Isoquinoline TCF4 binders

Abstract

The present invention provides compounds of Formula I: and pharmaceutically acceptable salts thereof, compositions thereof, and methods of using the same in methods of treating diseases, disorders, and conditions such as Fuchs endothelial corneal dystrophy (FECD).

Description

ISOQUINOLINE DMPK BINDERSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U. S. Provisional Application Nos. US 63 / 827.479, filed June 20. 2025; and US 63 / 715,976, filed November 4. 2024; the entirety of each of which is incorporated herein by reference.TECHNICAL FIELD OF THE INVENTION

[0002] The present invention relates to compounds and use thereof for modulating the activity of TCF4. The invention also provides methods of treating various diseases, disorders, and conditions, such as TCF4-mediated diseases, which includes Fuchs endothelial comeal dystrophy (FECD).SEQUENCE LISTING STATEMENT

[0003] The content of the electronic sequence listing titled 394457-02 lWO_222753_SL.xml (Size: 1,742 bytes; and Date of Creation: November 3, 2025) is herein incorporated by reference in its entirety.BACKGROUND OF THE INVENTION

[0004] Fuchs endothelial comeal dystrophy (FECD) is a common age-related cause of heritable visual loss primarily affecting the comeal endothelium and is the leading indication for comeal transplantation in high-income countries. FECD occurs in 4% of the population in the United States over the age of 40 years and 70% of FECD in the United States is caused by an intronic CTG repeat expansion within the TCF4 gene. CUG repeat RNA transcripts from this trinucleotide repeat expansion accumulate in comeal endothelial cells and are thought to bind muscleblind-like (MBNL) protein, an important splicing factor. This binding reduces the cellular pool of MBNL protein and causes global splicing dysregulation. This splicing dysregulation and the differential expression of extracellular matrix genes likely account for the activation of fibrosis pathways and mitochondrial dysfunction leading to the observation of guttae and other physical manifestation of disease.

[0005] Small molecules and peptides capable of binding (CUG) repeat RNA and disrupting its interaction with splicing proteins are highly desirable as potential therapeutic agents to restore normal splicing. The development and synthesis of small molecules and peptides able to bind RNA with high affinity and selectivity continues to be a major focus of bioorganic chemistry. Despite recent developments in RNA binders, FECD remains incurable with therapeutic options.

[0006] There remains a need to develop small-molecule TCF4 modulators useful as therapeutic agents. Tire present invention addresses this need and provides other related advantages.SUMMARY OF THE INVENTION

[0007] In one aspect, the present invention provides compounds, such as those described below, that are useful in treating comeal dystrophy, such as Fuchs endothelial comeal dystrophy (FECD)). In some aspects, the present invention provides compounds that are useful in treating a TCF4-mediated disease, disorder, or condition, such as those described herein. Such diseases include those mediated by mutant forms of RNA transcribed from the TCF4 gene containing aberrant CUG repeats. In some aspects, the present invention provides compounds and compositions that are generally useful to treat a disease, disorder, or condition, such as a TCF4-mediated disease, disorder or condition, and / or for suppression of the aberrant functionality of a TCF4 protein, lowering of the expression level of a TCF4 protein, and / or the modulation of a TCF4 RNA transcript.

[0008] In some aspects, the present invention provides compounds that are modulators of a TCF4 protein. In some aspects, the present invention provides compounds that are modulators of a TCF4 mRNA, and in turn impact the abundance or activity of TCF4 protein. In some aspects, the present invention provides compounds that are modulators of a specific isoform of TCF4 mRNA. In some aspects, the present invention provides compounds that are useful in treating a TCF4-mediated disease, disorder, or condition that is characterized by the presence of a specific isoform of TCF4 mRNA.

[0009] In one aspect, the present invention provides a compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein:Ring X is phenyl, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each Rxis Ring Y or R', provided that no more than one Rxis Ring Y;Ring Y is an optionally substituted group selected from 4-8 membered saturated or partially unsaturatedmonocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-11 membered saturated or partially unsaturated bicyclic or spirocyclic carbocyclic ring, or a 7-11 membered saturated or partially unsaturated bicyclic or spirocyclic heterocyclic ring with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring Y is optionally substituted with y instances of Ry;each X1, X2, X3, X4, and X5is independently carbon or nitrogen;each L1and L2is independently a covalent bond or an optionally substituted Ci-s bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-3 methylene units of the chain are independently and optionally replaced with -Cy-, -C(R')2-, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, - S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, or-NRC(O)O-;R1is hydrogen or Ci-6 aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms, provided that R1is not hydrogen when L1is a covalent bond;R2is hydrogen, halogen, -CN, or Ci.6 aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms, provided that R2is not hydrogen when L2is a covalent bond;each R3is independently selected from Ci-g aliphatic, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, - S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -N(R)C(O)N(R)2, and -NRS(O)2R, wherein one instance of R3may be a ring selected from phenyl, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; w herein the ring is optionally substituted with x instances of Rx;each R', Ry, and R4is independently selected from Ci-6 aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms, halogen, -CN. -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, - C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR. -OC(O)R, -OC(O)NR2. -NRC(O)OR, -NRC(O)R. - N(R)C(O)N(R)2, and -NRS(O)2R;each -Cy- is independently an optionally substituted bivalent ring selected from phenylene, an 8-10 membered bicyclic carbocyclic aromatic ring, a 4-7 membered saturated or partially unsaturated carbocyclylene, a 6-11 membered saturated or partially unsaturated spirocyclic carbocyclylene, an 8-10 membered bicyclic, saturated or partially unsaturated, carbocyclylene, a 4-7 membered saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6-11 membered saturated or partially unsaturated spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic, saturated or partially unsaturated, heterocyclylene having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroarylene having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each R is independently hydrogen or an optionally substituted group selected from Ci-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur;w is 0. 1, or 2:x is 0, 1, 2, 3, or 4;y is 0, 1, 2, 3, or 4; andz is 0, 1, 2, or 3.

[0010] In certain embodiments, the present invention provides a compound of Formula I':or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0011] In certain embodiments, the present invention provides a compound of Formula I":or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS1. General Description of Certain Embodiments of the Invention:

[0012] It has now been found that the compounds disclosed herein and pharmaceutically acceptable salts, solvates, and hydrates thereof, are useful in modulating expression and function of one or more TCF4 transcripts, such as those described herein. In some embodiments, the compounds disclosed herein can also modulate the expression level and functionality of MBNL1 proteins (e.g., MBNL1). In some embodiments, the modulation of the expression level and functionality of MBNL proteins is mediated through the modulation of expression and function of one or more TCF4 RNA transcripts. In some embodiments, the modulation of the expression level and functional ity of MBNL proteins is mediated through the modulation of expression and function of a specific isoform of a TCF4 RNA transcript. In one aspect, the compounds are useful in treating one or more diseases, disorders, and conditions, such as those mediated by TCF4 or a MBNL protein, as described herein.

[0013] In one aspect, the disclosure provides methods of treating a TCF4-mediated disease, disorder, or condition in a patient in need thereof, including administering to the patient an effective amount of an RNA-modulating small molecule (rSM), such as a compound disclosed herein or a pharmaceutically acceptable salt thereof, to treat the TCF4-mediated disease, disorder, or condition. In another aspect, the present invention provides a method of treating a TCF4-mediated disease, disorder, or condition in a patient in need thereof, including administering to the patient an effective amount of a disclosed compound or a pharmaceutically acceptable salt thereof. In some embodiments, the TCF4-mediated disease, disorder, or condition is one treatable by modulation of the expression level, activity, or splicing of a TCF4 RNA transcript.

[0014] In some embodiments, tire TCF4-mediated disease, disorder, or condition is Fuchs endothelialcomeal dystrophy (FECD). In some embodiments, the disease, disorder, or condition is associated with sequestering important proteins such as the muscleblind-like 1 protein (MBNL1). In some embodiments, the disease, disorder, or condition is treated by an increase in the available cellular levels of MBNL1.

[0015] In one aspect the disclosure provides methods of treating a TCF4-mediated disease, disorder, or condition in a patient in need thereof, including administering to a subject (e.g., a human patient) an effective amount of an RNA-modulating small molecule (rSM) to treat the TCF4-mediated disease, disorder, or condition. In some embodiments, the administration of the rSM results modulation of the muscleblind-like 1 protein (MBNL1). In some embodiments, the administration of the rSM results in increased function of the muscleblind-like 1 protein (MBNL1).

[0016] It should be appreciated that the methods of treatment of a TCF4-mediated disease, disorder, or condition are not limited to a specific mechanism. In some embodiments, the compounds of the disclosure are effective in the treatment of a TCF4-mediated disease, disorder, or condition because the administration of the rSM results in increased MBNL1 activity. In some embodiments, the compounds of the disclosure are effective in the treatment of a TCF4-mediated disease, disorder, or condition because the administration of the rSM modulates the expression level of a MBNL1 protein (e.g. MBNL1). In some embodiments, the compounds of the disclosure are effective in the treatment of a TCF4-mediated disease, disorder, or condition because the administration of the rSM prevents sequestering of MBNL1 protein by expanded rCUG repeats in TCF4.

[0017] In some embodiments, the rSM is a small molecule. In some embodiments, the small molecule is a selective modulator of the MBNL protein, e.g., it prevents sequestering of MBNL1 protein by expanded rCUG repeats in TCF4. In some embodiments, the compounds provided herein prevent sequestering of MBNL1 protein by expanded rCUG repeats in TCF4.

[0018] In one aspect, the disclosure provides methods of treating a TCF4-mediated disease, disorder, or condition in a patient in need thereof, including administering to the patient an effective amount of an RNA-modulating small molecule (rSM) to treat the TCF4-mediated disease, disorder, or condition. In some embodiments, the administration of the rSM results in modulation of a TCF4 RNA transcript. In some embodiments, the administration of the rSM results in modulation of a TCF4 RNA transcript, which results in less sequestering of MBNL protein by expanded rCUG repeats in TCF4.

[0019] The term ‘RN A” (ribonucleic acid) as used herein, means a naturally-occurring or synthetic oligo-or polyribonucleotide independent of source (e.g., the RNA may be produced by a human, animal, plant, vims, or bacterium, or may be synthetic in origin), biological context (e.g., the RNA may be in the nucleus, circulating in the blood, in vitro, cell lysate, or isolated or pure form), or physical form (e.g., the RNA may be in single-, double-, or triple -stranded form (including RNA-DNA hybrids), may include epigeneticmodifications, native post-transcriptional modifications, artificial modifications (e.g., obtained by chemical or in vitro modification), or other modifications, may be bound to, e.g., metal ions, small molecules, protein chaperones, or co-factors, or may be in a denatured, partially denatured, or folded state including any native or unnatural secondary ortertiary structure such as junctions (e.g., cis or trans three -way junctions (3WJ)), quadruplexes (e g., G-quadruplexes), hairpins, triplexes, hairpins, bulge loops, pseudoknots, and internal loops, etc., and any transient forms or structures adopted by the RNA). In some embodiments, the target RNAis 100 or more nucleotides in length. In some embodiments, the target RNA is 250 or more nucleotides in length. In some embodiments, the target RNA is 350, 450, 500, 600, 750, or 1,000, 2,000, 3,000, 4,000, 5,000, 7,500, 10,000, 15,000, 25,000, 50,000, or more nucleotides in length. In some embodiments, the target RNA is between 250 and 1,000 nucleotides in length. In some embodiments, the RNA is a pre-RNA, pre-miRNA. or pre-transcript. In some embodiments, the RNA is a non-coding RNA (ncRNA), messenger RNA (mRNA), micro-RNA (miRNA). a ribozyme, riboswitch. IncRNA. lincRNA, snoRNA, snRNA, scaRNA, piRNA, ceRNA, pseudo-gene, viral RNA, or bacterial RNA.

[0020] The term “TCF4 RNA transcript” includes any RNA transcript or portion or mutant thereof that is transcribed from a TCF4 gene. Tire TCF4 RNA transcript includes both coding and non-coding regions, and includes unspliced isofomis, splicing intermediates, isoforms, fragments, and mutants of RNA transcripts derived from a TCF4 gene. In some embodiments, the TCF4 gene is a mammalian TCF4 gene, such as a human TCF4 gene; or a mutant of the gene. In one embodiment, the disclosure provides methods and compositions for targeting a specific isoform of a TCF4 RNA transcript.

[0021] In some embodiments, the transcript is bound to one or more RNA-binding proteins (RBPs). In some embodiments, the TCF4 RNA transcript is a pre-mRNA. In some embodiments, the TCF4 RNA transcript is an intron or exon of such pre-mRNA. In some embodiments, the TCF4 RNA transcript is a partially processed mRNA. In some embodiments, the TCF4 RNA transcript is a folly processed (mature) mRNA. In some embodiments, the TCF4 RNA transcript is a folly processed mRNA bound to one or more RNA-binding proteins (RBPs). In some embodiments, the TCF4 RNA transcript is single stranded.

[0022] In one aspect, the present invention provides a method of modulating the activity of a TCF4 RNA transcript (also referred to herein as a “TCF4 transcript” or “TCF4 RNA”) or an unspliced isoform, splicing intennediate, isofomi, fragment, or mutant thereof, comprising contacting the TCF4 RNA transcript or an unspliced isoform, splicing intermediate, isoform, fragment, or mutant thereof with an rSM or a pharmaceutically acceptable salt thereof that modulates the TCF4 RNA transcript or an unspliced isoform, splicing intermediate, isoform, fragment, or mutant thereof.

[0023] In another aspect, the present invention provides a method of modulating the activity (e.g., expression level) of a MBNL protein or mutant thereof, comprising contacting a corresponding TCF4 RNAtranscript or an unspliced isofbrm, splicing intermediate, isoform, fragment, or mutant thereof with an rSM or a pharmaceutically acceptable salt thereof that modulates the TCF4 RNA transcript or an unspliced isoform, splicing intermediate, isoform, fragment, or mutant thereof. In some embodiments, the TCF4 RNA transcript is a TCF4 pre-mRNA, splicing intermediate, or mature mRNA. In some embodiments, the rSM modulates only a specific isoform of a TCF4 RNA transcript.

[0024] A compound that modulates an RNA transcript as used herein (e.g., an rSM) refers to a compound that changes the abundance or activity of an RNA transcript. In some embodiments, the change in the abundance or activity of an RNA transcript results in the change in the abundance or activity of the protein corresponding to the RNA transcript. In some embodiments, the change in the abundance or activity of an RNA transcript results in the change in the abundance or activity of a protein that does not correspond to the RNA transcript, e g., MBNL1. In some embodiments, the RNA transcript is a TCF4 RNA and the corresponding protein is MBNL1. In some embodiments, the rSM modulates the RNA transcript by binding the RNA transcript. In some embodiments, the rSM modulates the RNA transcript by interaction with a cellular component, such as an RNA Binding protein (RBP), that in turn binds or interacts with the RNA transcript. In some embodiments, the rSM modulates the RNA transcript by modulating the activity of the RNA Binding Protein (RBP). For clarity, as provided herein, RBPs encompass any protein that interacts with RNA either directly (e g., by binding) or indirectly. In some embodiments, tire rSM modulates the RNA transcript by suppressing or inhibiting binding of the RBP to the RNA transcript. In some embodiments, the rSM modulates the RNA transcript by enhancing binding of the RBP to the RNA transcript. In some embodiments, the rSM modulates the RNA transcript by interaction with a cellular component, such as an RBP, and the RNA simultaneously. It should be appreciated that the compounds described herein are not limited to modulation of an RNA transcript and can treat TCF4-mediated diseases, disorders and conditions, e.g., by suppressing the aberrant function of the TCF4 RNA.

[0025] In some embodiments, a disclosed rSM binds to a target TCF4 RNA transcript such as a TCF4 pre-mRNA transcript, splicing intermediate, or mature mRNA and modulates the activity of MBNL1.

[0026] In some embodiments, the compounds and rSMs provided herein are a selective modulator of the TCF4 RNA transcript. In some embodiments, the compound or rSM interacts with a TCF4 RNA transcript preferentially (e g., more effectively) over other RNA transcripts. In some embodiments, the compound or rSM interacts with a specific isoform of an TCF4 RNA transcript preferentially (e.g., more effectively) over other isoforms of a TCF4 RNA transcript.

[0027] For example, in some embodiments, the selective modulator (e.g., inhibitor or antagonist) has an IC50 for a TCF4 RNA transcript that is at least 40 percent lower (i.e., more potent) than the IC50 for another RNA transcript, such as another transcript having at least 90% sequence homology, or another TCF4 RNAtranscript that is not the intended target. In some embodiments, tire selective modulator (e.g., inhibitor or antagonist) has an IC50 for the TCF4 RNA transcript that is at least 50 percent lower than the IC50 for the other, non-target RNA transcript. In some embodiments, the selective modulator (e.g., inhibitor or antagonist) has an IC50 for tire TCF4 RNA transcript that is at least 60, 70, 80, 90, or 95 percent lower than the IC50 for the non-target RNA transcript. In some embodiments, the selective modulator (e.g., antagonist or inhibitor) of a TCF4 RNA transcript exerts essentially no inhibitory effect on the non-target RNA transcript. In some embodiments, the selective modulation of the TCF4 RNA transcript results in selective modulation of the MBNL (e.g., MBNL1) protein, e.g., in that it suppresses the aberrant functionality of TCF4 RNA preferentially (e.g., more effectively) over other RNA. In some embodiments, the TCF4 RNA transcript is a specific isofomi of TCF4 RNA and the non-target RNA transcript is a different isoform of TCF4 RNA.

[0028] In some embodiments, the selective modulator (e.g.. inhibitor or antagonist) modulates the activity of a TCF4 RNA transcript at least 2-fold more efficiently than a non-target TCF4 transcript. In some embodiments, the selective modulator (e.g., inhibitor or antagonist) modulates the activity of a TCF4 RNA transcript at least 5 -fold more efficiently than a non-target RNA transcript. In some embodiments, the selective modulator (e.g., inhibitor or antagonist) modulates the activity of a TCF4 RNA transcript at least 10-, 20-, 50-, 100, 1000-. 10000-, or 100000-fold more efficiently than a non-target RNA transcript. In some embodiments, the selective modulation of tire TCF4 RNA transcript results in selective modulation of MBNL (e.g., MBNL1) protein, e g., in that it suppresses the aberrant functionality or expression level of a MBNL protein preferentially (e.g., more effectively) over other proteins. In some embodiments, the TCF4 RNA transcript is a specific isoform of TCF4 RNA and the non-target RNA transcript is a different isofomi of TCF4 RNA.

[0029] In some embodiments of the methods provided herein, the TCF4 RNA transcript comprises a 5' untranslated region (UTR) of TCF4 and an open reading frame (ORF) of TCF4. Without wishing to be bound by theory, it is understood that the noncoding regions of mRNA such as the 5' untranslated regions (5' UTR), the 3' UTR, and introns can play regulatory roles in affecting mRNA expression levels, alternative splicing, translational efficiency, and mRNA and protein subcellular localization. It is furthermore believed that RNA secondary and tertiary structures are associated with these regulatory activities. Accordingly, modulation of the activity of a TCF4 RNA transcript or an unspliced isoform, splicing intennediate, isoform, fragment, or mutant thereof is possible by interaction of a disclosed compound (rSM) at one or more RNA secondary and tertiary structures on the TCF4 RNA transcript.2. Compoun ds an d Defin itions:

[0030] Compounds and compositions described herein are generally useful for the modulation ofexpression and function of one or more TCF4 transcripts, such as those described herein. In some embodiments, the compounds disclosed herein can also modulate the expression level and functionality of MBNL1 proteins (e.g., MBNL1). In some embodiments, the modulation of the expression level and functionality of MBNL proteins is mediated through the modulation of expression and function of one or more TCF4 RNA transcripts. In some embodiments, the modulation of the expression level and functionality of MBNL proteins is mediated through the modulation of expression and function of a specific isoform of a TCF4 RNA transcript. In one aspect, the compounds are useful in treating one or more diseases, disorders, and conditions, such as those mediated by TCF4 or a MBNL protein, as described herein.

[0031] Tire terms “TCF4 protein” and “TCF4” refer to all members of the TCF4 protein kinase family.

[0032] Compounds of the present invention include those described generally herein, and are further illustrated by tire classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd. Additionally, general principles of organic chemistry are described in “Organic Chemistry ”, Thomas Sorrell, University Science Books, Sausalito: 1999, and Marchs' Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, M. B. Smith and J. March, 7thEdition, John Wiley & Sons: 2013; the entire contents of which are hereby incorporated by reference.

[0033] The term “aliphatic” or “aliphatic group,” as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic, bicyclic, bridged bicyclic, or spirocyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocycle,” “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refers to a monocyclic Ch-C, hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. As used herein, “haloaliphatic” refers to an aliphatic group that is substituted with at least one halogen, i.e., wherein at least one hydrogen atom is replaced with F, Cl, Br, or I and including replacement of each hydrogen with an independently selected halogen. As used herein, “haloalkoxy” refers to an aliphaticgroup that is substituted with one or more halogen atoms and connected via an oxygen (e.g., -OCHF2) to the remainder of the compound. As used herein, “hydroxyhaloaliphatic” refers to an aliphatic group that is substituted with one or more halogen atoms and a hydroxyl group. “Haloalkyl,” ‘‘haloalkoxy,” and “hydroxyhaloalkyl” shall have corresponding meanings, i.e., they refer to alkyl groups with substituents and atom replacements as defined above. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0034] As used herein, the term ‘'bridged bicyclic” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a “bridge” is an unbranched chain of atoms or an atom or a valence bond comiecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bridged bicyclics include:

[0035] The term “lower alkyl” refers to a C1-4 straight or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0036] The term “lower haloalkyl” refers to a C1-4 straight or branched alkyl group that is substituted with one or more halogen atoms.

[0037] The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quatemized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3.4-dihydro-2 / / -pyrrolyl). NH (as in pyrrolidinyl) or NR (as in N-substituted pyrrolidinyl)).

[0038] The term “unsaturated,” as used herein, means that a moiety has one or more units of unsaturation.

[0039] As used herein, the term “bivalent Ci.g (or Ci.e) saturated or unsaturated, straight or branched, hydrocarbon chain”, refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.

[0040] Tire term “alkylene” refers to a bivalent alkyl group. An “alkylene chain” is a polymethylene group, i.e., -(CHj)n-, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0041] Tire term “alkenylene” refers to a bivalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0042] The term “halogen” means F, Cl, Br, or I.

[0043] The term “aryl” used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in tire system contains3 to 7 ring members. The term '‘aryl” may be used interchangeably with the term “and ring.” In certain embodiments of the present invention, "‘ary l” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “ary l,” as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.

[0044] The terms “heteroaryl” and “heteroar-,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 n, electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. Tire term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quatemized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl. pyrrolyl, imidazolyl, pyrazolyl, triazolyl. tetrazolyl, oxazolyl, isoxazolyL oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyL pyridyl, pyridazinyL pyrimidiny 1, pyrazinyL indolizinyl, purinyl, naphthyridiny 1, and pteridinyl. The terms "heteroaryl" and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl. indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 477-quinolizinyl, carbazolyl, acridiny 1, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-l,4-oxazin-3(4H)-one. A heteroar l group may be mono- or bicyclic. A heteroaryl ring may include one or more oxo (=0) or thioxo (=S) substituent. The temi “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which tenns include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted with a heteroaryl. wherein the alkyl and heteroaryl portions independently are optionally substituted.

[0045] As used herein, the terms “heterocycle,” “heterocycly l,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, such as one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxy gen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-277-pyrrolyl), NH (as in pyrrolidinyl), or+NR (as in A-substituted pyrrolidinyl).

[0046] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofiiranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms “heterocycle,” "heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3 7-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. A heterocyclyl group may be monocyclic, bicyclic, bridged bicyclic, or spirocyclic. A heterocyclic ring may include one or more oxo (=0) or thioxo (=S) substituent. The term “heterocyclylalkyl” refers to an alkyl group substituted with a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.

[0047] As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include ar l or hctcroar l moieties, as herein defined.

[0048] As described herein, compounds of the invention may contain “optionally substituted” moieties. In general, the tenn “substituted”, whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent (“optional substituent”) at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every’ position. Combinations of substituents envisioned by this invention are preferably those that result in the fonnation of stable or chemically feasible compounds. Hie term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0049] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; -(CH:),,4RC; -(CEEX OR0; -0(CH2)O 4R°, -O-(CH2)C C(O)OR°: -(CH ),4CH(OR°)-< -(CHA,4SR°: -(CHq„4Ph. which may be substituted with R°; -(CH2)o^O(CH2)o i Ph which may be substituted with R°; -CEI=CHPh, which may be substituted with R°; -(CH2),, O(CH:), i-pyridyl which may be substituted with R°; -NCE; -CN; -N4; -(C H4),, N(R°) -(CH:), N(R°)C(O)R°: -N(R°)C(S)R°; -(CH2), N(R°)C(0)NRO2: -N(RO)C(S)NR°2; -(CH;),,4N(R°)C(O)OR°; N(R°)N(Ro)C(0)R°; -N(R°)N(RO)C(O)NR°2: -N(R°)N(R°)C(O)OR°; -(CH;),,4C(O)R°: -C(S)R°; -(CH2)O^C(0)OR°; -(CH2)O-4C(0)SRO: -(CH2)O.C(0)0SIRC,: -(CH2)O-40C(0)RO: -0C(0)(CH2),4SRO: -(CH2)„ SC(O)R°: (CH2)jC(O)NR°2: C(S)NR°2; C(S)SR°; SC(S)SR°, -(CH2)04OC(O)NR°2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(0)CH2C(0)RO; -C(NOR°)R°; -(CH2)„4SSRO: -(CH2)OS(O)2RO; -(CH2)O4S(0R0RO: -(CH2)0^OS(O)2RO; -S(O)2NRO2; -(CH2)OS(0)RO: -N(R°)S(O)2NRO2; -N(R°)S(O)2R°; -N(OR°)R°; -C(NH)NRO2; -(CH2)O 4P(0)2RO: (CH2),,4P(O)R°2: -(CH2)„4P(O)(ORC)2: -(CH2), 0P(0)RO2; -(CH2)U4OP(O)(OR°)2; SiR°2: -(Ci^j straight or branched alkylene)O-N(R°)2; or -(Ci-4straight or branched alkylene)C(O)O-N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, Ci_6aliphatic, -CH2Ph, -O(CH2)0-iPh, -CH2-(5-6 membered heteroaryl ring), or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0050] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen. -(CH2)o_2R*, -(haloR*). -(CH2)02OH, -(CH2)O 2OR*. -(CH2)O 2CH(OR*)2: -O(haloR’), -CN, -N3, -(CH2)0 2C(O)R*, -(CH2)0 2C(O)OH, -(CH2)0 2C(O)OR*, -(CH2)O 2SR*, -(CH2)O 2SH, -(CH2)O 2NH2, -(CH2)O 2NHR*, -(CH2)O 2NR, -NO2, -SiR*3, -OSiR*3, -C(O)SR* -(C^ straight or branched alkylene)C(O)OR*, or -SSR* wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from Ci^ aliphatic, -CH2Ph, -0(CH2)o-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

[0051] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =0, =S, =NNR*2, =NNHC(0)R*, =NNHC(0)0R*, =NNHS(O)2R*, =NR*, =N0R*, -O(C(R*2))2-3O-, or -S(C(R*2))2-3S-, wherein each independent occurrence of R* is selected from hydrogen, Ci-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -O(CR*2)2-3O-, wherein each independent occurrence of R* is selected from hydrogen, CI G aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0052] Suitable substituents on the aliphatic group of R* include halogen, -R*, -(haloR*). -OH, -OR’, -O(haloR*), -CN, -C(O)OH, -C(O)OR*, -NH2, -NHR*, -NR*2, or-NCh, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently Ci-4 aliphatic, -CH2Ph, -O(CH2)0-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0053] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include -Rt, -NR1,, -C(O)R1, -C(O)ORt -C(O)C(O)Rt -C(O)CH2C(O)Rt, -S(O)2Rt, -S(O)2NRt2, -C(S)NRf2. -C(NH)NR2, or -NfR'jSfOfR': wherein each R' is independently hydrogen, C i-6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R1', taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono-or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0054] Suitable substituents on the aliphatic group of R are independently halogen, -Re, -(haloR*). -OH, -OR’, -O(haloR’), -CN, -C(O)OH, -C(O)OR’, -NH2, -NHR*, -NR*2, or -NO2, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently CM aliphatic, -CH2Ph, -0(CH2)o-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0055] As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethane sulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonatc, mcthancsulfonatc, 2-naphthalcncsulfonatc, nicotinate, nitrate,oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

[0056] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N (Ci 4alkyl) salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate. In some embodiments, the provided compounds are purified in salt form for convenience and / or ease of purification, e.g., using an acidic or basic mobile phase during chromatography. Salts forms of the provided compounds formed during chromatographic purification are contemplated herein and are readily apparent to those having skill in the art.

[0057] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric fonns of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a13C- or14C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.

[0058] Compounds containing one or more stereocenters are a mixture of stereoisomers, unless otherwise stated or described (for example, with use of dashed or wedged bonds denoting stereochem istry ). Generally, enhanced stereochemical representation introduces three types of identifiers that can be attached to a stereogenic center. A stereochemical group label is composed of an identifier and a group number. Each stereogenic center marked with a dashed or w edged bonds belongs to one (and only one) stereochemical group. Grouping allows to specify relative relationships among stereogenic centers.

[0059] As used herein, the designations “S” or “R” or '‘abs” denote a stereogenic center where the absolute configuration is known.

[0060] As used herein, the designation “or”, such as “orl”, “or2” etc., denotes a stereogenic center wherethe relative configuration is known and the absolute configuration is unknown, but represents a single stereoisomer of a fixed configuration. Compound structures which contain “or” designation at certain stereocenters, such as “orl” or “or2”, are intended to represent compounds wherein the stereochemistry at said stereocenters is cither the stereochemistry shown or wherein the marked stereocenters have a configuration opposite to what is shown, i.e., the absolute stereochemistry at each stereocenter is not known. At tire same time, the relative stereochemistry between stereocenters with the same “or” label, such as “orl”, is defined as drawn. The relative stereochemistry between the stereocenters with different “or” labels, such as “orl” and “or2”, is not defined and can be either as drawn or can be opposite to what is drawn.

[0061] As used herein, the designations “and” or “&”, such as “andl” or “&1”, are used interchangeably and denote a mixture of stereoisomers, e g., a pair of enantiomers or diastereomers, with respect to the designated stereogenic center. Compound structures which contain “&” or “and” designations at certain stereocenters, such as “&1” or “andl”, are intended to represent the compound material which is a mixture of R and. S'-configurcd stereoisomers w ith respect to the marked stereocenters. At the same time, the relative stereochemistry betw een stereocenters with the sameor “and” label, such as “&1” or “andl”, is defined as drawn. Hie relative stereochemistry betw een the stereocenters with different “&” or “and” labels, such as “&1” and “&2”, is not defined and can be either as drawn or can be opposite to what is drawn.

[0062] Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known to those skilled in the art, such as, for example, by chromatography and / or fractional crystallization. Enantiomers can be separated by methods known to those skilled in the art, such as for example, by chiral chromatography. Alternatively, enantiomers can be separated or by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride), separating tire diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Further, a particular enantiomer of a compound of the present invention may be prepared by asymmetric synthesis. Still further, where the molecule contains a basic functional group (such as amino) or an acidic functional group (such as carboxylic acid) diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of tire diastereomers thus formed by fractional crystallization or chromatographic means known in the art. and subsequent recovery of the pure enantiomers.

[0063] Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. Chiral center) s) in a compound of the present invention can have the S or R configuration asdefined by the IUPAC 1974 Recommendations. Further, to the extent a compound described herein may exist as an atropisomer (e.g., substituted biaryls), all forms of such atropisomers are considered part of this invention.

[0064] As used herein, the term “provided compound” refers to any genus, subgenus, and / or species set forth herein.

[0065] As used herein, the term “inhibitor” is defined as a compound that binds to and / or modulates or inhibits TCF4 with measurable affinity. In certain embodiments, an inhibitor has an ICso and / or binding constant of less than about 100 pM, than about 50 pM, less than about 1 pM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM.

[0066] The terms “measurable affinity” and “measurably inhibit,” as used herein, means a measurable change in a downstream biological effect between a sample comprising a compound of the present invention, or composition thereof, and an equivalent sample comprising TCF4, in the absence of said compound, or composition thereof.

[0067] The term “RNA” (ribonucleic acid) as used herein, means a naturally-occurring or synthetic oligo-or polyribonucleotide independent of source (e.g., the RNA may be produced by a human, animal, plant, virus, or bacterium, or may be synthetic in origin), biological context (e.g., the RNAmay be in the nucleus, circulating in the blood, in vitro, cell lysate, or isolated or pure fonn), or physical form (e.g.. the RNA may be in single-, double-, or triple-stranded form (including RNA-DNA hybrids), may include epigenetic modifications, native post-transcriptional modifications, artificial modifications (e.g., obtained by chemical or in vitro modification), or other modifications, may be bound to, e.g., metal ions, small molecules, protein chaperones, or co-factors, or may be in a denatured, partially denatured, or folded state including any native or unnatural secondary or tertiary structure such as junctions (e.g., cis or trans three-way junctions (3WJ)), quadruplexes, hairpins, triplexes, hairpins, bulge loops, pseudoknots, and internal loops, etc., and any transient forms or structures adopted by the RNA). In some embodiments, the RNA is 100 or more nucleotides in length. In some embodiments, the RNA is 250 or more nucleotides in length. In some embodiments, the RNA is 350, 450, 500, 600, 750, or 1,000, 2,000, 3,000, 4,000, 5,000, 7,500, 10,000, 15,000, 25,000, 50,000, or more nucleotides in length. In some embodiments, the RNA is between 250 and 1,000 nucleotides in length. In some embodiments, the RNA is a pre-RNA, pre-miRNA, or pretranscript. In some embodiments, the RNA is a non-coding RNA (ncRNA). messenger RNA (mRNA), micro-RNA (miRNA), a ribozyme, riboswitch, IncRNA, lincRNA, snoRNA, snRNA, scaRNA, piRNA, ceRNA, pseudo-gene, viral RNA, or bacterial RNA. The term “target RNA” or “target TCF4 RNA transcript” as used herein, means any type of RNA having or capable of adopting a secondary or tertiary' structure that is capable of binding a small molecule ligand described herein. The target RNA may be inside a cell, in a celllysate, or in isolated form prior to contacting the small molecule.

[0068] As used herein, the term “independently” means independently for each occurrence.3. Compounds of the invention:

[0069] In certain embodiments, the present invention provides a compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein:Ring X is phenyl, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each Rxis Ring Y or R', provided that no more than one Rxis Ring Y;Ring Y is an optionally substituted group selected from 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-11 membered saturated or partially unsaturated bicyclic or spirocyclic carbocyclic ring, or a 7-11 membered saturated or partially unsaturated bicyclic or spirocyclic heterocyclic ring with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring Y is optionally substituted with y instances of Ry;each X1. X2. X3, X4, and X5is independently carbon or nitrogen:each L1and L2is independently a covalent bond or an optionally substituted Ci-s bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-3 methylene units of the chain are independently and optionally replaced with -Cy-, -C(R')2-, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, - S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, or-NRC(O)O-;R1is hydrogen or Ci-6 aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms, provided that R1is not hydrogen when L1is a covalent bond;R2is hydrogen, halogen, -CN, or Cue aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms, provided that R2is not hydrogen when L2is a covalent bond;each R3is independently selected from Ci.g aliphatic, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, - S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -N(R)C(O)N(R)2, and -NRS(O)2R, wherein one instance of R3may be a ring selected from phenyl, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is optionally substituted with x instances of Rx;each R', Ry, and R4is independently selected from C1-6 aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, - C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, - N(R)C(O)N(R)2, and -NRS(O)2R;each -Cy- is independently an optionally substituted bivalent ring selected from phenylene, an 8-10 membered bicyclic carbocyclic aromatic ring, a 4-7 membered saturated or partially unsaturated carbocyclylene, a 6-11 membered saturated or partially unsaturated spirocyclic carbocyclylene, an 8-10 membered bicyclic, saturated or partially unsaturated carbocyclylene, a 4-7 membered saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6-11 membered saturated or partially unsaturated spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic, saturated or partially unsaturated, heterocyclylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroarylene having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each R is independently hydrogen or an optionally substituted group selected from C1-6aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur;w is 0, 1, or 2;x is 0, 1, 2, 3, or 4;y is 0, 1, 2, 3, or 4; andz is 0, 1, 2, or 3.

[0070] In certain embodiments, the present invention provides a compound of Formula I':or a pharmaceutically acceptable salt thereof, wherein:Ring X is phenyl, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each Rxis Ring Y or R', provided that no more than one Rxis Ring Y;Ring Y is an optionally substituted group selected from 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-11 membered saturated or partially unsaturated bicyclic, bridged bicyclic, or spirocyclic carbocyclic ring, or a 7-11 membered saturated or partially unsaturated bicyclic, bridged bicyclic, or spirocyclic heterocyclic ring with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring Y is optionally substituted with y instances of Ry:each X1, X2, X3, X4, and X3is independently carbon or nitrogen;each L1and L2is independently a covalent bond or an optionally substituted Ci-s bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-3 methylene units of the chain are independently and optionally replaced with -Cy-, -C(R')2-, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, - S(O)-, -S(O)2-, -NRS(O)2-. -S(O)2NR-. -NRC(O)-, -C(O)NR-, -OC(O)NR-, or-NRC(O)O-;R1is hydrogen, Ci-6 aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms, a 5-11 membered saturated or partially unsaturated spirocyclic carbocyclic ring, a 4-10 membered bicyclic, saturated or partially unsaturated, carbocyclic ring, a 5-11 membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 4-10 membered bicyclic or bridged bicyclic, saturated or partially unsaturated, heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, provided that R1is not hydrogen when L1is a covalent bond;R2is hydrogen, halogen, -CN, Ci-e aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms, a 5-11 membered saturated or partially unsaturated spirocyclic carbocyclic ring, a 4-10 membered bicyclic, saturated or partially unsaturated carbocyclic ring, a 5-11 membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 4-10 membered bicyclic or bridged bicyclic, saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, provided that R2is not hydrogen when L2is a covalent bond;each R3is independently selected from Ci-e aliphatic, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, - S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -N(R)C(O)N(R)2, and -NRS(O)2R, wherein one instance of R3may be a ring selected from phenyl, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is optionally substituted with x instances of Rx;each R' and R4is independently selected from Ci-e aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, - C(O)OR. -C(O)NR2, -C(O)NROR, -OC(O)R -OC(O)NR2, -NRC(O)OR, -NRC(O)R_ -N(R)C(O)N(R)2, and -NRSfO R, ortwo R' groups on the same saturated carbon atom are optionally taken together to form =0; each Ryis independently selected from a C1-6 aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms, a 4-7 membered saturated or partially unsaturated carbocyclic ring, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, - C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR. -OC(O)R, -OC(O)NR2. -NRC(O)OR, -NRC(0)R. - N(R)C(O)N(R)2, and -NRS(O)2R, ortwo Rygroups on the same saturated carbon atom are optionally taken together to form =0; each -Cy- is independently an optionally substituted bivalent ring selected from phenylene, an 8-10 membered bicyclic carbocyclic aromatic ring, a 4-7 membered saturated or partially unsaturated carbocyclylene, a 6-11 membered saturated or partially unsaturated spirocyclic carbocyclylene, an 8-10 membered bicyclic, saturated or partially unsaturated, carbocyclylene, a 4-7 membered saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-11 membered saturated or partially unsaturated spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 memberedbicyclic or bridged bicyclic, saturated or partially unsaturated, heterocyclylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered hcteroar lcnc having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroary lene having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen or an optionally substituted group selected from Ci-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently- selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur;w is 0, 1, or 2;x is 0, 1, 2, 3, or 4;y is 0, 1, 2, 3, or 4; andz is 0, 1, 2, or 3.

[0071] For purposes of clarity, it is understood that X'-X' can be N or C, wherein each C atom is substituted by a sufficient number of hydrogen atoms for a complete valence. It is also understood that one or more substitutable hydrogen atoms of X'-X3may be replaced by R3or R4, as shown in Formulas I, and I', and I", and other formulas herein.

[0072] In certain embodiments, tire present invention provides a compound of Formula I”:or a pharmaceutically acceptable salt thereof, wherein:Ring X is phenyl, a 5-6 membered monocyclic hctcroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each Rxis Ring Y or R', provided that no more than one Rxis Ring Y;Ring Y is an optionally substituted group selected from a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-11 membered saturated or partially unsaturated bicyclic, bridged bicyclic, or spirocyclic carbocyclic ring, or a 7-12 membered saturated or partially unsaturated bicyclic, bridged bicyclic, tricyclic, or spirocyclic heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring Y is optionally substituted with y instances of Ry:each X1, X2, X3, X4, and X5is independently CH or N;each L1and L2is independently a covalent bond or an optionally substituted Ci-s bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-4 methylene units of the chain are independently and optionally replaced with -Cy-, -C(R')2-, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, - S(O)-, -S(O)2-. -NRS(O)2-. -S(O)2NR-. -NRC(O)-, -C(O)NR-, -OC(O)NR-, or-NRC(O)O-;R1is hydrogen, Ci.e aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms, a 5-11 membered saturated or partially unsaturated spirocyclic carbocyclic ring, a 4-10 membered bicyclic, saturated or partially unsaturated carbocyclic ring, a 5-11 membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 4-10 membered bicyclic or bridged bicyclic, saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, provided that R1is not hydrogen when L1is a covalent bond;R2is hydrogen, halogen, -CN, Ci-6 aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms, a 5-11 membered saturated or partially unsaturated spirocyclic carbocyclic ring, a 4-10 membered bicyclic, saturated or partially unsaturated carbocyclic ring, a 5-11 membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 4-10 membered bicyclic or bridged bicyclic, saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, provided that R2is not hydrogen when L2is a covalent bond;each R3is independently selected from optionally substituted Cue aliphatic, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -P(O)R2. -P(O)(OR)2, -C(O)R, -C(O)OR, -C(O)NR2. -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -N(R)C(O)N(R)2, and -NRS(O)2R, wherein one instance of R3may be a ring selected from phenyl, a 5-6 membered monocyclic heteroaromatic ring having 1 -4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is optionally substituted with x instancesof Rx;each R' and R4is independently selected from Ci-6 aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, - C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -N(R)C(O)N(R)2, and -NRS(O)2R, ortwo R' groups on the same saturated carbon atom are optionally taken together to form =0; each Ryis independently selected from an optionally substituted Ci.e aliphatic, an optionally substituted 3- 7 membered saturated or partially unsaturated carbocyclic ring, an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, halogen, -CN, -N02, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, - C(O)R, -C(O)OR, -C(0)NR2, -C(0)NR0R, -OC(O)R, -0C(0)NR2, -NRC(O)OR, -NRC(0)R. - N(R)C(0)N(R)2. -NRS(O)2R, and -C1.4 alkylene-Cy, or:two Rygroups on the same saturated carbon or sulfur atom are optionally taken together to form =O:each - Cy- is independently an optionally substituted bivalent ring selected from phenylene, an 8-10 membered bicyclic carbocyclic aromatic ring, a 4-7 membered saturated or partially unsaturated carbocyclylene, a 6-11 membered saturated or partially unsaturated spirocyclic carbocyclylene, an 8-10 membered bicyclic, saturated or partially unsaturated carbocyclylene, a 4-7 membered saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-11 membered saturated or partially unsaturated spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6-10 membered bicyclic or bridged bicyclic, saturated or partially unsaturated, heterocyclylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic hctcroarylcnc having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur: each R is independently hydrogen or an optionally substituted group selected from Ci-e aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur;w is 0, 1, or 2;x is 0, 1, 2, 3, or 4;y is 0, 1, 2, 3, 4, 5, or 6; andz is 0, 1, 2, or 3.

[0073] In some embodiments, the compound is not selected from one of the following:thereof.

[0074] In some embodiments, the compound is not selected from one of those described in US 2023 / 0193265, which is incorporated in its entirety herein by reference.

[0075] In some embodiments, when X5is CH substituted by R3, then R3is not optionally substituted Ci-6 aliphatic, halogen, -OR, or -NO2.

[0076] In some embodiments of Formula I, I', and I", the compound is of Formula I-a, I-b, I-c, I-d, I-e, or I-f:or a pharmaceutically acceptable salt thereof.

[0077] In some embodiments, the compound is of Formula I-a-1, 1-a-2, or I-a-3:or a pharmaceutically acceptable salt thereof.

[0078] In some embodiments, the compound is of Formula I-a-4:I-a-4or a pharmaceutically acceptable salt thereof.

[0079] In some embodiments, tire compound is of Formula I-a-5:La-5or a pharmaceutically acceptable salt thereof.

[0080] In some embodiments, the compound is of Formula La-6:La-6or a pharmaceutically acceptable salt thereof.

[0081] In some embodiments, the compound is of Formula I-d-1:Ld-1or a pharmaceutically acceptable salt thereof.

[0082] In some embodiments, the compound is of Formula Ld-2:I-d-2or a pharmaceutically acceptable salt thereof.

[0083] In some embodiments, the compound is of Formula I-d-3:I-d-3or a pharmaceutically acceptable salt thereof.

[0084] In certain embodiments, the present invention provides a compound of Formula II:or a pharmaceutically acceptable salt thereof, wherein:Ring Y is selected from a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-11 membered saturated or partially unsaturated bicyclic, bridged bicyclic, or spirocyclic carbocyclic ring, or a 7-12 membered saturated or partially unsaturated bicyclic, bridged bicyclic, tricyclic, or spirocyclic heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each L1and L2is independently a covalent bond or an optionally substituted C bivalent straight orbranched saturated or unsaturated hydrocarbon chain wherein 1-4 methylene units of the chain are independently and optionally replaced with -Cy-, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, - S(O)2-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, or-NRC(O)O-;R1is hydrogen, Ci-6 aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms, a 5-11 membered saturated or partially unsaturated spirocyclic carbocyclic ring, a 4-10 membered bicyclic, saturated or partially unsaturated carbocyclic ring, a 5-11 membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 4-10 membered bicyclic or bridged bicyclic, saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, provided that R1is not hydrogen when L1is a covalent bond;R2is hydrogen, halogen, -CN, Ci-6 aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms, a 5-11 membered saturated or partially unsaturated spirocyclic carbocyclic ring, a 4-10 membered bicyclic, saturated or partially unsaturated carbocyclic ring, a 5-11 membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 4-10 membered bicyclic or bridged bicyclic, saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, provided that R2is not hydrogen when L2is a covalent bond;R3ais an optionally substituted Ci-6 aliphatic, halogen, -OR or -NO2;R3band R3care independently selected from hydrogen, halogen, -CN, -NO2, -OR, -SR -NR2, -S(O)2R, - S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -N(R)C(O)N(R)2, -NRS(O)2R and an optionally substituted Ci-e aliphatic;R4is selected from hydrogen, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R. -OC(O)NR2, -NRC(O)OR. -NRC(O)R, - N(R)C(O)N(R)2, -NRS(O)2R, and Ci-6 aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms;each Rxis independently selected from hydrogen, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, - S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -N(R)C(O)N(R)2, -NRS(O)2R, and Ci-6 aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms;each Ryis independently selected from halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, - N(R)C(O)N(R)2, -NRS(O)2R, -CI-4 alkylene-Cy, an optionally substituted Ci-e aliphatic, an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring, and an optionallysubstituted 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, ortwo Rygroups on the same saturated carbon or sulfur atom are optionally taken together to form =0;each -Cy- is independently an optionally substituted bivalent ring selected from phenylene, an 8-10 membered bicyclic carbocyclic aromatic ring, a 4-7 membered saturated or partially unsaturated carbocyclylene, a 6-11 membered saturated or partially unsaturated spirocyclic carbocyclylene, an 8-10 membered bicyclic, saturated or partially unsaturated carbocyclylene, a 4-7 membered saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-11 membered saturated or partially unsaturated spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6-10 membered bicyclic or bridged bicyclic, saturated or partially unsaturated, heterocyclylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroarylene having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen or an optionally substituted group selected from Ci-e aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur;x is 1 or 2; andy is 0, 1, 2, 3, or 4.

[0085] In certain embodiments, the present invention provides a compound of Formula Il-a:Il-aor a pharmaceutically acceptable salt thereof, wherein:Ring Y is a 6-7 membered saturated or partially unsaturated monocyclic heterocycle having 1 -3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-12 membered saturated or partially unsaturated bicyclic or tricyclic, heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-11 membered saturated or partially unsaturated bridged bicyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered saturated or partially unsaturated spirocyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Ring S is phenyl, a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-9 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 3-6 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Ring T is phenyl, a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 5-6 membered monocyclic heteroaromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially unsaturated monocyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6-10 membered saturated or partially unsaturated bicyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6-10 membered saturated or partially unsaturated bridged bicyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 6-10 membered saturated or partially unsaturated spirocyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;L1is a covalent bond or an optionally substituted C i bivalent straight or branched, saturated or unsaturated hydrocarbon chain wherein 1-4 methylene units of the chain are independently and optionally replaced with -O-. -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, - C(O)NR-, -OC(O)NR-, or-NRC(O)O-;R3ais an optionally substituted Ci-6 aliphatic, halogen, -OR or -NO2;R3band R3care independently selected from hydrogen, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, - S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -N(R)C(O)N(R)2, -NRS(O)2R, and Ci-6 aliphatic optionally substituted with 1, 2, or 3deuterium or halogen atoms;R4is selected from hydrogen, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -N(R)C(O)N(R)2, -NRS(O)2R, and C1-6aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms;each Rxis independently selected from hydrogen, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -N(R)C(O)N(R)2, -NRS(O)2R, and C1-6aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms;each Ry, Rs, and R‘ is independently selected from halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -N(R)C(O)N(R)2, -NRS(O)2R, an optionally substituted C1-6aliphatic, an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring, and an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; ortwo Rygroups on the same saturated carbon atom are optionally taken together to form =O, or two Rsgroups on the same saturated carbon atom are optionally taken together to form =O, or two Rtgroups on the same saturated carbon atom are optionally taken together to form =O; each R is independently hydrogen or an optionally substituted group selected from C1-6aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur;s is 0, 1, 2, 3, or 4;t is 0, 1, 2, 3, or 4;x is 1 or 2; andy is 0, 1, 2, 3, or 4.

[0086] In some embodiments, the compound is of Formula II-a-1, II-a-2, or II-a-3:II-a-3or a pharmaceutically acceptable salt thereof.

[0087] In some embodiments, the compound is of Formula II-a-4, II-a-4', or II-a-4":II-a-4"or a pharmaceutically acceptable salt thereof.

[0088] In some embodiments, the compound is of Formula II-a-5, II-a-5', or II-a-5":or a pharmaceutically acceptable salt thereof.

[0089] In some embodiments, the compound is of Formula II-a-6:or a pharmaceutically acceptable salt thereof.

[0090] In some embodiments, the compound is of Formula II, II-a-1, II-a-2, II-a-3, II-a-4, or II-a-5:IIor a pharmaceutically acceptable salt thereof, wherein:Ring Y is:

[0091] In some embodiments, for any one of the foregoing formulas, R3ais halogen.

[0092] In some embodiments, for any one of the foregoing formulas, R3ais fluoro.

[0093] In some embodiments, for any one of the foregoing formulas, R3ais -OR.

[0094] In some embodiments, for any one of the foregoing formulas, R3ais -OMe.

[0095] In some embodiments, for any one of the foregoing formulas, R3bis hydrogen.

[0096] In some embodiments, for any one of tire foregoing fonnulas, R3bis fluoro.

[0097] In some embodiments, for any one of the foregoing formulas, R3cis hydrogen.

[0098] In some embodiments, for any one of the foregoing formulas. R3cis methyl.

[0099] In some embodiments, for any one of the foregoing formulas, Rxis hydrogen.

[0100] In some embodiments, for any one of the foregoing formulas, R4is hydrogen.

[0101] In some embodiments, for any one of the foregoing formulas, R3band R3care each hydrogen.

[0102] In some embodiments, for any one of tire foregoing fonnulas, R3b, R3c, and Rxare each hydrogen.

[0103] In some embodiments, for any one of the foregoing formulas, R3b. R3c, and R4are each hydrogen.

[0104] In some embodiments, for any one of the foregoing formulas. R3b, R3c. Rx, and R4are each hydrogen.

[0105] In some embodiments, the compound is of Formula II-a-7:II-a-7or a pharmacally acceptable salt thereof.

[0106] As defined generally above, each X1, X2, X3, X4, and X' is independently carbon or nitrogen.

[0107] In some embodiments, X1is carbon. In some embodiments, X1is nitrogen. In some embodiments, X2is carbon. In some embodiments, X2is nitrogen. In some embodiments, X3is carbon. In some embodiments, X3is nitrogen. In some embodiments, X4is carbon. In some embodiments, X4is nitrogen. In some embodiments, X5is carbon. In some embodiments, X5is nitrogen.

[0108] In some embodiments, X1is nitrogen and X2, X3, X4, and X5are carbon. In some embodiments, X1and X2are nitrogen and X3, X4, and X5are carbon. In some embodiments, X2is nitrogen and X1, X3, X4, and Xsare carbon. In some embodiments, X1and X are nitrogen and X2, X3, and X5are carbon. In some embodiments, X1, X3and X4are nitrogen and X2and X5are carbon. In some embodiments, X1, X4and X5are nitrogen and X2and X3are carbon.

[0109] In some embodiments, X1is selected from those depicted in the compounds of Table la or Table lb below.

[0110] In some embodiments, X2is selected from those depicted in the compounds of Table la or Table lb below.[OHl] In some embodiments, X3is selected from those depicted in tire compounds of Table la or Table lb below.

[0112] In some embodiments, X4is selected from those depicted in the compounds of Table la or Table lb below.

[0113] In some embodiments, Xsis selected from those depicted in the compounds of Table la or Table lb below.

[0114] As defined generally above, Ring X is phenyl, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0115] In some embodiments, Ring X is phenyl. In some embodiments, Ring X is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring X is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0116] In some embodiments. Ring Xis selected from those depicted in the compounds of Table la or Table lb below.,.. In some embodiments. Ring X is. In some embodiments. Ring X is. In someembodiments. Ring X is. In some embodiments, Ring X is. In some embodiments,Ring

[0119] In some embodiments, Ring X is

[0120] As defined generally above, each Rxis Ring Y or R', provided that no more than one Rxis Ring Y.

[0121] In some embodiments, one Rxis Ring Y. In some embodiments, each Rxis R'.

[0122] In some embodiments, one or more Rxis -CH3. In some embodiments, one or more Rxis -OMc. In some embodiments, one or more Rxis -Cl. In some embodiments, one or more Rxis -F. In some embodiments, one or more Rxis -N(Me)2.

[0123] In some embodiments, Rxis -NH2.

[0124] In some embodiments, Rxis -N(R)CH2-Ring Y, wherein Ring Y is optionally substituted with 0, 1, 2, 3, or 4 instances of Ry. In some embodiments, Rxis -NHCH2-Ring Y, wherein Ring Y is optionally substituted with 0, 1, 2, 3, or 4 instances of Ry.

[0125] In some embodiments,some embodiments,

[0126] In some embodiments, Rxis selected from those depicted in the compounds of Table la or Table lb below.

[0127] In some embodiments, Ring X taken together with (Rx)x

[0131] In some embodiments. Ring X taken togetherIn someembodiments, Ring X taken togethersome embodiments, Ring Xtaken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xisIn someembodiments, Ring X taken togethersome embodiments, Ring X takentogetherIn some embodiments, Ring X taken together with (Rx)xissome embodiments, Ring X taken togetherIn some embodiments, Ringsome embodiments, Ring X taken togetherIn some embodiments. Ringsome embodiments, Ring XX taken togethersome embodiments, Ring X taken together with (Rx)xIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring X taken togetherIn some embodiments, Ring X taken togethersome embodiments, Ring X taken togetherIn some embodiments, Ring X taken togetherIn some embodiments, Ring X taken togetherIn some embodiments. Ring X taken togetherIn some embodiments, Ring X taken togetherIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring X taken togetherembodiments, Ring X taken togethersome embodiments, Ring X taken togetherIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring X taken togetherIn some embodiments, Ring X taken togethersome embodiments, Ring X taken togethersome embodiments, Ring X taken together withx,In some embodiments, Ring X taken together with (Rx)xisIn some embodiments. Ring X taken togetherIn some embodiments, Ring X takenembodiments, Ring X taken together with (Rx)xisIn some embodiments. Ring X taken together withIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring X taken togetherembodiments, Ringtogether with (Rx)xisIn some embodiments. Ring X taken together with (Rx)xisIn some embodiments. Ring X taken togethersome embodiments. Ring X taken togetherIn some embodiments, Ring X taken together with (Rx)xis. In some embodiments. Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xis. In some embodiments. Ring X taken together with (Rx)xisIn some embodiments. Ring X taken togetherembodiments. Ring X taken togethersome embodiments, Ring X taken togetherIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together. In someIn some embodiments, Ring X taken togetherIn some embodiments, Ring X taken togetherIn some embodiments. Ring X taken togethersome embodiments. Ring X taken together withIn some embodiments, Ring X taken together. In some embodiments, Ring X taken togethersome embodiments, Ring X taken togethersome embodiments, Ring X taken togetherIn some embodiments, Ring X taken togetherIn some embodiments,,embodiments, Ring X taken togethersome embodiments, Ring X takentogether withIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments. Ring X taken together with (Rx)xissome embodiments, Ring X taken togetherIn some embodiments,Ring X taken together withIn some embodiments. Ring X taken togetherIn some embodiments. Ring X taken together with (Rx)xissome embodiments, Ring X taken togethersome embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together,Ring X taken together

[0132] In some embodiments, Ring X taken togetherIn someembodiments, Ring X taken togetherIn some embodiments, Ring Xtaken togetherIn some embodiments, Ring X taken together with ( R )some embodiments, Rsome embodiments. Ring X taken togethersome embodiments,Ring X taken togetherIn some embodiments. Ring X taken togethersome embodiments, Ring X taken together. In some embodiments, Ring X taken together with (Rx)xisIn some embodiments. Ring X taken together with (Rx)xisIn some embodiments, Ring X taken togetherRing X taken togetherIn some embodiments, Ring X taken together withsome embodiments, Ring X taken togetherIn some embodiments, Ring X taken togethersome embodiments, Ring X taken togetherIn some embodiments. Ring X taken together with (Rx)xembodiments, Ring X taken togetherIn some embodiments, Ring X taken togetherIn some embodiments, Ring X taken together with (Rx)xisents, Ring X taken togetherIn some embodiments, Ring X taken together withIn some embodiments, Ring X taken togethergx., g gxIn some embodiments, Ring X taken togetherembodiments, Ring X taken togetherIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring X taken togethersome embodiments, Ring X taken togethersome embodiments, RingIn some embodiments, Ring X taken togetherIn some embodiments, Ring X taken togethersome embodiments, Ring X taken togetherIn some embodiments. Ring X taken togethersome embodiments. Ring X taken togetherIn some embodiments, Ring X taken togetherIn some embodiments. Ring X taken together with ( R )In some embodiments. Ring X taken togethersome embodiments, Ring X taken togethersome embodiments, Ring.some embodiments. RiX taken togethersome embodiments, Ring X taken together with (Rx)xIn some embodiments.some embodiments, Ring X taken togethersome embodiments, RingIn some embodiments, Ring X taken togethersome embodiments.Ring X taken togethersome embodiments. Ring X taken togetherIn some embodiments, Ring X taken togetherIn some embodiments, Ring X taken together with (Rx)xIn some embodiments, Ring X taken togethersome embodiments, Ring X taken together,In some embodiments, Ring X taken together withIn some embodiments,Ring X taken together. In some embodiments, Ring X taken together with (Rx)xRing X taken togethersome embodiments, Ring X taken together,. In some embodiments. Ring X taken togethersome embodiments, Ring Xtaken togetherIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring X taken togetherembodiments, Ring X taken togetherIn some embodiments, Ring X taken togethersome embodiments, Ring X taken together with (Rx):.Ring X taken togethersome embodiments, Ring X taken together,In some embodiments, Ring X taken togetherIn some embodiments, Ring X taken togetherIn some embodiments, RingIn some embodiments, Ring X taken together with (Rx)xisembodiments, Ring X taken togethersome embodiments, Ring X takentogether with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xis,In some embodiments. Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xis In some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xis

[0134] In some embodiments, Ring X taken togetherIn some embodiments,Ring X taken togetherIn some embodiments, Ring X taken together with (Rx)xIn some embodiments, Ring X taken togetherIn some embodiments, Ring X taken togetherIn some embodiments, Ring XIn some embodiments, Ring X taken togetherIn some embodiments, Ring X taken togethersome embodiments, Ring Xtaken togetherIn some embodiments, Ring X taken together with (Rx)xissome embodiments, Ring X taken togethersome embodiments, Ring,some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xemX taken together with (Rx)xisIn some embodiments. Ring X taken together with (Rx)xIn some embodiments, Ring X taken together with (Rx)xis In some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xisembodiments, Ring X taken togethersome embodiments, Ring X. g gxsIn some embodiments, Ring X taken together with (Rx)xis

[0135] As defined generally above. Ring Y is an optionally substituted group selected from 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-11 membered saturated or partially unsaturated bicyclic, bridged bicyclic, or spirocyclic carbocyclic ring, or a 7-11 membered saturated or partially unsaturated bicyclic, bridged bicyclic, or spirocyclic heterocyclic ring with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring Y is optionally substituted with y instances of Ry.

[0136] In some embodiments, Ring Y is an optionally substituted group selected from 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-11 membered saturated or partially unsaturated bicyclic or spirocyclic carbocyclic ring, or a 7- 11 membered saturated or partially unsaturated bicyclic or spirocyclicheterocyclic ring with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring Y is optionally substituted with y instances of Ry.

[0137] In some embodiments, Ring Y is an optionally substituted group selected from 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring Y is optionally substituted with y instances of Ry. In some embodiments, Ring Y is a 7-11 membered saturated or partially unsaturated bicyclic or spirocyclic carbocyclic ring, wherein Ring Y is optionally substituted with y instances of Ry. In some embodiments. Ring Y is a 7-11 membered saturated or partially unsaturated bicyclic or spirocyclic heterocyclic ring with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring Y is optionally substituted with y instances of Ry.

[0138] In some embodiments, Ring Y is a 7-11 membered saturated or partially unsaturated bicyclic, bridged bicyclic, or spirocyclic carbocyclic ring, wherein Ring Y is optionally substituted with y instances of Ry. In some embodiments. Ring Y is a 7-11 membered saturated or partially unsaturated bicyclic, bridged bicyclic, or spirocyclic heterocyclic ring with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring Y is optionally substituted with y instances of Ry.

[0139] As defined generally above for Formula I", Ring Y is an optionally substituted group selected from 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-11 membered saturated or partially unsaturated bicyclic, bridged bicyclic, or spirocyclic carbocyclic ring, or a 7-12 membered saturated or partially unsaturated bicyclic, bridged bicyclic, tricyclic, or spirocyclic heterocyclic ring with 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring Y is optionally substituted with y instances of Ry.

[0140] In some embodiments, Ring Y is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Y is a 7-11 membered saturated or partially unsaturated bicyclic, bridged bicyclic, tricyclic, or spirocyclic heterocyclic ring with 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0141] In some embodiments, Ring Y is a 7-11 membered saturated or partially unsaturated bicyclic heterocyclic ring with 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments. Ring Y is a 7-11 membered saturated or partially unsaturated bridged bicyclic heterocyclic ring with 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments. Ring Y is a 7-11 membered saturated or partially unsaturated tricyclic heterocyclic ring with 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Y is a7-11 membered saturated or partially unsaturated spirocyclic heterocyclic ring with 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0142] As defined generally above for Formula II, Ring Y is selected from a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-11 membered saturated or partially unsaturated bicyclic, bridged bicyclic, or spirocyclic carbocyclic ring, or a 7-12 membered saturated or partially unsaturated bicyclic, bridged bicyclic, tricyclic or spirocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0143] In some embodiments, Ring Y is selected from 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-11 membered saturated or partially unsaturated bicyclic, bridged bicyclic, or spirocyclic carbocyclic ring, or a 7-12 membered saturated or partially unsaturated bicyclic, bridged bicyclic, tricyclic or spirocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0144] As defined generally above for Formula Il-a, Ring Y is a 6-7 membered saturated or partially unsaturated monocyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-12 membered saturated or partially unsaturated bicyclic or tricyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-11 membered saturated or partially unsaturated bridged bicyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered saturated or partially unsaturated spirocyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0145] In some embodiments, Ring Y is a 6-7 membered saturated or partially unsaturated monocyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Y is a 7-12 membered saturated or partially unsaturated bicyclic or tricyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Y is a 7-11 membered saturated or partially unsaturated bridged bicyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Y is a 7-10 membered saturated or partially unsaturated spirocyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments. Ring Y is a an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0146] In some embodiments, Ring Y isH<" N—

[0149] In some embodiments, Ring Y is. In some embodiments, Ring Y is. Insome embodiments. Ring Y is. In some embodiments, Ring Y isIn someembodiments, Ring Y is. In some embodiments, Ring Y is. In some embodiments,HN' X N— IRing YIn some embodiments, Ring Y is v v « In some embodiments, Ring Y is. In some embodiments. Ring Y is. In some embodiments, Ring Y is. Insome embodiments, Ring Y isIn some embodiments, Ring Y is O. In someembodiments, Ring Y is. In some embodiments, Ring Y. In someembodiments, Ring Y isIn some embodiments. RingIn someembodiments, Ring

[0150] In some embodiments, Ring Y is. In some embodiments, Ring Y is. Insome embodiments, Ring Y is. In some embodiments, Ring Y is. In someembodiments, Ring Y isIn some embodiments, Ring Y isIn someembodiments, Ring Y isIn some embodiments, Ring Y isIn some HN j N-embodiments, Ring Y is. In some embodiments, Ring Y is. In some embodiments,Ring Y is. In some embodiments, Ring Y is. In some embodiments, Ring Y isIn some embodiments, Ring Y isIn some embodiments, Ring Y isH HIn some embodiments, Ring Y isIn some embodiments, Ring Y is. In someembodiments. Ring Y isIn some embodiments, Ring Y isIn some embodiments, Ring

[0151] In some embodiments, Ring Y isIn some embodiments, Ringsomeembodiments, Ring Y isIn some embodiments, Ring Y isIn some embodiments. In some embodiments, Ring Y isIn some embodiments, Ring Y isbodiments, Ring Y isIn some embodiments, Ring Y issome embodiments, Ring Y isIn some embodiments, Ring Y isIn some embodiments. Ring Y isIn some embodiments. Ring Y isIn some embodiments, Ring Y isIn some embodiments, Ring YIn some embodiments, Ring Y isIn some embodiments, Ring Y isIn some embodiments, Ring Y is. In some embodiments, Ring Y isIn some embodiments, Ring Y isembodiments, Ring Y isIn some embodiments, Ring Y isIn some embodiments,Ring Y isIn some embodiments, Ring Y isIn some embodiments. Ring Y isXIn some embodiments, Ring Y is O. In some embodiments, Ring Y is. In some embodiments, Ring Y is. In some embodiments, RingIn some embodiments, Ring Y isIn some embodiments, RingIn some embodiments, Ring Y isIn some embodiments. RingIn some embodiments. Ring Y isIn some embodiments. Ring Y isIn some embodiments, Ring Y isIn someembodiments, RingIn some embodiments. Ringsome embodiments,Ringsome embodiments, Ring Y isIn some embodiments, Ring Y isIn some embodiments, Ring Y is ° In some embodiments, Ring Y isIn some embodiments, Ring Y isIn some embodiments, Ring Y isIn some embodiments, Ring Y isIn some embodiments, Ring Y isIn some embodiments, Ring Y isIn some embodiments, Ring Y isIn some embodiments, Ring Y isIn some embodiments, Ring Y isIn some embodiments, Ring

[0152] In some embodiments, Ring Y isIn some embodiments. Ringsomeembodiments, RingIn some embodiments. Ring Y isIn some,, embodiments, RingIn some embodiments, Ring Y isIn some embodiments, Ring Y isIn some embodiments, Ring Y isIn some embodiments, Ring Y isIn some embodiments, Ring Y isIn someembodiments, Ring Y is0In some embodiments, Ring Y isIn some embodiments. Ring Y isIn some embodiments, Ring Y isIn someembodiments, Ring Y isIn some embodiments. Ring Y isIn someembodiments, Ring Y isIn some embodiments, Ring

[0153] In some embodiments, Ring Y is selected from those depicted in tire compounds of Table la or Table lb below.

[0154] As defined generally above for Formula I, each R', Ry, and R4is independently selected from Ci-e aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -N(R)C(O)N(R)2, and -NRS(O)2R.

[0155] As defined generally above for Formula I', each R' and R4is independently selected from Ci-6 aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -N(R)C(O)N(R)2, and -NRS(O)2R, or two R' groups on tire same saturated carbon atom are optionally taken together to form =0.

[0156] In some embodiments, each R' is independently selected from Cue aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -N(R)C(O)N(R)2, and -NRS(O)2R.

[0157] In some embodiments, one or more R' is Ci-6 aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms. In some embodiments, one or more is Ci-6 aliphatic. In some embodiments, one or more R' is halogen. In some embodiments, one or more R' is -CN. In some embodiments, one or more R' is -NO2. In some embodiments, one or more R' is -OR. In some embodiments, one or more R' is -SR. In some embodiments, one or more R' is -NR2. In some embodiments, one or more R' is -S(O)2R. In some embodiments, one or more R' is -S(O)2NR2. In some embodiments, one or more R' is -S(O)R. In some embodiments, one or more R' is -C(O)R. In some embodiments, one or more R' is -C(O)OR. In some embodiments, one or more R' is -C(O)NR2. In some embodiments, one or more R' is -C(O)NROR. In some embodiments, one or more R' is -OC(O)R. In some embodiments, one or more R' is -OC(O)NR2. In some embodiments, one or more R' is -NRC(O)OR. In some embodiments, one or more R' is -NRC(O)R. In some embodiments, one or more R' is -N(R)C(O)N(R)2. In some embodiments, one or more R' is -NRS(O)2R.

[0158] In some embodiments, two R' groups on the same saturated carbon atom are taken together to form =0

[0159] In some embodiments, R' is -CF3.

[0160] In some embodiments, R' is selected from those depicted in tire compounds of Table la or Table lb below.

[0161] In some embodiments, each Ryis independently selected from Ci-6 aliphatic, halogen, -CN. -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -N(R)C(O)N(R)2, and -NRS(O)2R.

[0162] In some embodiments, one or more Ryis Ci-e aliphatic. In some embodiments, one or more Ryis halogen. In some embodiments, one or more Ryis -CN. In some embodiments, one or more Ryis -NO2. In some embodiments, one or more Ryis -OR. In some embodiments, one or more Ryis -SR. In some embodiments, one or more Ryis -NR2. In some embodiments, one or more Ryis -S(O)2R. In some embodiments, one or more Ryis -S(O)2NR2. In some embodiments, one or more Ryis -S(O)R. In some embodiments, one or more Ryis -C(O)R. In some embodiments, one or more Ryis -C(O)OR. In some embodiments, one or more Ryis -C(O)NR2. In some embodiments, one or more Ryis -C(O)NROR. In some embodiments, one or more Ryis -OC(O)R. In some embodiments, one or more Ryis -OC(O)NR2. In some embodiments, one or more Ryis -NRC(O)OR. In some embodiments, one or more Ryis -NRC(O)R. In some embodiments, one or more Ryis -N(R)C(O)N(R)2. In some embodiments, one or more Ryis -NRS(O)2R.

[0163] As defined generally above for Formula I', each Ryis independently selected from Ci-e aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms, a 4-7 membered saturated or partially unsaturated carbocyclic ring, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfiir, halogen. -CN, -NO2. -OR, -SR, -NR2, -S(O)2R. -S(O)2NR2. -S(O)R, -C(O)R. -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -N(R)C(O)N(R)2, and -NRS(O)2R, ortwo Rygroups on the same saturated carbon atom are optionally taken together to form =0.

[0164] In some embodiments, Ryis a 4-7 membered saturated or partially unsaturated carbocyclylene. In some embodiments, Ryis a 4-7 membered saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two Rygroups on the same saturated carbon atom are taken together to form =0.

[0165] As defined generally above for Formula I", each Ryis independently selected from an optionally substituted Cue aliphatic, an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring, an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclicring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -N(R)C(O)N(R)2, -NRS(O)2R, and -C1.4 alkylene-Cy, or: two Rygroups on tire same saturated carbon or sulfur atom are optionally taken together to form =0.

[0166] In some embodiments, Ryis an optionally substituted C1-6 aliphatic. In some embodiments, Ryis an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, Ryis an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0167] . In some embodiments, Ryis halogen. In some embodiments, Ryis -CN. In some embodiments, Ryis -NO2. In some embodiments, Ryis -OR. In some embodiments, Ryis -SR. In some embodiments, Ryis -NR2. In some embodiments, Ryis -S(O)2R. In some embodiments, Ryis -S(O)2NR2. In some embodiments. Ryis -S(O)R. In some embodiments. Ryis -C(O)R. In some embodiments, Ryis -C(O)OR. In some embodiments, Ryis -C(O)NR2. In some embodiments, Ryis -C(O)NROR. In some embodiments, Ryis -OC(O)R. In some embodiments, Ryis -OC(O)NR2. In some embodiments, R' is -NRC(O)OR. In some embodiments, Ryis -NRC(O)R. In some embodiments, Ryis -N(R)C(O)N(R)2. In some embodiments, Ryis -NRS(O)2R. In some embodiments, Ryis -C1.4 alkylene-Cy.

[0168] In some embodiments, Ryis methyl, ethyl, isopropyl, t-butyl,

[0171] In some embodiments, Ryis methyl. In some embodiments, Ryis ethyl. In some embodiments, RyOHis isopropyl. In some embodiments, Ryis t-butyl. In some embodiments, Ryisjnsome oembodiments, RyisIn some embodiments, RyisIn some embodiments, Ryis F, In some embodiments, Ryissomeembodiments, RyisIn some embodiments, RyisIn some embodiments, Ryis., , In someembodiments, Ryis. In some embodiments, Ryis. In some embodiments, Ryis, . In some embodiments. RyisIn someOembodiments, Ryis. In some embodiments, Ryis. In some embodiments, RyisO., . In some embodiments, Ryis.

[0172] In some embodiments, Ryis -CN. In some embodiments, Ryis -OMe. In some embodiments, Ryis chloro. In some embodiments, Ryis. In some embodiments, Ryis

[0173] In some embodiments. Ryis deuterium. In some embodiments. Ryis hydroxy. In some Oembodiments, Ryis fluoro. In some embodiments, Ryis. In some embodiments, Ryis. In some embodiments, Ryis. In some embodiments, Ryis. In some embodiments, Ryis., In some embodiments, RyisIn someembodiments, Ryis. In some embodiments, RyisIn some embodiments, Ryis OIn some embodiments, Ryis In some embodiments, RyisIn some embodiments, Ry, In some embodiments,some Iembodiments, RyisIn some embodiments, Ryis. In some embodiments, Ryis, In some embodiments, Ryissomeembodiments, Ryis. In some embodiments, Ryis

[0174] In some embodiments, two Rygroups on the same atom are oxo.

[0175] In some embodiments, Ryis selected from those depicted in the compounds of Table la or Table lb below.

[0179] In some embodiments, Ring Y taken together with. In some embodiments,Ring X taken together with (Rx)xIn some embodiments, Ring Y taken together withIn some embodiments, Ring X taken together with (Rx)xisIn someembodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring Y takenVN^,,Ztogether with (Ry)yisyIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments. Ring X taken together with (Rx)xis. In some embodiments. RingY taken together with (Ry)yisIn some embodiments. Ring X taken together with (Rx)xisIn someem o i e t, i g t kb m s n ad n R Y en together with (Ry)yis. In some embodiments, Ring Y takentogether with (Ry)yis. In some embodiments, Ring X taken together with (Rx)xis. In some embodiments. Ring X taken together with (Rx)xis. In some embodiments,Ring X taken together with (Rx)xis. In some embodiments, Ring X taken together with (Rx)x. In some embodiments, Ring X taken together with (Rx)xis. In someembodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring Y takentogether with (Ry)yis. In some embodiments, Ring X taken together with (Rx)xis. In some embodiments, Ring Y taken together withIn some cdembodiments, Ring X taken together with (Rx)xis. In some embodiments. Ring Y takentogether with (Ry)yisIn some embodiments. Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xisembodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring Y takentogetherIn some embodiments. Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments.Ring X taken together with (Rx)xisIn some embodiments. Ring X taken together with (Rx)xIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xis'TNVN^'some embodiments. Ring X taken together with (Rx)xis In some embodiments, Ring Y takentogether with (Ry)yis. In some embodiments, Ring X taken together with (Rx)xis. In some embodiments, Ring X taken together with (Rx)xisIn someembodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring Y taken[Ntogether with (Ry)yisIn some embodiments, Ring X taken together with (Rx)xis N.In some embodiments, Ring Y taken together withIn some embodiments, Ring Yta e t g t e w t (yysk n o e h r i h R ) i. In some embodiments, Ring X taken together with (Rx)xisO In some embodiments, Ring X taken together with (Rx)xisIn someembodiments, Ring X taken together with (Rx)xisjn somcembodiments, Ring Y taken, g gyembodiments, Ring X taken together with (Rx)xIn some embodiments. Ring Y takentogether with (Ry)yis. In some embodiments. Ring Y taken together with (Ry)y isIn some embodiments, Ring Y taken together with (Ry)y is H In someembodiments, Ring Y taken togetherIn some embodiments, Ring Y takentogethersome embodiments, Ring X taken together with (Rx)xis. In some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xisIn someembodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments. Ring X taken together with (Rx)xis. In someembodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring Y takentogether. In some embodiments, Ring X taken together with (Rx)xis,In some embodiments, Ring Y taken togetherIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring Y taken,yembodiments, Ring X taken together with (Rx)xis O In some embodiments, Ring Y takenembodiments, Ring X taken together with (Rx)xIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments. Ring Y taken together with (R ). isIn some embodiments. Ring X taken together with (Rx)xisIn some embodiments. Ring X taken together with (Rx)xisIn some embodiments. Ring Y taken togethersome embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xis. In some embodiments. Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring Y taken togetherIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xIn some embodiments, Ring X taken together with (Rx)xis

[0180] In some embodiments, Ring X taken together with (Rx)xisIn some embodiments,Ring Y taken togethersome embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xis. In some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring Y takentogether with (Ry)yisIn some embodiments. Ring X taken together with (Rx)xis. In some embodiments, Ring X taken together with (Rx)xis. In some embodiments. Ring Ytaken together with (RyyisIn some embodiments. Ring Y taken together with (RyyisIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xIn some embodiments, Ring Y takentogether with (Ry)yisIn some embodiments, Ring X taken together with (Rx)xis. In some embodiments. Ring X taken together with (Rx)xis F In some embodiments. Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring Y takentogetherIn some embodiments, Ring X taken together with (Rx)xis. In some embodiments, Ring Y taken togethersome embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring Y taken together withIn someembodiments, Ring X taken together with (Rx)xis FNA O J. In some embodiments, Ring Y taken Otogether with (Ry)yisIn some embodiments, Ring X taken together with (Rx)xisIIn some embodiments, Ring X taken together with (Rx)xIn some IL / "- Iembodiments, Ring X taken together with (Rx)xisNO J. In some embodiments, Ring Y taken I v L / "-A A together with (Ry)yis l~NA, O J. In some embodiments. Ring X taken together with (Rx)xis AA. In some embodiments, Ring X taken together with (Rx)xisIn some embodiments. Ring Ytaken togetherIn some embodiments. Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xisIn someembodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring Y takentogether with (Ry)yisIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments. Ring Y taken togetherIn someembodiments, Ring Y taken togetherIn some embodiments, Ring Y taken, g gyembodiments. Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xIn some embodiments, Ring Y takentogether with (Ry)yisIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments. Ring Y taken togetherIn someembodiments. Ring Y taken togethersome embodiments. Ring Y takentogetherIn some embodiments. Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xisIn someembodiments, Ring Y taken together withIn some embodiments, Ring Y takentogetherIn some embodiments, Ring Y taken togetherIn some embodiments, Ring Y taken togetherIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments. Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments. Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xis. In some embodiments, Ring X taken together with (Rx)xis HOIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments. Ring X taken together with (Rx)xisIn some embodiments, Ring Y taken together withIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring Y taken together with(Ry)y isIn some embodiments, Ring X taken together with (Rx)xsome embodiments. Ring X taken together with (Rx)xisIn some embodiments, Ring Yembodiments, Ring X taken together with (Rx)xisIn some embodiments. Ring Y taken,yembodiments. Ring X taken together with (Rx)xisIn some embodiments, Ring Y taken.yembodiments, Ring X taken together with (Rx)xIn some embodiments, Ring Y taken, g gyembodiments, Ring Y taken togetherIn some embodiments, Ring Y takentogether with (Ry)yisIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring Y taken togetherIn someembodiments. Ring X taken together with (Rx)xisIn some embodiments, Ring Y takentogether with (Ry)yisIn some embodiments. Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xis F. In someembodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring Y takentogether with (Ry)yisIn some embodiments. Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xisIn someembodiments, Ring Y taken togetherIn some embodiments, Ring Y takentogether with (Ry)yis. In some embodiments, Ring X taken together with (Rx)xisH. In some embodiments, Ring X taken together with (Rx)xis H

[0181] In some embodiments, Ring Y taken togethersome embodiments, RingY taken togetherIn some embodiments, Ring X taken together with (Rx)xis. In some embodiments, Ring Y taken together. In some embodiments,Ring X taken together with (Rx)xis. In some embodiments, Ring X taken together with (Rx)xIn some embodiments, Ring Y taken together withIn someembodiments. Ring X taken together with (Rx)xIn some embodiments. Ring Y takentogether with (Ry)yisIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xisIn someembodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring Y takentogether with (Ry)yis O In some embodiments. Ring X taken together with (Rx)xis N-y0Ny.,; / o. In some embodiments. Ring X taken together with (Rx)xis0In someembodiments, Ring Y taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xisIn someembodiments, Ring Y taken togetherIn some embodiments, Ring Y takentogether with (Ry)yisIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xisIn someembodiments, Ring X taken together with (Rx)xisIn some embodiments. Ring X taken together with (Rx)xisIn some embodiments. Ring Y taken together with (Rx)xis. In some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xisembodiments, Ritogether with (Ry)yisIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring Y takentogether with (Ry)yis F In some embodiments, Ring X taken together with (Rx)xisIn some embodiments. Ring Y taken togethersomeembodiments. Ring X taken together with (Rx)xisIn some embodiments, Ring Y takentogether with (Ry)yisIn some embodiments, Ring X taken together with (Rx)xis. In some embodiments, Ring Y taken togetherIn some embodiments, Ring X taken together with (Rx)xisIn some embodiments, Ring Y taken

[0182] In some embodiments, each R3is independently selected from Ci-6 aliphatic, halogen, -CN. -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -N(R)C(O)N(R)2, and -NRS(O)2R, wherein one instance of R3may be a ring selected from phenyl, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is optionally substituted with x instances of Rx.

[0183] In some embodiments, one or more R3is Ci-6 aliphatic. In some embodiments, one or more R3is halogen. In some embodiments, one or more R3is -CN. In some embodiments, one or more R3is -NO2. In some embodiments, one or more R3is -OR. In some embodiments, one or more R3is -SR. In some embodiments, one or more R3is -NR2. In some embodiments, one or more R3is -S(O)2R. In some embodiments, one or more R3is -S(O)2NR2. In some embodiments, one or more R3is -S(O)R. In some embodiments, one or more R3is -C(O)R. In some embodiments, one or more R3is -C(O)OR. In some embodiments, one or more R3is -C(O)NR2. In some embodiments, one or more R3is -C(O)NROR. In some embodiments, one or more R3is -OC(O)R. In some embodiments, one or more R3is -OC(O)NR2. In some embodiments, one or more R3is -NRC(O)OR. In some embodiments, one or more R3is -NRC(O)R. In some embodiments, one or more R3is -N(R)C(O)N(R)2. In some embodiments, one or more R3is -NRS(O)2R. In some embodiments, one instance of R3is a ring selected from phenyl, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is optionally substituted with x instances of Rx.

[0184] As generally defined above for Formula I", each R3is independently selected from optionally substituted Ci-6 aliphatic, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -P(O)R2, -P(O)(OR)2, -C(O)R, -C(O)OR, -C(O)NR2. -C(O)NROR. -OC(O)R, -OC(O)NR2. -NRC(O)OR. -NRC(O)R, -N(R)C(O)N(R)2, and -NRS(O)2R, wherein one instance of R3may be a ring selected from phenyl, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is optionally substituted with x instances of Rx.

[0185] In some embodiments, one or more R3is an optionally substituted Ci-6 aliphatic. In some embodiments, R3is a Ci-6 aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms and optionally substituted with one -OR, -NR2, -CN, or -SR group. In some embodiments, R3is Ci-e haloaliphatic. In some embodiments, R3is Ci-e haloalkoxy. In some embodiments, R3is Ci-e hydroxyhaloaliphatic.Ill

[0186] In some embodiments, R3is methyl, fluoro, chloro, bromo, amino, -CF -OH, -OMe, -CN, -NO2,

[0187] In some embodiments, R3is -OH. In some embodiments, R3is -OMe. In some embodiments, R3In some embodiments, R3is methyl. In some embodiments, R3is -CF3. In some embodiments, R3is fluoro. In some embodiments. R3is chloro. In some embodiments, R3is bromo. In some embodiments, R3is -CN. In some embodiments, R3is -NO2. In some embodiments, R3is -NH2. In some embodiments, R3is - P(O)(Me)2. In some embodiments, R3is -CH2OH. In some embodiments. R3is. someembodiments,

[0188] In some embodiments, R3isIn some embodiments, R3isIn some

[0189] In some embodiments, R3is selected from those depicted in the compounds of Table la or Table lb below.

[0190] In some embodiments, each R4is independently selected from Ci-6 aliphatic, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, - OC(O)NR2, -NRC(O)OR, -NRC(O)R, -N(R)C(O)N(R)2, and -NRS(O)2R.

[0191] In some embodiments, one or more R4is Ci-6 aliphatic. In some embodiments, one or more R4is halogen. In some embodiments, one or more R4is -CN. In some embodiments, one or more R4is -NO2. In some embodiments, one or more R4is -OR. In some embodiments, one or more R4is -SR. In some embodiments, one or more R4is -NR2. In some embodiments, one or more R4is -S(O)2R. In some embodiments, one or more R4is -S(O)2NR2. In some embodiments, one or more R4is -S(O)R. In some embodiments, one or more R4is -C(O)R. In some embodiments, one or more R4is -C(O)OR. In some embodiments, one or more R4is -C(O)NR2. In some embodiments, one or more R4is -C(O)NROR. Insome embodiments, one or more R4is -OC(O)R. In some embodiments, one or more R4is -OC(O)NR2. In some embodiments, one or more R4is -NRC(O)OR. In some embodiments, one or more R4is -NRC(O)R. In some embodiments, one or more R4is -N(R)C(O)N(R)2. In some embodiments, one or more R4is -NRS(O)2R.

[0192] In some embodiments, R4is selected from those depicted in the compounds of Table la or Table lb below.

[0193] As generally defined above, each L1and L2is independently a covalent bond or an optionally substituted Ci-s bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-4 methylene units of the chain are independently and optionally replaced with -Cy-, -C(R')2-, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, or -NRC(O)O-.

[0194] Without limitation, the points of attachment of L1or L2can be bidirectional, for example when L1

[0195] In some embodiments, each L1and L2is independently a covalent bond or an optionally substituted Ci-s bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-3 methylene units of the chain are independently and optionally replaced with -Cy-, -C(R')2-, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, or -NRC(O)O-.

[0196] In some embodiments, L1is a covalent bond or an optionally substituted Ci-s bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-4 methylene units of the chain are independently and optionally replaced with -Cy-, -C(R')2-. -O-, -NR-, -S-. -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, or-NRC(O)O-.

[0197] In some embodiments, L1is a covalent bond or an optionally substituted Ci.g bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-3 methylene units of tire chain are independently and optionally replaced with -Cy-, -C(R')2-, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, or -NRC(O)O-.

[0198] In some embodiments, L1is an optionally substituted Ci.8 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-3 methylene units of the chain are independently and optionally replaced with -Cy-, -C(R')2-, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, or-NRC(O)O-.

[0199] In some embodiments, L1is an optionally substituted Ci-4 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-3 methylene units of the chain are independently and optionally replaced with -Cy-, -C(R')2-, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, or-NRC(O)O-.

[0200] In some embodiments, L1is an optionally substituted C2-4 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-3 methylene units of the chain are independently and optionally replaced with -Cy-, -C(R')2-, -O-. -NR-, -S-, -OC(O)-. -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-. -S(O)2NR-. -NRC(O)-. -C(O)NR-, -OC(O)NR-, or-NRC(O)O-.

[0201] In some embodiments, L1is an optionally substituted C2bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-3 methylene units of the chain are independently and optionally replaced with -Cy-, -C(R)2-, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-_ -NRC(O)-, -C(O)NR-, -OC(O)NR-, or-NRC(O)O-.

[0202] In some embodiments, L1is an optionally substituted C3 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-3 methylene units of the chain are independently and optionally replaced with -Cy-, -C(R)2-, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, or-NRC(O)O-.

[0203] In some embodiments, L1is an optionally substituted C4 bivalent straight or branched saturated or unsaturated hy drocarbon chain wherein 1-3 methylene units of the chain are independently and optionally replaced with -Cy-, -C(R)2-, -O-, -NR-, -S-. -OC(O)-. -C(O)O-, -C(O)-, -S(O)-, -S(O)2-. -NRS(O)2-, -S(O)2NR-. -NRC(O)-. -C(O)NR-, -OC(O)NR-, or-NRC(O)O-.

[0204] In some embodiments, L1is optionally substituted -NR-Co-4alkylene-Cy-NR-. In some embodiments, L1is optionally substituted -NR-Co-4alkylene-Cy-. In some embodiments, L1is optionally substituted -NR-Ci-4alkylene-NR-.

[0205] In some embodiments, L1is a covalent bond. In some embodiments, L1is -NR-. In some embodiments, L1is -NRCH₂-. In some embodiments, L1is -NRCH2CH2-. In some embodiments, L1is -O-

[0206] In some embodiments,.H

[0207] In some embodiments, L1issome embodiments, L1is V°. In some embodiments.

[0208] In some embodiments, L1is selected from those depicted in the compounds of Table 1 a or Table lb below.

[0209] In some embodiments, L2is a covalent bond or an optionally substituted Cus bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-4 methylene units of the chain are independently and optionally replaced with -Cy-, -C(R')?-, -O-, -NR-, -S-. -OC(O)-, -C(O)O-, -C(O)-, -S(O)-_ -S(O)2-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-_ -OC(O)NR-, or-NRC(O)O-.

[0210] In some embodiments, L2is a covalent bond or an optionally substituted Ci.g bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-3 methylene units of the chain are independently and optionally replaced with -Cy-, -C(R')2-, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, or-NRC(O)O-.

[0211] In some embodiments, L2is a covalent bond.

[0212] In some embodiments, L2is an optionally substituted Cn? bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-3 methylene units of the chain are independently and optionally replaced with -Cy-, -C(R')2-, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, or-NRC(O)O-.

[0213] In some embodiments, L2is an optionally substituted C1.4 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-3 methylene units of the chain are independently and optionally replaced with -Cy-, -C(R')2-, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, or-NRC(O)O-.

[0214] In some embodiments, L2is an optionally substituted C2.4 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-3 methylene units of the chain are independently and optionally replaced with -Cy-, -C(R')2-, -O-. -NR-, -S-, -OC(O)-. -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-. -S(O)2NR-. -NRC(O)-. -C(O)NR-, -OC(O)NR-, or-NRC(O)O-.

[0215] In some embodiments, L2is an optionally substituted C2bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-3 methylene units of the chain are independently and optionally replaced with -Cy-, -C(R')2-, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, or-NRC(O)O-.

[0216] In some embodiments, L2is an optionally substituted C3 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-3 methylene units of the chain are independently and optionally replaced with -Cy-, -C(R')2-, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, or-NRC(O)O-.

[0217] In some embodiments, L2is an optionally substituted C4 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-3 methylene units of the chain are independently and optionally replaced with -Cy-, -C(R')2-, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, or-NRC(O)O-.

[0218] In some embodiments, L2is optionally substituted -NR-Co-ialkyl-Cy-. In some embodiments, L2is optionally substituted -NRC(O)O-Ci-4alkyl-NR-. In some embodiments, L2is optionally substituted -Cy-.

[0219] In some embodiments, L2is selected from those depicted in the compounds of Table la or Table lb below.

[0220] As generally defined above, each -Cy- is independently an optionally substituted bivalent ring selected from phenylene, an 8-10 membered bicyclic carbocyclic aromatic ring, a 4-7 membered saturated or partially unsaturated carbocyclylene, a 6-11 membered saturated or partially unsaturated spirocyclic carbocyclylene, an 8-10 membered bicyclic, saturated or partially unsaturated, carbocyclylene, a 4-7 membered saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6-11 membered saturated or partially unsaturated spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic, saturated or partially unsaturated, heterocyclylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroarylene having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0221] In some embodiments, each -Cy- is independently an optionally substituted bivalent ring selected from phenylene, an 8-10 membered bicyclic carbocyclic aromatic ring, a 4-7 membered saturated or partially unsaturated carbocyclylene. a 6-11 membered saturated or partially unsaturated spirocyclic carbocyclylene, an 8-10 membered bicyclic, saturated or partially unsaturated, carbocyclylene, a 4-7 membered saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6-11 membered saturated or partially unsaturated spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic or bridged bicyclic, saturated or partially unsaturated, heterocyclylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroarylene having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0222] In some embodiments, one or more -Cy- is an optionally substituted phenylene. In some embodiments, one or more -Cy- is an optionally substituted 8-10 membered bicyclic carbocyclic aromaticring. In some embodiments, one or more -Cy- is an optionally substituted 4-7 membered saturated or partially unsaturated carbocyclylene. In some embodiments, one or more -Cy- is an optionally substituted 6-11 membered saturated or partially unsaturated spirocyclic carbocyclylene. In some embodiments, one or more -Cy- is an optionally substituted 8-10 membered bicyclic, saturated or partially unsaturated, carbocyclylene. In some embodiments, one or more -Cy- is an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, one or more -Cy- is an optionally substituted 6- 11 membered saturated or partially unsaturated spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, one or more -Cy- is an optionally substituted 8-10 membered bicyclic, saturated or partially unsaturated, heterocyclylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, one or more -Cy- is an optionally substituted 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, one or more -Cy- is an optionally substituted 8-10 membered bicyclic heteroarylene having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0223] In some embodiments, one or more -Cy- is an optionally substituted 8-10 membered bridged bicyclic, saturated or partially unsaturated, heterocyclylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0224] In some embodiments, one or more -Cy- is a phenylene. In some embodiments, one or more -Cy-is an 8-10 membered bicyclic carbocyclic aromatic ring. In some embodiments, one or more -Cy- is a 4-7 membered saturated or partially unsaturated carbocyclylene. In some embodiments, one or more -Cy- is a 6-11 membered saturated or partially unsaturated spirocyclic carbocyclylene. In some embodiments, one or more -Cy- is an 8-10 membered bicyclic, saturated or partially unsaturated, carbocyclylene. In some embodiments, one or more -Cy- is a 4-7 membered saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, one or more -Cy- is a 6-11 membered saturated or partially unsaturated spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, one or more -Cy- is an 8-10 membered bicyclic, saturated or partially unsaturated, heterocyclylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, one or more -Cy- is a 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, one or more -Cy- is an 8-10 membered bicyclic heteroarylene having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0225] In some embodiments, one or more -Cy- is an 8-10 membered bridged bicyclic, saturated orpartially unsaturated, heterocyclylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0226] In some embodiments, -Cy-is selected from those depicted in the compounds of Table la or Table lb below.

[0227] As generally defined above, each R is independently hydrogen or an optionally substituted group selected from Ci-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur.

[0228] In some embodiments, one or more R is hydrogen. In some embodiments, one or more R is an optionally substituted Ci.e aliphatic. In some embodiments, one or more R is an optionally substituted phenyl. In some embodiments, one or more R is an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, one or more R is an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R groups on the same nitrogen are optionally taken together with their intervening atoms to form an optionally substituted 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur.

[0229] In some embodiments, one or more R is a Ci-e aliphatic. In some embodiments, one or more R is a phenyl. In some embodiments, one or more R is a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, one or more R is a 5 -6 membered heteroaryl ring having 1 -4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur.

[0230] In some embodiments, Ris selected from those depicted in the compounds of Table la or Table lb below.

[0231] As generally defined above for Formula I, R1is hydrogen or Ci-e aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms, provided that R1is not hydrogen when L1is a covalent bond.

[0232] In some embodiments, R1is hydrogen. In some embodiments, R1is a Ci-6 aliphatic optionallysubstituted with 1, 2, or 3 deuterium or halogen atoms. In some embodiments, R1is a Ci-6 aliphatic.

[0233] As generally defined above for Formula I', R1is hydrogen, Ci-6 aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms, a 5-11 membered saturated or partially unsaturated spirocyclic carbocyclic ring, a 4-10 membered bicyclic, saturated or partially unsaturated carbocyclic ring, a 5-11 membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 4-10 membered bicyclic or bridged bicyclic, saturated or partially unsaturated, heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, provided that R1is not hydrogen when L1is a covalent bond.

[0234] In some embodiments, R1is a 5-11 membered saturated or partially unsaturated spirocyclic carbocyclic ring. In some embodiments, R1is a 4-10 membered bicyclic, saturated or partially, unsaturated carbocyclic ring. In some embodiments, R1is a 5-11 membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R1is a 4-10 membered bicyclic, saturated or partially unsaturated, heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R1is a 4-10 membered bridged bicyclic, saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0235] In some embodiments, R1is a 6-7 membered bicyclic, saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0236] In some embodiments, R1is selected from those depicted in the compounds of Table la or Table lb below.

[0237] As generally defined above for Formula I, R2is hydrogen, halogen, -CN, or C i aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms, provided that R2is not hydrogen when L2is a covalent bond.

[0238] In some embodiments, R2is hydrogen. In some embodiments, R2is halogen. In some embodiments, R2is -CN. In some embodiments, R2is a Ci.6 aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms. In some embodiments, R2is a Ci-6 aliphatic.

[0239] As generally defined above for Formula I', R2is hydrogen, halogen, -CN, Ci-g aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms, a 5 - 11 membered saturated or partially unsaturated spirocyclic carbocyclic ring, a 4-10 membered bicyclic, saturated or partially unsaturated, carbocyclic ring, a 5-11 membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 4-10 membered bicyclic or bridged bicyclic, saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, provided that R2is not hydrogen when L2is a covalent bond.

[0240] In some embodiments, R2is a 5-11 membered saturated or partially unsaturated spirocyclic carbocyclic ring. In some embodiments, R2is a 4-10 membered bicyclic, saturated or partially unsaturated carbocyclic ring. In some embodiments, R2is a 5-11 membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2is a 4-10 membered bicyclic, saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2is a 4-10 membered bridged bicyclic, saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0241] In some embodiments, R2is selected from those depicted in the compounds of Table la or Table lb below.

[0244] In some embodiments, L1-R1isIn some embodiments, L’-R1isIn some embodiments, L’-R1is H In some embodiments, L’-R1In someembodiments, L’-R1isIn some embodiments, L’-R1is H In some embodiments, L’-R1isIn some embodiments, L’-R1isIn someembodiments, L’-R1isIn some embodiments, L’-R1In some embodiments, In some embodiments, L’-R1In some embodiments, L’-R1is some embodiments, L’-R1isIn some embodiments, L’-R1isIn some embodiments, L’-R1isIn some embodiments, L’-R1isH. In some embodiments, L -R is H. In some embodiments, L -R is. In some embodiments, L'-R1is. In some embodiments, L’-R1isIn somezSyembodiments. L'-R1is '. In some embodiments,some embodiments. L'-R1is,,. ,,.H. In some embodiments, L’-R1is H. In some embodiments, L -R is Hsomeembodiments. L'-R1isIn some embodiments. L'-R1In someembodiments, L'-R'some embodiments, L’-R1is Hsomeembodiments, L'-R' is, In some O~N__Z IHN' / Ny embodiments, L'-R' is '. In some embodiments, L'-R1isIn some H \ / embodiments, L'-R1is °y '. In some embodiments, L'-R1is Y 'N''X'O / ' In some embodiments, L'-, . In some embodiments, L'-R' is, some embodiments, L'-R1In some embodiments, L’-R1isIn some embodiments, L'-R1is, some embodiments, L’-, In some embodiments, L’-R1In some embodiments, L’-R1isIn some embodiments, L’-R’ isn some embodiments, L’-R1isIn some embodiments, L’-R1isIn some embodiments, L'-R1isIn some embodiments, L’-R’ isH In some embodiments, L’-R1isIn some embodiments, L’-R’ is HN— j, In some embodiments, L’-R1is, In some embodiments, L’-R’ is, In some embodiments, L’-R’ is, In some embodiments, L’-R1isIn some embodiments, L’-R’ isIn some embodiments, L’-R1isIn some embodiments, L’-R’In some embodiments, L’-R1isIn some embodiments, L'-R1is In some embodiments, L’-R1isIn some embodiments, L'-R1In some embodiments, L'-R1is, ,some embodiments, L'-R1is H. In some embodiments, L’-R1isembodiments, L'-R1is H In some embodiments. L’-R1isembodiments, L'-R1is H In some embodiments, L'-R1is H In someil * embodiments, L'-R1isIn some embodiments, L’-R1is b> In someembodiments, L'-R1is. In some, , O. Y H HN^\ / N'. In some embodiments, L -R is. In some embodiments,In some embodiments.some embodiments,some embodiments,, some embodiments,....In some embodiments, L'-R1is H In some embodiments, L -R is H In someembodiments, L'-R' is. In some embodiments, L'-R' isHN—

[0245] In some embodiments, L'-R' is. In some embodiments, L'-R' is. In some HN—embodiments, L'-R' is. In some embodiments, L'-R' is. In some embodiments,L'-R' is H Tn some embodiments, L'-R' is H. In some embodiments,H. In some embodiments, L'-R' is. In some embodiments, L'-R' is V^N H-. In someembodiments, L'-R' is. In some embodiments, L'-R' is. In some embodiments,HN— HN— HN—,. In some embodiments, L'-R' isHN—. In some embodiments, L'-R' is. In some embodiments, L'-R' is. In someembodiments, L'-R1isIn some embodiments, L'-R' isIn someembodiments, L’-R1In some embodiments, L’-R1isIn someembodiments, L'-R1In some embodiments,some embodiments, L'-R1In some embodiments, L'-R1isIn someembodiments, L1-R1isIn some embodiments, L1-R1isIn some embodiments, L1-. In some embodiments, L -R' is. In some embodiments, L'-R1is some embodiments, L'-R1In some embodiments, L’-R1isn some embodiments, L’-R1isIn some embodiments, L’-R1is, In some embodiments, L'-R1is. In some embodiments, L'-R1isIn some embodiments, L'-R1isembodiments, L'-R1some embodiments, L'-R1isIn some embodiments, L'-R1some embodiments, L’-R1isIn some embodiments, L'-R1In some embodiments, L’-R1isIn someembodiments, L'-R1isIn some embodiments,some embodiments,, In some embodiments, L'-R1is, In some embodiments, L’-R1isn some embodiments, L’-R1In some embodiments, L'-R1isIn some embodiments, L'-R1In some embodiments, L'-R1isIn some embodiments, L'-R1In some embodiments, L'-R1isIn some embodiments,In some embodiments, L'-R1issome embodiments, L'-R1isIn some embodiments, L’-R1is,

[0246] In some embodiments, L'-R1In some embodiments, L’-R1issome embodiments, L’-R1isIn some embodiments, L'-R1isIn someembodiments. L'-R1isIn some embodiments, L'-R1isIn some embodiments, L'-R1isIn some embodiments, L'-R1isIn some embodiments,, In some embodiments, L'-R1is, In some embodiments, L’-R1isIn some embodiments, L'-R1isIn some embodiments, L’-R1is H In some embodiments, L'-R1isIn some embodiments, L’-R1isIn some embodiments,, In some embodiments, L'-R1is, In some embodiments, L'-R1isIn some embodiments, L’-R1isIn some embodiments, L'-R1isIn someembodiments,In some embodiments,In some embodiments,In some embodiments, L'-R1In some embodiments, L'-R1issome embodiments, L'-R1is H In some embodiments, L’-R1isIn some embodiments, L'-R1isIn some embodiments. L'-R1isH. In some embodiments, L'-R' is. In some embodiments, L'-R1isIn some embodiments, L'-R1In some embodiments. L'-R1isHsome embodiments, L’-R1isIn some embodiments, L'-R1isIn someembodiments, L'-R1is H In some embodiments. L'-R1issomeembodiments, L'-R1isIn some embodiments, L'-R1issomeembodiments.In some embodiments, L’-R1isIn someembodiments,some embodiments, L'-R1issomeembodiments.some embodiments, L'-R1isIn someembodiments, L'-R1issome embodiments, L’-R1is Hsomeembodiments, L'-R1is. In some embodiments, L'-R1is H. In some embodiments,HL'-R1is H. In some embodiments, L'-R1isIn some embodiments, L'-R1is,In some embodiments, L'-R1issome embodiments, L'-R1isIn some embodiments, L’-R1isembodiments,some embodiments,

[0247] In some embodiments, L’-R1is NH In some embodiments, L’-R1In some, ,. In some embodiments, L'-R1is H H'VIn some embodiments, L'-R1is HN In some embodiments, L'-R1In someembodiments, L’-R1In some embodiments, L’-R1isIn some,, In some embodiments,In some embodiments,some embodiments, L'-R1is. In someembodiments, L'-R' is H In some embodiments, L'-R1In some embodiments,, In some embodiments, L’-R1is, In some embodiments, L’-R1isIn some embodiments,some embodiments.embodiments, L'-R1isIn some embodiments, L’-R1isIn some embodiments,In some embodiments, L’-R1In some embodiments, L'-R1issome embodiments,In some embodiments, L'-R' issome embodiments.In some embodiments. L'-R1is

[0250] In some embodiments, L2-R2is hydrogen. In some embodiments, L2-R2is chloro. In some embodiments, L2-R2is methyl. In some embodiments, L2-R2is t-butyl. In some embodiments, L2-R2is - OH. In some embodiments, L2-R2is -OMe. In some embodiments, L2-R2is -NH2. In some embodiments,L2-R2is H in some embodiments, L2-R2is H. In some embodiments, L2-R2is,In some embodiments, L2-R2isIn some embodiments. L2-R2isIn some embodiments, L2-R2isembodiments. L2-R2isIn some embodiments, L2-R2isIn some embodiments, L2-R2,In some embodiments, L2-R2is O O,In some embodiments, L2-, . In some embodiments,OL2-R2isIn some embodiments, L2-R2isIn someembodiments, L2-R2isIn some embodiments, L2-R2isoembodiments, L2-R2is,O Hsome embodiments,. In some embodiments, L2-R2is. In some Oembodiments, L -R is., In some embodiments, L2-R2is., . In Osome embodiments, L2-R2isIn some embodiments, L2-R2is 0, ,, In some O oembodiments, L2-R2,In someembodiments. L2-R2isIn some embodiments,In someembodiments, L2-R2is. In some embodiments, L2-R2isIn someembodiments, L2-R2is F. In some embodiments, L2-R2is. In some embodiments, L2-R2iso oembodiments, L2-R2is. In some embodiments,In some embodiments, L2-R2is N-N. In some embodiments, L2-R2is. In some embodiments, L2-R2In some embodiments, L2-R2isIn some embodiments, L2-R2is. In someembodiments, L2-R2is H In some embodiments. L2-R2isIn someembodiments, L2-R2is H In some embodiments, L2-R2is Hsomeembodiments, L2-R2some embodiments, L2-R2is H In someembodiments. L2-R2isin some embodiments, L2-R2isIn some embodiments,, . In some embodiments, L2-R2isF. In some embodiments, L2-R2is. In some embodiments, L2-R2is HN-N. In some F'" / / .embodiments, L2-R2is HN-N. In some embodiments, L2-R2is N-NH. In some embodiments,.. . L2-R2is N-N. In some embodiments, L2-R2is N-N. In some embodiments, L2-R2isIn some embodiments, L2-R2is N-N In some embodiments, L2-R2isIn someembodiments, L2-R2is. In some embodiments, L2-R2is. In some embodiments, L2-R2some embodiments, L2-R2isIn some embodiments, L2-R2isIn some embodiments, L2-R2isIn some embodiments, L2-R2isIn some embodiments, L2-R2is,

[0251] In some embodiments, L2-R2isIn some embodiments, L2-R2isIn some embodiments, L2-R2is. In some embodiments, L2-R2is. In some embodiments. L2-R2is HN-N. In some embodiments,. In some embodiments, L2-R2is. In some embodiments, L2-R2isIn some embodiments, L2-R2isIn some embodiments.,In some embodiments, L2-R2is N-NIn some embodiments, L2-R2isIn some embodiments,In someembodiments,In some embodiments, L2-R2isIn someembodiments, L2-R~ is. In some embodiments, L -R2is O~N. In some embodiments, L2-,In some embodiments. L2-R2is S-N. In some embodiments, L2-R2isIn some embodiments, L2-R2isIn some embodiments, L2-R2isIn some embodiments, L2-R2isIn someembodiments, L2-R2isIn some embodiments, L2-R2isIn some embodiments,. .bodiments,N'-N'N ^_ / N^

[0252] In some embodiments, L2-R2is \= / . In some embodiments, L2-R2is N — '. In someembodiments, L2-R2isIn some embodiments, L2-R2isIn some embodiments, L2-R2,In some embodiments, L2-R2is. In someembodiments, L2-R2isIn some embodiments, L2-R2isIn some embodiments.,In some embodiments, L2-R2issome embodiments, L2-R2isIn some embodiments. L2-R2isIn some embodiments, L2-R2isIn some embodiments, L2-R2isIn some embodiments, L2-R2In some embodiments, L2-R2isIn some embodiments, L2-R2isIn some embodiments, L2-R2isn some embodiments, L2-R2isIn some embodiments, L2-R2is

[0253] In some embodiments, L2-R2is H In some embodiments, L -R2is H. In someembodiments, L2-R2is H In some embodiments, L2-R2is

[0254] As generally defined above, w is 0, 1, or 2.

[0255] In some embodiments, w is 0. In some embodiments, w is 1. In some embodiments, w is 2. In some embodiments, w is 0 or 1.

[0256] In some embodiments, wis selected from those depicted in the compounds of Table la or Table lb below.

[0257] AS generally defined above, x is 0, 1, 2, 3, or 4.

[0258] In some embodiments, x is 0. In some embodiments, x is 1. In some embodiments, x is 2. In some embodiments, x is 3. In some embodiments, x is 4. In some embodiments, x is 1. 2, or 3.

[0259] In some embodiments, x is selected from those depicted in the compounds of Table la or Table lb below.

[0260] As generally defined above, y is 0, 1, 2, 3, 4, 5, or 6.

[0261] In some embodiments, y is 0, 1, 2, 3, or 4.

[0262] In some embodiments, y is 0. In some embodiments, y is 1. In some embodiments, y is 2. In some embodiments, y is 3. In some embodiments, y is 4. In some embodiments, y is 5. In some embodiments, y is 6. In some embodiments, y is 1, 2, or 3.

[0263] In some embodiments, y is selected from those depicted in the compounds of Table la or Table lb below.

[0264] As generally defined above, z is 0, 1, 2, or 3.

[0265] In some embodiments, z is 0. In some embodiments, z is 1. In some embodiments, z is 2. In some embodiments, z is 3. In some embodiments, z is 1, 2, or 3.

[0266] In some embodiments. Ring z is selected from those depicted in the compounds of Table la or Table lb below.

[0267] As generally defined above, R3ais an optionally substituted Ci.g aliphatic, halogen -OR, or -NO2. In some embodiments, R3ais an optionally substituted C1-6 aliphatic. In some embodiments, R3ais halogen.In some embodiments, R3ais -OR. In some embodiments, R?ais -NO2.

[0268] In some embodiments, R3ais fluoro, chloro, -OMe, -NO2,.

[0269] In some embodiments, R3ais fluoro. In some embodiments, R3ais chloro. In some embodiments, R3ais -OMe. In some embodiments, R3ais -NO2. In some embodiments, R3ais 1=. In some A Aembodiments, R3ais. In some embodiments, R3ais F O

[0270] In some embodiments, R3ais selected from those depicted in the compounds of Table la or Table lb below.

[0271] As generally defined above, R3band R3care independently selected from hydrogen, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R. -N(R)C(O)N(R)2, -NRS(O)2R and an optionally substituted C1-6 aliphatic.

[0272] In some embodiments, R3band R3care independently selected from hydrogen, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -N(R)C(O)N(R)2, and -NRS(O)2R, and Cn6aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms.

[0273] In some embodiments, R3band R3care independently selected from hydrogen, halogen, -CN, -NO2, -OR, -SR. -NR2, -S(O)2R. -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR. -OC(O)R, -OC(O)NR2. -NRC(O)OR. -NRC(O)R. -N(R)C(O)N(R)2, and -NRS(O)2R. and Ci.6aliphatic.

[0274] In some embodiments, R3bis selected from hydrogen, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -N(R)C(O)N(R)2, -NRS(O)2Rand an optionally substituted Ci.g aliphatic.

[0275] In some embodiments, R3bis selected from hydrogen, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R. -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R. -OC(O)NR2. -NRC(O)OR, -NRC(O)R, -N(R)C(O)N(R)2, and -NRS(O)2R, and Ci-6 aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms.

[0276] In some embodiments, R3bis selected from hydrogen, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -N(R)C(O)N(R)2, and -NRS(O)2R, and Ci.6aliphatic.

[0277] In some embodiments. R3bis hydrogen. In some embodiments, R3bis halogen. In some embodiments, R3bis -CN. In some embodiments, R3bis -NO2. In some embodiments, R3bis -OR. In some embodiments, R3bis -SR. In some embodiments, R3bis -NR2. In some embodiments, R3bis -S(O)2R. Insome embodiments, R3bis -S(O)2NR.2. In some embodiments, R3bis -S(O)R. In some embodiments, R3bis -C(O)R. In some embodiments, R3bis -C(O)OR. In some embodiments, R3bis -C(O)NR2. In some embodiments, R3bis -C(O)NROR. In some embodiments, R3bis -OC(O)R. In some embodiments, R3bis -OC(O)NR2. In some embodiments, R3bis -NRC(O)OR. In some embodiments, R3bis -NRC(O)R. In some embodiments, R3bis -N(R)C(O)N(R)2. In some embodiments, R3bis -NRS(O)2R. In some embodiments, R3bis an optionally substituted Ci-6 aliphatic. In some embodiments. R3bis a Ci-6 aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms. In some embodiments, R3bis Ci-6 aliphatic.

[0278] In some embodiments, R3bis fluoro.. In some embodiments, R3bis chloro. In some embodiments, R3bis bromo.

[0279] In some embodiments, R3bis selected from those depicted in the compounds of Table la or Table lb below.

[0280] In some embodiments, R3cis selected from hydrogen, halogen. -CN, -NO2, -OR, -SR. -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -N(R)C(O)N(R)2, -NRS(O)2R and an optionally substituted C1-6 aliphatic.

[0281] In some embodiments, R3cis selected from hydrogen, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2. -NRC(O)OR, -NRC(O)R, -N(R)C(O)N(R)2, and -NRS(O)2R, and C1-6 aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms.

[0282] In some embodiments, R3cis selected from hydrogen, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -N(R)C(O)N(R)2, and -NRS(O)2R, and Ci.6aliphatic.

[0283] In some embodiments, R3cis hydrogen. In some embodiments, R3cis halogen. In some embodiments, R3cis -CN. In some embodiments, R3cis -NO2. In some embodiments, R3cis -OR. In some embodiments, R3cis -SR. In some embodiments, R3cis -NR2. In some embodiments, R3cis -S(O)2R. In some embodiments, R3cis -S(O)2NR2. In some embodiments, R3cis -S(O)R. In some embodiments, R3cis -C(O)R. In some embodiments, R3cis -C(O)OR. In some embodiments, R3cis -C(O)NR2. In some embodiments, R3cis -C(O)NROR. In some embodiments, R3cis -OC(O)R. In some embodiments, R3cis -OC(O)NR2. In some embodiments, R3cis -NRC(O)OR. In some embodiments, R3cis -NRC(O)R. In some embodiments, R3cis -N(R)C(O)N(R)2. In some embodiments, R3cis -NRS(O)2R. In some embodiments, R3cis Ci-6 aliphatic.

[0284] In some embodiments, R3cis an optionally substituted Ci-e aliphatic. In some embodiments, R3cis a Ci.6 aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms.

[0285] In some embodiments, R3band R3carc each hydrogen.

[0286] In some embodiments, R3cis selected from those depicted in the compounds of Table la or Table lb below.

[0287] As generally defined above, Ring S is phenyl, a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-9 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 3-6 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0288] In some embodiments, Ring S is phenyl. In some embodiments, Ring S is a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, Ring S is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring S is a 7-9 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments. Ring S is a 3-6 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0289] In some embodiments, Ring S is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-9 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 3-6 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0290] In some embodiments, Ring S is a 5-6 membered monocyclic heteroaromatic ring having 1-3 nitrogen heteroatoms or a 7-9 membered bicyclic heteroaromatic ring having 1-3 nitrogen heteroatoms.

[0291] In some embodiments, Ring S is a 5 membered monocyclic heteroaromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0293] In some embodiments, RingIn some embodiments, Ring S isIn someembodiments, Ring S is. In some embodiments, Ring S is. In some embodiments, Ring

[0294] In some embodiments, Ring S is selected from those depicted in the compounds of Table la or Table lb below.

[0295] As generally defined above, each Rs, and R’ is independently selected from, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -N(R)C(O)N(R)2, -NRS(O)2R, an optionally substituted Cn6aliphatic, an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring, an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur or two Rsgroups on the same saturated carbon atom are optionally taken together to form =0, or two R‘ groups on the same saturated carbon atom are optionally taken together to form =0.

[0296] In some embodiments, each Rsis independently selected from halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R_ -S(O)2NR2. -S(O)R, -C(O)R_ -C(O)OR, -C(0)NR2, -C(0)NR0R, -OC(O)R, -0C(0)NR2, -NRC(O)OR, -NRC(0)R, -N(R)C(O)N(R)2, -NRS(0)2R, an optionally substituted Ci.e aliphatic, an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring, and an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two Rsgroups on the same saturated carbon atom are optionally taken together to form =0.

[0297] In some embodiments, each Rsis independently selected from halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(0)NR2, -C(0)NR0R, -OC(O)R, -0C(0)NR2, -NRC(O)OR, -NRC(0)R, -N(R)C(O)N(R)2, -NRS(O)2R, Ci-e aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms, a 4-7 membered saturated or partially unsaturated carbocyclic ring, and a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two Rsgroups on the same saturated carbon atom are optionally taken together to form =0.

[0298] In some embodiments, each Rsis independently selected from halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(0)NR2, -C(0)NR0R, -OC(O)R, -0C(0)NR2, -NRC(O)OR, -NRC(0)R, -N(R)C(O)N(R)2, -NRS(O)2R, and Ci.6aliphatic.

[0299] In some embodiments, one or more Rsis halogen. In some embodiments, one or more Rsis -CN. In some embodiments, one or more Rsis -NO2. In some embodiments, one or more Rsis -OR. In some embodiments, one or more Rsis -SR. In some embodiments, one or more Rsis -NR2. In some embodiments, one or more Rsis -S(O)2R. In some embodiments, one or more Rsis -S(O)2NR2. In some embodiments, one or more Rsis -S(O)R. In some embodiments, one or more Rsis -C(O)R. In some embodiments, one or more Rsis -C(O)OR. In some embodiments, one or more Rsis -C(O)NR2. In some embodiments, oneor more Rsis -C(O)NROR. In some embodiments, one or more Rsis -OC(O)R. In some embodiments, one or more Rsis -OC(O)NR2. In some embodiments, one or more Rsis -NRC(O)OR. In some embodiments, one or more Rsis -NRC(O)R. In some embodiments, one or more Rsis -N(R)C(O)N(R)2. In some embodiments, one or more Rsis -NRS(O)2R. In some embodiments, Rsis an optionally substituted Ci-6 aliphatic. In some embodiments, one or more Rsis Ci-6 aliphatic. In some embodiments, Rsis an optionally substituted 4-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, Rsis an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rsis a 4-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, Rsis a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two Rsgroups on the same saturated carbon atom are taken together to form =0. / LOH

[0300] In some embodiments, Rsis methyl, ethyl, methoxy,. or.

[0301] In some embodiments, Rsis methyl. In some embodiments, Rsis ethyl. In some embodiments, Rsis methoxy. In some embodiments, Rsis. In some embodiments, Rsis. In some embodiments, Rsis z J<fOH

[0302] In some embodiments, Rsis selected from those depicted in the compounds of Table la or Table lb below.

[0304] In some embodiments, Ring S taken together with (Rs)sis. In some embodiments, RingS taken together with (Rs)sisIn some embodiments. Ring S taken together with (Rs)sis. In some embodiments, Ring S taken together with (Rs)sis. In some embodiments,Ring S taken together withsome embodiments, Ring S taken together with (Rs)sis. In some embodiments, Ring S taken together with (Rs)sis. In some embodiments,Ring S taken together with (Rs)sIn some embodiments. Ring S taken together with (Rs)sisIn some embodiments, Ring S taken together with (Rs)sis. In some embodiments.Ring S taken together with (Rs)sis H. In some embodiments, Ring S taken together with (Rs)sisIn some embodiments, Ring S taken together with (Rs)sisIn some embodiments,Ring S taken together w ith (Rs)sis

[0305] In some embodiments, Ring S taken together with (Rs)s is selected from those depicted in the compounds of Table la or Table lb below.

[0306] As generally defined above, Ring T is a ring selected from phenyl, a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 5-6 membered monocyclic heteroaromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially unsaturated monocyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6-10 membered saturated or partially unsaturated bicyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6-10 membered saturated or partially unsaturated bridged bicyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 6- 10 membered saturated or partially unsaturated spirocyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0307] In some embodiments, Ring T is phenyl. In some embodiments, Ring T is a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, Ring T is a 5-6membered monocyclic heteroaromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring T is a 4-7 membered saturated or partially unsaturated monocyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring T is a 6-10 membered saturated or partially unsaturated bicyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring T is a 6-10 membered saturated or partially unsaturated bridged bicyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments. Ring T is a 6-10 membered saturated or partially unsaturated spirocyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0308] In some embodiments, Ring T is a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 4-7 membered saturated or partially unsaturated monocyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6-10 membered saturated or partially unsaturated bicyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6-10 membered saturated or partially unsaturated bridged bicyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 6-10 membered saturated or partially unsaturated spirocyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0309] In some embodiments, Ring T is a 3-6 membered saturated monocyclic carbocyclic ring, a 4-7 membered saturated monocyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen and oxygen, a 6-10 membered saturated bicyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen and oxygen, a 6-10 membered saturated bridged bicyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen and oxygen, or a 6-10 membered saturated or partially unsaturated spirocyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen and oxygen.

[0310] In some embodiments, Ring T is a 4-6 membered saturated monocyclic carbocyclic ring, a 4-7 membered saturated monocyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen and oxygen, or a 6-10 membered saturated bicyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen and oxygen.

[0312] In some embodiments, Ring T isIn some embodiments, Ring T isIn some embodiments, Ring T isIn some embodiments, Ring T isIn some embodiments, RingT isIn some embodiments, Ring T isIn some embodiments, Ring T isIn some embodiments, Ring T is. In some embodiments. Ring T issome embodiments. Ring T is In some embodiments, Ring T is In some embodiments, Ring T isIn some embodiments, Ring T isIn some embodiments, Ring T isIn some embodiments, Ring T isIn some embodiments, Ring TIn someembodiments, Ring T isIn some embodiments, Ring T isIn some embodiments, RingIn some embodiments, Ring T isIn some embodiments, Ring T issome embodiments, Ring T isIn some embodiments, Ring T isIn someembodiments, Ring T is. In some embodiments, Ring T is. In some embodiments,Ring T is. In some embodiments, Ring T is. In some embodiments, Ring T is,. In some embodiments, Ring T is. Insome embodiments, Ring T isIn some embodiments, Ring T isIn someembodiments. Ring T is. In some embodiments. Ring T is. In some embodiments,In some embodiments, Ring T is. In some embodiments, Ring T is. mbodiments. Ring T is. In some embodiments, Ring T isIn some embodiments, Ring T is. In some embodiments, Ring T is. In someembodiments, Ring T is. In some embodiments, Ring T is. In some embodiments,Ring T isIn some embodiments, Ring TIn some embodiments, Ring T is

[0313] In some embodiments, Ring T is selected from those depicted in the compounds of Table la or Table lb below.

[0314] In some embodiments, each Rlis independently selected from halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -N(R)C(O)N(R)2, -NRS(O)2R, an optionally substituted C1-6 aliphatic, an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring, and an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two Rsgroups on the same saturated carbon atom are optionally taken together to form =0.

[0315] In some embodiments, each Rlis independently selected from halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -N(R)C(O)N(R)2, -NRS(O)2R, C1-6 aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms, a 4-7 membered saturated or partially unsaturated carbocyclic ring, and a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two Rlgroups on the same saturated carbon atom are optionally taken together to form =0.

[0316] In some embodiments, each R‘ is independently selected from halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(0)NR2, -C(0)NR0R, -OC(O)R, -0C(0)NR2, -NRC(O)OR, -NRC(0)R, -N(R)C(O)N(R)2, -NRS(O)2R. and Ci6aliphatic.

[0317] In some embodiments, one or more Rlis halogen. In some embodiments, one or more Rlis -CN. In some embodiments, one or more Rlis -NO2. In some embodiments, one or more Rlis -OR. In some embodiments, one or more Rlis -SR. In some embodiments, one or more Rlis -NR2. In some embodiments, one or more R' is -S(O)2R. In some embodiments, one or more Rlis -S(O)2NR2. In some embodiments, one or more R is -S(O)R. In some embodiments, one or more Rlis -C(O)R. In some embodiments, one or more R‘ is -C(O)OR. In some embodiments, one or more Rlis -C(O)NR2. In some embodiments, one or more Rlis -C(O)NROR. In some embodiments, one or more Rlis -OC(O)R. In some embodiments, one or more Rlis -OC(O)NR2. In some embodiments, one or more Rlis -NRC(O)OR. In some embodiments, one or more Rlis -NRC(O)R. In some embodiments, one or more Rlis -N(R)C(O)N(R)2. In someembodiments, one or more R’ is -NRS(O)2R. In some embodiments, Rlis an optionally substituted Ci.6 aliphatic. In some embodiments, one or more R‘ is Ci-e aliphatic. In some embodiments, Rlis an optionally substituted 4-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R‘ is an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R* is a 4-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, Rlis a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R‘ groups on the same saturated carbon atom are taken together to form =0.

[0318] In some embodiments, R‘ is methyl, fluoro, -NHMe, -OMe, -OCI fOMc. or -C(0)N(Me)2.

[0319] In some embodiments, R‘ is methyl. In some embodiments, R‘ is fluoro. In some embodiments, R‘ is -NHMe. In some embodiments, Rlis -OMe. In some embodiments. Rlis -OCH2OMe. In some embodiments, Rlis -C(0)N(Me)2.

[0320] In some embodiments, R‘ is selected from those depicted in the compounds of Table la or Table lb below.

[0322] In some embodiments, Ring T taken together with ( R )tis. In some embodiments, RingT taken together with (R‘)tis. In some embodiments, Ring T taken together with (R‘)tisN'' ■; / Ring T taken together with (R‘)tis H. In some embodiments, Ring T taken together with (R‘)ttogether with (R‘)tisIn some embodiments, Ring T taken together with (R‘)tis H In some embodiments, Ring T taken together with (R’)tisIn some embodiments, Ring T taken together with (Rl)tisIn some embodiments. Ring T taken together with (Rl)tisIn someembodiments, Ring T taken together with (R‘)tisIn some embodiments, Ring T takentogether with (R‘)tis HN. In some embodiments, Ring T taken together with (R')tisIn some embodiments, Ring T taken together with (R')tis. In some embodiments, Ring Ttaken together withIn some embodiments, Ring T taken together with (Rl)tisIn some embodiments. Ring T taken together with (R ) isIn someembodiments, Ring T taken together with (R )tisIn some embodiments, Ring T takentogether with (Rl)tis H In some embodiments. Ring T taken together with (Rl)tisIn some embodiments, Ring T taken together with (Rl)tisIn some embodiments, RingT taken together with (R‘)tis H In some embodiments, Ring T taken together with (R‘)tisIn some embodiments. Ring T taken together with (Rl)tisIn someembodiments, Ring T taken together with (R‘)tisIn some embodiments, Ring T takentogether with (Rl)tisIn some embodiments, Ring T taken together with (Rl)tisIn some embodiments, Ring T taken together with (R‘)tisIn some embodiments, Ring T taken together with (R‘)tisIn some embodiments, Ring T taken together with (R‘)tisIn some embodiments, Ring T taken together with (R‘)tisIn some embodiments. Ring T taken together withIn some embodiments, Ring T taken, g gtembodiments, Ring T taken together with (R‘)tisIn some embodiments, Ring T taken together with (R’)t isIn some embodiments, Ring T taken together with (R‘)tisIn some embodiments. Ring T taken together with (Rl)tisIn some embodiments, Ring T taken together with (R‘)tisIn some embodiments, Ring T taken together with (R‘)tisIn some embodiments, Ring T taken together with (Rl)tisIn some embodiments, Ring T taken together with (R)tis H In some Hembodiments. Ring T taken together with (Rl)tis. In some embodiments, Ring T takentogether with (Rl)tisIn some embodiments, Ring T taken together with (R )tisIn some embodiments, Ring T taken togetherTable la. Exemplary CompoundsTable lb. Exemplary Compounds

[0323] In some embodiments, the present invention provides a compound set forth in Table la or Table lb, above, or a pharmaceutically acceptable salt thereof.4. General Methods of Providing the Present Compounds

[0324] The compounds of this invention may be prepared or isolated in general by synthetic and / or semisynthetic methods known to those skilled in the art for analogous compounds and by methods described in detail in the Examples, herein.

[0325] In the Schemes below, where a particular protecting group (PG), leaving group, or transformation condition is depicted, one of ordinary skill in the art will appreciate that other protecting groups, leaving groups, and transformation conditions are also suitable and are contemplated. Such groups andtransformations are described in detail in March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, M. B. Smith and J. March, 5thEdition, John Wiley & Sons, 2001, Comprehensive Organic Transformations, R. C. Larock, 2ndEdition, John Wiley & Sons, 1999, and Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, the entirety of each of which is hereby incorporated herein by reference.

[0326] As used herein, the phrase "‘oxygen protecting group"’ includes, for example, carbonyl protecting groups, hydroxyl protecting groups, etc. Hydroxyl protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, the entirety of each of which is herein incorporated by reference. Examples of suitable hydroxyl protecting groups include, but are not limited to, esters, allyl ethers, ethers, silyl ethers, alkyl ethers, arylalkyl ethers, and alkoxyalkyl ethers. Examples of such esters include formates, acetates, carbonates, and sulfonates. Specific examples include formate, benzoyl formate, chloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, p-chlorophenoxyacetate, 3 -phenylpropionate, 4-oxopentanoate, 4,4-(ethylenedithio)pentanoate, pivaloate (trimethylacetyl), crotonate, 4-methoxy-crotonate, benzoate, p-benylbenzoate, 2,4,6-trimethylbenzoate, carbonates such as methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, vinyl, allyl, and p-nitrobenzyl. Examples of such silyl ethers include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, and other trialkylsilyl ethers. Alkyl ethers include methyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, trityl, t-butyl, allyl, and allyloxycarbonyl ethers or derivatives. Alkoxyalkyl ethers include acetals such as methoxymethyl, methylthiomethyl, (2 -methoxy ethoxy )methyl, benzyloxymethyl, beta-(trimethylsilyl)ethoxymethyl, and tetrahydropyranyl ethers. Examples of arylalkyl ethers include benzyl, p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, O-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, and 2- and 4-picolyL

[0327] Amino protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, the entirety of each of which is herein incorporated by reference. Suitable amino protecting groups include, but are not limited to, aralkylamines, carbamates, cyclic imides, allyl amines, amides, and tire like. Examples of such groups include t-butyloxycarbonyl (BOC), ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyloxocarbonyl (CBZ), allyl, phthalimide, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, phenylacetyl, trifluoroacetyl, benzoyl, and the like.

[0328] One of skill in the art will appreciate that various functional groups present in compounds of the invention such as aliphatic groups, alcohols, carboxylic acids, esters, amides, aldehydes, halogens andnitriles can be interconverted by techniques well known in the art including, but not limited to reduction, oxidation, esterification, hydrolysis, partial oxidation, partial reduction, halogenation, dehydration, partial hydration, and hydration. “March’s Advanced Organic Chemistry". 5thEd., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, the entirety of which is incorporated herein by reference. Such interconversions may require one or more of the aforementioned techniques, and certain methods for synthesizing compounds of the invention are described below in the Exemplification.

[0329] One of ordinary skill in the art would understand that protecting groups are used to protect reactive functionalities from reacting in an undesired fashion as described herein and as known in the art. Protecting groups can be exchanged or removed as appropriate to get to the final compounds. In the schemes below, where a provided compound is formed having a reactive moiety (e.g., amine, alcohol, etc.), it is not shown but it is generally appreciated and well known by those having ordinary skill in the art that the reactivity of said reactive moiety may be masked by employing a suitable protecting group that can thereafter be removed in situ or during a separate synthetic step.

[0330] As described in the schemes below, R is a substituent as described in the genera disclosed herein.

[0331] Compounds set forth in Table la or Table lb above were prepared according to tire following general approaches or related synthetic strategies.Scheme A: Synthesis of isoquinoline intermediateDioxane, RT Scheme B: Alternate synthesis of isoquinoline intermediateScheme C: Synthesis of functionalized pyridazine intermediate,Scheme D: Synthesis of isoquinoline derivativesPd catalyst, basesolvent, APd catalyst, base, solvent, AScheme E: Alternate synthesis of isoquinoline derivativesScheme F: Synthesis of isoquinoline derivatives5. Uses, Formulation and AdministrationPharmaceutically acceptable compositions

[0332] According to another embodiment, the invention provides compositions comprising a compound of this invention (e.g., an rSM) or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. Tire amount of compound in compositions of this invention is such that is effective to measurably suppress the aberrant functionality of a TCF4 RNA, and / or the modulate a TCF4 RNA transcript to treat a disease, disorder, or condition, such as a TCF4-mediated disease or condition.

[0333] In certain embodiments, tire amount of compound in compositions of this invention is such that is effective to measurably suppress the aberrant functionality of a TCF4 RNA, and / or the modulate a TCF4 RNA transcript, in a biological sample or in a patient. In certain embodiments, a composition of this invention is formulated for administration to a patient in need of such composition. In some embodiments, a composition of this invention is formulated for oral administration to a patient.

[0334] The term '‘patient” or “subject,” as used herein, means an animal, such as a mammal, and, for example, a human.

[0335] Tire term “pharmaceutically acceptable carrier, adjuvant, or vehicle” refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of tire compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylenepolyoxypropylene -block polymers, polyethylene glycol and wool fat.

[0336] A '‘pharmaceutically acceptable derivative” means any non-toxic salt, ester, salt of an ester or other derivative of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof.

[0337] Compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The tenn “parenteral” as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrastemal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions arc administered orally, intraperitoneally or intravenously. Sterile injectable forms of thecompositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water. Ringer’s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0338] For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long -chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

[0339] Pharmaceutically acceptable compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and com starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule fomi, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsify ing and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

[0340] Alternatively, pharmaceutically acceptable compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release tire drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

[0341] Pharmaceutically acceptable compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0342] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation(see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.

[0343] For topical applications, provided pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0344] For ophthalmic use, provided pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic. pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.

[0345] Pharmaceutically acceptable compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in tire art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0346] Most preferably, pharmaceutically acceptable compositions of this invention are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this invention are administered without food. In other embodiments, pharmaceutically acceptable compositions of this invention are administered with food.

[0347] The amount of compounds of the present invention that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration. Preferably, provided compositions should be formulated so that a dosage of between 0.01 - 100 mg / kg body weight / day of the inhibitor can be administered to a patient receiving these compositions.

[0348] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of tire particular disease being treated. Tire amount ofa compound of the present invention in the composition will also depend upon the particular compound in the composition.Uses of Compounds and Pharmaceutically Acceptable Compositions

[0349] Compounds and compositions described herein are generally useful to treat a disease, disorder, or condition, such as a TCF4-mediated disease, disorder or condition, and / or for suppression of the aberrant functionality of a TCF4 RNA, and / or the modulation of a TCF4 RNA transcript.

[0350] The activity of a compound utilized in this invention to treat the TCF4-mediated disease disorder or condition, suppress the aberrant functionality of a TCF4 protein, and / or the modulate a TCF4 RNA transcript may be assayed in vitro, in vivo or in a cell line. In vitro assays include assays that quantitate the ability of the compound to modulate, e.g., bind, the TCF4 RNA transcript. In vivo or cell line assays include those that, for example, measure expression or functionality of a TCF4 RNA, a cell phenotype, or cell apoptosis. Detailed conditions for assaying a compound utilized in this invention to treat a TCF4-mediated disease disorder or condition or measurably suppress the aberrant functionality of a TCF4 protein, and / or the modulate a TCF4 RNA transcript are set forth in the Examples below.

[0351] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in tire absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g.. in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.

[0352] In one aspect, the provided compounds are therefore useful for treating TCF4-mediated diseases, disorders or conditions. In some embodiments, the provided compounds can suppress the aberrant functionality of a TCF4 protein, lower the expression level of a TCF4 protein, and / or modulate a TCF4 RNA transcript and are therefore useful for treating TCF4-mediated diseases, disorders or conditions. In some embodiments, the compounds can suppress the aberrant functionality of a TCF4 protein, lower the expression level of a TCF4 protein, and / or the modulate a TCF4 RNA transcript and are therefore useful for treating one or more disorders associated with or affected by (e.g., downstream of) the translation of the TCF4 RNA transcript into a protein. Tirus, in certain embodiments, the present invention provides a method for treating an TCF4-mediated disorder comprising the step of administering to a subject in need thereof a compound of the present invention, or pharmaceutically acceptable salt or composition thereof.

[0353] As described below, the present invention also provides methods for the treatment or prevention ofcomeal dystrophy (e.g., Fuchs endothelial comeal dystrophy (FECD)). Such methods comprise the step of administering to the subject in need thereof an effective amount of a disclosed compound, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer, or a pharmaceutical composition thereof.

[0354] In certain embodiments, the subject being treated is a mammal. In certain embodiments, the subject is a human. In certain embodiments, the subject is a domesticated animal, such as a dog. cat, cow. pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal such as a dog or cat. In certain embodiments, the subject is a livestock animal such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal such as a rodent, dog, or non-human primate. In certain embodiments, the subj ect is a non-human transgenic animal such as a transgenic mouse or transgenic pig.

[0355] The present disclosure provides treatment modalities, methods, strategies, compositions, combinations, and dosage forms for the treatment of various diseases, disorders, and conditions. In some embodiments, tire disease, disorder, or condition is corneal dystrophy (e.g., Fuchs endothelial comeal dystrophy (FECD)), such as one associated with aberrant activity or function of the TCF4 RNA.

[0356] In some embodiments, the disease, disorder, or condition is TCF4-mediated. As used herein, a “TCF4-mediated” disease, disorder, or condition is one in which a TCF4 RNA transcript, or an unspliced isoform, splicing intermediate, isoform, fragment, or mutant thereof, is associated or plays a causative role. In some embodiments, “TCF4-mediated” means that the disease, disorder, or condition is capable of being treated, ameliorated, or prevented by modulating the activity of a TCF4 RNA transcript, or an unspliced isoform, splicing intermediate, isoform, fragment, or mutant thereof, or its downstream protein. In some embodiments,£'TCF4-mediated” means that the disease, disorder, or condition is affected by (e.g., downstream of) the TCF4 RNA transcript, or an unspliced isoform, splicing intermediate, isofonn, fragment, or mutant thereof, or the protein expressed thereof.

[0357] The term ‘'biological sample” refers to any sample including tissue samples (such as tissue sections and needle biopsies of a tissue); cell samples (e.g., cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection); samples of whole organisms (such as samples of yeasts or bacteria); or cell fractions, fragments or organelles (such as obtained by lysing cells and separating the components thereof by centrifugation or otherwise). Other examples of biological samples include blood, serum, urine, semen, fecal matter, cerebrospinal fluid, interstitial fluid, mucus, tears, sweat, pus, biopsied tissue (e.g., obtained by a surgical biopsy or needle biopsy), nipple aspirates, milk, vaginal fluid, saliva, swabs (such as buccal swabs), or any material containing biomolecules that is derived from a first biological sample. Biological samples also include those biological samples that arc transgenic, such as transgenicoocyte, sperm cell, blastocyst, embryo, fetus, donor cell, or cell nucleus.

[0358] As used herein, the term “responsiveness” is interchangeable with terms “responsive,” “sensitive,” and “sensitivity,” and it is meant that a subject is showing a therapeutic response when administered a composition of the disclosure. In some embodiments, a “response” also means that a subject will have or has a higher probability, relative to the population at large, of showing therapeutic responses when administered a disclosed compound.

[0359] In some embodiments, the compounds provided herein modulate a MBNL 1 protein or a TCF4 RNA transcript. Modulating refers to stimulating or inhibiting an activity of a target (e.g. aberrant functionality of an RNA). In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt or solvate or hydrate thereof, modulates the activity of a target if it stimulates or inhibits the activity of the target by at least 2-fold relative to the activity of the target under the same conditions but lacking only the presence of the compound. In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof, modulates the activity of a target if it stimulates or inhibits the activity of the target by at least 5-fold, at least 10-fold, at least 20-fold, at least 50-fold, at least 100-fold relative to the activity of the target under the same conditions but lacking only the presence of the compound. Hie activity of a target may be measured by any reproducible means. The activity of a target may be measured in vitro or in vivo, by methods such as those described herein.

[0360] In some embodiments, the present invention provides a method of treating corneal FECD by administering an effective amount of a disclosed compound, or a pharmaceutically acceptable salt or solvate or hydrate thereof, to a subject in need thereof, wherein administration of the compound, or a pharmaceutically acceptable salt or solvate or hydrate thereof.

[0361] As used herein, “therapeutic index” is the maximum tolerated dose divided by the efficacious dose.

[0362] One skilled in the art may refer to general reference texts for detailed descriptions of known techniques 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 (3rdedition), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000); Coligan et al.. Current Protocols in Immunology, John Wiley & Sons, N. Y.; Enna et al., Current Protocols in Pharmacology, John Wiley & Sons, N. Y; Fingl et al., The Pharmacological Basis of Therapeutics (1975), and Remington ’s Pharmaceutical Sciences, Mack Publishing Co., Easton. PA. 18thedition (1990); each of which is hereby incorporated by reference in its entirety. These texts can, of course, also be referred to in making or using an aspect of the disclosure.Combination Therapies

[0363] The disclosure also provides pharmaceutical compositions comprising a compound of the disclosure or pharmaceutically acceptable salts thereof, and one or more other therapeutic agents disclosed herein, mixed with pharmaceutically suitable carriers or excipient(s) at doses to treat or prevent a disease or condition as described herein. Tire pharmaceutical compositions of the disclosure can also be administered in combination with other therapeutic agents or therapeutic modalities simultaneously, sequentially, or in alternation.

[0364] Mixtures of compositions of the disclosure can also be administered to the patient as a simple mixture or in suitable formulated pharmaceutical compositions. For example, some aspects of the disclosure relate to a pharmaceutical composition comprising a therapeutically effective dose of a compound of the disclosure, or a pharmacally acceptable salt, hydrate, enantiomer or stereoisomer thereof; one or more other therapeutic agents, and a pharmaceutically acceptable diluent or carrier.

[0365] A “pharmaceutical composition7’ is a formulation containing the compounds of the disclosure in a form suitable for administration to a subject. A compound of the disclosure and one or more other therapeutic agents described herein each can be formulated individually or in multiple pharmaceutical compositions in any combinations of the active ingredients.

[0366] Accordingly, one or more administration routes can be properly elected based on the dosage form of each pharmaceutical composition. Alternatively, a compound of the disclosure and one or more other therapeutic agents described herein can be fonnulated as one pharmacal composition.

[0367] In some embodiments, the pharmaceutical composition is in bulk or in unit dosage form. The unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler or a vial. The quantity of active ingredient (e.g., a fonnulation of the disclosed compound or salt, hydrate, solvate or isomer thereof) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved. One skilled in the art will appreciate that it is sometimes necessary to make routine variations to the dosage depending on the age and condition of the patient. The dosage will also depend on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like. Dosage fonns for the topical or transdermal administration of a compound of this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. In some embodiments, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required.

[0368] A pharmaceutical composition of the disclosure is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous,intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes, or multiple dose vials made of glass or plastic.

[0369] Tire term “therapeutically effective amount,” as used herein, refers to an amount of a pharmacal agent to treat, ameliorate, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend upon the subject's body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration. Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician. In some aspects, the disease or condition to be treated is Fuchs endothelial corneal dystrophy (FECD).

[0370] In certain embodiments the therapeutically effective amount of each pharmacal agent used in combination will be lower when used in combination in comparison to monotherapy with each agent alone. Such lower therapeutically effective amount could afford for lower toxicity of the therapeutic regimen.

[0371] For any compound, the therapeutically effective amount can be estimated initially either in cell culture assays, e.g., of neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs. Hie animal model may also be used to detennine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic / prophylactic efficacy and toxicity may be determined by standard pharmacal procedures in cell cultures or experimental animals, e.g., ED50(the dose therapeutically effective in 50% of the population) and LD50(the dose lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD50 / ED50. Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage may van’ within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.

[0372] The additional pharmaceutical agent(s) may synergistically augment suppression of aberrant functionality of TCF4 or other TCF4 family members induced by the inventive compounds or compositions of this invention in the biological sample or subject.Formulations and Routes of Administration

[0373] The compounds and compositions, according to a method of the present invention, may be administered using any amount and any route of administration effective for treating or lessening the severity of Fuchs endothelial comeal dystrophy (FECD) or other disease, disorder, or condition disclosed herein. The exact amount required will vary from subject to subject, depending on tire species, age. and general condition of tire subject, the severity of the infection, the particular agent, its mode of administration, and the like. Compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression ‘unit dosage form” as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of tire compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. Tire specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts.

[0374] Pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracistemally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated. In certain embodiments, the compounds of the invention may be administered orally or parenterally at dosage levels of about 0.01 mg / kg to about 50 mg / kg and preferably from about 1 mg / kg to about 25 mg / kg. of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.

[0375] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to tire active compounds, the liquid dosage forms may contain inert diluents commonly used in tire art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfiiryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0376] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3 -butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U. S. P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0377] Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0378] In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0379] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[0380] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage fonns, the active compound is mixed with at least one inert, pharmacally acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginicacid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0381] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and tire like.

[0382] The active compounds can also be in micro-encapsulated fonn with one or more excipients as noted above. Tire solid dosage fonns of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0383] Dosage forms for topical or transdemial administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the present invention contemplates the use of transdcrmal patches, which have the added advantage of providing controlled delivery of acompound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.EXEMPLIFICATIONGeneral Synthetic Methods

[0384] The following examples are intended to illustrate tire invention and are not to be construed as being limitations thereon. Temperatures are given in degrees centigrade, if not mentioned otherwise, all evaporations are performed under reduced pressure, preferably between about 15 mm Hg and 100 mm Hg (= 20-133 rnbar). The structure of final products, intermediates and starting materials is confirmed by standard analytical methods, e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR, NMR. Abbreviations used are those conventional in tire art.

[0385] All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts utilized to synthesis the compounds of the present invention are either commercially available or can be produced by organic synthesis methods known to one of ordinary skill in the art (Houben-Weyl 4th Ed. 1952, Methods of Organic Synthesis, Thieme, Volume 21). Further, the compounds of the present invention can be produced by organic synthesis methods known to one of ordinary skill in the art as shown in the following examples.

[0386] All reactions are carried out under nitrogen or argon unless otherwise stated.

[0387] Proton NMR ('H NMR) is conducted in deuterated solvent. In certain compounds disclosed herein, one or more 'H shifts overlap with residual proteo solvent signals: these signals have not been reported in the experimental provided hereinafter.

[0388] As depicted in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present invention, the following general methods, and other methods known to one of ordinary skill in the art, can be applied to all compounds and subclasses and species of each of these compounds, as described herein. Similarly, assays and other analyses can be adapted according to the knowledge of one of ordinary skill in the art.AbbreviationsAc: acetylACN: acetonitrileAcOH: acetic acidBINAP: (2.2'-bis(di phenyl phosph ino)-l. I '-binaphthyl)BnBr: Benzyl bromideBoc: tert-butoxycarbonylBoc2O: di-tert-butyl dicarbonateCbz: benzyloxy carbonylCOD: 1,5 -CyclooctadieneDCE: 1.2-di chloroethaneDCM: dichloromethanedcpp: 1,3-Bis(dicyclohexylphosphino)propane bis(tetrafluoroborate)DDQ: 2.3 -Dichloro-5,6-dicyano- 1,4-benzoquinoneDIAD: l,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate)DIPEA or DIE A: N, N -diisopropylethylamineDMAP: 4-dimethylaminopyridineDMF: N, N-dimethylfonnamideDMSO: dimethyl sulfoxideEA: ethyl acetateEDC or EDCI: 1 -(3 -dimethylaminopropyl)-3 -ethylcarbodiimide hydrochlorideee: enantiomeric excesseq: equivalentsEtI: ethyl iodideEtOAc: ethyl acetateEtOH: ethanolFA: formic acidh or hrs: hoursHATU: N, N, N’, N’-tetramethyl-O-(7-azabenzotriazol-l-yl)uronium hexafluorophosphateHBTU: (2-( IH-benzotriazol- 1 -yl)- 1, 1,3,3-tetramethyluronium hexafluorophosphate, hexafluorophosphate benzotriazole tetramethyl uronium)HMPA: HexamethylphosphoramideHO Ac: acetic acidHOAt: 1 -Hydroxy-7-azabenzotriazoleHOBt: HydroxybenzotriazoleHPLC: high performance liquid chromatographyhr, hrs, or h: hourIPA or i-PrOH: isopropyl alcoholM: molarM: molarityMeCN: acetonitrileMeOH: methanolMhz megahertzmin: minutesmL: millilitersmm: millimetersmM: millimolarmmol: millimolesMS: mass spectrometry or mass spectrometerMS: Molecule sievesMTBE: Methyl tert-butyl etherNaOBH(OAc)3: Sodium triacetoxyborohydrideNBS: A-bromosuccinimideNMR: Nuclear Magnetic ResonancePd(dppf)C12: [1,1 '-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) PE: petroleum etherpsi: pounds per square inchR. T. or rt: room temperatureRf: retention factorRt: retention timesat: saturatedSFC: supercritical fluid chromatographyt-BuONa: Sodium tert-butoxideTEA: tri ethylamineTFA: trifluoracetic acidTFE: 2,2,2-trifluoroethanolTHF: tetrahydrofiiranTLC: thin layer chromatographyTMSI: trimethylsilyl iodidepm: micrometerspmol: micromolesv / v: volume per volumeXPhos: Dicyclohexyl[2',4',6'-tris(propan-2-yl)[1,1'-biphenyl]-2-yl]phosphaneXPhos Pd G3: (2-Dicyclohexylphosphino-2’,4’,6'-triisopropyl-l,r-biphenyl)[2-(2'-amino-l,r- biphenyl)]palladium(II) methanesulfonate, XPhos-G3-Palladacycle. XPhos-Pd-G3General Methods

[0389] Mass spectra were acquired on a Water Acquity UPLC - H Class equipped with a photodiode array (PDA) and QDa detector using electrospray, chemical and electron impact ionization methods as described in Table A below. [M+H]+refers to protonated molecular ion of the chemical species.

[0390] HPLC spectrum were detected at 254nm and 220nm, unless indicated otherwise.

[0391] NMR spectra were recorded on a Bruker 400 MHz i-Probe spectrophotometer (400MHz for 'H NMR and 100MHz for13C NMR), and spectra were integrated in Topspin 4.0.9 software. Chemical shifts were reported in 5 ppm (parts per million) with residual solvent protons as internal standard. Coupling constant (J) values are given in Hertz (Hz). Splitting patterns are designated as s (singlet), d (doublet), t (triplet), q (quartet), dd (double doublet), m (multiplet), and bs (broad singlet). Spectra were measured at 298°K, unless indicated otherwise, and were referenced relative to the solvent resonance.Table A: LCMS / HPLC MethodsExample 1: Synthesis of Compounds of the InventionScheme 1: Synthesis of 2-(dimethylamino)ethyl (l-((2-(dimethylamino)ethyl)amino)-5-(6-(4-methylpiperazin-l-yl)pyridazin-4-yl)isoquinolin-3-yl)carbamate (1-141)Step 1:

[0392] To a stirred solution of 5 -Bromo- 1,3 -dichloroisoquinoline 1 (2 g, 7.22 mmol) and tert-butyl (2-aminoethyl)carbamate 2 (1.504 g, 9.39 mmol) in dioxane (50 mL) was added DIPEA (2.5 mL, 14.04 mmol). The reaction mixture was stirred at 110 °C for 16 h. The progress of the reaction was monitored by UPLC.

[0393] The organics were evaporated in vacuo. The obtained crude was purified by column chromatography (silica gel 230-400 mesh; column eluted with 0-60% EtOAc in petroleum ether (gradient) to get tert-butyl (2-((5-bromo-3-chloroisoquinolin-l-yl)amino)ethyl)carbamate 3 (2 g, 4.92 mmol, 68.1% yield) as an off-white solid. LCMS: m / z = 400.0 [M+H]+Step 2:

[0394] To a stirred solution of tert-butyl (2-((5-bromo-3-chloroisoquinolin-l-yl)amino)ethyl)carbamate 3 (2 g.4.99 mmol) and bis(pinacolato)diboron (3.80 g, 14.97 mmol) in dioxane (40 mL) was added potassium acetate (0.980 g, 9.98 mmol). The resulting reaction mixture was purged with N2 for 10 min. and then added PdCl2(dppf) (0.548 g, 0.749 mmol) to the reaction mixture. The reaction mixture was again purged with N2 for 10 min and stirred at 80 °C for 4 hours. The progress of the reaction was monitored by UPLC.

[0395] Tire organics were evaporated in vacuo. The obtained crude product was purified by flash column chromatography (silica gel 230-400 mesh, eluted with 0-60% EtOAc in petroleum ether) to get tert-butyl (2-((3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-yl)amino)ethyl)carbamate 5 (2g, 4.13 mmol, 83% yield) as yellow gum. LCMS: m / z = 448.2 [M+H]+Step 3:

[0396] To a repeatedly nitrogen purged solution of tert-butyl (2-((3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-yl)amino)ethyl)carbamate 5 (1.468 g, 3.280 mmol) in THF (80 mL) & water (4 mL) were added K3PO4 (2.2 g, 10.4 mmol) and 5-bromo-3-(4-methylpiperazin-l-yl)pyridazine 6 (0.88 g, 3.45 mmol). Tire resulting solution was again purged with N2 for 10 min. Then PdCl2(dppf) (250 mg, 0.35 mmol) was added to the reaction mixture and the solution was purged with nitrogen for 10 min. The resulting reaction mixture was heated at 70 °C for 3 h. The progress of the reaction was monitored by LCMS.

[0397] The reaction mixture was filtered through a celite bed, washed with MeOH (100 mL). The organics were evaporated in vacuo to give crude mass. The obtained crude product was purified PREP-HPLC to get tert-butyl (2-((3 -chloro-5-(6-(4-methylpiperazin- 1 -yl)pyridazin-4-yl)isoquinolin- 1 -yl)amino)ethyl)carbamate 7 (0.67 g, 1.35 mmol, 39% yield) as a yellow solid. LCMS: m / z = 498.2 [M+H]+Step 4:

[0398] To stirred solution of tert-butyl(2-((3-chloro-5-(6-(4-methylpiperazin-l-yl)pyridazin-4-yl)isoquinolin-l-yl)amino)ethyl)carbamate 7 (408 mg, 819 mmol), 2-(dimethylamino)ethyl carbamate 8 (228 mg, 1.723 mmol) and XPhos (42 mg, 0.088 mmol) in THF (30 mL) was added CS2CO3 (1.3 g, 3.98 mmol). The resulting mixture was purged with N2 for 10 min. Then XPhos Pd G3 (52 mg, 0.066 mmol) was added to the reaction mixture and then purged with N2 for 10 min. The reaction mixture was heated at 60 °C for 2 h. The progress of the reaction was monitored by LCMS.

[0399] The reaction mixture was filtered through a pad of celite and washed with MeOH. The combined organic phase was concentrated in vacuo to get crude mass. Tire obtained crude was purified by PREP-HPLC to get tert-butyl (2-((3-(((2-(dimethylamino)ethoxy)carbonyl)amino)-5-(6-(4-methylpiperazin-l-yl)pyridazin-4-yl)isoquinolin-l-yl)amino)ethyl)carbamate 9 (268 mg, 0.436 mmol, 55% yield) as yellow solid. LCMS: m / z = 594.2 [M+H]+Step 5:

[0400] To a stirred solution of tert-buty l (2-((3-(((2-(dimethylamino)ethoxy)carbonyl)amino)-5-(6-(4-methylpiperazin-l-yl)pyridazin-4-yl)isoquinolin-l-yl)amino)ethyl)carbamate 9 (160 mg, 0.269 mmol) in DCM (10 mL) was added HC1 in dioxane (4 M, 0.337 mL, 1.347 mmol) was added dropwise to the reaction mixture. The resulting reaction mixture was stirred at room temperature for 2 h. The reaction was monitored by TLC. The organics were evaporated in vacuo to give 2-(dimethylamino)ethyl (l-((2-aminoethyl)amino)-5-(6-(4-methylpiperazin-l-yl)pyridazin-4-yl)isoquinolin-3-yl)carbamate 10 (133 mg, 0.263 mmol, 98%yield) as yellow solid, which was used without purification.Step 6:

[0401] To stirred solution of 2-(dimethylamino)ethyl (l-((2-aminoethyl)amino)-5-(6-(4-methylpiperazin-l-yl)pyridazin-4-yl)isoquinolin-3-yl)carbamate 10 (133 mg, 0.269 mmol) was dissolved in MeOH (2 mL) was added triethylamine (0.2 mL, 1.435 mmol, ) in dropwise (The pH of solution was maintained between 7-10). Then formaldehyde (87 mg, 1.078 mmol, 0.25 mL) and sodium triacetoxyborohydride (228 mg, 1.078 mmol) and acetic acid (20 mg, 0.333 mmol) were added successively. Hie resulting reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by LCMS.

[0402] The organics were evaporated in vacuo. The crude obtained was purified by PREP-HPLC using H2O: ACN (0.1% TFA). The combined pure fractions were concentrated to get as an orange gummy liquid (TFA salt). Tire salt was treated with 200 mg potassium carbonate in DCM: MeOH (95:5), filtered and concentrated. Tire residue obtained was dissolved in ACN: Water and lyophilized to give 1-141 as a yellow solid (80 mg, 0.149 mmol, 55.4 % yield). LCMS: m / z = 522.2 [M+H]+

[0403] 'H-NMR (400 MHz, DMSO-r / 5): 8 9.52 (s. 1H), 8.63 (d. J = 1.60 Hz, 1H), 8.21 (d, J = 8.40 Hz, 1H), 7.57 (dd, J = 0.80, 7.20 Hz, 1H), 7.49 (t, J = 5.60 Hz, 1H), 7.40 - 7.37 (m, 1H), 7.30 (t, J = 11.20 Hz, 2H), 4.11 (t, J = 6.00 Hz, 2H), 3.68 (t, J = 5.20 Hz, 4H), 3.63 - 3.59 (m, 2H), 2.50 - 2.44 (m, 8H), 2.24 (s, 3H), 2.22 (s, 6H), 2.17 (s, 6H).Scheme 2: Synthesis of Nl-(3-chloro-5-(6-(4-methylpiperazin-l-yl)pyridazin-4-yl)isoquinolin-l-yl)-N3, N3-dimethylpropane-l,3-diamine (1-135)Step 1:

[0404] To a stirred solution of 5-bromo-l,3-dichloroisoquinoline 1 (15 g, 54.2 mmol) in dioxane (150 mL) was added tert-butyl (3-aminopropyl)carbamate 2 (11.33 g, 65.0 mmol) and DIEA (18.87 mL. 108 mmol) at RT. The reaction mixture was heated at 100 °C for 3 h. The progress of the reaction was monitored by LCMS.

[0405] The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phase was washed with anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude was purified with column chromatography (silica gel 60-120 mesh; eluted 15% of ethyl acetate in petroleum ether) to afford tert-butyl (3-((5-bromo-3-chloroisoquinolin-l-yl)amino)propyl)carbamate 3 (15.5 g, 68%) as a yellow solid. LCMS: m / z = 416.0 [M+H]+Step 2:

[0406] To a solution of tert-butyl (3-((5-bromo-3-chloroisoquinolin-l-yl)amino)propyl)carbamate 3 (26 g, 62.7 mmol) in dioxane (260 mL) were added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) 4 (23.88 g, 94 mmol) and potassium acetate (18.46 g, 188 mmol). The reaction mixture was purged with nitrogen for 10 minutes followed by addition of Pd(dppf)CT (5.12 g, 6.27 mmol) at RT. Then the reaction mixture was stirred at 60 °C for 3 hrs. Hie progress of the reaction was monitored by TLC.

[0407] The reaction mixture was then filtered through celite pad and washed with DCM. Then thecombined organic phase was concentrated under reduced pressure. The obtained crude product was purified with column chromatography (silica gel 60-120; eluted 15% of ethyl acetate in petroleum ether) to get tertbutyl (3-((3-chloro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-l-yl)amino)propyl) carbamate 5 (25 g, 86%) as a brown solid. LCMS: m / z = 462.2 [M+H]+Step 3:

[0408] To a solution of tert-butyl (3-((3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-yl)amino)propyl)carbamate 5 (24 g, 52.0 mmol) in dioxane (240 mL) and water (24 mL) were added 5-bromo-3-chloropyridazine 6 (10.05 g. 52.0 mmol) and CS2CO3 (50.8 g, 156 mmol). The reaction mixture was purged with nitrogen 10 min. and added Pd(dppf)Ch (2.122 g, 2.60 mmol) at RT. The reaction mixture was stirred at 90°C for 3 h. The progress of the reaction was monitored by TLC.

[0409] Tire reaction mixture was filtered through celite pad and washed with DCM. Then combined organic phase was concentrated under reduced pressure. The obtained crude product was purified with column chromatography (using silica gel 60-120; eluted 35-50% of ethyl acetate in petroleum ether) to get tert-butyl (3-((3-chloro-5-(6-chloropyridazin-4-yl)isoquinolin-l-yl)amino)propyl)carbamate 7 (18 g, 38.9 mmol, 74.9% yield) as a yellow solid. LCMS: m / z = 448.2 [M+H]+Step 4 (i):

[0410] To a stirred solution of tert-butyl (3-((3-chloro-5-(6-chloropyridazin-4-yl)isoquinolin-l-yl)amino)propyl)carbamate 7 (18 g, 40.1 mmol) in DCM (180 mL) was added 4M HCl in 1,4-dioxane (180 mL, 720 mmol) at 0 °C. The reaction mixture was stirred in RT for 2 h. The progress of the reaction was monitored by LCMS.

[0411] The reaction mixture was concentrated under reduced pressure to obtain crude, then the obtained crude was washed with petroleum ether and dried under reduced pressure to get Nl-(3-chloro-5-(6-chloropyridazin-4-yl)isoquinolin-l-yl)propane-l,3-diamine (13.5 g, 38.1 mmol, 95% yield) as a dark orange solid. LCMS: m / z = 348.2 [M+H]+Step 4 (ii):

[0412] To a stirred solution of Nl-(3-chloro-5-(6-chloropyridazin-4-yl)isoquinolin-l-yl)propane-l,3-diamine (5.5 g, 15.79 mmol) in MeOH (55 mL) was added triethylamine (4.40 mL, 31.6 mmol) at 0 °C. A basic PH was maintained during the addition of formaldehyde (1.740 mL, 63.2 mmol) at 0 °C. The reaction mixture was stirred at RT for 10 min and then added acetic acid (0.912 mL, 15.79 mmol) at 0 °C. The reaction mixture was stirred at RT for 1 h. Then sodium triacetoxyborohydride (13.39 g, 63.2 mmol) was added at 0 °C, the reaction mixture was stirred at RT for 2 h. The progress of the reaction was monitored by LCMS.

[0413] The reaction mixture was cooled to 0 °C and diluted with sodium bicarbonate solution (150 mL) then extracted with DCM, separated organic layer was dried over sodium sulphate and concentrated under reduced pressure to get Nl-(3-chloro-5-(6-chloropyridazin-4-yl)isoquinolin-l-yl)-N3, N3-dimethylpropane-l,3-diamine 8 (5.9 g, 14.61 mmol, 93% yield). LCMS: m / z = 378 [M+H]+Step 5:

[0414] To a stirred solution of Nl-(3-chloro-5-(6-chloropyridazin-4-yl) isoquinolin-l-yl)-N3, N3-dimethylpropane-l,3-diamine 8 (4.9 g, 13.02 mmol) in DMSO (49 mL) were added cesium fluoride (6.13 g, 40.4 mmol) and 1 -methylpiperazine 9 (2.174 mL, 19.53 mmol) at RT. The reaction mixture was stirred at 130 °C for 2 h. The progress of the reaction was monitored by LCMS.

[0415] The reaction mixture was concentrated under reduced pressure. The obtained crude product was extracted with 10% MeOH in DCM. Tire combined organic phase was concentrated under reduced pressure. Tire obtained crude product was purified by PREP-HPLC (Column: X Select 250 mm C18: Mobile phase A: 10 mm NH4HCO3; Mobile phase B: ACN). The product fraction was concentrated under vacuum to give 1-135 as pale-brown solid (Yield: 3 g, 51.4%). LCMS: m / z = 440.3 [M+H]+

[0416] 'H-NMR (400 MHz, DMSO-r / fi): 5 8.62 (d, J= 1.60 Hz, 1H), 8.32 (d, J= 8.80 Hz, 1H), 8.13 (t, J = 5.20 Hz, 1H), 7.67 (dd, J = 0.80, 7.20 Hz, 1H), 7.60 (t, J= 7.20 Hz, 1H), 7.31 (d, J= 1.60 Hz, 1H), 6.57 (s, 1H), 3.67 (t, J= 4.80 Hz, 4H), 3.52 - 3.48 (m, 2H), 2.44 (t, J= 4.80 Hz, 4H), 2.33 (t, J= 6.80 Hz, 2H), 2.24 (s, 3H). 2.17 (s. 6H), 1.83 - 1.78 (m, 2H).Scheme 3: Synthesis of Nl, Nl-dimethyl-N2-(5-(6-(4-methyIpiperazin-l-yl)pyridazin-4-yl)-3-(lH-pyrazol-5-yl)isoquinolin-l-yl)ethane-l,2-diamine (1-34)Step 1:

[0417] To a solution of Nl-(3-chloro-5-(6-(4-methylpiperazin-l-yl)pyridazin-4-yl)isoquinolin-l-yl)-N2, N2-dimethylethane-l,2-diamine (Intermediate 2) (1 g, 2.348 mmol) in 1,4-dioxane (80 mL) and water (20 mL) were added 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole 2 (1.093 g, 5.63 mmol) and K2CO3 (1.363 g, 9.86 mmol) successively. Tire reaction mixture was purged with nitrogen for 10 mins. Then 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride (0.344 g, 0.470 mmol) was added andthe resulting mixture was heated at 100 °C for 3 h. The progress of the reaction was monitored by LCMS.

[0418] The reaction mixture was filtered and concentrated under reduced pressure, diluted with water and extracted with ethyl acetate. The combined organic phase was washed with brine solution and dried with sodium sulphate, concentrated in vacuo. The obtained residue was purified by PREP-HPLC (Column: X Bridge 250 mm C18; Mobile phase A: 10 mm NH4HCO3; Mobile phase B: ACN). Hie product fractions were combined and lyophilized to afford 1-34 (650 mg, 60% yield) as a yellow solid. LCMS: m / z = 458.3 [M+H]+

[0419] 'H-NMR (400 MHz, DMSO-r / fi): 5 12.82 (s, 1H), 8.66 (d, J = 1.60 Hz, 1H), 8.32 (t, J= 8.40 Hz, 1H), 7.73 - 7.53 (m, 4H), 7.35 - 7.29 (m, 2H), 6.76 (s, 1H), 3.75 - 3.68 (m, 6H), 2.60 (t, J= 6.80 Hz, 2H), 2.46 (t, J = 5.20 Hz, 4H), 2.24 (s, 9H).Scheme 4: Synthesis of Nl-(2-(dimethylamino)ethyl)-N3-(5-methyl-l,3,4-oxadiazoL2-yl)-5-(6-(4-methylpiperazin-l-yl)pyridazin-4-yl)isoquinoline-l,3-diamine (1-4)Step 1:

[0420] To a stirred solution of Nl-(3-chloro-5-(6-(4-methylpiperazin-l-yl)pyridazin-4-yl)isoquinolin-l-yl)-N2, N2-dimethylethane-l,2-diamine (Intermediate 2) (200 mg, 0.470 mmol) in L4-dioxane (4 mL) were added 5-methyl-l,3,4-oxadiazol-2-amine 1 (93 mg, 0.939 mmol) and CS2CO3 (459 mg, 1.470 mmol) successively. The mixture was purged with nitrogen for 10 mins. Then Pd2(dba)s (43 mg, 0.047 mmol) and XPhos (44.8 mg, 0.094 mmol) were added. The resulting mixture was heated at 100 °C for 3 h. Hie progress of the reaction was monitored by LCMS.

[0421] The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by PREP-HPLC (Column: X Bridge 250 mm C18: Mobile phase A: 10 mm NH4HCO3: Mobile phase B: ACN). Hie combined product fraction was lyophilized to give 1-4 (185 mg, 78 % yield) as a paleyellow solid. LCMS: m / z = 489.2 [M+H]+

[0422] 'H-NMR (400 MHz, CD3OD): 88.65 (d, J= 1.60 Hz, 1H), 8.13 (d, J= 8.40 Hz, 1H), 7.59 (dd, J= 1.20, 7.20 Hz, 1H), 7.44 - 7.39 (m, 3H), 3.82 - 3.77 (m, 6H). 2.74 (t, J= 6.80 Hz, 2H), 2.65 (t, J= 4.80 Hz,4H), 2.44 (s, 3H), 2.39 (d, J= 4.00 Hz, 9H).Scheme 5: Synthesis of Nl, Nl-dimethyl-N2-(3-methyl-5-(6-(4-methylpiperazin-l-yl)pyridazin-4-yl)isoquinolin-l-yl)ethane-l,2-diamine (1-91)Step 1:

[0423] To a solution of Nl-(3-chloro-5-(6-(4-methylpiperazin-l-yl)pyridazin-4-yl)isoquinolin-l-yl)-N2, N2-dimethylethane-l,2-diamine (Intermediate 2) (200 mg, 0.470 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL) were added potassium trifluoro(methyl)borate (68.7 mg, 0.563 mmol) followed by potassium phosphate (199 mg, 0.939 mmol). The mixture was purged with nitrogen for 10 mins. Then CataCXium A Pd G4 (69.7 mg, 0.094 mmol) was added. The reaction mixture was stirred at 100 °C for 12 h. The progress of the reaction was monitored by LCMS.

[0424] After completion of the reaction, the reaction mixture was filtered and concentrated under reduced pressure. The obtained crude product was purified by PREP-HPLC (Column: X Bridge 250 mm C18; Mobile phase AMO mm NH4HCO3; Mobile phase B: CN). The combined product fraction 'as lyophilized to give 1-91 (30 mg, 15% yield) as yellow solid. LCMS: m / z = 406.3 [M+H]+

[0425] 'H-NMR (400 MHz, DMSO-cfc): 88.61 (d, J= 1.60 Hz, 1H), 8.25 (d, J= 8.40 Hz, 1H), 7.59 - 7.57 (m, 1H). 7.49 (t. J= 7.20 Hz, 1H). 7.38 (t. J= 5.20 Hz, 1H). 7.29 (d, J= 1.60 Hz, 1H), 6.50 (s, 1H). 3.68 -3.59 (m, 6H), 2.55 - 2.50 (m, 6H), 2.34 (s, 3H), 2.33 (s, 9H).Scheme 6: Synthesis of 2,2-difluoro-Nl, Nl-dimethyl-N3-(5-(6-(4-methylpiperazin-l-yl)pyridazin-4-yl)-3-(lH-pyrazol-5-yl)isoquinolin-l-yl)propane-l,3-diamine (1-363)Step 1:

[0426] To a stirred solution of l,3-dichloro-5-(6-(4-methylpiperazin-l-yl)pyridazin-4-yl)isoquinoline (Intermediate 6) (900 mg, 2.406 mmol) in DMSO (9 mL) were added Cesium fluoride (1.827 g, 12.03 mmol) followed by 2,2-difluoropropane-l,3-diamine 1 (795 mg, 7.215 mmol). The reaction mixture was irradiated at 130 °C for 1 h in microwave. The progress of the reaction was monitored by LCMS.

[0427] After completion of tire reaction, the solvent was evaporated under reduced pressure. The residue obtained was purified by PREP-HPLC (Column: X Select 250 mm C18; Mobile phase A: 10 mm NH4HCO3; Mobile phase B: ACN). The combined product fraction was concentrated under vacuum to get N 1 -(3 -chloro-5 -(6-(4-methylpiperazin- 1 -yl)pyridazin-4-yl)isoquinolin- 1 -yl)-2,2-difluoropropane- 1,3-diamine 2 (270 mg, 0.589 mmol, 73.5 % yield) as an off-white solid. LCMS: m / z = 448.2 [M+H]+

[0428] 'H-NMR (400 MHz, DMSO-r / fi): 88.64 (d, J= 1.60 Hz, 1H), 8.45 (d, J= 8.40 Hz, 1H), 8.30 (d, J = 6.00 Hz, 1H), 7.73 (t, J= 0.80 Hz, 1H), 7.66 (t, J= 7.20 Hz, 1H), 7.33 (d, J= 1.60 Hz, 1H), 6.71 (s, 1H), 4.06 (d, J= 5.20 Hz, 2H), 3.68 (t, J= 4.80 Hz, 4H), 2.87 (t, J= 14.00 Hz, 2H), 2.45 (t, J = 4.80 Hz, 4H), 2.24 (s, 3H). 1.90 (s. 2H);Step 2:

[0429] To a stirred solution of Nl-(3-chloro-5-(6-(4-methylpiperazin-l-yl)pyridazin-4-yl)isoquinolin-l-yl)-2,2-difluoropropane- 1,3 -diamine 2 (270 mg, 0.603 mmol) in MeOH (5 mL) was added 37% aqueous formaldehyde solution (0.96 mL, 12.06 mmol) followed by acetic acid (0.517 mL, 9.04 mmol). Tire reaction mixture was stirred at room temperature for 1 h. Then sodium triacetoxyborohydride (1916 mg, 9.04 mmol) was added. The reaction mixture was stirred at room temperature for 16 h. Tire progress of the reaction was monitored by LCMS.

[0430] After completion of reaction, the reaction mixture was concentrated and extracted with aqueous 5% MeOH in DCM (200 mL). The organic layer was washed with 10%NaHCOj solution (5 mL) followed by water (5 mL) and brine solution (5 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by PREP-HPLC (Column: X Select 250 mm C18; Mobile phase A: 10 mm NH4HCO3; Mobile phase B: ACN). The combined product fraction was concentrated by vacuum to get Nl-(3-chloro-5-(6-(4-methylpiperazin-l-yl)pyridazin-4-yl)isoquinolin-l-yl)-2,2-difluoro-N3, N3-dimethylpropane-l,3-diamine 3 (180 mg, 0.337 mmol, 55.9% yield) as white solid. LCMS: m z = 476.2 [M+H]+

[0431] 'H-NMR (400 MHz, DMSO-r / 6): 5 8.64 (d, J= 1.60 Hz, 1H), 8.45 (d, J= 8.40 Hz, 1H), 8.21 (t, J = 6.00 Hz, 1H), 7.73-7.71 (m, 1H), 7.67-7.63 (m, 1H), 7.34 (d, J= 1.60 Hz, 1H), 6.69 (s, 1H), 4.18-4.09 (m, 2H). 3.67 (t. J= 4.80 Hz, 4H), 2.80 (t, J= 14.40 Hz, 2H), 2.44 (t, J = 4.80 Hz, 4H). 2.34 (s, 6H), 2.24 (s- 3H);Step 3:

[0432] To a solution of Nl-(3-chloro-5-(6-(4-methylpiperazin-l-yl)pyridazin-4-yl)isoquinolin-l-yl)-2,2-difluoro-N3, N3-dimethylpropane-l,3-diamine 3 (160 mg, 0.336 mmol) in dioxane (4.5 mL) / water (0.5 mL), were added 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole 4 (85 mg, 0.437 mmol) and K2CO3 (139 mg, 1.008 mmol) successively. The reaction mixture was purged with nitrogen for 10 mins. Then 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (54.9 mg, 0.067 mmol) was added. The reaction mixture was stirred at 100 °C for 6 h.

[0433] The progress of the reaction was monitored by LCMS. The reaction mixture was filtered and concentrated under reduced pressure. The erode product was purified by PREP-HPLC (Column: X Bridge 250 mm C18; Mobile phase A: 10 mm NH4HCO3; Mobile phase B: CAN). The combined product fraction was lyophilized to give 1-363 (66 mg, 0.127 mmol, 37.8% yield) as an off-white solid. LCMS: m / z = 508.2 [M+H]+

[0434] 'H-NMR (400 MHz, DMSO-d6): 5 12.64 (s, 1H), 8.66 (d. J= 1.60 Hz, 1H), 8.38 (d, J= 8.00 Hz, 1H). 7.67-7.56 (m, 4H). 7.38 (s. 1H), 7.28 (d. J = 1.60 Hz, 1H). 6.76 (s. 1H), 4.35-4.26 (m. 2H), 3.71 (t, J = 4.80 Hz, 4H), 2.88 (t, J= 15.20 Hz, 2H), 2.52-0.48 (m, 4H), 2.34 (s, 6H), 2.28 (s, 3H).Scheme 7: Synthesis of Nl, Nl-dimethyl-N2-(8-(6-(4-methylpiperazin-l-yl)pyridazin-4-yl)-2-(lH-pyrazol-5-yl)quinazolin-4-yl)ethane-l,2-diamine (1-373)1-373Step 1:

[0435] Astirred solution of 8-bromo-2,4-dichloroquinazoline 1 (15 g, 54.0 mmol) in 1,4-dioxane (100 mL) was added tert-butyl (2-aminoethyl)carbamate 2 (10.38 g, 64.8 mmol) and DIPEA (28.2 mL, 162 mmol). The resulting reaction mixture was heated at 100 °C for 16 h. The progress of the reaction was monitored by LCMS.

[0436] After completion of reaction, the solvent was evaporated under reduced pressure. The crude productwas purified by flash chromatography (silica gel 230-400 mesh and 60-75% ethyl acetate in petroleum ether) to get tert-butyl (2-((8-bromo-2-chloroquinazolin-4-yl)amino)ethyl)carbamate 3 (20 g, 49.3 mmol, 91% yield) as off white solid. LCMS: m / z = 403.0 [M+H]Step 2:

[0437] To a nitrogen purged solution of tert-butyl (2-((8-bromo-2-chloroquinazolin-4-yl)amino)ethyl)carbamate 3 (3 g, 7.47 mmol), bis(pinacolato)diboron (3.79 g, 14.94 mmol) and potassium acetate (2.199 g. 22.41 mmol) in 1,4-dioxane (50 mL) was added PdCh(dppf) DCM adduct (0.305 g, 0.373 mmol). The resulting solution was heated at 65 °C for 4 h. The progress of the reaction was monitored by LCMS.

[0438] After completion, reaction mixture was filtered off through celite bed and the filtrate was concentrated under reduced pressure to get crude tert-butyl (2-((2-chloro-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinazolin-4-yl)amino)ethyl)carbamate 4 (3 g, 4.68 mmol, 62.7% yield) as a brown gummy. LCMS: m / z = 367.1 [M+H]+.Step 3:

[0439] To a nitrogen purged solution of tert-butyl (2-((2-chloro-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinazolin-4-yl)amino)ethyl)carbamate 4 (3 g, 6.69 mmol), 5-bromo-3-chloropyridazine 5 (1.293 g, 6.69 mmol) and cesium carbonate (6.53 g, 20.06 mmol) in 1,4-dioxane (50 mL) and water (5 mL) was added PdCL(dppf) DCM adduct (0.273 g, 0.334 mmol). The resulting solution was heated at 65 °C for 4 h. Tire reaction was monitored by LCMS.

[0440] After completion, the reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel 230-400 mesh using 80-100% ethyl acetate in petroleum ether) to get tert-butyl (2-((2-chloro-8-(6-chloropyridazin-4-yl)quinazolin-4-yl)amino)ethyl)carbamate 6 (1.1 g, 1.744 mmol, 26.1% yield) as a brown solid. LCMS: m,z = 437.1 [M+H]+.Step 4:

[0441] A stirred solution of tert-butyl (2-((2-chloro-8-(6-chloropyridazin-4-yl)qumazolin-4-yl)amino)ethyl)carbamate 6 (1.5 g, 3.45 mmol), 1 -methylpiperazine 7 (0.421 mL, 3.79 mmol)

[0442] and DIPEA (1.801 mL, 10.34 mmol) in pyridine (25 mL) was heated at 100 °C for 12 h. Hie reaction was monitored by LCMS.

[0443] After completion, the reaction mixture was diluted with water and the extracted with ethyl acetate. The combined organic phase was washed with water, brine solution, dried over sodium sulphate and concentrated under reduced pressure to get crude tert-butyl (2-((2-chloro-8-(6-(4-methylpiperazin-l-yl)pyridazin-4-yl)quinazolin-4-yl)amino)ethyl)carbamate 8 (1.5 g, 1.954 mmol, 56.7% yield) as a brown solid. LCMS: m'z = 499.2 [M+H]+Step 5:

[0444] To a nitrogen purged solution of tert-butyl (2-((2-chloro-8-(6-(4-methylpiperazin-l-yl)pyridazin-4-yl)quinazolin-4-yl)amino)ethyl)carbamate 8 (300 mg, 0.601 mmol), l-(tetralrydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole 9 (334 mg, 1.202 mmol) and cesium carbonate (588 mg, 1.804 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was added SPhos-Pd G3 (23.45 mg, 0.030 mmol). The resulting solution was heated at 80 °C for 12 h. The progress reaction was monitored by LCMS.

[0445] After completion, the reaction mixture was filtered through celite bed and the filtrate was concentrated under reduced pressure to get crude tert-butyl (2-((8-(6-(4-methylpiperazin-l-yl)pyridazin-4-yl)-2-( 1 -(tetrahydro-2H-pyran-2-yl)- lH-pyrazol-5-yl)quinazolin-4-yl)amino)ethyl)carbamate 10 (420 mg, 0.383 mmol, 63.6% yield) as a brown gummy. LCMS: m'z = 615.3 [M+H]+Step 6:

[0446] A solution of tert-butyl (2-((8-(6-(4-methylpiperazin-l-yl)pyridazin-4-yl)-2-(l-(tetraliydro-2H-pyran-2-yl)-lH-pyrazol-5-yl)quinazolin-4-yl)amino)ethyl)carbamate 10 (420 mg, 0.683 mmol) and HC1 in dioxane (0.104 mL, 3.42 mmol) in dichloromethane (10 mL) was stirred at 25 °C for 2 h. The reaction was monitored by LCMS.

[0447] After completion of reaction, solvent was evaporated under reduced pressure to get crude Nl-(8-(6-(4-methylpiperazin- 1 -yl)pyridazin-4-yl)-2-( lH-pyrazol-5-yl)quinazolin-4-yl)ethane- 1,2-diamine hydrochloride 11 (400 mg, 0.385 mmol, 56.4% yield) as brown gummy. LCMS: m / z = 431.2 [M+H]+Step 7:

[0448] A solution of Nl-(8-(6-(4-methylpiperazin-l-yl)pyridazin-4-yl)-2-(lH-pyrazol-5-yl)quinazolin-4-yl)ethane-l,2-diamine hydrochloride 11 (400 mg, 0.857 mmol) and triethylamine (0.239 mL, 1.713 mmol) in methanol (10 mL) was stirred at 25 °C for 10 minutes. To this, formaldehyde (0.094 mL, 3.43 mmol) and acetic acid (2.452 mL, 42.8 mmol) were added and stirred for 30 minutes. Then sodium triacetoxyborohydride (726 mg, 3.43 mmol) was added. The reaction was stirred at 25 °C for 12 h. The reaction was monitored by LCMS. After completion of reaction, the solvent was evaporated under reduced pressure. The crude product was purified by PREP-HPLC to yield Nl. Nl-dimetliyl-N2-(8-(6-(4-methylpiperazin-l-yl)pyridazin-4-yl)-2-(lH-pyrazol-5-yl)quinazolin-4-yl)ethane-l,2-diamine 1-373 (150 mg, 0.311 mmol, 36.3% yield) as yellow solid. LCMS: m / z = 459.2 [M+H]+

[0449] 1H-NMR (400 MHz, CD3OD: 9.56 (s, 1H), 8.80 (s, 1H), 8.02 (dd, J = 1.60, 8.20 Hz, 1H), 7.90 (dd, J = 1.20, 7.20 Hz, 1H), 7.84 (s, 1H), 7.27 (t, J = 7.20 Hz, 1H), 7.15 (s, 1H), 3.92 (s, 4H), 3.79 (t, J =6.80 Hz, 2H), 2.74 (t, J = 6.80 Hz, 2H), 2.52 (t, J = 4.80 Hz, 4H), 2.40 (s, 6H), 2.36 (s, 3H). Scheme 8: Synthesis of 3-((3-chloro-5-(6-(4-methylpiperazin-l-yl)pyridazin-4-yl)isoquinolin-l-yl)oxy)-N, N-dimethylpropan-l-amine (1-366)Intermediate-6 1-366Step 1:

[0450] To a solution of l,3-dichloro-5-(6-(4-methylpiperazin-l-yl)pyridazin-4-yl)isoquinoline (Intermediate 4) (750 mg. 2.004 mmol) in DMSO (7.5 mL) were added cesium fluoride (1521 mg, 10.02mmol) and 3-(dimethylamino)propan-l-ol 1 (414 mg, 4.008 mmol) successively. The reaction mixture was irradiated at 100 °C in microwave for 1 h. The reaction was monitored by LCMS.

[0451] After completion of reaction, the solvent was evaporated under reduced pressure. The residue obtained was purified by PREP-HPLC (Column: Xselect 250 mm C18; Flow rate: 15 mL / min; Mobile phase A: 10 mm NH4HCO3; Mobile phase B: ACN). The combined product fraction was lyophilized to give 1-366 (75 mg, 0.164 mmol, 24.49% yield) as a brown solid. LCMS: m / z = 441.2 [M+H]+

[0452] ‘H-NMR (400 MHz, DMSO-r / fi): 58.68 (d, J= 1.60 Hz, 1H), 8.32 (d, J= 8.00 Hz, 1H), 7.87-7.85 (m, 1H), 7.79-7.75 (m, 1H), 7.38 (d, J= 1.60 Hz, 1H), 7.17 (d, J = 0.40 Hz, 1H), 4.53 (t, J= 6.40 Hz, 2H), 3.70-3.67 (m, 4H), 2.45 (t, J= 5.20 Hz, 6H), 2.24 (s, 3H), 2.18 (s, 6H), 2.04-1.97 (m, 2H);Scheme 9: Synthesis of 2-(dimethylamino)ethyl (l-((2-(dimethylamino)ethyl)amino)-5-(6-(4-methyl-3-oxopiperazin-l-yl)pyridazin-4-yl)isoquinolin-3-yl)carbamate (1-12)Step 1:

[0453] To a stirred solution of Nl-(3-chloro-5-(6-chloropyridazin-4-yl)isoquinolin-l-yl)-N2, N2-dimethylethane-1.2-diamine (intermediate 7) (350 mg. 0.966 mmol) in DMSO (3 mL) was added 1-methylpiperazin-2-one 2 (221 mg, 1.932 mmol), CsF (440 mg, 2.90 mmol). Then the reaction mixture was heated at 130 °C for 3 h. The progress of the reaction was monitored by LCMS.

[0454] Tire reaction mixture was cooled to RT, quenched with water and extracted with DCM. The combined organic phase was concentrated under reduced pressure. The obtained crude brown gum was purified by PREP-HPLC. The combined product fraction was concentrated under reduced pressure to get 4-(5-(3-chloro-l-((2-(dimethylamino)ethyl)amino)isoquinolin-5-yl)pyridazin-3-yl)-l-methylpiperazin-2-one 3 (110 mg, 0.240 mmol, 24.85 % yield) as a yellow solid. LCMS: m / z = 440.2 [M+H]+Step 2:

[0455] To a solution of 4-(5-(3-chloro-l-((2-(dimethylamino)ethyl)amino)isoquinolin-5-yl)pyridazin-3-yl)-l-methylpiperazin-2-one 3 (110 mg, 0.250 mmol) in dioxane (2 mL) were added 2-(dimethylamino)ethyl carbamate 4 (33.0 mg, 0.250 mmol), cesium carbonate (244 mg, 0.750 mmol) successively. The reaction mixture was degassed with N2for 10 mins. Then XPhos (23.84 mg, 0.050 mmol) and XPhos Pd G3 (21.16 mg, 0.025 mmol) were added. The reaction mixture was stirred at 60 °C for 2 h. The progress of the reaction was monitored by LCMS.

[0456] After completion, the reaction mixture was filtered through celite bed and concentrated under reduced pressure. The obtained crude product was purified by PREP-HPLC (0.1%NLLHCO3 in ACN). The combined product fractions was lyophilised to give 1-12 (45 mg, 0.082 mmol, 32.9% yield) as a pale yellowsolid, m / z = 536.2 [M+H]+

[0457] 'H-NMR (400 MHz, MeOD): 58.71 (d, J = 1.60 Hz, 1H), 8.13 (d, J = 8.40 Hz, 1H), 7.62-7.60 (m, 1H), 7.46-7.41 (m, 3H), 4.38 (s, 2H), 4.25 (t, J = 5.60 Hz, 2H), 4.07 (t, J = 5.60 Hz, 2H), 3.75 (t, J = 6.40 Hz, 2H), 3.63 (t, J = 5.20 Hz, 2H), 3.08 (s, 3H), 2.73 (t, J = 6.80 Hz, 2H), 2.67 (t, J = 5.60 Hz, 2H), 2.40 (s, 6H). 2.33 (s, 6H). LCMS:Scheme 10: Synthesis of 2-(dimethylamino)ethyl (l-((2-(dimethylamino)ethyl)amino)-6-(6-(4-methylpiperazin-l-yl)pyridazin-4-yl)isoquinolin-3-yl)carbamate (1-81)Step 1:

[0458] To a stirred solution of 6-bromo- 1,3 -dichloroisoquinoline 1 (1.5 g, 5.42 mmol) in dioxane (30 mL) was added DIPEA (1.3 mL, 10.23 mmol), followed by added N1, N1 -dimethylethane- 1,2-diamine 2 (0.573 g, 6.50 mmol) at RT. The reaction mixture was heated at 110 °C for 12 h. The progress of the reaction was monitored by LCMS.

[0459] The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phase was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified with reverse column chromatography by using 0.1% FA in ACN: H2O to get Nl-(6-bromo-3-chloroisoquinolin-l-yl)-N2, N2-dimethylethane- 1,2-diamine 3 (1.3 g, 3.88 mmol, 71.6% yield) as a brown gum. LCMS: m / z = 30.1 [M+H]+Step 2:

[0460] To a stirred solution of tert-butyl (2-((7-bromo-3-chloroisoquinolin-l-yl)amino)ethyl)carbamate (600 mg, 1.497 mmol) in dioxane (010 mL) was added bis(pinacolato)diboron (456 mg, 1.797 mmol), potassium acetate (441 mg, 4.49 mmol). The reaction mixture was purged with nitrogen 10 min. Then Pd(dppf )CL (54.7 mg, 0.075 mmol) was added at RT. The reaction mixture was then stirred at 60 °C for 4 h. The progress of the reaction was monitored by LCMS.

[0461] After that, the reaction mixture was filtered using sintered funnel, the filtrate was concentrated under reduced pressure to get Nl-(3-chloro-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-l-yl)-N2, N2-dimethylethane-l,2-diamine 4 (550 mg, 1.228 mmol, 82% yield). LCMS: m / z = 448.2 [M+H]+Step 3:

[0462] To a solution of Nl-(3-chloro-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-l-yl)-N2, N2-dimethylethane-l,2-diamine 4 (550 mg, 1.464 mmol) in dioxane (5 mL) and water (0.5 mL) were added CS2CO3 (1431 mg, 4.39 mmol) and 5-chloro-3-(4-methylpiperazin-l-yl)pyridazine 5 (311 mg, 1.464 mmol) successively. The reaction mixture was purged with nitrogen 10 mins. Then PdCL(dppf) (107 mg, 0.146 mmol) was added at RT. The reaction mixture was stirred at 90 °C for 12 h.. The progress of the reaction was monitored by LCMS. After that, the reaction mixture was filtered using sintered funnel, the filtrate was concentrated under reduced pressure to get crude product Nl-(3-chloro-6-(6-(4-methylpiperazin-l-yl)pyridazin-4-yl)isoquinolin-l-yl)-N2, N2-dimethylethane-l,2-diamine 6 as a yellow solid. LCMS: mz' = 426.3 [M+H]+Step 4:

[0463] To a solution of Nl-(3-chloro-6-(6-(4-methylpiperazin-l-yl)pyridazin-4-yl)isoquinolin-l-yl)-N2, N2-dimethylethane-l,2-diamine 6 (170 mg, 0.399 mmol) in dioxane (5 mL) was added cesium carbonate (390 mg, 1.197 mmol) and 2-(dimethylamino)ethyl carbamate 7 (54 mg, 0.399 mmol). The resulting reaction mixture was purged with N2 for 10 min. and then added XPhos (38.1 mg, 0.080 mmol, 0.2 eq.) and Xphos Pd G3 (33.8 mg, 0.040 mmol, 0.1 eq.) at RT. The reaction mixture was heated at 100 °C for 2 h. The progress of the reaction was monitored by LCMS.

[0464] After that, the reaction mixture was filtered using sintered funnel, the filtrate was concentrated under reduced pressure. The obtained crude product was purified by PREP-HPLC (0.1% TFA in H2O) to give 1-81 (125 mg, 0.230 mmol, 57.6 % yield) as a pale brown solid.

[0465] 1H-NMR (400 MHz, DMSO-6): 5 10.01 (s, 1H), 9.44 (s, 1H), 9.20 (d, J = 1.60 Hz, 1H), 8.22 (t, J = 5.60 Hz, 1H), 8.10-8.08 (m, 1H), 7.78 (d, J = 1.60 Hz, 1H), 7.13 (s, 1H), 4.70 (d, J = 14.00 Hz, 2H), 3.86-3.82 (m. 2H), 3.61-3.58 (m, 2H), 3.41-3.33 (m, 4H), 3.17-3.15 (m, 2H), 2.92-2.89 (m, 9H). LCMS: m / z =522.3 [M+H]+Scheme 11: Synthesis of Nl-(3-chloro-7-(6-(4-methylpiperazin-l-yl)pyridazin-4-yl)isoquinolin-l-yl)- N2, N2-dimethylethane-l,2-diamine (1-80)Step 1:

[0466] To a stirred solution of 7-bromo-l,3-dichloroisoquinoline 1 (1 g, 3.61 mmol) in dioxane (30 mL) were added and N1, N1 -dimethyl ethane- 1,2-diamine 2 (0.382 g, 4.33 mmol) and DIPEA (0.8 mL, 4.59 mmol) successively. The reaction mixture was heated at 100 °C for 16 h. The progress of the reaction was monitored by UPLC.

[0467] After that, tire organics were evaporated in vacuo to give black crude mass. Tire obtained crude product was purified by column chromatography (silica gel 60-120 mesh eluted with 0-20% MeOH in DCM to getN l-(7-bromo-3-chloroisoquinolin-l-yl)-N2, N2-dimethylethane-l,2-diamine 3 (540 mg, 1.528 mmol, 42.3% yield) as a brown gum. LCMS: m / z = 328.3 [M+H]+Step 2:

[0468] Nl-(7-bromo-3-chloroisoquinolin-l-yl)-N2, N2-dimethylethane- 1,2-diamine 3 (1,17 g, 3.56 mmol) in dioxane (50 mL) was added bis(pinacolato)diboron (2.71 g, 10.68 mmol) and potassium acetate (0.699 g, 7.12 mmol). Tire resulting reaction mixture was purged with N? for 10 min. Then added PdCL(dppf) (0.391 g, 0.534 mmol) and heated the reaction mixture at 100 °C for 5 h. The progress of the reaction was monitored by LCMS.

[0469] The organics were evaporated in vacuo and the crude was dissolved in EtOAc in MeOH (8:2). The solution was filtered through a pad of silica gel, washed with a mixture of EtOAc / MeOH (8:2) (50mL X3). The combined filtrate was concentrated in in vacuo to get Nl-(3-chloro-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-l-yl)-N2, N2-dimethylethane-l,2-diamine 4 (1.7 g, 3.45 mmol, 97% yield) as black solid, which was used for the further step without any purification. LCMS: IM / Z = 376.2 [M+H]+Step 3:

[0470] To a nitrogen purged solution of Nl-(3-chloro-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-l-yl)-N2, N2-dimethylethane-l,2-diamine 4 (410 mg, 1.088 mmol, 1 eq.) in THF (40 mL) and water (4 mL) were added K3PO4 (232 mg, 1.088 mmol) and 5-bromo-3-(4-methylpiperazin-l-yl)pyridazine 5 (280 mg, 0, 1.088 mmol, 1 eq.) successively. The resulting solution was purged with N2 for 10 min. Then PdCL(dppf) (80 mg, 0.11 mmol, 0.1 eq.) was added, he reaction mixture was heated at 70 °C for 3 h. The progress of the reaction was monitored by LCMS.

[0471] Tire reaction mixture was filtered through a celite pad and washed with MeOH (100 mL). The combined filtrated was evaporated in vacuo. Tire obtained crude product was purified using PREP-HPLC to give 1-80 (150 mg, 0.225 mmol, 25% yield) as yellow solid.

[0472] 1HNMR: (400 MHz, DMSO-e): 5 10.09 (br s, 1H), 9.50 (br s, 1H), 9.25 (d, J = 1.6 Hz, 1H), 8.75 (s, 1H), 8.34-8.27(m, 2H), 7.92(d, J = 8.8 Hz, 1H), 7.75 (d, J = 1.6 Hz, 1H), 7.17 (s, 1H), 4.70-4.67 (m, 2H), 3.90-3.85 (m, 2H), 3.62-3.58 (m, 2H), 3.42-3.29 (m, 4H), 3.23-3.08 (m, 2H), 2.96-2.78 (m, 9H). LCMS: m / z = 426.2 [M+H]+Scheme 12: Synthesis of rac-N-((lR,5R,7R)-2-azabicyclo[3.2.0]heptan-7-yl)-5-(6-(4-methylpiperazin-l-yl)pyridazin-4-yl)-3-(thiazol-4-yl)isoquinolin-l-amine (1-399), N-((lS,5S,7R)-2-azabicyclo[3.2.0]heptan-7-yl)-5-(6-(4-methylpiperazin-l-yl)pyridazin-4-yl)-3-(thiazol-4-yl)isoquinolin-l-amine (1-383) and N-((lR,5R,7S)-2-azabicyclo[3.2.0]heptan-7-yl)-5-(6-(4-methylpiperazin-l-yl)pyridazin-4-yl)-3-(thiazol-4-yl)isoquinolin-l -amine (1-532)1-383 1-532Step 1: l,3-dichloro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinoline (2)

[0473] To a stirred solution of 5-bromo-l,3-dichloroisoquinoline 1 (5 g, 18.05 mmol) in 1,4-dioxane (300 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (1.5 g, 27.1 mmol) and potassium acetate (3 g, 5.32 mmol) at room temperature. Hie reaction mixture was degassed with nitrogen for 15 minutes then PdC12(dppf) (0.66 g. 0.90 mmol) was added and the resulting mixture was stirred at 100 °C for 2 h under nitrogen atmosphere. After 2 h, the reaction mixture was further degassed with nitrogen for 15 minutes and then PdCL(dppf) (0.265 g, 0.36 mmol) was added. The resulting mixture was stirred at 100 °C for another 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature and filtered through celite bed and washed with ethyl acetate. Tire filtrate was evaporated under reduced pressure. Hie obtained residue was purified by a column chromatography and eluted with ethyl acetate / petroleum ether to give 1.3 -dichloro-5 -(4, 4.5. -tetramethyl- 1,3-2-dioxabo rolan-2-yl)isoquinoline 2 (3 g, 31% yield) as an off white solid.Step 2: l,3-dichloro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinoline (4)

[0474] To a stirred solution of l,3-dichloro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinoline 2 (3 g, 9.26 mmol) in 1,4-dioxane (100 mL) and water (25 mL) was added 5-bromo-3-(4-methylpiperazin-l-yl)pyridazine (3) (1.90 g, 7.41 mmol), potassium carbonate ( 3.84 g, 27.8 mmol) at room temperature. The reaction mixture was degassed with nitrogen for 15 minutes then PdC12(dppf) DCM ( (0.378 g, 0.463 mmol) was added. The reaction mixture was stirred at room temperature for 12 h under nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through celite bed and washed with ethyl acetate. Tire filtrate was evaporated under reduced pressure. The obtained crude product was purified by reverse-phase HPLC [LEO (0.1 %FA) - ACN| to give l,3-dichloro-5-(4,4,5.5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinoline 4 (1.7 g, 50% yield) as an off white solid.Step 3: Synthesis of tert-butyl (lR,5R,7R)-7-((3-chloro-5-(6-(4-methylpiperazin-l-yl)pyridazin-4-yl)isoquinolin-l-yl)amino)-2-azabicyclo[3.2.0]heptane-2-carboxylate (6)

[0475] To a solution of l,3-dichloro-5-(6-(4-methylpiperazin-l-yl)pyridazin-4-yl)isoquinoline (4) (3.6 g, 9.62 mmol) in DMSO (36 mL), were added cesium fluoride (4.38 g, 28.86 mmol) followed by rac -tert-butyl (lS,5S,7R)-7-amino-2-azabicyclo[3.2.0]heptane-2-carboxylate 5 (2.45 g, 11.54 mmol). Tire reaction mixture was irradiated at 80 °C for 2.5 h in microwave. The reaction was monitored by LCMS. After completion of the reaction, solvent was evaporated under reduced pressure. The obtained crude product was purified with column chromatography (silica gel 230-400 mesh: eluted 5% of MeOH H1CH2CI2) to afford tert-butyl ( 1 S,5 S,7R)-7 -((3 -chloro-5 -(6-(4-methylpiperazin- 1 -yl)pyridazin-4-yl)isoquinolin- 1 -yl)amino)-2 -azabicyclo [3.2.0]heptane-2 -carboxylate 6 (2.5 g, 47% yield) as off-white solid.Step 4: Synthesis of tert-butyl (lS,5S,7R)-7-((5-(6-(4-methylpiperazin-l-yl)pyridazin-4-yl)-3-(thiazol-4-yl)isoquinolin-l-yl)amino)-2-azabicyclo[3.2.0]heptane-2-carboxylate (8)

[0476] To a solution of tert-butyl (lS,5S,7R)-7-((3-chloro-5-(6-(4-methylpiperazin-l-yl)pyridazin-4-yl)isoquinolin-l-yl)amino)-2-azabicyclo[3.2.0]heptane-2-carboxylate 6 (2.5 g, 4.54 mmol) in 1,4-dioxane (50 mL) was added 4-(tributylstannyl)thiazole 7 (2.55 g, 6.81 mmol). The reaction mixture was purged with nitrogen for 10 minutes followed by addition of XphosPdGs (370 mg, 0.454 mmol). After addition, the reaction mass was stirred at 100 °C for 6 h. The progress of the reaction was monitored by LCMS. The reaction mixture was then filtered through celite and washed with 5% Methanol in DCM. Then the filtrate was concentrated under reduced pressure. Hie obtained crude product was purified with column chromatography (silica gel 230-400: eluted 6% Methanol in DCM with TEA) to get tert-butyl (1S,5S.7R)-7-((5-(6-(4-methylpiperazin-l-yl)pyridazin-4-yl)-3-(thiazol-4-yl)isoquinolin-l-yl)amino)-2-azabicyclo[3.2.0]heptane-2-carboxylate 8 (1.7 g, 62% yield) as a brown solid.Step 5: Synthesis of rac-N-((lR,5R,7S)-2-azabicyclo[3.2.0]heptan-7-yl)-5-(6-(4-methylpiperazin-l-yl)pyridazin-4-yl)-3-(thiazol-4-yl)isoquinolin-l-amine (1-399)

[0477] To a stirred solution of tert-butyl (lS,5S,7R)-7-((5-(6-(4-methylpiperazin-l-yl)pyridazin-4-yl)-3-(thiazol-4-yl)isoquinolin-l-yl)amino)-2-azabicyclo[3.2.0]heptane-2-carboxylate (1.7 g, 3.51 mmol) in DCM (20 ml) was added 4M HC1 in dioxane (4.5 ml, 17.55 mmol) at 0 °C and slowly warmed to RT and stirred for 1 h. The reaction mixture was concentrated under reduced pressure. The obtained crude product was purified by PREP-HPLC (Column: X Select 250 mm C18; Mobile phase A: 0.1% HCOOH; Mobile phase B: ACN). The product fraction was concentrated under vacuum to get N-((lS,5S,7R)-2-azabicyclo[3.2.0]heptan-7-yl)-5-(6-(4-methylpiperazin-l-yl)pyridazin-4-yl)-3-(thiazol-4-yl)isoquinolin-l-amine 1-399 (0.85 g, 60% yield) as a yellow solid.Step 6: SFC resolution

[0478] The compound A-((lS,5S,7R)-2-azabicyclo[3.2.0]heptan-7-yl)-5-(6-(4-methylpiperazin-l-yl)pyridazin-4-yl)-3-(thiazol-4-yl)isoquinolin-l-amine (0.85 g) was purified by SFC.

[0479] 1-383: The desired product fraction was concentrated and the residue was dissolved in 5% MeOH in DCM (100 mL) and washed with water (3 x 5 mL), dried over sodium sulphate and concentrated to afford (195 mg) as yellow solid and was purified by PREP-HPLC (Column: Xbridge-C8; Mobile phase A: 0.1% HCOOH; Mobile phase B: ACN). The product fraction was lyophilized to get N-((lS,5S,7R)-2-azabicyclo[3.2.0]heptan-7-yl)-5-(6-(4-methylpiperazin-l-yl)pyridazin-4-yl)-3-(thiazol-4-yl)isoquinolin-l-amine (61 mg, 14% yield) as a yellow solid.

[0480] 1-532: The desired product fraction was concentrated and the residue was dissolved in 5% MeOH in DCM (100 mL) and washed with water (3 x 5 mL), dried over sodium sulphate and concentrated to afford (190 mg) as yellow solid and was purified by PREP-HPLC (Column: Xbridge-C8; Mobile phase A: 0.1% HCOOH; Mobile phase B: ACN). The product fraction was lyophilized to get N-((lS,5S,7R)-2-azabicyclo[3.2.0]heptan-7-yl)-5-(6-(4-methylpiperazin-l-yl)pyridazin-4-yl)-3-(thiazol-4-yl)isoquinolin-l-amine (52 mg, 12% yield) as a yellow solid.Scheme 13: Synthesis of tert-butyl 7-amino-2-azabicyclo[3.2.0]heptane-2-carboxylateStep-1: Synthesis of ((4-nitrophenyl)sulfonyl)glycine

[0481] To a solution of glycine (CAS# 56-40-6, 1.5 kg, 19,981 mmol) in water (7.5 L) at 7°C was added IN NaOH (30 L) and the mixture was allowed to stir for about 4 hours. Nosyl chloride (CAS# 98-74-8, 3.54 kg, 15,985 mmol) was then added portion-wise and the resulting reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was then cooled to 0°C and 6N HC1 (5 L) was added to adjust the pH to 4-5. The resulting solids were collected via a Nutsche filter, resuspended in water (50 L), stirred for 15 minutes, and dried using a centrifuge. The solids were then collected by filtration via a Buchner funnel, washed with n-hexane (20 L). and dried under reduced pressure to afford ((4-nitrophenyl)sulfonyl)glycine as an off white solid (3 kg, 11,528 mmol, 58% yield). 1H NMR (400MHz, DMSO- / s): 5 12.83 (bs, 1H), 8.51 (bs, 1H), 8.40 (dd, Ji = 1.6 Hz, J2= 6.8 Hz, 2H) 8.05 (dd, Ji = 2.0 Hz, J2= 9.2 Hz, 2H), 3.70 (d, J = 2.4 Hz, 2H), LCMS (Method 10):: Rt: 1.674 min, [M-H]+: 259.Step-2: Synthesis of 4-nitro-N-(2-oxo-2-(pyrrolidin-l-yl)ethyl)benzenesulfonamide

[0482] To a solution of methyl ((4-nitrophenyl)sulfonyl)glycine (4 kg, 15,371 mmol) in DCM (40 L) at 0-3 °C as added DIPEA (5.96 kg, 46, 114 mmol) portion wise over 30 minutes, and the reaction mixture was stirred for an additional 30 minutes. Subsequently, 2-(lH-Benzotriazole-l-yl)-l,1.3.3-tetramethylaminium tetrafluoroborate (TBTU, 5.92 kg, 18,445 mmol) was added at 0 °C, and the resulting suspension was stirred at the same temperature for 3 hours. Pyrrolidine (CAS# 123-75-1, 1.64 kg, 23,057 mmol) was then added portion wise at 0 °C. The reaction mixture was then stirred at 25°C for about 16 hours. The reaction mixturewas then diluted with water (50 L) and extracted with DCM (2 x 50 L). The combined organic extracts were concentrated under reduced pressure and the resulting solids were stirred in water (20 L) and fdtered through a Buchner funnel. The collected solids were resuspended in diethyl ether (5 L), collected by filteration through a Buchner funnel, and dried under reduced pressure to afford the 4-nitro-N-(2-oxo-2-(pyrrolidin-l-yl)ethyl)benzenesulfonamide (3.65 kg, 11,649 mmol, 76 % yield) as an off white solid. 1H NMR (400MHz, DMSO-d6): 5 8.39 (d. J = 8.4 Hz. 2H), 8.25 (bs, 1H). 8.07 (d, J = 8.8 Hz, 2H). 3.75 (s, 2H), 3.35 - 3.31 (m, 2H), 3.16 (t, J = 6.8 Hz, 2H), 1.86 - 1.79 (m, 2H), 1.74 - 1.67 (m, 2H). LCMS: Rt: 1.825 mm [M+H]+: 314.2.Step-3: Synthesis of N-(but-3-en-l-yl)-4-nitro-N-(2-oxo-2-(pyrrolidin-l-yl)ethyl)benzenesulfonamide

[0483] To a stirred solution of 4-nitro-N-(2-oxo-2-(pyrrolidin-l-yl)ethyl)benzenesulfonamide (1 kg, 3191.5 mmol) in DMF (10 L) at room temperature was added CS2CO3 (3.12 kg, 9574.6 mmol) over 30 min followed by tire addition of 4-bromobut-l-ene (CAS# 5162-44-7, 3.016 kg, 22340 mmol). The resulting reaction mixture was heated to 70°C and stirred at for about 4h. The reaction mixture was then cooled to room temperature, diluted with cold water (10 L), and extracted with EtOAc (10 L x 2). The combined organic extracts were washed with cold water (10 L x 5), the organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was triturated with diethyl ether (2.5 L x 2) to afford N-(but-3-en-l-yl)-4-nitro-N-(2-oxo-2-(pyrrolidin-l-yl)ethyl)benzenesulfonamide (77% yield).1H NMR (400MHz, DMSO-rfe): 58.37 (d, J = 8.8 Hz, 2H), 8.09 (d, J= 8.8 Hz, 2H), 5.74 - 5.67 (m, 1H), 5.06 - 4.97 (m, 2H). 4.16 (s. 2H), 3.41 (t, J = 6.8 Hz, 2H). 3.29 (t, J= 7.4 Hz, 2H). 3.20 (t. J= 6.8 Hz, 2H), 2.26 (q, J = 7.2 Hz, 2H), 1.89 - 1.86 (m, 2H), 1.76 - 1.73 (m, 2H). LCMS (Method 10):: Rt: 2.151 min [M+H]+: 368.33.Step-4: Synthesis of 2-((4-nitrophenyl)sulfonyl)-2-azabicyclo[3.2.0]heptan-7-one

[0484] To a stirred solution of N-(but-3-en-l-yl)-4-nitro-N-(2-oxo-2-(pyrrolidin-l-yl)cthyl)bcnzcncsulfonamidc (450 g, 1224.8 mmol) in 1,2-dichlorocthanc (9L) at 0 °C was added trifluoromethanesulfonic anhydride (TI2O. 308.5 mL, 1837.1 mmol) in DCE (2.7 L) dropwise followed by the dropwise addition of 2,4,6-collidine (CAS# 108-75-8, 162.5 mL. 1224.8 mmol) in DCE (2.7 L) at 0 °C. The resulting reaction mixture was then heated to 90 °C and stirred for about 2 hours. The reaction was then cooled to room temperature and concentrated under reduced pressure. The residue was diluted with toluene (2.7 L) and water (2.7 L) and stirred at 90 °C for an additional 2 hours. Afterward, the mixture was cooled to room temperature, the layers were separated, and the aqueous layer was extracted with dichloromcthanc (3L x 2). Hie toluene layere and combined extracts were dried over anhydrous NaiSCL. filtered andconcentrated under reduced pressure. Tire resulting residue was purified via trituration with ethyl acetate (1000 mLx 2) to afford 2-((4-nitrophenyl)sulfonyl)-2-azabicyclo[3.2.0]heptan-7-one as alight brown solid (78% yield). 1HNMR (400MHz, CDC13): 88.39 (d, J= 8.8 Hz, 2H), 8.11 (d, J= 92 Hz, 2H), 5.19- 5.16 (m, 1H), 4.03 - 3.98 (m, 1H), 3.28 - 3.18 (m, 2H), 3.17 - 3.10 (m, 1H), 2.60 - 2.52 (m, 1H), 2.23 - 2.13 (m, 1H). 1.96-1.92 (m, 1H).Step-5: Synthesis of N, N-dibenzyl-2-((4-nitrophenyl)sulfonyl)-2-azabicyclo[3.2.0]heptan-7-amine

[0485] To a stirred solution of 2-((4-nitrophenyl)sulfonyl)-2-azabicyclo[3.2.0]heptan-7-one (850 g, 2868.7 mmol) in MeOH (8.5 L) at 0°C was added dibenzyl amine (566 g. 2868.7 mmol) and acetic acid (340 mL, 0.4 V). The resulting reaction mixture was stirred at 0°C for about 2h and mp-cyanoborohydride (850 g, 100% w / w) was added. The reaction mixture was allowed to warm to room temperature and stirred for about 16 h. The reaction mixture was filtered and the solids were washed with methanol. The solid material was again washed with 10% MeOH in DCM (10 Lz2). and tire filtrate was concentrated under reduced pressure. Hie residue was triturated with diethyl ether (2L x 2) to afford N, N -dibenzyl -2-((4-nitrophenyl)sulfonyl)-2-azabicyclo[3.2.0]heptan-7-amine as an off white solid (58% yield). 1H NMR (400 MHz, DMSO-de): 8 8.37 (d, J= 8.8 Hz, 2H), 8.12 (d, J= 8.4 Hz, 2H ) 7.35 - 7.29 (m, 8H), 7.26 - 7.19 (m, 2H), 4.64 (t, J= 5.6 Hz, 1H ), 4.02 - 3.97 (m, 1H), 3.74 - 3.66 (m, 3H), 3.37 (s, 2H), 3.32 - 3.24 (m, 1H), 2.67 - 2.62 (m, 1H), 2.16 - 2.09 (m, 1H), 1.50 - 1.43 (m, 1H), 1.36 - 1.31 (m, 1H), 0.73-0.67 (m, 1H). LCMS: Rt: 2.212 min, [M+H]+: 478.41Step-6: Synthesis of tert-butyl 7-(dibenzylamino)-2-azabicyclo[3.2.0]heptane-2-carboxylate

[0486] To a stirred solution of N, N-dibenzyl-2-((4-nitrophenyl)sulfonyl)-2-azabicyclo[3.2.0]heptan-7-amine (800 g, 1675.1 mmol) in MeCN (8 L) at room temperature was added thiophenol (276.9 g, 2512.6 mmol) and CS2CO3 (1637 g, 5025.3 mmol) and the resulting mixture was stirred for about 16h. Boc anhydride (548.4 g, 2512.6 mmol) was then added to the reaction mixture and stirred at for additional Ih. The reaction mixture was then diluted with water (10 L), and extracted with EtOAc (10 L x 3). The combined organic extracts were dried over anhydrous ISfeSCE, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (Normal phase, Silica gel, Mesh size 60-120, 2-3% EtOAc in Hexane) to afford tert-butyl 7-(dibenzylamino)-2-azabicyclo[3.2.0]heptane-2-carboxylate as a light-yellow gummy liquid (62% yield). IH NMR (400 MHz, CDCI3): 87.33 - 7.28 (m, 8H), 7.25 - 7.22 (m, 2H), 4.58 - 4.50 (m, IH), 4.27 - 4.02 (m, IH), 3.82 (t, J= 14.2 Hz, 2H), 3.57 - 3.51 (m, IH), 3.44 (t, J= 13.8 Hz, 2H), 3.30 - 3.27 (m, IH), 2.88 - 2.79 (m, IH), 2.22 - 2.19 (m, IH), 1.74 -1.60 (m, 2H), 1.56 - 1.52 (m, IH), 1.40 - 1.33 (m, 9H). LCMS: Rt: 2.103 min, [M+H]+: 393.46.Step-7: Synthesis of tert-butyl 7-amino-2-azabicyclo [3.2.0] heptane-2-carboxylate

[0487] To a stirred solution of tert-butyl 7-(dibenzylamino)-2-azabicyclo[3.2.0]heptane-2 -carboxylate (40 g, 101.9 mmol) in 2,2,2-trifluroethanol (1.4 L, 35 V) at room temperature was added acetic acid (160 mL, 4 V) and 10% Pd / C (80 g, 200% w / w, procured from TCI, catalogue no. P1491). The reaction mixture was stirred under a pressurized hydrogen atmosphere (30 bar) at room temperature for about 4 h. Tire reaction mixture was the filtered through celite, washed with 10% MeOH in DCM (5 L), and the filtrate was concentrated under reduced pressure. The crude material was purified by column chromatography (Reverse phase, C18-Silica gel, 16-20% MeCN in (5% NH4OH in water)) and tire eluted product was extracted with the solution of 20% MeOH in DCM (2.5L x 3). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford tert-butyl 7-amino-2-azabicyclo[3.2.0]heptane-2-carboxylate as a brown oil (76% yield). 1H NMR (400 MHz, CDCI3): 54.32 - 4.19 (m, 1H), 3.99 - 3.82 (m, 1H). 3.57 - 3.40 (m. 2H), 2.79 - 2.72 (m, 1H), 2.51 - 2.43 (m, 1H), 1.82 -1.75 (m. 1H), 1.67 - 1.62 (m, 1H), 1.49 - 1.47 (m, 9H). 1.33 - 1.26 (m, 1H). LCMS: Rt: 1.507 mm, [(M-56)+H]+: 157.2Scheme 14: Synthesis of (lR,2S)-Nl-methyl-N2-(5-(6-(4-methylpiperazin-l-yl)pyridazin-4-yl)-3-(lH-l,2,4-triazol-l-yl)isoquinolin-l-yl)cyclopentane-l,2-diamine (1-799)Step-1: tert-butyl ((lR,2S)-2-((3-chloro-5-(6-(4-methylpiperazin-l-yl)pyridazin-4-yl)isoquinolin-l-yl)amino)cyclopentyl)carbamate (3)

[0488] To a solution of l,3-dichloro-5-(6-(4-methylpiperazin-l-yl)pyridazin-4-yl)isoquinoline 1 (500 mg, 1.336 mmol) in DMSO (10 mL) was added CsF (812 mg, 5.34 mmol) and tert-butyl ((lR.2S)-2-aminocyclopentyl)carbamate 2 (321 mg, 1.603 mmol). The reaction mixture was irradiated at 80°C for about 2 h in a microwave. After about 2 h, ice cold water was added to the reaction mixture and the precipitated solid was fdtered and dried to afford compound 3 (500 mg. 67% yield). LCMS: 538.2 [M+l]+.Step-2: tert-butyl ((lR,2S)-2-((5-(6-(4-methylpiperazin-l-yl)pyridazin-4-yl)-3-(lH-l,2,4-triazol-l-yl)isoquinolin-l-yl)amino)cyclopentyl)carbamate (5)

[0489] To a stirred solution of tert-butyl ((lR,2S)-2-((3-chloro-5-(6-(4-methylpiperazin-l-yl)pyridazin-4-yl)isoquinolin-l-yl)amino)cyclopentyl)carbamate 3 (500 mg, 0.93 mmol) in 1,4-Dioxane (10 mL), was added 4H-1.2.4-triazole 4 (321 mg, 4.65 mmol) and CS2CO3 (910 mg, 2.79 mmol). The reaction mixturewas purged with nitrogen for 10 mins and tBuBrettphos Pd G, (i.e., |(2-Di-tcrt-butylphosphino-3.6-dimethoxy-2 ’,4 ’,6’ -triisopropyl- 1, 1 ’ -biphenyl)-2-(2 ’ -amino- 1,1’ -biphenyl)]palladium(II) methanesulfonate) (159 mg, 0.19 mmol) was added at RT and the mixture was heated to 120 °C and stirred for about 6 h. Tire reaction mixture was filtered through celite bed and the filtrate was concentrated under reduced pressure to afford the crude product, which was purified by reverse phase flash chromatography to afford compound 5 (380 mg, 70% yield). LCMS: 571.2 [M+l]+.Step-3: (lS,2R)-Nl-(5-(6-(4-methylpiperazin-l-yl)pyridazin-4-yl)-3-(lH-l,2,4-triazol-l-yl)isoquinolin-l-yl)cyclopentane-l,2-diamine (HC1 salt) (6)

[0490] To a stirred solution of tert-butyl ((lR,2S)-2-((5-(6-(4-methylpiperazin-l-yl)pyridazin-4-yl)-3-(lH-l,2,4-triazol-l-yl)isoquinolin-l-yl)amino)cyclopentyl)carbamate (5, 380 mg, 0.665 mmol) in DCM (8 mL) at 0 °C, was added 4M HC1 in dioxane (3.8 mL, 10 vol). The reaction mixture was stirred at RT for about 1 h. Hie reaction mixture was evaporated under vacuum to afford compound 6 (380 mg, HC1 salt) as a yellow solid. LCMS: 471.5 [M+l]+.Step-4: Synthesis of 1-799

[0491] To a stirred solution of sodium methanolate (131 mg, 2.423 mmol) in methanol (5 mL) at RT. was added powdered molecular sieves (380 mg, 1.880 mmol), (lS,2R)-Nl-(5-(6-(4-methylpiperazin-l-yl)pyridazin-4-yl)-3-(lH-l,2,4-triazol-l-yl)isoquinolin-l-yl)cyclopentane-l,2-diamine (380 mg, 0.808 mmol) in methanol (5 mL) followed by a 37% formaldehyde solution (49.1 mg, 0.606 mmol). After about 4h, the mixture was cooled to 0°C and sodium tetrahydroborate (407 mg, 6.46 mmol) was added and stirred for about 2 h. Hie reaction mixture was quenched with saturated NJLCl (3 mL) and 10% MeOH in DCM (50 mL) was added and stirred for about 2 mins. The crude mixture was filtered through celite and concentrated under reduced pressure to the crude product, which was purified by PREP-HPLC to afford I-799 (35 mg, 10% yield) as an off-white solid. LCMS: 484.9 [M+l]+.Scheme 15: Synthesis of l,3-dichloro-5-(6-chloropyridazin-4-yl)-8-fluoroisoquinolineStep-1: Synthesis of 7-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,3-dihydro-lH-inden-1-one

[0492] To a stirred solution of 4-bromo-7-fluoro-2,3-dihydro-lH-inden-l-one (100g, 436.5 mmol) in 1,4-dioxane (1000 mL) were added B2Pin2 (147.4g, 580.6 mmol) and KOAc (111.41g, 1135 mmol) at room temperature and purged with N2(g) for 15 min. PdCL(dppf) (15.9g, 21 mmol) was then added and the reaction mixture was stirred at 100 °C for 4h. After an indicated time, the reaction mixture was cooled to room temperature, filtered over a celite bed, and washed with EtOAc (2000mL). The filtrate was concentrated under a reduced pressure and residue was purified by column chromatography (Biotage selekt, normal phase, 230-400, 0-40 % EtOAc in Hexane) to afford 7-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,3-dihydro-lH-inden-l-one as a white solid (100g, 362.7 mmol, 82% yield). LCMS: Rt: 1.572 min Boronic acid [M+H] ': 195 & Rt: 2.478 min Boronic ester [M+H]1: 277.2. 1H NMR (400 MHz, DMSO-d6): 57.97 - 7.93 (m, 1H), 7.15 (t, J= 9.2 Hz, 1H), 3.25 - 3.22 (m, 2H), 2.65 - 2.62 (m, 2H), 1.32 (s, 12H).Step-2: Synthesis of 4-(6-chloropyridazin-4-yl)-7-fluoro-2,3-dihydro-lH-inden-l-one

[0493] To a stirred solution of 7-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,3-dihydro-lH-inden-l-one (100g, 362.1 mmol) and 5-bromo-3-chloropyridazine (105g, 543.1 mmol) in 1,4 dioxane (800 mL) and water (200mL) was added CS2CO3 (234.5g, 724.2 mmol) at room temperature and tire reaction mixture was purged with N2 (g) for 15 min. PdC12(dppf) ( 13.17g, 18.1 mmol) was then added to the reaction mixture and stirred at 100°C for Ih. After an indicated time, the reaction mixture was cooled to room temperature, and filtered over a celite bed. The filtrate was washed with water (1500mL) and extracted with EtOAc (1500mL x 3). The combined organic layer was concentrated under a reduced pressure and residuewas purified by column chromatography (Biotage selekt, normal phase, 230-400, 0-50 % EtOAc in hexane) to afford 4-(6-chloropyridazin-4-yl)-7-fluoro-2,3-dihydro-lH-inden-l-one as a light brown solid (60g, 228.4 mmol, 63% yield). lHNMR(400 MHz, DMSO-d6): 59.51 (s, 1H), 8.19 (s, 1H), 7.99 - 7.95 (m, 1H), 7.41 (t, J= 8.8 Hz, 1H), 3.30 - 3.27 (m, 2H), 2.71 - 2.68 (m, 2H).Step-3: Synthesis of (Z)-4-(6-chloropyridazin-4-yl)-7-fluoro-2-(hydroxyimino)-2,3-dihydro-lH-inden-l-one

[0494] To a stirred solution of 4-(6-chloropyridazin-4-yl)-7-fluoro-2.3-dihydro-lH-inden-l-one (60 g, 228.4 mmol) in diethyl ether (720 mL), DCM (120 mL) & MeOH (360 mL) was added 2M HC1 in diethyl ether (300 ml) dropwise at 0°C over the period of 10 min. A solution oftert-Butyl nitrite (59.7 mL, 51.8g, 502.5 mmol) in MeOH (300 mL) was then added dropwise at 0°C and the resulting reaction mixture was stirred at room temperature for 16 h. After an indicated time, the reaction mixture was concentrated under a reduced pressure and residue was triturated with diethyl ether to afford (Z)-4-(6-chloropyridazin-4-yl)-7-fluoro-2-(hydroxyimino)-2,3-dihydro-lH-inden-l-one as a yellow solid (60g, 205.7 mmol, 90% yield). LCMS: Rt: 1.690 mm [M+H]+: 292.1.Step-4: Synthesis of l,3-dichloro-5-(6-chloropyridazin-4-yl)-8-fhioroisoquinoline

[0495] To a stirred solution of (Z)-4-(6-chloropyridazin-4-yl)-7-fluoro-2-(hydroxyimino)-2,3-dihydro-IH-inden-l-one (60 g, 205.7 mmol) in SOCL (600 mL) at 0°C was added DMF (420 mL) and the resulting reaction mixture was stirred at room temperature for 16 h. After an indicated time, the reaction mixture was washed with NaHCOii jsolution (1000 mL) and extracted with EtOAc (lOOOmL x 3). Tire combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under a reduced pressure. Hie residue was purified by column chromatography (Biotage selekt, normal phase, 230-400, 0-20 % EtOAc in hexane) to afford l,3-dichloro-5-(6-chloropyridazin-4-yl)-8-fluoroisoquinoline as a light yellow solid (10g, 30.44 mmol, 14% yield). LCMS: Rt: 1.761 min [M+H]+: 328.1. 1HNMR (400 MHz, DMSO-d6): 59.39 (d, J= 0.8 Hz, 1H), 8.16 (d, J= 0.8 Hz, 1H), 8.06 - 8.03 (m, 1H), 7.93 (d, J= 1.2 Hz, 1H), 7.83 - 7.78 (m, 1H).Scheme 16: Synthesis of tert-butyl ((lR,2S)-2-aminocyclobutyl)(methyl)carbamate and tert-butyl ((lS,2R)-2-aminocyclobutyl)(methyl)carbamatebzStep-1: Synthesis of benzyl (2-oxocyclobutyl)carbamate

[0496] To a stirred solution of l,2-bis((trimethylsilyl)oxy)cyclobut-l-ene of (CAS# 17082-61-0, 1.0 kg, 4345.55 mmol) in 4M HCI in 1,4 dioxane (10 L) at 0 °C was added benzyl carbamate (CAS # 621-84-1, 788 g, 5214.67 mmol) and the reaction mixture was stirred at 80°C for about 4 h. The reaction mixture was then diluted with ice-cold water (4.5 L) and extracted with EtOAc (4.5 L x 3). The combined organic extracts were dried over anhydrous Na2SO4, fdtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (Normal phase, Silica gel, Mesh size 60-120, 0-10% EtOAc in Hexane) to afford benzyl (2-oxocyclobutyl)carbamatc as a light brown semi-solid (60% yield).'H-NMR (400MHz, DMSO-rf6): 57.86 (d, J= 8.4 Hz, 1H), 7.39-7.30 (m, 5H), 5.04-4.97 (m, 2H), 4.78-4.71 (m. 1H), 2.95-2.83 (m, 1H), 2.69-2.62 (m, 1H). 2.27-2.19 (m, 1H), 2.02-1.95 (m. 1H).Step-2: Synthesis of benzyl (2-(methylamino)cyclobutyl)carbamate

[0497] To a stirring solution of benzyl (2-oxocyclobutyl)carbamate (250.0 g, 1141.50 mmol) in MeOH (2.5 L) at room temperature was added methyl amine (2M in THF) (2.28 L, 4566.21 mmol) and acetic acid dropwise (68 mL) and the reaction mixture was stirred at room temperature for about 30 min. The reaction mixture was then cooled to 0 °C and sodium triacetoxyborohydride (725 g, 3424.65 mmol) was added portion-wise and the resulting mixture was stirred at room temperature for about 2 h. Hie reaction mixture was then neutralized with an aqueous NaHCOs solution (6 L) and the MeOH and THF were removed under reduced pressure. The mixture was then extracted with EtOAc (5L x 4) and the combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford benzyl (2-(methylamino)cyclobutyl)carbamate as a brown oil (quantitative yield). LCMS: Rt: 1.529 min, [M+H]+: 235.3.Step-3: Synthesis of tert-butyl (2-(((benzyloxy)carbonyl)amino)cyclobutyl)(methyl) carbamate

[0498] To a stirred solution of benzyl (2-(methylamino)cyclobutyl)carbamate (510 g, 2176.69 mmol) in DCM (5.1 L) at room temperature was added triethylamine (220 g, 310mL, 2176.69 mmol). Tire reaction mixture was then cooled to 0 °C, Boc anhydride (475 g, 2176.69 mmol) was added dropwise and the reaction mixture was stirred at room temperature for about 1 h. The reaction mixture was then concentrated under reduced pressure and the crude material was purified by column chromatography (Normal phase, Silica gel, Mesh size 60-120, 15-20% EtOAc in Hexane) to afford tert-butyl (2-(((benzyloxy)carbonyl)amino)cyclobutyl)(methyl)carbamate (45% yield). ’H-NMR (400MHz, DMSO-d6): 57.65-7.63 (m, 1H), 7.33-7.31 (m, 5H), 4.99 (s, 2H), 4.21 (bs, 1H), 4.07 (t, J= 8.4 Hz, 1H), 2.80-2.66 (m, 3H), 2.09-2.03 (m, 1H), 1.94-1.72 (m, 2H), 1.69-1.62 (m, 1H), 1.37-1.34 (m, 9H). LCMS: Rt: 4.193 min and 4.271 min [M+H]+: 335.4Step-4 and Step-5: Synthesis of rel-tert-butyl ((lR,2S)-2-aminocyclobutyl)(methyl) carbamate and rel-tert-butyl ((lR,2R)-2-aminocyclobutyl)(methyl)carbamate

[0499] To a stirred solution of tert-butyl (2-(((benzyloxy)carbonyl)amino)cyclobutyl)(methyl)carbamate (150 g, 448.54 mmol) in 2,2,2-trifluoroethanol (750 mL) at room temperature was added Pd / C (75.0 g,1 / 2 / w). The reaction mixture bubbled with hydrogen gas at room temperature for about 16 h. Tire reaction mixture was then filtered through celite bed and washed with MeOH (30 L). The filtrate was concentrated under reduced pressure to afford tert-butyl (2-aminocyclobutyl)(methyl)carbamate (1050 g, 5242.66 mmol, quantitative yield) as a brown oil. The crude material was purified by column chromatography (Normal phase. Silica gel, Mesh size 60-120) where the cis isomer was eluted at 3% MeOH in DCM to afford rel-tert-butyl ((lR,2S)-2-aminocyclobutyl)(methyl)carbamate (197 g, 983.61 mmol, 19% yield) as ayellow oil and the trans isomer was eluted at 5% MeOH in DCM to afford rel-tert-butyl ((lR,2R)-2-aminocyclobutyl)(mcthyl)carbamatc (380 g, 1897.34 mmol, 36% yield) as a light brown oil.

[0500] Cis isomer ’H-NMR (High temp NMR, 400MHz, DMSO-rf6): 54.01-3.99 (m, 1H), 3.58-3.55 (m, 1H). 2.84 (s, 3H). 2.43-2.38 (m, 1H), 2.06-1.90 (m, 2H), 1.41-1.38 (m. 12H). LCMS: Rt: 1.261 min, [M+H]+: 201.2

[0501] Trans isomer ’H-NMR (High temp NMR, 400MHz, DMSO-< Z6): 53 87-3 81 (m, 1H), 3 33-3 27 (m, 1H), 2.75 (s, 3H), 1.95-1.88 (m, 1H), 1.81-1.74 (m, 1H), 1.58-1.51 (m, 1H), 1.42 (s, 9H), 1.29-1.20 (m,lH). LCMS: Rt: 1.236 min, [M+H]+: 201.2...

Claims

CLAIMS1. A compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein:Ring X is phenyl, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each Rxis Ring Y or R', provided that no more than one Rxis Ring Y;Ring Y is an optionally substituted group selected from 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-11 membered saturated or partially unsaturated bicyclic or spirocyclic carbocyclic ring, or a 7-11 membered saturated or partially unsaturated bicyclic or spirocyclic heterocyclic ring with 1 -3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring Y is optionally substituted with y instances of Ry;each X1, X2, X3, X4, and X5is independently carbon or nitrogen:each L1and L2is independently a covalent bond or an optionally substituted Ci-s bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-3 methylene units of the chain are independently and optionally replaced with -Cy-, -C(R')2-, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, - S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, or-NRC(O)O-;R1is hydrogen or Ci-6 aliphatic optionally substituted w ith 1, 2, or 3 deuterium or halogen atoms, provided that R1is not hydrogen when L1is a covalent bond;R2is hydrogen, halogen, -CN. or Ci-6 aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms, provided that R2is not hydrogen when L2is a covalent bond;each R3is independently selected from Cue aliphatic, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -N(R)C(O)N(R)2, and -NRS(O)2R, wherein one instance of R3may be a ring selected from phenyl, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is optionally substituted with x instances of R\ provided that, when X5is CH substituted by R3, then R3is not optionally substituted Ci.e aliphatic, halogen, -OR, or -NO2;each R', Ry, and R4is independently selected from Ci-6 aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, - C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, - N(R)C(O)N(R)2, and -NRS(O)2R;each -Cy- is independently an optionally substituted bivalent ring selected from phenylene, an 8-10 membered bicyclic carbocyclic aromatic ring, a 4-7 membered saturated or partially unsaturated carbocyclylene, a 6-11 membered saturated or partially unsaturated spirocyclic carbocyclylene, an 8-10 membered bicyclic, saturated or partially unsaturated, carbocyclylene, a 4-7 membered saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6-11 membered saturated or partially unsaturated spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic, saturated or partially unsaturated, heterocyclylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroarylene having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each R is independently hydrogen or an optionally substituted group selected from Ci-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur;w is 0, 1, or 2;x is 0, 1, 2, 3, or 4;y is 0, 1, 2, 3, or 4; andz is 0, 1, 2, or 3.

2. A compound of Formula I':or a pharmaceutically acceptable salt thereof, wherein:Ring X is phenyl, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each Rxis Ring Y or R', provided that no more than one Rxis Ring Y;Ring Y is an optionally substituted group selected from 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-11 membered saturated or partially unsaturated bicyclic, bridged bicyclic, or spirocyclic carbocyclic ring, or a 7-11 membered saturated or partially unsaturated bicyclic, bridged bicyclic, or spirocyclic heterocyclic ring with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring Y is optionally substituted with y instances of Ry;each X1, X2, X3, X4, and X5is independently carbon or nitrogen:each L1and L2is independently a covalent bond or an optionally substituted Ci-s bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-3 methylene units of the chain are independently and optionally replaced with -Cy-, -C(R')2-, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, - S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, or-NRC(O)O-;R1is hydrogen, Ci-6 aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms, a 5-11 membered saturated or partially unsaturated spirocyclic carbocyclic ring, a 4-10 membered bicyclic, saturated or partially unsaturated carbocyclic ring, a 5-11 membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 4-10 membered bicyclic or bridged bicyclic, saturated or partially unsaturated heterocyclicring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, provided that R1is not hydrogen when L1is a covalent bond;R2is hydrogen, halogen, -CN, Ci-e aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms, a 5-11 membered saturated or partially unsaturated spirocyclic carbocyclic ring, a 4-10 membered bicyclic, saturated or partially unsaturated carbocyclic ring, a 5-11 membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 4-10 membered bicyclic or bridged bicyclic, saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, provided that R2is not hydrogen when L2is a covalent bond;each R3is independently selected from Ci-e aliphatic, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, - S(O)2NR2, -S(O)R. -C(O)R, -C(O)OR. -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2. -NRC(O)OR, -NRC(O)R, -N(R)C(O)N(R)2, and -NRS(O)2R, wherein one instance of R3may be a ring selected from phenyl, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein tire ring is optionally substituted with x instances of Rx, provided that, when X5is CH substituted by R3, then R3is not optionally substituted Cue aliphatic, halogen, -OR, or -NO2:each R' and R4is independently selected from C1-6 aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, - C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -N(R)C(O)N(R)2, and -NRS(O)2R, ortwo R' groups on the same saturated carbon atom are optionally taken together to fonn =0; each Ryis independently selected from C1-6 aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms, a 4-7 membered saturated or partially unsaturated carbocyclic ring, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, - C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, - N(R)C(0)N(R)2, and -NRS(O)2R, ortwo Rygroups on tire same saturated carbon atom are optionally taken together to form =0; each -Cy- is independently an optionally substituted bivalent ring selected from phenylene, an 8-10 membered bicyclic carbocyclic aromatic ring, a 4-7 membered saturated or partially unsaturated carbocyclylene, a 6-11 membered saturated or partially unsaturated spirocyclic carbocyclylene, an 8-10 membered bicyclic, saturated or partially unsaturated, carbocyclylene, a 4-7 membered saturated orpartially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-11 membered saturated or partially unsaturated spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic or bridged bicyclic, saturated or partially unsaturated, heterocyclylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroarylene having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen or an optionally substituted group selected from Ci-e aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur;w is 0, 1, or 2;x is 0, 1. 2, 3, or 4;y is 0, 1, 2, 3, or 4; andz is 0, 1, 2, or 3.

3. A compound of Formula I":or a pharmaceutically acceptable salt thereof, wherein:Ring X is phenyl, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen.and sulfur;each Rxis Ring Y or R, provided that no more than one Rxis Ring Y;Ring Y is an optionally substituted group selected from 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-11 membered saturated or partially unsaturated bicyclic, bridged bicyclic, or spirocyclic carbocyclic ring, or a 7-12 membered saturated or partially unsaturated bicyclic, bridged bicyclic, tricyclic, or spirocyclic heterocyclic ring with 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring Y is optionally substituted with y instances of Ry;each X1, X2, X3, X4, and X5is independently CH or N;each L1and L2is independently a covalent bond or an optionally substituted Ci-s bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-4 methylene units of the chain are independently and optionally replaced with -Cy-, -C(R')2-, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, - S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, or-NRC(O)O-;R1is hydrogen, Ci-6 aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms, a 5-11 membered saturated or partially unsaturated spirocyclic carbocyclic ring, a 4-10 membered bicyclic, saturated or partially unsaturated carbocyclic ring, a 5-11 membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 4-10 membered bicyclic or bridged bicyclic, saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, provided that R1is not hydrogen when L1is a covalent bond;R2is hydrogen, halogen, -CN, Ci-e aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms, a 5-11 membered saturated or partially unsaturated spirocyclic carbocyclic ring, a 4-10 membered bicyclic, saturated or partially unsaturated carbocyclic ring, a 5-11 membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 4-10 membered bicyclic or bridged bicyclic, saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, provided that R2is not hydrogen when L2is a covalent bond;each R3is independently selected from optionally substituted Ci-6 aliphatic, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R. -S(O)2NR2. -S(O)R, -P(O)R2. -P(O)(OR)2, -C(O)R. -C(O)OR, -C(O)NR2. -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR. -NRC(O)R, -N(R)C(O)N(R)2. and -NRS(O)2R, wherein one instance of R3may be a ring selected from phenyl, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur; wherein the ring is optionally substituted with x instances of Rx, provided that, when X5is CH substituted by R3, then R3is not optionally substituted Ci-e aliphatic, halogen, -OR, or -NO2;each and R4is independently selected from C1-6 aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O) R, -S(O)2NR2, -S(O)R, -C(O)R, - C(O)OR. -C(O)NR2, -C(O)NROR. -OC(O)R, -OC(O)NR2, -NRC(O)OR. -NRC(O)R. -N(R)C(0)N(R)2, and -NRS(O)2R, ortwo R' groups on the same saturated carbon atom are optionally taken together to form =0; each Ryis independently selected from an optionally substituted Cue aliphatic, an optionally substituted 3- 7 membered saturated or partially unsaturated carbocyclic ring, an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(0)2R, -S(O)2NR2. -S(O)R, - C(O)R, -C(O)OR, -C(O)NR2, -C(0)NR0R, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(0)R, - N(R)C(0)N(R)2, -NRS(0)2R, and -C1.4 alkylene-Cy, or:two Rygroups on the same saturated carbon or sulfur atom are optionally taken together to form =0;each -Cy- is independently an optionally substituted bivalent ring selected from phenylene, an 8-10 membered bicyclic carbocyclic aromatic ring, a 4-7 membered saturated or partially unsaturated carbocyclylene, a 6-11 membered saturated or partially unsaturated spirocyclic carbocyclylene, an 8-10 membered bicyclic, saturated or partially unsaturated carbocyclylene, a 4-7 membered saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-11 membered saturated or partially unsaturated spirocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6-10 membered bicyclic or bridged bicyclic, saturated or partially unsaturated, heterocyclylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered hctcroarylcnc having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroary lene having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen or an optionally substituted group selected from Ci-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or hctcroaryl ring having 0-3heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur;w is 0, 1, or 2;x is 0, 1, 2, 3, or 4;y is 0, 1. 2, 3, 4, 5. or 6; andz is 0, 1. 2, or 3.

4. Tire compound of any one of claims 1-3, wherein the compound is not selected from one of the following:acceptable salt thereof.

5. Tire compound of any one of claims 1-4, wherein the compound is of Formula I-a, I-b, I-c, I-d, I-e, or I-f:I-aor a pharmaceutically acceptable salt thereof.

6. The compound of any one of claims 1-4, wherein the compound is of Formula I-a-1, 1-a-2, or I-a- 3:or a pharmaceutically acceptable salt thereof.

7. The compound of any one of claims 1-4, wherein the compound is of Formula I-a-4:I-a-4or a pharmaceutically acceptable salt thereof.

8. The compound of claim 5, wherein the compound is of Formula I-a-5 or I-a-6:La-6or a pharmaceutically acceptable salt thereof.

9. The compound of any one of claims 1-3, wherein X1is nitrogen.

10. The compound of any one of claims 1-7, wherein Ring X is11. The compound of any one of claims 1-6, wherein Rxis Ring Y.

12. The compound of any one of claims 1-6, wherein Ring X taken together with (Rx)xisLVi14. The compound of any one of claims 1-12, wherein Ryis -CN, -OMe, -Cl, methyl, ethyl, isopropyl,16. The compound of any one of claims 1-15, wherein L1is an optionally substituted C1-4 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-3 methylene units of the chain are independently and optionally replaced with -Cy-, -C(R')2-, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, - S(O)-. -S(O)2-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-. -OC(O)NR-, or-NRC(O)O-.

18. The compound of any one of claims 1-17, wherein L2is an optionally substituted C1.4 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-3 methylene units of the chain are independently and optionally replaced with -Cy-, -C(R')2-, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, - S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, or-NRC(O)O-.

19. The compound of any one of claims 1-17, wherein L2-R2is -Cl, methyl, t-butyl, -OH, -OMe, -NH2,20. The compound of any one of claims 1-19, wherein R3is methyl, fluoro, chloro, bromo, amino, -21. The compound of any one of claims 1-4, wherein X1is N and X2, X3, X4, and Xsare each CH.

22. Tire compound of any one of claims 1-4, wherein z is 0.

23. The compound of any one of claims 1-22, wherein R4is hydrogen.

24. The compound of claim 21, wherein Ring X isand Ryis Ring Y.

25. A compound selected from one of those shown in Table la or Table lb, or a pharmaceutically acceptable salt thereof.

26. A pharmaceutical composition comprising a compound of any one of claims 1-25, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable excipient.

27. A method of treating a TCF4-mediated disease, disorder, or condition in a patient in need thereof, comprising administering to the patient an effective amount of the compound of any one of claims 1-25, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 26.

28. The method of claim 27, wherein the TCF4-mediated disease is Fuchs endothelial corneal dystrophy (FECD).

29. A method of modulating the activity of a TCF4 RNA transcript or an unspliced isoform, splicing intennediate, isofomi, fragment, or mutant thereof, comprising contacting the TCF4 RNA transcript or an unspliced isofonn, splicing intermediate, isoform, fragment, or mutant thereof with the compound of anyone of claims 1-25, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 26.

30. The method of claim 29, wherein the compound or pharmacally acceptable salt thereof, or pharmaceutical composition, modulates the expression level and functionality of an MBNL1 protein.

31. A method of modulating the activity of a MBNL protein or mutant thereof, comprising contacting a corresponding TCF4 RNA transcript or an unspliced isofonn, splicing intermediate, isofonn, fragment, or mutant thereof with the compound of any one of claims 1-25, or a pharmacally acceptable salt thereof, or the pharmaceutical composition of 26, that modulates the TCF4 RNA transcript or an unspliced isoform, splicing intermediate, isoform, fragment, or mutant thereof.

32. The method of claim 31, wherein the TCF4 RNA transcript is a TCF4 pre-mRNA, splicing intermediate, or mature mRNA.

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