Helicase inhibitors and uses thereof

Abstract

The disclosure provides for compounds and compositions methods for modulating or inhibiting DHX9.

Description

WSGR Docket No. 69600-701.601HELICASE INHIBITORS AND USES THEREOFCROSS-REFERENCE

[0001] This application claims the benefit of U. S. Provisional Application Serial No. 63 / 711,843 filed October 25, 2024; which is hereby incorporated by reference in its entirety.BACKGROUND

[0002] DHX9, also known as RNA Helicase A (RHA) or Nuclear DNA Helicase II (NDH II), is a DExH-box RNA helicase, which shuttles between nucleus and cytoplasm, and can use all four NTPs to power cycles of directional movement from 3’ to 5’. Functionally, DHX9 can bind to and unwind or resolve dsDNA / RNA, ssDNA / RNA, DNA: RNA hybrids (such as R-loops), circular RNA, and DNA / RNA G quadruplexes. As such, DHX9 has regulatory roles in various RNA and DNA related cellular processes, such as transcription, translation, RNA splicing, editing, RNA transport and processing, microRNA genesis, and maintenance of genomic stability.

[0003] Due to its regulatory role in processes such as transcription and maintenance of genomic stability, DHX9 has shown to be a key regulator in a variety of cancer types. DHX9 has been shown to be involved in the regulation of genes associated with sustained proliferative signaling, evasion of growth suppressors, evasion of apoptosis, angiogenesis, and metastasis, all of which are hallmarks of cancer. Specifically, micro satellite instable cancers, such as Micro satellite Instable (MSI) colorectal cancer, and tumors with defective MisMatch Repair (MMR) exhibit a strong dependence on DHX9.

[0004] In addition to its role in cancer, DHX9 has been implicated in other diseases involving gene replication, translation, or regulation. These diseases include viral infections and autoimmune disease. Thus, there is a need for DHX9 inhibitors as potential therapeutic agents for treating diseases or disorders that are responsive to DHX9 inhibition.SUMMARY

[0005] In one aspect, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof,Formula (I) as disclosed herein.

[0006] Further disclosed herein is a pharmaceutical composition comprising a herein disclosed compound, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient.WSGR Docket No. 69600-701.601

[0007] Further disclosed herein is a method of treating a DHX9-mediated disease or disorder in a subject, comprising administering to the subject a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, as disclosed herein, or a pharmaceutical composition disclosed herein In some embodiments, the disease or disorder is an autoimmune disease, cancer, or a viral infection. In some embodiments, the disease or disorder is cancer. In some embodiments, the cancer is bladder cancer, blood cancer, bone cancer, brain cancer, breast cancer, colorectal cancer, endometrial cancer, gastric cancer, head and neck cancer, hematopoietic cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, or soft-tissue cancer. In some embodiments, the cancer is a micro satellite instability (MSI) cancer. In some embodiments, the cancer has mutations or defects in DNA mis-match repair (MMR), and / or mutations or defects in RNA splicing and the kinetochore complex. In some embodiments, the cancer is a micro satellite instability -high (MSI-H) colorectal cancer.

[0008] Further disclosed herein are methods of treatment and methods of use comprising administering the disclosed compound and composition to a subject.INCORPORATION BY REFERENCE

[0009] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.BRIEF DESCRIPTION OF THE DRAWINGS

[0010] The novel features of the present disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the present disclosure are utilized, and the accompanying drawings of which:

[0011] FIG. 1 shows tumor volumes over time for an in vivo efficacy study of example 66 in LS411N Xenografts.

[0012] FIG. 2 shows body weight change over time for the in vivo efficacy study of example 66 in LS411N Xenografts.DETAILED DESCRIPTIONDefinitions

[0013] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the invention may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments. Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” andWSGR Docket No. 69600-701.601variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to. ” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0014] Reference throughout this specification to “some embodiments” or “an embodiment” means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and / or” unless the content clearly dictates otherwise.

[0015] The terms below, as used herein, have the following meanings, unless indicated otherwise:

[0016] “oxo” refers to =0.

[0017] “Carboxyl” refers to -COOH.

[0018] “Cyano” refers to -CN.

[0019] “Alkyl” refers to a straight-chain or branched- chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2-methyl-l -propyl, 2-methyl-2-propyl, 2-methyl-l-butyl, 3-methyl-l-butyl, 2-methyl-3-butyl, 2, 2- dimethyl- 1 -propyl, 2-methyl-l -pentyl, 3 -methyl- 1 -pentyl, 4-methyl-l -pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l-butyl, 3,3-dimethyl-1 -butyl, 2-ethyl-l -butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl and the like. Whenever it appears herein, anumerical range such as “Ci-Ce alkyl” or “Ci-ealkyl”, means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, the alkyl is a Ci-ioalkyl. In some embodiments, the alkyl is a Ci-ealkyl. In some embodiments, the alkyl is a Ci-salkyl. In some embodiments, the alkyl is a Ci-4alkyl. In some embodiments, the alkyl is a Ci-3alkyl. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen.

[0020] “Alkenyl” refers to a straight- chain or branched- chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms. The group may be in either the cis or trans conformation about the double bond(s) and should be understood to include both isomers. Examples include but are not limited toWSGR Docket No. 69600-701.601ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl and the like. Whenever it appears herein, a numerical range such as “C2-C6 alkenyl” or “C2-ealkenyl”, means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkenyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkenyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen.

[0021] “Alkynyl” refers to a straight- chain or branched- chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and the like. Whenever it appears herein, a numerical range such as “C2-C6 alkynyl” or “C2-ealkynyl”, means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkynyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkynyl is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen.

[0022] “Alkylene” refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkylene is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen.

[0023] “Alkoxy” refers to a radical of the formula -Oalkyl where alkyl is as defined above. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.WSGR Docket No. 69600-701.601

[0024] “Aryl” refers to a radical derived from a hydrocarbon ring system comprising 6 to 30 carbon atoms and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is Ce-Cio aryl. In some embodiments, the aryl is a 6-membered aryl (phenyl). Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenal ene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiment^ the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.

[0025] “CycloaJkyl” refers to a partially or fully saturated, monocyclic, or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom), spiro, or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (e.g., C3-C15 fully saturated cycloalkyl or C3-C15 cycloalkenyl), from three to ten carbon atoms (e.g., C3-C10 fully saturated cycloalkyl or C3-C10 cycloalkenyl), from three to eight carbon atoms (e.g., C3-C8 fully saturated cycloalkyl or C3-C8 cycloalkenyl), from three to six carbon atoms (e.g., C3-C6 fully saturated cycloalkyl or C3-C6 cycloalkenyl), from three to five carbon atoms (e.g., C3-C5 fully saturated cycloalkyl or C3-C5 cycloalkenyl), or three to four carbon atoms (e.g., C3-C4 fully saturated cycloalkyl or C3-C4 cycloalkenyl). In some embodiments, the cycloalkyl is a 3- to 10-membered fully saturated cycloalkyl or a 3- to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3- to 6-membered fully saturated cycloalkyl or a 3- to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5- to 6-membered fully saturated cycloalkyl or a 5- to 6-membered cycloalkenyl.Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans- decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2. l]heptanyl. Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydrox l, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a cycloalkyl isWSGR Docket No. 69600-701.601optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiment^ the cycloalkyl is optionally substituted with halogen. As used herein, “cycloalkylene” refers to a bivalent cycloalkyl radical as described herein. In some embodiments, when a cycloalkylene comprises a cycloalkyl fused with an aryl or a heteroaryl ring, the cycloalkylene is bonded at the cycloalkyl and the aryl, or the cycloalkyl and the heteroaryl. In some embodiments, when a cycloalkylene comprises a cycloalkyl fused with an aryl or a heteroaryl ring, the cycloalkylene is bonded only at the cycloalkyl.

[0026] “Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0027] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0028] “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0029] “Aminoalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0030] “Heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a Ci-Ce heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a Ci-Ce heteroalkyl comprising one or two oxygen, nitrogen, or sulfur wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a Ci-Ce heteroalkyl comprising one oxygen, nitrogen, or sulfur wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyl are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless stated otherwise specifically in the specification, a heteroalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen,WSGR Docket No. 69600-701.601methyl, ethyl, -CN, -CF3, -OH, or-OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.

[0031] “Heterocycloalkyl” refers to a 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, silicon, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl comprises one to three nitrogens. In some embodiments, the heterocycloalkyl comprises one or two nitrogens. In some embodiments, the heterocycloalkyl comprises one nitrogen. In some embodiments, the heterocycloalkyl comprises one nitrogen and one oxygen. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom), spiro, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. Representative heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (e.g., C2-C15 fully saturated heterocycloalkyl or C2-C15 heterocycloalkenyl), from two to ten carbon atoms (e.g., C2-C10 fully saturated heterocycloalkyl or C2-C10 heterocycloalkenyl), from two to eight carbon atoms (e.g., C2-Cs fully saturated heterocycloalkyl or C2-C8 heterocycloalkenyl), from two to seven carbon atoms (e.g., C2-C7 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), from two to six carbon atoms (e.g., C2-C6 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), from two to five carbon atoms (e.g., C2-C5 fully saturated heterocycloalkyl or C2-C5 heterocycloalkenyl), or two to four carbon atoms (e.g., C2-C4 fully saturated heterocycloalkyl or C2-C4 heterocycloalkenyl). Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 1-methylpyridin-2(lH)-one, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-l-yl, 3-oxo-l,3-dihydroisobenzofuran-l-yl, methyl-2-oxo-l,3-dioxol-4-yl, and 2-oxo-1, 3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides, and the oligosaccharides. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e., skeletal atoms of the heterocycloalkyl ring). In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is aWSGR Docket No. 69600-701.6013- to 7-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkenyl. Unless stated otherwise specifically in the specification, a hetero cycloalkyl may be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiment^ the heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen. As used herein, “heterocycloalkylene” refers to a bivalent heterocycloalkyl radical as described herein. In some embodiments, when a heterocycloalkylene comprises a heterocycloalkyl fused with an aryl or a heteroaryl ring, the heterocycloalkylene is bonded at the heterocycloalkyl and the aryl, or the heterocycloalkyl and the heteroaryl. In some embodiments, when a heterocycloalkylene comprises a heterocycloalkyl fused with an aryl or a heteroaryl ring, the heterocycloalkylene is bonded only at the heterocycloalkyl.

[0032] “Heteroaryl” refers to a 5- to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl comprises one to three nitrogens. In some embodiments, the heteroaryl comprises one or two nitrogens. In some embodiments, the heteroaryl comprises one nitrogen. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized. In some embodiments, the heteroaryl is a 5 - to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl. In some embodiments, the heteroaryl is a 6-membered heteroaryl. In some embodiments, the heteroaryl is a 5-membered heteroaryl. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl,WSGR Docket No. 69600-701.601carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1 -phenyl- IH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, 2-pyridone (i.e., 2(lH)-pyridone), and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.

[0033] The term “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” means either “alkyl” or “substituted alkyl” as defined above. Further, an optionally substituted group may be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), mono-substituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.). It will be understood by those skilled in the art with respect to any group containing one or more substituents that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical and / or synthetically non-feasible. Thus, any substituents described should generally be understood as having a maximum molecular weight of about 1,000 daltons, and more typically, up to about 500 daltons.

[0034] The term “each alkyl is independently optionally substituted with one or more R” means that any alkyl moiety is independently optionally substituted with one or more R. For example, the alkyl moiety in a deuteroalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, or heteroalkyl is independently optionally substituted with one or more R.

[0035] The term “one or more” when referring to an optional substituent means that the subject group is optionally substituted with one, two, three, four, or more substituents. In some embodiments, the subject group is optionally substituted with one, two, three or four substituents. In some embodiments, the subject group is optionally substituted with one, two, or three substituents. In some embodiments, the subject group is optionally substituted with one or two substituents. In some embodiments, the subject group is optionally substituted with one substituent. In some embodiments, the subject group is optionally substituted with two substituents.WSGR Docket No. 69600-701.601

[0036] An “effective amount” or “therapeutically effective amount” refers to an amount of a compound administered to a mammalian subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.

[0037] The terms “treat,” “treating,” or “treatment,” as used herein, include alleviating, abating, or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition.

[0038] As used herein, a “disease or disorder associated with DHX9” or, alternatively, “a DHX9-mediated disease or disorder” means any disease or other deleterious condition in which DHX9, or a mutant thereof, is known or suspected to play a role.Compounds

[0039] Described herein are compounds, or a pharmaceutically acceptable salt, or stereoisomer thereof useful in treatment of a disease associated with DHX9.

[0040] Described herein are compounds of Formula (I), or a pharmaceutically acceptable salt, or stereoisomer thereof:Formula (I),wherein:Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;each R1is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -S(=O)(=NRb)Rb, -S(=NRb)(=NRb), -NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)(Rb)2, -C(=O)Ra, - C(=O)ORb, -C(=O)NRcRd, -P(=O)(Rb)2, -P(=O)(ORb)2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;and / or two R1on the same atom are taken together to form an oxo;n is 0, 1, 2, 3, or 4;Ring B is a 5-membered heteroaryl;WSGR Docket No. 69600-701.601each R10is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, -L-cycloalkyl, or -L-heterocycloalkyl;m is 0, 1, 2, 3, or 4;R5is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl;X is halogen;R6is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl;R7is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl;Y is -O- or -NR8-;R8is hydrogen, C1-C6alkyl, or C1-C6haloalkyl;or R8and R7are taken together to form a heterocycloalkyl or heteroaryl; each independently optionally substituted with one or more R;Ring C is cycloalkyl or heterocycloalkyl;each R11is independently halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci- Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl. or - L-heterocycloalkyl;and / or two R11on the same atom are taken together to form an oxo;p is 0, 1, 2, 3, or 4;each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;and / or two Rbare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R;Rcand Rdare each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;and / or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R;L is absent or C1-C4 alkylene optionally substituted with one or more R; andeach R is independently halogen, -CN, -OH, -SF5, -SH, -S(=O)Ci-C3alkyl, -S(=O)2Ci-C3alkyl, - S(=O)2NH2, -S(=O)2NHCi-C3alkyl, -S(=O)2N(Ci-C3alkyl)2, -S(=O)(=NCi-C3alkyl)(Ci-C3alkyl), - NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, -N=S(=O)(Ci-C3alkyl)2, -O-Ci-C4alkylene-OH, -O-Ci- C4aJkylene-NH2, -C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, -C(=O)NHCi-WSGR Docket No. 69600-701.601C3alkyl, -C(=O)N(Ci-C3alkyl)2, -P(=O)(Ci-C3alkyl)2, Ci-C3alkyl, Ci-C3alkoxy, Ci-C3haloalkyl, Ci- C3haloalkoxy, Ci -C3hydroxy alkyl, Ci-C3aminoalkyl, Ci-C3heteroalkyl, C3-Cecycloalkyl, or 3- to 6- membered heterocycloalkyl;or two R on the same atom form an oxo.

[0041] In some embodiments of a compound of Formula (I), Ring B is a 5-membered heteroaryl comprising one, two, three, or four heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I), Ring B is a 5-membered heteroaryl comprising one or two heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I), RingB is a 5-membered heteroaryl comprising one heteroatom selected from the group consisting of O, S, andN. In some embodiments of a compound of Formula (I), Ring B is a 5-membered heteroaryl comprising one heteroatom that is S. In some embodiments of a compound of Formula (I), Ring B is a 5 -membered heteroaryl comprising one heteroatom that is N. In some embodiments, ring B is thiophenyl. In some embodiments, ring B is pyrrolyl.

[0042] In some embodiments of a compound of Formula (I), Ring B is, wherein the ** represents the attachment point to Ring A.

[0043] In some embodiments of a compound of Formula (I), each R10is independently halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, -L-cycloalkyl, or -L-heterocycloalkyl. In some embodiments of a compound of Formula (I), each R10is independently halogen, -CN, C1-C6alkyl, or -L-cycloalkyl. In some embodiments, R10is halogen. In some embodiments, R10is -CN. In some embodiments, R10is Ci-Cealkyl. In some embodiments, R10is Ci-C3alkyl. In some embodiments, R10is C3-Ce cycloalkyl.

[0044] In some embodiments of a compound of Formula (I), each R10is independently -CH3or -CH₂CH₃. In some embodiments of a compound of Formula (I), each R10is independently -CH3and each -CH3is -CD3.

[0045] In some embodiments of a compound of Formula (I), m is 0, 1, or 2. In some embodiments of a compound of Formula (I), m is 0 or 1. In some embodiments of a compound of Formula (I), m is 0. In some embodiments of a compound of Formula (I), m is 1.WSGR Docket No. 69600-701.601

[0046] In some embodiments of a compound of Formula (I), the compound has a structure of FormulaFormula (la),whereinR2is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, -L-cycloalkyl, or -L- heterocycloalkyl; andR3is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, or Ci-Cehaloalkyl.

[0047] In some embodiments of a compound of Formula (I), the compound has a structure of FormulaFormula (lb),whereinR3is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, or Ci-Cehaloalkyl;R4is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, or Ci-Cehaloalkyl; andRNis hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, -L-cycloalkyl, or -L-heterocycloalkyl.

[0048] In some embodiments of a compound of Formula (I), the compound has a structure of FormulaFormula (Ic),whereinR2is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, -L-cycloalkyl, or -L- heterocycloalkyl;R3is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, or Ci-Cehaloalkyl; andR4is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, or Ci-Cehaloalkyl.

[0049] In some embodiments of a compound of Formula (I), one or more R10is R2. In some embodiments of a compound of Formula (I), one or more R10is R3. In some embodiments of a compoundWSGR Docket No. 69600-701.601of Formula (I), one or more R10is R4. In some embodiments of a compound of Formula (I), one or more R10is RN

[0050] In some embodiments of a compound of Formula (I), (la) or (Ic), R2is hydrogen, halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, -L-cycloalkyl, or -L-heterocycloalkyl. In some embodiments of a compound of Formula (I), (la) or (Ic), R2is hydrogen, halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, or -L-cycloalkyl. In some embodiments of a compound of Formula (I), (la) or (Ic), R2is hydrogen, halogen, -CN, Ci-Cealkyl, or -L-cycloalkyl. In some embodiments of a compound of Formula (I), (la) or (Ic), R2is hydrogen, halogen, -CN, Ci-Cealkyl, or -L-cycloalkyl. In some embodiments of a compound of Formula (I), (la) or (Ic), R2is Ci-Cealkyl. In some embodiments of a compound of Formula (I), (la) or (Ic), R2is -CH3. In some embodiments of a compound of Formula (I), (la) or (Ic), R2is -CH3 and -CH3 is -CD3.

[0051] In some embodiments of a compound of Formula (I), (la), (lb), or (Ic), R3is hydrogen, halogen, Ci-Cealkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (I), (la), (lb), or (Ic), R3is hydrogen, halogen, or Ci-Cealkyl. In some embodiments of a compound of Formula (I), (la), (lb), or (Ic), R3is hydrogen or halogen. In some embodiments of a compound of Formula (I), (la), (lb), or (Ic), R3is hydrogen Ci-Cealkyl. In some embodiments of a compound of Formula (I), (la), (lb), or (Ic), R3is hydrogen.

[0052] In some embodiments of a compound of Formula (I), (lb) or (Ic), R4is hydrogen, halogen, Ci-Cealkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (I), (lb) or (Ic), R4is hydrogen, halogen, or Ci-Cealkyl. In some embodiments of a compound of Formula (I), (lb) or (Ic), R4is hydrogen or halogen. In some embodiments of a compound of Formula (I), (lb) or (Ic), R4is hydrogen or Ci-Cealkyl. In some embodiments of a compound of Formula (I), (lb) or (Ic), R4is hydrogen.

[0053] In some embodiments of a compound of Formula (I) or (lb), RNis hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, -L-cycloalkyl, or -L-heterocycloalkyl. In some embodiments of a compound of Formula (I) or (lb), RNis hydrogen, Ci-Cealkyl, -L-cycloalkyl, or -L-heterocycloalkyl. In some embodiments of a compound of Formula (I) or (lb), RNis hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, or -L-cycloalkyl. In some embodiments of a compound of Formula (I) or (lb), RNis hydrogen, Ci-Cealkyl, or -L-cycloalkyl. In some embodiments of a compound of Formula (I) or (lb), RNis hydrogen, Ci-Cealkyl, or -L-cycloalkyl. In some embodiments of a compound of Formula (I) or (lb), RNis Ci-Cealkyl or -L-cycloalkyl. In some embodiments of a compound of Formula (I) or (lb), RNis Ci-Cealkyl. In some embodiments of a compound of Formula (I) or (lb), RNis -CH3 or -CH2CH3. In some embodiments of a compound of Formula (I) or (lb), RNis -CH3. In some embodiments of a compound of Formula (I) or (lb), RNis -CH3 and -CH3 is -CD3.WSGR Docket No. 69600-701.601

[0054] In some embodiments of a compound of Formulaor, wherein the ** represents the attachment point to Ring A.

[0055] In some embodiments of a compound of Formulawherein the ** represents the attachment point toRing A. In some embodiments of a compound of Formula, or, wherein the ** represents the attachment point to Ring A. In someembodiments of a compound of Formulawherein the ** represents the attachment point to Ring A.

[0056] In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), Ring C isheterocycloalkyl.WSGR Docket No. 69600-701.601

[0057] In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), Ring C is 4- to 6-membered heterocycloalkyl comprising one or two heteroatoms selected from the group consisting of O, S, and N.

[0058] In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), Ring C is 4- to 5-membered heterocycloalkyl comprising one or two heteroatoms selected from the group consisting of O, S, and N.

[0059] In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), Ring C is 4- to 5-membered heterocycloalkyl comprising one heteroatom that is O.

[0060] In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), Ring C is. In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), Ring C isIn some embodiments of a compound of Formula (I), (la), (lb) or (Ic), Ring C is

[0061] In some embodiments of a compound of Formula (I), (la), (lb) or (Ic),some embodiments of a compound of Formula (I), (la), (lb) or (Ic),

[0062] In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), each R11is independently halogen, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, -L-cycloalkyl, or -L-heterocycloalkyl. In some embodiments of a compound of F ormula (I), (la), (lb) or (Ic), each R11is independently halogen, -OH, -ORa, -NRcRd, Ci-Cealkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), each R11is independently halogen, -ORa, -NRcRd, Ci-Cealkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), each R11is independently halogen, Ci-Cealkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), each R11is independently C1-C6alkyl or C1-C6haloalkyl. In some embodiments, one or more R11is halogen (e.g., F). In some embodiments, one or more R11is -CN. In some embodiments, one or more R11is -Ci-Cealkyl. In some embodiments, one or more R11is -Ci-Csalkyl. In some embodiments, one or more R11is -Ci-Cehaloalkyl. In some embodiments, one or more R11is -Ci-Cshaloalkyl. In some embodiments, one or more R11is -CF3, -CH2F, or -CHF 2. In some embodiments, one or more R11is -Ci-Cealkoxyl. In some embodiments, one or more R11is -Ci-Csalkoxyl. In some embodiments, one or more R11is -NRcRd(e.g, -NH2, or -N(CH3)2).WSGR Docket No. 69600-701.601

[0063] In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), p is 0, 1, or 2. In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), p is 0 or 1. In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), p is 0. In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), p is 1. In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), p is 2.c -(R11)p

[0064] In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), ' is.In some embodiments of a compound of Formula (I), (Ia), (Ib) or (Ic), R⁵ is hydrogen, halogen, C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiments of a compound of Formula (I), (Ia), (Ib) or (Ic), R⁵ is hydrogen, halogen, or C₁-C₆alkyl. In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), R5is hydrogen or Ci-Cealkyl. In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), R5is hydrogen or halogen. In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), R5is hydrogen.

[0065] In some embodiments of acompound of Formula (I), (la), (lb) or (Ic), R6is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of acompound of Formula (I), (la), (lb) or (Ic), R6is hydrogen, halogen, or Ci-Cealkyl. In some embodiments of a compound of Formula (I), (la), (lb) or (lc), R6is hydrogen or Ci-Cealkyl. In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), R6is hydrogen or halogen. In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), R6is hydrogen.

[0066] In some embodiments of acompound of Formula (I), (la), (lb) or (Ic), R7is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of acompound of Formula (I), (la), (lb) or (Ic), R7is hydrogen, halogen, or Ci-Cealkyl. In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), R7is hydrogen or Ci-Cealkyl.

[0067] In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), R7is hydrogen or halogen. In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), R7is hydrogen.

[0068] In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), X is fluoro, chloro, or bromo. In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), X is fluoro. In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), X is chloro. In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), X is bromo. In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), X is iodo.WSGR Docket No. 69600-701.601

[0069] In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), Y is -NR8-. In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), Y is -O-.

[0070] In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), R8is hydrogen or Ci-Cealkyl. In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), R8is hydrogen.

[0071] In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), R8and R7are taken together to form a heterocycloalkyl or heteroaryl; each independently optionally substituted with one or more R. In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), R8and R7are taken together to form a heteroaryl optionally substituted with one or more R. In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), R8and R7are taken together to forma 5 -membered heteroaryl comprising one or two heteroatoms selected from the group consisting of O, S, and N, independently optionally substituted with one or more R.

[0072] In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), Ring A is cycloalkyl or heterocycloalkyl.

[0073] In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), Ring A is fully saturated cycloalkyl or cycloalkenyl. In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), Ring A is C₃-C₈ fully saturated cycloalkyl or C₃-C₈ cycloalkenyl. In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), Ring A is C4-C6 fully saturated cycloalkyl or C4-C6 cycloalkenyl. In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), Ring A is cyclohexyl or cyclohexenyl.

[0074] In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), Ring A is fully saturated heterocycloalkyl or heterocycloalkenyl. In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), Ring A is C3-C8 fully saturated heterocycloalkyl or C3-C8 heterocycloalkenyl. In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), Ring A is C4-C6 fully saturated heterocycloallyl or C4-C6 heterocycloalkenyl. In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), Ring A is 6-membered fully saturated heterocycloalkyl or 6-membered heterocycloalkenyl.

[0075] In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), Ring A is aryl or heteroaryl. In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), Ring A is phenyl or 5-or 6-membered heteroaryl. In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), Ring A is phenyl. In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), Ring A is pyridyl, pyrimidinyl, or pyrazinyl. In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), Ring A is pyridyl.

[0076] In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), each R1is independently halogen, -CN, -OH, -ORa, -SF5, -SH, -SRa, -S(=O)(=NRb)Rb, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, -P(=O)(Rb)2, -P(=O)(ORb)2, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R; and / or two R1on the same atom are taken together to form an oxo.

[0077] In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), each R1is independently halogen, -CN, -OH, -ORa, -SF5, -SH, -SRa, -S(=O)(=NRb)Rb, -NRcRd, -C(=O)ORb, -P(=O)(Rb)2, Ci-WSGR Docket No. 69600-701.601Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceheteroalkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R; and / or two R1on the same atom are taken together to form an oxo.

[0078] In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), each R1is independently halogen, -CN, -OH, -ORa, -SF₅, -SH, -SRa, -S(=O)(=NRb)Rb, -NRcRd, -C(=O)ORb, -P(=O)(Rb)2, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, or Ci-Ceheteroalkyl.

[0079] In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), each R1is independently halogen, -CN, -OH, -ORa, -SF5, -SH, -SRa, -S(=O)(=NRb)Rb, -NRcRd, Ci-C6alkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), each R1is independently halogen, -ORa, -SRa, -S(=O)(=NRb)Rb, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), each R1is independently halogen or Ci -Cealkyl. In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), each R1is independently halogen.

[0080] In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), n is 0, 1, 2, or 3. In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), n is 1, 2, or 3. In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), n is 2 or 3. In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), nisO, 1, or 2. In some embodiments of a compound of Formula (I), (la), (lb) or(Ic), n is 1. In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), n is 2. In some embodiments of a compound of Formula (I), (la), (lb) or (Ic), n is 3.

[0081] In some embodiments of a compound of FormulaWSGR Docket No. 69600-701.601

[0083] Also disclosed herein is a compound of Formula (II), or a pharmaceutically acceptable salt or stereoisomer thereof:WSGR Docket No. 69600-701.601wherein:Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;each R1is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -S(=O)(=NRb)Rb, -S(=NRb)(=NRb), -NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)(Rb)2, -C(=O)Ra, - C(=O)ORb, -C(=O)NRcRd, -P(=O)(Rb)2, -P(=O)(ORb)2, Ci-C6alkyl, Ci-C6haloalkyl, Ci- Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L- heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;and / or two R1on the same atom are taken together to form an oxo;n is 0, 1, 2, 3, or 4;Ring D is, or, wherein the ** represents the attachment point to Ring A;R2is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, -L-cycloalkyl, or -L- heterocycloalkyl;R3is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, or Ci-Cehaloalkyl;R4is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, or Ci-Cehaloalkyl;RNis hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, -L-cycloalkyl, or -L-heterocycloalkyl;R5is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl;X is halogen;R6is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl;R7is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl;Y is -O- or -NR8-;R8is hydrogen, C1-C6alkyl, or C1-C6haloalkyl;R9is Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the alkyl,WSGR Docket No. 69600-701.601heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;or R8and R9are taken together to form a heterocycloalkyl optionally substituted with one or more R; or R8and R7are taken together to form a heterocycloalkyl or heteroaryl; each independently optionally substituted with one or more R;each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;and / or two Rbare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R;Rcand Rdare each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;and / or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R;L is absent or C1-C4 alkylene optionally substituted with one or more R; andeach Ris independently halogen, -CN, -OH, -SF5, -SH, -S(=O)Ci-C3alkyl, -S(=O)2Ci-C3alkyl, - S(=O)2NH2, -S(=O)2NHCi-C3alkyl, -S(=O)2N(Ci-C3alkyl)2, -S(=O)(=NCi-C3alkyl)(Ci-C3alkyl), - NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, -N=S(=O)(Ci-C3alkyl)2, -O-Ci-C4alkylene-OH, -O-Ci- C4alkylene-NH2, -C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, -C(=O)NHCi- C3alkyl, -C(=O)N(Ci-C3alkyl)2, -P(=O)(Ci-C3alkyl)2, Ci-C3alkyl, Ci-C3alkoxy, Ci-C3haloalkyl, Ci- C3haloalkoxy, Ci -C3hydroxy alkyl, Ci-C3aminoalkyl, Ci-C3heteroalkyl, C3-Cecycloalkyl, or 3- to 6- membered heterocycloalkyl;or two R on the same atom form an oxo;WSGR Docket No. 69600-701.601

[0084] In some embodiments, the compound is of F ormula (Ila), or a pharmaceutically acceptable salt or stereoisomer thereof:wherein:Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;each R1is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -S(=O)(=NRb)Rb, -S(=NRb)(=NRb), -NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)(Rb)2, -C(=O)Ra, - C(=O)ORb, -C(=O)NRcRd, -P(=O)(Rb)2, -P(=O)(ORb)2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;and / or two R1on the same atom are taken together to form an oxo;WSGR Docket No. 69600-701.601n is 0, 1, 2, 3, or 4;R2is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, -L-cycloalkyl, or -L- heterocycloalkyl;R3is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, or Ci-Cehaloalkyl;R5is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl;X is halogen;R6is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl;R7is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl;Y is -O- or -NR8-;R8is hydrogen, C1-C6alkyl, or C1-C6haloalkyl;R9is Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;or R8and R9are taken together to form a heterocycloalkyl optionally substituted with one or more R; or R8and R7are taken together to form a heterocycloalkyl or heteroaryl; each independently optionally substituted with one or more R;each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;and / or two Rbare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R;Rcand Rdare each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;and / or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R;L is absent or C1-C4 alkylene optionally substituted with one or more R; andeach Ris independently halogen, -CN, -OH, -SF5, -SH, -S(=O)Ci-C3alkyl, -S(=O)2Ci-C3alkyl, - S(=O)2NH2, -S(=O)2NHCi-C3alkyl, -S(=O)2N(Ci-C3alkyl)2, -S(=O)(=NCi-C3alkyl)(Ci-C3alkyl), - NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, -N=S(=O)(Ci-C3alkyl)2, -O-Ci-C4alkylene-OH, -O-Ci- C4alkylene-NH2, -C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, -C(=O)NHCi-WSGR Docket No. 69600-701.601C3alkyl, -C(=O)N(Ci-C3alkyl)2, -P(=O)(Ci-C3alkyl)2, Ci-C3alkyl, Ci-C3alkoxy, Ci-C3haloalkyl, Ci- C3haloalkoxy, Ci -C3hydroxy alkyl, Ci-C3aminoalkyl, Ci-C3heteroalkyl, C3-Cecycloalkyl, or 3- to 6- membered heterocycloalkyl;or two R on the same atom form an oxo.

[0085] In some embodiments, the compound of Formula (Ila) is not

[0086] In some embodiments of a compound of Formula (II) or (Ila), R2is hydrogen, halogen, -CN, Ci- Cealkyl, Ci-Cehaloalkyl, -L-cycloalkyl, or -L-heterocycloalkyl. In some embodiments of a compound of Formula (II) or (Ila), R2is hydrogen, halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, or -L-cycloalkyl. In some embodiments of a compound of Formula (II) or (Ila), R2is hydrogen, halogen, -CN, Ci-Cealkyl, or -L-cycloalkyl. In some embodiments of a compound of Formula (II) or (Ila), R2is hydrogen, halogen, -CN, Ci-Cealkyl, or -L-cycloalkyl. In some embodiments of a compound of Formula (II) or (Ila), R2is Ci-Cealkyl. In some embodiments of a compound of Formula (II) or (Ila), R2is -CH3. In some embodiments of a compound of Formula (II) or (Ila), R2is -CH3and -CH3is -CD3.

[0087] In some embodiments of a compound of Formula (II) or (Ila), R3is hydrogen, halogen, Ci-Cealkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (II) or (Ila), R3is hydrogen, halogen, or Ci-Cealkyl. In some embodiments of a compound of Formula (II) or (Ila), R3is hydrogen or halogen. In some embodiments of a compound of Formula (II) or (Ila), R3is hydrogen Ci-Cealkyl. In some embodiments of a compound of Formula (II) or (Ila), R3is hydrogen.represents the attachment point to Ring A.

[0089] In some embodiments, the compound is of Formula (lib), or a pharmaceutically acceptable salt or stereoisomer thereof:WSGR Docket No. 69600-701.601Formula (lib),wherein:Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;each R1is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -S(=O)(=NRb)Rb, -S(=NRb)(=NRb), -NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)(Rb)2, -C(=O)Ra, - C(=O)ORb, -C(=O)NRcRd, -P(=O)(Rb)2, -P(=O)(ORb)2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;and / or two R1on the same atom are taken together to form an oxo;n is 0, 1, 2, 3, or 4;R3is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, or Ci-Cehaloalkyl;R4is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, or Ci-Cehaloalkyl;RNis hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, -L-cycloalkyl, or -L-heterocycloalkyl;R5is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl;X is halogen;R6is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl;R7is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl;Y is -O- or -NR8-;R8is hydrogen, C1-C6alkyl, or C1-C6haloalkyl;R9is Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;or R8and R9are taken together to form a heterocycloalkyl optionally substituted with one or more R; or R8and R7are taken together to form a heterocycloalkyl or heteroaryl; each independently optionally substituted with one or more R;each Rais independently Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxy alkyl, Ci-Ceaminoalkyl, Ci- Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-WSGR Docket No. 69600-701.601heteroaryl, wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;and / or two Rbare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R;Rcand Rdare each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;and / or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R;L is absent or C1-C4 alkylene optionally substituted with one or more R; andeach Ris independently halogen, -CN, -OH, -SF5, -SH, -S(=O)Ci-C3alkyl, -S(=O)2Ci-C3alkyl, - S(=O)2NH2, -S(=O)2NHCi-C3alkyl, -S(=O)2N(Ci-C3alkyl)2, -S(=O)(=NCi-C3alkyl)(Ci-C3alkyl), - NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, -N=S(=O)(Ci-C3alkyl)2, -O-Ci-C4alkylene-OH, -O-Ci- C4alkylene-NH2, -C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, -C(=O)NHCi- C3alkyl, -C(=O)N(Ci-C3alkyl)2, -P(=O)(Ci-C3alkyl)2, Ci-C3alkyl, Ci-C3alkoxy, Ci-C3haloalkyl, Ci- C3haloalkoxy, Ci -C3hydroxy alkyl, Ci-C3aminoalkyl, Ci-C3heteroalkyl, C3-Cecycloalkyl, or 3- to 6- membered heterocycloalkyl;or two R on the same atom form an oxo.

[0090] In some embodiments of a compound of Formula (II) or (lib), R3is hydrogen, halogen, Ci-Cealkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (II) or (lib), R3is hydrogai, halogen, or Ci-Cealkyl. In some embodiments of a compound of Formula (II) or (lib), R3is hydrogen or halogen. In some embodiments of a compound of Formula (II) or (lib), R3is hydrogen Ci-Cealkyl. In some embodiments of a compound of Formula (II) or (lib), R3is hydrogen.

[0091] In some embodiments of a compound of Formula (II) or (lib), R4is hydrogen, halogen, Ci-Cealkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (II) or (lib), R4is hydrogai, halogen, or Ci-Cealkyl. In some embodiments of a compound of Formula (II) or (lib), R4is hydrogen or halogen. In some embodiments of a compound of Formula (II) or (lib), R4is hydrogen or Ci-Cealkyl. In some embodiments of a compound of Formula (II) or (lib), R4is hydrogen.

[0092] In some embodiments of a compound of Formula (II) or (lib), RNis hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, -L-cycloalkyl, or -L-heterocycloalkyl. In some embodiments of a compound of Formula (II) or (lib), RNis hydrogen, Ci-Cealkyl, -L-cycloalkyl, or -L-heterocycloalkyl. In some embodiments of a compound of Formula (II) or (nb), RNis hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, or -L-cycloalkyl. In some embodiments of a compound of Formula (II) or (lib), RNis hydrogen, Ci-Cealkyl, or -L-cycloalkyl. InWSGR Docket No. 69600-701.601some embodiments of a compound of Formula (II) or (lib), RNis hydrogen, Ci-Cealkyl, or -L-cycloalkyl. In some embodiments of a compound of Formula (II) or (lib), RNis Ci-Cealkyl or -L-cycloalkyl. In some embodiments of a compound of Formula (II) or (lib), RNis Ci-Cealkyl. In some embodiments of a compound of Formula (II) or (lib), RNis -CH3 or -CH2CH3. In some embodiments of a compound of Formula (II) or (lib), RNis -CH3. In some embodiments of a compound of Formula (II) or (lib), RNis -CH3 and the -CH3 is -CD3.

[0093] In some embodiments of a compound of Formula (II) or (lib)wherein the ** represents the attachment point to Ring A.

[0094] In some embodiments, the compound is of Formula (lie), or a pharmaceutically acceptable salt or stereoisomer thereof:wherein:Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;each R1is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -S(=O)(=NRb)Rb, -S(=NRb)(=NRb), -NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)(Rb)2, -C(=O)Ra, - C(=O)ORb, -C(=O)NRcRd, -P(=O)(Rb)2, -P(=O)(ORb)2, Ci-C6alkyl, Ci-C6haloalkyl, Ci- Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L- heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;and / or two R1on the same atom are taken together to form an oxo;n is 0, 1, 2, 3, or 4;WSGR Docket No. 69600-701.601R2is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, -L-cycloalkyl, or -L- heterocycloalkyl;R3is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, or Ci-Cehaloalkyl;R4is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, or Ci-Cehaloalkyl;R5is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl;X is halogen;R6is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl;R7is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl;Y is -O- or -NR8-;R8is hydrogen, C1-C6alkyl, or C1-C6haloalkyl;R9is Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;or R8and R9are taken together to form a heterocycloalkyl optionally substituted with one or more R; or R8and R7are taken together to form a heterocycloalkyl or heteroaryl; each independently optionally substituted with one or more R;each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;and / or two Rbare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R;Rcand Rdare each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;and / or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R;L is absent or C1-C4 alkylene optionally substituted with one or more R; andeach Ris independently halogen, -CN, -OH, -SF5, -SH, -S(=O)Ci-C3alkyl, -S(=O)2Ci-C3alkyl, - S(=O)2NH2, -S(=O)2NHCi-C3alkyl, -S(=O)2N(Ci-C3alkyl)2, -S(=O)(=NCi-C3alkyl)(Ci-C3alkyl), - NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, -N=S(=O)(Ci-C3alkyl)2, -O-Ci-C4alkylene-OH, -O-Ci- C4alkylene-NH2, -C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, -C(=O)NHCi-WSGR Docket No. 69600-701.601C3alkyl, -C(=O)N(Ci-C3alkyl)2, -P(=O)(Ci-C3alkyl)2, Ci-C3alkyl, Ci-C3alkoxy, Ci-C3haloalkyl, Ci- C3haloalkoxy, Ci -C3hydroxy alkyl, Ci-C3aminoalkyl, Ci-C3heteroalkyl, C3-Cecycloalkyl, or 3- to 6- membered heterocycloalkyl;or two R on the same atom form an oxo.

[0095] In some embodiments, the compound of Formula (lie) is not

[0096] In some embodiments of a compound of Formula (II) or (lie), R2is hydrogen, halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, -L-cycloalkyl, or -L-heterocycloalkyl. In some embodiments of a compound of Formula (II) or (He), R2is hydrogen, halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, or -L-cycloalkyl. In some embodiments of a compound of Formula (II) or (lie), R2is hydrogen, halogen, -CN, Ci-Cealkyl, or -L-cycloalkyl. In some embodiments of a compound of Formula (II) or (He), R2is hydrogen, halogen, -CN, Ci-Cealkyl, or -L-cycloalkyl. In some embodiments of a compound of Formula (II) or (lie), R2is Ci-Cealkyl. In some embodiments of a compound of Formula (II) or (lie), R2is -CH3. In some embodiments of a compound of Formula (II) or (He), R2is -CH3and -CH3is -CD3.

[0097] In some embodiments of a compound of Formula (II) or (He), R3is hydrogen, halogen, Ci-Cealkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (II) or (lie), R3is hydrogen, halogen, or Ci-Cealkyl. In some embodiments of a compound of Formula (II) or (He), R3is hydrogen or halogen. In some embodiments of a compound of Formula (II) or (lie), R3is hydrogen Ci-Cealkyl. In some embodiments of a compound of Formula (II) or (lie), R3is hydrogen.

[0098] In some embodiments of a compound of Formula (II) or (He), R4is hydrogen, halogen, Ci-Cealkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (II) or (He), R4is hydrogen, halogen, or Ci-Cealkyl. In some embodiments of a compound of Formula (II) or (lie), R4is hydrogen or halogen. In some embodiments of a compound of Formula (II) or (lie), R4is hydrogen or Ci-Cealkyl. In some embodiments of a compound of Formula (II) or (lie), R4is hydrogen.WSGR Docket No. 69600-701.601

[0099] In some embodiments of a compound of Formula (II) or (lie)wherein the ** represents the attachment point to Ring A.

[0100] In some embodiments of a compound of Formula (II), (Ila), (nb), or (He), R9is Ci-Cealkyl, Ci-Cehaloalkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.

[0101] In some embodiments of a compound of Formula (II), (Ila), (nb), or (lie), R9is Ci-Cealkyl or Ci-Cehaloalkyl.

[0102] In some embodiments of a compound of Formula (II), (Ila), (nb), or (lie), R9is -L-cycloalkyl or -L-heterocycloalkyl; wherein the cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R.

[0103] In some embodiments of a compound of Formula (II), (Ila), (lib), or (lie), R9is cycloalkyl or heterocycloalkyl; wherein the cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R.

[0104] In some embodiments of a compound of Formula (II), (Ila), (nb), or (lie), R9is heterocycloalkyl independently optionally substituted with one or more R.

[0105] In some embodiments of a compound of Formula (II), (Ila), (lib), or (lie), R9is 4- to 6-membered heterocycloalkyl comprising one or two heteroatoms selected from the group consisting of O, S, and N, independently optionally substituted with one or more R.

[0106] In some embodiments of a compound of Formula (II), (Ila), (lib), or (lie), R9is 4- to 5-membered heterocycloalkyl comprising one or two heteroatoms selected from the group consisting of O, S, and N, independently optionally substituted with one or more R.

[0107] In some embodiments of a compound of Formula (II), (Ila), (lib), or (lie), R9is 4- to 5-membered heterocycloalkyl comprising one heteroatom that is O, independently optionally substituted with one or more R.

[0108] In some embodiments of a compound of Formula (II), (Ila), (lib), or (lie), R9isor, independently optionally substituted with one or more R.

[0109] In some embodiments of a compound of Formula (II), (Ila), (lib), or (lie), R9isindependently optionally substituted with one or more R.

[0110] In some embodiments of a compound of Formula (II), (Ila), (lib), or (lie), R9isindependently optionally substituted with one or more R.WSGR Docket No. 69600-701.601

[0111] In some embodiments of a compound of Formula (II), (Ila), (lib), or (lie), R9isr~Q

[0112] In some embodiments of a compound of Formula (II), (Ila), (lib), or (lie), R9is ' or

[0113] In some embodiments of a compound of Formula (II), (Ila), (nb), or (lie), R9is substituted with one or more R, and wherein each R is independently halogen, -CN, -OH, -NH2, -NHC1-C3alkyl, -N(Ci-C3alkyl)2, Ci-Csalkyl, Ci-Csalkoxy, Ci-Cshaloalkyl, Ci-Cshaloalkoxy, Ci-Cshydroxy alkyl, Ci-Csaminoalkyl, Ci-Csheteroalkyl, Cs-Cecycloalkyl, or 3- to 6-membered heterocycloalkyl. In some embodiments of a compound of Formula (II), (Ila), (lib), or (He), R9is substituted with one or more R, and wherein each R is independently halogen, -CN, -OH, -NH2, -NHCi-Csalkyl, -N(Ci-C3alkyl)2, Ci-Csalkyl, Ci-Csalkoxy, Ci-Cshaloalkyl, or Ci-Cshaloalkoxy.

[0114] In some embodiments of a compound of Formula (II), (Ila), (lib), or (lie), R5is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of acompound of Formula (II), (Ila), (lib), or (lie), R5is hydrogen, halogen, or Ci-Cealkyl. In some embodiments of a compound of Formula (II), (Ila), (lib), or (lie), R5is hydrogen or Ci-Cealkyl. In some embodiments of a compound of Formula (II), (Ila), (lib), or (He), R5is hydrogen or halogen. In some embodiments of a compound of Formula (II), (Ila), (lib), or (lie), R5is hydrogen.

[0115] In some embodiments of a compound of Formula (II), (Ila), (lib), or (He), R6is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of acompound of Formula (II), (Ila), (lib), or (He), R6is hydrogen, halogen, or Ci-Cealkyl. In some embodiments of a compound of Formula (II), (Ila), (lib), or (lie), R6is hydrogen or Ci-Cealkyl. In some embodiments of a compound of Formula (II), (Ila), (lib), or (He), R6is hydrogen or halogen. In some embodiments of a compound of Formula (II), (Ila), (lib), or (lie), R6is hydrogen.

[0116] In some embodiments of a compound of Formula (II), (Ila), (lib), or (lie), R7is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of acompound of Formula (II), (Ila), (lib), or (lie), R7is hydrogen, halogen, or Ci-Cealkyl. In some embodiments of a compound of Formula (II), (Ila), (lib), or (lie), R7is hydrogen or Ci-Cealkyl.

[0117] In some embodiments of a compound of Formula (II), (Ila), (lib), or (lie), R7is hydrogen or halogen. In some embodiments of a compound of Formula (II), (Ila), (lib), or (He), R7is hydrogen.WSGR Docket No. 69600-701.601

[0118] In some embodiments of a compound of Formula (II), (Ila), (lib), or (lie), X is fluoro, chloro, or bromo. In some embodiments of a compound of Formula (II), (Ila), (lib), or (lie), X is fluoro. In some embodiments of a compound of Formula (II), (Ila), (lib), or (He), X is chloro. In some embodiments of a compound of Formula (II), (Ila), (lib), or (lie), X is bromo. In some embodiments of a compound of Formula (II), (Ila), (lib), or (He), X is iodo.

[0119] In some embodiments of a compound of Formula (II), (Ila), (lib), or (lie), Y is -NR8-. In some embodiments of a compound of Formula (II), (Ila), (lib), or (He), Y is -O-.

[0120] In some embodiments of a compound of Formula (II), (Ila), (lib), or (lie), R8is hydrogen or Ci-Cealkyl. In some embodiments of a compound of Formula (II), (Ila), (lib), or (lie), R8is hydrogen.

[0121] In some embodiments of a compound of Formula (II), (Ila), (lib), or (lie), R8and R7are taken together to form a heterocycloalkyl or heteroaryl; each independently optionally substituted with one or more R. In some embodiments of a compound of Formula (II), (Ila), (lib), or (lie), R8and R7are taken together to form a heteroaryl optionally substituted with one or more R. In some embodiments of a compound of Formula (II), (Ila), (lib), or (lie), R8and R7are taken together to form a 5 -membered heteroaryl comprising one or two heteroatoms selected from the group consisting of O, S, and N, independently optionally substituted with one or more R.

[0122] In some embodiments of a compound of Formula (II), (Ila), (lib), or (lie), Ring A is cycloalkyl or heterocycloalkyl.

[0123] In some embodiments of a compound of Formula (II), (Ila), (lib), or (lie), Ring A is fully saturated cycloalkyl or cycloalkenyl. In some embodiments of a compound of Formula (II), (Ila), (lib), or (lie), Ring A is Cs-Cs fully saturated cycloalkyl or Cs-Cs cycloalkenyl. In some embodiments of a compound of Formula (II), (Ila), (lib), or (lie), Ring A is C4-C6 fully saturated cycloalkyl or C4-C6 cycloalkenyl. In some embodiments of a compound of Formula (II), (Ila), (lib), or (He), Ring A is cyclohexyl or cyclohexenyl.

[0124] In some embodiments of a compound of Formula (II), (Ila), (lib), or (lie), Ring A is fully saturated heterocycloalkyl or heterocycloalkenyl. In some embodiments of a compound of Formula (II), (Ila), (lib), or (lie), Ring A is C3-C8 fully saturated heterocycloalkyl or C3-C8 heterocycloalkenyl. In some embodiments of a compound of Formula (II), (Ila), (lib), or (lie), Ring A is C4-C6 fully saturated heterocycloalkyl or C4-C6 heterocycloalkenyl. In some embodiments of a compound of Formula (II), (Ila), (lib), or (lie), Ring A is 6-membered fully saturated heterocycloalkyl or 6-membered heterocycloalkenyl.

[0125] In some embodiments of a compound of Formula (II), (Ila), (lib), or (lie), Ring A is aryl or heteroaryl. In some embodiments of a compound of Formula (II), (Ila), (lib), or (lie), Ring A is phenyl or 5- or 6-membered heteroaryl. In some embodiments of a compound of Formula (II), (Ila), (lib), or (He), Ring A is phenyl. In some embodiments of a compound of Formula (II), (Ila), (lib), or (He), Ring A is pyridyl, pyrimidinyl, or pyrazinyl. In some embodiments of a compound of Formula (II), (Ila), (lib), or (He), Ring A is pyridyl.WSGR Docket No. 69600-701.601

[0126] In some embodiments of a compound of Formula (II), (Ila), (lib), or (lie), each R1is independently halogen, -CN, -OH, -ORa, -SF₅, -SH, -SRa, -S(=O)(=NRb)Rb, -NRcRd, Ci-Cealkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (II), (Ila), (lib), or (lie), each R1is independently halogen, -ORa, -SRa, -S(=O)(=NRb)Rb, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (II), (Ila), (lib), or (lie), each R1is independently halogen or C1-C6alkyl. In some embodiments of a compound of Formula (II), (Ila), (lib), or (He), each R1is independently halogen.

[0127] In some embodiments of a compound of Formula (II), (Ila), (lib), or (He), n is 0, 1, 2, or 3. In some embodiments of a compound of Formula (II), (Ila), (lib), or (lie), n is 1, 2, or 3. In some embodiments of a compound of Formula (II), (Ila), (lib), or (lie), n is 2 or 3. In some embodiments of a compound of Formula (II), (Ila), (lib), or (lie), n is 0, 1, or 2. In some embodiments of a compound of Formula (II), (Ila), (lib), or (He), n is 1. In some embodiments of a compound of Formula (II), (Ila), (lib), or (He), n is 2. In some embodiments of a compound of Formula (II), (Ila), (lib), or (He), n is 3.WSGR Docket No. 69600-701.601

[0130] In some embodiments of a compound disclosed herein, each Rais independently Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, -L-cycloalkyl, or -L-heterocycloalkyl, wherein each alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rais independently Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl,WSGR Docket No. 69600-701.601cycloalkyl, or heterocycloalkyl, wherein each alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rais independently Ci-Cealkyl, Ci-Cehaloalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rais independently Ci-Cealkyl, Ci-Cehaloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound disclosed herein, each Rais independently Ci-Cealkyl or Ci-Cehaloalkyl. In some embodiments of a compound disclosed herein, each Rais independently Ci-Cealkyl.

[0131] In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, -L-cycloalkyl, or -L-heterocycloalkyl, wherein each alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, Ci-Cealkyl, or Ci-Cehaloalkyl. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen or Ci-Cealkyl. In some embodiments of a compound disclosed herein, each Rbis hydrogen. In some embodiments of a compound disclosed herein, each Rbis independently Ci-Cealkyl.

[0132] In some embodiments of a compound disclosed herein, two Rbare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R.

[0133] In some embodiments of a compound disclosed herein, Rcand Rdare each independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, -L-cycloalkyl, or -L-heterocycloalkyl, wherein each alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, Rcand Rdare each independently hydrogen, Ci-Cealk l. Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, Rcand Rdare each independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, Rcand Rdare each independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound disclosed herein, Rcand Rdare each independently hydrogen, Ci-Cealkyl, or Ci-Cehaloalkyl. In some embodiments of a compound disclosedWSGR Docket No. 69600-701.601herein, Rcand Rdare each independently hydrogen or Ci-Cealkyl. In some embodiments of a compound disclosed herein, Rcand Rdare each hydrogen. In some embodiments of a compound disclosed herein, Rcand Rdare each independently Ci-Cealkyl.

[0134] In some embodiments of a compound disclosed herein, Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R.

[0135] In some embodiments of a compound disclosed herein, L is absent. In some embodiments of a compound disclosed herein, L is C1-C4 alkylene optionally substituted with one or more R. In some embodiments of a compound disclosed herein, L is C1-C4 alkylene. In some embodiments of a compound disclosed herein, L is -CH2-. In some embodiments of a compound disclosed herein, L is -CH2CH2-. In some embodiments of a compound disclosed herein, L is -CH2CH2CH2-.

[0136] In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -NH2, -NHC1-C3 alkyl, -N(Ci-C3alkyl)2, Ci-Csalkyl, Ci-Csalkoxy, Ci-Cshaloalkyl, Ci-Cshaloalkoxy, Ci-Cshydroxyalkyl, Ci-Csaminoalkyl, Ci-Csheteroalkyl, Cs-Cecycloalkyl, or 3- to 6-membered heterocycloalkyl; or two R on the same atom form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -NH2, -NHC1-C3alkyl, -N(Ci-C3alkyl)2, Ci-Csalkyl, Ci-Csalkoxy, or Ci-Cshaloalkyl; or two R on the same atom form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen, -NH2, -NHC1-C3 alkyl, -N(Ci-C3alkyl)2, Ci-Csalkyl, Ci-Csalkoxy, or Ci-Cshaloalkyl; or two R on the same atom form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen, C1-C6alkyl, or C1-C6haloalkyl; or two R on the same atom form an oxo.

[0137] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds.

[0138] In some embodiments the compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, is one of the compounds in Table 1.WSGR Docket No. 69600-701.601WSGR Docket No. 69600-701.601WSGR Docket No. 69600-701.601WSGR Docket No. 69600-701.601WSGR Docket No. 69600-701.601WSGR Docket No. 69600-701.601WSGR Docket No. 69600-701.601WSGR Docket No. 69600-701.601WSGR Docket No. 69600-701.601WSGR Docket No. 69600-701.601WSGR Docket No. 69600-701.601WSGR Docket No. 69600-701.601WSGR Docket No. 69600-701.601WSGR Docket No. 69600-701.601WSGR Docket No. 69600-701.601WSGR Docket No. 69600-701.601WSGR Docket No. 69600-701.601WSGR Docket No. 69600-701.601WSGR Docket No. 69600-701.601WSGR Docket No. 69600-701.601WSGR Docket No. 69600-701.601WSGR Docket No. 69600-701.601WSGR Docket No. 69600-701.601Further Forms of Compounds Disclosed HereinIsomers / Stereoisomers

[0139] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers, resulting from a single preparative step, combination, or inter conversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation / resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.WSGR Docket No. 69600-701.601Isotopically enriched compounds

[0140] Unless otherwise stated, compounds described herein may exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure. For example, hydrogen has three naturally occurring isotopes, denoted1H (protium),2H (deuterium), and3H (tritium). Protium is the most abundant isotope of hydrogen in nature. Enriching for deuterium may afford some therapeutic advantages, such as increased in vivo half-life and / or exposure, or may provide a compound useful for investigating in vivo routes of drug elimination and metabolism.

[0141] For example, the compounds described herein may be artificially enriched in one or more particular isotopes. In some embodiments, the compounds described herein may be artificially enriched in one or more isotopes that are not predominantly found in nature. In some embodiments, the compounds described herein may be artificially enriched in one or more isotopes selected from deuterium (2H), tritium (3H), iodine-125 (125I) or carbon- 14 (14C). In some embodiments, the compounds described herein are artificially enriched in one or more isotopes selected from2H,11C,13C,14C,15C,12N,13N,15N,16N,16O,17O,14F,15F,16F,17F,18F,33S,34S,35S,36S,35C1,37C1,79Br,81Br,131I, and125I. In some embodiments, the abundance of the enriched isotopes is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% by molar.

[0142] In some embodiments, the compound is deuterated in at least one position. In some embodiments, the compounds disclosed herein have some or all of the1H atoms replaced with2H atoms.

[0143] The methods of synthesis for deuterium- containing compounds are known in the art and include, by way of non-limiting example only, the procedure described in U. S. Patent Nos. 5,846,514 and 6,334,997, and the following synthetic methods. For example, deuterium substituted compounds may be synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem, 1981, 64(1-2), 9-32.Pharmaceutically acceptable salts

[0144] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.WSGR Docket No. 69600-701.601

[0145] In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or stereoisomer thereof, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.

[0146] Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid or inorganic base, such salts including, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-l,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne- 1,6- di oate, hydroxybenzoate, y-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1 -napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, undecanoate, and xylenesulfonate.

[0147] Further, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p -toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2] oct-2-ene-l -carboxylic acid, glucoheptonic acid, 4,4’-methylenebis-(3-hydroxy-2-ene-l -carboxylic acid), 3 -phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxy naphthoic acid, salicylic acid, stearic acid and muconic acid. In some embodiments, other acids, such as oxalic, while not in themselves pharmaceutically acceptable, are employed in the preparation of salts useful as intermediates in obtaining the compounds disclosed herein, or stereoisomer thereof and their pharmaceutically acceptable acid addition salts.

[0148] In some embodiments, those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary,WSGR Docket No. 69600-701.601secondary, tertiary, or quaternary amine. Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(CI-4 alkyl)4, and the like.

[0149] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be understood that the compounds described herein also include the quatemization of any basic nitrogencontaining groups they contain. In some embodiments, water or oil -soluble or dispersible products are obtained by such quatemization.Tautomers

[0150] In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH.Method of Treatment

[0151] Disclosed herein are methods of modulating helicase in a subject in need thereof, comprising administering to the subject a compound described herein, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0152] Disclosed herein are methods of inhibiting helicase in a subject in need thereof, comprising administering to the subject a compound described herein, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0153] Disclosed herein are methods of modulating DHX9 in a subject in need thereof, comprising administering to the subject a compound described herein, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0154] Disclosed herein are methods of inhibiting DHX9 in a subject in need thereof, comprising administering to the subject a compound described herein, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0155] Disclosed herein are methods of treating a disease or condition, comprising administering to a subject in need thereof a compound described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the disease or condition is associated with an overexpression of DHX9.

[0156] In some embodiments, the disease or condition is a cancer, a viral infection, or an autoimmune disease. In some embodiments, the disease or condition is cancer.

[0157] In some embodiments, the cancer is bladder cancer, blood cancer, bone cancer, brain cancer, breast cancer, colorectal cancer, endometrial cancer, gastric cancer, head and neck cancer, hematopoieticWSGR Docket No. 69600-701.601cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, or soft-tissue cancer.

[0158] In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is Ewing’s sarcoma.

[0159] In some embodiments, the cancer is a microsatellite instable (MSI) cancer. In some embodiments, the cancer is MSI-high cancer. In other embodiments, the cancer is MSI-low cancer. MSI is determined by PCR analysis of 5 different nucleotide repeats, which is dependent on the cancer type. MSI-low cancers are characterized by instability at only 1 of the 5 sites; while MSI-high cancers are characterized by instability at 2 or more of the 5 sites.

[0160] MSI-high cancer is additionally characterized by defective mismatch repair (dMMR). For example, dMMR in colorectal cancer can be determined by MLH1 promoter hypermethylation, rendering MLH1 inactive, which comprises about 80-90% of MSI-high colorectal cancers. MSI-high colorectal cancer with inactivated MLH1 is also named sporadic MSI-high colorectal cancer. Alternatively, dMMR can be determined by immunohistochemistry mutation status of MLH1, MSH2, MSH6, MSH3, PMS1 and / or PMS2 mismatch repair (MMR) proteins. In MSI-high colorectal cancer, MLH1 and MSH2 are the 2 predominantly mutated MMR proteins. They are mutated in about 10-20% of MSI-high colorectal cancers. MSI-high colorectal cancers with these mutations are also known as Lynch Syndrome cancers.

[0161] In some embodiments, the cancer is a MSI cancer and / or has mutations or defects in DNA mismatch repair (MMR), and / or mutations or defects in RNA splicing and the kinetochore complex.

[0162] In some embodiments, the compounds described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, are used to decrease the expression or activity of DHX9, or to otherwise affect the properties and / or behavior of DHX9 in a cell. In some embodiments, the disclosure includes a method of decreasing the expression or activity of DHX9, or to otherwise affect the properties and / or behavior of DHX9 in a subject comprising administering to said subject an effective amount of at least one compound described herein, or a pharmaceutically acceptable salt or stereoisomer thereof.Dosing

[0163] In certain embodiments, the compositions containing the compound(s) described herein are administered for therapeutic treatments. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient’s health status, weight, and response to the drugs, and the judgment of the treating physician.Routes of Administration

[0164] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. In addition, by way of example only, parenteral delivery includes intramuscular,WSGR Docket No. 69600-701.601subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.Pharmaceutical Compositions / F ormulat ions

[0165] The compounds described herein are administered to a subject in need thereof, either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice. In some embodiments, the compounds described herein are administered to animals.

[0166] In another aspect, provided herein are pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, and at least one pharmaceutically acceptable excipient. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N. Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkinsl999), herein incorporated by reference for such disclosure.EXAMPLES

[0167] The following examples are offered to illustrate, but not to limit the claimed invention. The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope.

[0168] In some embodiments, a compound of the present disclosure is made from racemic starting materials (and / or intermediate) and separated into the individual enantiomers by chiral chromatography as an intermediate or final product. Unless indicated, it is understood that the absolute configuration of the separated intermediates or final compounds is not determined. Unless indicated, it is understood that the absolute stereochemistry of the enantiomers as drawn is arbitrarily assigned.

[0169] The following synthetic schemes are provided for purposes of illustration, not limitation. The following examples illustrate the various methods of making compounds described herein. It is understood that one skilled in the art may be able to make these compounds by similar methods or by combining other methods known to one skilled in the art. It is also understood that one skilled in the art would be able to make, in a similar manner as described below by using the appropriate starting materials and modifying the synthetic route as needed. In general, starting materials and reagents can be obtained from commercial vendors or synthesized according to sources known to those skilled in the art or prepared as described herein.WSGR Docket No. 69600-701.601Intermediate synthesis3-Chloro-5-(3,3-difluoroazetidin-l-yl)aniline (MMC2-intl5)l-(3-ChIoro-5-nitrophenyI)-3,3-difluoroazetidine (compound 2)

[0170] In a sealed tube, l-chloro-3-fluoro-5-nitrobenzene (6.0 g, 34.18 mmol, 1.0 equiv), 3,3-difluoroazeti dine hydrochloride (6.64 g, 51.27 mmol, 1.5 equiv) andDIEA(17.86 mL, 102.54 mmol, 3.0 equiv) in DMSO (120 mL) was stirred at 135 °C for 24 hours. The mixture was extracted with EtOAc (150 mL) and washed with H2O (100 mLx 3). The combined organic layer was washed with brine (100 mL x 2), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 28% EA in PE to give l-(3-chloro-5-nitrophenyl)-3,3-difluoroazetidine (6.5 g, 26.15 mmol, crude) as a yellow solid. The crude adduct was used for the next step without further purification.3-Chloro-5-(3,3-difluoroazetidin-l-yl)aniline (MMC2-intl5)

[0171] To asolution of l-(3-chloro-5-nitrophenyl)-3,3-difluoroazetidine (6.5 g, 26.15 mmol, 1.0 equiv) in EtOH / H2O (150 mL / 30 mL) in a sealed tube was added Fe (8.76 g, 156.9 mmol, 6.0 equiv) and NH4CI (16.79 g, 313.8 mmol, 12.0 equiv). Then the mixture was stirred at 90 °C for 1 hour. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 5% MeOH in DCM to give 3-chloro-5-(3,3-difluoroazetidin-l-yl)aniline (3.5 g, 16.01 mmol, 61.2%) as ayellow oil. LCMS m / z = 219.0 (M+H)+.5-Fluoro-Nl-(oxetan-3-yl)benzene-l,3-diamine (MMC2-int49)Fj (1.0 equiv)Fe (6.0 equiv) Ij5) DIEA (3.0 equiv) NH4CI (12.0 equiv) O2N^^ T DMSO, 130 °C, 16 hsealed tubeMMC2-int49 N-(3-Fluoro-5-nitrophenyl)oxetan-3-amine (compound 2)

[0172] To asolution of l,3-difluoro-5-nitrobenzene (1.0 g, 6.29 mmol, 1.0 equiv) and oxetan-3 -amine hydrochloride (689.0 mg, 6.29 mmol, 1.0 equiv) in DMSO (5 mL) in a sealed tube was added DIEA (3.28 mL, 18.87 mmol, 3.0 equiv). The solution was stirred at 130 °C for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure to give N-(3-fluoro-5-nitrophenyl)oxetan-3-amine (1.0 g crude) as ayellow oil. This crude adduct was used for the next step without further purification.5-Fluoro-N1-(oxetan-3-yl)benzene-l,3-diamineWSGR Docket No. 69600-701.601

[0173] To a solution of N-(3-fluoro-5-nitrophenyl)oxetan-3-amine (1.0 g, 4.72 mmol, 1.0 equiv) in EtOH / H2O (15 mL / 5 mL) was added Fe (1.58 g, 28.3 mmol, 6.0 equiv) and NH4CI (3.0 g, 56.6 mmol, 12.0 equiv). Then the mixture was stirred at 80 °C for 1 hour. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 25 % EA inPE to give 5-fluoro-Nl-(oxetan-3-yl)benzene-l,3-diamine (100.0 mg, 0.55 mmol, 11.6%) as a black oil. LCMS m / z = 183.0 (M+H)+.5-Chloro-Nl-(oxetan-3-yl)benzene-l,3-diamine (MMC2-intl6)N-(3-ChIoro-5-nitrophenyI)oxetan-3-amine (compound 2)

[0174] In a sealed tube, 1 -chi oro-3-fluoro-5-nitrobenzene (200.0 mg, 1.14 mmol, 1.0 equiv), oxetan-3-amine hydrochloride (187.0 mg, 1.71 mmol, 1.5 equiv) and DIEA (0.59 mL, 3.42 mmol, 3.0 equiv) in DMSO (5 mL) was stirred at 110 °C for 16 hours. The mixture was extracted with EtOAc (50 m) and diluted with H2O (30 mL x 3). The combined organic layer was washed with brine (30 mL x 2), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 28% EA in PE to give N-(3-chloro-5-nitrophenyl)oxetan-3-amine (150.0 mg, 0.66 mmol, 57%) as a yellow solid. The crude adduct was used for the next step without further purification. LCMS m / z = 229.1 (M+H)+.5-Chloro-Nl-(oxetan-3-yl)benzene-l,3-diamine

[0175] To a solution of N-(3-chloro-5-nitrophenyl)oxetan-3-amine (150.0 mg, 0.66 mmol, 1.0 equiv) in EtOH / H2O (8 mL / 2 mL) was added Fe (220.0 mg, 3.94 mmol, 6.0 equiv) and NH4CI (437.0 mg, 7.87 mmol, 12.0 equiv). Then the mixture was stirred at 90 °C for 1 hour. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 5% MeOH in DCM to give 5-chloro-Nl-(oxetan-3-yl)benzene-l,3-diamine (115.0 mg, 0.58 mmol, 88%) as a yellow oil. LCMS m / z = 199.1 (M+H)+.5-Bromo-Nl-(oxetan-3-yl)benzene-l,3-diamine (MMC2-int47)PO HCIH2N(15 euiv)N-(3-Bromo-5-nitrophenyl)oxetan-3-amine (compound 2)

[0176] In a sealed tube, to amixture of l-bromo-3-fluoro-5-nitrobenzene (1.0 g, 4.54 mmol, 1.0 equiv) and oxetan-3 -amine hydrochloride (747 mg, 6.82 mmol, 1.5 equiv) in DMSO (14 mL) was added DIEA (1.76 g, 13.64 mmol, 3.0 equiv) under Argon atmosphere. Then the mixture was stirred at 130 °C for 16WSGR Docket No. 69600-701.601hours. The reaction was diluted with H2O (60 mL x 3) and extracted with EtOAc (60 mL). The combined organic layer was washed with brine (40 mL x 3), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 25% EtOAc in PE to giveN-(3-bromo-5-nitrophenyl)oxetan-3-amine (313.0 mg, 1.15 mmol, 25%) as ayellow solid. LCMS m / z = 275.0 (M+H)+.5-Bromo-Nl-(oxetan-3-yl)benzene-l,3-diamine

[0177] To a solution of N-(3-bromo-5-nitrophenyl)oxetan-3-amine (313.0 mg, 1.15 mmol, 1.0 equiv) in EtOH / H2O (8 mL / 2 mL) was added Fe (384.0 mg, 6.87 mmol, 6.0 equiv) and NH4CI (763.0 mg, 13.75 mmol, 12.0 equiv). Then the mixture was stirred at 80 °C for 1 hour. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 4% MeOH in DCM to give 5-bromo-Nl-(oxetan-3-yl)benzene-l,3-diamine (268.0 mg, 1.10 mmol, 96%) as ayellow oil. LCMS m / z = 245.0 (M+H)+.Large scale synthesis of 5-Bromo-Nl-(oxetan-3-yI)benzene-l,3-diamine (MMC2-int47)N-(3-Bromo-5-nitrophenyI)oxetan-3-amine (compound 2)

[0178] In a sealed tube, to a mixture of l-bromo-3-fluoro-5-nitrobenzene (25.0 g, 113.64 mmol, 1.0 equiv) and oxetan-3-amine hydrochloride (20.7 g, 284.09 mmol, 2.5 equiv) in DMSO (125 mL) was added DIEA (36.6 g, 284.09 mmol, 2.5 equiv) under Argon atmosphere. Then the mixture was stirred at 110 °C for 16 hours. The reaction was diluted with H2O (700 mL x 3) and extracted with EA (500 mL x 2). The combined organic layer was washed with brine (400 mL x 2), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 25% EA in PE to give A-(3-bromo-5-nitrophenyl)oxetan-3-amine (30.0 g, 109.89 mmol, 97%) as a yellow solid.5-Bromo-Nl-(oxetan-3-yl)benzene-l,3-diamine (MMC2-int47)

[0179] To a solution of / V-(3-bromo-5-nitrophenyl)oxetan-3-amine (30.0 g, 109.89 mmol, 1.0 equiv) in EtOH / H2O (400 mL / 100 mL) was added Fe (36.8 g, 659.34 mmol, 6.0 equiv) and NH4CI (70.54 g, 1318.68 mmol, 12.0 equiv). Then the mixture was stirred at 80 °C for 4 hours. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 20% EA in DCM to give 5-bromo- / Vl-(oxetan-3-yl)benzene- 1,3 -diamine (18.0 g, 74.04 mmol, 67%) as ayellow oil.5-Chloro-Nl-(3-methyloxetan-3-yl)benzene-l,3-diamine (MMC2-int88)equiv)Pd2(dba)3(0.1 equiv)1 2 MMC2-int88 N-(3-chloro-5-nitrophenyl)-3-methyloxetan-3-amine (compound 2)WSGR Docket No. 69600-701.601

[0180] To a solution of l-bromo-3-chloro-5-nitrobenzene (4.0 g, 16.92 mmol, 1.0 equiv) in 1,4-di oxane (48 mL) ina sealed tube was added 3-methyloxetan-3-amine (1.03 g, 11.84 mmol, 2.0 equiv), Xantphos (1.96 g, 3.38 mmol, 0.2 equiv), Pd2(dba)3 (1.55 g, 1.69 mmol, 0.1 equiv) and NaOtBu (3.25 g, 33.83 mmol, 2.0 equiv) under Argon atmosphere. The mixture was stirred at 100 °C for 16 hours. The reaction was filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 5% EtOAc in DCMto giveN-(3-chloro-5-nitrophenyl)-3-methyloxetan-3-amine (1.15 g, 4.74 mmol, 28%) as a yellow solid. LCMS m / z = 243.1 (M+H)+.5-Chloro-Nl-(3-methyloxetan-3-yl)benzene-l,3-diamine

[0181] To a solution of N-(3-chloro-5-nitrophenyl)-3-methyloxetan-3-amine (1.15 g, 4.74 mmol, 1.0 equiv) in EtOH / H2O (28 mL / 7 mL) was added Fe (1.59 g, 28.43 mmol, 6.0 equiv) and NH4CI (3.15 g, 56.83 mmol, 12.0 equiv). Then the mixture was stirred at 80 °C for 1 hour. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 40% EtOAc in DCM to give 5-chloro-Nl-(3-methyloxetan-3-yl)benzene-l,3-diamine (741.0 mg, 3.48 mmol, 73%) as ayellow oil. LCMS m / z = 213.1 (M+H)+.1H NMR (400 MHz, DMSO-d6) 55.99 (s, 1H), 5.84 (t, J= 1.8 Hz, 1H), 5.58 (t, J= 2.0 Hz, 1H), 5.47 (t, J=2.0Hz, 1H), 5.09 (s, 2H), 4.55 (d, J = 5.6 Hz, 2H), 4.40 (d, J= 5.8 Hz, 2H), 1.52 (s, 3H).5-Chloro-N1-(3-(trifluoromethyl)oxetan-3-yl)benzene-l,3-diamine (MMC2-int89)N-(3-ChIoro-5-nitrophenyI)-3-(trifluoromethyI)oxetan-3-amine (compound 3)[00182JA solution of l-bromo-3-chloro-5-nitrobenzene (200.0 mg, 0.85 mmol, 1.0 equiv) and 3-(trifluoromethyl)oxetan-3 -amine (105.0 mg, 0.59 mmol, 0.7 equiv) in dioxane (5 mL) was added Pd2(dba)3 (78 mg, 0.08 mmol, 0.1 equiv) and XPhos (81.0 mg, 0.17 mmol, 0.2 equiv) and tBuONa (78.0 mg, 1.7 mmol, 2.0 equiv). The solution was stirred at 100 °C for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 25 % EtOAc in PE to give N-(3-chloro-5-nitrophenyl)-3- (trifluoromethyl)oxetan-3-amine (160.0 mg, 0.54 mmol, 63.5%) as ayellow solid. LCMS m / z = 295.0 (M-H)-.5-Chloro-N1-(3-(trifluoromethyl)oxetan-3-yl)benzene-l,3-diamine

[0183] To a solution of N-(3-chloro-5-nitrophenyl)-3-(trifluoromethyl)oxetan-3-amine (160.0 mg, 0.54 mmol, l. O equiv) in EtOH / H2O (6 mL / 2 mL) was added Fe (182.0 mg, 3.24 mmol, 6.0equiv) and NH4Cl (343.0 mg, 6.48 mmol, 12.0 equiv). Then the mixture was stirred at 80 °C for 1 hour. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica columnWSGR Docket No. 69600-701.601chromatography eluting with 25 % EtOAc in PE to give S-chloro-N'-iS-itrifluoromethyljoxetan-S-yl)benzene- 1,3 -diamine (60.0 mg, 0.25 mmol, 42.6 %) as ayellow solid. LCMS m / z = 267.1 (M+H)+.5-ChIoro-Nl-(l-(fluoromethyI)cyclopropyl)benzene-l,3-diamine (MMC2-intl45)3-Chloro-N-(l-(fluoromethyl)cyclopropyl)-5-nitroaniline (compound 2)

[0184] To a solution of l-bromo-3-chloro-5-nitrobenzene (300.0 mg, 1.28 mmol, 1.0 equiv) in dioxane (15 mL) in a sealed tube was added 1 -(fluoromethyl)cy cl opropan-1 -amine hydrochloride (200.0 mg, 1.92 mmol, 1.5 equiv), Xantphos (148.0 mg, 0.256 mmol, 0.2 equiv) andNaOtBu (250.0 mg, 2.56 mmol, 2.0 equiv), and Pd2(dba)3 (234 mg, 0.256 mmol, 0.1 equiv) under Argon atmosphere. Then the mixture was stirred at 100 °C for 16 hours. The mixture was diluted with H2O (40 mL x 3) and extracted with EtOAc (30 mL). The combined organic layer was washed with brine (30 mL x 2), dried over Na2SO4, and concentrated under reduced pressure. The crude adduct was used directly in the next step without further purification.5-ChIoro-Nl-(l-(fhioromethyI)cyclopropyl)benzene-l,3-diamine

[0185] To a mixture of the crude N-(3-chloro-5-nitrophenyl)oxetan-3-amine in EtOH / H2O (10 mL / 5 mL) was added Fe (414.0 mg, 7.68 mmol, 6.0 equiv) and NH4CI (829.0 mg, 15.36 mmol, 12.0 equiv). Then the mixture was stirred at 80 °C for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 5% MeOH in DCM to give 5 -chloro-Nl-(l-(fhroromethyl)cyclopropyl)benzene-l,3-diamine (10.0 mg, 0.046 mmol, 3.6%) as ayellow oil. LCMS m / z = 215.1 (M+H)+.5-Chloro-Nl-(3-(fluoromethyl)oxetan-3-yl)benzene-l,3-diamine (MMC2-intl37)1 2 MMC2-int137 Methyl N-(3-chloro-5-nitrophenyl)-3-(fluoromethyl)oxetan-3-amine (compound 2)

[0186] To a solution of methyl l-bromo-3-chloro-5-nitrobenzene (500.0 mg, 2.1 mmol, 1.0 equiv) in dioxane (10 mL) was added 3-(fluoromethyl)oxetan-3-amine (229.0 mg, 2.1 mmol, 1.0 equiv), xantphos (243.0 mg, 0.42 mmol, 0.2 equiv) and Pd2(dba)3 (192 mg, 0.21 mmol, 0.1 eq) andNaOtBu (103 mg, 1.38 mmol, 3.0 equiv). Then the mixture was stirred at 90 °C for 16 hours. The residue was purified by silica column chromatography eluting with 25% EtOAc in PE to give methyl N-(3-chloro-5-nitrophenyl)-3-(fluoromethyl)oxetan-3-amine (300.0 mg, 1.15 mmol, 55%).WSGR Docket No. 69600-701.6015-Chloro-Nl-(3-(fluoromethyl)oxetan-3-yl)benzene-l,3-diamine

[0187] To a solution of N-(3-chloro-5-nitrophenyl)-3-(fluoromethyl)oxetan-3-amine (400.0 mg, 1.53 mmol, 1.0 equiv) in EtOH / H₂O (10 mL / 2 mL) was added Fe (514.0 mg, 9.1 mmol, 6.0 equiv) and NH₄Cl (973.0 mg, 18.36 mmol, 6.0 equiv). Then the mixture was stirred at 80 °C for 1 hour. This reaction is filtered to produce a crude product and purified silica column chromatography eluting with 25% EtOAc in PE give 5-chloro-Nl-(3-(fluoromethyl)oxetan-3-yl)benzene-l,3-diamine (200.0 mg, 0.86 mmol, 56%). LCMS m / z = 230.9 (M+H)+.5-ChIoro-Nl-(l,l,l-trifluoropropan-2-yI)benzene-l,3-diamine (compound 3)3-ChIoro-5-nitro-N-(l,l,l-trifhioropropan-2-yI)aniIine (compound 2)

[0188] To a solution of l-bromo-3-chloro-5-nitrobenzene (200.0 mg, 0.85 mmol, 1.0 equiv) and 1,1,1-trifluoropropan-2-amine (95.0 mg, 0.85 mmol, 1.0 equiv) in dioxane (2 mL) in a sealed tube was added Pd2(dba)3 (77.0 mg, 0.08 mmol, 0.1 equiv) and XPhos (81.0 mg, 0.17 mmol, 0.2 equiv) and tBuONa (82.0 mg, 3.4 mmol, 4.0 equiv). The solution was stirred at 100 °C for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure to give 3-chloro-5-nitro-N-(l, l,l-trifluoropropan-2-yl)aniline (20.0 mg, crude) as a yellow solid.5-chIoro-Nl-(l,l,l-trifluoropropan-2-yI)benzene-l,3-diamine (compound 3)

[0189] To asolutionof3-chloro-5-nitro-N-(l,l,l-trifluoropropan-2-yl)aniline(20.0mg,0.07 mmol, 1.0 equiv) in EtOH / H₂O (2 mL / 1 mL) was added Fe (25.0 mg, 0.45 mmol, 6.0 equiv) and NH4CI (47.0 mg, 0.89 mmol, 12.0 equiv). Then the mixture was stirred at 80 °C for 1 hour. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 25 % EtOAc in PE to give 5 -chi oro-N1-(l,l,l-trifluoropropan-2-yl)benzene- 1,3 -diamine (17.0 mg, 0.07 mmol, 100 %) as a yellow oil. LCMS m / z = 267.1 (M+H)+.5-Chloro-N1-(2,2,2-trifluoroethyl)benzene-l,3-diamine (MMC2-int43)N-(3-ChIoro-5-nitrophenyI)-2,2,2-trifluoroacetamide (compound 2)WSGR Docket No. 69600-701.601

[0190] To a solution of 3 -chi oro-5 -nitroaniline (200.0 mg, 1.16 mmol, 1.0 equiv) in THF (5 mL) was added TFAA (0.32 mL, 2.32 mmol, 3.0 equiv) and TEA (0.32 mL, 2.32 mmol, 3.0 equiv). The mixture was stirred at 50 °C for 16 hours. The mixture was concentrated under reduced pressure and used for the next step without further purification. LCMS m / z =266.9 (M+H)+.3-Chloro-5-nitro-N-(2,2,2-trifluoroethyl)aniline (compound 3)

[0191] To asolution ofN-(3-chloro-5-nitrophenyl)-2,2,2-trifluoroacetamide (200.0 mg, 1.16 mmol, 1.0 equiv) in THF (3 mL) was added 1.0 M solution of BH3. THF (3.72 mL, 3.72 mmol, 5.0 equiv). Then the mixture was stirred at 50 °C for 16 hours. The mixture was filtered and concentrated under reduced pressure. The residue was used directly for the next step without further purification. LCMS m / z =253.0 (M-H)'.5-Chloro-N1-(2,2,2-trifluoroethyl)benzene-l,3-diamine

[0192] To a solution of 3-chloro-5-nitro-N-(2,2,2-trifluoroethyl)aniline (150.0 mg, 0.59 mmol, 1.0 equiv) in EtOH / H₂O (5 mL / 2 mL) was added Fe (198.0 mg, 3.54 mmol, 6.0 equiv) and NH4CI (382.0 mg, 7.08 mmol, 12.0 equiv). Then the mixture was stirred at 80 °C for 1 hour. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 7% MeOH in DCM to give 5-chloro-N1-(2,2,2-trifluoroethyl)benzene-l,3-diamine (100.0 mg, 0.45 mmol, 75%) as a yellow oil. LCMS m / z =225.1 (M+H)+.5-Chloro-N1-(2,2-difluoroethyl)benzene-1,3-diamine (MMC2-int44)N-(3-Chloro-5-nitrophenyl)-2,2-difluoroacetamide (compound 3)

[0193] To asolution of 3 -chi oro-5 -nitroaniline (300.0 mg, 1.74 mmol, 1.0 equiv) and 2,2-difluoroacetic acid (184.0 mg, 1.91 mmol, 1.1 equiv) in DCM (10 mL) was added Pyridine (0.29 mL, 3.48 mmol, 2.0 equiv) and POCI3 (0.26 mL, 2.61 mmol, 1.5 equiv). The mixture was stirred at 25 °C for 2 hours. The mixture added water (10 mL) and extracted with DCM (10 mL x 2), the organic layer was collected and concentrated under reduced pressure to give N-(3-chloro-5-nitrophenyl)-2,2-difluoroacetamide (450.0 mg, crude) and used directly for the next step without further purification. LCMS m / z = 249.0 (M-H)'.3-Chloro-N-(2,2-difluoroethyl)-5-nitroaniline (compound 4)

[0194] To asolution of N-(3-chloro-5-nitrophenyl)-2,2-difluoroacetamide (450.0 mg, 1.79 mmol, 1.0 equiv) in THF (3 mL) was added 1.0 M solution of BH3. THF (8.96 mL, 8.96 mmol, 5.0 equiv). Then theWSGR Docket No. 69600-701.601mixture was stirred at 70 °C for 16 hours. The mixture was quenched with CH3OH (10 mL) and concentrated under reduced pressure to give 3-chloro-N-(2,2-difluoroethyl)-5-nitroaniline (350.0 mg, crude). The crude was used directly for the next step without further purification. LCMS m / z = 237.1 (M+H)+.5-ChIoro-Nl-(2,2-difluoroethyI)benzene-l,3-diamine

[0195] To a solution of 3-chloro-N-(2,2-difluoroethyl)-5-nitroaniline (350.0 mg, 1.48 mmol, 1.0 equiv) in EtOH / H₂O (10 mL / 2 mL) was added Fe (497.0 mg, 8.88 mmol, 6.0 equiv) and NH4CI (941.0 mg, 17.76 mmol, 12.0 equiv). Then the mixture was stirred at 80 °C for 1 hour. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 7% MeOH in DCM to give 5-chloro-Nl-(2,2-difluoroethyl)benzene-l,3-diamine (280 mg, 1.36 mmol, 92%) as a yellow oil. LCMS m / z: 207.1(M+H)+.3-Chloro-5-(oxetan-3-yloxy)aniline (MMC2-int243)3-(3-Chloro-5-nitrophenoxy)oxetane (compound 2)

[0196] To a mixture of 3 -chi oro-5 -nitrophenol (500.0 mg, 2.88 mmol, 1.0 equiv), loxetan-3-ol (213.0 mg, 2.88 mmol, 1.0 equiv) and PPhs (906.0 mg, 3.46 mmol, 1.2 equiv) in toluene (25 mL) was added DIAD (757.0 mg, 3.74 mmol, 1.3 equiv) under Argon atmosphere. Then the mixture was stirred at 80 °C for 16 hours. The reaction was concentrated under reduced pressure to give 3-(3-chloro-5-nitrophenoxy)oxetane (660.0 mg crude) as a yellow oil. The crude adduct was used for the next step without further purification.3-Chloro-5-(oxetan-3-yloxy)aniline

[0197] To a solution of 3-(3-chloro-5-nitrophenoxy)oxetane (660.0 mg, 2.87 mmol, 1.0 equiv) in EtOH / H₂O (20 mL / 4 mL) was added Fe (963.0 mg, 17.24 mmol, 6.0 equiv) and NH₄Cl (1.91 g, 34.49 mmol, 12.0 equiv). Then the mixture was stirred at 80 °C for 1 hour. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 30% EtOAc in PE to give 3-chloro-5-(oxetan-3-yloxy)aniline (438.0 mg, 2.19 mmol, 76%) as a brown oil. LCMS m / z = 241.0 (M+41+H)+.5-Chloro-Nl-(tetrahydrofuran-3-yl)benzene-l,3-diamine (MMC2-int254)MMC2-int254 N-(3-Chloro-5-nitrophenyl)tetrahydrofuran-3-amine (compound 2)WSGR Docket No. 69600-701.601

[0198] To a mixture of l-chloro-3-fluoro-5-nitrobenzene (500.0 mg, 2.86 mmol, 1.0 equiv) and tetrahydrofuran-3-amine (374.0 mg, 4.29 mmol, 1.5 equiv) in DMSO (12 mL) in a sealed tube was added DIEA (1.11 g, 8.59 mmol, 3.0 equiv). Then the mixture was stirred at 130 °C for 16 hours. The reaction was diluted with H2O (60 mL x 3) and extracted with EA (40 mL x 2). The combined organic layer was washed with brine (40 mL x 2), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 45% EtOAc in PE to give N-(3-chloro-5-nitrophenyl)tetrahydrofuran-3-amine (527.0 mg, 2.17 mmol, 76%) as ayellow solid. LCMS m / z = 243.0 (M+H)+.5-Chloro-Nl-(tetrahydrofuran-3-yl)benzene-l,3-diamine

[0199] To a solution of N-(3-chloro-5-nitrophenyl)tetrahydrofuran-3-amine (527.0 mg, 2.17 mmol, 1.0 equiv) in EtOH / H₂O (15 mL / 4 mL) was added Fe (728.0 mg, 13.03 mmol, 6.0 equiv) and NH₄Cl (1.45 g, 26.06 mmol, 12.0 equiv). Then the mixture was stirred at 80 °C for 1 hour. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 4% MeOH in DCM to give 5-chloro-Nl-(tetrahydrofuran-3-yl)benzene-l,3-diamine (450.0 mg, 2.11 mmol, 97%) as a brown oil. LCMS m / z = 213.0 (M+H)+.5-Bromo-Nl-(tetrahydrofuran-3-yl)benzene-l,3-diamine (MMC2-int271)N-(3-Bromo-5-nitrophenyl)tetrahydrofuran-3-amine (compound 2)

[0200] To a solution of l-bromo-3-fluoro-5-nitrobenzene (2.0 g, 9.19 mmol, 1.0 equiv) in DMSO (10 mL) were added tetrahydrofuran-3 -amine (1.19 g, 13.67 mmol, 2.5 equiv) and DIEA (4.79 mL, 4.79 mmol, 3 equiv). The mixture was heated to 130 °C for 16 hours. The reaction mixture was poured into water (60 mL) and extracted with EtOAc (20 x 3 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 30% EtOAc in PE to giveN-(3-bromo-5-nitrophenyl)oxetan-3-amine (1.7 g, 5.9 mmol, 64.2%) as ayellow solid. LCMS m / z = 289.0 (M+H)+.5-Bromo-Nl-(tetrahydrofuran-3-yI)benzene-l,3-diamine

[0201] To a solution of N-(3-bromo-5-nitrophenyl)tetrahydrofuran-3-amine (1.7 g, 5.9 mmol, 1 equiv) in EtOH / H₂O (20mL / 10 mL) were added Fe (1.95 g, 35.45 mmol, 6 equiv) and NH4CI (3.9 g, 70.28 mmol, 12 equiv). Then the mixture was stirred at 80 °C for 3 hours. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 4% MeOH in DCM to give 5-bromo-Nl-(tetrahydrofuran-3-yl)benzene-l,3-diamine (0.97 g, 3.77 mmol, 63.8%) as a brown oil. LCMS m / z = 259.0 (M+H)+.5-Iodo-Nl-(tetrahydrofuran-3-yl)benzene-l,3-diamine (MMC2-int287)WSGR Docket No. 69600-701.601,0 (1.5 equiv)N-(3-Iodo-5-nitrophenyl)tetrahydrofuran-3-amine (compound 2)

[0202] In a sealed tube, to a mixture of l-fluoro-3-iodo-5-nitrobenzene (1.0 g, 3.74 mmol, 1.0 equiv) and tetrahydrofuran-3-amine (489.0 mg, 5.62 mmol, 1.5 equiv) in DMSO (14 mL) was added DIEA (1.45 g, 11.24 mmol, 3.0 equiv). Then the mixture was stirred at 130 °C for 16 hours. The reaction was diluted with H2O (70 mL x 3) and extracted with EA (40 mL x 2). The combined organic layer was washed with brine (40 mL x 2), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 25% EtOAc in PE to give N-(3-iodo-5-nitrophenyl)tetrahydrofuran-3-amine (235.0 mg, 0.70 mmol, 19%) as a yellow oil. LCMS m / z = 335.0 (M+H)+.5-Iodo-Nl-(tetrahydrofuran-3-yI)benzene-l,3-diamine

[0203] To a solution of N-(3-iodo-5-nitrophenyl)tetrahydrofuran-3-amine (235.0 mg, 0.70 mmol, 1.0 equiv) in EtOH / H₂O (10 mL / 3 mL) was added Fe (236.0 mg, 4.22 mmol, 6.0 equiv) and NH4CI (468.0 mg, 8.44 mmol, 12.0 equiv). Then the mixture was stirred at 80 °C for 1 hour. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 4% MeOH in DCM to give 5-iodo-Nl-(tetrahydrofuran-3-yl)benzene-l,3-diamine (189.0 mg, 0.62 mmol, 89%) as ayellow oil. LCMS m / z = 305.0 (M+H)+. 'H NMR (400 MHz, CDCh) 5 6.46 (s, 1H), 6.39 (t, J= 1.6 Hz, 1H), 5.88 (t, J= 1.8 Hz, 1H), 4.02 - 3.97 (m, 1H), 3.96- 3.88 (m, 2H), 3.85 -3.80 (m, 1H), 3.67 (dd, J= 9.2, 2.8 Hz, 1H), 2.27 - 2.18 (m, 1H), 1.88 - 1.80 (m, 1H).3-Bromo-5-(oxetan-3-yloxy)aniline (Int266) / -■oA HCTBr (1.0 equiv) Br Br PPh3(1.2 equiv) J. Fe (6.0 equiv) DIAD (1.3 equiv) l| ] / "° NH4CI (12.0 equiv) OH t°l, 80 °C, 16 h O2N'X^<'O'>^ / EtOH / H2O, 80 °C, 1 h1 2 Int 266 3-(3-Chloro-5-nitrophenoxy)oxetane (compound 2)

[0204] To a mixture of 3 -bromo-5 -nitrophenol (622.0 mg, 2.88 mmol, 1.0 equiv), loxetan-3-ol (213.0 mg, 2.88 mmol, 1.0 equiv) and PPhs (906.0 mg, 3.46 mmol, 1.2 equiv) in toluene (25 mL) was added DIAD (757.0 mg, 3.74 mmol, 1.3 equiv) under Argon atmosphere. Then the mixture was stirred at 80 °C for 16 hours. The reaction was concentrated under reduced pressure to give 3-(3-bromo-5-nitrophenoxy)oxetane (786.0 mg) as ayellow oil. This crude adduct was used for the next step without further purification.3-Bromo-5-(oxetan-3-yloxy)anilineWSGR Docket No. 69600-701.601

[0205] To a solution of crude 3-(3-chloro-5-nitrophenoxy)oxetane (786.0 mg, 2.87 mmol, 1.0 equiv) in EtOH / H₂O (20 mL / 4 mL) was added Fe (963.0 mg, 17.24 mmol, 6.0 equiv) and NH₄Cl (1.91 g, 34.49 mmol, 12.0 equiv). Then the mixture was stirred at 80 °C for 1 hour. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 30% EtOAc in PE to give 3-bromo-5-(oxetan-3-yloxy)aniline (501.0 mg, 2.07 mmol, 72%) as a brown oil. LCMS m / z = 245.9 (M+H)+.6-Bromo-l-(oxetan-3-yl)-lH-indol-4- amine (MMC2-int205)Br1°BrBrJL (1.1 equiv) J Fe (6.0 equiv). I.f| Cs2CO3(2.0 equiv) [| NH4CI (12.0 equiv) f| O2N^ NH DMF.100 °C O2N^r^N-- / ^0EtOH / H20, 80 °C, 1 h H2N^r^N-Xy° \= / nW, 2 h L- / L— / 1 2 MMC2-int205 6-Bromo-4-nitro-l-(oxetan-3-yl)-lH-indole (compound 2)

[0206] To a solution of 6-bromo-4-nitro-lH-indole (500.0 mg, 2.0 mmol, 1.0 equiv) in DMF (5 mL) was added 3-iodooxetane (404.5 mg, 2.2 mmol, 1.1 equiv) and Cs2CO3 (1.35 g, 4.0 mmol, 2.0 equiv) under Argon atmosphere. Then the mixture was stirred at 110 °C for 2 hours. The residue was purified by silica column chromatography eluting with 20% EtOAc in PE to give 6-bromo-4-nitro-l-(oxetan-3-yl)-lH-indole (400.0 mg, 1.35 mmol, 67.5%) as a yellow solid.6-Bromo-l-(oxetan-3-yl)-lH-indol-4- amine

[0207] To a mixture of 6-bromo-4-nitro-l -(oxetan- 3-yl)- IH-indole (400.0 mg, 1.4 mmol, 1.0 equiv) in EtOH / H₂O (10 mL / 5 mL) was added Fe (784.0 mg, 14.0 mmol, 10.0 equiv) and NH4CI (756.0 mg, 14 mmol, 10.0 equiv). Then the mixture was stirred at 80 °C for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 50% EtOAc in PE to give 6-bromo-l-(oxetan-3-yl)-lH-indol-4-amine (170 mg, 0.64 mmol, 45.6%) as a yellow oil. LCMS m / z = 268.9 (M+H)+.( / ?)-5-Chloro- / Vl-(tetrahydrofuran-3-yl)benzene-l,3-diamine (MMC2-int291)(R)-N-(3-chIoro-5-nitrophenyI)tetrahydrofuran-3-amine (compound 2)

[0208] A mixture of l-chloro-3-fluoro-5-nitrobenzene (2.0 g, 11.4 mmol, 1.0 equiv) and (R)-tetrahydrofuran-3-amine (1.49 g, 17.1 mmol, 1.5 equiv), DIPEA (6.63 g, 51.4 mmol, 3.0 equiv) in DMSO (10 mL) was stirred at 130 °C for 16 hours. The mixture was diluted with H2O then extracted with EtOAc, the organic phase was concentrated under reduced pressure to afford ( / ?)-N-(3-chloro-5-nitrophenyl)tetrahydrofuran-3-amine (2.8 g, crude) as a yellow oil.(7?)-5-chloro-Nl-(tetrahydrofuran-3-yl)benzene-l,3-diamine (MMC2-int291)WSGR Docket No. 69600-701.601

[0209] A mixture of ( / ?)-N-(3-chloro-5-nitrophenyl)tetrahydrofuran-3-amine (2.8 g, 11.57 mmol, 1.0 equiv) andFe(6.47 g, 115.7 mmol, 10.0 equiv), NH4CI (6.13g, 115.7 mmol, 10.0 equiv) in EtOH (30 mL) and H2O (30 mL) was stirred at 80 °C for 2 hours. The mixture was concentrated under reduced pressure and the residue was purified by silica column chromatography eluting with 50% EtOAc in PE to afford (R)-5-chloro-Nl-(tetrahydrofuran-3-yl)benzene-1,3-diamine (1.16 g, 5.47 mmol, 47%) as ayellow oil. LCMS m / z = 213.0 (M+H)+.(5)-5-Bromo-Afl-(tetrahydrofuran-3-yl)benzene-l,3-diamine (MMC2-int290)(5)-A-(3-Bromo-5-nitrophenyl)tetrahydrofuran-3-amine (compound 2)

[0210] To a solution of l-bromo-3-fluoro-5-nitrobenzene (50 g, 227.27 mmol, 1.0 equiv) in DMSO (450 mL) were added (5)-tetrahydrofuran-3-amine (29.67 g, 340.91 mmol, 1.5 equiv) and DIEA (119 mL, 681.82 mmol, 3.0 equiv). The mixture was stirred at 130 °C for 48 hours. The reaction mixture was poured into H2O (2200 mL) and extracted with EtOAc (900 mL x 2). The organic layer was diluted with H2O (2000 mL x 3) and washed with brine (1600 mL x 2). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure to give (S)- / V-(3-bromo-5-nitrophenyl)tetrahydrofuran-3-amine (61.83 g, 215.35 mmol, 95%) as ayellow solid. LCMS m / z = 289.0 (M+H)+.(5)-5-Bromo-Afl-(tetrahydrofuran-3-yl)benzene-l,3-diamine (MMC2-int290)

[0211] To a solution of (5')-#-(3-bromo-5-nitrophenyl)tetrahydrofuran-3-amine (61.83 g, 215.35 mmol, 1 equiv) in EtOH / H₂O (400mL / 100 mL) were added Fe (72.16 g, 1292.12 mmol, 6.0 equiv) and NH4CI (143.40 g, 2584.24 mmol, 12.0 equiv). Then the mixture was stirred at 80 °C for 5 hours. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 50% (EA / DCM=1:1) in PE to give GS')-5-bromo-M-(tetrahydrofuran-3-yl)benzene- 1,3 -diamine (39.9 g, 155.17 mmol, 74%) as ayellow solid. LCMS m / z = 298.0 (M+H+42)+. > HNMR (400 MHz, DMSO-6) 85.97 (t, J= 1.8Hz, 1H), 5.93 (t, J= 1.8Hz, 1H), 5.76 - 5.73 (m, 2H), 5.06 (s, 2H), 3.86 - 3.75 (m, 3H), 3.72 - 3.66 (m, 1H), 3.48 - 3.44 (m, 1H), 2.15 - 2.07 (m, 1H), 1.75 -1.67 (m, 1H).5-Bromo-Afl-((3A,47?)-4-methoxytetrahydrofuran-3-yl)benzene-l,3-diamine (MMC2-int348)WSGR Docket No. 69600-701.601(3 / ?,- / A)-4-Aminotetrahydrofuran-3-ol (compound 2)[00212|Compound tert-butyl((35'.4 / ?)-4-hydroxytetrahydrofuran-3-yl)carbamate (3 g, 14.76 mmol, 1.0 equiv) was stirred in 25 mL DCM / TFA (4:1) at room temperature for 2 hours. The mixture was concentrated under reduced pressure to give (3 / ?.4N)-4-aminotetrahydrofuran-3-ol (1.52 g, crude) as a colorless oil. LCMS m / z = 104.2 (M+H)+.C? / ?,- / A)-4-(Dibenzylamino)tetiahydrofuian-3-ol (compound 3)

[0213] To a mixture of (3 / ?. LS)-4-aminotetrahydrofuran-3-ol (1.52 g, 14.76 mmol, 1.0 equiv) in ACN (25 mL) was added BnBr (5 g, 29.52 mmol, 2.0 equiv), K2CO3 (6.1 g, 44.28 mmol, 3.0 equiv) and TBAB (950 mg, 2.95 mmol, 0.2 equiv). Then the mixture was stirred at room temperature for 16 hours. The reaction was diluted with H2O (70 mL) and extracted with EA (40 mL x 2). The combined organic layer was washed with brine (50 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 37% EA in PE to give (3R, 4S)-4-(dibenzylamino)tetrahydrofuran-3-ol (2.8 g, 9.88 mmol, 67%) as a colorless oil. LCMS m / z = 284.2 (M+H)+.(3A,- / / ?)-N, N-Dibenzyl-4-methoxytetiahydrofuian-3- amine (compound 4)

[0214] To asolution of (3R,4S)-4-(dibenzylamino)tetrahydrofuran-3-ol (2.4g, 8.47 mmol, 1.0 equiv) in DMF (25 mL) were added NaH (305 mg, 12.71 mmol, 1.5 equiv) and Mel (1.8 g, 12.71 mmol, 1.5 equiv) slowly at 0 °C under Ar. The reaction was stirred at 0 °C for 2 hours, then mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 6% EA in PE to give (35'.4 / ?)-N. N-dibenzyl-4-methoxytetrahydrofuran-3-amine (2.5 g, 8.41 mmol, 98%) as a light yellow oil. LCMS m / z = 298.2 (M+H)+.(3A,- / / ?)-4- ethoxy tetrahydiofuran-3-amine hydrochloride (compound 5)

[0215] To asolution of (3S,4R)-N, N-dibenzyl-4-methoxytetrahydrofuran-3-amine (2.4 g, 8.07 mmol, 1.0 equiv) in THF (20 mL) were added Pd / C (2.57 g, 24.21 mmol, 3.0 equiv) and 2 MHC1 (40 mL, 75.45 mmol, 9.35 equiv). The mixture was stirred at 40 °C for 16 hours under H2 atmosphere. The resulting mixture was filtered through a Celite pad and concentrated under reduced pressure to give (3S.4R)-4-methoxytetrahydrofuran-3- amine hydrochloride (531 mg, 3.47 mmol, 43%) as ayellow oil. LCMS m / z = 118.2 (M+H)+.WSGR Docket No. 69600-701.601tert-Butyl (3-bromo-5-nitrophenyl)carbamate (compound 7)

[0216] To a mixture of 3 -bromo-5 -nitroaniline (1.0 g, 4.61 mmol, 1.0 equiv) in DCM (25 mL) was added DMAP (563 mg, 4.61 mmol, 1.0 equiv) and (Boc)2O (1.21 g, 5.53 mmol, 1.2 equiv). The mixture was stirred at 25 °C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica column chromatography eluting with 10% EA in PE to give tert-butyl (3-bromo-5-nitrophenyl)carbamate (1.43g, 4.51 mmol, 98%) as ayellow oil. LCMS m / z = 316.9 (M-H)‘. tert-Butyl (3-(((3A,4 / ?)-4-methoxytetrahydrofuran-3-yI)amino)-5-nitrophenyI)carbamate (compound 8)

[0217] To a mixture of tert-butyl (3-bromo-5-nitrophenyl)carbamate (1 g, 3.16 mmol, 1.0 equiv) and (3S,4R)-4-methoxytetrahydrofuran-3-amine hydrochloride (531 mg, 3.47 mmol, 1.1 equiv) in 1,4-di oxane (20 mL) was added Xphos Pd G3 (267 mg, 0.31 mmol, 0.1 equiv) and CS2CO3 (2.05 g, 6.32 mmol, 2.0 equiv) under Argon atmosphere. Then the mixture was stirred at 90 °C for 16 hours. The reaction was filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 33% EA in PE to give tert-butyl (3-(((3S.4 / ?)-4-methoxytetrahydrofuran-3-yl)amino)-5-nitrophenyl)carbamate (899 mg, 2.54 mmol, 80%) as ayellow solid.LCMS m / z = 298.2 (M-56+H)+.Nl-((AS',- / / ?)-4-IVIethoxytetrahydrofiiran-3-yl)-5-nitrobenzene-l,3-diamine (compound 9)

[0218] tert-Butyl (3-(((3S.4R)-4-methoxytetrahydrofuran-3-yl)amino)-5-nitrophenyl)carbamate (899 mg, 2.54 mmol, 1.0 equiv) was stirred in 20 mL DCM / TFA (4:1) at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to afford N I -((AS’.4R)-4-methoxytetrahydrofuran-3-yl)-5-nitrobenzene-l,3-diamine (642 mg, crude) as a brown solid. LCMS m / z = 254.2 (M+H)+.(31S,, 7?)-N-(3-Bromo-5-nitrophenyl)-4-methoxytetrahydrofuran-3-amine (compound 10)

[0219] To a mixture of N I -((35'.4R)-4-methoxytetrahydrofuran-3-yl)-5-nitrobenzene- 1,3-diamine (642 mg, 2.53 mmol, 1.0 equiv) in DCM / H2O (10 mL / 10 mL) was added Bromotri chloromethane (2.5 g, 12.65 mmol, 5.0 equiv), NaNCL (873 mg, 12.65 mmol, 5.0 equiv) and AcOH (3 g, 50.6 mmol, 20.0 equiv). The mixture was stirred at room temperature for 16 hours. The reaction was diluted with H2O (50 mL) and extracted with DCM (40.0 mL x 2). The combined organic layer was washed with brine (40 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 19% EA in PE to give (AS'_ 4 / ?)-N-(3-bromo-5-nitrophen l)-4-methoxytetrahydrofuran-3-amine (140 mg, 0.44 mmol, 17%) as ayellow oil.5-Bromo-Nl-((31S,,4 / ?)-4-methoxytetrahydrofuran-3-yl)benzene-l,3-diainine (MMC2-int348)

[0220] To a solution of (3S,4R)-N-(3-bromo-5-nitrophenyl)-4-methoxytetrahydrofuran-3-amine (140 mg, 0.44 mmol, 1.0 equiv) in EtOH / H₂O (12 mL / 3 mL) were added Fe (148 mg, 2.65 mmol, 6.0 equiv) and NH4CI (282 mg, 5.28 mmol, 12.0 equiv). Then the mixture was stirred at 80 °C for 1 hour. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 3% MeOH in DCM to give 5-bromo-Nl-((35, 4R)-4-WSGR Docket No. 69600-701.601methoxytetrahydrofuran-3-yl)benzene-l,3-diamine (70 mg, 0.24 mmol, 56%) as a yellow solid. LCMS m / z = 287.1 (M+H)+.5-Bromo-A^l-((37?,4iS)-4-methoxytetrahydrofuran-3-yl)benzene-l,3-diamine (MMC2-int471)tert- Butyl (3-(((37?,45)-4-methoxytetrahydrofuran-3-yl)amino)-5-nitrophenyl)carbamate (compound 6)

[0221] To a mixture of tert-butyl (3-bromo-5-nitrophenyl)carbamate (4.13 g, 13.02 mmol, 1.0 equiv) and (3R, 4< S)-4-methoxytetrahydrofuran-3-amine hydrochloride (2.2 g, 14.32 mmol, 1.1 equiv) in 1,4-dioxane (100 mL) were added Xphos Pd G3 (1.1 g, 1.3 mmol, 0.1 equiv) and CS2CO3 (8.46 g, 26.04 mmol, 2.0 equiv) under Argon atmosphere. Then the mixture was stirred at 90 °C for 16 hours. The reaction was filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 27% EA in PE to give / c / 7- butyl (3-(((37?,4S)-4-methoxy tetrahydrofuran-3-yl)amino)-5-nitrophenyl)carbamate (3.03 g, 8.57 mmol, 66%) as a yellow solid.LCMS m / z = 298.1 (M+H-56)+. / Vl-((3 / ?,4A)-4-IVIethoxytetrahydrofuran-3-yl)-5-nitrobenzene-l,3-diamine (compound 7)

[0222] Compound tert-butyl (3-(((37?,4< S)-4-methoxytetrahydrofuran-3-yl)amino)-5-nitrophenyl)carbamate (3.0 g, 8.50 mmol, 1.0 equiv) was stirred in 30 mL DCM / TFA (4:1) at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to afford Al-((37?,4S)-4-methoxytetrahydrofuran-3-yl)-5-nitrobenzene-l,3-diamine (2.15 g, crude) as a yellow oil. LCMS m / z = 254.1 (M+H)+.(37?,45)-A-(3-Bromo-5-nitrophenyl)-4-methoxytetrahydrofuran-3-amine (compound 8)

[0223] To a mixture of Al -((3 / ?.45')-4-methoxytetrahydrofuran-3-yl)-5-nitrobenzene- 1,3-diamine (2.15 g, 8.50 mmol, 1.0 equiv) in DCM / H2O (20 mL / 20 mL) was added Bromotri chloromethane (8.42 g, 42.49 mmol, 5.0 equiv), NaNCh (2.9 g, 42.49 mmol, 5.0 equiv) and AcOH (9.7 mL, 169.96 mmol, 20.0 equiv). The mixture was stirred at room temperature for 16 hours. The reaction was diluted with H2O (50 mL) and extracted with DCM (40.0 mL x 2). The combined organic layer was washed with brine (40 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 14% EA in PE to give (3R,4S)-N-(3-bromo-5-nitrophenyl)-4-methoxytetrahydrofuran-3-amine (612 mg, 1.93 mmol, 23%) as a yellow oil.LCMS m / z = 318.0 (M+H)+.WSGR Docket No. 69600-701.6015-Bromo-N1-((3R,4S)-4-methoxytetrahydrofuran-3-yl)benzene-1,3-diamine (compound 9)

[0224] To a solution of (3R,4S)-N-(3-bromo-5-nitrophenyl)-4-methoxytetrahydrofuran-3-amine (600 mg, 1.89 mmol, 1.0 equiv) in EtOH / H2O (12 mL / 3 mL) were added Fe (625 mg, 11.36 mmol, 6.0 equiv) and NH4CI (1.2 g, 22.71 mmol, 12.0 equiv). Then the mixture was stirred at 90 °C for 2 hours. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 5% EA in DCM to give 5-bromo-N1-((3R,4S)-4-methoxytetrahydrofuran-3-yl)benzene-1,3-diamine (390 mg, 1.36 mmol, 72%) as a yellow oil. LCMS m / z = 289.0 (M+H)+.Example 1: N-(3-Chloro-5-(3,3-difluoroazetidin-1-yl)phenyl)-4-(3-methylpyridin-2-yl)thiophene-2-carboxamideMethyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (compound 5)

[0225] To a mixture of methyl 4-bromothiophene-2-carboxylate (1.0 g, 4.52 mmol, 1.0 equiv) and B2Pin2 (1.38 g, 5.43 mmol, 1.2 equiv) in 1,4-dioxane (15 mL) was added KOAc (1.33 g, 13.57 mmol, 3.0 equiv) and Pd(dppf)C12 (331.0 mg, 0.45 mmol, 0.1 equiv) under Argon atmosphere. Then the mixture was stirred at 100 °C for 2 h. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 7% EtOAc in PE to give methyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (500.0 mg, 1.88 mmol, 41%) as a yellow oil. LCMS m / z = 269.1 (M+H)+.Methyl 4-(3-methylpyridin-2-yl)thiophene-2-carboxylate (compound 6)

[0226] To a mixture of methyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (200.0 mg, 0.75 mmol, 1.0 equiv) and 2-bromo-3-methylpyridine (129.0 mg, 0.75 mmol, 1.0 equiv) in l,4-dioxane / H2O (10 mL / 2 mL) was added K2CO3 (310.0 mg, 2.25 mmol, 3.0 equiv) and Pd(dppf)C12 (55.0 mg, 0.07 mmol, 0.1 equiv). The mixture was stirred at 80 °C for 16 h. The mixture was filtered andWSGR Docket No. 69600-701.601concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 20% EtOAc in PE to give methyl 4-(3-methylpyridin-2-yl)thiophene-2-carboxylate (160.0 mg, 0.69 mmol, 92%) as a white solid. LCMS m / z = 234.1 (M+H)+.4-(3-Methylpyridin-2-yl)thiophene-2-carboxylic acid (compound 7)

[0227] To a solution of methyl 4-(3-methylpyridin-2-yl)thiophene-2-carboxylate (200.0 mg, 0.86 mmol, 1.0 equiv) in EtOH / H2O (5 mL / 1 mL) was added LiOH (62.0 mg, 2.58 mmol, 3.0 equiv). Then the mixture was stirred at room temperature for 1 hour. The mixture was adjusted pH to 6 with HC1 (2.0 N). The precipitated solids were collected by filtration and washed with H2O. This resulted in 4-(pyridin-2-yl)thiophene-2-carboxylic acid (100 mg, 0.46 mmol, 53%) as a white solid. LCMS m / z = 220.0 (M+H)+.N-(3-Bromo-5-chlorophenyl)-4-(3-methylpyridin-2-yl)thiophene-2-carboxamide

[0228] To a solution of 4-(3-methylpyridin-2-yl)thiophene-2-carboxylic acid (70.0 mg, 0.31 mmol, 1.0 equiv) in ACN (5 mL) was added 3-bromo-5-chloroaniline (65.0 mg, 0.31 mg, 1.0 equiv), TCFH (90.0 mg, 0.46 mmol, 1.5 equiv) andNMI (56.0 mg, 0.91 mmol, 3.0 equiv). Then the mixture was stirred at 25 °C for 2 hours. The residue was purified by silica column chromatography eluting with 20% EtOAc in PE to give N-(3-bromo-5-chlorophenyl)-4-(3-methylpyridin-2-yl)thiophene-2-carboxamide (80.0 mg, 0.19 mmol, 63%) as a white solid. LCMS m / z = 408.9 (M+H)+. 'H NMR (400 MHz, DMSO-d6) 8 10.91 (s, 1H), 8.68 (s, 1H), 8.65 (d, J = 5.2Hz, 1H), 8.36 (s, 1H), 8.14 (d, J= 7.2 Hz, 1H), 8.09 - 8.08 (m, 1H), 8.01 (t, J = 1.6 Hz, 1H), 7.68 - 7.60 (m, 1H), 7.46 (t, J = 1.6 Hz, 1H), 2.55 (s, 3H).N-(3-chloro-5-(3,3-difluoroazetidin-1-yl)phenyl)-4-(3-methylpyridin-2-yl)thiophene-2-carboxamide

[0229] To a solution ofN-(3-bromo-5-chlorophenyl)-4-(3-methylpyridin-2-yl)thiophene-2-carboxamide (84.0 mg, 0.20 mmol, 1.0 equiv) in dioxane (5 mL) was added 3, 3 -difluoroazetidine hydrochloride (26.0 mg, 0.20 mmol, 1.0 equiv), Xantphos (23.0 mg, 0.04 mmol, 0.2 equiv) and NaOtBu (40.0 mg, 0.41 mmol, 2.0 equiv), and Pd2(dba)3 (19.0 mg, 0.02 mmol, 0.1 equiv) under Ar. Then the mixture was stirred at 80 °C for 16 hours. The residue was purified by silica column chromatography eluting with 40% EtOAc in PE to give N-(3-chloro-5-(3,3-difluoroazetidin-l-yl)phenyl)-4-(3-methylpyridin-2-yl)thiophene-2-carboxamide (55.0 mg, 0.13 mmol, 65%). LCMS m / z = 419.6 (M+H)+.1H NMR (400 MHz, CD3OD) 8 8.71 (dd, J=6.0, 8.0Hz, 1H), 8.60 (d, J= 7.6 Hz, 1H), 8.32 (d, J= 1.2Hz, 1H), 8.24 (d, J = 6.0Hz, 1H), 8.00 (dd, J= 8.0, 6.0 Hz, 1H), 7.08 (dd, J= 13.2, 1.6 Hz, 2H), 6.57 (t, J= 1.6 Hz, 1H), 3.91 (t, J= 13.2 Hz, 2H), 3.70 (t, J= 13.2 Hz, 2H), 2.63 (s, 3H).19F NMR (377 MHz, CD3OD) 8 -108.40.Example 3: N-(3-Chloro-5-((3-methyloxetan-3-yl)amino)phenyl)-4-(3-methylpyridin-2-yl)thiophene-2-carboxamideWSGR Docket No. 69600-701.601

[0230] To a solution of 5-chloro-Nl-(3-methyloxetan-3-yl)benzene-l,3-diamine (MMC2-int88 - 100.0 mg, 0.47 mmol, 1.0 equiv) and 4-(3-methylpyridin-2-yl)thiophene-2-carboxylic acid (103.0 mg, 0.47 mmol, 1.0 equiv) in ACN (3 mL) was added TCFH (202.0 mg, 0.71 mmol, 1.5 equiv) and NMI (117.0 mg, 1.41 mmol, 3.0 equiv). Then the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and purified by prep-HPLC eluting with 0-40% ACN in H2O (0.1% NH4HCO3) to give N-(3-chloro-5-((3-methyloxetan-3-yl)amino)phenyl)-4-(3-methylpyridin-2-yl)thiophene-2-carboxamide (68.0 mg, 0.16 mmol, 35%). LCMS m / z = 414.1(M+H)+. 1H NMR (400 MHz, CD3OD) δ 8.42 (d, J= 4.2 Hz, 1H), 8.15 (d, J= 1.2 Hz, 1H), 7.94 (d, J= 1.2Hz, 1H), 7.77 (d, J = 7.8Hz, 1H), 7.32 (dd, J= 7.7, 4.8Hz, 1H), 7.02 (t, J= 1.8 Hz, 1H), 6.78 (t, J= 1.8 Hz, 1H), 6.27 (t, J = 1.8 Hz, 1H), 4.77 (d, J= 5.8 Hz, 2H), 4.57 (d, J= 6.0 Hz, 2H), 2.48 (s, 3H), 1.67 (s, 3H).Example 4: N-(3-Chloro-5-((2,2-difluoroethyl)amino)phenyl)^l-(3-methylpyridin-2-yl)thiophene-2-carboxamide

[0231] To asolution of 5-chloro-Nl-(2,2-difluoroethyl)benzene-l,3-diamine (MMC2-int44 - 100.0 mg, 0.48 mmol, 1.0 equiv) and 4-(3-methylpyridin-2-yl)thiophene-2-carboxylic acid (106.0 mg, 0.488 mmol, 1.0 equiv) in ACN (3 mL) was added TCFH (202.0 mg, 0.72 mmol, 1.5 equiv) and NMI (118.0 mg, 1.44 mmol, 3.0 equiv). Then the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and purified by prep-HPLC eluting with 0-40% ACN in H2O (0.1% NH4HCO3) to give N-(3-chloro-5-((2,2-difluoroethyl)amino)phenyl)-4-(3-methylpyri din-2 -yl)thiophene-2-carboxamide (78.0 mg, 0.19 mmol, 40%). LCMS m / z = 408.1 (M+H)+. 1H NMR (400 MHz, CD3OD) δ 8.42 (d, J = 4.2 Hz, 1H), 8.15 (d, J = 1.2 Hz, 1H), 7.94 (d, J= 1.2 Hz, 1H),7.77 (d, J = 7.2 Hz, 1H), 7.32 (dd, J = 7.8, 4.9Hz, 1H), 7.07 (d, J = 1.6 Hz, 1H),7.03 (d, J = 1.8Hz, 1H), 6.50 (t, J= 1.8 Hz, 1H), 5.95 (tt, J = 56.2, 4.1 Hz, 1H), 3.50 (td, J = 14.8, 4.1 Hz, 2H), 2.48 (s, 3H).19F NMR (400 MHz, CD3OD) 8 -123.79.Example 5: N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-4-(5-fluoropyridin-2-yl)-5-methylthiophene-2-carboxamideWSGR Docket No. 69600-701.601

[0232] To a solution of 5-chloro-Nl-(oxetan-3-yl)benzene-l,3-diamine (MMC2-intl6 - 115.0 mg, 0.58 mmol, 1.0 equiv) and 4-(5-fluoropyridin-2-yl)-5-methylthiophene-2-carboxylic acid (124.0 mg, 0.52 mmol, 0.9 equiv) in ACN (8 mL) was added TCFH (244.0 mg, 0.87 mmol, 1.5 equiv) and NMI (143.0 mg, 1.74 mmol, 3.0 equiv). Then the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and purified by prep-HPLC eluting with 0-65% ACN in H2O (0.1% NH3 H2O) to give N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-4-(5-fluoropyridin-2-yl)-5-methylthiophene-2-carboxamide (121.79 mg, 0.29 mmol, 50%). LCMS m / z = 418.3 (M+H)+. 'HNMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.68 (d, J= 2.8 Hz, 1H), 8.32 (s, 1H), 7.88 (td, J= 8.8, 3.2 Hz, 1H), 7.76 (dd, J= 8.8, 4.4 Hz, 1H), 7.10 (s, 1H), 6.90 (s, 1H), 6.77 (d, J= 6.0 Hz, 1H), 6.25 (s, 1H), 4.85 (t, J= 6.0 Hz, 2H), 4.54 - 4.46 (m, 1H), 4.42 (t, J= 6.0 Hz, 2H), 2.68 (s, 3H).19F NMR (377 MHz, DMSO-d6) δ -129.32.Example 6: N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-4-(3-fluoropyridin-4-yl)-5-methylthiophene-2-carboxamideMethyl 4-(3-fluoropyridin-4-yl)-5-methylthiophene-2-carboxylate (compound 2)

[0233] To amixture of 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (700.0 mg, 3.13 mmol, 2.0 equiv) and methyl 4-bromo-5-methylthiophene-2-carboxylate (704.0 mg, 3.13 mmol, 2.0WSGR Docket No. 69600-701.601equiv) in dioxane / H2O (15 mL / 3 mL) was added K2CO3 (1.29 g, 9.39 mmol, 6.0 equiv), and Pd(dppf)C12 (256.0 mg, 0.31 mmol, 0.2 equiv). The mixture was stirred at 80 °C for 16 hours. The mixture was concentrated under reduced pressure to give methyl 4-(3-fluoropyridin-4-yl)-5-methylthiophene-2-carboxylate (140.0 mg, crude) as a white solid. LCMS m / z = 232.2 (M+H)+.l-Methyl-5-(3-methylpyridin-2-yl)-lH-pyrazole-3-carboxylic acid (compound 3)

[0234] To a solution of methyl l-methyl-5-(3-methylpyridin-2-yl)-lH-pyrazole-3-carboxylate (446.0 mg, 1.93 mmol, 2.0 equiv) in EtOH / H2O (15 mL / 3 mL) was added Li OH (224.0 mg, 9.35 mmol, 8 equiv). The mixture was stirred at 30 °C for 1 hour. The mixture was concentrated under reduced pressure and adjusted pH to 7 with acetic acid. The precipitated solids were collected by filtration and washed with H2O. This resulted in l-methyl-5-(3-methylpyridin-2-yl)-lH-pyrazole-3-carboxylic acid (125.0 mg, 3.13 mmol, 87%) as a white solid. LCMS m / z = 218.2 (M+H)+.N-(3-Chloro-5-((cyclopropylmethyl)sulfonamido)phenyl)-4-(3-methylpyridin-2-yl)thiophene-2-carboxamide

[0235] To a solution of l-methyl-5-(3-methylpyridin-2-yl)-lH-pyrazole-3-carboxylic acid (65.0 mg, 3.13 mmol, 2.0 equiv) in ACN (25 mL) was added 5-chloro-Nl-(oxetan-3-yl)benzene-l,3-diamine (MMC2-intl6 - 47 mg, 0.23 mmol, 2.0 equiv), TCFH (99.0 mg, 0.35 mmol, 3.0 equiv) and NMI (57.0 mg, 0.69 mmol, 6.0 equiv). The mixture was stirred at 25 °C for 3 hours. The mixture was concentrated under reduced pressure and purified by prep-HPLC eluting with 50% ACN in H2O (0.05% HC1) to give N-(3-chloro-5-((cyclopropylmethyl)sulfonamido)phenyl)-4-(3-methylpyridin-2-yl)thiophene-2-carboxamide (62.0 mg, 0.15 mmol, 61%). LCMS m / z = 498.4 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 10.03 (s, 1H), 8.57 (d, J = 3.8Hz, 1H),7.84 (d, J = 7.8Hz, 1H), 7.42 (dd, J= 7.8, 4.8 Hz, 1H), 7.24 (t, J = 1.8 Hz, 1H), 7.03 (s, 1H), 6.97 (s, 1H), 6.72 (d, J= 6.0 Hz, 1H), 6.25 (t, J= 1.8 Hz, 1H), 4.85 (t, J = 6.4 Hz, 2H), 4.56 - 4.37 (m, 3H), 3.91 (s, 3H), 2.35 (s, 3H).Example 7: / V-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-l-methyl-5-(3-methylpyridin-2-yl)-lH-pyrrole- 3-carboxamide

[0236] To a solution of 1-methyl-5-(3-methylpyridin-2-yl)-1H-pyrrole-3-carboxylic acid (100.0 mg, 0.46 mmol, 1.0 equiv) in ACN (5 mL) was added 5-chloro-Nl-(oxetan-3-yl)benzene-l,3-diamine (MMC2-int16 - 91.0 mg, 0.46 mmol, 1.0 equiv), TCFH (198.0 mg, 0.69 mmol, 1.5 equiv) and NMI (107.0 mg, 1.38 mmol, 3.0 equiv). Then the mixture was stirred at 25 °C for 2 hours. The residue was purified by silica column chromatography eluting with 50% EtOAc in PE to give N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-l-methyl-5-(3-methylpyridin-2-yl)-lH-pyrrole-3-carboxamide (150.0 mg, 0.38 mmol,WSGR Docket No. 69600-701.60183%). LCMS m / z = 397.3 (M+H)+. 'H NMR (400 MHz, CD3OD) δ 8.45 (d, J = 4.4Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.56 (d, J= 2.0 Hz, 1H), 7.34 (dd, J=7.6, 4.8 Hz, 1H), 7.04(t, J= 1.6 Hz, 1H), 6.87 - 6.82 (m, 2H), 6.31 (t, J=2.0Hz, 1H),4.98 (t, J=6.4Hz, 2H), 4.64-4.58 (m, 1H), 4.57 - 4.53 (m, 2H), 3.61 (s, 3H), 2.38 (s, 3H).Example8: N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-5-(3-fluorophenyl)-l-methyl-lH-pyrrole-3-Methyl 5-(3-Fluorophenyl)-l-methyl-lH- pyrrole- 3-carboxylate (compound 3)

[0237] To asolution of methyl 5-bromo-l-methyl-lH-pyrrole-3-carboxylate (400.0 mg, 1.8 mmol, 1.0 equiv) in dioxane / H2O (10 mL / 2mL) was added 2-(3-fluorophenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (600.0 mg, 2.7 mmol, 1.5 equiv), K2CO3 (745.2 mg, 5.4 mmol, 3.0 equiv), Pd(dppf)Cl2 (146.8 mg, 0.18 mmol, 0.1 equiv) under Argon atmosphere. Then the mixture was stirred at 80 °C for 2 hours. The residue was purified by silica column chromatography eluting with 25% EtOAc in PE to give methyl 5-(3-fluorophenyl)-l -methyl- 1H- pyrrol e-3-carboxylate (410.0 mg, 1.7 mmol, 94%) as a white solid. LCMS m / z = 234.1 (M+H)+.5-(3-Fluorophenyl)-l-methyl-lH-pyrrole-3-carboxylic acid (compound 4)

[0238] To asolution of methyl 5 -(3-fluorophenyl)-l -methyl- lH-pyrrole-3-carboxylate (400.0 mg, 1.7 mmol, 1.0 equiv) in EtOH / H2O (10 mL / 2 mL) was added LiOH (204.0 mg, 8.5 mmol, 5.0 equiv). Then the mixture was stirred at 60 °C for 1 hour. The residue was purified by Cl 8 reverse phase eluting with 30% ACN in H2O to give 5-(3-fluorophenyl)-1-methyl-1H-pyrrole-3-carboxylic acid (200.0 mg, 0.9 mmol, 53%) as a white solid. LCMS m / z = 220.2 (M+H)+.N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-5-(3-fluorophenyl)-l-methyl-lH-pyrrole-3-carboxamide

[0239] To a solution of 5-(3-fluorophenyl)-l-methyl-lH-pyrrole-3-carboxylic acid (25.0 mg, 0.12 mmol, 1.0 equiv) in ACN (5 mL) was added 5-chloro-Nl-(oxetan-3-yl)benzene-l,3-diamine (MMC2-intl6 -23.0 mg, 0.12 mmol, 1.0 equiv), TCFH (50.0 mg, 0.18 mmol, 1.5 equiv) and NMI (29.5 mg, 0.36 mmol, 3.0 equiv). Then the mixture was stirred at 25 °C for 2 hours. The residue was purified by prep-HPLC eluting with 0-65% ACN in H2O (0.1% NH4HCO3) to give N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-5-WSGR Docket No. 69600-701.601(3-fluorophenyl)-l-methyl-lH-pyrrole-3-carboxamide (10.0 mg, 0.03 mmol, 25%). LCMS m / z = 400.3 (M+H)+.1HNMR(400MHz, DMSO-d6) δ 9.44 (s, 1H), 7.62 (d, J= 1.8 Hz, 1H), 7.50 (dd, J= 14.6, 8.1 Hz, 1H), 7.35 (d, J= 7.8 Hz, 2H), 7.25 - 7.11 (m, 1H), 6.91 (s, 1H), 6.85 (d, J= 1.8 Hz, 1H), 6.70 (d, J= 6.1 Hz, 1H), 6.19 (s, 1H), 4.84 (t, J= 6.4 Hz, 2H), 4.55 - 4.36 (m, 3H), 3.73 (s, 3H).19F NMR(377 MHz, DMSO) 8 -112.69.Example 9: N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-5-methyl-l-(3-methylpyridin-2-yl)-lH-pyrrole- 3-carboxamide

[0240] To asolution of 5-methyl-l-(3-methylpyridin-2-yl)-lH-pyrrole-3-carboxylic acid (50.0 mg, 0.24 mmol, 1.0 equiv) and 5-chloro-Nl-(oxetan-3-yl)benzene-l,3-diamine (MMC2-intl6 - 67.0 mg, 0.36 mmol, 1.5 equiv) in ACN (5 mL) was added TCFH (95.0 mg, 0.36 mmol, 1.5 equiv) and NMI (58.0 mg, 0.72 mmol, 3.0 equiv). The mixture was stirred at 30 °C for 1 hour. The mixture was concentrated under reduced pressure and purified by prep-HPLC eluting with 0-60% ACN in H2O (0.1% NH4OH) to give N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-4-(4-(methylthio)pyridin-2-yl)thiophene-2-carboxamide (7.6 mg, 0.02 mmol, 8%). LCMS m / z = 397.0 (M+H)+. 'H NMR (400 MHz, CD3OD) 8 8.42 (d, J= 3.6 Hz, 1H), 7.95 (d, J= 7.6 Hz, 1H), 7.58 - 7.39 (m, 2H), 7.04 (t, J= 2.0 Hz, 1H), 6.85 (t, J= 2.0 Hz, 1H), 6.58 (d, J = 0.8 Hz, 1H), 6.31 (t, J=2.0Hz, 1H), 4.98 (t, J = 6.4Hz, 2H), 4.58 - 4.53 (m, 3H), 2.16 (s, 3H), 2.04 (s, 3H).Example 10: N-(3-chloro-5-((2,2-difluoroethyl)amino)phenyl)-4-(5-fluoropyridin-2-yl)-5-methylthiophene-2-carboxamide

[0241] To a solution of 4-(5-fluoropyridin-2-yl)-5-methylthiophene-2-carboxylic acid (50.0 mg, 0.21 mmol, 1.0 equiv) and 5-chloro-Nl-(2,2-difluoroethyl)benzene-l,3-diamine (MMC2-int44 - 44.0 mg, 0.21 mmol, 1.0 equiv) in ACN (5 mL) was added TCFH (88.0 mg, 0.32 mmol, 1.5 equiv) and NMI (52.0 mg,WSGR Docket No. 69600-701.6010.63 mmol, 3.0 equiv). Then the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and purified by prep-HPLC eluting with 0-65% ACN in H2O (0.1% NH4HCO3) to give N-(3-chloro-5-((2,2-difluoroethyl)amino)phenyl)-4-(5-fluoropyridin-2-yl)-5-methylthiophene-2-carboxamide (84.33 mg, 0.20 mmol, 94%). LCMS m / z = 426.2 (M+H)+. 1H NMR (400 MHz, CD3OD) δ 8.54 - 8.53 (m, 1H), 8.08 (s, 1H), 7.70 (d, J = 2.4 Hz, 1H), 7.68 (d, J = 1.6 Hz, 1H), 7.05 (t, J= 1.4Hz, 1H), 7.01 (t, J = 2.0Hz, 1H), 6.48 (t, J=2.0Hz, 1H), 6.09 - 5.81 (m, 1H), 3.50 (td, J= 14.8, 4.0 Hz, 2H), 2.67 (s, 3H).19F NMR (377 MHz, CD3OD) 8 -123.79, -131.13.Example 11: N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-4-(5-fluoropyrimidin-2-yl)thiophene-2-carboxamideMethyl 4-(5-fluoropyrimidin-2-yl)thiophene-2-carboxylate (compound 2)

[0242] To a mixture of 2-bromo-5-fluoropyrimidine (1.0 g, 5.65 mmol, 1.0 equiv) and methyl methyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (1.82 g, 6.78 mmol, 1.2 equiv) in l,4-dioxane / H2O (24 mL / 6 mL) was added K2CO3 (3.21 g, 16.95 mmol, 3.0 equiv) and Pd(dppf)C12 (413 mg, 0.56 mmol, 0.1 equiv) under Argon atmosphere. The mixture was stirred at 80 °C for 16 hours. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 10% EtOAc in PE to give methyl 4-(5-fluoropyrimidin-2-yl)thiophene-2-carboxylate (1.11 g, 4.66 mmol, 82%) as a yellow solid. LCMS m / z = 239.0 (M+H)+.4-(5-Fluoropyrimidin-2-yl)thiophene-2-carboxylic acid (MMC2-int33)

[0243] To a solution of methyl 4-(5-fluoropyrimidin-2-yl)thiophene-2-carboxylate (1.11 g, 4.66 mmol, 1.0 equiv) in THF / H2O (8 mL / 8 mL) was added NaOH (559 mg, 13.98 mmol, 3.0 equiv). Then the mixture was stirred at 80 °C for 1 hour. The mixture was concentrated under reduced pressure and adjusted pH to 5 with citric acid solution. The precipitated solids were collected by filtration and washedWSGR Docket No. 69600-701.601with H2O. This resulted in 4-(5-fluoropyrimidin-2-yl)thiophene-2-carboxylic acid (890 mg, 3.67 mmol, 85%) as a white solid. LCMS m / z = 225.1 (M+H)+. 'H NMR (400 MHz, DMSO-d6) δ 13.36 (s, 1H), 8.95 (s, 2H), 8.60 (d, J= 1.2 Hz, 1H), 8.27 (d, J= 1.6 Hz, 1H).19F NMR (377 MHz, DMSO-d6) δ -139.50 (s).N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-4-(5-fluoropyriniidin-2-yl)thiophene-2-carboxainide

[0244] To a solution of 4-(5-fluoropyrimidin-2-yl)thiophene-2-carboxylic acid (53.7 mg, 0.24 mmol, 1.0 equiv) and 5-chloro-Nl-(oxetan-3-yl)benzene-l,3-diamine (MMC2-intl6 - 71.0 mg, 0.36 mmol, 1.5 equiv) in ACN (5 mL) was added TCFH (95.0 mg, 0.36 mmol, 1.5 equiv) andNMI (58.0 mg, 0.72 mmol, 3.0 equiv). The mixture was stirred at 25 °C for 2 hours. The mixture was concentrated under reduced pressure and purified by prep-HPLC eluting with 0-65% ACN in H2O (0.1% NH4OH) to give N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-4-(5-fluoropyrimidin-2-yl)thiophene-2-carboxamide (31.7 mg, 0.08 mmol, 32%). LCMS m / z = 404.9 (M+H)+. 1H NMR (400 MHz, CD3OD) δ 8.76 (s, 2H), 8.62 (d, J= 1.2 Hz, 1H), 8.52 (s, 1H), 7.09 (s, 1H), 6.86 (s, 1H), 6.36 (d, J= 2.0 Hz, 1H), 4.99 (t, J= 6.4 Hz, 2H), 4.65 -4.58 (m, 1H), 4.58 - 4.54 (m, 2H).Example 12: N-(3-Chloro-5-((2,2,2-trifluoroethyl)amino)phenyl)-4-(5-(S-methylsulfonimidoyl)pyridin-2-yl)thiophene-2-carboxainideMethyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (compound 2)

[0245] To a mixture of methyl 4-bromothiophene-2-carboxylate (5.0 g, 22.61 mmol, 1.0 equiv) and B2Pin2 (8.61 g, 33.92 mmol, 1.5 equiv) in 1,4-dioxane (120 mL) was added KOAc (6.66 g, 67.85 mmol, 3.0 equiv) and Pd(dppf)Ch (1.65 g, 2.26 mmol, 0.1 equiv) under Argon atmosphere. Then the mixture was stirred at 90 °C for 16 h. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 5% EtOAc in PE to give methyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (8.67 g, crude) as a yellow solid. LCMS m / z = 269.1 (M+H)+.Methyl 4-(5-(methylthio)pyridin-2-yl)thiophene-2-carboxylate (compound 3)WSGR Docket No. 69600-701.601

[0246] To a mixture of methyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (1.76 g, 6.56 mmol, 1.0 equiv) and 2-bromo-5-(methylthio)pyridine (1.07 g, 5.24 mmol, 0.8 equiv) in l,4-dioxane / H2O (24 mL / 6 mL) was added K2CO3 (2.68 g, 19.69 mmol, 3.0 equiv) and Pd(dppf)Ch (480 mg, 0.66 mmol, 0.1 equiv) under Argon atmosphere. Then the mixture was stirred at 80 °C for 16 h. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 13% EtOAc in PE to give methyl 4-(5-(methylthio)pyridin-2-yl)thiophene-2-carboxylate (1.23 g, 4.63 mmol, 71%) as a yellow solid. LCMS m / z = 266.0 (M+H)+.4-(5-(Methylthio)pyridin-2-yl)thiophene-2-carboxylic acid (compound 4)

[0247] To a solution of methyl 4-(5-(methylthio)pyridin-2-yl)thiophene-2-carboxylate (1.23 g, 4.63 mmol, 1.0 equiv) in EtOH / THF / FhO (5 mL / 5 mL / 5 mL) was added LiOH (333.0 mg, 13.91 mmol, 3.0 equiv). Then the mixture was stirred at 40 °C for 1 hour. The mixture was adjusted pH to 6 with saturated citric acid solution. The precipitated solids were collected by filtration and washed with H2O. This resulted in 4-(5-(methylthio)pyridin-2-yl)thiophene-2-carboxyhc acid (964.0 mg, 3.83 mmol, 83%) as a white solid. LCMS m / z = 252.1 (M+H)+.4-(5-(S-Methylsulfonimidoyl)pyridin-2-yl)thiophene-2-carboxylic acid (5)

[0248] To a solution of 4-(5-(methylthio)pyridin-2-yl)thiophene-2-carboxylic acid (500 mg, 1.99 mmol, 1.0 equiv) in MeOH (10 mL) was added PhI(OAc)2 (1.20 g, 4.0 mmol, 2.0 equiv), NH4COONH2 (280 mg, 4.0 mmol, 2.0 equiv) and. Then the mixture was stirred at 25 °C for 2 hours. The residue was purified by silica column chromatography eluting with 5% MeOH in DCM to give 4-(5-(S- Methylsulfonimidoyl)pyridin-2-yl)thiophene-2-carboxylic acid (500 mg, 1.77 mmol, 89%) as a yellow solid.N-(3-Chloro-5-((2,2,2-trifluoroethyl)amino)phenyl)-4-(5-(S-methylsulfonimidoyl)pyridin-2-yl)thiophene-2-carboxamideTo a mixture of 4-(5-(S-methylsulfonimidoyl)pyridin-2-yl)thiophene-2-carboxylic acid (30.0 mg, 0.11 mmol, 1.0 equiv) and 5-chloro-N1-(2,2,2-trifluoroethyl)benzene-l,3-diamine (MMC2-int43 - 24.0 mg, 0.11 mmol, 1.0 equiv) in ACN (2 mL) was added TCFH (46.0 mg, 0.17 mmol, 1.5 equiv) and NMI (27.0 mg, 0.33 mmol, 3.0 equiv). The mixture was stirred at 25 °C for 1 hour. The mixture was concentrated under reduced pressure and purified by prep-HPLC eluting with 50% ACN in H2O (0.1% NH4HCO3) to give N-(3-chloro-5-((2,2,2-trifluoroethyl)amino)phenyl)-4-(5-(S-methylsulfonimidoyl)pyridin-2-yl)thiophene-2-carboxamide (11.86mg, 0.02mmol, 22.1%). LCMS m / z =488.8 (M+H)+.1HNMR(400 MHz, CD3OD) δ 9.14 (d, J= 2.0 Hz, 1H), 8.60 (d, J= 1.2Hz, 1H), 8.51 (d, J= 1.2Hz, 1H), 8.39 (dd, J= 8.4, 2.4Hz, 1H), 8.05 (d, J= 8.4 Hz, 1H), 7.11 (dt, J= 13.2, 1.6Hz, 2H), 6.53 (t, J= 2.0 Hz, 1H), 3.83 (q, J= 9.2 Hz, 2H), 3.25 (s, 3H).19F NMR (377 MHz, CD3OD) 8 -73.82.Example 13: N-(3-Chloro-5-((2,2-difluoroethyl)amino)phenyl)-4-(5-(S-methylsulfonimidoyl)pyridin-2-yl)thiophene-2-carboxamideWSGR Docket No. 69600-701.601

[0249] To a mixture of 4-(5-(S-methylsulfonimidoyl)pyridin-2-yl)thiophene-2-carboxylic acid (30.0 mg, 0.11 mmol, 1.0 equiv) and 5-chloro-N1-(2,2-difluoroethyl)benzene-1,3-diamine (MMC2-int44 - 22.0 mg, 0.11 mmol, 1.0 equiv) in ACN (2 mL) was added TCFH (46.0 mg, 0.17 mmol, 1.5 equiv) and NMI (27 mg, 0.33 mmol, 3.0 equiv). The mixture was stirred at 25 °C for 1 hour. The mixture was concentrated under reduced pressure and purified by prep-HPLC eluting with 50% ACN in H2O (0.1% NH4HCO3) to give N-(3-chloro-5-((2,2-difluoroethyl)amino)phenyl)-4-(5-(S-methylsulfonimidoyl)pyridin-2-yl)thiophene-2-carboxamide (8.33 mg, 0.02 mmol, 16.1%). LCMS m / z =470.8 (M+H)+.1HNMR(400 MHz, CD₃OD) δ 9.13 (d, J= 2.0 Hz, 1H), 8.59 (d, J= 1.2 Hz, 1H), 8.50 (d, J= 1.2 Hz, 1H), 8.38 (dd, J= 8.4, 2.4Hz, 1H), 8.04 (d, J= 8.4 Hz, 1H), 7.07 (dt, J= 20.4, 1.6Hz, 2H), 6.51 (t, J= 2.0 Hz. 1H), 5.96 (tt, J=56.0, 4.0 Hz, 1H), 3.51 (td, J= 14.8, 4.0 Hz, 2H), 3.24 (s, 3H).19F NMR (377 MHz, CD₃OD) δ -123.79.Example 14: N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-4-(4-(methylthio)pyridin-2-yl)thiophene-2-carboxamide4-(4-(Methylthio)pyridin-2-yl)thiophene-2-carboxylic acid (compound 2)

[0250] To a solution of 4-bromothiophene-2-carboxylic acid (800.0 mg, 3.88 mmol, 1.0 equiv) and 2-bromo-4-(methylthio)pyridine (566.0 mg, 4.26 mmol, 1.1 equiv) in MeOH / H2O (18 mL / 4 mL) was added B2Pin2 (3.37 g, 12.5 mmol, 3.0 equiv), Pd(OAc)2 (175.0 mg, 0.77 mmol, 0.2 equiv), cataCXium A Pd G3 (564.0 mg, 0.77 mmol, 0.2 equiv) and NaOH (620.0 mg, 15.52 mmol, 4.0 equiv). Then the mixture was stirred at 80 °C for 16 h. The mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC eluting with 0-50% ACN in H2O (0.1% FA) to give 4-(4-(methylthio)pyridin-2-yl)thiophene-2-carboxylic acid (600.0 mg, 2.46 mmol, 63%) as a white solid. LCMS m / z = 251.9 (M+H)+.WSGR Docket No. 69600-701.601N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-4-(4-(methylthio)pyridin-2-yl)thiophene-2-carboxamide

[0251] To a solution of 4-(4-(methylthio)pyridin-2-yl)thiophene-2-carboxylic acid (60.0 mg, 0.24 mmol, 1.0 equiv) and 5-chloro-Nl-(oxetan-3-yl)benzene-l,3-diamine (MMC2-intl6 - 71.0 mg, 0.36 mmol, 1.5 equiv) in ACN (5 mL) was added TCFH (100.0 mg, 0.36 mmol, 1.5 equiv) and NMI (62.0 mg, 0.72 mmol, 3.0 equiv). The mixture was stirred at 30 °C for 1 hour. The mixture was concentrated under reduced pressure and purified by prep-HPLC eluting with 0-65% ACN in H2O (0.1% FA) to give N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-4-(4-(methylthio)pyridin-2-yl)thiophene-2-carboxamide (7.6 mg, 0.02 mmol, 8%). LCMS m / z = 431.9 (M+H)+.1H NMR(400 MHz, CD₃OD) δ 8.42 (s, 1H), 8.36 (d, J = 5.2 Hz, 1H), 8.29 (s, 1H), 7.65(s, 1H), 7.20 (d, J= 5.2 Hz, 1H), 7.07 (s, 1H), 6.88 (s, 1H), 6.35 (s, 1H), 4.99 (t, J= 6.0 Hz, 2H), 4.65 - 4.59 (m, 1H), 4.59 - 4.53 (m, 2H), 2.60 (s, 3H).Example 15: N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-5-methyl-4-(l-methyl-lH-pyrazol-4-5-Methyl-4-(l-methyl-lH-pyrazol-4-yl)thiophene-2-carboxylic acid (MMC2-intl24)

[0252] To a mixture of 4-bromo-5-methylthiophene-2-carboxylic acid (500.0 mg, 2.26 mmol, 1.0 equiv) and l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (565.0 mg, 2.71 mmol, 1.2 equiv) in l,4-dioxane / H2O (15 mL / 2 mL) was added K2CO3 (924.0 mg, 6.78 mmol, 3.0 equiv) and Pd(PPh3)4 (261.0 mg, 0.23 mmol, 0.1 equiv). The mixture was stirred at 80 °C for 16 h. The mixture was filtered and concentrated under reduced pressure. The crude was adjusted pH to 7 with AcOH and purified by C18 reverse phase eluting with 43% ACN in H2O to give 5-methyl-4-(l-methyl-lH-pyrazol-4-yl)thiophene-2-carboxylic acid (104.0 mg, 0.47 mmol, 21%) as a white solid. LCMS m / z = 222.9 (M+H)+N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-5-methyl-4-(l-methyl-lH-pyrazol-4-yl)thiophene-2-carboxamide

[0253] To a solution of 5-methyl-4-(l -methyl- lH-pyrazol-4-yl)thiophene-2-carboxylic acid (40.0 mg, 0.18 mmol, 1.0 equiv) and 5-chloro-Nl-(oxetan-3-yl)benzene-l,3-diamine (MMC2-intl6 - 36.0 mg, 0.18 mmol, 1.0 equiv) in ACN (5 mL) was added TCFH (76.0 mg, 0.27 mmol, 1.5 equiv) and NMI (44.0 mg, 0.54 mmol, 3.0 equiv). Then the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and purified by prep-HPLC eluting with 0-50% ACN in H2O (0.1% NH4HCO3) to give N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-5-methyl-4-(l-methyl-lH-pyrazol-4-yl)thiophene-2-carboxamide (25.63 mg, 0.06 mmol, 35%). LCMS m / z = 403.2 (M+H)+.1H NMR (400WSGR Docket No. 69600-701.601MHz, DMSO-d6) δ 9.99 (s, 1H), 8.02 (d, J = 18.0 Hz, 2H), 7.70 (s, 1H), 7.07 (s, 1H), 6.88 (s, 1H), 6.77 (d, J= 5.6 Hz, 1H), 6.24(s, 1H), 4.85 (t, J= 6.4 Hz, 2H), 4.54 - 4.46 (m, 1H), 4.41 (t, J= 5.8 Hz, 2H), 3.90 (s, 3H), 2.50 - 2.49 (m, 3H), 2.50 (s, 3H).Example 16: N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-5-methyl-4-(3-methylpyridin-2-yl)thiophene-2-carboxamide

[0254] To a solution of 5-methyl-4-(3-methylpyridin-2-yl)thiophene-2-carboxylic acid (50.0 mg, 0.24 mmol, 1.0 equiv) and 5-chloro-Nl-(oxetan-3-yl)benzene-l,3-diamine (MMC2-intl6 - 59.0 mg, 0.36 mmol, 1.5 equiv) in ACN (5 mL) was added TCFH (95.0 mg, 0.36 mmol, 1.5 equiv)and NMI (58.0 mg, 0.72 mmol, 3.0 equiv). The mixture was stirred at 30 °C for 1 hour. The mixture was concentrated under reduced pressure and purified by prep-HPLC eluting with 0-55% ACN in H₂O (0.1% NH₄OH) to give N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-5-methyl-4-(3-methylpyridin-2-yl)thiophene-2-carboxamide (27.8 mg, 0.07 mmol, 29%). LCMS m / z = 413.9 (M+H)+.1H NMR (400 MHz, CD3OD) 5 8.77 (d, J = 5.2 Hz, 1H), 8.65 (d, J= 8.0 Hz, 1H), 8.06 (dd, J= 8.0, 6.0 Hz, 1H), 7.97 (s, 1H), 7.28 (s, 1H), 7.25 (s, 1H), 6.71 (t, J= 2.0 Hz, 1H), 3.78 - 3.68 (m, 5H), 2.47 (d, J= 8.0 Hz, 6H).Example 17: N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-4-(5-fluoropyridin-2-yl)thiophene-2-carboxamide

[0255] To a solution of 4-(5-fluoropyridin-2-yl)thiophene-2-carboxylic acid (100.0 mg, 0.45 mmol, 1.0 equiv) in ACN (5 mL) was added 5-chloro-Nl-(oxetan-3-yl)benzene-l,3-diamine (MMC2-intl6 - 89.0 mg, 0.45 mmol, 1.0 equiv), TCFH (187.0 mg, 0.68 mmol, 1.5 equiv) andNMI (90.0 mg, 1.35 mmol, 3.0 equiv). Then the mixture was stirred at 25 °C for 2 hours. The residue was purified by prep-HPLC eluting with 0-35% ACN in H2O (0.1% FA) to give N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-4-(5-fluoropyridin-2-yl)thiophene-2-carboxamide (120.0 mg, 0.29 mmol, 66%). LCMS m / z = 404.1 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 10.28 (s, 1H), 8.66 (d, J= 1.2 Hz, 1H), 8.64 (d, J= 2.8 Hz, 1H), 8.46 (d, J= 1.2 Hz, 1H), 8.00 (dd, J= 8.8, 4.4 Hz, 1H), 7.87 (td, J= 8.8, 2.8 Hz, 1H), 7.14 (t, J= 1.6 Hz, 1H),WSGR Docket No. 69600-701.6016.92 (t, J= 2.0 Hz, 1H), 6.79 (d, J= 6.0 Hz, 1H), 6.27 (t, J= 2.0 Hz, 1H), 4.86 (t, J= 6.4 Hz, 2H), 4.51 (dd, J= 12.4, 6.4 Hz, 1H), 4.42 (t, J= 6.0 Hz, 2H).19F NMR (377 MHz, DMSO-d6) δ -128.93 (s).Example 18: N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-4-(5-ethoxypyridin-2-yl)thiophene-2-carboxamideMethyl 4-(5-ethoxypyridin-2-yl)thiophene-2-carboxylate (compound 2)

[0256] To a mixture of 2-bromo-5-ethoxypyridine (1.0 g, 4.95 mmol, 1.0 equiv) and methyl 4-(4, 4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (1.59 g, 5.94 mmol, 1.2 equiv) in 1,4-dioxane / H2O (24 mL / 6 mL) was added K2CO3 (2.02 g, 14.85 mmol, 3.0 equiv) and Pd(dppf)C12 (362 mg, 0.49 mmol, 0.1 equiv) under Argon atmosphere. The mixture was stirred at 80 °C for 16 hours. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 12% EtO Ac in PE to give methyl 4-(5-ethoxypyridin-2-yl)thiophene-2-carboxylate (1.23 g, 4.67 mmol, 94%) as a white solid. LCMS m / z = 264.1 (M+H)+.4-(5-Ethoxypyridin-2-yl)thiophene-2-carboxylic acid (MMC2-int34)

[0257] To a solution of methyl 4-(5-ethoxypyridin-2-yl)thiophene-2-carboxylate (1.23 g, 4.67 mmol, 1.0 equiv) in THF / H2O (10 mL / 10 mL) was added NaOH (560 mg, 14.01 mmol, 3.0 equiv). Then the mixture was stirred at 80 °C for 1 hour. The mixture was concentrated under reduced pressure and adjusted pH to 6 with saturated aqueous citric acid. The precipitated solids were collected by filtration and washed with H2O. This resulted in 4-(5-ethoxypyri din-2 -yl)thiophene-2-carboxylic acid (1.07 g, 4.29 mmol, 92%) as a white solid. LCMS m / z = 250.1 (M+H)+.1H NMR (400 MHz, DMSO-d6) 8 13.16 (s, 1H), 8.31 (dd, J= 5.2, 2.2Hz, 2H), 8.25 (d, J= 1.6Hz, 1H), 7.88 (d, J= 8.8 Hz, 1H), 7.44 (dd, J= 8.8, 3.0 Hz, 1H), 4.14 (q, J= 7.0 Hz, 2H), 1.36 (t, J= 7.0 Hz, 3H).N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-4-(5-ethoxypyridin-2-yl)thiophene-2-carboxamide WSGR Docket No. 69600-701.601

[0258] To a solution of 4-(5-ethoxypyridin-2-yl)thiophene-2-carboxylic acid (40.0 mg, 0.16 mmol, 1.0 equiv) and 5-chloro-Nl-(oxetan-3-yl)benzene-l,3-diamine (MMC2-intl6 - 35.0 mg, 0.17 mmol, 1.1 equiv) in ACN (5 mL) was added TCFH (67.0 mg, 0.24 mmol, 1.5 equiv) andNMI (39.0 mg, 0.48 mmol, 3.0 equiv). Then the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and purified by prep-HPLC eluting with 0-55% ACN in H2O (0.1% NH4HCO3) to give N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-4-(5-ethoxypyridin-2-yl)thiophene-2-carboxamide (24.82 mg, 0.06 mmol, 36%). LCMS m / z = 430.2 (M+H)+. 'H NMR (400 MHz, DMSO-d6) 5 10.25 (s, 1H), 8.63 (s, 1H), 8.32 (d, J=4.8Hz, 2H), 7.85 (d, J = 8.4Hz, 1H), 7.50 (dd, J= 8.8, 2.8 Hz, 1H), 7.15 (s, 1H), 6.93 (s, 1H), 6.78 (d, J= 6.0Hz, 1H), 6.26 (s, 1H), 4.86 (t, J= 6.4 Hz, 2H), 4.56 - 4.47 (m, 1H), 4.42 (t, J= 6.0 Hz, 2H), 4.16 (q, J= 7.0 Hz, 2H), 1.37 (t, J= 6.8 Hz, 3H).Example 19: N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-4-(3-fluoropyridin-2-yl)thiophene-2-carboxamide4-(3-Fluoropyridin-2-yl)thiophene-2-carboxylic acid (MMC2-int63)

[0259] To a mixture of 4-bromothiophene-2-carboxylic acid (2.0 g, 9.66 mmol, 1.0 equiv) and 2-bromo-3-fluoropyridine (2.55 g, 14.49 mmol, 1.5 equiv) in MeOHLLO (30 mL / 6 mL) was added B2Pin2 (7.3 g, 28.98 mmol, 3.0 equiv) andPd(OAc)2 (436.0 mg, 1.93 mmol, 0.2 equiv) and CataCXium APd G3 (1.4 g, 1.93 mmol, 0.2 equiv) under Argon atmosphere. The mixture was stirred at 80 °C for 16 hours. The mixture was filtered and concentrated under reduced pressure. The crude was adjusted pH to 7 with AcOH and purified by Cl 8 reverse phase eluting with 43% ACN in H2O to give 4-(3-fluoropyridin-2-yl)thiophene-2-carboxylic acid (800.0 mg, 3.59 mmol, 37.1%) as a white solid. LCMS m / z = 224.1 (M+H)+.N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-4-(3-fluoropyridin-2-yl)thiophene-2-carboxamide

[0260] To a solution of 4-(3-fluoropyridin-2-yl)thiophene-2-carboxylic acid (53.5 mg, 0.24 mmol, 1.0 equiv) and 5-chloro-Nl-(oxetan-3-yl)benzene-l,3-diamine (MMC2-intl6 - 71.28 mg, 0.36 mmol, 1.5 equiv) in ACN (5 mL) was added TCFH (95.0 mg, 0.36 mmol, 1.5 equiv) andNMI (58.0 mg, 0.72 mmol, 3.0 equiv). The mixture was stirred at 25 °C for 2 hours. The mixture was concentrated under reduced pressure and purified by prep-HPLC eluting with 0-65% ACN in H2O (0.1% NH4OH) to give N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-4-(3-fluoropyridin-2-yl)thiophene-2-carboxamide (15.7 mg, 0.03 mmol, 15%). LCMS m / z =404.1 (M+H)+.1H NMR (400 MHz, CD₃OD) δ 8.57 (s, 1H), 8.47 (dd, J= 3.2, 1.6Hz, 1H), 8.34(t, J= 1.2Hz, 1H), 7.70 (ddd, J= 11.6, 8.4, 1.2Hz, 1H), 7.40 (dt, J= 8.4, 4.4Hz, 1H), 7.09 (t, J= 2.0 Hz, 1H), 6.87 (t, J= 2.0 Hz, 1H), 6.36 (t, J= 2.0 Hz, 1H), 4.99 (t, J= 6.4 Hz, 2H), 4.63 - 4.54 (m, 3H).19F NMR (377 MHz, MeOD) δ -123.59.WSGR Docket No. 69600-701.601Example 20: 5-Chloro-N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-4-(3-methylpyridin-2-yl)thiophene-2-carboxamideMethyl 5-chloro-4-(3-methylpyridin-2-yl)thiophene-2-carboxylate (compound 2)

[0261] To a mixture of methyl 4-(3-methylpyridin-2-yl)thiophene-2-carboxylate (1.5 g, 6.44 mmol, 1.0 equiv) in DMF (15 mL) was added NCS (1.29 g, 9.66 mmol, 1.5 equiv) under Argon atmosphere. The mixture was stirred at 85 °C for 16 hours. The mixture was concentrated under reduced pressure and the residue was purified by silica column chromatography eluting with 19% EtOAc in PE to give methyl 5 -chloro-4-(3-methylpyridin-2-yl)thiophene-2-carboxylate (880.0 mg, 3.29 mmol, 51.1%) as a yellow solid. LCMS m / z = 268.0 (M+H)+.5-Chloro-4-(3-methylpyridin-2-yl)thiophene-2-carboxylic acid (MMC2-int52)

[0262] To a solution of methyl 5-chloro-4-(3-methylpyridin-2-yl)thiophene-2-carboxylate (880.0 mg, 3.29 mmol, 1.0 equiv) in EtOH / H₂O (15 mL / 5 mL) was added LiOH (158.0 mg, 6.57 mmol, 2.0 equiv). Then the mixture was stirred at 25 °C for 1 hour. The mixture was concentrated under reduced pressure and adjusted pH to 6 with citric acid solution. The precipitated solids were collected by filtration and washed with H2O. This resulted in 5-chloro-4-(3-methylpyridin-2-yl)thiophene-2-carboxylic acid (700 mg, 2.77 mmol, 84.1%) as a white solid. LCMS m / z = 254.0 (M+H)+.5-Chloro-N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-4-(3-methylpyridin-2-yl)thiophene-2-carboxamide

[0263] To a solution of 5-chloro-4-(3-methylpyridin-2-yl)thiophene-2-carboxylic acid (40.0 mg, 0.16 mmol, 1.0 equiv) and 5-chloro-N1-(oxetan-3-yl)benzene-l,3-diamine (MMC2-intl6 - 31.0 mg, 0.16 mmol, 1.0 equiv) in ACN (3 mL) was added TCFH (67.0 mg, 0.24 mmol, 1.5 equiv) and NMI (40.0 mg, 0.49 mmol, 3.0 equiv). Then the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and purified by prep-HPLC eluting with 0-50% ACN in H2O (0.1% NH4HCO3) to give 5-chloro-N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-4-(3-methylpyridin-2-yl)thiophene-2-carboxamide (50.0 mg, 0.12 mmol, 72.2%). LCMS m / z = 433.8 (M+H)+.1H NMR (400 MHz, CD₃OD) δ 8.46 (d, J= 4.4 Hz, 1H), 7.84 (d, J= 7.6 Hz, 1H), 7.81 (s, 1H), 7.43 (dd, J = 7.6, 4.8WSGR Docket No. 69600-701.601Hz, 1H), 7.01 (t, J= 1.6 Hz, 1H), 6.83 (t, J = 2.0 Hz, 1H), 6.34 (t, J= 2.0 Hz, 1H), 4.97 (t, J= 6.2 Hz, 2H), 4.62 - 4.58 (m, 1H), 4.56 - 4.53 (m, 2H), 2.30 (s, 3H).Example 21: N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-5-cyano-4-(3-methylpyridin-2-yl)thiophene-2-carboxamideMethyl 5-cyano-4-(3-methylpyridin-2-yl)thiophene-2-carboxylate (compound 2)

[0264] To a mixture of methyl 4-bromo-5-cyanothiophene-2-carboxylate (800.0 mg, 3.52 mmol, 1.0 equiv) in DMF (15 mL) was added 3-methyl-2-(tributylstannyl)pyridine (1.8 g, 4.88 mmol, 1.5 equiv) and Cui (200.0 mg, 1.06 mmol, 0.3 equiv) and Pd(PPh3)2C12 (494 mg, 0.70 mmol, 0.2 equiv) under Argon atmosphere. The mixture was stirred at 100 °C for 16 hours. The mixture was concentrated under reduced pressure and the residue was purified by silica column chromatography eluting with 12% EtOAc in PE to give methyl 5-cyano-4-(3-methylpyridin-2-yl)thiophene-2-carboxylate (660.0 mg, 2.55 mmol, 72.6%) as a white solid. LCMS m / z = 259.0 (M+H)+.5-Cyano-4-(3-methylpyridin-2-yl)thiophene-2-carboxylic acid (MMC2-int54)

[0265] To a solution of methyl 5-cyano-4-(3-methylpyridin-2-yl)thiophene-2-carboxylate (660.0 mg, 2.56 mmol, l. Oequiv) in EtOH / H2O (15 mL / 5 mL) was added LiOH (121.0 mg, 5.11 mmol, 2.0 equiv). Then the mixture was stirred at 25 °C for 1 hour. The mixture was concentrated under reduced pressure and adjusted pH to 6 with citric acid solution. The precipitated solids were collected by filtration and washed with H2O. This resulted in 5-cyano-4-(3-methylpyridin-2-yl)thiophene-2-carboxylic acid (300.0 mg, 1.23 mmol, 48%) as a white solid. LCMS m / z = 245.0 (M+H)+.N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-5-cyano-4-(3-methylpyridin-2-yl)thiophene-2-carboxamide

[0266] To a solution of 5-cyano-4-(3-methylpyridin-2-yl)thiophene-2-carboxylic acid (50.0 mg, 0.21 mmol, 1.0 equiv) and 5-chloro-N1-(oxetan-3-yl)benzene-l,3-diamine (MMC2-intl6 - 41.0 mg, 0.21 mmol, 1.0 equiv) in ACN (3 mL) was added TCFH (89.0 mg, 0.32 mmol, 1.5 equiv) and NMI (52.0 mg, 0.63 mmol, 3.0 equiv). Then the mixture was stirred at room temperature for 1 hour. The mixture wasWSGR Docket No. 69600-701.601concentrated under reduced pressure and purified by prep-HPLC eluting with 0-50% ACN in H2O (0.1% NH4HCO3) to give N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-5-cyano-4-(3-methylpyridin-2-yl)thiophene-2-carboxamide (18.0 mg, 0.04 mmol, 20.2%). LCMS m / z = 424.9 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.58 (d, J= 5.6 Hz, 1H), 8.31 (s, 1H), 7.88 (d, J= 7.6 Hz, 1H), 7.49 - 7.46 (m, 1H), 7.06 (s, 1H), 6.88 - 6.85 (m, 2H), 6.30 (s, 1H), 4.84 (t, J= 6.0 Hz, 2H), 4.53 - 4.50 (m, 1H), 4.41 (t, J= 5.6 Hz, 2H), 2.41 (s, 3H).Example 22: N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-4-(5-ethoxypyridin-2-yl)-5-methylthiophene-2-carboxamide4-(5-Ethoxypyridin-2-yl)-5-methylthiophene-2-carboxylic acid (MMC2-int39)

[0267] To a solution of 2-bromo-5-ethoxypyridine (48.0 mg, 0.24 mmol, 1.0 equiv) in dioxane (10 mL) and H2O (2 mL)was added 5-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)thiophene-2-carboxylic acid (69.6 mg, 0.26 mmol, 1.1 equiv), Pd(dppf)C12 (14.6 mg, 0.02 mmol, 0.1 equiv) and CS2CO3 (156.0 mg, 0.48 mmol, 2.0 equiv) under Argon atmosphere. The mixture was stirred at 100 °C for 16 hours. The mixture was concentrated under reduced pressure and purified by prep-HPLC eluting with 0-35% ACN in H2O (0.1% NH4OH) to give 4-(5-ethoxypyridin-2-yl)-5-methylthiophene-2-carboxylic acid (50.6 mg, 0.17 mmol, 73%) as a white solid. LCMS m / z = 264.0 (M+H)+.N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-4-(5-ethoxypyridin-2-yl)-5-methylthiophene-2-carboxamide

[0268] To a solution of 4-(5-ethoxypyridin-2-yl)-5-methylthiophene-2-carboxylic acid (63.1 mg, 0.24 mmol, 1.0 equiv) and 5-chloro-Nl-(oxetan-3-yl)benzene-l,3-diamine (MMC2-intl6 - 71.2 mg, 0.36 mmol, 1.5 equiv) in ACN (5 mL) was added TCFH (95.0 mg, 0.36 mmol, 1.5 equiv)andNMI (58.0 mg, 0.72 mmol, 3.0 equiv). The mixture was stirred at 25 °C for 2 hours. The mixture was concentrated under reduced pressure and purified by prep-HPLC eluting with 0-70% ACN in H2O (0.1% NH4OH) to give N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-4-(5-ethoxypyridin-2-yl)-5-methylthiophene-2-carboxamide (24.5 mg, 0.05 mmol, 23%). LCMS m / z = 443.9 (M+H)+.1H NMR (400 MHz, CD₃OD) δ 8.29 (d, J= 2.8 Hz, 1H), 7.99 (s, 1H), 7.54 (d, J= 8.8 Hz, 1H), 7.46 (dd, J= 8.8, 2.8 Hz, 1H), 7.03 (s, 1H), 6.83 (s, 1H), 6.33 (s, 1H), 4.98 (t, J= 6.0 Hz, 2H), 4.60 - 4.52 (m, 3H), 4.16 (q, J= 6.8 Hz, 2H), 2.63 (s, 3H), 1.44 (t, J= 7.2 Hz, 3H).Example 23: N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-4-(5-(difluoromethoxy)pyridin-2-yl)thiophene-2-carboxamideWSGR Docket No. 69600-701.601Methyl 4-(5-(difluoromethoxy)pyridin-2-yl)thiophene-2-carboxylate (compound 2)

[0269] To a solution of methyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (200.0 mg, 0.74 mmol, 1.0 equiv) in dioxane / H₂O (10 mL / 1 mL) was added 2-bromo-5-(difluoromethoxy)pyridine (165.0 mg, 0.74 mmol, 1.0 equiv), K2CO3 (202 mg, 1.48 mmol, 2.0 equiv), Pd (dppf)Ch (48 mg, 0.074 mmol, 0.1 equiv) under Argon atmosphere. Then the mixture was stirred at 80 °C for 16 hours. The residue was purified by silica column chromatography eluting with 25% EtOAc in PE to give methyl 4-(5-(difluoromethoxy)pyridin-2-yl)thiophene-2-carboxylate (160.0 mg, 0.56 mmol, 75%) as a white solid. LCMS m / z = 286.0 (M+H)+.4-(5-(Difluoromethoxy)pyridin-2-yl)thiophene-2-carboxylic acid (compound 3)

[0270] To a solution of methyl 4-(5-(difluoromethoxy)pyridin-2-yl)thiophene-2-carboxylate (160.0 mg, 0.56 mmol, 1.0 equiv) in THF / H₂O (10 mL / 2 mL) was added LiOH (28.0 mg, 1.12 mmol, 2.0 equiv). Then the mixture was stirred at 25 °C for 1 hour. The residue was purified by Cl 8 reverse phase eluting with 30% ACN in H2O to give 4-(5-(difluoromethoxy)pyridin-2-yl)thiophene-2-carboxylic acid (120.0 mg, 0.44 mmol, 79%) as a white solid. LCMS m / z = 271.9 (M+H)+.N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-4-(5-(difluoromethoxy)pyridin-2-yl)thiophene-2-carboxamide

[0271] To a solution of 4-(5-(difluoromethoxy)pyridin-2-yl)thiophene-2-carboxylic acid (120.0 mg, 0.44 mmol, 1.0 equiv) in ACN (5 mL) was added 5-chloro-Nl-(oxetan-3-yl)benzene-l,3-diamine (MMC2-intl6 - 87.0 mg, 0.44 mmol, 1.0 equiv), TCFH (152 mg, 0.66 mmol, 1.5 equiv) and NMI (115.0 mg, 1.32 mmol, 3.0 equiv). Then the mixture was stirred at 25 °C for 2 hours. The residue was purified by prep-HPLC eluting with 0-65% ACN in H2O (0.1% NH4HCO3) to give N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-4-(5-(difluoromethoxy)pyridin-2-yl)thiophene-2-carboxamide (60.0 mg, 0.13 mmol, 30%). LCMS m / z = 452.1 (M+H)+.1H NMR (400 MHz, CD₃OD) δ 8.46 (t, J= 3.2 Hz, 2H), 8.26 (d, J = 1.2 Hz, 1H), 7.87 (d, J= 8.4 Hz, 1H), 7.68 (dd, J= 8.8, 2.8 Hz, 1H), 7.15 - 6.77 (m, 3H), 6.35 (t, J = 2.0 Hz, 1H), 4.99 (t, J= 6.4 Hz, 2H), 4.65 - 4.51 (m, 3H).19F NMR (377 MHz, CD₃OD) δ -84.04. Example 24: N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-4-(5-(trifluoromethoxy)pyridin-2-yl)thiophene-2-carboxamideWSGR Docket No. 69600-701.601Methyl 4-(5-(trifluoromethoxy)pyridin-2-yl)thiophene-2-carboxylate (compound 2)

[0272] To a solution of methyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (200.0 mg, 0.74 mmol, 1.0 equiv) in dioxane / H2O (10 mL / 1 mL) was added 2-bromo-5-(trifluoromethoxy)pyridine (178.0 mg, 0.74 mmol, l. Oequiv), K2CO3 (202.0 mg, 1.48 mmol, 2.0 equiv), Pd(dppf)C12 (48.0 mg, 0.074 mmol, 0.1 equiv). Then the mixture was stirred at 80 °C for 16 hours. The residue was purified by silica column chromatography eluting with 25% EtOAc in PE to give methyl 4-(5-(trifluoromethoxy)pyridin-2-yl)thiophene-2-carboxylate (170.0 mg, 0.56 mmol, 75%) as a white solid. LCMS m / z = 304.0 (M+H)+.4-(5-(Trifluoromethoxy)pyridin-2-yl)thiophene-2-carboxylic acid (compound 3)

[0273] To a solution of methyl 4-(5-(trifluoromethoxy)pyridin-2-yl)thiophene-2-carboxylate (170.0 mg, 0.56 mmol, 1.0 equiv) in THF / H₂O (10 mL / 2 mL) was added LiOH (28.0 mg, 1.12 mmol, 2.0 equiv). Then the mixture was stirred at 25 °C for 1 hour. The residue was purified by Cl 8 reverse phase eluting with 30% ACN in H2O to give 4-(5-(trifluoromethoxy)pyridin-2-yl)thiophene-2-carboxylic acid (155.0 mg, 0.44 mmol, 95%) as a white solid. LCMS m / z = 289.9 (M+H)+.N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-4-(5-(trifluoromethoxy)pyridin-2-yl)thiophene-2-carboxamide

[0274] To a solution of 4-(5-(trifluoromethoxy)pyridin-2-yl)thiophene-2-carboxylic acid (170.0 mg, 0.56 mmol, 1.0 equiv) in ACN (5 mL) was added 5-chloro-N1-(oxetan-3-yl)benzene-1,3-diamine (MMC2-int16 - 93.0 mg, 0.56 mmol, 1.0 equiv), TCFH (152.0 mg, 0.84 mmol, 1.5 equiv) and NMI (115.0 mg, 1.32 mmol, 3.0 equiv). Then the mixture was stirred at 25 °C for 2 hours. The residue was purified by prep-HPLC eluting with 0-65% ACN in H2O (0.1% NH4HCO3) to give N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-4-(5-(trifluoromethoxy)pyri din-2 -yl)thiophene-2-carboxamide (60.0 mg, 0.13 mmol, 23%). LCMS m / z = 469.9 (M+H)+.1H NMR (400 MHz, CD₃OD) δ 8.58 (d, J = 2.4Hz, 1H), 8.50 (d, J= 1.2Hz, 1H), 8.33 (d, J= 1.2 Hz, 1H), 7.94 (d, J= 8.8 Hz, 1H), 7.85 - 7.79 (m, 1H), 7.08 (t, J =WSGR Docket No. 69600-701.6011.6 Hz, 1H), 6.87 (t,. / = 2.0 Hz. 1H), 6.36 (t, J =2.0 Hz, 1H), 4.99 (t, J= 6.4 Hz, 2H), 4.65 - 4.54 (m, 3H).19F NMR (377 MHz, CD3OD) 8 -59.91.Example 25: N-(3-ChIoro-5-(oxetan-3-yIamino)phenyI)-4-(3,5-difluoropyridin-2-yI)thiophene-2-carboxamideMethyl 4-(3,5-difluoropyridin-2-yl)thiophene-2-carboxylate (compound 2)

[0275] To a solution of methyl 4-(3,5-difluoropyridin-2-yl)thiophene-2-carboxylate (200.0 mg, 0.74 mmol, 1.0 equiv) in dioxane / H2O (10 mL / 1 mL) was added 2-bromo-3,5-difluoropyridine (168.0 mg, 0.74 mmol, 1.0 equiv), K2CO3 (202.0 mg, 1.48 mmol, 2.0 equiv), Pd(dppf)Cl2 (48 mg, 0.074 mmol, 0.1 equiv). Then the mixture was stirred at 90 °C for 16 hours. The residue was purified by silica column chromatography eluting with 25% EtOAc in PE to give methyl 4-(3,5-difluoropyridin-2-yl)thiophene-2-carboxylate (170.0 mg, 0.67 mmol, 90%) as a white solid. LCMS m / z = 225.9 (M+H)+.4-(3,5-Difluoropyridin-2-yl)thiophene-2-carboxylic acid (compound 3)

[0276] To asolution of methyl 4-(5-(difluoromethoxy)pyridin-2-yl)thiophene-2-carboxylate (170.0 mg, 0.67 mmol, 1.0 equiv) in THF / H2O (10 mL / 2 mL) was added LiOH (32.0 mg, 1.34 mmol, 2.0 equiv). Then the mixture was stirred at 25 °C for 1 hour. The residue was purified by Cl 8 reverse phase eluting with 30% ACN in H2O to give 4-(3,5-difluoropyridin-2-yl)thiophene-2-carboxylic acid (155.0 mg, 0.44 mmol, 65%) as a white solid. LCMS m / z = 241.9 (M+H)+N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-4-(3,5-difluoropyridin-2-yl)thiophene-2-carboxamide

[0277] To asolution of 4-(3,5-difluoropyridin-2-yl)thiophene-2-carboxylic acid (57.8 mg, 0.24 mmol, 1.0 equiv) and 5-chloro-Nl-(oxetan-3-yl)benzene-l,3-diamine (MMC2-intl6 - 71.28 mg, 0.36 mmol, 1.5 equiv) in ACN (5 mL) was added TCFH (95.0 mg, 0.36 mmol, 1.5 equiv) andNMI (58.0 mg, 0.72 mmol, 3.0 equiv). The mixture was stirred at 25 °C for 2 hours. The mixture was concentrated under reduced pressure and purified by prep-HPLC eluting with 0-55% ACN in H2O (0.1% NH4OH) to give N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-4-(3,5-difluoropyridin-2-yl)thiophene-2-carboxamide (25.5 mg,WSGR Docket No. 69600-701.6010.06 mmol, 30%). LCMS m / z=422.1 (M+H)+. 'H NMR (400 MHz, CD3OD) δ 8.56 (s, 1H), 8.45 (d, J = 2.4 Hz, 1H), 8.30 (s, 1H), 7.68(ddd, J = 11.2, 8.4, 2.4 Hz, 1H), 7.09(1, J= 2.0 Hz, 1H), 6.86 (t, J= 2.0 Hz, 1H), 6.35 (t, J= 2.0 Hz, 1H), 4.99 (t, J= 6.4 Hz, 2H), 4.65 - 4.52 (m, 3H).19F NMR (377 MHz, CD3OD) δ -119.63 (d, J= 6.6 Hz), -127.02 (d, J= 6.8 Hz).Example 26: 5-Chloro-N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-4-(5-(difluoromethoxy)pyridin-2-yl)thiophene-2-carboxamideMethyl 4-(5-(difluoromethoxy)pyridin-2-yl)thiophene-2-carboxylate (compound 3)

[0278] To a mixture of methyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (1.0 g, 3.73 mmol, 1.0 equiv) and 2-bromo-5-(difluoromethoxy)pyridine (835.0 mg, 3.73 mmol, 1.0 equiv) in l,4-dioxane / H2O (15 mL / 3 mL) was added K2CO3 (1.0 g, 7.46 mmol, 2.0 equiv) and Pd(dppf)Ch (270.0 mg, 0.37 mmol, 0.1 equiv). The mixture was stirred at 90 °C for 16 hours. The mixture was filtered and concentrated under reduced pressure. The mixture was concentrated under reduced pressure and the residue was purified by silica column chromatography eluting with 15% EtOAc in PE to give methyl 4-(5-(difluoromethoxy)pyridin-2-yl)thiophene-2-carboxylate (1.0 g, 3.5 mmol, 93.8%) as a yellow solid. LCMS m / z = 286.0 (M+H)+.Methyl 5-chloro-4-(5-(difluoromethoxy)pyridin-2-yl)thiophene-2-carboxylate (compound 4)

[0279] To amixture of methyl 4-(5-(difluoromethoxy)pyridin-2-yl)thiophene-2-carboxylate (1.0 g, 3.5 mmol, 1.0 equiv) in DMF (15 mL) was added NCS (700.0 mg, 5.3 mmol, 1.5 equiv) under Argon atmosphere. The mixture was stirred at 85 °C for 16 hours. The mixture was concentrated under reduced pressure and the residue was purified by silica column chromatography eluting with 19% EtOAc in PE to give methyl 5-chloro-4-(5-(difluoromethoxy)pyridin-2-yl)thiophene-2-carboxylate (940.0 mg, 2.94 mmol, 84%) as a yellow solid. LCMS m / z = 319.9 (M+H)+.5-Chloro-4-(5-(difluoromethoxy)pyridin-2-yl)thiophene-2-carboxylic acid (MMC2-int75)

[0280] To a solution of methyl 5-chloro-4-(5-(difluoromethoxy)pyridin-2-yl)thiophene-2-carboxylate (940.0 mg, 2.94 mmol, 1.0 equiv) in EtOH / H2O (15 mL / 5 mL) was added LiOH (141.0 mg, 5.88 mmol,WSGR Docket No. 69600-701.6012.0 equiv). Then the mixture was stirred at 25 °C for 1 hour. The mixture was concentrated under reduced pressure and adjusted pH to 6 with citric acid solution. The precipitated solids were collected by filtration and washed with H2O. This resulted in 5-chloro-4-(5-( difluoromethoxy )pyridin-2-yl)thiophene-2-carboxylic acid (850.0 mg, 2.79 mmol, 94.8%) as a white solid. LCMS m / z = 306.1 (M+H)+.5-Chloro-N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-4-(5-(difluoromethoxy)pyridin-2-yl)thiophene-2-carboxamide

[0281] To a solution of 5-chloro-4-(5-(difluoromethoxy)pyridin-2-yl)thiophene-2-carboxylic acid (50.0 mg, 0.16 mmol, 1.0 equiv) and 5-chloro-N'-(oxetan-3-yl)benzene- 1.3-diamine (MMC2-intl6 - 39.0 mg, 0.20 mmol, 1.0 equiv) in ACN (3 mL) was added TCFH (69.0 mg, 0.25 mmol, 1.5 equiv) and NMI (40 mg, 0.49 mmol, 3.0 equiv). Then the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and purified by prep-HPLC eluting with 0-50% ACN in H2O (0.1% NH4HCO3) to give N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-4-(4-methylpyridin-3-yl)thiophene-2-carboxamide (40.0 mg, 0.10 mmol, 43.6%). LCMS m / z = 486.1 (M+H)+.1H NMR (400 MHz, CD3OD) δ 8.54 (d, J= 2.8 Hz, 1H), 8.22 (s, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.74 (dd, J= 8.8, 2.8 Hz, 1H), 7.07 (t, J = 36.4 Hz, 2H), 6.82 (d, J= 3.6 Hz, 1H), 6.34 (s, 1H), 4.97 (t, J= 6.0 Hz, 2H), 4.62 - 4.53 (m, 3H).19F NMR (377 MHz, CD3OD) 8 -84.26.Example 27: N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-4-(4-fluorophenyl)-5-methylthiophene-2-carboxamide4-(4-Fluorophenyl)-5-methylthiophene-2-carboxylic acid (MMC2-int99)

[0282] To a mixture of 4-bromo-5-methylthiophene-2-carboxylic acid (500.0 mg, 2.26 mmol, 1.0 equiv) and 2-(4-fluorophenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (603.0 mg, 2.71 mmol, 1.2 equiv) in 1,4-dioxane / H2O (15 mL / 4 mL) was added Pd(PPh3)4 (261.0 mg, 0.22 mmol, 0.1 equiv) and K2CO3 (924.0 mg, 6.78 mmol, 3.0 equiv) under Argon atmosphere. The mixture was stirred at 80 °C for 16 hours. The reaction was diluted with H2O (20 mL x 3) and extracted with EtOAc (40 mL). The combined aqueous phase was adjusted pH to 7 with acetic acid, the precipitated solids were collected by filtration and washed with H2O. This resulted in 4-(4-fluorophenyl)-5-methylthiophene-2-carboxylic acid (339.0 mg, 1.43 mmol, 63%) as abrown solid. LCMS m / z = 236.9 (M+H)+.[HNMR (400 MHz, DMSO-d6) 813.00 (s, 1H), 7.67 (s, 1H), 7.53 - 7.48 (m, 2H), 7.31 - 7.25 (m, 2H), 2.49 (s, 3H).19F NMR (377 MHz, DMSO-6) 8 -114.92.N-(3-ChIoro-5-(oxetan-3-yIamino)phenyI)-4-(4-fluorophenyI)-5- methylthiophene- 2-carboxamideWSGR Docket No. 69600-701.601

[0283] To a solution of 4-(4-fluorophenyl)-5-methylthiophene-2-carboxylic acid (40.0 mg, 0.17 mmol, 1.0 equiv) and 5-chloro-Nl-(oxetan-3-yl)benzene-l,3-diamine (MMC2-intl6 - 34.0 mg, 0.17 mmol, 1.0 equiv) in ACN (4 mL) was added TCFH (71.0 mg, 0.25 mmol, 1.5 equiv) andNMI (42.0 mg, 0.51 mmol, 3.0 equiv). Then the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and purified by prep-HPLC eluting with 0-70% ACN in H2O (0.1% NH4HCO3) to give N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-4-(4-fluorophenyl)-5-methylthiophene-2-carboxamide (41.46 mg, 0.10 mmol, 58%). LCMS m / z = 417.0 (M+H)+. 'H NMR (400 MHz, DMSO-d6) 5 10.00 (s, 1H), 8.03 (s, 1H), 7.56 - 7.51 (m, 2H), 7.36 - 7.30 (m, 2H), 7.08 (t, J= 1.6 Hz, 1H), 6.88 (t, J = 1.8 Hz, 1H), 6.77 (d, J= 6.0 Hz, 1H), 6.24 (t, J= 1.8 Hz, 1H), 4.84 (t, J= 6.4 Hz, 2H), 4.54 - 4.46 (m, 1H), 4.41 (t, J= 5.8 Hz, 2H), 2.51 (s, 3H).19F NMR (377 MHz, DMSO-6) 8 -114.84.Example 28: N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-5-methyl-4-(2-(trifluoromethyl)pyridin-4-yl)thiophene-2-carboxamide5-methyl-4-(2-(trifluoromethyl)pyridin-4-yl)thiophene-2-carboxylic acid (MMC2-int95)

[0284] To a mixture of 4-bromo-5-methylthiophene-2-carboxylic acid (500.0 mg, 2.26 mmol, 1.0 equiv) and4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine (792.0 mg, 2.49 mmol, 1.1 equiv) in l,4-dioxane / H2O (15 mL / 3 mL) was added K2CO3 (936.0 mg, 6.78 mmol, 3.0 equiv) and Pd(dppf)Ch (168.0 mg, 0.23 mmol, 0.1 equiv). The mixture was stirred at 80 °C for 16 hours. The mixture was filtered and concentrated under reduced pressure. The crude was adjusted pH to 7 with AcOH and purified by Cl 8 reverse phase eluting with 43% ACN in H2O to give 4-(4-methylpyridin-3-yl)thiophene-2-carboxylic acid (700.0 mg crude) as a brown solid. LCMS m / z = 288.0 (M+H)+.N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-5-methyl-4-(2-(trifluoromethyl)pyridin-4-yl)thiophene-2-carboxamide

[0285] To a solution of 5-methyl-4-(2-(trifluoromethyl)pyridin-4-yl)thiophene-2-carboxylic acid (50.0 mg, 0.17 mmol, 1.0 equiv) and 5-chloro-Nl-(oxetan-3-yl)benzene-l,3-diamine (MMC2-intl6 - 35.0 mg, 0.17 mmol, 1.0 equiv) in ACN (2 mL) was added TCFH (73.0 mg, 0.26 mmol, 1.5 equiv) andNMI (42.0 mg, 0.51 mmol, 3.0 equiv). Then the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and purified by prep-HPLC eluting with 0-50% ACN in H2O (0.1% NH4HCO3) to give N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-5-methyl-4-(2-(trifluoromethyl)pyridin-4-yl)thiophene-2-carboxamide (30.0 mg, 0.06 mmol, 37.7%). LCMS m / z = 467.9 (M+H)+.! H NMR (400 MHz, DMSO-d6) δ 10.09 (s, 1H), 8.87 (s, 1H), 8.20 (s, 1H), 8.00 (s, 1H),WSGR Docket No. 69600-701.6017.88 (s, 1H), 7.07 (s, 1H), 6.88 (s, 1H), 6.80 (s, 1H), 6.26 (s, 1H), 4.84 (t, J= 6.4 Hz, 2H), 4.50 (d, J= 7.2 Hz, 1H), 4.41 (dd, J= 6.4, 4.4 Hz, 2H), 2.63 (s, 3H).19F NMR (377 MHz, DMSO-d6) δ -66.40. Example 29: 5-ChIoro-N-(3-chIoro-5-(oxetan-3-yIamino)phenyI)-4-(5-fluoropyridin-2-yI)thiophene- 2-carboxamideMethyl 4-(5-fluoropyridin-2-yl)thiophene-2-carboxylate (compound 2)

[0286] To a mixture of 2-bromo-5 -fluoropyridine (3.0 g, 16.95 mmol, 1.0 equiv) and methyl 4-(4, 4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (5.0 g, 18.65 mmol, 1.1 equiv) in 1,4-dioxane / H2O (60 mL / 12 mL) was added Pd(dppf)Cl2 (1.24 g, 1.69 mmol, 0.1 equiv) and K2CO3 (6.93 g, 50.85 mmol, 3.0 equiv) under Argon atmosphere. The mixture was stirred at 80 °C for 16 hours. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 20% EtOAc in PE to give methyl 4-(5-fluoropyridin-2-yl)thiophene-2-carboxylate (4.0 g, 16.86 mmol, 99%) as a white solid. LCMS m / z = 238.0 (M+H)+.Methyl 5-chloro-4-(5-fluoropyridin-2-yl)thiophene-2-carboxylate (compound 3)

[0287] To a mixture of methyl 4-(5-fluoropyri din-2 -yl)thiophene-2-carboxylate (1.1 g, 4.63 mmol, 1.0 equiv) in DMF (20 mL) was added NCS (928 mg, 6.95 mmol, 1.5 equiv) under Argon atmosphere. The mixture was stirred at 85 °C for 16 hours. The reaction was diluted with H2O (80 mL x 3) and extracted with EtOAc (80 mL). The combined organic layer was washed with brine H2O (50 mL x 2), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 3% EtOAc in PE to give methyl 5-chloro-4-(5-fluoropyridin-2-yl)thiophene-2-carboxylate (1.22 g, 4.49 mmol, 97%) as a white solid. LCMS m / z = 272.1 (M+H)+.1H NMR (400 MHz, DMSO) 88.70 (d, J= 2.8 Hz, 1H), 8.09(s, 1H), 8.01 (dd, J= 8.8, 4.4 Hz, 1H), 7.92 -7.86 (m, 1H), 3.86 (s, 3H).5-Chloro-4-(5-fhioropyridin-2-yl)thiophene-2-carboxylic acid (MMC2-int57)

[0288] To a solution of methyl 5-chloro-4-(5-fluoropyridin-2-yl)thiophene-2-carboxylate (1.22 g, 4.49 mmol, 1.0 equiv) in EtOH / H2O (12 mL / 6 mL) was added LiOH (323.0 mg, 13.47 mmol, 3.0 equiv). Then the mixture was stirred at 60 °C for 1 hour. The mixture was concentrated under reduced pressure andWSGR Docket No. 69600-701.601adjusted pH to 7 with acetic acid. The precipitated solids were collected by filtration and washed with H2O. This resulted in 5-chloro-4-(5-fluoropyridin-2-yl)thiophene-2-carboxylic acid (1.09 g, 4.23mmol, 94%) as a white solid. LCMS m / z = 257.9 (M+H)+. 'H NMR (400 MHz, DMSO-d6) 8 8.68 (d, J= 3.2 Hz, 1H), 7.97 (dd, J= 8.8, 4.4 Hz, 1H), 7.88 - 7.83 (m, 1H), 7.79 (s, 1H).19F NMR (377 MHz, DMSO-d6) 8 -127.75.5-Chloro-N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-4-(5-fluoropyridin-2-yl)thiophene-2-carboxamide

[0289] To a solution of 5-chloro-4-(5-fluoropyridin-2-yl)thiophene-2-carboxylic acid (40.0 mg, 0.15 mmol, 1.0 equiv) and 5-chloro-Nl-(oxetan-3-yl)benzene-l,3-diamine (MMC2-intl6 - 31.0 mg, 0.15 mmol, 1.0 equiv) in ACN (4 mL) was added TCFH (65.0 mg, 0.23 mmol, 1.5 equiv) and NMI (38.0 mg, 0.46 mmol, 3.0 equiv). Then the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and purified by Cl 8 reverse phase eluting with 0-70% ACN in H2O (0.1% NH3H2O) to give 5-chloro-N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-4-(5-fluoropyridin-2-yl)thiophene-2-carboxamide (31.26 mg, 0.07 mmol, 46%). LCMS m / z = 438.1 (M+H)+.1H NMR (400 MHz, DMSO-d6) 810.34 (s, 1H), 8.75 (d, J = 2.8Hz, 1H), 8.46 (s, 1H), 8.04 (dd, J= 8.8, 4.4 Hz, 1H), 7.93 (td, J= 8.8, 3.0 Hz, 1H), 7.10 (t, J= 1.6 Hz, 1H), 6.89 (t, J= 1.6 Hz, 1H), 6.80 (d, J= 6.4 Hz, 1H), 6.27 (t, J= 1.8 Hz, 1H), 4.85 (t, J=6.4Hz, 2H), 4.54-4.46(m, 1H), 4.41 (t, J= 5.8 Hz, 2H).19F NMR (377 MHz, DMSO-6) 8 -127.06.Example 30: N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-5-fluoro-4-(5-fluoropyridin-2-yl)thiophene-2-carboxamideMethyl 5-fluoro-4-(5-fluoropyridin-2-yl)thiophene-2-carboxylate (compound 2)

[0290] To a mixture of methyl 4-(5-fluoropyri din-2 -yl)thiophene-2-carboxylate (500.0 mg, 2.11 mmol, 1.0 equiv) in ACN (20 mL) was added Selectfluor (1.12 g, 3.16 mmol, 1.5 equiv) under Argon atmosphere. The mixture was stirred at 70 °C for 4 days. The mixture was concentrated under reduced pressure and the residue was purified by silica column chromatography eluting with 4% EtOAc in PE to give methyl 5-fluoro-4-(5-fluoropyridin-2-yl)thiophene-2-carboxylate (202.0 mg, 0.79 mmol, 37%) as a white solid. LCMS m / z = 256.0 (M+H)+.WSGR Docket No. 69600-701.6015-Fluoro-4-(5-fluoropyridin-2-yl)thiophene-2-carboxylic acid (MMC2-int56)

[0291] To a solution of methyl 5-fluoro-4-(5-fluoropyridin-2-yl)thiophene-2-carboxylate (202.0 mg, 0.79 mmol, 1.0 equiv) in EtOH / H2O (5 mL / 2 mL) was added Li OH (57.0 mg, 2.37 mmol, 3.0 equiv). Then the mixture was stirred at 60 °C for 1 hour. The mixture was concentrated under reduced pressure and adjusted pH to 6 with citric acid solution. The precipitated solids were collected by filtration and washed with H₂O. This resulted in 5-fluoro-4-(5-fluoropyridin-2-yl)thiophene-2-carboxylic acid (132.0 mg, 0.56 mmol, 69%) as ayellow solid. LCMS m / z = 242.0 (M+H)+.1H NMR (400 MHz, DMSO-6) 8 8.68 - 8.66 (m, 1H), 7.87 - 7.83 (m, 3H).N-(3-ChIoro-5-(oxetan-3-yIamino)phenyI)-5-fluoro-4-(5-fluoropyridin-2-yI)thiophene-2-carboxamide

[0292] To a solution of 5-fluoro-4-(5-fluoropyridin-2-yl)thiophene-2-carboxylic acid (40.0 mg, 0.16 mmol, 1.0 equiv) and 5-chloro-Nl-(oxetan-3-yl)benzene-l,3-diamine (MMC2-intl6 - 33.0 mg, 0.16 mmol, 1.0 equiv) in ACN (4 mL) was added TCFH (70.0 mg, 0.25 mmol, 1.5 equiv) and NMI (41.0 mg, 0.50 mmol, 3.0 equiv). Then the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and purified by prep-HPLC eluting with 0-60% ACN in H2O (0.1% NH4HCO3) to give N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-5-fluoro-4-(5-fluoropyridin-2-yl)thiophene-2-carboxamide (29.19 mg, 0.07 mmol, 43%). LCMS m / z = 422.1 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.72 (d, J= 2.8 Hz, 1H), 8.47 (d, J= 4.0 Hz, 1H), 7.93 - 7.84 (m, 2H), 7.11 (t, J= 1.6Hz, 1H), 6.89(s, 1H), 6.80 (d, J= 6.0 Hz, 1H), 6.27 (t, J= 1.8 Hz, 1H), 4.85 (t, J= 6.4 Hz, 2H), 4.54 - 4.46 (m, 1H), 4.42 (t, J= 6.0 Hz, 2H).19F NMR (377 MHz, DMSO-6) 8 -122.01, -127.43.Example 31: N-(3-Chloro-5-((3-methyloxetan-3-yl)amino)phenyl)-4-(5-fluoropyridin-2-yl)-5-methylthiophene-2-carboxamide

[0293] To a solution of 5-chloro-Nl-(3-methyloxetan-3-yl)benzene-l,3-diamine (MMC2-int88 - 27.0 mg, 0.13 mmol, 1.0 equiv) and 4-(5-fluoropyridin-2-yl)-5-methylthiophene-2-carboxylic acid (30.0 mg, 0.13 mmol, 1.0 equiv) in ACN (4 mL) was added TCFH (53.0 mg, 0.19 mmol, 1.5 equiv) and NMI (31.0 mg, 0.38 mmol, 3.0 equiv). Then the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and purified by prep-HPLC eluting with 0-55% ACN in H2O (0.1% NH4HCO3) to give N-(3-chloro-5-((3-meihyloxetan-3-yl)amino)phenyl)-4-(5-fluoropyridin-2-yl)-5-methylthiophene-2-carboxamide (25.32 mg, 0.06 mmol, 45%). LCMS m / z = 432.2 (M+H)+.1H NMRWSGR Docket No. 69600-701.601(400 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.68 (d, J= 2.8 Hz, 1H), 8.30 (s, 1H), 7.88 (td, J= 8.8, 3.0 Hz, 1H), 7.77 (dd, J= 8.8, 4.4 Hz, 1H), 7.08 (t, J= 1.6 Hz, 1H), 6.75 (t, J= 1.8 Hz, 1H), 6.50 (s, 1H), 6.16 (t, J= 1.8Hz, 1H), 4.60 (d, J= 6.0 Hz, 2H), 4.47 (d, J= 6.0 Hz, 2H), 2.68 (s, 3H), 1.58 (s, 3H).19F NMR (377 MHz, DMSO-6) 8 -129.31.Example 32: N- (3- Chloro-5- ((3-methyloxetan-3-yl) amino) phenyl) -5-methyl-4- (5-(trifluoromethyl)pyridin-2-yl)thiophene-2-carboxamideMethyl 5-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)thiophene-2-carboxylate (compound 2)

[0294] To amixture of 2-bromo-5-(trifluoromethyl)pyridine (1.8 g, 8.03 mmol, 1.0 equiv) and methyl 5-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (3.0 g, 10.60 mmol, 1.2 equiv) in dioxane / H2O (50 mL / 10 mL) was added K2CO3 (3.3 g, 24.5 mmol, 3.0 equiv) and Pd(dppf)C12 (660.0 mg, 0.81 mmol, 0.1 equiv) under Argon atmosphere. Then the mixture was stirred at 80 °C for 16 hours. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 20% EtOAc in PE to give methyl 4-(5-fluoropyridin-2-yl)-5-methylthiophene-2-carboxylate (2.0 g, 7.96 mmol, 98%) as a white solid. LCMS m / z = 302.2 (M+H)+.5-Methyl-4-(5-(trifluoromethyl)pyridin-2-yl)thiophene-2-carboxylic acid (MMC2-int38)

[0295] To a solution of methyl 5-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)thiophene-2-carboxylate (1.5 g, 4.90 mmol, 1.0 equiv) in EtOHTEO (15 mL / 3 mL) was added Li OH (1.4 g, 59.00 mmol, 10.0 equiv). Then the mixture was stirred at 25 °C for 2 hours. The mixture was adjusted pH to 6 with HC1 (2.0 N). The precipitated solids were collected by filtration and washed with H2O. This resulted in 5-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)thiophene-2-carboxylic acid (1.1 g, 3.83 mmol, 85%) as a white solid. LCMS m / z =288.0 (M+H)+.N-(3-ChIoro-5-((3-methyIoxetan-3-yI)amino)phenyI)-5-methyI-4-(5-(trifhioromethyI)pyridin-2-yl)thiophene-2-carboxamide

[0296] To a solution of 5-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)thiophene-2-carboxylic acid (40.0 mg, 0.14 mmol, 1.0 equiv) and 5-chloro-Nl-(3-methyloxetan-3-yl)benzene-l,3-diamine (MMC2-int88 -30.0 mg, 0.14 mmol, 1.0 equiv) in ACN (4 mL) was added TCFH (59.0 mg, 0.21 mmol, 1.5 equiv) and NMI (34.0 mg, 0.42 mmol, 3.0 equiv). Then the mixture was stirred at room temperature for 1 hour. TheWSGR Docket No. 69600-701.601mixture was concentrated under reduced pressure and purified by prep-HPLC eluting with 0-70% ACN in H2O (0.1% NH4HCO3) to give N-(3-chloro-5-((3-methyloxetan-3-yl)amino)phenyl)-5-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)thiophene-2-carboxamide (38.64 mg, 0.08 mmol, 56%). LCMS m / z = 482.2 (M+H)+. ¹H NMR (400 MHz, DMSO-d6) δ 10.16 (s, 1H), 9.06 (s, 1H), 8.41 (s, 1H), 8.35 (dd, J = 8.4, 2.0 Hz, 1H), 7.93 (d, J= 8.4 Hz, 1H), 7.08 (s, 1H), 6.76 (s, 1H), 6.51 (s, 1H), 6.17 (t, J= 1.8 Hz, 1H), 4.61 (d, J= 6.0 Hz, 2H), 4.48 (d, J= 6.0 Hz, 2H), 2.75 (s, 3H), 1.58 (s, 3H).19F NMR (377 MHz, DMSO-6) 8 -60.64.Example 33: N-(3-Chloro-5-((3-(trifluoromethyl)oxetan-3-yl)amino)phenyl)-4-(5-fluoropyridin-2-yl)-5-methylthiophene-2-carboxamide

[0297] To a solution of 4-(5-fluoropyridin-2-yl)-5-methylthiophene-2-carboxylic acid (40.0 mg, 0.17 mmol, 1.0 equiv) and 5-chloro-N1-(3-(trifluoromethyl)oxetan-3-yl)benzene-l,3-diamine (MMC2-int89 -60.0 mg, 0.23 mmol, 1.5 equiv) in ACN (2 mL) was added TCFH (71.0 mg, 0.25 mmol, 1.5 equiv) and NMI (41.0mg, 0.51 mmol, 3.0 equiv). Then the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and purified by prep-HPLC eluting with 0-50% ACN in H2O (0.1% NH4OH) to give N-(3-chloro-5-((3-(trifluoromethyl)oxetan-3-yl)amino)phenyl)-4-(5-fluoropyridin-2-yl)-5-methylthiophene-2-carboxamide (38.0 mg, 0.08 mmol, 47.1%). LCMS m / z = 486.2 (M+H)+.1HNMR(400MHz, DMSO- 6) 810.16 (s, 1H), 8.69 (d, J = 2.8Hz, 1H), 8.30(s, 1H), 7.88 (td,.7 = 8.8, 3.2Hz, 1H), 7.77 (dd, J= 8.8, 4.4 Hz, 1H), 7.20 - 7.17 (m, 2H), 6.87 (s, 1H), 6.21 (s, 1H), 4.85 (d, J = 7.6Hz, 2H), 4.76 (d, J= 7.2 Hz, 2H), 2.68 (s, 3H).19F NMR (377 MHz, DMSO- 6) 8 -77.83, -129.28.Example 34: N-(3-Chloro-5-((l,l,l-trifluoropropan-2-yl)amino)phenyl)-4-(5-fluoropyridin-2-yl)-5-methylthiophene-2-carboxamideWSGR Docket No. 69600-701.601

[0298] To a solution of 4-(5-fluoropyridin-2-yl)-5-methylthiophene-2-carboxylic acid (17.0 mg, 0.07 mmol, 1.0 equiv) and 5-chloro-N1-(l,l,l-trifluoropropan-2-yl)benzene-l,3-diamine (17.0 mg, 0.07 mmol, 1.5 equiv) in ACN (1 mL) was added TCFH (30.0 mg, 0.11 mmol, 1.5 equiv) and NMI (17.0 mg, 0.21 mmol, 3.0 equiv). Then the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and purified by prep-HPLC eluting with 0-50% ACN in H2O (0.1% NH4OH) to give N-(3-chloro-5-((l, 1, 1 -trifluoropropan-2-yl)amino)phenyl)-4-(5-fluoropyridin-2-yl)-5-methylthiophene-2-carboxamide (10.0 mg, 0.02 mmol, 31.2 %). LCMS m / z = 457.9 (M+H)+. ¹H NMR (400 MHz, DMSO-d6) δ 10.14 (s, 1H), 8.68 (d, J = 2.8 Hz, 1H), 8.33 (s, 1H), 7.88 (td, J= 8.8, 3.0 Hz, 1H), 7.76 (dd, J= 8.8, 4.4 Hz, 1H), 7.15 (s, 1H), 7.09 (s, 1H), 6.56 (s, 1H), 6.39 (d, J= 8.8 Hz, 1H), 4.34 -4.25 (m, 1H), 2.68 (s, 3H), 1.31 (d, J = 6.8Hz, 3H).19F NMR (377 MHz, DMSO- 6) 8 -75.68, -129.34.Example 35: N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-4-(3-methylpyridin-4-yl)thiophene-2-carboxamide4-(3-Methylpyridin-4-yl)thiophene-2-carboxylic acid (compound 2)

[0299] To a mixture of 3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (500.0 mg, 2.28 mmol, 1.0 equiv) and 4-bromothiophene-2-carboxylic acid (46.08 mg, 2.28 mmol, l. Oequiv) in 1,4-dioxane / H2O (20 mL / 4 mL) was added K2CO3 (624.0 mg, 4.56 mmol, 2.0 equiv) and Pd(dppf)C12 (160.0 mg, 0.228 mmol, 0.1 equiv). Then the mixture was stirred at 80 °C for 16 hours. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 5% MeOH in DCM to give 4-(3-methylpyridin-4-yl)thiophene-2-carboxylic acid (400.0 mg, 1.83 mmol, 80%) as a white solid. LCMS m / z = 220.2 (M+H)+.N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-4-(3-methylpyridin-4-yl)thiophene-2-carboxamide

[0300] To a solution of 4-(3-methylpyridin-4-yl)thiophene-2-carboxylic acid (100.0 mg, 0.45 mmol, 1.0 equiv) in ACN (5 mL) was added 5-chloro-Nl-(oxetan-3-yl)benzene-l,3-diamine (MMC2-intl6 - 89.0 mg, 0.45 mmol, 1.0 equiv), TCFH (187.0 mg, 0.68 mmol, 1.5 equiv) and NMI (90.0 mg, 1.35 mmol, 3.0 equiv.). Then the mixture was stirred at 25 °C for 2 hours. The residue was purified by prep-HPLC eluting with 0-35% ACN in H2O (0.1% NH4HCO3) to give N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-4-(3-methylpyridin-4-yl)thiophene-2-carboxamide (65.0 mg, 0.16 mmol, 36%). LCMS m / z = 400.0 (M+H)+.1HNMR(400MHz, CD3OD) 88.47 (s, 1H), 8.41 (d, J= 5.2Hz, 1H), 8.08(d, J= 1.2 Hz, 1H), 7.91 (d, J= 1.2Hz, 1H), 7.43 (d, J= 5.2 Hz, 1H), 7.05 (t, J= 2.0 Hz, 1H), 6.86 (t, J = 2.0 Hz, 1H), 6.35 (t, J =2.0 Hz, 1H), 4.98 (t, J= 6.4 Hz, 2H), 4.64 - 4.53 (m, 3H), 2.45 (s, 3H).Example 36: N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-5-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)thiophene-2-carboxamideWSGR Docket No. 69600-701.6015-MethyI-4-(5-(trifluoromethyI)pyridin-2-yI)thiophene-2-carboxyIic acid (MMC2-int38)

[0301] To a solution of 5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylic acid (64.3 mg, 0.24 mmol, 1.0 equiv) in dioxane (10 mL) and H2O (2 mL) was added 2-bromo-5-(trifluoromethyl)pyridine (58.24 mg, 0.26 mmol, 1.1 equiv), Pd(dppf)C12 (14.6 mg, 0.02 mmol, 0.1 equiv) and CS2CO3 (156.0 mg, 0.48 mmol, 2.0 equiv) under Argon atmosphere. The mixture was stirred at 100 °C for 16 hours. The mixture was concentrated under reduced pressure and purified by prep-HPLC eluting with 0-30% ACN in H2O (0.1% NH4OH) to give 5-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)thiophene-2-carboxylic acid (50.6 mg, 0.17 mmol, 73%) as a white solid. LCMS m / z = 288.0 (M+H)+.N-(3-chIoro-5-(oxetan-3-ylamino)phenyl)-5-methyI-4-(5-(trifluoromethyI)pyridin-2-yI)thiophene-2-carboxamide

[0302] To a solution of 5-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)thiophene-2-carboxylic acid (68.8 mg, 0.24 mmol, 1.0 equiv) and 5-chloro-Nl-(oxetan-3-yl)benzene-l,3-diamine (MMC2-intl6 - 71.2 mg, 0.36 mmol, 1.5 equiv) in ACN (5 mL) was added TCFH (95.0 mg, 0.36 mmol, 1.5 equiv) and NMI (58.0 mg, 0.72 mmol, 3.0 equiv). The mixture was stirred at 25 °C for 2 hours. The mixture was concentrated under reduced pressure and purified by prep-HPLC eluting with 0-70% ACN in H2O (0.1% NH4OH) to give N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-5-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)thiophene-2-carboxamide (25.7 mg, 0.05 mmol, 23%). LCMS m / z =467.9 (M+H)+.1H NMR (400 MHz, CD3OD) 8 8.94 (s, 1H), 8.28 (s, 1H), 8.18 (d, J= 6.4 Hz, 1H), 7.88 (d, J= 8.4 Hz, 1H), 7.08 (s, 1H), 6.85 (s, 1H), 6.34 (s, 1H), 4.99 (t, J= 6.0 Hz, 2H), 4.57 (dt, J= 11.6, 6.0 Hz, 3H), 2.77 (s, 3H).19F NMR (377 MHz, CD3OD) 8 -63.81 (s).Example 37: N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-5-methyl-4-(3-methylpyridin-4-yl)thiophene-2-carboxamideWSGR Docket No. 69600-701.601Methyl 5-methyl-4-(3-methylpyridin-4-yl)thiophene-2-carboxylate (compound 2)

[0303] To a mixture of methyl 4-bromo-5-methylthiophene-2-carboxylate (100.0 mg, 0.43 mmol, 1.0 equiv) in dioxane / H2O (3 mL / 1 mL) was added 3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (93.0 mg, 0.43 mmol, 1.0 equiv) and K2CO3 (119.0 mg, 0.86 mmol, 2.0 equiv) and Pd(dppf)Ch (32 mg, 0.04 mmol, 0.1 equiv) under Argon atmosphere. The mixture was stirred at 90 °C for 16 hours. The mixture was concentrated under reduced pressure and the residue was purified by silica column chromatography eluting with 12% EtOAc in PE to give methyl 5-methyl-4-(3-methylpyridin-4-yl)thiophene-2-carboxylate (90.0 mg, 0.36 mmol, 84.6%) as ayellow solid. LCMS m / z = 247.9 (M+H)+.5-Methyl-4-(3-methylpyridin-4-yl)thiophene-2-carboxylic acid (MMC2-intl61)

[0304] To a solution of methyl 5-methyl-4-(3-methylpyridin-4-yl)thiophene-2-carboxylate (90.0 mg, 0.36 mmol, 1.0 equiv) in EtOH / H2O (5 mL / 2 mL) was added Li OH (17.0 mg, 0.73 mmol, 2.0 equiv). Then the mixture was stirred at 25 °C for 1 hour. The mixture was concentrated under reduced pressure and adjusted pH to 6 with acetic acid solution. The precipitated solids were collected by filtration and washed with H2O. This resulted in 5-methyl-4-(3-methylpyridin-4-yl)thiophene-2-carboxylic acid (60.0 mg, 0.26 mmol, 72.2%) as a white solid. LCMS m / z = 234.1 (M+H)+.N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-5-methyl-4-(3-methylpyridin-4-yl)thiophene-2-carboxamide

[0305] To a solution of 5-methyl-4-(3-methylpyridin-4-yl)thiophene-2-carboxylic acid (60.0 mg, 0.26 mmol, 1.0 equiv) and 5-chloro-N1-(oxetan-3-yl)benzene-l,3-diamine (MMC2-intl6 - 61.0 mg, 0.31 mmol, 1.2 equiv) in ACN (3 mL) was added TCFH (108.0 mg, 0.39 mmol, 1.5 equiv) and NMI (63.0 mg, 0.77 mmol, 3.0 equiv). Then the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and purified by prep-HPLC eluting with 0-50% ACN in H2O (0.1% NH3. H2O) to give N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-5-methyl-4-(3-methylpyridin-4-yl)thiophene-2-carboxamide (43.0 mg, 0.10 mmol, 40.0%). LCMS m / z = 414.2 (M+H)+.1H NMR (400WSGR Docket No. 69600-701.601MHz, DMS0- 6) 59.98 (s, 1H), 8.57 (s, 1H), 8.47 (d, J= 4.8 Hz, lH),7.88 (s, 1H), 7.25 (d, J= 4.8 Hz, 1H), 7.07 (s, 1H), 6.86 (s, 1H), 6.78 (d, J= 6.0 Hz, 1H), 6.24 (s, 1H), 4.84 (t, J= 6.4 Hz, 2H), 4.49 (dd, J = 12.4, 6.0 Hz, 1H), 4.41 (t, J= 6.0 Hz, 2H), 2.31 (s, 3H), 2.19 (s, 3H).Example 38: N-(3-Bromo-5-(oxetan-3-ylamino)phenyl)-5-methyl-4-(3-methylpyridin-4-yl)thiophene-2-carboxamide

[0306] To a solution of 5-methyl-4-(3-methylpyridin-4-yl)thiophene-2-carboxylic acid (55.9 mg, 0.24 mmol, 1.0 equiv) and 5-bromo-Nl-(oxetan-3-yl)benzene-l,3-diamine (MMC2-int47 - 87.1 mg, 0.36 mmol, 1.5 equiv) in ACN (5 mL) was added TCFH (95.0 mg, 0.36 mmol, 1.5 equiv) and NMI (58.0 mg, 0.72 mmol, 3.0 equiv). The mixture was stirred at 25 °C for 2 hours. The mixture was concentrated under reduced pressure and purified by prep-HPLC eluting with 0-65% ACN in H2O (0.1% NH4OH) to give N-(3-bromo-5-(oxetan-3-ylamino)phenyl)-5-methyl-4-(3-methylpyridin-4-yl)thiophene-2-carboxamide (25.9 mg, 0.05 mmol, 23%). LCMS m / z =460.1 (M+H)+. 'H NMR (400 MHz, DMSO-d6) 59.96 (s, 1H), 8.57 (s, 1H), 8.47 (d, J = 4.8Hz, lH),7.87 (s, 1H),7.25 (d, J = 4.8Hz, 1H), 7.19 (t, J= 1.6 Hz, 1H), 6.90 (t, J= 1.6 Hz, 1H), 6.76 (d, J= 6.0 Hz, 1H), 6.38 (t, J= 1.6 Hz, 1H), 4.83 (t, J=6.4 Hz. 2H), 4.49 (dd, J = 12.4, 6.4 Hz, 1H), 4.40 (t, J= 6.0 Hz, 2H), 2.31 (s, 3H), 2.18 (s, 3H).Example 39: N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-4-(4-fluoro-lH-pyrazol-l-yl)-5-methylthiophene-2-carboxamide4-(4-Fluoro-lH-pyrazol-l-yl)-5-methylthiophene-2-carboxylic acid (MMC2-intl22)

[0307] To a mixture of 4-fluoro-lH-pyrazole (500.0 mg, 5.81 mmol, 1.0 equiv) and methyl 4-bromo-5-methylthiophene-2-carboxylate (680.0 mg, 2.91 mmol, 0.5 equiv) in DMF (6 mL) was added CS2CO3 (2.8 g, 8.72 mmol, 1.5 equiv) and Cui (220.0 mg, 1.16 mmol, 0.2 equiv) and L-proline (140.0 mg, 1.16 mmol, 0.2 equiv) under Argon atmosphere. The sealed vial was irradiated in the microwave on a Biotage Smith Synthesis at 120°C for 2 hours. The mixture was filtered and concentrated under reduced pressure. The crude was adjusted pH to 7 with AcOH and purified by Cl 8 reverse phase eluting with 43% ACN inWSGR Docket No. 69600-701.601H2Otogive4-(4-fluoro-lH-pyrazol-l-yl)-5-methylthiophene-2-carboxylic acid (140.0 mg, 0.62 mmol, 21.3%) as ayellow solid. LCMS m / z = 227.0 (M+H)+.N-(3-ChIoro-5-(oxetan-3-yIamino)phenyI)-4-(4-fluoro-lH-pyrazol- l-yl)-5- methylthiophene- 2-carboxamide

[0308] To a solution of 4-(4-fluoro-lH-pyrazol-l-yl)-5-methylthiophene-2-carboxylic acid (50.0 mg, 0.22 mmol, 1.0 equiv) and 5-chloro-N1-(oxetan-3-yl)benzene-l,3-diamine (MMC2-intl6 - 53.0 mg, 0.27 mmol, 1.2 equiv) in ACN (2 mL) was added TCFH (93.0 mg, 0.33 mmol, 1.5 equiv) and NMI (54.0 mg, 0.66 mmol, 3.0 equiv). Then the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and purified by prep-HPLC eluting with 0-70% ACN in H2O (0.1% NH3. H2O) to give N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-4-(4-fluoro-lH-pyrazol-l-yl)-5-methylthiophene-2-carboxamide (12.0 mg, 0.06 mmol, 27.3%). LCMS m / z = 468.1 (M+H)+. 'H NMR (400 MHz, DMSO- 6) 510.14 (s, 1H), 8.37 (s, 1H), 8.15 (s, 1H), 7.86(s, 1H), 7.09 (s, 1H), 6.86 (s, 1H), 6.80 (s, 1H), 6.25 (s, 1H), 4.84 (t, J= 6.4 Hz, 2H), 4.49 (s, 1H), 4.41 (t,.7=6,4 Hz. 2H), 2.52 (s, 3H).19F NMR (377 MHz, DMSO- 6) 5 -177.02Example 40: N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-4-(2,6-dimethylpyridin-4-yl)-5-(methyl-d3)thiophene-2-carboxamideMethyl 5-(methyl-d3)thiophene-2-carboxylate (compound 2)

[0309] To asolution of thiophene-2-carboxylic acid (1.0g, 7.80 mmol, 1.0 equiv) in THF (10 mL) was added 2M LDA (9.8 mL, 19.51 mmol, 2.5 equiv) at -78 °C for 1 h under Argon atmosphere. Then the mixture was added CD3I (1.4 g, 9.36 mmol, 1.20 equiv) at -78 °C. After 1 h, the mixture was added CH3I (2.2g, 15.61 mmol, 2.0equiv) andK2CO3 (2.2g, 15.61 mmol, 2.0 equiv) at 40 °C for 16 h. The reaction was filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 2% EtOAc in methyl 5-(methyl-d3)thiophene-2-carboxylate (430.0 mg crude) as ayellow oil. LCMS m / z = 160.1 (M+H)+.Methyl 4-bromo-5-(methyl-d3)thiophene-2-carboxylate (compound 3)WSGR Docket No. 69600-701.601

[0310] To a solution of methyl 5-(methyl-d3)thiophene-2-carboxylate (430.0 mg, 2.70 mmol, 1.0 equiv) in DMF (5 mL) was added N-Bromosuccinimide (528.8 mg, 2.97 mmol, 1.1 equiv). The mixture was stirred at 25 °C for 16 hours. The reaction was filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC eluting with 0-45% ACN in H2O to give methyl 4-bromo-5-(methyl-d3)thiophene-2-carboxylate (150.0 mg, 0.63 mmol, 23.3%) as ayellow oil. LCMS m / z = 240.0 (M+3H)+.Methyl 4-(2,6-dimethylpyridin-4-yl)-5-(methyl-d3)thiophene-2-carboxylate (compound 4)

[0311] To a solution of methyl 4-bromo-5-(methyl-d3)thiophene-2-carboxylate (150.0 mg, 0.63 mmol, 1.0 equiv) and 2,6-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (161.5 mg, 0.69 mmol, 1.1 equiv) in l,4-dioxane / H2O (5 mL / 1 mL) was added Pd(dppf)Ch (23.0 mg, 0.031 mmol, 0.05 equiv) and K2CO3 (174.1 mg, 1.26 mmol, 2.0 equiv). The mixture was stirred at 90 °C for 16 hours. The reaction was filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 10% EtOAc in PE to methyl 4-(2,6-dimethylpyridin-4-yl)-5-(methyl-d3)thiophene-2-carboxylate (100.0 mg, 0.40 mmol, 63.4 %) as a white solid. LCMS m / z = 265.1 (M+H)+.4-(2,6-Dimethylpyridin-4-yl)-5-(methyl-d3)thiophene-2-carboxylic acid (compound MMC2-int248)

[0312] To a solution of methyl 4-(2,6-dimethylpyridin-4-yl)-5-(methyl-d3)thiophene-2-carboxylate (100.0 mg, 0.38 mmol, 1.0 equiv) in MeOH / H2O (3 mL / 1 mL) was added LiOH (18.1 mg, 0.76 mmol, 2.0 equiv). Then the mixture was stirred at 60 °C for 16 hour. The mixture was concentrated under reduced pressure and adjusted pH to 7 with acetic acid. The precipitated solids were collected by filtration and washed with H2O. This resulted in 4-(2,6-dimethylpyridin-4-yl)-5-(methyl-d3)thiophene-2-carboxylic acid (50.0 mg, 0.20 mmol, 52.8%) as a white solid. LCMS m / z = 251.1 (M+H)+.N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)^4-(2,6-dimethylpyridin-4-yl)-5-(methyl-d3)thiophene-2-carboxamide

[0313] To a solution of 4-(2,6-dimethylpyridin-4-yl)-5-(methyl-d3)thiophene-2-carboxylic acid (40.0 mg, 0.16 mmol, 1.0 equiv) and 5-chloro-Nl-(oxetan-3-yl)benzene-l,3-diamine (MMC2-intl6 - 31.7 mg, 0.16 mmol, 1.0 equiv) in ACN (2 mL) was added TCFH (67.3 mg, 0.24 mmol, 1.5 equiv) andNMI (39.4 mg, 0.48 mmol, 3.0 equiv). Then the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure and purified by prep-HPLC eluting with 0-55% ACN in H2O (0.1% NH4HCO3) to give N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-4-(2,6-dimethylpyridin-4-yl)-5-(methyl-d3)thiophene-2-carboxamide (23.6 mg, 0.055 mmol, 34.3%). LCMS m / z = 431.1 (M+H)+. 'H NMR (400 MHz, DMSO-d6) 5 10.04 (s, 1H), 8.10 (s, 1H), 7.18 (s, 2H), 7.08 (s, 1H), 6.88 (s, 1H), 6.78 (d, J = 6.2 Hz, 1H), 6.25 (d, J = 1.8 Hz, 1H), 4.84 (t, J = 6.4 Hz, 2H), 4.50 (dd, J = 12.4, 6.2 Hz, 1H), 4.41 (t, J = 6.0 Hz, 2H), 2.49 (s, 6H).Example 41: N-(3-ChIoro-5-((l-(fluoromethyI)cyclopropyl)amino)phenyI)-5-(4-fhiorophenyI)-l-methyl- lH-pyrrole-3-carboxamideWSGR Docket No. 69600-701.601

[0314] To a5-(4-fluorophenyl)-l-methyl-lH-pyrrole-3-carboxylic acid (50 mg, 0.22 mmol, 1.0 equiv) in ACN (5 mL) was added 5-chloro-Nl-(l-(fluoromethyl)cyclopropyl)benzene-l,3-diamine (MMC2-intl45 - 48.0 mg, 0.22 mmol, 1.0 equiv), TCFH (91.0 mg, 0.33 mmol, 1.5 equiv) and NMI (60.0 mg, 0.66 mmol, 3.0 equiv). Then the mixture was stirred at 25 °C for 2 hours. The residue was purified by prep-HPLC eluting with 0-35% ACN in H2O (0.1% FA) to give N-(3-chloro-5-((l- (fluoromethyl)cyclopropyl)amino)phenyl)-5-(4-fluorophenyl)-l-methyl-lH-pyrrole-3-carboxamide (5.0 mg, 0.01 mmol, 4%). LCMS m / z = 416.0 (M+H)+. Tf NMR (400 MHz, CD3OD) 87.50 - 7.45 (m, 3H), 7.22 - 7.15 (m, 2H), 7.09 (t, J= 2.0 Hz, 1H), 7.02 (t, J=1.6 Hz, 1H), 6.70 (d, J= 2.0 Hz, 1H), 6.48 (t, J= 2.0Hz, 1H), 4.47 (s, 1H), 4.35 (s, 1H), 3.68 (s, 3H), 0.96 (m, 2H), 0.89 (m, 2H).19F NMR (377 MHz, CD3OD) 8 -217.83.Example 42: N-(3-Bromo-5-((l,l,l-tiifliioropropan-2-yl)amino)phenyl)^l-(5-fliioropyridiii-2-yl)-5-methylthiophene-2-carboxamide

[0315] To a solution of 5-bromo-Nl-(l,l,l-trifhroropropan-2-yl)benzene-l,3-diamine (85.0 mg, 0.30 mmol, 1.0 equiv) and 4-(5-fluoropyridin-2-yl)-5-methylthiophene-2-carboxylic acid (71.0 mg, 0.30 mmol, 1.0 equiv) in ACN (4 mL) was added TCFH (126.0 mg, 0.45 mmol, 1.5 equiv) and NMI (123.0 mg, 1.50 mmol, 5.0 equiv). Then the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and purified by prep-HPLC eluting with 0-60% ACN in H2O (0.1% NH4HCO3) to give N-(3-bromo-5-((l, 1, l-trifluoropropan-2-yl)amino)phenyl)-4-(5-fluoropyridin-2-yl)-5-methylthiophene-2-carboxamide (44.73 mg, 0.09 mmol, 30%). LCMS m / z = 503.9 (M+H)+. 'H NMR (400 MHz, DMSO- 6) 8 10.13 (s, 1H), 8.68 (d, J = 2.8Hz, 1H), 8.33(s, 1H), 7.88 (td, J= 8.8, 3.0 Hz, 1H), 7.76 (dd, J= 8.8, 4.4 Hz, 1H), 7.21 (d, J= 10.8 Hz, 2H), 6.69 (s, 1H), 6.38 (d, J= 8.8 Hz, 1H),WSGR Docket No. 69600-701.6014.33 -4.24 (m, 1H), 2.68 (s, 3H), 1.31 (d, J = 6.8Hz, 3H).19F NMR(377 MHz, DMSO-d6) 8 -75.67, -129.33.Example 42A and 42B: (R)-N-(3-Bromo-5-((l,l,l-trifluoropropan-2-yl)amino)phenyl)-4-(5-fluoropyridin-2-yI)-5-methyIthiophene-2-carboxamide &(S)-N-(3-Bromo-5-((l,l,l-trifluoropropan-2-yl)amino)phenyl)-4-(5-fluoropyridin-2-yl)-5-methyIthiophene-2-carboxamide[00316JSFC separation was carried out for example 42 (38.0 mg). The SFC separation information are shown as following:Analytical separation method:Instrument: Waters UPCC (CA-060), Column: DAICELCHIRALCEL®SJ, 100 x 3 mm, 3pm, Mobile phase: A for CO2 and B for MeOH (0.1%DEA), GradientB: 0-35%, Flow rate: 1.5 mL / min, Back pressure: 1800psi, Column temperature: 35°C, Wavelength: 254 nmPreparative separation method:

[0317] Instrument: Waters SFC80, Column: DAICELCHIRALCEL®IJ, 250 x 30 mm, 10pm, Mobile phase: A for CO2 andB for MeOH (+0.1% 7.0mol / l Ammonia in MeOH), Gradient B: 55%, Flow rate:80 mL / min, Back pressure: 100 bar, Column temperature: RT, Wavelength: 214 nm, Cycle time:4.38 min, Sample preparation: Sample was dissolved in about 34 mL MeOH, Injection: 4.5 mL per injection.

[0318] After separation, Example 42A (14.77 mg, >99% ee) was obtained (with a shorter retention time than42B). LCMS m / z= 504 (M+H)+.XH NMR (400 MHz, DMSO-d6) 8 10.13 (s, 1H), 8.68 (d, J= 2.8 Hz, 1H), 8.33 (s, 1H), 7.88 (td, J= 8.8, 3.0Hz, 1H), 7.76 (dd, J=8.8, 4.4Hz, 1H), 7.23 - 7.18 (m, 2H), 6.69 (s, 1H), 6.38 (d, J= 8.8 Hz, 1H), 4.33 - 4.26 (m, 1H), 2.68 (s, 3H), 1.31 (d, J= 6.8 Hz, 3H).19F NMR (377 MHz, DMSO-d6) 8 -75.67, -129.33.

[0319] Example 42B (19.61 mg, >99% ee) was obtained. LCMS m / z = 504 (M+H)+.1H NMR (400 MHz, DMSO-d6) 810.14 (s, 1H), 8.68 (d, J = 2.8Hz, 1H), 8.34 (s, 1H), 7.88 (td, J= 8.8, 3.0 Hz, 1H), 7.77 (dd, J= 8.8, 4.4 Hz, 1H), 7.22 (d, J= 10.6 Hz, 2H), 6.69 (s, 1H), 6.38 (d, J= 8.8 Hz, 1H), 4.33 -4.23 m, 1H), 2.68 (s, 3H), 1.31 (d, J= 6.8 Hz, 3H).19F NMR (377 MHz, DMSO-d6) 8 -75.67, -129.34.Example 43: N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-5-(4-fluorophenyl)-l-methyl-lH-pyrrole-3-carboxamideWSGR Docket No. 69600-701.601Methyl 5-(4-fluorophenyI)-l-methyI-lH-pyrrole-3-carboxyIate (compound 2)

[0320] To a solution of methyl 5-bromo-l-methyl-lH-pyrrole-3-carboxylate (200.0 mg, 0.92 mmol, 1.0 equiv) in dioxane / H2O (10 mL / lmL) was added 2-(4-fluorophenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (212.0 mg, 0.92 mg, 1.0 equiv), K2CO3 (252.0 mg, 1.84 mmol, 2.0 equiv), Pd (dppf)C12 (67.0 mg, 0.092 mmol, 0.1 equiv). Then the mixture was stirred at 80 °C for 2 hours. The residue was purified by silica column chromatography eluting with 25% EtOAc in PE to give methyl 5-(4-fluorophenyl)-l-methyl-lH-pyrrole-3-carboxylate (160.0 mg, 0.68 mmol, 75%) as a white solid. LCMS m / z = 234.0 (M+H)+.5-(4-Fluorophenyl)-l-methyl-lH-pyrrole-3-carboxylic acid (compound 3)

[0321] To asolution of methyl 5-(4-fluorophenyl)-l-methyl-lH-pyrrole-3-carboxylate (160.0 mg, 0.68 mmol, 1.0 equiv) in THF / H2O (10 mL / 2 mL) was added LiOH (32.4 mg, 1.36 mmol, 2.0 equiv). Then the mixture was stirred at 25 °C for 1 hour. The residue was purified by Cl 8 reverse phase eluting with 30% ACN in H2O to give 5-(4-fluorophenyl)-l -methyl- lH-pyrrole-3-carboxy lie acid (120.0 mg, 0.51 mmol, 75%) as a white solid. LCMS m / z = 220.0 (M+H)+.N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-5-(4-fluorophenyl)-l-methyl-lH-pyrrole-3-carboxamide

[0322] To asolution of 5-(4-fluorophenyl)-l-methyl-lH-pyrrole-3-carboxylic acid (50.0 mg, 0.23 mmol, 1.0 equiv) in ACN (5 mL) was added 5-chloro-Nl-(oxetan-3-yl)benzene-l,3-diamine (MMC2-intl6 -46.0 mg, 0.23 mmol, 1.0 equiv), TCFH (100.0 mg, 0.35 mmol, 1.5 equiv) and NMI (54.0 mg, 0.69 mmol, 3.0 equiv). Then the mixture was stirred at 25 °C for 2 hours. The residue was purified by prep-HPLC eluting with 0-65% ACN in H2O (0.1% NH4HCO3) to give N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-5-(4-fluorophenyl)-l-methyl-lH-pyrrole-3-carboxamide (60.0 mg, 0.15 mmol, 65%). LCMS m / z = 400.1 (M+H)+.1HNMR(400MHz, CD3OD) 87.47 (dd, J= 8.4, 4.8 Hz, 3H), 7.18 (t, J= 8.8 Hz, 2H), 7.04 (s, 1H), 6.84 (t, J = 2.0 Hz, 1H), 6.69 (d, J = 2.0 Hz, 1H),6.31 (t, J =2.0 Hz, 1H), 4.98 (t, J= 6.4 Hz, 2H), 4.62 - 4.51 (m, 3H), 3.68 (s, 3H).19F NMR (377 MHz, CD3OD) 8 -116.56.Example 44: N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-5-(3-fluorophenyl)-l-methyl-lH-pyrrole-3-carboxamide is the same as example 8.WSGR Docket No. 69600-701.601Example 45: N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-5-(3,5-difluorophenyl)-l-methyl-lH-pyrrole-3-carboxamideMethyl 5-(3,5-difluorophenyl)-l-methyl-lH-pyrrole-3-carboxylate (compound 2)

[0323] To a solution of methyl 5-bromo-l-methyl-lH-pyrrole-3-carboxylate (200.0 mg, 0.92 mmol, 1.0 equiv) and2-(3,5-difhrorophenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (243.0 mg, 1.01 mmol, 1.1 equiv) in l,4-dioxane / H2O (6 mL / 1 mL) was added Pd(dppf)C12 (67.0 mg, 0.09 mmol, 0.1 equiv) and K2CO3 (377.0 mg, 2.76 mmol, 3.0 equiv) under Argon atmosphere. Then the mixture was stirred at 90 °C for 2 hours. The reaction was filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 12% EtOAc in PE to give methyl 5-(3,5-difluorophenyl)-l-methyl-lH-pyrrole-3-carboxylate (180. Omg, 0.72 mmol, 78%) as a white solid. LCMS m / z = 252.10 (M+H)+.5-(3,5-Difluorophenyl)-l-methyl-lH-pyrrole-3-carboxylic acid (compound 3)

[0324] To a solution of methyl 5-(3,5-difluorophenyl)-l-methyl-lH-pyrrole-3-carboxylate (180.0 mg, 0.72 mmol, 1.0 equiv) in THF / MeOH / FLO (6 mL / 2 mL / 3 mL) was added NaOH (172.0 mg, 4.32 mmol, 6.0 equiv). Then the mixture was stirred at 70 °C for 2 hours. The mixture was adjusted pH to 6 with HC1 (2.0 N). The precipitated solids were collected by filtration and washed with H2O. This resulted in 5-(3,5-difluorophenyl)-! -methyl- 1H- pyrrole-3-carboxylic acid (139.0 mg, 0.59 mmol, 82%) as a white solid. LCMS m / z =238.3 (M+H)+.N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-5-(3,5-difluorophenyl)-l-methyl-lH-pyrrole-3-carboxamide

[0325] To a solution of 5-(3,5-difluorophenyl)-l-methyl-lH-pyrrole-3-carboxylic acid (36.0 mg, 0.15 mmol, 1.0 equiv) and 5-chloro-Nl-(oxetan-3-yl)benzene-l,3-diamine (MMC2-intl6 - 30.0 mg, 0.15 mmol, l. O equiv) in ACN (4 mL) was added TCFH (64.0 mg, 0.23 mmol, 1.5 equivjandNMI (37.0 mg, 0.45 mmol, 3.0 equiv). Then the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and purified by prep-HPLC eluting with 0-60% ACN in H2O (0.1% NH4HCO3) to give N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-5-(3,5-difluorophenyl)-l-methyl-lH-pyrrole-3-carboxamide (25.3 mg, 0.06 mmol, 40%). LCMS m / z = 418.1 (M+H)+. 'H NMR (400 MHz,WSGR Docket No. 69600-701.601CD3OD) 87.53 (d, J= 1.6 Hz, 1H), 7.11 (dd, J= 10.0, 3.6 Hz, 2H), 7.04 (t, J= 1.6 Hz, 1H), 6.96 (tt, J = 9.6, 2.4 Hz, 1H), 6.85 - 6.82 (m, 2H), 6.31 (t, J= 2.0 Hz, 1H), 4.98 (t, J= 6.0 Hz, 2H), 4.59 (dd, J = 10.0, 3.6 Hz, 1H), 4.57 - 4.54 (m, 2H), 3.76 (s, 3H).19F NMR(376 MHz, CD3OD) 8 -111.33.Example 46: N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-5-(2,3-difluorophenyl)-l-methyl-lH-pyrrole-3-carboxamideMethyl 5-(2,3-difluorophenyl)-l-methyl-lH-pyrrole-3-carboxylate (compound 2)

[0326] To amixture of methyl l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrrole-3-carboxylate (200.0 mg, 0.75 mmol, 1.0 equiv) and l-bromo-2,3-difluorobenzene (145.0 mg, 0.75 mmol, 1.0 equiv) in l,4-dioxane / H2O (10 mL / 2 mL) was added K2CO3 (207.0 mg, 1.5 mmol, 2.0 equiv) and Pd(dppf)Ch (61.2 mg, 0.075 mmol, 0.1 equiv). The mixture was stirred at 90°C for 16 hours. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 6% EtOAc in PE to give methyl 5-(2,3-difluorophenyl)-l-methyl-lH-pyrrole-3-carboxylate (120.0 mg, 0.48 mmol, 63.7%) as a white solid.5-(2,3-Difluorophenyl)-l-methyl-lH-pyrrole-3-carboxylic acid (MMC2-int211)

[0327] To a solution of methyl 5-(2,3-difluorophenyl)-l-methyl-lH-pyrrole-3-carboxylate (120.0 mg, 0.48 mmol, 1.0 equiv.) in MeOH / H2O(8 mL / 2 mL) was addedNaOH (38.4 mg, 0.96 mmol, 2.0 equiv.). Then the mixture was stirred at 60 °C for 1 hour. The mixture was concentrated under reduced pressure and adjusted pH to 6 with citric acid solution. The precipitated solids were collected by filtration and washed with H2O. This resulted in 5-(2,3-difluorophenyl)-l-methyl-lH-pyrrole-3-carboxylic acid (80.0 mg, 0.34 mmol, 70%) as a yellow solid. LCMS m / z = 238.1 (M+H)+.N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-5-(2,3-difluorophenyl)-l-methyl-lH-pyrrole-3-carboxamide

[0328] To a solution of 5-(2,3-difluorophenyl)-l-methyl-lH-pyrrole-3-carboxylic acid (50.0 mg, 0.21 mmol, 1.0 equiv.) and 5-chloro-Nl-(oxetan-3-yl)benzene-l,3-diamine (MMC2-intl6 - 42.0 mg, 0.21 mmol, 1.0 equiv.) in ACN (5 mL) was added TCFH (88.2 mg, 0.31 mmol, 1.5 equiv.) andNMI (51.6 mg, 0.63 mmol, 3.0 equiv.). The mixture was stirred at 25°C for 2 hours. The mixture was concentrated under reduced pressure and purified by prep-HPLC eluting with 0-75% ACN in H2O (0.1% NH4OH) to giveWSGR Docket No. 69600-701.601N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-5-(2,3-di fluorophenyl)- 1 -methyl- 1H- pyrrol e-3-carboxamide (8.0 mg, 0.02 mmol, 9%). LCMS m / z =418.0 (M+H)+.1H NMR (400 MHz, DMSO-d6) 89.48 (s, 1H), 7.69 (d, J= 1.6Hz, 1H), 7.51 (d, J = 7.2Hz, 1H), 7.32 (dd, J= 6.8, 3.2 Hz, 2H), 7.13 (s, 1H), 6.90 (s, 1H), 6.83 (s, 1H), 6.70 (d, J=6.1 Hz, 1H), 6.19 (s, 1H), 4.84 (t, J= 6.4 Hz, 2H), 4.49 (dd, J= 12.0, 6.0 Hz, 1H), 4.41 (t, J= 6.0Hz, 2H), 3.60 (s, 3H).19F NMR (377 MHz, DMSO-d6) 8 -138.19 (d, J= 22.5 Hz), -140.22 (d, J= 23.1 Hz).Example 47: N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-5-(2,5-difluorophenyl)-l-methyl-lH-pyrrole-3-carboxamideMethyl 5-(2,5-difluorophenyl)-l-methyl-lH-pyrrole-3-carboxylate (compound 2)

[0329] To amixture of methyl l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrrole-3-carboxylate (200.0 mg, 0.75 mmol, 1.0 equiv) and l-bromo-2,3-difluorobenzene (145.0 mg, 0.75 mmol, 1.0 equiv) in l,4-dioxane / H2O (10 mL / 2 mL) was added K2CO3 (207.0 mg, 1.5 mmol, 2.0 equiv) and Pd(dppf)Ch (61.2 mg, 0.075 mmol, 0.1 equiv). The mixture was stirred at 90°C for 16 hours. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 6% EtOAc in PE to give methyl 5-(2,5-difluorophenyl)-l-methyl-lH-pyrrole-3-carboxylate (80.0 mg, 0.32 mmol, 42%) as a white solid. LCMS m / z =252.1 (M+H)+.5-(2,5-Difluorophenyl)-l-methyl-lH-pyrrole-3-carboxylic acid (MMC2-int212)To a solution of methyl 5-(2,5-difluorophenyl)-l-methyl-lH-pyrrole-3-carboxylate (80.0 mg, 0.32 mmol, 1.0 equiv) in MeOH / H2O (8 mL / 2 mL) was added NaOH (25.6 mg, 0.64 mmol, 2.0 equiv). Then the mixture was stirred at 60 °C for 1 hour. The mixture was concentrated under reduced pressure and adjusted pH to 6 with citric acid solution. The precipitated solids were collected by filtration and washed with H2O. This resulted in 5-(2,5-difluorophenyl)-1-methyl-1H-pyrrole-3-carboxylic acid (50.0 mg, 0.34 mmol, 65%) as a yellow solid. LCMS m / z = 238.4 (M+H)+.N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-5-(2,5-difluorophenyl)-l-methyl-lH-pyrrole-3-carboxamide

[0330] To a solution of 5-(2,5-difluorophenyl)-l-methyl-lH-pyrrole-3-carboxylic acid (50.0 mg, 0.21 mmol, 1.0 equiv) and 5-chloro-Nl-(oxetan-3-yl)benzene-l,3-diamine (MMC2-intl6 - 42.0 mg, 0.21WSGR Docket No. 69600-701.601mmol, 1.0 equiv) in ACN (5 mL) was added TCFH (88.2 mg, 0.31 mmol, 1.5 equiv) and NMI (51.6 mg, 0.63 mmol, 3.0 equiv). The mixture was stirred at 25°C for 2 hours. The mixture was concentrated under reduced pressure and purified by prep-HPLC eluting with 0-75% ACN in H2O (0.1% NH4OH) to give N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-5-(2,5-di fluorophenyl)- 1 -methyl- 1H- pyrrol e-3-carboxamide (13.0 mg, 0.03 mmol, 15%). LCMS m / z =418.2 (M+H)+. 'H NMR (400 MHz, DMSO-d6) 59.47 (s, 1H), 7.67 (s, 1H), 7.45 -7.30 (m, 3H), 7.13 (s, lH),6.90 (s, lH),6.82(s, 1H), 6.70 (d, J= 6.0 Hz, 1H), 6.18 (s, 1H), 4.84 (t, J= 6.0 Hz, 2H), 4.49(dd, J= 12.2, 6.0 Hz, 1H),4.41 (t, J = 6.0Hz, 2H),3.60(s, 3H).19F NMR (377 MHz, DMSO-J6) 8 -118.32, -119.80.Example 48: N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-l-methyl-5-(2,4,5-trifluorophenyl)-lH-pyrrole-3-carboxamideMethyl 1-methyl-5-(2,4,5-trifluorophenyl)-1H-pyrrole-3-carboxylate (compound 2)

[0331] To amixture of methyl l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrrole-3-carboxylate (300.0 mg, 1.13 mmol, 1.0 equiv) in Dioxane / H2O (20 mL / 4 mL) was added K2CO3 (309.0 mg, 2.26 mmol, 2.0 equiv), and Pd(dppf)C12(44.0 mg, 0.06 mmol, 0.05 equiv). l-bromo-2,4,5-trifluorobenzene (235.0 mg, 1.13 mmol, 1.0 equiv). The mixture was stirred at 90 °C for 16 hours. The reaction was diluted with H2O (80 mL x 3) and extracted with EtOAc (40 mL x 2). The combined organic layer was washed with brine H2O (50 mL x 2), dried over Na2SCh. and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 10% EtOAc in PE to give methyl l-methyl-5-(2,4,5-trifluorophenyl)-lH-pyrrole-3-carboxylate (200.0 mg, 0.74 mmol, 66%) as a white solid. LCMS m / z = 270.0 (M+H)+.1-ethyl-5-(2,4,5-trifluorophenyl)-1H-pyrrole-3-carboxylic acid (compound 4)

[0332] To a solution of methyl l-ethyl-5-(5-fluoropyridin-2-yl)-lH-pyrrole-3-carboxylate (180.0 mg, 0.73 mmol, 1.0 equiv) in EtOH / H₂O (15 mL / 3 mL) was added NaOH (58.4 mg, 1.46 mmol, 2.0 equiv). The mixture was stirred at 60 °C for 1 hour. The mixture was concentrated under reduced pressure andWSGR Docket No. 69600-701.601adjusted pH to 7 with acetic acid. The precipitated solids were collected by filtration and washed with H2O (10 mL). This resulted in l-ethyl-5-(5-fluoropyridin-2-yl)-lH-pyrrole-3-carboxylic acid (150.0 mg, 0.64 mmol, 87%) as a white solid. LCMS m / z = 297.3 (M+CAN+H)+.N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-1-methyl-5-(2,4,5-trifluorophenyl)-1H-pyrrole-3-carboxamide

[0333] To a solution of l-ethyl-5-(5-fluoropyridin-2-yl)-lH-pyrrole-3-carboxylic acid (50.0 mg, 0.2 mmol, 1.0 equiv) in ACN (10 mL) was added 5-bromo-Nl-(oxetan-3-yl)benzene-l,3-diamine (MMC2-int47 - 4.02 mg, 0.21 mmol, 1.0 equiv), TCFH (89.0 mg, 0.32 mmol, 1.5 equiv) andNMI (52.0 mg, 0.63 mmol, 3.0 equiv). Then the mixture was stirred at 25 °C for 2 hours. The residue was purified by silica column chromatography eluting with 60% EtOAc in PE to give N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-l-methyl-5-(2,4,5-trifluorophenyl)-lH-pyrrole-3-carboxamide (60.0 mg, 0.14 mmol, 69%). LCMS m / z = 436.1 (M+H)+. 'H NMR (400 MHz, CD3OD) 87.55 (d, J = 2.0Hz, 1H), 7.43 -7.28 (m, 2H), 7.04 (t, J= 2.0 Hz, 1H), 6.84 (t, J= 2.0 Hz, 1H), 6.75 (d, J = 2.0 Hz, 1H), 6.31 (t, J = 2.0 Hz, 1H), 4.98 (t, J= 6.4 Hz, 2H), 4.57 (m, 3H),3.61 (d, J= 1.2 Hz, 3H).19F NMR(377 MHz, CD3OD) 8 -116.56.Example 49: N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-l-methyl-5-(2,3,6-trifluorophenyl)-lH-pyrrole-3-carboxamideMethyl l-methyl-5-(2,3,6-trifluorophenyl)-lH-pyrrole-3-carboxylate (compound 2)

[0334] To a solution of methyl l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrrole-3-carboxylate (1.0 g, 4.00 mmol, 1.0 equiv) in dioxane (18 mL) and H2O (3 mL)was added 2-bromo-l,3,4-trifluorobenzene (1.6 g, 6.00 mmol, 1.5 equiv), Pd(dppf)C12 (146.4 mg, 0.2 mmol, 0.05 equiv) and K2CQ3 (1.1 g, 8.0 mmol, 2.0 equiv) under Argon atmosphere. The mixture was stirred at 80 °C for 16 hours. The combined organic layer was washed with brine (30 mLx 2), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 65% EtOAc in PE to give methyl l-methyl-5-(2,3,6-trifluorophenyl)-lH-pyrrole-3-carboxylate (620.2 mg, 2.30 mmol, 57%) as a white solid. LCMS m / z = 270.0 (M+H)+.l-Methyl-5-(2,3,6-trifluorophenyl)-lH-pyrrole-3-carboxylic acid (MMC2-int214)WSGR Docket No. 69600-701.601

[0335] To a solution of methyl l-methyl-5-(2,3,6-trifluorophenyl)-lH-pyrrole-3-carboxylate (269.0 mg, 1.00 mmol, 1.0 equiv) in EtOH / H₂O (9 mL / 3 mL) was added Li OH (47.9 mg, 2.00 mmol, 2.0 equiv). Then the mixture was stirred at 25 °C for 1 hour. The mixture was adjusted pH to 6 with HC1 (2.0 N). The precipitated solids were collected by filtration and washed with H2O. This resulted in l-methyl-5-(2,3,6-trifluorophenyl)-lH-pyrrole-3-carboxylic acid (100.0 mg, 0.39 mmol, 39%) as a white solid. LCMS m / z =297.0 (M+41+H)+.N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-1-methyl-5-(2,3,6-trifluorophenyl)-1H-pyrrole-3-carboxamide

[0336] To a solution of l-methyl-5-(2, 3, 6-trifluorophenyl)-lH-pyrrole-3-carboxylic acid (61.2 mg, 0.24 mmol, 1.0 equiv) and 5-chloro-Nl-(oxetan-3-yl)benzene-l,3-diamine (MMC2-intl6 - 71.2 mg, 0.36 mmol, 1.5 equiv) in ACN (5 mL) was added TCFH (95.0 mg, 0.36 mmol, 1.5 equiv) and NMI (58.0 mg, 0.72 mmol, 3.0 equiv). The mixture was stirred at 25 °C for 2 hours. The mixture was concentrated under reduced pressure and purified by prep-HPLC eluting with 0-70% ACN in H2O (0.1% NH4OH) to give N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-l-methyl-5-(2,3,6-trifluorophenyl)-lH-pyrrole-3-carboxamide (20.5 mg, 0.04 mmol, 19%). LCMS m / z =435.9 (M+H)+.! HNMR(400 MHz, CD3OD) 57.63 (d, J= 2.0 Hz, 1H), 7.46-7.36(m, 1H), 7.17 - 7.08 (m, 1H),7.05 (t, J= 2.0Hz, 1H), 6.87 - 6.79 (m, 2H), 6.31 (t, J= 2.0 Hz, 1H), 4.98 (t, J= 6.4 Hz, 2H), 4.63 - 4.53 (m, 3H), 3.58 (s, 3H).19F NMR (377 MHz, CD3OD) 8 -117.84, -136.58, -144.10.Example 50: N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-l-methyl-5-(4-(trifluoromethyl)phenyl)-lH-pyrrole-3-carboxamideMethyl l-methyl-5-(2,4,6-trifluorophenyl)-lH-pyrrole-3-carboxylate (compound 2)

[0337] To asolutionof2-bromo-l,3,5-trifluorobenzene(400.0mg, 1.9mmol, 1.0 equiv) and methyl 1-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 1 H -pyrrole- 3-carboxylate (604.0 mg, 2.28 mmol, 1.2 equiv) in dioxane (4 mL) andH2O (2 mL) was added Pd(dppf)C12 (78.0 mg, 0.095 mmol, 0.05 equiv) and K2CO3 (496.0 mg, 3.6 mmol, 2.0 equiv). The reaction mixture was stirred at 80 °C for 16 hours. TheWSGR Docket No. 69600-701.601mixture was concentrated under reduced pressure and the residue was purified by silica column chromatography eluting with 20% EtOAcinPEto afford methyl l-methyl-5-(2,4,6-trifluorophenyl)-lH-pyrrole-3-carboxylate (125.0 mg, 0.46 mmol, 24%) as a white solid.l-Methyl-5-(2,4,6-trifluorophenyl)-lH-pyrrole-3-carboxylic acid (MMC2-int217)

[0338] To a solution of methyl l-methyl-5-(2,4,6-trifluorophenyl)-lH-pyrrole-3-carboxylate (125.0 mg, 0.46 mmol, 1.0 equiv) in EtOH / H₂O (2 mL / 1 mL) was added NaOH (37.0 mg, 0.92 mmol, 2.0 equiv). Then the mixture was stirred at 80 °C for 1 hour. The mixture was concentrated under reduced pressure and adjusted pH to 6 with citric acid solution. The precipitated solids were collected by filtration and washed with H2O. This resulted in l-methyl-5-(2,4,6-trifluorophenyl)-lH-pyrrole-3-carboxylic acid (125.0 mg, 0.49 mmol,) as a yellow solid.N-(3-Bromo-5-(oxetan-3-ylamino)phenyl)-1-methyl-5-(2,4,6-trifluorophenyl)-1H-pyrrole-3-carboxamide

[0339] To a solution of l-methyl-5-(2,4,6-trifluorophenyl)-lH-pyrrole-3-carboxylic acid (125.0 mg, 0.49 mmol, 1.0 equiv) and 5-bromo-Nl-(oxetan-3-yl)benzene-l,3-diamine (MMC2-int47 - 120.0 mg, 0.49 mmol, 1.0 equiv) in ACN (4 mL) was added TCFH (206.0 mg, 0.735 mmol, 1.5 equiv) and NMI (120.0 mg, 1.47 mmol, 3.0 equiv). Then the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure and purified by prep-HPLC eluting with 0-60% ACN in H2O (0.1% NH4HCO3) to give N-(3-bromo-5-(oxetan-3-ylamino)phenyl)-l-methyl-5-(2,4,6-trifluorophenyl)-lH-pyrrole-3-carboxamide(17.15mg, 0.035 mmol, 18%). LCMS m / z = 482.0 (M+H)+. > HNMR (400 MHz, DMSO-d6) 87.50 (d, J = 2.0 Hz, 1H), 7.44 (s, 4H), 7.04 (t, J = 1.8 Hz, 1H), 6.84 (t, J = 2.0 Hz, 1H), 6.74 (d, J = 2.0 Hz, 1H), 6.30 (t, J = 2.0 Hz, 1H), 4.98 (dd, J = 8.6, 3.8 Hz, 2H), 4.59 (dd, J = 10.0, 4.0 Hz, 1H), 4.55 (dd, J = 6.8, 4.4 Hz, 2H), 3.70 (s, 3H).19F NMR (377 MHz, DMSO-d6) 8 -106.48, -108.15.Example 51: N-(3-Bromo-5-(oxetan-3-ylamino)phenyl)-1-methyl-5-(2,3,6-trifluorophenyl)-1H-pyrrole-3-carboxamide

[0340] To a solution of l-methyl-5-(2, 3, 6-trifluorophenyl)-lH-pyrrole-3-carboxylic acid (50.0 mg, 0.20 mmol, 1.0 equiv) and 5-bromo-Nl-(oxetan-3-yl)benzene-l,3-diamine (MMC2-int47 - 47.0 mg, 0.20 mmol, 1.0 equiv) in ACN (3 mL) was added TCFH (85.0 mg, 0.30 mmol, 1.5 equiv) and NMI (49.0 mg, 0.60 mmol, 3.0 equiv). Then the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure and purified by prep-HPLC eluting with 0-60% ACN in H2O (0.1% NH4HCO3) to give N-(3-bromo-5-(oxetan-3-ylamino)phenyl)-l-methyl-5-(2,3,6-trifluorophenyl)-lH-WSGR Docket No. 69600-701.601pyrrole-3-carboxamide (30.93 mg, 0.06 mmol, 33%). LCMS m / z = 481.7 (M+H)+. 'H NMR (400 MHz, DMSO-O 89.50 (s, 1H), 7.74 (d, J = 2.0 Hz, 1H), 7.64 (qd, J= 9.6, 5.2 Hz, 1H), 7.32 (tdd, J= 9.2, 4.0, 2.0Hz, 1H), 7.26 (t, J= 1.6 Hz, 1H), 6.94 (t, J = 2.0Hz, 1H), 6.86 (d, J= 2.0 Hz, 1H), 6.70 (d, J= 6.0 Hz, 1H), 6.32 (t, J= 2.0 Hz, 1H), 4.84 (t, J= 6.4 Hz, 2H), 4.51 - 4.45 (m, 1H), 4.40 (t, J = 6.0 Hz, 2H), 3.54 (s, 3H).19F NMR(377 MHz, DMSO-d6) δ -116.25, -134.91, -141.80.Example 52: 5-(2-Chloro-4-fluorophenyl)-N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-l-methyl-lH-pyrrole-3-carboxamideMethyl 5-(2-chloro-4-fluorophenyl)-l-methyl-lH-pyrrole-3-carboxylate (compound 2)

[0341] To a solution of methyl 5-bromo-l-methyl-lH-pyrrole-3-carboxylate (864.0 mg, 4.00 mmol, 1.0 equiv) in dioxane (18 mL) and H2O (3 mL)was added 2-(2-chloro-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.5 g, 6.00 mmol, 1.5 equiv), Pd(dppf)C12 (146.4 mg, 0.2 mmol, 0.05 equiv) and K2CO3 (1.1 g, 8.0 mmol, 2.0 equiv) under Argon atmosphere. The mixture was stirred at 80 °C for 16 hours. The combined organic layer was washed with brine (30 mL x 2), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 65% EtOAc in PE to give methyl 5 -(2-chloro-4-fluorophenyl)-l -methyl- lH-pyrrole-3-carboxylate (660.2 mg, 2.47 mmol, 61%) as a white solid. LCMS m / z = 268.3 (M+H)+.5-(2-Chloro-4-fluorophenyl)-1-methyl-1H-pyrrole-3-carboxylic acid (MMC2-int218)

[0342] To a solution of methyl 5-(2-chloro-4-fluorophenyl)-l-methyl-lH-pyrrole-3-carboxylate (267.0 mg, 1.00 mmol, 1.0 equiv) in EtOH / H2O (9 mL / 3 mL) was added LiOH (47.9 mg, 2.00 mmol, 2.0 equiv). Then the mixture was stirred at 25 °C for 1 hour. The mixture was adjusted pH to 6 with HC1 (2 N). The precipitated solids were collected by filtration and washed with H2O. This resulted in 5-(2-chloro-4-fluorophenyl)-l-methyl-lH-pyrrole-3-carboxylic acid (110.0 mg, 0.43 mmol, 43%) as a white solid. LCMS m / z =254.1 (M+41+H)+.N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-1-methyl-5-(2,3,6-trifluorophenyl)-1H-pyrrole-3-carboxamideWSGR Docket No. 69600-701.601

[0343] To a solution of 5-(2-chloro-4-fluorophenyl)-l-methyl-lH-pyrrole-3-carboxytic acid (60.7 g, 0.24 mmol, 1.0 equiv) and 5-chloro-Nl-(oxetan-3-yl)benzene-l,3-diamine (MMC2-intl6 - 71.2 mg, 036 mmol, 1.5 equiv) in ACN (5 mL) was added TCFH (95.0 mg, 0.36 mmol, 1.5 equiv) and NMI (58.0 mg, 0.72 mmol, 3.0 equiv). The mixture was stirred at 25 °C for 2 hours. The mixture was concentrated under reduced pressure and purified by prep-HPLC eluting with 0-70% ACN in H2O (0.1%NH4OH) to give 5-(2-chloro-4-fluorophenyl)-N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-l-methyl-lH-pyrrole-3-carboxamide (21.5 mg, 0.05 mmol, 19%). LCMS m / z =434.0 (M+H)+.1H NMR (400 MHz, CD3OD) 8 7.52 (d, J= 2.0 Hz, 1H), 7.41 (ddd, J= 11.2, 8.8,4.4Hz, 2H), 7.19 (td, J= 8.4, 2.8 Hz, 1H), 7.04 (t, J = 2.0 Hz, 1H), 6.84 (t, J = 2.0 Hz, 1H), 6.65 (d, J = 2.0 Hz, 1H), 6.31 (t, J= 2.0 Hz, 1H), 4.98 (t, J= 6.4 Hz, 2H), 4.61 - 4.53 (m, 3H), 3.50 (s, 3H).19F NMR (377 MHz, MeOD-d4) 8 -112.58.Example 53: 5-(3-Chloro-4-fluorophenyl)-N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-l-methyl-lH-pyrrole-3-carboxamideMethyl 5-(3-chloro-4-fluorophenyl)-l-methyl-lH-pyrrole-3-carboxylate (compound 2)

[0344] To a solution of methyl 5-bromo-l-methyl-lH-pyrrole-3-carboxylate (864.0 mg, 4.00 mmol, 1.0 equiv) in dioxane (18 mL) and H2O (3 mL)was added 2-(3-chloro-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.5 g, 6.00 mmol, 1.5 equiv), Pd(dppf)C12 (146.4 mg, 0.2 mmol, 0.05 equiv) and K2CO3 (1.1 g, 8.0 mmol, 2.0 equiv). The mixture was stirred at 80 °C for 16 hours. The combined organic layer was washed with brine (30 mL x 2), dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 55% EtOAc in PE to give methyl 5-(3-chloro-4-fluorophenyl)-l-methyl-lH-pyrrole-3-carboxylate (658.2 mg, 2.47 mmol, 61%) as a white solid. LCMS m / z = 268.0 (M+H)+.5-(3-Chloro-4-fluorophenyl)-1-methyl-1H-pyrrole-3-carboxylic acid (MMC2-int225)

[0345] To a solution of methyl 5-(3-chloro-4-fluorophenyl)-l-methyl-lH-pyrrole-3-carboxylate (267.0 mg, 1.00 mmol, 1.0 equiv) in EtOH / H2O (9 mL / 3 mL) was added LiOH (47.9 mg, 2.00 mmol, 2.0 equiv). Then the mixture was stirred at 25 °C for 1 hour. The mixture was adjusted pH to 6 with HC1 (2 N). TheWSGR Docket No. 69600-701.601precipitated solids were collected by filtration and washed with H2O. This resulted in 5-(3-chloro-4-fluorophenyl)-l-methyl-lH-pyrrole-3-carboxylic acid (108.0 mg, 0.43 mmol, 43%) as a white solid. LCMS m / z =254.1 (M+41+H)+.5-(3-Chloro-4-fluorophenyl)-N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-l-methyl-lH-pyrrole-3-carboxamide

[0346] To a solution of 5-(3-chloro-4-fluorophenyl)-l-methyl-lH-pyrrole-3-carboxylic acid (60.7 mg, 0.24 mmol, 1.0 equiv) and 5-chloro-Nl-(oxetan-3-yl)benzene-l,3-diamine (MMC2-intl6 - 71.2 mg, 036 mmol, 1.5 equiv) in ACN (5 mL) was added TCFH (95.0 mg, 0.36 mmol, 1.5 equiv) and NMI (58.0 mg, 0.72 mmol, 3.0 equiv). The mixture was stirred at 25 °C for 2 hours. The mixture was concentrated under reduced pressure and purified by prep-HPLC eluting with 0-70% ACN in H2O (0.1%NH4OH) to give 5-(2-chloro-4-fluorophenyl)-N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-l-methyl-lH-pyrrole-3-carboxamide (20.9 mg, 0.05 mmol, 19%). LCMS m / z =434.1 (M+H)+.1H NMR (400 MHz, CD3OD) 8 7.59 (dd, J= 7.2, 2.4 Hz, 1H), 7.50 (d, J= 2.0 Hz, 1H), 7.42 (ddd, J= 8.4, 4.8, 2.4 Hz, 1H), 7.33 (t, J = 8.8 Hz, 1H), 7.04 (t, J= 2.0 Hz, 1H), 6.84 (t, J= 2.0 Hz, 1H), 6.74 (d, J = 2.0 Hz, 1H), 6.31 (t, J = 2.0 Hz, 1H), 4.98 (t, J= 6.4 Hz, 2H), 4.57 (dt, J= 18.0, 5.6 Hz, 3H), 3.70 (s, 3H).19F NMR (377 MHz, CD3OD) 8 -119.29.Example 54: 5-(4-Chloro-3-fluorophenyl)-N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-l-methyl-lH-pyrrole-3-carboxamideMethyl 5-(4-chloro-3-fluorophenyl)-l-methyl-lH-pyrrole-3-carboxylate (compound 2)

[0347] To a solution of methyl l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrrole-3-carboxylate (350.0 mg, 1.32 mmol, 1.0 equiv) and 4-bromo-l-chloro-2-fluorobenzene (304.2 mg, 1.45 mmol, 1.1 equiv) in l,4-dioxane / H2O (10mL / 2 mL) was added Pd(dppf)Ch (48.3 mg, 0.066 mmol, 0.05 equiv) and K2CO3 (364.9 mg, 2.64 mmol, 2.0 equiv) under Argon atmosphere. The mixture was stirred at 90 °C for 2 hours. The reaction was filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 10% EtOAc in PE to give methyl 5-(4-chloro-3-WSGR Docket No. 69600-701.601fluorophenyl)- l-methyl-lH-pyrrole-3-carboxylate (220.0 mg, 0.82 mmol, 62.3%) as a white solid. LCMS m / z = 268.0 (M+H)+.5-(4-chloro-3-fluorophenyl)-l-methyl-lH-pyrrole-3-carboxylic acid (compound 3)

[0348] To a solution of methyl 5-(4-chloro-3-fluorophenyl)-l-methyl-lH-pyrrole-3-carboxylate (220.0 mg, 0.82 mmol, 1.0 equiv) in EtOH / H2O (5 mL / 1 mL) was added Li OH (59.0 mg, 2.47 mmol, 2.0 equiv). Then the mixture was stirred at 60 °C for 16 hours. The mixture was concentrated under reduced pressure and adjusted pH to 7 with acetic acid. The precipitated solids were collected by filtration and washed with H2O. This resulted in 5-(4-chloro-3-fluorophenyl)-l-methyl-lH-pyrrole-3-carboxylic acid (150.0 mg, 0.59 mmol, 72%) as a white solid. LCMS m / z = 254.0 (M+H)+.5-(4-Chloro-3-fluorophenyl)-N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-1-methyl-1H-pyrrole-3-carboxamide

[0349] To a solution of 5-(4-chloro-3-fluorophenyl)-l-methyl-lH-pyrrole-3-carboxylic acid (35.0 mg, 0.14 mmol, 1.0 equiv) and 5-chloro-Nl-(oxetan-3-yl)benzene-l,3-diamine (MMC2-intl6 - 27.4 mg, 0.14mmol, 1.0 equiv) in ACN (2 mL) was added TCFH (58.1 mg, 0.21 mmol, 1.5 equiv) and NMI (34.0 mg, 0.41 mmol, 3.0 equiv). Then the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure and purified by prep-HPLC eluting with 0-55% ACN in H2O (0.1% NH4HCO3) to give 5-(4-chloro-3-fluorophenyl)-N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-l-methyl-lH-pyrrole-3-carboxamide (6.0 mg, 0.014 mmol, 10%). LCMS m / z = 434.1 (M+H)+. 'HNMR (400 MHz, DMSO-d6) 59.46 (s, 1H), 7.73 - 7.62 (m, 2H), 7.59 (d, J= 10.4 Hz, 1H), 7.38 (d, J= 8.0 Hz, 1H), 7.13 (s, 1H), 6.89 (d, J= 5.3 Hz, 2H), 6.70 (d, J= 5.6 Hz, 1H), 6.18 (s, 1H), 4.84 (t, J= 6.2 Hz, 2H), 4.49 (d, J= 6.0 Hz, 1H), 4.41 (t, J= 5.8 Hz, 2H), 3.74 (s, 3H).19F NMR (377 MHz, DMSO-d6) 8 -115.73 (s).Example 55: N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-5-(4-fluoro-3-methoxyphenyl)-l-methyl-lH-pyrrole-3-carboxamideMethyl 5-(4-fluoro-3-methoxyphenyl)-l-methyl-lH-pyrrole-3-carboxylate (compound 2)WSGR Docket No. 69600-701.601

[0350] To a solution of methyl 5-bromo-1-methyl-1H-pyrrole-3-carboxylate (500.0 mg, 2.1 mmol, 1.0 equiv) in dioxane / H₂O (10 mL / 2mL) was added 2-(4-fluoro-3-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (529.0 mg, 2.1 mmol, 1.0 equiv), K2CO3 (869.0 mg, 6.3mmol, 3.0 equiv), Pd (dppf)Ch (85.0 mg, 0.105 mmol, 0.05 equiv) under Argon atmosphere. Then the mixture was stirred at 90 °C for 2 hours. The residue was purified by silica column chromatography eluting with 25% EtOAc in PE to give methyl 5-(4-fluoro-3-methoxyphenyl)-l-methyl-lH-pyrrole-3-carboxylate (400.0 mg, 1.6 mmol, 96%) as a white solid. LCMS m / z = 264.1 (M+H)+.5-(4-fluoro-3-methoxyphenyl)-1-methyl-1H-pyrrole-3-carboxylic acid (compound 3)

[0351] To asolution of 5-(4-fluoro-3-methoxyphenyl)-l-methyl-lH-pyrrole-3-carboxylate (400.0 mg, 1.6 mmol, 1.0 equiv) in EtOH / H2O (10 mL / 2 mL) was added NaOH (60.8 mg, 1.52 mmol, 1.0 equiv). Then the mixture was stirred at 60 °C for 1 hour. The residue was purified by Cl 8 reverse phase eluting with 30% ACN in H2O to give 5-(4-fluoro-3-methoxyphenyl)-l-methyl-lH-pyrrole-3-carboxylic acid (200.0 mg, 1.1 mmol, 53%) as a white solid. LCMS m / z = 250.1 (M+H)+.N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-5-(4-fluoro-3-methoxyphenyl)-1-methyl-1H-pyrrole-3-carboxamide

[0352] To asolution of 5-(4-fluoro-3-methoxyphenyl)-1-methyl-1H-pyrrole-3-carboxylic acid (40.0 mg, 0.16 mmol, 1.0 equiv) in ACN (5 mL) was added 5-chloro-Nl-(oxetan-3-yl)benzene-l,3-diamine (MMC2-intl6- 31 mg, 0.16 mmol, 1.0 equiv), TCFH (67.0 mg, 0.24 mmol, 1.5 equiv) andNMI (39.0 mg, 0.48 mmol, 3.0 equiv). Then the mixture was stirred at 25 °C for 2 hours. The residue was purified by prep-HPLC eluting with 0-65% ACN in H2O (0.1% NH4HCO3) to give N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-5-(4-fluoro-3-methoxyphenyl)-l -methyl- lH-pyrrole-3-carboxami de (10.0 mg, 0.04 mmol, 25%). LCMS m / z = 430.1 (M+H)+. Tf NMR (400 MHz, DMSO-d6) 8 9.43 (s, 1H), 7.60 (d, J = 1.8 Hz, 1H), 7.34 -7.19 (m, 2H),7.14(s, 1H), 7.04 (ddd, J = 8.4, 4.4, 2.0 Hz, 1H),6.91 (s, 1H), 6.77 (d, J = 1.8Hz, 1H), 6.69 (d, J = 6.2 Hz, 1H), 6.18(t, J = 1.8 Hz, 1H), 4.84 (t, J = 6.4 Hz, 2H), 4.60 - 4.37 (m, 3H), 3.90 (s, 3H), 3.69 (s, 3H).19F NMR (377 MHz, DMSO) 8 -136.91.Example 56: N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-5-(3-fluoro-4-methylphenyl)-l-methyl-lH-pyrrole-3-carboxamideWSGR Docket No. 69600-701.601Methyl 5-(3-fluoro-4-methylphenyl)-l-methyl-lH-pyrrole-3-carboxylate (compound 2)

[0353] To a solution of methyl 5-bromo-l-methyl-lH-pyrrole-3-carboxylate (500.0 mg, 2.1 mmol, 1.0 equiv) in dioxane / H2O (10 mL / 2 mL) was added 2-(3-fluoro-4-methylphenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (466.0 mg, 2.1 mmol, 1.0 equiv), K2CO3 (869.0 mg, 6.3 mmol, 3.0 equiv), Pd(dppf)C12 (85.0 mg, 0.105 mmol, 0.05 equiv) under Argon atmosphere. Then the mixture was stirred at 80 °C for 2 hours. The residue was purified by silica column chromatography eluting with 25% EtOAc in PE to give methyl 5-(3-fluorophenyl)-l -methyl- 1H- pyrrol e-3-carboxylate (410.0 mg, 1.7 mmol, 94%) as a white solid. LCMS m / z = 248.1 (M+H)+.5-(3-Fluoro-4-methylphenyl)-l-methyl-lH-pyrrole-3-carboxylic acid (compound 3)

[0354] To a solution of methyl 5-(3-fluorophenyl)-l-methyl-lH-pyrrole-3-carboxylate (400.0 mg, 1.61 mmol, 1.0 equiv) in EtOH / H₂O (10 mL / 2 mL) was added NaOH (64.4 mg, 1.61 mmol, 1.0 equiv). Then the mixture was stirred at 60 °C for 1 hour. The residue was purified by Cl 8 reverse phase eluting with 30% ACN in H2O to give 5-(3-fluoro-4-methylphenyl)-l -methyl- lH-pyrrole-3-carboxy lie acid (200.0 mg, 0.9 mmol, 53%) as a white solid. LCMS m / z = 234.1 (M+H)+.N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-5-(3-fluorophenyl)-l-methyl-lH-pyrrole-3-carboxamide

[0355] To a solution of 5-(3-fluoro-4-methylphenyl)-l-methyl-lH-pyrrole-3-carboxylic acid (40.0 mg, 0.17 mmol, 1.0 equiv) in ACN (5 mL) was added 5-chloro-Nl-(oxetan-3-yl)benzene-l,3-diamine (MMC2-intl6 - 33.0 mg, 0.17 mmol, 1.0 equiv), TCFH (71.0 mg, 0.255 mmol, 1.5 equiv) andNMI (41.0 mg, 0.51 mmol, 3.0 equiv). Then the mixture was stirred at 25 °C for 2 hours. The residue was purified by prep-HPLC eluting with 0-65% ACN in H2O (0.1% NH4HCO3) to give N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-5-(3-fluoro-4-methylphenyl)-l-methyl-lH-pyrrole-3-carboxamide (10 mg, 0.03 mmol, 25%). LCMS m / z = 414.2 (M+H)+. 'H NMR (400 MHz, DMSO-d6) 59.43 (s, 1H), 7.59 (d, J = 1.8 Hz, 1H), 7.43 - 7.20 (m, 3H), 7.13 (t, J = 1.8 Hz, 1H),6.91 (s, 1H), 6.80 (d, J = 2.0 Hz, 1H), 6.69 (d, J = 6.2 Hz, 1H), 6.18 (t, J = 1.8 Hz, 1H), 4.84 (t, J = 6.4 Hz, 2H), 4.58 - 4.37 (m, 3H), 3.71 (s, 3H), 2.30 (d, J = 20.6 Hz, 3H).19F NMR (377 MHz, DMSO) 8 -117.13.WSGR Docket No. 69600-701.601Example 57: N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-5-(2-fluoro-4-methylphenyl)-l-methyl-lH-pyrrole-3-carboxamideMethyl 5-(2-fluoro-4-methylphenyl)-l-methyl-lH-pyrrole-3-carboxylate (compound 2)

[0356] To a solution of methyl 5-bromo-l-methyl-lH-pyrrole-3-carboxylate (500.0 mg, 2.29 mmol, 1.0 equiv) and2-(2-fluoro-4-methylphenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (595.5 mg, 2.52 mmol, 1.1 equiv) in l,4-dioxane / H2O (lOmL / 2 mL) was added Pd(dppf)C12 (83.9 mg, 0.11 mmol, 0.05 equiv) and K2CO3 (633.8 mg, 4.59 mmol, 2 equiv). The mixture was stirred at 90 °C for 2 hours. The reaction was filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 10% EtOAc in PE to give methyl 5-(2-fluoro-4-methylphenyl)-l-methyl-IH-pyrr ole-3 -carboxylate (400.0 mg, 1.62 mmol, 70.6 %) as a white solid. LCMS m / z = 248.1 (M+H)+.5-(2-Fluoro-4-methylphenyl)-l-methyl-lH-pyrrole-3-carboxylic acid (compound 3)

[0357] To a solution of methyl 5-(2-fluoro-4-methylphenyl)-l-methyl-lH-pyrrole-3-carboxylate (400.0 mg, 1.62 mmol, 1.0 equiv) in EtOH / H₂O (5 mL / 1 mL) was added LiOH (77.5 mg, 3.2 mmol, 2.0 equiv). Then the mixture was stirred at 60 °C for 16 hours. The mixture was concentrated under reduced pressure and adjusted pH to 7 with acetic acid. The precipitated solids were collected by filtration and washed with H₂O. This resulted in 5-(2-fluoro-4-methylphenyl)-l -methyl- lH-pyrrole-3-carboxylic acid (300.0 mg, 1.3 mmol, 79.5%) as a white solid. LCMS m / z = 234.1 (M+H)+.N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-5-(2-fluoro-4-methylphenyl)-l-methyl-lH-pyrrole-3-carboxamide

[0358] To a solution of 5-fluoro-4-(5-fluoro-6-methylpyridin-2-yl)thiophene-2-carboxylic acid (35.0 mg, 0.15 mmol, 1.0 equiv) and 5-chloro-Nl-(oxetan-3-yl)benzene-l,3-diamine (MMC2-intl6 - 29.8 mg, 0.15 mmol, 1.0 equiv) in ACN (2 mL) was added TCFH (63.2 mg, 0.23 mmol, 1.5 equiv) andNMI (37.0 mg, 0.46 mmol, 3.0 equiv). Then the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and purified by prep-HPLC eluting with 0-55% ACN in H2O (0.1% NH4HCO3) to give N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-5-(2-fluoro-4-methylphenyl)-l-methyl-lH-pyrrole-3-carboxamide (13.0 mg, 0.031 mmol, 20.9%). LCMS m / z = 414.1 (M+H)+.1H NMRWSGR Docket No. 69600-701.601(400 MHz, DMSO-d6) 89.44 (s, 1H), 7.63 (d, J = 1.7 Hz, lH), 7.34 (t, J = 7.9 Hz, 1H), 7.20 - 7.11 (m, 3H), 6.90 (s, 1H), 6.72 - 6.68 (m, 2H), 6.18 (s, 1H), 4.84 (t, J = 6.3 Hz, 2H), 4.48 (d, J = 6.1 Hz, 1H), 4.41 (t, J = 5.9 Hz, 2H), 3.54 (s, 3H), 2.38 (s, 3H). 19F NMR (377 MHz, DMSO-d6) 8 -114.97. Example 58: N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-5-(2-cyclopropoxy-4-fluorophenyl)-l-methyl-lH-pyrrole-3-carboxamide1-Bromo-2-cyclopropoxy-4-fluorobenzene (compound 2)

[0359] To a solution of 2-bromo-5-fluorophenol (764.0 mg, 4.00 mmol, 1.0 equiv) in DMA (15 mL) was added bromocyclopropane (720.0 mg, 6.00 mmol, 1.5 equiv) and CS2CO3 (9.1 g, 28.0 mmol, 7.0 equiv). The mixture was stirred at 150 °C for 48 hours. The combined organic layer was washed with brine (30 mL x 2), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 5% EtOAc in PE to give 1 -bromo-2-cyclopropoxy-4-fluorobenzene (550.2 mg, 2.38 mmol, 59%) as a white solid.5-(2-Cyclopropoxy-4-fluorophenyl)-l-methyl-lH-pyrrole-3-carboxylic acid (compound 3)

[0360] To a solution of l-bromo-2-cyclopropoxy-4-fluorobenzene (229.0 mg, 1.00 mmol, 1.0 equiv) in dioxane (10 mL) and H2O (2 mL)was added methyl l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)- 1H- pyrrol e-3-carboxylate (397.5 mg, 1.50 mmol, 1.5 equiv), Pd(dppf)C12 (36.6 mg, 0.05 mmol, 0.05 equiv) and K2CO3 (275.0 mg, 2.0 mmol, 2.0 equiv) under Argon atmosphere. The mixture was stirred at 90 °C for 16 hours. The combined organic layer was washed with brine (30 mL x 2), dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 35% EtOAc in PE to give methyl 5-(2-cyclopropoxy-4-fluorophenyl)-l-methyl-lH-pyrrole-3-carboxylate (200.2 mg, 0.69 mmol, 69%) as a white solid. LCMS m / z = 290.1 (M+H)+.5-(2-Cyclopropoxy-4-fluorophenyl)-l-methyl-lH-pyrrole-3-carboxylic acid (compound 4)WSGR Docket No. 69600-701.601

[0361] To a solution of methyl methyl methyl 5-(2-cyclopropoxy-4-fluorophenyl)-l-methyl-lH-pyrrole-3-carboxylate (144.6 mg, 0.50mmol, 1.0 equiv) in EtOH / H2O (9 mL / 3 mL) was added LiOH (23.9 mg, 1.00 mmol, 2.0 equiv). Then the mixture was stirred at 25 °C for 1 hour. The mixture was adjusted pH to 6 with HC1 (2.0 N). The precipitated solids were collected by filtration and washed with H2O. This resulted in 5-(2-cyclopropoxy-4-fluorophenyl)-l-methyl-lH-pyrrole-3-carboxylic acid (100.0 mg, 0.36 mmol, 72%) as a white solid. LCMS m / z =276.1 (M+H)+.N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-5-(2-cyclopropoxy-4-fluorophenyl)-l-methyl-lH-pyrrole-3-carboxamide

[0362] To a solution of 5-(2-cyclopropoxy-4-fluorophenyl)-l-methyl-lH-pyrrole-3-carboxylic acid (66.0 mg, 0.24 mmol, 1.0 equiv) and 5-chloro-Nl-(oxetan-3-yl)benzene-l,3-diamine (MMC2-intl6 -71.2 mg, 0.36 mmol, 1.5 equiv) in ACN (5 mL) was added TCFH (95.0 mg, 0.36 mmol, 1.5 equiv) and NMI (58.0 mg, 0.72 mmol, 3.0 equiv). The mixture was stirred at 25 °C for 2 hours. The mixture was concentrated under reduced pressure and purified by prep-HPLC eluting with 0-65% ACN in H2O (0.1% NH4OH) to give N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-5-(2-cyclopropoxy-4-fluorophenyl)- 1 -methyl-lH-pyrrole-3-carboxamide (25.3 mg, 0.05 mmol, 23%). LCMS m / z =456.1 (M+H)+. 'HNMR (400 MHz DMSO-d6) 59.37 (s, 1H), 7.54 (d, J= 2.0 Hz, 1H), 7.31 - 7.23 (m, 2H), 7.13 (t, J= 2.0 Hz, 1H), 6.92 -6.86 (m, 2H), 6.68 (s, lH),6.54(d, J= 2.0 Hz, 1H), 6.17 (t, J= 2.0 Hz, 1H), 4.83 (t, J= 6.4 Hz, 2H), 4.47 (d,.7= 5.6 Hz. 1H), 4.41 (t,.7=6,0 Hz. 2H), 3.90 (tt, J= 6.0, 2.8 Hz, lH),3.38 (s, 3H), 0.83 (q, J = 6.0 Hz, 2H), 0.73 - 0.60 (m, 2H).19F NMR (377 MHz, DMSO-d6) 8 -110.43.Example 59: N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-5-(3-cyclopropoxy-4-fluorophenyl)-l-methyl- lH-pyrrole-3-carboxamide4-Bromo-2-cyclopropoxy-l-fluorobenzene (compound 2)

[0363] To a solution of 5-bromo-2-fluorophenol (700.0 mg, 3.66 mmol, 1.0 equiv) in DMA (15 mL) was added bromocyclopropane (619.0 mg, 5.12 mmol, 1.5 equiv) and CS2CO3 (8.34 g, 25.6 mmol, 7.0 equiv). The mixture was stirred at 150 °C for 48 hours. The mixture was extracted with EtOAc (50 m)WSGR Docket No. 69600-701.601and diluted with H2O (30 mL x 3). The combined organic layer was washed with brine (30 mL x 2), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 7% EtOAc in PE to give 4-bromo-2-cyclopropoxy-l -fluorobenzene (715.0 mg, 3.09 mmol, 84%) as a white solid.Methyl 5-(3-cyclopropoxy-4- fluorophenyl)- 1-methyI-lH- pyrrole- 3-carboxyIate (compound 3)

[0364] To a solution of 4-bromo-2-cyclopropoxy-l-fluorobenzene (300.0 mg, 1.31 mmol, 1.0 equiv) in dioxane (10 mL) and H2O (2 mL)was added methyl l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)- 1H- pyrrol e-3-carboxylate (347.0 mg, 1.31 mmol, 1.0 equiv), Pd(dppf)C12 (48.0 mg, 0.07 mmol, 0.05 equiv) and K2CO3 (362.0 mg, 2.62 mmol, 2.0 equiv) under Argon atmosphere. The mixture was stirred at 90 °C for 16 hours. The mixture was extracted with EtOAc (50 mL) and diluted with H2O (30 mL x 3). The combined organic layer was washed with brine (30 mL x 2), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 32% EtOAc in PE to give methyl 5-(3-cyclopropoxy-4-fluorophenyl)-l-methyl-lH-pyrrole-3-carboxylate (315.0 mg, 1.09 mmol, 83%) as a white solid. LCMS m / z = 290.1 (M+H)+.5-(3-Cyclopropoxy-4-fluorophenyl)-l-methyl-lH-pyrrole-3-carboxylic acid (compound 4)

[0365] To a solution of methyl 5-(3-cyclopropoxy-4-fluorophenyl)-l-methyl-lH-pyrrole-3-carboxylate (315.0 mg, 1.09 mmol, 1.0 equiv) in EtOH / H₂O (9 mL / 3 mL) was added NaOH (262.0 mg, 6.54 mmol, 6.0 equiv). Then the mixture was stirred at 70 °C for 2 hours. The mixture was adjusted pH to 6 with HC1 (2.0 N). The precipitated solids were collected by filtration and washed with H2O. This resulted in 5-(3-cyclopropoxy-4-fluorophenyl)-l-methyl-lH-pyrrole-3-carboxylic acid (287.0 mg, 1.04 mmol, 96%) as a white solid. LCMS m / z =276.1 (M+H)+.N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-5-(3-cyclopropoxy-4-fluorophenyl)-l-methyl-lH-pyrrole- 3-carboxamide

[0366] To a solution of 5-(3-cyclopropoxy-4-fluorophenyl)-l-methyl-lH-pyrrole-3-carboxylic acid (40.0 mg, 0.15 mmol, 1.0 equiv) and 5-chloro-Nl-(oxetan-3-yl)benzene-l,3-diamine (MMC2-intl6 -29.0mg, 0.15 mmol, 1.0 equiv) in ACN (3 mL) were added TCFH (61.0 mg, 0.23 mmol, 1.5 equiv) and NMI (36.0 mg, 0.45 mmol, 3.0 equiv). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure and purified by prep-HPLC eluting with 0-66% ACN in H2O (0.1% NH4OH) to give N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-5-(3-cyclopropoxy-4-fluorophenyl)-l-methyl-lH-pyrrole-3-carboxamide (33.18 mg, 0.07 mmol, 50%). LCMS m / z =456.1 (M+H)+.1HNMR(400MHz, CD3OD) 57.49 (d, J = 1.6 Hz, 1H), 7.42 (dd, J = 8.0, 1.6 Hz, 1H), 7.15 (dd, J= 11.2, 8.4 Hz, 1H), 7.04- 6.99 (m, 2H),6.85(s, 1H), 6.72 (d, J = 1.6 Hz, 1H), 6.31 (s, 1H), 4.98 (t,.7=6,0 Hz. 2H), 4.61 (dd, J= 12.0, 6.0 Hz, 1H), 4.63 - 4.58 (m, 2H), 4.57 - 4.54 (m, 1H), 3.71 (s, 3H), 0.84(dd, J= 11.6, 6.4Hz, 2H),0.78(dd, J= 12.4, 3.6 Hz, 2H).19F NMR(376 MHz, CD3OD) 8 -138.19.Example 60: N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-5-(4-fluoro-3-hydroxyphenyl)-l-methyl-lH-pyrrole-3-carboxamideWSGR Docket No. 69600-701.601Methyl 5-(4-fluoro-3-hydroxyphenyl)-l-methyl-lH-pyrrole-3-carboxylate (compound 2)

[0367] To asolution of methyl 5-bromo-l-methyl-lH-pyrrole-3-carboxylate (400.0 mg, 1.84 mmol, 1.0 equiv) in dioxane / H2O (10 mL / 2 mL) was added (4-fluoro-3-hydroxyphenyl)boronic acid (316.0 mg, 2.02 mmol, 1.1 equiv), K2CO3 (764.0 mg, 5.52 mmol, 3.0 equiv) and Pd(dppf)C12 (67.0 mg, 0.09mmol, 0.05 equiv). The mixture was stirred at 80 °C for 2 hours. The mixture was extracted with EtOAc (50 mL) and diluted with H2O (30 mL x 3). The combined organic layer was washed with brine (30 mL x 2), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 32% EtOAc in PE to give methyl 5-(4-fluoro-3-hydroxyphenyl)-l-methyl-IH-pyrr ole-3 -carboxylate (385.0 mg, 1.55 mmol, 84%) as a colorless oil. LCMS m / z = 250.2 (M+H)+.5-(4-Fluoro-3-hydroxyphenyl)-l-methyl-lH-pyrrole-3-carboxylic acid (compound 3)

[0368] To asolution of methyl 5-(4-fluoro-3-hydroxyphenyl)-l-methyl-lH-pyrrole-3-carboxylate (200.0 mg, 0.80 mmol, 1.0 equiv) in THF / MeOH / FLO (6 mL / 2 mL / 3mL) was added NaOH (193.0 mg, 4.80 mmol, 6.0 equiv). Then the mixture was stirred at 70 °C for 2 hours. The mixture was adjusted pH to 6 with HC1 (2.0 N). The precipitated solids were collected by filtration and washed with H2O. This resulted in 5-(4-fluoro-3-hydroxyphenyl)- 1-methyl- 1 H-pyrrole-3-carbox lic acid (139.0 mg, 0.59 mmol, 74%) as a white solid. LCMS m / z =236.1 (M+H)+.N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-5-(4-fluoro-3-hydroxyphenyl)-l-methyl-lH-pyrrole-3-carboxamide

[0369] To asolution of 5-(4-fluoro-3-hydroxyphenyl)-l -methyl- lH-pyrrole-3-carboxy lie acid (40.0 mg, 0.17 mmol, 1.0 equiv) and 5-chloro-Nl-(oxetan-3-yl)benzene-l,3-diamine (MMC2-intl6 - 34.0 mg, 0.17 mmol, 1.0 equiv) in ACN (3 mL) were added TCFH (74.0 mg, 0.26 mmol, 1.5 equiv) andNMI (42.0 mg, 0.51 mmol, 3.0 equiv). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure and purified by prep-HPLC eluting with 0-37% ACN in H2O (0.1% NH4OH) to give N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-5-(4-fluoro-3-hydroxyphenyl)-l -methyl- 1H-pyrrole-3-carboxamide (5.04 mg, 0.01 mmol, 7%). LCMS m / z =416.1 (M+H)+. 'H NMR (400 MHz,WSGR Docket No. 69600-701.601CD3OD) 57.46 (d, J = 2.0Hz, 1H), 7.11 (dd, J= 11.2, 8.4 Hz, 1H), 7.04 (t, J= 1.6 Hz, 1H), 6.99 (dd, J= 8.4, 2.0 Hz, 1H), 6.89-6.85 (m, 2H), 6.66 (d, J= 2.0 Hz, 1H),6.3O (t, J= 2.0 Hz, 1H), 4.98 (t, J= 6.0 Hz, 2H), 4.63 - 4.58 (m, 1H), 4.57 - 4.54 (m, 2H), 3.67 (s, 3H).19F NMR(377 MHz, CD3OD) 8 -140.50.Example 61: N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-5-(4-chlorophenyl)-l-methyl-lH-pyrrole-3-carboxamideMethyl 5-(4-chlorophenyl)-l-methyl-lH-pyrrole-3-carboxylate (compound 2)

[0370] To asolution of methyl 5-bromo-l-methyl-lH-pyrrole-3-carboxylate (400.0 mg, 1.83 mmol, 1.0 equiv) and 2-(4-chlorophenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (525.0 mg, 2.20 mmol, 1.2 equiv) in dioxane (4 mL) and H2O (2 mL) was added Pd(dppf)C12 (134.0 mg, 0.18 mmol, 0.10 equiv) and K2CO3 (750.0 mg, 5.50 mmol, 3.0 equiv). The reaction mixture was stirred at 80 °C for 16 hours. The mixture was concentrated under reduced pressure and the residue was purified by silica column chromatography eluting with 20% EtOAc in PE to afford methyl 5 -(4-chlorophenyl)-l -methyl- 1H-pyrrole-3-carboxylate (167.0 mg, 0.67 mmol, 36%) as a white solid. LCMS m / z = 250.1 (M+H)+.5-(4-Chlorophenyl)-l-methyl-lH-pyrrole-3-carboxylic acid (MMC2-int244)

[0371] To asolution of methyl 5-(4-chlorophenyl)-l-methyl-lH-pyrrole-3-carboxylate (167.0 mg, 0.67 mmol, 1.0 equiv) in EtOH / H2O (2 mL / 2 mL) was added Li OH (32.0 mg, 1.34 mmol, 2.0 equiv). Then the mixture was stirred at 25 °C for 1 hour and 80 °C for 2 hours. The mixture was concentrated under reduced pressure and adjusted pH to 6 with citric acid solution. The precipitated solids were collected by filtration and washed with H2O. This resulted in 5-(4-chlorophenyl)-l -methyl- lH-pyrrole-3-carboxylic acid (59.0 mg, 0.25 mmol, 37%) as ayellow solid. LCMS m / z = 236.0 (M+H)+.N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-5-(4-chlorophenyl)-l-methyl-lH-pyrrole-3-carboxamide

[0372] To asolution of -(4-chlorophenyl)-l-methyl-lH-pynole-3-carboxylic acid (59.0 mg, 0.25 mmol, 1.0 equiv) and 5-chloro-Nl-(oxetan-3-yl)benzene-l,3-diamine (MMC2-intl6 - 59.0 mg, 0.30 mmol, 1.1 equiv) in ACN (4 mL) was added TCFH (104.0 mg, 0.37 mmol, 1.5 equiv) and NMI (61.0 mg, 0.75 mmol, 3.0 equiv). Then the mixture was stirred at room temperature for 2 hours. The mixture wasWSGR Docket No. 69600-701.601concentrated under reduced pressure and purified by prep-HPLC eluting with 0-60% ACN in H2O (0.1% NH4HCO3) to give N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-5-(4-chlorophenyl)-l-methyl-lH-pyrrole-3-carboxamide (10.04 mg, 0.02 mmol). LCMS m / z = 416.0 (M+H)+. 'H NMR (400 MHz, DC₃OD) d 7.50 (d,.7=2,0 Hz. 1H), 7.44 (s, 4H), 7.04 (t, J= 1.8 Hz, 1H), 6.84 (t, J= 2.0 Hz, 1H), 6.74 (d, J= 2.0 Hz, 1H), 6.30 (t, J= 2.0 Hz, 1H), 4.98 (dd, J= 8.6, 3.8 Hz, 2H), 4.59 (dd, J= 9.9, 4.0Hz, 1H), 4.55 (dd, J= 6.8, 4.4 Hz, 2H), 3.70 (s, 3H).Example 62: N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-5-(4-cyanophenyl)-l-methyl-lH-pyrrole-3-carboxamide5-(4-Cyanophenyl)-l-methyl-lH-pyrrole-3-carboxylic acid (MMC2-int245)

[0373] To a solution of 5-bromo-l-methyl-lH-pyrrole-3-carboxylic acid (816.0 mg, 4.00 mmol, 1.0 equiv) in dioxane (15 mL) and H2O (3 mL)was added 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzonitrile (1.4 g, 6.00 mmol, 1.5 equiv), Pd(dppf)C12 (146.4 mg, 0.2 mmol, 0.05 equiv) and K2CO3 (1.1 g, 8.0 mmol, 2.0 equiv) under Argon atmosphere. The mixture was stirred at 90 °C for 16 hours. The combined organic layer was washed with brine (30 mLx 2), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 65% EtOAc in PE to give 5-(4-cyanophenyl)-l-methyl-IH-pyrrole-3-carboxylic acid (550.2 mg, 2.43 mmol, 60%) as a white solid. LCMS m / z = 227.1 (M+H)+.N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-5-(4-cyanophenyl)-l-methyl-lH-pyrrole-3-carboxainide

[0374] To a solution of 5-(4-cyanophenyl)-l-methyl-lH-pyrrole-3-carboxylic acid (54.24 mg, 0.24 mmol, 1.0 equiv) and 5-chloro-Nl-(oxetan-3-yl)benzene-l,3-diamine (MMC2-intl6 - 71.2 mg, 0.36 mmol, 1.5 equiv) in ACN (5 mL) was added TCFH (95.0 mg, 0.36 mmol, 1.5 equiv) and NMI (58.0 mg, 0.72 mmol, 3.0 equiv). The mixture was stirred at 25 °C for 2 hours. The mixture was concentrated under reduced pressure and purified by prep-HPLC eluting with 0-65% ACN in H2O (0.1% NH4OH) to give N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-5-(4-cyanophenyl)-l-methyl-lH-pyrrole-3-carboxamide (15.3 mg, 0.04 mmol, 16%). LCMS m / z =406.9 (M+H)+.1H NMR (400 MHz, DMSO-d6) 59.49 (s, 1H), 7.96 -7.88 (m, 2H), 7.75 - 7.66 (m, 3H), 7.13 (t, J= 1.6Hz, 1H), 6.97 (d, J = 2.0 Hz, 1H), 6.90 (t, J= 2.0 Hz 1H), 6.71 (s, 1H), 6.19(t, J=2.0Hz, 1H), 4.84 (t, J= 6.4Hz, 2H), 4.48(d, J= 6.0 Hz, 1H), 4.41 (t, J = 6.0 Hz, 2H), 3.77 (s, 3H).Example 63: N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-l-methyl-5-(4-(trifluoromethyl)phenyl)-lH-pyrrole-3-carboxamideWSGR Docket No. 69600-701.601Methyl l-methyl-5-(4-(trifluoromethyl)phenyl)-lH-pyrrole-3-carboxylate (compound 2)

[0375] To asolution of methyl 5-bromo-l-methyl-lH-pynole-3-carboxylate (400.0 mg, 1.83 mmol, 1.0 equiv) and 4,4,5,5-tetramethyl-2-(4-(trifluoromethyl)phenyl)-l,3,2-dioxaborolane (598.0 mg, 2.20 mmol, 1.2 equiv) in dioxane (4 mL) and H2O (2 mL) was added Pd(dppf)C12 (73.0 mg, 0.09 mmol, 0.05 equiv) and K2CO3 (505.0 mg, 3.66 mmol, 2.0 equiv). The reaction mixture was stirred at 80 °C for 16 hours. The mixture was concentrated under reduced pressure and the residue was purified by silica column chromatography eluting with 20% EtOAc in PE to afford methyl l-methyl-5-(4-(trifluoromethyl)phenyl)-lH-pyrrole-3-carboxylate (600.0 mg, 2.12 mmol) as a white solid.l-methyl-5-(4-(trifluoromethyl)phenyl)-lH-pyrrole-3-carboxylic acid (MMC2-int248)

[0376] To asolution of methyl l-methyl-5-(4-(trifluoromethyl)phenyl)-lH-pyrrole-3-carboxylate (600.0 mg, 2.12 mmol, 1.0 equiv) in EtOH / H₂O (10 mL / 4 mL) was added NaOH (170.0 mg, 1.34 mmol, 2.0 equiv). Then the mixture was stirred at 80 °C for 1 hour. The mixture was concentrated under reduced pressure and adjusted pH to 6 with citric acid solution. The precipitated solids were collected by filtration and washed with H₂O. This resulted in l-methyl-5-(4-(trifluoromethyl)phenyl)-lH-pyrrole-3-carboxylic acid (760.0 mg, 2.82 mmol) as a yellow solid.N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-l-methyl-5-(4-(trifluoromethyl)phenyl)-lH-pyrrole-3-carboxamide

[0377] To a solution of l-methyl-5-(4-(trifluoromethyl)phenyl)-lH-pyrrole-3-carboxylic acid (200.0 mg, 0.74 mmol, 1.0 equiv) and 5-chloro-Nl-(oxetan-3-yl)benzene-l,3-diamine (MMC2-intl6 - 175.0 mg, 0.88 mmol, 1.2 equiv) in ACN (4 mL) was added TCFH (310.0 mg, 1.11 mmol, 1.5 equiv) and NMI (182.0 mg, 2.22 mmol, 3.0 equiv). Then the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure and purified by prep-HPLC eluting with 0-60% ACN in H2O (0.1% NH4HCO3) to give N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-l-methyl-5-(4-(trifluoromethyl)phenyl)-lH-pyrrole-3-carboxamide (61.28 mg, 0.136 mmol, 18%). LCMS m / z = 450.1 (M+H)+.1H NMR (400 MHz, DMSO) 9.50 (s, 1H), 7.78 (dd, J = 27.6, 8.4 Hz, 4H), 7.68 (d, J = 2.0 Hz, 1H), 7.14 (t, J = 1.6 Hz, 1H), 6.97-6.87 (m, 2H), 6.71 (d, J = 6.1 Hz, 1H), 6.20 (t, J = 2.0 Hz, 1H), 4.85 (t, J = 6.4 Hz,WSGR Docket No. 69600-701.6012H), 4.49 (dt, J = 12.4, 6.4 Hz, 1H), 4.42 (t, J = 6.0 Hz, 2H), 3.77 (s, 3H).19F NMR(377 MHz, DMSO) 8 -60.89.Example 64: 5-(4-Chloro-2-fluorophenyl)-N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-l-methyl-lH-pyrrole- 3-carboxamideMethyl 5-(4-chloro-2-fluorophenyl)-l-methyl-lH-pyrrole-3-carboxylate (compound 2)

[0378] To a solution of methyl 5-bromo-l-methyl-lH-pyrrole-3-carboxylate (200.0 mg, 0.92 mmol, 1.0 equiv) and2-(4-chloro-2-fluorophenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (260.0 mg, 1.01 mmol, 1.1 equiv) in l,4-dioxane / H2O (6 mL / 1 mL) was added Pd(dppf)C12 (67.0 mg, 0.09 mmol, 0.1 equiv) and K2CO3 (377.0 mg, 2.76 mmol, 3.0 equiv) under Argon atmosphere. Then the mixture was stirred at 90 °C for 2 hours. The reaction was filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 12% EtOAc in PE to give methyl 5-(4-chloro-2-fluorophenyl)-l-methyl-lH-pyrrole-3-carboxylate (120.0 mg, 0.45 mmol, 49%) as a white solid. LCMS m / z = 268.10 (M+H)+.5-(4-Chloro-2-fluorophenyl)-l-methyl-lH-pyrrole-3-carboxylic acid (compound 3)

[0379] To a solution of methyl 5-(4-chloro-2-fluorophenyl)-l-methyl-lH-pyrrole-3-carboxylate (120.0 mg, 0.45 mmol, 1.0 equiv) in THF / MeOH / H2O (6 mL / 2 mL / 3 mL) was added NaOH (108.0 mg, 2.7 mmol, 6.0 equiv). Then the mixture was stirred at 70 °C for 2 hours. The mixture was adjusted pH to 6 with HC1 (2.0 N). The precipitated solids were collected by filtration and washed with H2O. This resulted in 5-(4-chloro-2-fluorophenyl)-l-methyl-lH-pyrrole-3-carboxylic acid (80.0 mg, 0.32 mmol, 70%) as a white solid. LCMS m / z =295.2 (M+41+H)+.5-(4-Chloro-2-fluorophenyl)-N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-l-methyl-lH-pyrrole-3-carboxamide

[0380] To a solution of 5-(4-chloro-2-fluorophenyl)-l-methyl-lH-pyrrole-3-carboxylic acid (38.0 mg, 0.15 mmol, 1.0 equiv) and 5-chloro-N1-(oxetan-3-yl)benzene-l,3-diamine (MMC2-intl6 - 30.0 mg, 0.15 mmol, 1.0 equiv) in ACN (4 mL) was added TCFH (64.0 mg, 0.23 mmol, 1.5 equiv) and NMI (37.0 mg, 0.45 mmol, 3.0 equiv). Then the mixture was stirred at room temperature for 1 hour. The mixture wasWSGR Docket No. 69600-701.601concentrated under reduced pressure and purified by prep-HPLC eluting with 0-60% ACN in H2O (0.1% NH4HCO3) to give 5-(4-chloro-2-fluorophenyl)-N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-l-methyl-lH-pyrrole-3-carboxamide (21.20 mg, 0.05 mmol, 33%). LCMS m / z = 434.0 (M+H)+. 'H NMR (400 MHz, CD3OD) 87.55 (d, J= 2.0 Hz, 1H), 7.41 (t, J= 8.0 Hz, 1H), 7.37-7.30 (m, 2H), 7.04 (t, J = 1.6 Hz, 1H), 6.84 (t, J= 2.0 Hz, 1H), 6.74 (d,.7 = 2,0 Hz. 1H), 6.31 (t,.7= 2.0 Hz. 1H), 4.99 (s, 2H), 4.60 (dd, J = 12.0, 6.0Hz, 1H), 4.55 (dd, J=6.8, 4.4Hz, 2H), 3.60 (s, 3H).19F NMR (376 MHz, CD3OD) 8 -112.69 (d, J= 3.6 Hz).Example 65: N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-5-(5-fluoropyridin-2-yl)-l-methyl-lH-pyrrole- 3-carboxamideMethyl 5-(5-fluoropyridin-2-yl)-l-methyl-lH-pyrrole-3-carboxylate (compound 2)

[0381] To a mixture of 2-bromo-5 -fluoropyridine (167.0 mg, 0.95 mmol, 1.0 equiv) and methyl 1-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 1 H-pyrrole-3-carboxylate (250.0 mg, 0.95 mmol, 1.0 equiv) in 1,4-dioxane / H2O (12 mL / 2 mL) was added K2CO3 (388.0 mg, 2.84 mmol, 3.0 equiv) and Pd(dppf)Ch (69.0 mg, 0.09 mmol, 0.1 equiv). Then the mixture was stirred at 80 °C for 16 hours. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 10% EtOAc in PE to give methyl 5 -(5-fluoropyridin-2-yl)-l -methyl- 1H-pyrrole-3-carboxylate (142.0 mg, 0.61 mmol, 64%) as a white solid. LCMS m / z = 235.1 (M+H)+.5-(5-Fluoropyridin-2-yl)-l-methyl-lH-pyrrole-3-carboxylic acid (MMC2-intl00)

[0382] To a solution of methyl 5-(5-fluoropyridin-2-yl)-l-methyl-lH-pyrrole-3-carboxylate (142.0 mg, 0.61mmol, 1.0 equiv) in THF / EtOH / H2O (1 mL / 1 mL / 1 mL) was added NaOH (73.0 mg, 1.82 mmol, 3.0 equiv). Then the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and adjusted pH to 5 with citric acid solution. The precipitated solids were collected by filtration and washed with H2O. This resulted in 5-(5-fluoropyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxylic acid (109.0 mg, 0.49 mmol, 81%) as a white solid. LCMS m / z = 221.1 (M+H)+.WSGR Docket No. 69600-701.6011H NMR (400 MHz, DMSO-6) 8 11.88 (s, 1H), 8.57 (d, J = 2.8Hz, 1H), 7.82 (dd, J= 9.2, 4.4 Hz, 1H), 7.78-7.74 (m, 1H), 7.53 (d, J = 2.0Hz, 1H), 6.93 (d, J = 2.0Hz, 1H), 3.92(s, 3H).19F NMR (377 MHz, DMSO-6) 8 -130.37 (s).N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-5-(5-fluoropyridin-2-yl)-l-methyl-lH-pyrrole-3-carboxamide

[0383] To a solution of 5-(5-fluoropyridin-2-yl)-l-methyl-lH-pyrrole-3-carboxylic acid (40.0 mg, 0.18 mmol, 1.0 equiv) and 5-chloro-Nl-(oxetan-3-yl)benzene-l,3-diamine (MMC2-intl6 - 36.0 mg, 0.18 mmol, 1.0 equiv) in ACN (4 mL) was added TCFH (76.0 mg, 0.27 mmol, 1.5 equiv) and NMI (74.0 mg, 0.91 mmol, 5.0 equiv). Then the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and purified by prep-HPLC eluting with 0-50% ACN in H2O (0.1% NH4HCO3) to give N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-5-(5-fluoropyridin-2-yl)-l-methyl-lH-pyrrole-3-carboxamide (39.79 mg, 0.10 mmol, 55%). LCMS m / z = 401.2 (M+H)+. 'H NMR (400 MHz, DMSO- 6) 89.50 (s, 1H), 8.59 (d, J= 2.0 Hz, 1H), 7.82 - 7.75 (m, 2H), 7.65 (s, 1H), 7.18 - 7.13 (m, 2H), 6.91 (s, 1H), 6.71 (d, J = 5.6Hz, 1H), 6.19 (s, 1H), 4.84 (t, J= 6.0 Hz, 2H), 4.50 (dt, J= 12.4, 6.4 Hz, 1H), 4.42 (t, J= 6.0 Hz, 2H), 3.95 (s, 3H).19F NMR (377 MHz, DMSO-d6) 8 -130.35.Example 66: N-(3-Bromo-5-(oxetan-3-ylamino)phenyl)-5-(4-fluorophenyl)-1-methyl-1H-pyrrole-3-carboxamide

[0384] To a solution of 5-(4-fluorophenyl)-l -methyl- lH-pyrrole-3-carboxylic acid (200.0 mg, 0.91 mmol, 1.0 equiv) in ACN (10 mL) was added 5-bromo-Nl-(oxetan-3-yl)benzene-l,3-diamine (MMC2-int47 - 219.0 mg, 0.91 mmol, 1.0 equiv), TCFH (387.0 mg, 1.36 mmol, 1.5 equiv) and NMI (212.0 mg, 2.73 mmol, 3.0 equiv). Then the mixture was stirred at 25 °C for 2 hours. The residue was purified by silica column chromatography eluting with 60% EtOAc in PE to give N-(3-bromo-5-(oxetan-3-ylamino)phenyl)-5-(4-fluorophenyl)-l-methyl-lH-pyrrole-3-carboxamide (230.0 mg, 0.52 mmol, 57%). LCMS m / z = 446.0 (M+H)+.1H NMR (400 MHz, CD3OD) 87.48 - 7.44 (m, 3H), 7.19 - 7.16 (m, 3H), 6.88 (s, 1H), 6.69 (s, 1H), 6.46 (s, 1H), 4.97 (dd, J = 6.0 Hz, 2H), 4.61 - 4.53 (m, 3H), 3.67 (s, 3H).19F NMR (377 MHz, CD3OD) 8 -116.53.Large scale synthesis of N-(3-Bromo-5-(oxetan-3-ylamino)phenyl)-5-(4-fluorophenyl)-1-methyl-1H-pyrrole-3-carboxamide

[0385] To a solution of 5-(4-fluorophenyl)-1-methyl-1H-pyrrole-3-carboxylic acid (2.0g, 9.1 mmol, 1.0 equiv) in ACN (100 mL) were added 5-bromo-1-(oxetan-3-yl)benzene-1,3-diamine (2.19 g, 9.1 mmol, 1.0 equiv), TCFH (3870 mg, 13.6 mmol, 1.5 equiv) and NMI (2.12 g, 27.3 mmol, 3.0 equiv). Then theWSGR Docket No. 69600-701.601mixture was stirred at 25 °C for 2 hours. The residue was purified by silica column chromatography eluting with 60% EA in PE to give -(3-bromo-5-(oxetan-3-ylamino)phenyl)-5-(4-fluorophenyl)-1-methyl-1H-pyrrole-3-carboxamide (2.3 g, 5.2 mmol, 57%).Example 67: N-(3-Bromo-5-(oxetan-3-ylamino)phenyl)-5-(2-chloro-4-fluorophenyl)-l-methyl-lH-pyrrole-3-carboxamide

[0386] To a solution of 5-(2-chloro-4-fluorophenyl)-l-methyl-lH-pyrrole-3-carboxylic acid (50.0 mg, 0.20 mmol, 1.0 equiv) and 5-bromo-Nl-(oxetan-3-yl)benzene-l,3-diamine (MMC2-int47 - 48.0 mg, 0.20 mmol, 1.0 equiv) in ACN (3 mL) was added TCFH (85.0 mg, 0.30 mmol, 1.5 equiv) and NMI (49.0 mg, 0.60 mmol, 3.0 equiv). Then the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure and purified by prep-HPLC eluting with 0-60% ACN in H2O (0.1% NH4HCO3) to give N-(3-bromo-5-(oxetan-3-ylamino)phenyl)-5-(2-chloro-4-fluorophenyl)-l-methyl-lH-pyrrole-3-carboxamide (33.63 mg, 0.07 mmol, 36%). LCMS m / z = 479.9 (M+H)+. 'H NMR (400 MHz, DMSO-6) δ 9.43 (s, 1H), 7.66 - 7.59 (m, 2H), 7.53 (dd, J= 8.6, 6.4 Hz, 1H), 7.34 (td, J= 8.5, 2.6 Hz, 1H), 7.27 (t, J= 1.8 Hz, 1H), 6.93 (t, J= 1.8 Hz, 1H), 6.71 - 6.65 (m, 2H), 6.32 (t, J= 1.8 Hz, 1H), 4.83 (t, J = 6.4 Hz, 2H), 4.53 - 4.44 (m, 1H), 4.41 (t, J= 6.0 Hz, 2H), 3.46 (s, 3H).19F NMR (377 MHz, DMSO-6) δ -110.76.Example 68: N-(3-Bromo-5-(oxetan-3-ylamino)phenyl)-l-ethyl-5-(4-fluorophenyl)-lH-pyrrole-3-carboxamide

[0387] To a solution of l-ethyl-5-(4-fluorophenyl)-lH-pyrrole-3-carboxylic acid (100.0 mg, 0.43 mmol, 1.0 equiv) in ACN (5 mL) was added 5-bromo-Nl-(oxetan-3-yl)benzene-l,3-diamine (MMC2-int47 -106.0 mg, 0.43 mmol, 1.0 equiv), TCFH (187.0 mg, 0.68 mmol, 1.5 equiv) and NMI (90.0 mg, 1.35 mmol, 3.0 equiv). Then the mixture was stirred at 25 °C for 2 hours. The residue was purified by prep-HPLC eluting with 0-35% ACN in H2O (0.1% FA) to give N-(3-bromo-5-(oxetan-3-ylamino)phenyl)-1-WSGR Docket No. 69600-701.601ethyl-5-(4-fluorophenyl)- 1 H-pyrrole-3-carboxamide (120.0 mg, 0.30 mmol, 65%). LCMS m / z = 460.2 (M+H)+.1H NMR (400 MHz, CD3OD) 87.58 (d, J= 1.6 Hz, 1H), 7.44 (m, 2H), 7.19 (m, 3H), 6.88 (s, 1H), 6.65 (d, J= 2.0 Hz, 1H), 6.46 (s, 1H), 4.98 (t, J= 6.0 Hz, 2H), 4.60 (d, J= 5.6 Hz, 1H), 4.54 (d, J = 5.6 Hz, 2H), 4.01 (q, J= 7.2 Hz, 2H), 1.29 (t, J= 7.2 Hz, 3H).19F NMR (377 MHz, DMSO-6) δ -116.31.Example 69: N-(3-Bromo-5-(oxetan-3-ylamino)phenyl)-5-(3,5-difluorophenyl)-l-methyl-lH-pyrrole-3-carboxamideMMC2-int228

[0388] To a solution of 5-(3,5-difluorophenyl)-l-methyl-lH-pyrrole-3-carboxylic acid (50.0 mg, 0.21 mmol, 1.0 equiv) and 5-bromo-Nl-(oxetan-3-yl)benzene-l,3-diamine (MMC2-int47 - 51.0 mg, 0.21 mmol, 1.0 equiv) in ACN (3 mL) was added TCFH (91.0 mg, 0.32 mmol, 1.5 equiv) and NMI (52.0 mg, 0.63 mmol, 3.0 equiv). Then the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure and purified by prep-HPLC eluting with 0-60% ACN in H2O (0.1% NH4HCO3) to give N-(3-bromo-5-(oxetan-3-ylamino)phenyl)-5-(3,5-difluorophenyl)-l-methyl-lH-pyrrole-3-carboxamide (58.4 mg, 0.13 mmol, 60%). LCMS m / z = 463.9 (M+H)+.1H NMR (400 MHz, DMSO-6) δ 9.45 (s, 1H), 7.65 (d, J= 1.8 Hz, 1H), 7.27 - 7.20 (m, 4H), 6.95 (t, J= 1.6 Hz, 1H), 6.92 (d, J = 2.0Hz, 1H), 6.70 (d, J= 6.0 Hz, 1H),6.33 (t, J= 1.8 Hz, 1H), 4.84 (t, J= 6.4 Hz, 2H), 4.52 - 4.45 (m, 1H), 4.41 (t, J= 6.0 Hz, 2H), 3.76 (s, 3H).19F NMR (377 MHz, DMSO-d6) 8 -109.39.Example 70: N-(3-Bromo-5-(oxetan-3-ylamino)phenyl)-5-(2,5-difluorophenyl)-l-methyl-lH-pyrrole-3-carboxamide

[0389] To a solution of 5-(2,5-difluorophenyl)-l-methyl-lH-pyrrole-3-carboxylic acid (35.0 mg, 0.15 mmol, 1.0 equiv) and 5-bromo-Nl-(oxetan-3-yl)benzene-l,3-diamine (MMC2-int47 - 35.9 mg, 0.14 mmol, 1.0 equiv) in ACN (2 mL) was added TCFH (62.1 mg, 0.22 mmol, 1.5 equiv) and NMI (36.3 mg, 0.44 mmol, 3.0 equiv). Then the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure and purified by prep-HPLC eluting with 0-55% ACN in H2O (0.1%WSGR Docket No. 69600-701.601NH4HCO3) to give N-(3-bromo-5-(oxetan-3-ylamino)phenyl)-5-(2,5-difluorophenyl)-l-methyl-lH-pyrrole-3-carboxamide (20.0 mg, 0.043 mmol, 29.3%). LCMS m / z = 462.0 (M+H)+.1H NMR (400 MHz, DMSO-6) δ 9.46 (s, 1H), 7.67 (s, 1H), 7.44 - 7.30 (m, 3H), 7.26 (s, 1H), 6.94 (s, 1H), 6.82 (s, 1H), 6.69 (d, = 6.0 Hz, 1H), 6.33 (s, 1H), 4.84(t, J = 6.2Hz, 2H), 4.48 (dd, J= 12.2, 6.1 Hz, 1H), 4.41 (t, J= 6.0 Hz, 2H), 3.60 (s, 3H).19F NMR (376 MHz, DMSO-6) δ -118.32, -119.80.Example 71: N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-l-cyclopropyl-5-(5-fluoropyridin-2-yl)-lH-pyrrole- 3-carboxamide1-Cyclopropyl-1H-pyrrole-3-carboxylate (compound 2)

[0390] To a solution of methyl lH-pyrrole-3-carboxylate (2.0 g, 15.98 mmol, 1.0 equiv), cyclopropylboronic acid (2.8 g, 31.97 mmol, 2.0 equiv) and 2,2'-Bipyridine (2.5 g, 15.98 mmol, 1.0 equiv) in ACN (30 mL) was added Na2CO3(3.4 g, 31.97 mmol, 2.0 equiv) and Cu(OAc)2 (3.5 g, 19.18 mmol, 1.2 equiv). The mixture was stirred at 70 °C for 3 days. The reaction was filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 5% EtOAc in PE to give l-cyclopropyl-lH-pyrrole-3-carboxylate (2.2 g, 13.32 mmol, 83.3 %) as a yellow solid. LCMS m / z = 166.5 (M+H)+.5-Bromo-l-cyclopropyl-lH-pyrrole-3-carboxylate (compound 3)

[0391] To a solution of methyl 1 -cyclopropyl- lH-pyrrole-3-carboxylate (2.2 g, 13.32 mmol, 1.0 equiv) in DMF (30 mL) was added NBS (2.4 g, 13.32 mmol, 1.0 equiv). The resulting mixture was stirred at 25 °C for 2 hours. The reaction was filtered and concentrated under reduced pressure. The residue wasWSGR Docket No. 69600-701.601purified by silica column chromatography eluting with 3% EtOAc in PE to give 5 -bromo- 1-cyclopropyl-lH-pyrrole-3-carboxylate (2.5 g, 10.24 mmol, 76.9%) as ayellow solid. LCMS m / z = 244.3 (M+H)+.Methyl 1-cyclopropyl-5-(5-fluoropyridin-2-yl)-1H-pyrrole-3-carboxylate (compound 4)

[0392] To asolution of methyl 5-bromo-l-cyclopropyl-lH-pyrrole-3-carboxylate (500.0 mg, 2.05 mmol, 1.0 equiv), Cs2CO3(2.67 mg, 8.19 mmol, 4.0 equiv) and (5-fluoropyridin-2-yl)boronic acid (288.6 mg, 2.05 mmol, 1.0 equiv) in DMF (10 mL) was added Pd(OAc)2 (23.0 mg, 0.10 mmol, 0.05 equiv), CuCl (202.8 mg, 2.05 mmol, 1.0 equiv) and dppf (113.6 mg, 0.20mmol, 0.1 equiv) under Argon atmosphere. The mixture was stirred at 100 °C for 16 hours. The reaction was filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 5% EtOAc in PE to give methyl l-cyclopropyl-5-(5-fluoropyridin-2-yl)-lH-pyrrole-3-carboxylate (190.0 mg, 0.73 mmol, 35.6%) as a white solid. LCMS m / z = 261.1 (M+H)+.1-Cyclopropyl-5-(5-fluoropyridin-2-yl)-1H-pyrrole-3-carboxylic acid (compound 5)

[0393] To asolution of methyl l-cyclopropyl-5-(5-fluoropyridin-2-yl)-lH-pyrrole-3-carboxylate (190.0 mg, 0.73 mmol, 1.0 equiv) in EtOH / H₂O (5 mL / 1 mL) was added LiOH (52.5 mg, 2.19 mmol, 2.0 equiv). Then the mixture was stirred at 60 °C for 16 hours. The mixture was concentrated under reduced pressure and adjusted pH to 7 with acetic acid. The precipitated solids were collected by filtration and washed with H2O. This resulted in 1-cyclopropyl-5-(5-fluoropyridin-2-yl)-1H-pyrrole-3-carboxylic acid (150.0 mg, 0.61 mmol, 83.4%) as a white solid. LCMS m / z = 247.1 (M+H)+.N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-1-cyclopropyl-5-(5-fluoropyridin-2-yl)-1H-pyrrole-3-carboxamide

[0394] To asolution of l-cyclopropyl-5-(5-fluoropyridin-2-yl)-lH-pyrrole-3-carboxylic acid (35.0 mg, 0.14 mmol, 1.0 equiv) and 5-chloro-Nl-(oxetan-3-yl)benzene-l,3-diamine (MMC2-intl6 - 28.2 mg, 0.14 mmol, 1.0 equiv) in ACN (2 mL) was added TCFH (59.8 mg, 0.21 mmol, 1.5 equiv) and NMI (35.0 mg, 0.43 mmol, 3.0 equiv). Then the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure and purified by prep-HPLC eluting with 0-60% ACN in H2O (0.1% NH4HCO3) to give N-(3-chloro-5-(oxetan-3-ylamino)phenyl)-l-cyclopropyl-5-(5-fluoropyridin-2-yl)-lH-pyrrole-3-carboxamide (29.0 mg, 0.68 mmol, 47.8%). LCMS m / z = 427.1 (M+H)+.1H NMR (400 MHz, DMSO-6) δ 9.48 (s, 1H), 8.61 (d, J = 2.5 Hz, 1H), 7.83- 7.79 (m,2H),7.69 (s, 1H), 7.10(d, J= 9.2 Hz, 2H), 6.91 (s, 1H), 6.71 (d, J = 6.0Hz, 1H), 6.19 (s, 1H), 4.84 (t, J= 6.3 Hz, 2H), 4.51 - 4.47 (m, 1H), 4.41 (t, J= 5.9 Hz, 2H), 3.97 - 3.92 (m, 1H), 0.94 (d, J= 5.7 Hz, 2H), 0.84 (s, 2H).19F NMR (377 MHz, DMSO-d6) 8 -130.12.Example 72: N-(3-Chloro-5-(oxetan-3-ylamino)phenyl)-l-ethyl-5-(5-fluoropyridin-2-yl)-lH-pyrrole-3-carboxamideWSGR Docket No. 69600-701.601Methyl 5-(5-fluoropyridin-2-yl)-1H-pyrrole-3-carboxylate (compound 2)

[0395] To a mixture of methyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrrole-3-carboxylate (300.0 mg, 1.2 mmol, 1.0 equiv) in dioxane / H2O (20 mL / 4 mL) was added K2CO3 (328.0 mg, 2.4 mmol, 2.0 equiv), and Pd(dppf)C12(44.0 mg, 0.06 mmol, 0.05 equiv). The mixture was stirred at 90 °C for 16 hours. The reaction was diluted with H2O (80 mL x 3) and extracted with EtOAc (80 mL). The combined organic layer was washed with brine H2O (50 mL x 2), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 3% EtOAc in PE to give methyl 5-(5-fluoropyridin-2-yl)-lH-pyrrole-3-carboxylate (200.0 mg, 0.91 mmol, 75%) as a white solid. LCMS m / z = 221.0 (M+H)+.Methyl 1-ethyl-5-(5-fluoropyridin-2-yl)-1H-pyrrole-3-carboxylate (compound 3)

[0396] To a mixture of methyl 5-bromo-1H-pyrrole-3-carboxylate (200.0 mg, 0.91 mmol, 1.0 equiv) in DMSO (10 mL) was added CS2CO3 (250.0 mg, 1.82 mmol, 2.0 equiv), and EtI (5.2 g, 1.82 mmol, 1.5 equiv). The mixture was stirred at 25 °C for 1 hour. The reaction was diluted with H2O (80 mL x 3) and extracted with EtOAc (80 mL). The combined organic layer was washed with brine H2O (50 mL x 2), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 3% EtOAc in PE to give methyl l-ethyl-5-(5-fluoropyridin-2-yl)-lH-pyrrole-3-carboxylate (180.0 mg, 0.73 mmol, 79%) as a white solid. LCMS m / z = 249.1 (M+H)+. l-Ethyl-5-(5-fhioropyridin-2-yl)-lH-pyrrole-3-carboxylic aci...

Claims

WSGR Docket No. 69600-701.601CLAIMS WHAT IS CLAIMED IS:

1. A compound of Formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof:Formula (I),wherein:Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;each R1is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -S(=O)(=NRb)Rb, -S(=NRb)(=NRb), -NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)(Rb)2, -C(=O)Ra, - C(=O)ORb, -C(=O)NRcRd, -P(=O)(Rb)2, -P(=O)(ORb)2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;and / or two R1on the same atom are taken together to form an oxo;n is 0, 1, 2, 3, or 4;Ring B is a 5-membered heteroaryl;each R10is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, -L-cycloalkyl, or -L-heterocycloalkyl;m is 0, 1, 2, 3, or 4;R5is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl;X is halogen;R6is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl;R7is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, or C1-C6haloalkyl;Y is -O- or -NR8-;R8is hydrogen, C1-C6alkyl, or C1-C6haloalkyl;or R8and R7are taken together to form a heterocycloalkyl or heteroaryl; each independently optionally substituted with one or more R;Ring C is cycloalkyl or heterocycloalkyl;each R11is independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, or -L-heterocycloalkyl;WSGR Docket No. 69600-701.601and / or two R11on the same atom are taken together to form an oxo;p is 0, 1, 2, 3, or 4;each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;and / or two Rbare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R;Rcand Rdare each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;and / or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R;L is absent or C1-C4alkylene optionally substituted with one or more R; andeach R is independently halogen, -CN, -OH, -SF5, -SH, -S(=O)Ci-C3alkyl, -S(=O)2Ci-C3alkyl, - S(=O)2NH2, -S(=O)2NHCi-C3alkyl, -S(=O)2N(Ci-C3alkyl)2, -S(=O)(=NCi-C3alkyl)(Ci-C3alkyl), - NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, -N=S(=O)(Ci-C3alkyl)2, -O-Ci-C4alkylene-OH, -O-Ci- C4aJkylene-NH2, -C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, -C(=O)NHCi- C3alkyl, -C(=O)N(Ci-C3alkyl)2, -P(=O)(Ci-C3alkyl)2, Ci-C3alkyl, Ci-C3alkoxy, Ci-C3haloalkyl, Ci- C3haloalkoxy, Ci -C3hydroxy alkyl, Ci-C3aminoalkyl, Ci-C3heteroalkyl, C3-Cecycloalkyl, or 3- to 6- membered heterocycloalkyl;or two R on the same atom form an oxo.

2. The compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:Ring B is a 5-membered heteroaryl comprising one, two, three, or four heteroatoms selected from the group consisting of O, S, and N.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:Ring B is a 5 -membered heteroaryl comprising one or two heteroatoms selected from the group consisting of O, S, and N.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:WSGR Docket No. 69600-701.601Ring B is a 5-membered heteroaryl comprising one heteroatom selected from the group consisting of O, S, and N.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:Ring B is a 5-membered heteroaryl comprising one heteroatom that is S.

6. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:Ring B is a 5-membered heteroaryl comprising one heteroatom that is N.

7. The compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:Ringwherein the ** represents the attachment point to Ring A.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:each R10is independently halogen, -CN, C1-C6alkyl, C1-C6haloalkyl, -L-cycloalkyl, or -L-heterocycloalkyl.

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:each R10is independently halogen, -CN, C1-C6alkyl, or -L-cycloalkyl.

10. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:each R10is independently -CH3 or -CH2CH3.

11. The compound of claim 10, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the -CH3 is -CD3.

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:m is 0 or 1.

13. The compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof,wherein:WSGR Docket No. 69600-701.601, wherein the ** represents the attachment point to Ring A.

14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:Ring C is heterocycloalkyl.

15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:Ring C is 4- to 6-membered heterocycloalkyl comprising one or two heteroatoms selected from the group consisting of O, S, and N.

16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:Ring C is 4- to 5-membered heterocycloalkyl comprising one or two heteroatoms selected from the group consisting of O, S, and N.

17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:Ring C is 4- to 5-membered heterocycloalkyl comprising one heteroatom that is O.

18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:Ring19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:Ring20. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:WSGR Docket No. 69600-701.601Ring21. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:each R11is independently C1-C6alkyl or C1-C6haloalkyl.

22. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:p is 0 or 1.

23. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:p is 0.

24. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

25. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

26. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:R5is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl.

27. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:R5is hydrogen.

28. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:R6is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl.

29. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:R6is hydrogen.

30. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:WSGR Docket No. 69600-701.601R7is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl.

31. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:R7is hydrogen.

32. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:X is fluoro, chloro, or bromo.

33. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:Y is -NR8-.

34. The compound of any one of claims 1-33, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:R8is hydrogen.

35. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:Y is -O-.

36. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:R8and R7are taken together to form a heterocycloalkyl or heteroaryl; each independently optionally substituted with one or more R.

37. The compound of claim 36, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:R8and R7are taken together to form a heteroaryl optionally substituted with one or more R.

38. The compound of any one of claims 1-37, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:Ring A is cycloalkyl or heterocycloalkyl.

39. The compound of any one of claims 1-37, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:Ring A is cyclohexyl or cyclohexenyl.

40. The compound of any one of claims 1-37, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:Ring A is aryl or heteroaryl.

41. The compound of any one of claims 1-37, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:Ring A is phenyl or 5- or 6-membered heteroaryl.

42. The compound of any one of claims 1-37, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:Ring A is phenyl.WSGR Docket No. 69600-701.60143. The compound of any one of claims 1-37, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:Ring A is pyridyl.

44. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:each R1is independently halogen, -CN, -OH, -ORa, -SF₅, -SH, -SRa, -S(=O)(=NRb)Rb, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, -P(=O)(Rb)2, -P(=O)(ORb)2, Ci-C6alkyl, Ci- Cehaloalkyl, Ci-Cehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, -L-cycloalkyl, or -L- heterocycloalkyl; wherein each alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R; and / or two R1on the same atom are taken together to form an oxo.

45. The compound of any one of claims 1-44, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:each R1is independently halogen, -CN, -OH, -ORa, -SF₅, -SH, -SRa, -S(=O)(=NRb)Rb, -NRcRd, - C(=O)ORb, -P(=O)(Rb)2, Ci-Cealkyl, Ci-Cdialoalkyl, Ci-C6hydroxyalkyl, Ci-C6heteroalkyl, - L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R; and / or two R1on the same atom are taken together to form an oxo.

46. The compound of any one of claims 1-45, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:each R1is independently halogen, -CN, -OH, -ORa, -SF₅, -SH, -SRa, -S(=O)(=NRb)Rb, -NRcRd, - C(=O)ORb, -P(=O)(Rb)2, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, or Ci- Ceheteroalkyl.

47. The compound of any one of claims 1-46, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:each R1is independently halogen, -CN, -OH, -ORa, -SF₅, -SH, -SRa, -S(=O)(=NRb)Rb, -NRcRd, Ci-Cealkyl, or Ci-Cehaloalkyl.

48. The compound of any one of claims 1-47, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:each R1is independently halogen, -ORa, -SRa, -S(=O)(=NRb)Rb, C1-C6alkyl, or C1-C6haloalkyl.

49. The compound of any one of claims 1-48, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:each R1is independently halogen or C1-C6alkyl.

50. The compound of any one of claims 1-49, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:n is 0, 1, or 2.

51. The compound of any one of claims 1-50, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:WSGR Docket No. 69600-701.601n is 1 or 2.

52. The compound of any one of claims 1-51, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

53. The compound of any one of claims 1-51, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:WSGR Docket No. 69600-701.60154. The compound of any one of claims 1-53, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is a compound of Table 1.

55. A pharmaceutical composition comprising a compound of any one of claims 1-54, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

56. A method of treating a DHX9-mediated disease or disorder in a subject, comprising administering to the subject a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, of any one of claims 1-54, or the pharmaceutical composition of claim 55.

57. The method of claim 56, wherein the disease or disorder is an autoimmune disease, cancer, or a viral infection.

58. The method of claim 57, wherein the disease or disorder is cancer.

59. The method of claim 58, wherein the cancer is bladder cancer, blood cancer, bone cancer, brain cancer, breast cancer, colorectal cancer, endometrial cancer, gastric cancer, head and neck cancer, hematopoietic cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, or soft-tissue cancer.

60. The method of claim 58 or 59, wherein the cancer is a micro satellite instability (MSI) cancer.WSGR Docket No. 69600-701.60161. The method of claim 58 or 59, wherein the cancer has mutations or defects in DNA mis-match repair (MMR), and / or mutations or defects in RNA splicing and the kinetochore complex.

62. The method of claim 61, wherein the cancer is a micro satellite instability -high (MSI-H) colorectal cancer.

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