl-3-methylpyrrolidine-1-carboxylate,which was used in the subsequent step without purification. 1H NMR (400 MHz, CHLOROFORM-d) δ3.61 - 3.38 (m, 3H), 3.26 - 3.15 (m, 1H), 2.16 -2.10 (m, 2H), 1.86 - 1.76 (m, 1H), 1.47 (s, 9H), 1.36 (s,3H).Step 3:

[0397] To a solution of 4-bromo-6-chloropyridazin-3-amine (2.2 g, 10.6 mmol, 1.0 eq) and tert-butyl 3-ethynyl-3-methylpyrrolidine-1-carboxylate (2.6 g, 12.7 mmol, 1.2 eq) in DMF (25 mL) was addedPd(PPh3)2Cl2 (740.8 mg, 1.1 mmol, 0.1 eq), CuI (301.5 mg, 1.6 mmol, 0.15 eq), and TEA (5.3 g, 52.8mmol, 7.3 mL, 5.0 eq) at 20 °C under N2. The mixture was then heated to 40 °C and stirred for 2 h.Another 750 mg scale reaction was set up as described above; both reactions were combined for workupand purification. The combined reaction mixtures were diluted with water (15 mL) and extracted withethyl acetate (2 × 15 mL). The combined organic layers were washed with brine (20 mL), dried overNa2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purifiedby column chromatography (SiO2, 5 to 20% EtOAc in petroleum ether) to give tert-butyl 3-((3-amino-6-chloropyridazin-4-yl)ethynyl)-3-methylpyrrolidine-1-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ7.52 (s, 1H), 6.79 (s, 2H), 3.62 (d, J = 10.4 Hz, 1H), 3.46 - 3.38 (m, 2H), 3.23 (dd, J = 6.8, 10.4 Hz, 1H),2.30 - 2.19 (m, 1H), 1.98 - 1.86 (m, 1H), 1.41 (s, 12H).Step 4:

[0398] A mixture of tert-butyl 3-((3-amino-6-chloropyridazin-4-yl)ethynyl)-3-methylpyrrolidine-1-carboxylate (2.5 g, 7.4 mmol, 1.0 eq) and TBAF (1.0 M, 29.7 mL, 4.0 eq) in THF (25 mL) was degassedand purged with N2. The mixture was then stirred at 80 °C for 2 h under a N2 atmosphere. Another 1.1 gscale reaction was set up as described above; both reactions were combined for workup and purification.The combined reaction mixtures were partitioned between ethyl acetate (30 mL) and water (20 mL). Theorganic layer was washed with brine (20 mL), dried over Na2SO4, and filtered. The filtrate wasconcentrated under reduced pressure to give tert-butyl 3-(3-chloro-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-methylpyrrolidine-1-carboxylate, which was used in the subsequent step without purification. 1H NMR(400 MHz, DMSO-d6) δ 12.62 (s, 1H), 7.89 (s, 1H), 6.37 (s, 1H), 3.69 (dd, J = 2.8, 10.8 Hz, 1H), 3.41 (d,J = 10.8 Hz, 2H), 3.30 (s, 1H), 2.40 - 2.30 (m, 1H), 2.09 - 2.00 (m, 1H), 1.45 (s, 3H), 1.39 (d, J = 4.0 Hz,9H).Step 5:

[0399] To a solution of tert-butyl 3-(3-chloro-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-methylpyrrolidine-1-carboxylate (2.7 g, 8.0 mmol, 1.0 eq) and [2-(methoxymethoxy)phenyl]boronic acid (1.9 g, 10.4 mmol,1.3 eq) in dioxane (54 mL) and H2O (27 mL) was added Cs2CO3 (15.7 g, 48.1 mmol, 6.0 eq) and XPhos-Pd-G3 (1.0 g, 1.2 mmol, 0.15 eq) at 20 °C under N2. The mixture was then heated to 100 °C and stirredfor 2 h. The reaction mixture was partitioned between ethyl acetate (40 mL) and H2O (20 mL). Theorganic phase was separated, washed with brine (20 mL), dried over Na2SO4, and filtered. The filtratewas concentrated under reduced pressure, and the residue was purified by column chromatography(SiO2, 25 to 75% EtOAc in petroleum ether) to give tert-butyl 3-(3-(2-(methoxymethoxy)phenyl)-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-methylpyrrolidine-1-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ12.37 (d, J = 4.4 Hz, 1H), 8.01 (s, 1H), 7.69 (dd, J = 1.6, 7.6 Hz, 1H), 7.42 - 7.37 (m, 1H), 7.26 (d, J =8.0 Hz, 1H), 7.17 - 7.11 (m, 1H), 6.39 (d, J = 1.6 Hz, 1H), 5.20 (s, 2H), 3.73 (dd, J = 5.2, 10.8 Hz, 1H),3.46 - 3.40 (m, 2H), 3.38 - 3.33 (m, 1H), 3.30 (s, 3H), 2.44 - 2.34 (m, 1H), 2.11 - 2.00 (m, 1H), 1.48 (s,3H), 1.40 (d, J = 4.8 Hz, 9H).Step 6:

[0400] To a solution of tert-butyl 3-(3-(2-(methoxymethoxy)phenyl)-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-methylpyrrolidine-1-carboxylate (1.0 g, 2.3 mmol, 1.0 eq) in DMF (20 mL) was added NBS (426.2 mg,2.4 mmol, 1.05 eq) in portions at 0 °C under N2. The mixture was then warmed up to 25 °C and stirredfor 1 h. The reaction mixture was quenched by addition of H2O (40 mL) at 0 °C, which resulted in aprecipitate. The mixture was filtered, and the filter cake was triturated with H2O (50 mL). The solid wasdried under vacuum to give tert-butyl 3-(5-bromo-3-(2-(methoxymethoxy)phenyl)-7H-pyrrolo[2,3- c]pyridazin-6-yl)-3-methylpyrrolidine-1-carboxylate, which was used in the subsequent step withoutpurification. 1H NMR (400 MHz, DMSO-d6) δ 12.80 (s, 1H), 8.00 - 7.94 (m, 1H), 7.75 (d, J = 7.2 Hz,1H), 7.47 - 7.41 (m, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 5.25 (s, 2H), 3.89 - 3.71 (m,2H), 3.44 (s, 2H), 3.35 (s, 3H), 2.43 - 2.35 (m, 2H), 1.46 (d, J = 4.8 Hz, 3H), 1.43 (s, 9H).Step 7:

[0401] To a solution of tert-butyl 3-(5-bromo-3-(2-(methoxymethoxy)phenyl)-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-methylpyrrolidine-1-carboxylate (1.4 g, 2.7 mmol, 1.0 eq) in DMF (25 mL) wasadded NaH (216.5 mg, 5.4 mmol, 60% purity, 2.0 eq) in portions at 0 °C under N2. After addition, themixture was stirred at the same temperature for 10 minutes. Subsequently, (2-chloromethoxyethyl)trimethylsilane (676.7 mg, 4.1 mmol, 718.32 μL, 1.5 eq) was added dropwise at 0°C. The resulting mixture was warmed up to 25 °C and stirred for 30 minutes. The reaction mixture wasquenched by addition of H2O (50 mL) at 0 °C and extracted with ethyl acetate (50 mL). The organic layerwas washed with brine (20 mL), dried over Na2SO4, and filtered. The filtrate was concentrated underreduced pressure, and the residue was purified by column chromatography (SiO2, 5 to 15% EtOAc in petroleum ether) to give tert-butyl 3-(5-bromo-3-(2-(methoxymethoxy)phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-methylpyrrolidine-1-carboxylate. 1HNMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 7.73 (dd, J = 1.6, 7.6 Hz, 1H), 7.62 - 7.55 (m, 1H), 7.41 (d, J= 8.4 Hz, 1H), 7.29 (t, J = 7.6 Hz, 1H), 6.33 - 6.23 (m, 2H), 5.39 (s, 2H), 4.00 - 3.90 (m, 2H), 3.73 - 3.59(m, 2H), 3.47 (s, 3H), 3.44 - 3.37 (m, 2H), 2.76 - 2.68 (m, 1H), 2.34 (td, J = 6.0, 12.4 Hz, 1H), 1.60 (s,3H), 1.52 (d, J = 6.8 Hz, 9H), 1.01 (t, J = 8.0 Hz, 2H), 0.00 (d, J = 3.2 Hz, 9H).Step 8:

[0402] To a solution of tert-butyl 3-(5-bromo-3-(2-(methoxymethoxy)phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-methylpyrrolidine-1-carboxylate (420.0 mg, 648.5 μmol, 1.0 eq) and cyclopropylboronic acid (1.1 g, 12.9 mmol, 20.0 eq) in dioxane (22 mL) and H2O (11 mL) was added Cs2CO3(1.3 g, 3.9 mmol, 6.0 eq) and Pd(dppf)Cl2(71.2 mg, 97.3μmol, 0.15 eq) under N2. The mixture was heated to 100 °C and stirred for 3 h. The reaction mixture waspartitioned between ethyl acetate (10 mL) and H2O (5 mL). The organic phase was separated, washedwith brine (5 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure,and the residue was purified by column chromatography (SiO2, 5 to 25% EtOAc in petroleum ether) togive tert-butyl 3-(5-cyclopropyl-3-(2-(methoxymethoxy)phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-methylpyrrolidine-1-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ8.25 (s, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.50 - 7.41 (m, 1H), 7.28 (d, J = 8.4 Hz, 1H), 7.20 - 7.10 (m, 1H),6.17 - 6.06 (m, 2H), 5.26 (s, 2H), 4.06 - 3.98 (m, 1H), 3.83 (t, J = 8.0 Hz, 2H), 3.68 - 3.56 (m, 1H), 3.45 -3.38 (m, 2H), 3.37 (s, 3H), 2.56 (s, 1H), 2.30 - 2.23 (m, 1H), 1.96 - 1.88 (m, 1H), 1.45 (s, 3H), 1.42 (d, J= 3.2 Hz, 9H), 0.96 (d, J = 8.0 Hz, 2H), 0.90 (t, J = 8.0 Hz, 2H), 0.78 - 0.67 (m, 2H), -0.10 (s, 9H).Step 9:

[0403] A solution of tert-butyl 3-(5-cyclopropyl-3-(2-(methoxymethoxy)phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-methylpyrrolidine-1-carboxylate (70.0mg, 114.9 μmol, 1.0 eq) in TFA (1 mL), Et3SiH (0.05 mL), and H2O (0.05 mL) was stirred at 25 °C for 1h. The reaction mixture was concentrated under reduced pressure to afford 2-(5-cyclopropyl-6-(3-methylpyrrolidin-3-yl)-7H-pyrrolo[2,3-c]pyridazin-3-yl)phenol, which was used in the subsequent stepwithout purification. m / z (ESI+): 335.1 (M+H)+.Step 10:

[0404] To a solution of 2-(5-cyclopropyl-6-(3-methylpyrrolidin-3-yl)-7H-pyrrolo[2,3-c]pyridazin-3-yl)phenol (60.0 mg, 106.7 μmol, 1.0 eq, 2·TFA salt) in DCM (1 mL) and saturated NaHCO3 aqueoussolution (1 mL) was added prop-2-enoyl prop-2-enoate (13.5 mg, 106.7 μmol, 1.0 eq) dropwise at 25 °C.The mixture was stirred at at the same temperature for 30 minutes. The reaction mixture was partitionedbetween dichloromethane (5 mL) and H2O (5 mL). The organic phase was separated, washed with brine(5 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and theresidue was purified by prep-TLC (SiO2, 30% ethyl acetate in dichloromethane) to give 1-{3-[3- cyclopropyl-5-(o-hydroxyphenyl)-1H-1,6,7-triazainden-2-yl]-3-methyl-1-pyrrolidinyl}-2-propen-1-one.1H NMR (400 MHz, METHANOL-d4) δ 8.43 (s, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.33 - 7.25 (m, 1H), 7.02- 6.95 (m, 2H), 6.75 - 6.62 (m, 1H), 6.33 (dd, J = 1.6, 16.8 Hz, 1H), 5.80 (ddd, J = 1.6, 8.0, 10.4 Hz, 1H),4.32 - 4.05 (m, 2H), 3.87 (dd, J = 6.4, 10.0 Hz, 1H), 3.78 - 3.68 (m, 1H), 2.69 - 2.59 (m, 1H), 2.58 - 2.51(m, 1H), 1.99 - 1.90 (m, 1H), 1.56 (d, J = 4.0 Hz, 3H), 1.19 - 1.13 (m, 2H), 0.87 - 0.80 (m, 2H).Example 5: Synthesis of 1-{3-[5-(o-hydroxyphenyl)-3-methyl-1H-1,6,7-triazainden-2-yl]-3-methyl- 1-pyrrolidinyl}-2-propen-1-one (Compound 32):Step 1:

[0405] A mixture of tert-butyl 3-(5-bromo-3-(2-(methoxymethoxy)phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-methylpyrrolidine-1-carboxylate (200.0 mg, 308.8 μmol, 1.0 eq), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (77.5 mg, 617.6 μmol, 86.3μL, 2.0 eq), K3PO4 (131.1 mg, 617.6 μmol, 2.0 eq), and bis(4-(di-tert-butylphosphanyl)-N,N-dimethylaniline)-palladium chloride (32.8 mg, 46.3 μmol, 32.8 μL, 0.15 eq) in dioxane (4 mL) and H2O(2 mL) was degassed and purged with N2. The mixture was heated to 60 °C and stirred for 2 h under a N2atmosphere. The reaction mixture was partitioned between ethyl acetate (10 mL) and H2O (10 mL). Theorganic phase was separated, washed with brine (10 mL), dried over Na2SO4, and filtered. The filtratewas concentrated under reduced pressure, and the residue was purified by prep-HPLC to give tert-butyl3-(3-(2-(methoxymethoxy)phenyl)-5-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-methylpyrrolidine-1-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 8.21 (s, 1H),7.55 (dd, J = 1.6, 7.6 Hz, 1H), 7.47 - 7.40 (m, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.15 (t, J = 7.2 Hz, 1H), 6.10(s, 2H), 5.24 (s, 2H), 3.82 (t, J = 8.0 Hz, 2H), 3.54 (dd, J = 10.8, 16.4 Hz, 1H), 3.44 - 3.36 (m, 3H), 3.33(s, 3H), 2.47 - 2.40 (m, 1H), 2.36 (s, 3H), 2.20 - 2.13 (m, 1H), 1.41 (d, J = 6.8 Hz, 12H), 0.92 - 0.88 (m,2H), -0.11 (d, J = 2.4 Hz, 9H).Step 2:

[0406] A solution of tert-butyl 3-(3-(2-(methoxymethoxy)phenyl)-5-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-methylpyrrolidine-1-carboxylate (57.0mg, 97.8 μmol, 1.0 eq) in TFA (1 mL), Et3SiH (0.05 mL), and H2O (0.05 mL) was stirred at 25 °C for 1h. The reaction mixture was concentrated under reduced pressure to afford 2-(5-methyl-6-(3-methylpyrrolidin-3-yl)-7H-pyrrolo[2,3-c]pyridazin-3-yl)phenol, which was used in the subsequent stepwithout purification. m / z (ESI+): 309.1 (M+H)+.Step 3:

[0407] To a solution of 2-(5-methyl-6-(3-methylpyrrolidin-3-yl)-7H-pyrrolo[2,3-c]pyridazin-3-yl)phenol(50.0 mg, 93.2 μmol, 1.0 eq, 2·TFA salt) in DCM (1 mL) and saturated aqueous NaHCO3 solution (1mL) was added prop-2-enoyl prop-2-enoate (11.7 mg, 93.2 μmol, 1.0 eq) dropwise at 25 C. The mixturewas stirred at 25 °C for 30 minutes. The reaction mixture was partitioned between dichloromethane (5mL) and H2O (5 mL). The organic phase was separated, washed with brine (5 mL), dried over Na2SO4,and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by prep-TLC (SiO2, 30% ethyl acetate in dichloromethane) to give 1-{3-[5-(o-hydroxyphenyl)-3-methyl-1H- 1,6,7-triazainden-2-yl]-3-methyl-1-pyrrolidinyl}-2-propen-1-one. 1H NMR (400 MHz, METHANOL-d4)δ 8.44 (s, 1H), 7.99 (dd, J = 1.6, 8.4 Hz, 1H), 7.28 (dt, J = 1.6, 7.2 Hz, 1H), 7.01 - 6.95 (m, 2H), 6.74 -6.63 (m, 1H), 6.33 (dd, J = 1.6, 17.6 Hz, 1H), 5.80 (ddd, J = 2.0, 6.4, 10.4 Hz, 1H), 4.16 - 4.05 (m, 1H),3.93 - 3.84 (m, 2H), 3.78 - 3.67 (m, 1H), 2.62 - 2.49 (m, 2H), 2.45 (d, J = 1.6 Hz, 3H), 1.54 (d, J = 3.6Hz, 3H). Example 6: Synthesis of 1-{3-[5-(o-hydroxyphenyl)-3-methyl-1H-1,6,7-triazainden-2-yl]-3-methyl- 1-pyrrolidinyl}-2-propen-1-one (Compound 19):

[0408] 1-{3-[5-(o-hydroxyphenyl)-3-methyl-1H-1,6,7-triazainden-2-yl]-3-methyl-1-pyrrolidinyl}-2-propen-1-one was separated by SFC (Column: DAICEL CHIRALCEL OJ (250mm × 30mm × 10µm);mobile phase: [CO2-MeOH(0.1%NH3H2O)]; B%: 45%, isocratic elution mode) to give 1-{3-[5-(o-hydroxyphenyl)-3-methyl-1H-1,6,7-triazainden-2-yl]-3-methyl-1-pyrrolidinyl}-2-propen-1-one (2ndeluting isomer). 1H NMR (400 MHz, METHANOL-d4) δ 8.43 (s, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.32 -7.23 (m, 1H), 7.01 - 6.94 (m, 2H), 6.76 - 6.59 (m, 1H), 6.33 (td, J = 0.8, 16.8 Hz, 1H), 5.80 (ddd, J = 2.0,6.4, 10.4 Hz, 1H), 4.18 - 4.05 (m, 1H), 3.92 - 3.84 (m, 2H), 3.80 - 3.66 (m, 1H), 2.65 - 2.47 (m, 2H), 2.45(d, J = 2.0 Hz, 3H), 1.54 (d, J = 3.6 Hz, 3H).Example 7: Synthesis of 1-{3-[5-(o-hydroxyphenyl)-3-methyl-1H-1,6,7-triazainden-2-yl]-3-methyl- 1-pyrrolidinyl}-2-propen-1-one (Compound 20):Step 1:

[0409] 1-{3-[5-(o-hydroxyphenyl)-3-methyl-1H-1,6,7-triazainden-2-yl]-3-methyl-1-pyrrolidinyl}-2-propen-1-one was separated by SFC (Column: DAICEL CHIRALCEL OJ (250mm × 30mm × 10µm);mobile phase: [CO2-MeOH(0.1%NH3H2O)]; B%: 45%, isocratic elution mode) to give 1-{3-[5-(o-hydroxyphenyl)-3-methyl-1H-1,6,7-triazainden-2-yl]-3-methyl-1-pyrrolidinyl}-2-propen-1-one (1steluting isomer). 1H NMR (400 MHz, METHANOL-d4) δ 8.44 (s, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.33 -7.24 (m, 1H), 7.01 - 6.95 (m, 2H), 6.75 - 6.61 (m, 1H), 6.36 - 6.29 (m, 1H), 5.80 (ddd, J = 2.0, 6.4, 10.4Hz, 1H), 4.18 - 4.04 (m, 1.5H), 3.92 - 3.85 (m, 1.5H), 3.79 - 3.66 (m, 1H), 2.67 - 2.47 (m, 2H), 2.45 (d, J= 2.4 Hz, 3H), 1.54 (d, J = 4.0 Hz, 3H).Example 8: 1-(2-((3-(2-hydroxyphenyl)-5-methyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)methyl)azetidin-1-yl)prop-2-en-1-one (Compound 295) S

[0410] To a solution of tert-butyl 2-(hydroxymethyl)azetidine-1-carboxylate (241.89 mg, 1.29 mmol, 2eq) in MTBE (6 mL) was added 5,7-di-tert-butyl-3-phenylbenzo[d]oxazol-3-ium tetrafluoroborate(459.56 mg, 1.16 mmol, 1.8 eq) in one portion. The resulting mixture was stirred at 20 °C for 5 min.Subsequently, a solution of pyridine (91.97 mg, 1.16 mmol, 93.85 μL, 1.8 eq) in MTBE (1.5 mL) wasadded dropwise to the reaction mixture, which was then stirred at 20 °C for 15 min. The mixture wasfiltered, and the filtrate was added to a solution of intermediate 1 (300 mg, 645.96 μmol, 1 eq),quinuclidine (143.65 mg, 1.29 mmol, 2 eq), NiBr2(dtbbpy) (31.45 mg, 64.60 μmol, 0.1 eq), andIr(ppy)2(dtbbpy)PF6(29.52 mg, 32.30 μmol, 0.05 eq) in DMA (6 mL). The resulting mixture was purged3 times with N2 and stirred at 20 °C for 12 h under 34W blue LED (455 nm). An additional five reactionswere set up as described above; all six reactions were combined for workup and purification. Thecombined reaction mixtures were partitioned between ethyl acetate (20 mL) and H2O (20 mL). Theorganic phase was separated, washed with brine (20 mL), dried over Na2SO4, and filtered. The filtratewas concentrated under reduced pressure, and the residue was purified by column chromatography (SiO2,Petroleum ether: Ethyl acetate = 2: 1) to give tert-butyl 2-((3-(2-(methoxymethoxy)phenyl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-c]pyridazin-6-yl)methyl)azetidine-1-carboxylate (2 g, 3.14 mmol, 80.93% yield) as a white solid.1H NMR (400 MHz, METHANOL-d4) δ 8.06 (s, 1H), 7.63 -7.59 (m, 1H), 7.45 - 7.39 (m, 1H), 7.31 (d, J = 7.6 Hz, 1H), 7.19 - 7.14 (m, 1H), 6.53 (s, 1H), 5.93 (s,2H), 5.19 (s, 2H), 4.76 - 4.67 (m, 1H), 3.93 - 3.80 (m, 2H), 3.68 - 3.59 (m, 3H), 3.40 - 3.35 (m, 1H), 3.33(s, 3H), 2.48 - 2.36 (m, 1H), 2.14 - 2.04 (m, 1H), 1.45 - 1.41 (m, 9H), 0.94 - 0.89 (m, 2H), -0.07 (s, 9H).Step 2:

[0411] To a solution of tert-butyl 2-((3-(2-(methoxymethoxy)phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-c]pyridazin-6-yl)methyl)azetidine-1-carboxylate (700 mg,1.26 mmol, 1 eq) in DMF (10 mL) was added NBS (235.81 mg, 1.32 mmol, 1.05 eq) at 20 °C. Theresulting mixture was stirred at the same temperature for 2 h. An additional reaction was set up asdescribed above; both reactions were combined for workup and purification. The combined reactionmixtures were diluted with water (20 mL) and extracted with ethyl acetate (10 mL × 2). The combinedorganic layers were washed with brine (10 mL × 2), dried over Na2SO4, and filtered. The filtrate wasconcentrated under reduced pressure to give tert-butyl 2-((5-bromo-3-(2-(methoxymethoxy)phenyl)-7- ((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-c]pyridazin-6-yl)methyl)azetidine-1-carboxylate (1.8 g, 93.80% yield) as a yellow oil, which was used in the subsequent step without purification.1H NMR(400 MHz, METHANOL-d4) δ = 8.01 (s, 1H), 7.68 - 7.64 (m, 1H), 7.48 - 7.41 (m, 1H), 7.32 (d, J = 8.4Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 6.03 - 5.93 (m, 2H), 5.22 (s, 2H), 4.79 - 4.71 (m, 1H), 3.93 - 3.84 (m,2H), 3.70 - 3.66 (m, 2H), 3.65 - 3.60 (m, 1H), 3.47 - 3.41 (m, 1H), 3.37 (s, 3H), 2.47 - 2.36 (m, 1H), 2.24- 2.12 (m, 1H), 1.31 - 1.22 (m, 9H), 0.96 - 0.91 (m, 2H), -0.06 (s, 9H).Step 3:

[0412] A mixture of tert-butyl 2-((5-bromo-3-(2-(methoxymethoxy)phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-c]pyridazin-6-yl)methyl)azetidine-1-carboxylate (250 mg, 394.54 μmol, 1 eq), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (148.59 mg, 1.18 mmol, 165.46 μL, 3eq), tripotassium phosphate (251.24 mg, 1.18 mmol, 3 eq), and bis(4-(di-tert-butylphosphanyl)-N,N-dimethylaniline)-palladium chloride (41.90 mg, 59.18 μmol, 41.90 μL, 0.15 eq) in dioxane (5 mL) andwater (2.5 mL) was degassed and purged 3-times with N2. The mixture was then heated to 80 C andstirred for 12 h under N2 atmosphere. An additional reaction was set up as described above; bothreactions were combined for workup and purification. The combined reaction mixtures were diluted withwater (10 mL) and extracted with ethyl acetate (10 mL × 2). The combined organic layers were washedwith brine (10 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reducedpressure, and the residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate =10: 1 to 1: 1) to give tert-butyl 2-((3-(2-(methoxymethoxy)phenyl)-5-methyl-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-c]pyridazin-6-yl)methyl)azetidine-1-carboxylate (460 mg)as a yellow oil. 1H NMR (400 MHz, METHANOL-d4) δ 8.02 (s, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.46 -7.38 (m, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 5.96 - 5.80 (m, 2H), 5.22 - 5.16 (m, 2H),4.72 - 4.61 (m, 1H), 4.32 - 4.23 (m, 0.5H), 4.15 - 4.05 (m, 0.5H), 3.85 (t, J = 7.6 Hz, 2H), 3.66 - 3.58 (m,3H), 3.35 - 3.33 (m, 3H), 2.36 (s, 3H), 2.26 - 2.13 (m, 1H), 2.10 - 2.03 (m, 1H), 1.33 - 1.24 (m, 9H), 0.94- 0.88 (m, 2H), -0.07 (s, 9H).Step 4:

[0413] A mixture of tert-butyl 2-((3-(2-(methoxymethoxy)phenyl)-5-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-c]pyridazin-6-yl)methyl)azetidine-1-carboxylate (130 mg,228.56 μmol, 1 eq) in TFA (3.07 g, 26.92 mmol, 2 mL, 117.80 eq), Et3SiH (0.1 mL), and water (0.1 mL)was stirred at 20 °C for 2 h under N2 atmosphere. The reaction mixture was concentrated under reducedpressure to give 2-(6-(azetidin-2-ylmethyl)-5-methyl-7H-pyrrolo[2,3-c]pyridazin-3-yl)phenol (65 mg,220.83 μmol, 96.62% yield) as a yellow oil, which was used in the subsequent step without purification.LCMS (ESI+): m / z 295.1 (M+H)+.Step 5:

[0414] To a solution of 2-(6-(azetidin-2-ylmethyl)-5-methyl-7H-pyrrolo[2,3-c]pyridazin-3-yl)phenol (65mg, 220.83 μmol, 1 eq) in NaHCO3 aq. (1N, 1 mL) and DCM (1 mL) was added acrylic anhydride (27.85mg, 220.83 μmol, 1 eq) in DCM (0.3 mL) dropwise at 20 °C. The resulting mixture was stirred at thesame temperature for 1 h. The reaction mixture was diluted with water (5 mL) and extracted with DCM(5 mL × 2). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, andfiltered. The filtrate was concentrated under reduced pressure, and the residue was purified by prep-TLC(SiO2, DCM: THF = 2: 1) to give 1-(2-((3-(2-hydroxyphenyl)-5-methyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)methyl)azetidin-1-yl)prop-2-en-1-one (45 mg, 23.40% yield) as a white solid. H NMR (400 MHz,METHANOL-d4) δ 8.43 - 8.38 (m, 1H), 8.01 - 7.97 (m, 1H), 7.31 - 7.25 (m, 1H), 7.01 - 6.94 (m, 2H),6.38 - 6.22 (m, 1.4H), 6.16 - 6.08 (m, 0.3H), 6.02 - 5.93 (m, 0.3H), 5.79 - 5.73 (m, 0.7H), 5.39 (d, J = 9.6Hz, 0.3H), 4.95 - 4.90 (m, 0.3H), 4.83 - 4.77 (m, 0.7H), 4.18 (t, J = 8.0 Hz, 1.4H), 4.07 - 3.98 (m, 0.6H),3.59 - 3.42 (m, 1H), 3.42 - 3.34 (m, 1H), 2.64 - 2.41 (m, 1H), 2.37 - 2.34 (m, 3H), 2.22 - 2.01 (m, 1H);LCMS (ESI+): m / z 349.1 (M+H)+.Example 9: Synthesis of (S)-1-(2-((5-cyclopropyl-3-(2-hydroxyphenyl)-7H-pyrrolo[2,3-c]pyridazin-6-yl)methyl)azetidin-1-yl)prop-2-en-1-one and (R)-1-(2-((5-cyclopropyl-3-(2-hydroxyphenyl)-7H- pyrrolo[2,3-c]pyridazin-6-yl)methyl)azetidin-1-yl)prop-2-en-1-one (Compounds 296 and 297)

[0415] A mixture of tert-butyl 2-((5-bromo-3-(2-(methoxymethoxy)phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-c]pyridazin-6-yl)methyl)azetidine-1-carboxylate (250 mg,394.54 μmol, 1 eq), cyclopropylboronic acid (677.80 mg, 7.89 mmol, 20 eq), Pd(dppf)Cl2(32.22 mg, 39.45 μmol, 0.1 eq) and Cs2CO3 (1.29 g, 3.95 mmol, 10 eq) in dioxane (5 mL) and water (2.5 mL) wasdegassed and purged 3 times with N2. The mixture was then heated to 80°C and stirred for 12 h under N2atmosphere. An additional reaction was set up as described above; both reactions were combined forworkup and purification. The combined reaction mixtures were diluted with water (10 mL) and extractedwith ethyl acetate (10 mL × 2). The combined organic layers were washed with brine (5 mL), dried overNa2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purifiedby column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 2 / 1) to give tert-butyl 2-((5- cyclopropyl-3-(2-(methoxymethoxy)phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- c]pyridazin-6-yl)methyl)azetidine-1-carboxylate (390 mg, 83.09% yield) as a yellow oil.1H NMR (400MHz, METHANOL-d4) δ 8.08 (s, 1H), 7.65 - 7.62 (m, 1H), 7.45 - 7.40 (m, 1H), 7.32 - 7.28 (m, 1H),7.19 - 7.14 (m, 1H), 5.94 - 5.89 (m, 2H), 5.21 - 5.19 (m, 2H), 4.77 - 4.72 (m, 1H), 3.87 (t, J = 7.6 Hz,2H), 3.65 - 3.61 (m, 3H), 3.38 - 3.35 (m, 3H), 2.47 - 2.38 (m, 1H), 2.24 - 2.10 (m, 2H), 1.99 - 1.89 (m,1H), 1.33 - 1.25 (m, 9H), 1.08 - 1.02 (m, 2H), 0.92 - 0.87 (m, 2H), 0.85 - 0.76 (m, 2H), -0.07 (s, 9H).Step 2:

[0416] A mixture of tert-butyl 2-((5-cyclopropyl-3-(2-(methoxymethoxy)phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-c]pyridazin-6-yl)methyl)azetidine-1-carboxylate (200 mg,336.24 μmol, 1 eq), TFA (6.14 g, 53.85 mmol, 4 mL, 160.15 eq), Et3SiH (0.2 mL), and water (0.2 mL)was stirred at 20 °C for 2 h under N2 atmosphere. The reaction mixture was concentrated under reducedpressure to give 2-(6-(azetidin-2-ylmethyl)-5-cyclopropyl-7H-pyrrolo[2,3-c]pyridazin-3-yl)phenol (100 mg, 92.83% yield) as a yellow oil, which was used in the subsequent step without purification. LCMS (ESI+): m / z 321.1 (M+H). Step 3:

[0417] To a solution of 2-(6-(azetidin-2-ylmethyl)-5-cyclopropyl-7H-pyrrolo[2,3-c]pyridazin-3-yl)phenol (50 mg, 156.06 μmol, 1 eq) in NaHCO3 aq. (1N, 1 mL) and DCM (1 mL) was added acrylicanhydride (19.68 mg, 156.06 μmol, 1 eq) in DCM (0.1 mL) dropwise at 20 °C. The resulting mixture wasstirred at the same temperature for 1 h. An additional reaction was set up as described above; bothreactions were combined for workup and purification. The combined reaction mixtures were diluted withwater (5 mL) and extracted with DCM (5 mL × 2). The combined organic layers were washed with brine(5 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and theresidue was purified by prep-TLC (SiO2, petroleum ether / ethyl acetate = 0 / 1) to give 1-(2-((5- cyclopropyl-3-(2-hydroxyphenyl)-7H-pyrrolo[2,3-c]pyridazin-6-yl)methyl)azetidin-1-yl)prop-2-en-1-one(21 mg, 17.97% yield) as a white solid. 1H NMR (400 MHz, METHANOL-d4) δ 8.39 - 8.33 (m, 1H),7.94 (d, J = 8.4 Hz, 1H), 7.32 - 7.25 (m, 1H), 7.02 - 6.95 (m, 2H), 6.34 - 6.28 (m, 1H), 6.18 - 5.98 (m,1H), 5.78 - 5.73 (m, 0.5H), 5.52 - 5.39 (m, 0.5H), 5.03 - 4.94 (m, 0.5H), 4.77 (s, 0.5H), 4.60 (s, 0.5H),4.26 - 4.18 (m, 1H), 4.06 - 4.00 (m, 0.5H), 3.72 - 3.63 (m, 0.5H), 3.61 - 3.53 (m, 0.5H), 3.49 - 3.40 (m,1H), 2.66 - 2.45 (m, 1H), 2.24 - 2.12 (m, 1H), 1.92 - 1.83 (m, 1H), 1.10 - 1.03 (m, 2H), 0.83 - 0.75 (m,2H); LCMS (ESI+): m / z 375.1 (M+H)+.Step 4:

[0418] 1-(2-((5-cyclopropyl-3-(2-hydroxyphenyl)-7H-pyrrolo[2,3-c]pyridazin-6-yl)methyl)azetidin-1-yl)prop-2-en-1-one (38 mg) was separated by SFC (column: DAICEL CHIRALCEL OJ(250mm*30mm,10um); mobile phase: [CO2-EtOH];B%:40%, isocratic elution mode) to give (S)-1-(2-((5-cyclopropyl-3-(2-hydroxyphenyl)-7H-pyrrolo[2,3-c]pyridazin-6-yl)methyl)azetidin-1-yl)prop-2-en-1-one and (R)-1-(2- ((5-cyclopropyl-3-(2-hydroxyphenyl)-7H-pyrrolo[2,3-c]pyridazin-6-yl)methyl)azetidin-1-yl)prop-2-en-1- one.

[0419] Compound 296 (1st eluting isomer, 9 mg, 23.68% yield) was obtained as a white solid. 1H NMR(400 MHz, METHANOL-d4) δ 8.40 - 8.34 (m, 1H), 7.98 - 7.91 (m, 1H), 7.28 (t, J = 7.2 Hz, 1H), 7.02 -6.95 (m, 2H), 6.38 - 6.22 (m, 1.4H), 6.18 - 5.97 (m, 0.6H), 5.79 - 5.72 (m, 0.6H), 5.41 (d, J = 8.8 Hz,0.4H), 4.29 - 4.16 (m, 1.3H), 4.09 - 3.98 (m, 0.7H), 3.72 - 3.64 (m, 0.6H), 3.61 - 3.54 (m, 0.4H), 3.50 -3.40 (m, 1.4H), 3.35 (s, 0.6H), 2.67 - 2.45 (m, 1H), 2.26 - 2.09 (m, 1H), 1.96 - 1.81 (m, 1H), 1.11 - 1.02(m, 2H), 0.84 - 0.75 (m, 2H); LCMS (ESI+): m / z 375.1 (M+H)+.

[0420] Compound 297 (2nd eluting isomer, 6 mg, 15.79% yield) was obtained as a white solid. 1H NMR(400 MHz, METHANOL-d4) δ 8.39 - 8.35 (m, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.29 (t, J = 7.6 Hz, 1H),7.02 - 6.95 (m, 2H), 6.39 - 6.23 (m, 1.3H), 6.16 - 5.98 (m, 0.7H), 5.79 - 5.73 (m, 0.6H), 5.44 - 5.38 (m,0.4H), 4.26 - 4.18 (m, 1.3H), 4.10 - 3.98 (m, 1H), 3.73 - 3.64 (m, 0.7H), 3.63 - 3.52 (m, 0.5H), 3.50 -3.45 (m, 1H), 3.43 (d, J = 7.6 Hz, 0.5H), 2.67 - 2.45 (m, 1H), 2.25 - 2.10 (m, 1H), 1.95 - 1.83 (m, 1H),1.10 - 1.04 (m, 2H), 0.84 - 0.72 (m, 2H); LCMS (ESI+): m / z 375.1 (M+H)+.Example 10: 1-((1R,5S,7r)-7-(3-(2-hydroxyphenyl)-5-methyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)prop-2-en-1-one (Compound 312)Step 1:

[0421] To a solution of tert-butyl (1R,5S)-7-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate(1.89 g, 7.75 mmol, 2 eq) in MTBE (12 mL) was added NHC-1 (2.76 g, 6.98 mmol, 1.8 eq) in one portion at 20 °C. After addition, the mixture was stirred at the same temperature for 5 min. Subsequently,a solution of pyridine (551.83 mg, 6.98 mmol, 1.8 eq) in MTBE (2 mL) was added dropwise at 20 °C.The resulting mixture was stirred at the same temperature for 15 min, then filtered to remove the formedprecipitate. A solution of intermediate 1 (1.8 g, 3.88 mmol, 1 eq), quinuclidine (861.85 mg, 7.75 mmol, 2 eq), NiBr2(dtbbpy) (188.71 mg, 387.57 μmol, 0.1 eq) and (Ir(ppy)2(dtbbpy)PF6 (177.11 mg, 193.79 μmol, 0.05 eq) in DMA (12 mL) was prepared, then mixed with the filtrate obtained. The resultingmixture was stirred at 20 °C for 4 h under 34W blue LED (455 nm). The reaction mixture was dilutedwith water (20 mL) and extracted with MTBE (20 mL × 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reducedpressure, and the residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate =10: 1 to 2: 1) to give tert-butyl (1R,5S,7r)-7-(3-(2-(methoxymethoxy)phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-oxa-9-azabicyclo[3.3.1]nonane-9- carboxylate (1.9 g, 3.11 mmol, 80.26% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.13 (s,1H), 7.85 - 7.74 (m, 1H), 7.57 - 7.47 (m, 1H), 7.41 - 7.33 (m, 1H), 7.28 - 7.21 (m, 1H), 6.61 (s, 1H), 5.97(s, 2H), 5.37 - 5.25 (m, 2H), 4.62 - 4.48 (m, 1H), 4.14 - 4.04 (m, 4H), 3.80 (br d, J = 11.6 Hz, 2H), 3.73 -3.64 (m, 2H), 3.42 (s, 3H), 2.38 - 2.23 (m, 2H), 2.04 - 1.93 (m, 2H), 1.50 (s, 9H), 0.97 - 0.89 (m, 2H),0.00 (s, 9H). Step 2:

[0422] To a solution of tert-butyl (1R,5S,7r)-7-(3-(2-(methoxymethoxy)phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-oxa-9-azabicyclo[3.3.1]nonane-9- carboxylate (200 mg, 327.43 μmol, 1 eq) in DMF (2 mL) was added NBS (64.11 mg, 360.17 μmol, 1.1eq) in one portion at 20 °C. The resulting mixture was stirred at 20 °C for 2 h. The reaction mixture wasthen quenched with ice water (10 mL), and the resulting precipitate was collected by vacuum filtration.The solid was washed with water and dried under high vacuum at 30 °C. Tert-butyl (1R,5S,7r)-7-(5- bromo-3-(2-(methoxymethoxy)phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-c]pyridazin- 6-yl)-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (170 mg, 246.48 μmol, 75.28% yield) was obtained as a white solid, which was used in the next step without purification. 1H NMR (400 MHz, DMSO-d6) δ8.05 (s, 1H), 7.85 - 7.74 (m, 1H), 7.57 - 7.47 (m, 1H), 7.40 - 7.31 (m, 1H), 7.28 - 7.18 (m, 1H), 6.02 (s,2H), 5.31 (s, 2H), 4.81 - 4.67 (m, 1H), 4.14 - 4.04 (m, 4H), 3.79 (d, J = 11.6 Hz, 2H), 3.73 - 3.61 (m,2H), 3.38 (s, 3H), 2.10 - 2.01 (m, 2H), 2.04 - 1.93 (m, 2H), 1.55 (s, 9H), 0.97 - 0.81 (m, 2H), 0.00 (s,9H). Step 3:

[0423] A mixture of tert-butyl (1R,5S,7r)-7-(5-bromo-3-(2-(methoxymethoxy)phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (150 mg, 217.48 μmol, 1 eq), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (273.02 mg, 2.17mmol, 304.03 μL, 10 eq), Pd(dppf)Cl2 (15.91 mg, 21.75 μmol, 0.1 eq), and K2CO3 (90.17 mg, 652.45μmol, 3 eq) in dioxane (2 mL) and water (0.2 mL) was degassed and purged 3-times with N2. Themixture was then heated to 80 °C and stirred for 12 h under N2. The reaction mixture was diluted withwater (5 mL) and extracted with EtOAc (5 mL × 2). The combined organic layers were washed withbrine (5 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, andthe residue was purified by prep-TLC (SiO2, petroleum ether: ethyl acetate = 2: 1) to give tert-butyl(1R,5S,7r)-7-(3-(2-(methoxymethoxy)phenyl)-5-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-c]pyridazin-6-yl)-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (120 mg, 192.05 μmol,88.31% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.09 (s, 1H), 7.81 - 7.71 (m, 1H), 7.55 -7.43 (m, 1H), 7.39 - 7.31 (m, 1H), 7.23 (t, J = 7.6 Hz, 1H), 5.99 - 5.89 (m, 2H), 5.28 (s, 2H), 4.81 - 4.67(m, 1H), 4.12 - 3.99 (m, 4H), 3.79 (d, J = 11.6 Hz, 2H), 3.73 - 3.61 (m, 2H), 3.38 (s, 3H), 2.38 (s, 3H),2.33 - 2.24 (m, 2H), 2.13 - 1.92 (m, 2H), 1.55 (s, 9H), 1.01 - 0.89 (m, 2H), 0.00 (s, 9H).Step 4:

[0424] A solution of tert-butyl (1R,5S,7r)-7-(3-(2-(methoxymethoxy)phenyl)-5-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (50 mg, 80.02 μmol, 1 eq) in TFA (1 mL), Et3SiH (0.2 mL), and water (0.2 mL) was stirredat 20 °C for 2 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure togive 2-(6-((1R,5S,7r)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-5-methyl-7H-pyrrolo[2,3-c]pyridazin-3- yl)phenol (40 mg, 114.15 μmol, 71.33% yield) as a yellow oil, which was used in the next step withoutpurification. LCMS (ESI+): m / z 351.1 (M+H)+.Step 5:

[0425] To a solution of 2-(6-((1R,5S,7r)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-5-methyl-7H-pyrrolo[2,3-c]pyridazin-3-yl)phenol (40 mg, 114.15 μmol, 1 eq) in DCM (0.5 mL) and NaHCO3 aq. (1N,0.5 mL) was added acrylic anhydride (21.59 mg, 171.23 μmol, 1.5 eq) at 20 °C. The resulting mixturewas stirred at at the same temperature for 0.5 h. The reaction mixture was diluted with water (1 mL) andextracted with DCM (1 mL × 2). The combined organic layers were washed with brine (1 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue waspurified by prep-HPLC to give 1-((1R,5S,7r)-7-(3-(2-hydroxyphenyl)-5-methyl-7H-pyrrolo[2,3- c]pyridazin-6-yl)-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)prop-2-en-1-one (7.3 mg, 18.05 μmol, 15.81%yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 14.38 (br s, 1H), 12.30 (s, 1H), 8.57 (s, 1H), 8.11 (dd, J = 1.2, 8.4 Hz, 1H), 7.30 - 7.25 (m, 1H), 6.97 - 6.92 (m, 2H), 6.89 - 6.81 (m, 1H), 6.25 (dd, J =2.4, 16.8 Hz, 1H), 5.77 (dd, J = 2.4, 10.4 Hz, 1H), 4.57 (s, 1H), 4.53 - 4.41 (m, 1H), 4.301 (s, 1H), 4.05(dd, J = 5.6, 11.2 Hz, 2H), 3.76 - 3.65 (m, 2H), 2.32 (s, 3H), 2.24 - 1.99 (m, 4H); LCMS (ESI+): m / z405.1 (M+H)+. Example 11: 1-(2-((3-(2-hydroxyphenyl)-5-isopropyl-7H-pyrrolo[2,3-c]pyridazin-6- yl)methyl)azetidin-1-yl)prop-2-en-1-one (Compound 319)Step 1:

[0426] A mixture of tert-butyl 2-((5-bromo-3-(2-(methoxymethoxy)phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-c]pyridazin-6-yl)methyl)azetidine-1-carboxylate (250 mg, 394.54 μmol, 1 eq), 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (99.45 mg, 591.81 μmol, 1.5 eq), Pd(dppf)Cl2 (28.87 mg, 39.45 μmol, 0.1 eq), and Cs2CO3 (771.29 mg, 2.37 mmol, 6 eq) in dioxane (5mL) and water (2.5 mL) was degassed and purged 3 times with N2. The mixture was then heated to 80 °Cand stirred for 12 h under N2 atmosphere. An additional reaction was set up as described above; both reactions were combined for workup and purification. The combined reaction mixtures were diluted withwater (10 mL) and extracted with ethyl acetate (10 mL × 2). The combined organic layers were washed with brine (10 mL × 2), dried over Na2SO4, and filtered. The filtrate was concentrated under reducedpressure, and the residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate =10 / 1 to 2 / 1) to give tert-butyl 2-((3-(2-(methoxymethoxy)phenyl)-5-(prop-1-en-2-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-c]pyridazin-6-yl)methyl)azetidine-1-carboxylate (350 mg,588.42 μmol, 74.57% yield) as a yellow oil. H NMR (400 MHz, METHANOL-d4) δ 8.06 (s, 1H), 7.66 -7.63 (m, 1H), 7.45 - 7.39 (m, 1H), 7.29 (d, J = 7.6 Hz, 1H), 7.19 - 7.14 (m, 1H), 6.02 - 5.95 (m, 2H), 5.45- 5.42 (m, 1H), 5.20 - 5.17 (m, 3H), 4.74 - 4.65 (m, 1H), 3.87 - 3.80 (m, 3H), 3.68 - 3.65 (m, 2H), 3.50 -3.41 (m, 1H), 3.34 (s, 3H), 2.43 - 2.33 (m, 1H), 2.09 - 1.97 (m, 1H), 1.44 (s, 3H), 1.30 - 1.23 (m, 9H),0.95 - 0.89 (m, 2H), -0.07 (s, 9H).Step 2:

[0427] To a solution of tert-butyl 2-((3-(2-(methoxymethoxy)phenyl)-5-(prop-1-en-2-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-c]pyridazin-6-yl)methyl)azetidine-1-carboxylate (350.00 mg, 588.42 μmol, 1 eq) in THF (4 mL) was added Pd / C (125.24 mg, 117.68 μmol, 10% purity, 0.2 eq) under N2atmosphere. The suspension was degassed and purged 3-times with H2. The mixture was stirredunder H2 (15 Psi) at 20 °C for 2 h. The mixture was filtered through a Celite pad, and the filtrate wasconcentrated under reduced pressure to give tert-butyl 2-((5-isopropyl-3-(2-(methoxymethoxy)phenyl)-7- ((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-c]pyridazin-6-yl)methyl)azetidine-1-carboxylate (320mg, 91.12% yield) as a yellow oil. 1H NMR (400 MHz, METHANOL-d4) δ 8.21 (s, 1H), 7.68 - 7.63 (m,1H), 7.46 - 7.40 (m, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 5.98 - 5.86 (m, 2H), 5.20 (s,2H), 4.66 - 4.59 (m, 1H), 3.88 - 3.78 (m, 3H), 3.67 - 3.61 (m, 2H), 3.57 - 3.50 (m, 1H), 3.41 (d, J = 6.4Hz, 1H), 3.36 (s, 3H), 2.44 - 2.35 (m, 1H), 2.11 - 2.02 (m, 1H), 1.45 (d, J = 1.6 Hz, 3H), 1.44 (s, 3H),1.29 (s, 9H), 0.90 - 0.86 (m, 2H), -0.09 (s, 9H).Step 3:

[0428] A solution of tert-butyl 2-((5-isopropyl-3-(2-(methoxymethoxy)phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-c]pyridazin-6-yl)methyl)azetidine-1-carboxylate (205 mg,343.48 μmol, 1 eq) in TFA (3.07 g, 26.92 mmol, 2 mL, 78.39 eq), Et3SiH (1 mL), and water (1 mL) wasstirred at 20 °C for 1 h under N2 atmosphere. The reaction mixture was concentrated under reducedpressure to give 2-(6-(azetidin-2-ylmethyl)-5-isopropyl-7H-pyrrolo[2,3-c]pyridazin-3-yl)phenol (110 mg,99.33% yield) as a yellow oil, which was used in the subsequent step without purification. LCMS (ESI+):m / z 323.1 (M+H)+.Step 4:

[0429] To a solution of 2-(6-(azetidin-2-ylmethyl)-5-isopropyl-7H-pyrrolo[2,3-c]pyridazin-3-yl)phenol(60 mg, 186.10 μmol, 1 eq) in NaHCO3aq. (1N, 1mL) and DCM (1 mL) was added a solution of acrylicanhydride (23.47 mg, 186.10 μmol, 1 eq) in DCM (0.5 mL) dropwise at 20 °C. The resulting mixture wasstirred at the same temperature for 1 h. The reaction mixture was diluted with water (5 mL) and extractedwith DCM (5 mL × 2). The combined organic layers were washed with brine (5 mL), dried over Na2SO4,and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by prep-TLC (SiO2, DCM: THF = 2: 1) to give 1-(2-((3-(2-hydroxyphenyl)-5-isopropyl-7H-pyrrolo[2,3- c]pyridazin-6-yl)methyl)azetidin-1-yl)prop-2-en-1-one (47 mg, 67.09% yield) as a white solid.1H NMR(400 MHz, DMSO-d6) δ 14.15 - 14.02 (m, 1H), 12.37 (s, 1H), 8.58 - 8.53 (m, 1H), 8.17 (d, J = 8.4 Hz,1H), 7.28 (t, J = 7.6 Hz, 1H), 6.99 - 6.92 (m, 2H), 6.34 - 6.24 (m, 0.5H), 6.18 - 6.01 (m, 1.5H), 5.72 -5.66 (m, 0.6H), 5.47 - 5.39 (m, 0.4H), 4.83 (s, 0.4H), 4.72 - 4.61 (m, 0.6H), 4.15 - 4.05 (m, 1.3H), 3.95 -3.81 (m, 1H), 3.56 - 3.49 (m, 0.7H), 3.28 - 3.17 (m, 2H), 2.25 (s, 1.4H), 2.15 - 2.03 (m, 1H), 2.01 - 1.91(m, 0.6H), 1.44 - 1.37 (m, 6H); LCMS (ESI+): m / z 377.1 (M+H)+.Example 12: 1-((1R,5S,7s)-7-(3-(2-hydroxyphenyl)-5-methyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3- oxa-9-azabicyclo[3.3.1]nonan-9-yl)prop-2-en-1-one (Compound 439)Step 1:

[0430] To a solution of tert-butyl (1R,5S)-7-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (5 g,20.72 mmol, 1 eq) in THF (100 mL) was added dropwise LiHMDS (1M, 31.08 mL, 1.5 eq) at -78 °C.The reaction was then stirred at the same temperature for 30 min before a solution of 1,1,1-trifluoro-N-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonamide (11.10 g, 31.08 mmol, 1.5 eq) in THF (100mL) was added dropwise. The solution was allowed to warm to 0 °C and stirred at the same temperaturefor 2 h. The reaction mixture was quenched by addition of aqueous NH4Cl (100 mL), then diluted withH2O (100 mL) and extracted with MTBE (100 mL ×2). The combined organic layers were washed withbrine (100 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure,and the residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=5 / 1 to 1 / 1)to give tert-butyl (1S,5R)-7-(((trifluoromethyl)sulfonyl)oxy)-3-oxa-9-azabicyclo[3.3.1]non-6-ene-9-carboxylate (3.1 g, 8.30 mmol, 40.07% yield) as an off-white oil. 1H NMR (400 MHz, CHLOROFORM-d) δ 5.90 (t, J = 6.4 Hz, 1H), 4.69 - 4.54 (m, 1H), 4.35 - 4.21 (m, 1H), 3.88 - 3.82 (m, 1H), 3.74 - 3.61 (m,3H), 2.95 - 2.84 (m, 1H), 2.39-2.32 (m, 1H), 1.48 (s, 9H).Step 2:

[0431] A mixture of tert-butyl (1S,5R)-7-(((trifluoromethyl)sulfonyl)oxy)-3-oxa-9-azabicyclo[3.3.1]non-6-ene-9-carboxylate (3 g, 8.04 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (2.45 g, 9.64 mmol, 1.2 eq), KOAc (2.37 g, 24.11 mmol, 3 eq),and Pd(dppf)Cl2 (587.96 mg, 803.55 μmol, 0.1 eq) in dioxane (30 mL) was degassed and purged 3 timeswith N2. The resulting mixture was heated to 80 °C and stirred for 2 h under N2 atmosphere. The reactionmixture was diluted with H2O (50 mL) and extracted with EtOAc (50 mL ×2). The combined organiclayers were washed with brine (50 mL), dried over Na2SO4, and filtered. The filtrate was concentratedunder reduced pressure, and the residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=5 / 1 to 1 / 1) to give tert-butyl (1S,5R)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-oxa-9-azabicyclo[3.3.1]non-6-ene-9-carboxylate (2.3 g, 6.55 mmol, 81.49% yield) as a white solid. 1HNMR (400 MHz, CHLOROFORM-d) δ 6.61 - 6.53 (m, 1H), 4.52 - 4.39 (m, 1H), 4.21 - 4.06 (m, 1H),3.82 - 3.73 (m, 2H), 3.63-3.59 (m, 2H), 2.68 - 2.62 (m, 1H), 2.27-2.21 (m, 1H), 1.46 (s, 9H), 1.27 (d, J =2.0 Hz, 12H). Step 3:

[0432] To a solution of 3-(2-(methoxymethoxy)phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-c]pyridazine (80 g, 207.51 mmol, 1 eq) in DMF (800 mL) was added NBS (35.09 g, 197.13 mmol, 0.95 eq) in portions at 20°C. The mixture was stirred at 20°C for 2 h. The reaction mixture wasdiluted with water (800 mL) and extracted with ethyl acetate (500 mL × 2). The combined organic layerswere washed with brine (1 L), dried over Na2SO4, filtered and the filtrate was concentrated under reducedpressure. The residue was purified by column chromatography (SiO2, PE / EA = 10 / 1 to 3 / 1) to give 5-bromo-3-(2-(methoxymethoxy)phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-c]pyridazine(78 g, 167.95 mmol, 80.94% yield) as a brown oil. 1H NMR (400 MHz, METHANOL-d4) δ 8.08 (d, J =4.8 Hz, 2H), 7.68 (dd, J = 1.6, 7.6 Hz, 1H), 7.52 - 7.42 (m, 1H), 7.36 - 7.28 (m, 1H), 7.18 (t, J = 7.2 Hz,1H), 5.86 (s, 2H), 5.23 (s, 2H), 3.66 (t, J = 8.0 Hz, 2H), 3.37 (s, 3H), 0.98 - 0.85 (m, 2H), -0.07 (s, 9H)Step 4:A solution of 5-bromo-3-(2-(methoxymethoxy)phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-c]pyridazine (60 g, 129.19 mmol, 1 eq), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (64.87g, 258.38 mmol, 72.24 mL, 2 eq), Pd(AmPhos)2Cl2 (13.72 g, 19.38 mmol, 13.72 mL, 0.15 eq) and K3PO4 (54.85 g, 258.38 mmol, 2 eq) in dioxane (300 mL) and water (150 mL) was degassed and then heated to 80°C for 1 h under N2. The reaction mixture was diluted with H2O (500 mL) and extracted with EtOAc (500 mL × 2). The combined organic layers were washed with brine (500 mL), dried over Na2SO4,filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / EA = 10 / 1 to 0 / 1) to give 3-(2-(methoxymethoxy)phenyl)-5-methyl-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-c]pyridazine (50 g, 110.12 mmol, 85.24% yield) as ayellow oil. 1H NMR (400 MHz, METHANOL-d4) δ = 8.11 (s, 1H), 7.69 - 7.58 (m, 2H), 7.49 - 7.35 (m,1H), 7.31 (d, J = 8.0 Hz, 1H), 7.17 (t, J = 7.2 Hz, 1H), 5.80 (s, 2H), 5.20 (s, 2H), 3.62 (t, J = 8.0 Hz, 2H),3.34 (s, 3H), 2.39 - 2.33 (m, 3H), 0.90 (t, J = 8.0 Hz, 2H), -0.08 (s, 9H).Step 5:

[0433] LDA (2 M, 156.42 mL, 2.5 eq) was added into a solution of 3-(2-(methoxymethoxy)phenyl)-5-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-c]pyridazine (45 g, 1 eq) in THF (900 mL)at -40°C. Then 1, 2-dibromoethane (74.052 g 3.5 eq) in THF (450 mL) was added into the above solution at -40°C using a flow reactor for 1 h. The reaction mixture was diluted with H2O (1000 mL) and extracted with ethyl acetate (500 mL × 2). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / EA = 10 / 1 to 0 / 1) to give 6-bromo-3-(2- (methoxymethoxy)phenyl)-5-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-c]pyridazine(40 g, 83.60 mmol, 66.81% yield) as a yellow solid.1H NMR (400 MHz, , METHANOL-d4) δ 8.08 (s, 1H), 7.62 (dd, J = 1.6, 7.6 Hz, 1H), 7.48 - 7.37 (m, 1H), 7.30 (dd, J = 0.8, 8.4 Hz, 1H), 7.16 (dt, J = 1.2,7.6 Hz, 1H), 5.88 (s, 2H), 5.20 (s, 2H), 3.71 - 3.61 (m, 2H), 3.34 (s, 3H), 2.32 (s, 3H), 0.92 - 0.83 (m,2H), -0.09 (s, 9H). Step 6:

[0434] A mixture of 6-bromo-3-(2-(methoxymethoxy)phenyl)-5-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-c]pyridazine (100 mg, 209.01 μmol, 1 eq), tert-butyl (1S,5R)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-oxa-9-azabicyclo[3.3.1]non-6-ene-9- carboxylate (88.09 mg, 250.81 μmol, 1.2 eq), Cs2CO3 (204.29 mg, 627.02 μmol, 3 eq), and Pd(dppf)Cl2(15.29 mg, 20.90 μmol, 0.1 eq) in dioxane (1 mL) and H2O (0.2 mL) was degassed and purged 3 timeswith N2. The resulting mixture was heated to 80 °C and stirred for 12 h under N2 atmosphere. Thereaction mixture was diluted with H2O (2 mL) and extracted with EtOAc (2 mL × 2). The combinedorganic layers were washed with brine (2 mL), dried over Na2SO4, and filtered. The filtrate wasconcentrated under reduced pressure, and the residue was purified by column chromatography (SiO2,petroleum ether / ethyl acetate=2 / 1 to 1 / 1) to give tert-butyl (1S,5R)-7-(3-(2-(methoxymethoxy)phenyl)-5- methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-oxa-9- azabicyclo[3.3.1]non-6-ene-9-carboxylate (100 mg, 160.56 μmol, 76.82% yield) as a light green solid.1H NMR (400 MHz, CHLOROFORM-d) δ 8.02 (s, 1H), 7.89 (dd, J = 1.2, 7.6 Hz, 1H), 7.43 - 7.35 (m, 1H),7.25 (s, 1H), 7.18 (t, J = 7.6 Hz, 1H), 6.08 (d, J = 5.2 Hz, 1H), 5.82 - 5.73 (m, 2H), 5.20 (s, 2H), 4.75 -4.56 (m, 1H), 4.37 - 4.19 (m, 1H), 3.99 - 3.91 (m, 1H), 3.89 - 3.82 (m, 1H), 3.81 - 3.74 (m, 3H), 3.74 -3.66 (m, 1H), 3.44 (s, 3H), 2.99 - 2.87 (m, 1H), 2.54 (dd, J = 9.6, 18.0 Hz, 1H), 2.26 (s, 3H), 1.53 (s, 9H),0.93 (dd, J = 7.2, 9.3 Hz, 2H), 0.03 (s, 9H); LCMS (ESI+): m / z 625.5 (M+H)+.Step 7:

[0435] To a solution of tert-butyl (1S,5R)-7-(3-(2-(methoxymethoxy)phenyl)-5-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-oxa-9-azabicyclo[3.3.1]non-6-ene-9-carboxylate (100 mg, 160.56 μmol, 1 eq) in THF (3 mL) was added Pd / C (100 mg, 93.97 μmol, 10%purity) under N2 atmosphere. The suspension was degassed and purged 3 times with H2. The mixture wasstirred under H2 (15 Psi), heated to 40 °C, and stirred for 24 h. The reaction mixture was filtered, and thefiltrate was concentrated under reduced pressure to afford tert-butyl (1R,5S)-7-(3-(2-(methoxymethoxy)phenyl)-5-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (92 mg, 147.24 μmol, 91.70% yield) as a white solid,which was used in the next step without purification. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.03 (d,J = 6.0 Hz, 1H), 7.90 - 7.79 (m, 1H), 7.46 - 7.38 (m, 1H), 7.22 - 7.17 (m, 1H), 7.06 - 6.93 (m, 1H), 5.23(s, 2H), 4.43 - 4.31 (m, 1H), 4.29 - 4.19 (m, 1H), 3.81 - 3.72 (m, 2H), 3.72 - 3.66 (m, 2H), 3.63 (dd, J =6.4, 9.6 Hz, 1H), 3.44 (s, 3H), 2.52 - 2.42 (m, 2H), 2.29 - 2.25 (m, 2H), 1.73 (s, 3H), 1.57 - 1.53 (m, 9H),1.44 (s, 4H), 0.94 - 0.88 (m, 2H), 0.08 (s, 9H); LCMS (ESI+): m / z 625.4 (M+H)+.Step 8:

[0436] A solution of tert-butyl (1R,5S)-7-(3-(2-(methoxymethoxy)phenyl)-5-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (80 mg, 128.04 μmol, 1 eq) in TFA (1 mL), Et3SiH (0.05 mL), and H2O (0.05 mL) wasstirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give 2-(6-((1R,5S)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-5-methyl-7H-pyrrolo[2,3-c]pyridazin-3-yl)phenol (40 mg, 114.15 μmol, 89.16% yield) as a red solid, which was used in the next step without purification. LCMS (ESI+): m / z 351.1 (M+H)+. Step 9:

[0437] To a solution of 2-(6-((1R,5S)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-5-methyl-7H-pyrrolo[2,3-c]pyridazin-3-yl)phenol (40 mg, 114.16 μmol, 1 eq) in DCM (1 mL) was added NaHCO3 (47.94 mg,570.76 μmol, 22.20 μL, 5 eq) in H2O (1 mL) and prop-2-enoyl prop-2-enoate (21.60 mg, 171.22 μmol,1.5 eq) at 20 °C. The mixture was stirred at at the same temperature for 1 h. The reaction mixture wasdiluted with H2O (3 mL) and extracted with DCM (3 mL × 2). The combined organic layers wereconcentrated under reduced pressure, and the residue was purified by column chromatography (SiO2,DCM / THF=2 / 1 to 1 / 1) to give 1-((1R,5S)-7-(3-(2-hydroxyphenyl)-5-methyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)prop-2-en-1-one (15 mg, 37.09 μmol, 32.49% yield) as awhite solid. LCMS (ESI+): m / z 405.2 (M+H)+.Step 10:

[0438] 1-((1R,5S)-7-(3-(2-hydroxyphenyl)-5-methyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)prop-2-en-1-one was purified by SFC (column: DAICEL CHIRALPAK IG(250 mm×30 mm,10 um); mobile phase: [CO2-EtOH (0.1% NH3H2O)]; B%: 50%, isocratic elutionmode) to give 1-((1R,5S,7s)-7-(3-(2-hydroxyphenyl)-5-methyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)prop-2-en-1-one (4 mg, 9.89 μmol, 26.67% yield) as a white solid. 1H NMR(400 MHz, DMSO-d6) δ 14.41 (s, 1H), 12.36 (s, 1H), 8.58 (s, 1H), 8.12 (d, J = 7.2 Hz, 1H), 7.28 (t, J =7.6 Hz, 1H), 6.98 - 6.92 (m, 2H), 6.92 - 6.85 (m, 1H), 6.29 - 6.21 (m, 1H), 5.79 (dd, J = 2.4, 10.0 Hz,1H), 4.72 (d, J = 8.0 Hz, 1H), 4.44 (d, J = 10.0 Hz, 1H), 3.69 (t, J = 11.2 Hz, 2H), 3.51 (t, J = 10.0 Hz,2H), 3.39 (s, 1H), 2.72 (dt, J = 6.4, 12.4 Hz, 1H), 2.27 (s, 3H), 2.20 - 2.09 (m, 3H).Example 13: Synthesis of 2-(6-((R)-1-acryloylpyrrolidin-3-yl)-5-methyl-7H-pyrrolo[2,3-c]pyridazin- 3-yl)phenyl L-valinate (Compound 460)Step 1:

[0439] To a solution of (R)-1-(3-(3-(2-hydroxyphenyl)-5-methyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)pyrrolidin-1-yl)prop-2-en-1-one (50 mg, 143.51 μmol, 1 eq) in DCM (2 mL) was added (2S)-2-(tert-butoxycarbonylamino)-3-methyl-butanoic acid (37.42 mg, 172.22 μmol, 1.2 eq), DCC (29.61 mg, 143.51μmol, 29.03 μL, 1 eq), and DMAP (2.10 mg, 17.22 μmol, 0.12 eq) at 20° C. The mixture was stirred atthe same temperature for 4 h. The reaction mixture was then partitioned between dichloromethane (4 mL)and H2O (4 mL). The organic phase was separated, washed with brine (4 mL), dried over Na2SO4, andfiltered. The filtrate was concentrated under reduced pressure, and the residue was purified by prep-TLC(SiO2, dichloromethane / tetrahydrofuran = 2:1) to give 2-(6-((R)-1-acryloylpyrrolidin-3-yl)-5-methyl-7H-pyrrolo[2,3-c]pyridazin-3-yl)phenyl (tert-butoxycarbonyl)-L-valinate (40 mg, 73.04 μmol, 50.89% yield) as a yellow solid. Step 2:

[0440] To a solution of 2-(6-((R)-1-acryloylpyrrolidin-3-yl)-5-methyl-7H-pyrrolo[2,3-c]pyridazin-3-yl)phenyl (tert-butoxycarbonyl)-L-valinate (40 mg, 73.04 μmol, 1 eq) in DCM (1 mL) was added TFA(3.07 g, 26.93 mmol, 2.00 mL, 368.63 eq) at 20 oC. The mixture was stirred at the same temperature for 2h. The reaction mixture was then concentrated under reduced pressure, and the residue was triturated withmethyl tert-butyl ether (2 mL) at 25 oC for 10 min to give 2-(6-((R)-1-acryloylpyrrolidin-3-yl)-5-methyl-7H-pyrrolo[2,3-c]pyridazin-3-yl)phenyl L-valinate (34.4 mg, 61.26 μ...

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula I:or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopically enriched analog, or tautomer thereof, wherein: n is 0, 1, or 2; R1 is OR12, halo, cyano, C1-4 alkoxy, N(R2)2, or C(O)CH(C1-4 alkyl)N(R2)2;each R2is independently hydrogen, C1-4alkyl, or C3-6cycloalkyl, wherein each alkyl or cycloalkyl is unsubstituted or substituted with one to three Z1; each R3is independently halo, cyano, C1-6alkyl, or C1-3haloalkyl; L1is a bond, C1-4 alkylene, -C1-4 alkylene-heteroaryl-, C2-3 alkenylene, C2-3 alkynylene, or -C(O)-; X is selected from:andp is 0, 1, or 2; Ring A is a monocyclic, spirocyclic, fused bicyclic, or bridged bicyclic 4-10 membered heterocyclyl or a monocyclic or fused bicyclic 5-10 membered heteroaryl; Ring B is a monocyclic, spirocyclic, fused bicyclic, or bridged bicyclic 3-10 membered cycloalkyl, a monocyclic, spirocyclic, fused bicyclic, or bridged bicyclic 4-10 membered heterocyclyl, ora monocyclic or fused bicyclic 5-10 membered heteroaryl; wherein the nitrogen atom and L1 may beattached anywhere on Ring B, including on the same carbon; each R4is independently oxo, halo, cyano, -NO2, -SF5, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -C(O)R11, -C(O)OR11, -S(O)0-2R11, -NR11S(O)0-2R11, -S(O)0-2N(R11)2, -NR11S(O)0-2N(R11)2, -NR11C(O)N(R11)2, -C(O)N(R11)2, -NR11C(O)R11, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to eight Z1; R5is hydrogen, halo, cyano, or C1-6alkyl optionally substituted with one to three Z1; R6is hydrogen, halo, cyano, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -C(O)R11, -C(O)OR11, -S(O)0-2R11, -NR11S(O)0-2R11, -S(O)0-2N(R11)2, -NR11S(O)0-2N(R11)2, -NR11C(O)N(R11)2, -C(O)N(R11)2, -NR11C(O)R11, -OC(O)N(R11)2, or-NR11C(O)OR11; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to eight Z1; R7is hydrogen, halo, cyano, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -C(O)R11, -C(O)OR11, -S(O)0-2R11, -NR11S(O)0-2R11, -S(O)0-2N(R11)2, -NR11S(O)0-2N(R11)2, -NR11C(O)N(R11)2, -C(O)N(R11)2, -NR11C(O)R11, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to eight Z1; R8is hydrogen or C1-6 alkyl optionally substituted with one to three Z1; R9 is hydrogen, -C(O)R13, -C(R13)2OC(O)R15, -C(O)OCH2OC(O)R15,-C(O)OCH(CH3)OC(O)R15, -C(O)OCH2OC(O)R15, -C(O)OCH(CH3)OC(O)R15, -(CH2)mOP(O)(OR14)2,-CH(CH3)OP(O)(OR14)2, -(CH2)mOP(O)(R14)(OR14), -CH(CH3)OP(O)(R14)(OR14),-(CH2)mOP(O)(N(R14)2)(OR14), -CH(CH3)OP(O)(N(R14)2)(OR14), -(CH2)mOP(O)(R14)(N(R14)2),-(CH2)mOP(O)(N(R14)2)2, or -C(CH3)OP(O)(N(R14)2)2;m is 1 or 2; each Z1is independently halo, cyano, -NO2, -SF5, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -P(O)(OR11)2, -C(O)R11, -C(O)OR11,-S(O)0-2R11, -NR11S(O)0-2R11, -S(O)0-2N(R11)2, -NR11S(O)0-2N(R11)2, -NR11C(O)N(R11)2, -C(O)N(R11)2,-NR11C(O)R11, -OC(O)N(R11)2, or -NR11C(O)OR11; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a; each R11is independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1a; each Z1ais independently hydroxy, halo, cyano, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl,C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R13)2, -OR13, -P(O)(OR13)2, -C(O)R13, -C(O)OR13,-S(O)0-2R13, -NR13S(O)0-2R13, -S(O)0-2N(R13)2, -NR13S(O)0-2N(R13)2, -NR13C(O)N(R13)2, -C(O)N(R13)2, -NR13C(O)R13, -OC(O)N(R13)2, or -NR13C(O)OR13; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1b; R12 is hydrogen, -C(O)R13, -C(O)N(R14)2, -P(O)(OR14)2, -CH2OP(O)(OR14)2,-CH(CH3)OP(O)(OR14)2, -P(O)(R14)(OR14), -CH2OP(O)(R14)(OR14), -CH(CH3)OP(O)(R14)(OR14),-P(O)(N(R14)2)(OR14), -CH2OP(O)(N(R14)2)(OR14), -CH(CH3)OP(O)(N(R14)2)(OR14),-P(O)(R14)(N(R14)2), -CH2OP(O)(R14)(N(R14)2), -CH(CH3)OP(O)(R14)(N(R14)2), -P(O)(N(R14)2)2,-CH2OP(O)(N(R14)2)2, or -CH(CH3)OP(O)(N(R14)2)2; each R13is independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl,C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to five Z1b; each R14is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, aryl, heteroaryl, or heterocyclyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is independently optionally substituted with one to five Z1b; or two R14together with the atom to which they are attached form a heterocyclyl; wherein said heterocyclyl is independently optionally substituted one to five Z1b; R15is independently R16, -OR16, -SR16, or -N(R16)2; each R16is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, aryl, heteroaryl, or heterocyclyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is independently optionally substituted with one to five Z1b; each Z1bis independently halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, -P(O)(OH)2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-C1-6alkyl, -L-C2-6alkenyl, -L-C2-6alkynyl, -L-C1-6haloalkyl, -L-C3-10cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; and each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6 alkyl)-, -N(C2-6 alkenyl)-, -N(C2-6 alkynyl)-, -N(C1-6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-6 alkyl)-, -C(O)N(C2-6 alkenyl)-, -C(O)N(C2-6 alkynyl)-, -C(O)N(C1-6haloalkyl)-, -C(O)N(C3-10cycloalkyl)-, -C(O)N(heterocyclyl)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)-, -S(O)2NH-, -P(O)(OH)O-, -P(O)(O-C1-6alkyl)O-, -P(O)(O-C2-6alkenyl)-O, -P(O)(O-C2-6alkynyl)O-, -P(O)(OC1-6 haloalkyl)O-, -P(O)(OC3-10 cycloalkyl)O-, -P(O)(O-heterocyclyl)O-, -P(O)(O-aryl)O-, or -P(O)(O-heteroaryl)O-; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, and heteroaryl of Z1band L is further independently optionally substituted with one to five hydroxy, halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C3-10cycloalkyl, heterocyclyl, aryl, or heteroaryl; and wherein the compound is not 1-[3-[3-(2-Hydroxyphenyl)-7H-pyrrolo[2,3-c]pyridazin-6-yl]- 1-azetidinyl]-2-propen-1-one.

2. The compound of claim 1, of Formula II:or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopically enriched analog, or tautomer thereof.

3. The compound of claim 2, of Formula IIA:or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopically enriched analog, or tautomer thereof.

4. The compound of claim 3, of Formula IIB:or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopically enriched analog, or tautomer thereof.

5. The compound of claim 1, of Formula III:or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopically enriched analog, or tautomer thereof.

6. The compound of claim 5, of Formula IIIA:or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopically enriched analog, or tautomer thereof.

7. The compound of claim 6, of Formula IVA:or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopically enriched analog, or tautomer thereof.

8. The compound of any one of claims 1, 2, or 5, or a pharmaceutically acceptable salt, solvate,stereoisomer, isotopically enriched analog, or tautomer thereof, wherein R1is hydroxy.

9. The compound of any one of claims 1, 2, or 5, or a pharmaceutically acceptable salt, solvate,stereoisomer, isotopically enriched analog, or tautomer thereof, wherein R9is hydrogen.

10. The compound of any one of claims 1-3, 5, 6, or 8-9, or a pharmaceutically acceptable salt,solvate, stereoisomer, isotopically enriched analog, or tautomer thereof, wherein L1is a bond.

11. The compound of any one of claims 1-3, 5, 6, or 8-9, or a pharmaceutically acceptable salt,solvate, stereoisomer, isotopically enriched analog, or tautomer thereof, wherein L1is -CH2-, -C(O)-, -CH2-heteroaryl, or ethynyl.

12. The compound of claim 11, or a pharmaceutically acceptable salt, solvate, stereoisomer,isotopically enriched analog, or tautomer thereof, wherein L1is -CH2-.

13. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, solvate,stereoisomer, isotopically enriched analog, or tautomer thereof, wherein Ring A is a monocyclic 4-10 membered heterocyclyl optionally substituted with one or two R4.

14. The compound of claim 13, or a pharmaceutically acceptable salt, solvate, stereoisomer,isotopically enriched analog, or tautomer thereof, wherein Ring A is selected from:and; wherein each Ring A is optionally substitutedwith one or two R4; ( ) represents the point of attachment to L1 or the 7H-pyrrolo[2,3-c]pyridazinemoiety; and (*) represents the point of attachment to the carbonyl moiety.

15. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, solvate,stereoisomer, isotopically enriched analog, or tautomer thereof, wherein Ring A is a spirocyclic 4-10 membered heterocyclyl optionally substituted with one or two R4.

16. The compound of claim 15, or a pharmaceutically acceptable salt, solvate, stereoisomer,isotopically enriched analog, or tautomer thereof, wherein Ring A is selected from:, , , , , ,and; wherein each Ring A is optionally substituted with one ortwo R4; ( ) represents the point of attachment to L1 or the 7H-pyrrolo[2,3-c]pyridazine moiety; and(*) represents the point of attachment to the carbonyl moiety.

17. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, solvate,stereoisomer, isotopically enriched analog, or tautomer thereof, wherein Ring A is a bridged bicyclic 4- 10 membered heterocyclyl optionally substituted with one or two R4.

18. The compound of claim 17, or a pharmaceutically acceptable salt, solvate, stereoisomer,isotopically enriched analog, or tautomer thereof, wherein Ring A is selected from:, , , , , ,, and; wherein each Ring A is optionally substituted with one or two R4; ( ) represents the point of attachment to L1 or the 7H-pyrrolo[2,3-c]pyridazine moiety; and (*) represents the point of attachment to the carbonyl moiety.

19. The compound of any one of claim 1-4, or a pharmaceutically acceptable salt, solvate,stereoisomer, isotopically enriched analog, or tautomer thereof, wherein Ring A is a fused bicyclic 4-10 membered heterocyclyl optionally substituted with one or two R4.

20. The compound of claim 19, or a pharmaceutically acceptable salt, solvate, stereoisomer,isotopically enriched analog, or tautomer thereof, wherein Ring A is selected from:, , , , ,, , , , , and; wherein each Ring A is optionally substituted with one or two R4; ( ) representsthe point of attachment to L1or the 7H-pyrrolo[2,3-c]pyridazine moiety; and (*) represents the point of attachment to the carbonyl moiety.

21. The compound of any one of claims 1 or 5-7, or a pharmaceutically acceptable salt, solvate,stereoisomer, isotopically enriched analog, or tautomer thereof, wherein Ring B is a monocyclic or bridged bicyclic 3-10 membered cycloalkyl or monocyclic 4-10 membered heterocyclyl; wherein each 3- 10 membered cycloalkyl or monocyclic 4-10 membered heterocyclyl is optionally substituted with one or two R4.

22. The compound of claim 21, or a pharmaceutically acceptable salt, solvate, stereoisomer,isotopically enriched analog, or tautomer thereof, wherein Ring B is selected from:and; wherein each Ring B is optionally substituted with one or two R4; ( ) represents the point ofattachment to L1or the 7H-pyrrolo[2,3-c]pyridazine moiety; and (*) represents the point of attachment to the nitrogen atom.

23. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer,isotopically enriched analog, or tautomer thereof, wherein the compound is represented by Formula IIIC, Formula IVA, Formula IVB, or Formula IVC:wherein v and w are each independently 0, 1, 2, 3, or 4; provided that the sum of v and w is at least 1;; orwherein X1is O or CH2.

24. The compound of any one of claim 1-23, or a pharmaceutically acceptable salt, solvate,stereoisomer, isotopically enriched analog, or tautomer thereof, wherein R5is hydrogen.

25. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt, solvate,stereoisomer, isotopically enriched analog, or tautomer thereof, wherein R6is hydrogen.

26. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt, solvate,stereoisomer, isotopically enriched analog, or tautomer thereof, wherein is R6is halo, cyano, C3-10 cycloalkyl, or C1-6 alkyl optionally substituted with one to eight Z1.

27. The compound of claim 26, or a pharmaceutically acceptable salt, solvate, stereoisomer,isotopically enriched analog, or tautomer thereof, wherein R6is C1-6alkyl optionally substituted with halo, -N(R11)2, or heterocyclyl optionally substituted with one to five Z1a.

28. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt, solvate,stereoisomer, isotopically enriched analog, or tautomer thereof, wherein R8is hydrogen.

29. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer,isotopically enriched analog, or tautomer thereof, wherein the compound is represented by Formula IIIC, Formula IVA’, Formula IVB’, or Formula IVC’:; orwherein X1is O or CH2.

30. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt, solvate,stereoisomer, isotopically enriched analog, or tautomer thereof, wherein p is 1 or 2.

31. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt, solvate,stereoisomer, isotopically enriched analog, or tautomer thereof, wherein each R4is independently halo, cyano, C1-6alkyl, -OR11, or -C(O)N(R11)2, wherein each C1-6alkyl is independently optionally substituted with one to eight Z1.

32. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt, solvate,stereoisomer, isotopically enriched analog, or tautomer thereof, wherein p is 0.

33. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt, solvate,stereoisomer, isotopically enriched analog, or tautomer thereof, wherein R7is hydrogen, halo, cyano, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R11)2, -OR11, -C(O)R11, or -C(O)N(R11)2, wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to eight Z1.

34. The compound of any one of claims 1-33, or a pharmaceutically acceptable salt, solvate,stereoisomer, isotopically enriched analog, or tautomer thereof, wherein R7is hydrogen.

35. The compound of any one of claims 1-33, or a pharmaceutically acceptable salt, solvate,stereoisomer, isotopically enriched analog, or tautomer thereof, wherein R7is halo.

36. The compound of any one of claims 1-33, or a pharmaceutically acceptable salt, solvate,stereoisomer, isotopically enriched analog, or tautomer thereof, wherein R7 is C1-6 alkyl, C2-6 alkenyl, orC2-6 alkynyl, wherein each C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl is independently optionally substitutedwith one to three Z1.

37. The compound of any one of claims 1-33, or a pharmaceutically acceptable salt, solvate,stereoisomer, isotopically enriched analog, or tautomer thereof, wherein R7 is C3-10 cycloalkyl orheterocyclyl, wherein each C3-10 cycloalkyl or heterocyclyl is independently optionally substituted with one to three Z1.

38. The compound of any one of claims 1-33, or a pharmaceutically acceptable salt, solvate,stereoisomer, isotopically enriched analog, or tautomer thereof, wherein R7is phenyl or 5-6 membered heteroaryl, wherein each phenyl or 5-6 membered heteroaryl is independently optionally substituted with one to three Z1.

39. A compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopically enrichedanalog, or tautomer thereof, selected from Table 1 or Table 2.

40. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and aneffective amount of a compound of any one of claims 1-39, or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopically enriched analog, or tautomer thereof .

41. A method for modulating or degrading protein which is expressed from the SMARCA2 gene,which method comprises contacting the protein with an effective amount of a compound according to any one of claims 1-39, or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopically enriched analog, or tautomer thereof.

42. A method for modulating or degrading protein which is expressed from the SMARCA4 gene,which method comprises contacting the protein with an effective amount of a compound according to any one of claims 1-39, or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopically enriched analog, or tautomer thereof.

43. A method for modulating or degrading protein which is expressed from the SMARCA2 gene in asubject, which method comprises administering to said subject an effective amount of a compound according to any one of claims 1-39, or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopically enriched analog, or tautomer thereof.

44. A method for modulating or degrading protein which is expressed from the SMARCA4 gene in asubject, which method comprises administering to said subject an effective amount of a compound according to any one of claims 1-39, or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopically enriched analog, or tautomer thereof.

45. A method for modulating or degrading protein which is expressed from the SMARCA2 gene in asubject, which method comprises administering to said subject an effective amount of a pharmaceutical composition according to claim 40.

46. A method for modulating or degrading protein which is expressed from the SMARCA4 gene in asubject, which method comprises administering to said subject an effective amount of a pharmaceutical composition according to claim 40.

47. A method for treating cancer in a subject in need thereof, which method comprises administeringto said subject an effective amount of a compound according to any one of claims 1-39, or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopically enriched analog, or tautomer thereof.

48. A method for treating cancer in a subject in need thereof, which method comprises administeringto said subject an effective amount of a pharmaceutical composition according to claim 40.

49. A method for treating hyperplasia in a subject in need thereof, which method comprisesadministering to said subject an effective amount of a compound according to any one of claims 1-39, ora pharmaceutically acceptable salt, solvate, stereoisomer, isotopically enriched analog, or tautomer thereof.

50. A method for treating hyperplasia in a subject in need thereof, which method comprisesadministering to said subject an effective amount of a pharmaceutical composition according to claim 40.