Alpha 4 beta 7 integrin modulators and uses thereof

Abstract

The present disclosure provides small molecule compounds and pharmaceutical compositions for the modulation of alpha 4 beta 7 integrin, useful for the treatment of inflammatory conditions such as inflammatory bowel disease, including ulcerative colitis and Crohn's disease.

Description

BACKGROUND OF THE INVENTION

[0001] Alpha 4 beta 7 integrin (α4ß7), also known as Lymphocyte Peyer patch adhesion molecule (LPAM) is a powerful signaling molecule embedded in the cell membranes of immune cells. α4ß7 is responsible for T-cell homing into gut-associated lymphoid tissues by binding to mucosal vascular addressin cell adhesion molecule (MAdCAM) located on high endothelial venules of mucosal lymphoid organs. It has been demonstrated that α4ß7is implicated in several immune system disorders, including inflammatory bowel disease (IBD) (including, e.g., Crohn’s disease (CD) and ulcerative colitis (UC)) and graft-versus-host disease (GVHD).

[0002] α4ß7 is a clinically-validated target for IBD, with ENTYVIO (vedolizumab), an injectable anti-α4ß7mAb, approved for the treatment of UC and CD. However, the accessibility of ENTYVIO is limited by the need for parenteral administration. Further, ENTYVIO causes a range of side effects (including nausea, vomiting, severe diarrhea, stomach cramps, weight loss, and pain), which can be difficult to manage due to ENTYVIO’s long half-life. Therefore, there is a need for highly active and / or selective α4ß7small molecule inhibitors that are orally bioavailable reduced side effects. SUMMARY OF THE INVENTION

[0003] In some aspects, the present disclosure provides a compound represented by the structure of Formula (I): I), or a pharmaceutically acceR1is selected from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; R2aand R2bare each independently selected from: hydrogen, halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -NO2, -CN; and C1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -NO2, and -CN; R3is selected from hydrogen and C1-6alkyl;Ring A is selected from C3-12 carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from (i), (ii), and (iii): (i) halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -OC(O)N(R13)2, -N(R13)C(O)OR13, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, =S, =NR13, and -CN; (ii) C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, =S, =NR13, and -CN; C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1-6 haloalkyl, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, =S, =NR13, and -CN; and (iii) C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -NO2, =O, =S, =NR13, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, =S, =NR13, and -CN; Ring B is selected from C3-12carbocycle, 3- to 6-membered heterocycle, and 7- to 12-membered heterocycle, the 3- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from: halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)OR14, -OC(O)R14, -OC(O)N(R14)2, -N(R14)C(O)OR14, -C(O)N(R14)2, -N(R14)C(O)R14, -NO2, =S, =NR14, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)OR14, -OC(O)R14,C3-12 carbocycle and 3- to 12-membered heterocycle any of which is optionally substituted with one or more substituents independently selected from halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)OR14, -OC(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, -NO2, =O, =S, =NR14, -CN, and C1-6alky, wherein the C1-6alkyl is optionally substituted with one or more substituents independently selected from halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)OR14, -OC(O)R14, - C(O)N(R14)2, -N(R14)C(O)R14, -NO2, =O, =S, =NR14, and -CN; wherein, when the 3- to 6-membered heterocycle is pyridinyl, the pyridinyl is further optionally substituted with one oxo group; and the C3-12carbocycle and 7- to 12-membered heterocycle, are each optionally substituted with one or substituents independently selected from: halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)OR15, -OC(O)R15, -OC(O)N(R15)2, -N(R15)C(O)OR15, -C(O)N(R15)2, -N(R15)C(O)R15, -NO2, =O, =S, =NR15, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)OR15, -OC(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -NO2, =O, =S, =NR15, and -CN; and C3-12carbocycle and 3- to 12-membered heterocycle any of which is optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)OR15, -OC(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -NO2, =O, =S, =NR15, -CN, and C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)OR15, -OC(O)R15, - C(O)N(R15)2, -N(R15)C(O)R15, -NO2, =O, =S, =NR15, and -CN; and R11, R12, R13, R14, and R15at each occurrence are independently selected from: hydrogen; C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2,-NO2, =O, -CN, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10 carbocycle and 3- to 10- membered heterocycle are optionally substituted with one or more substituentsC1-6 haloalkyl, -NH2, -NO2, =O, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6 alkyl, -O-C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2,-NO2, =O, and -CN.

[0004] In certain aspects, the present disclosure provides a pharmaceutical composition comprising pharmaceutically acceptable excipient and a compound or salt of Formula (I).

[0005] In certain aspects, the present disclosure provides a method of modulating alpha 4 beta 7 integrin in a subject in need thereof, comprising administering to the subject a compound or salt of Formula (I) or a pharmaceutical composition thereof.

[0006] In certain aspects, the present disclosure provides a method of treating an inflammatory disease or condition comprising administering to a subject in need thereof a compound or salt of Formula (I) or a pharmaceutical composition thereof. In some embodiments, the inflammatory disease or condition is selected from: inflammatory bowel disease, ulcerative colitis, Crohn’s disease, graft-versus-host disease, type 1 diabetes, immune-mediated colitis, checkpoint inhibitor induced colitis, and primary sclerosing cholangitis. INCORPORATION BY REFERENCE

[0007] 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. DETAILED DESCRIPTION OF THE INVENTION

[0008] Integrin alpha 4 beta 7 is an integrin family adhesion receptor that shares subunits with alpha 4 beta 1 (VLA4) and the E-Cadherin receptor, alpha E beta 7. α4ß7is critical for directing immune cells to intestinal mucosa, and is induced during T cell activation in Peyer’s patches or mesenteric lymph nodes. α4ß7is a clinically validated target for IBD, with selective α4ß7inhibition resulting in significant anti-inflammatory effects and reduction in symptoms. However, off-target binding to α4ß1can result in significant dose-limiting side effects. For example, TYSABRI (natalizumab), binds to both α4ß7 and α4ß1, and the binding of α4ß1 has been linked to progressive multifocal leukoencephalopathy, which resulted in the FDA restricting the use of TYSABRI in IBD.antagonist designed in a manner designed to mimic the anti-inflammatory actions of ENTYVIO, specifically its high selectivity for α4ß7over α4ß1. For example, in some embodiments, the present disclosure provides compounds having over 100-fold selectivity for α4ß7 over α4ß1. In some embodiments, the present disclosure provides compounds having over 1,000-fold selectivity for α4ß7 over α4ß1. Ulcerative Colitis Disease

[0010] UC is a form of IBD characterized by inflammation and ulcers in the large intestine. The clinical symptoms of UC are diarrhea and bloody stool. Its clinical course is marked by exacerbations and remissions, which may occur spontaneously or in response to dietary changes, alterations in treatment regimens, other illnesses, or stress.

[0011] UC can be debilitating and can sometimes lead to life-threatening complications. Frequent diarrhea and bloody stools can lead to weight loss, dehydration and anemia. Persistent UC is associated with an increased risk of developing colon cancer. The Centers for Disease Control estimates that there are three million individuals in the United States with IBD, of which roughly half have UC. A similar number of individuals in Europe are estimated to have UC.

[0012] UC is typically treated with anti-inflammatory drugs starting with more moderate and locally delivered drugs, and progressing to systemic immunosuppressive drugs for patients with refractory disease. First line therapy for patients with mild disease consists of 5-aminosalicylates such as mesalamine and sulfasalazine. Patients with more severe disease are treated with systemic corticosteroids, with the intent of inducing remission and transitioning patients to better-tolerated drugs such as 5-aminosalicylates for maintenance. Some patients may be treated with systemic immunomodulatory drugs such as azathioprine, cyclosporine and XELJANZ (tofacitinib). Anti-inflammatory biologics such as TNFα antagonists REMICADE (infliximab), HUMIRA (adalimumab) and SIMPONI (golimumab) and the IL-12 / IL-23 antagonist STELARA (ustekinumab) are effective in inducing remission in patients with moderate to severe UC.

[0013] ENTYVIO (vedolizumab), a monoclonal antibody that selectively targets α4ß7, was first approved by the FDA to treat UC and CD in 2014. In clinical trials, approximately 30% of patients receiving ENTYVIO achieved remission at the end of one year of treatment. ENTYVIO is administered as a 30-minute intravenous infusion at zero, two and six weeks, then every eight weeks thereafter. Long term therapy is generally well-tolerated in patients, but frequent dose adjustments have been reported to be required to maintain efficacy.

[0014] CD is a chronic inflammatory disease that most commonly affects the end of the small intestine and the beginning of the large intestine, although it may involve any part of the gastrointestinal tract. Both CD and UC are types of IBD and many of the symptoms and demographics overlap. In addition to the potential of CD developing in other segments of the intestine, CD differs from UC in that there can be normal healthy tissue in between patches of diseased tissue in CD, unlike UC where the inflammation is continuous. CD can also occur in all layers of the intestinal wall unlike UC which is limited to the inner most layer. It is estimated that there are 1.5 million individuals in the United States and 1.1 million individuals in Europe with CD.

[0015] The treatment paradigm for CD is very similar to that of UC with currently approved therapies focused on anti-inflammatory agents. Nearly 60% of CD patients will require surgery within twenty years of diagnosis to treat complications such as fistulas, or abnormal connections between body parts, life-threatening bleeding and intestinal obstructions.

[0016] While there are numerous approved therapeutics for UC and CD, there remains a significant unmet medical need for patients and clinicians to effectively and conveniently manage these chronic diseases, which could be facilitated by effective oral therapies.

[0017] In some aspects, the compounds of the present disclosure are used for the treatment and / or prevention of IBD. In some aspects of the present disclosure, the compounds provided herein are used for the treatment and / or prevention of UC. In some aspects of the present disclosure, the compounds provided herein are used for the treatment and / or prevention of CD.

[0018] Definitions

[0019] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference.

[0020] As used in the specification and claims, the singular form “a”, “an” and “the” includes plural references unless the context clearly dictates otherwise.

[0021] "Alkyl" refers to a straight or branched hydrocarbon chain monovalent radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, and preferably having from one to twelve carbon atoms (i.e., C1-C12 alkyl). The alkyl is attached to the remainder of the molecule through a single bond. In certain embodiments, an alkyl comprises one to twelve carbon atoms (i.e., C1-C12 alkyl). In certain embodiments, an alkyl comprises one to eight carbonC1-C5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (i.e., C1-C4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (i.e., C1-C3alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (i.e., C1-C2 alkyl). In other embodiments, an alkyl comprises one carbon atom (i.e., C1alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (i.e., C5-C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (i.e., C5-C8alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (i.e., C2-C5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (i.e., C3-C5alkyl). For example, the alkyl group may be attached to the rest of the molecule by a single bind, such as, methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl), and the like.

[0022] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and preferably having from two to twelve carbon atoms (i.e., C2-C12alkenyl). In certain embodiments, an alkenyl comprises two to eight carbon atoms (i.e., C2-C8 alkenyl). In certain embodiments, an alkenyl comprises two to six carbon atoms (i.e., C2-C6 alkenyl). In other embodiments, an alkenyl comprises two to four carbon atoms (i.e., C2-C4alkenyl). The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like.

[0023] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and preferably having from two to twelve carbon atoms (i.e., C2-C12 alkynyl). In certain embodiments, an alkynyl comprises two to eight carbon atoms (i.e., C2-C8alkynyl). In other embodiments, an alkynyl comprises two to six carbon atoms (i.e., C2-C6 alkynyl). In other embodiments, an alkynyl comprises two to four carbon atoms (i.e., C2-C4alkynyl). The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.

[0024] "Alkylene" refers to a straight divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation, and preferably having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment ofcarbons respectively. Alkylene chain may be optionally substituted by one or more substituents such as those substituents described herein. In certain embodiments, an alkylene comprises one to ten carbon atoms (i.e., C1-C10 alkylene). In certain embodiments, an alkylene comprises one to eight carbon atoms (i.e., C1-C8alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (i.e., C1-C5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (i.e., C1-C4alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (i.e., C1-C3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (i.e., C1-C2alkylene). In other embodiments, an alkylene comprises one carbon atom (i.e., C1 alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (i.e., C5-C8alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (i.e., C2-C5 alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (i.e., C3-C5alkylene).

[0025] "Alkenylene" refers to a straight divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and preferably having from two to twelve carbon atoms. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group are through the terminal carbons respectively. Alkenylene chain may be optionally substituted by one or more substituents such as those substituents described herein. In certain embodiments, an alkenylene comprises two to ten carbon atoms (i.e., C2-C10alkenylene). In certain embodiments, an alkenylene comprises two to eight carbon atoms (i.e., C2-C8 alkenylene). In other embodiments, an alkenylene comprises two to five carbon atoms (i.e., C2-C5alkenylene). In other embodiments, an alkenylene comprises two to four carbon atoms (i.e., C2-C4 alkenylene). In other embodiments, an alkenylene comprises two to three carbon atoms (i.e., C2-C3alkenylene). In other embodiments, an alkenylene comprises two carbon atom (i.e., C2 alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms (i.e., C5-C8alkenylene). In other embodiments, an alkenylene comprises three to five carbon atoms (i.e., C3-C5 alkenylene).

[0026] "Alkynylene" refers to a straight divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and preferably having from two to twelve carbon atoms. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radicalmolecule and to the radical group are through the terminal carbons respectively. Alkynylene chain may be optionally substituted by one or more substituents such as those substituents described herein. In certain embodiments, an alkynylene comprises two to ten carbon atoms (i.e., C2-C10alkynylene). In certain embodiments, an alkynylene comprises two to eight carbon atoms (i.e., C2-C8 alkynylene). In other embodiments, an alkynylene comprises two to five carbon atoms (i.e., C2-C5alkynylene). In other embodiments, an alkynylene comprises two to four carbon atoms (i.e., C2-C4 alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (i.e., C2-C3alkynylene). In other embodiments, an alkynylene comprises two carbon atoms (i.e., C2 alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (i.e., C5-C8alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms (i.e., C3-C5 alkynylene).

[0027] The term “Cx-y” when used in conjunction with a chemical moiety, such as alkyl, alkenyl, or alkynyl is meant to include groups that contain from x to y carbons in the chain. For example, the term “C1-6alkyl” refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from 1 to 6 carbons. The term -Cx-y alkylene- refers to a substituted or unsubstituted alkylene chain with from x to y carbons in the alkylene chain. For example, -C1-6alkylene- may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any one of which is optionally substituted.

[0028] The terms “Cx-y alkenyl” and “Cx-y alkynyl” refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively. The term -Cx-y alkenylene- refers to a substituted or unsubstituted alkenylene chain with from x to y carbons in the alkenylene chain. For example, - C2-6 alkenylene- may be selected from ethenylene, propenylene, butenylene, pentenylene, and hexenylene, any one of which is optionally substituted. An alkenylene chain may have one double bond or more than one double bond in the alkenylene chain. The term -Cx-yalkynylene- refers to a substituted or unsubstituted alkynylene chain with from x to y carbons in the alkynylene chain. For example, -C2-6 alkynylene- may be selected from ethynylene, propynylene, butynylene, pentynylene, and hexynylene, any one of which is optionally substituted. An alkynylene chain may have one triple bond or more than one triple bond in the alkynylene chain.

[0029] The term “carbocycle” as used herein refers to a saturated, unsaturated or aromatic ring in which each atom of the ring is carbon. Carbocycle include 3- to 10-membered monocyclic ringssaturated, unsaturated, and aromatic rings. Bicyclic carbocycles may be fused, bridged or spiro- ring systems. In some embodiments, the carbocycle is an aryl. In some embodiments, the carbocycle is a cycloalkyl. In some embodiments, the carbocycle is a cycloalkenyl. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, are included in the definition of carbocyclic. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. Carbocycle may be optionally substituted by one or more substituents such as those substituents described herein.

[0030] "Cycloalkyl" refers to a stable fully saturated monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, and preferably having from three to twelve carbon atoms (i.e., C3-12cycloalkyl). In certain embodiments, a cycloalkyl comprises three to ten carbon atoms (i.e., C3-10 cycloalkyl). In other embodiments, a cycloalkyl comprises five to seven carbon atoms (i.e., C5-7cycloalkyl). The cycloalkyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Cycloalkyl may be optionally substituted by one or more substituents such as those substituents described herein.

[0031] "Cycloalkenyl" refers to a stable unsaturated non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, preferably having from three to twelve carbon atoms and comprising at least one double bond (i.e., C3-12 cycloalkenyl). In certain embodiments, a cycloalkenyl comprises three to ten carbon atoms (i.e., C3-10cycloalkenyl). In other embodiments, a cycloalkenyl comprises five to seven carbon atoms (i.e., C5-7 cycloalkenyl). The cycloalkenyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Cycloalkenyl may be optionally substituted by one or more substituents such as those substituents described herein.

[0032] "Aryl" refers to a radical derived from an aromatic monocyclic or aromatic multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromaticand from five to eighteen carbon atoms, where at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) ^–electron system in accordance with the Hückel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. Aryl may be optionally substituted by one or more substituents such as those substituents described herein.

[0033] A “Cx-y carbocycle” is meant to include groups that contain from x to y carbons in a ring. For example, the term “C3-6carbocycle” can be a saturated, unsaturated or aromatic ring system that contains from 3 to 6 carbon atoms―any of which is optionally substituted as provided herein.

[0034] The term “heterocycle” as used herein refers to a saturated, unsaturated, non-aromatic or aromatic ring comprising one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycles include 3- to 10-membered monocyclic rings and 6- to 12- membered bicyclic rings. Each ring of a bicyclic heterocycle may be selected from saturated, unsaturated, and aromatic rings. In some embodiments, the heterocycle comprises at least one heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof. In some embodiments, the heterocycle comprises at least one heteroatom selected from oxygen, nitrogen, or any combination thereof. In some embodiments, the heterocycle comprises at least one heteroatom selected from oxygen, sulfur, or any combination thereof. In some embodiments, the heterocycle comprises at least one heteroatom selected from nitrogen, sulfur, or any combination thereof. The heterocycle may be attached to the rest of the molecule through any atom of the heterocycle, valence permitting, such as a carbon or nitrogen atom of the heterocycle. In some embodiments, the heterocycle is a heteroaryl. In some embodiments, the heterocycle is a heterocycloalkyl. Exemplary heterocycles include pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiophenyl, oxazolyl, thiazolyl, morpholinyl, indazolyl, indolyl, and quinolinyl. Heterocycle may be optionally substituted by one or more substituents such as those substituents described herein. Bicyclic heterocycles may be fused, bridged or spiro-ring systems. In an exemplary embodiment, a heterocycle, e.g., pyridyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Heterocycle may be optionally substituted by one or more substituents such as those substituents described herein.

[0035] "Heterocycloalkyl" refers to a stable 3 to 12 membered non-aromatic ring radical that comprises two to twelve carbon atoms and at least one heteroatom wherein each heteroatom maycomprises at least one heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof. In some embodiments, the heterocycloalkyl comprises at least one heteroatom selected from oxygen, nitrogen, or any combination thereof. In some embodiments, the heterocycloalkyl comprises at least one heteroatom selected from oxygen, sulfur, or any combination thereof. In some embodiments, the heterocycloalkyl comprises at least one heteroatom selected from nitrogen, sulfur, or any combination thereof. The heterocycloalkyl may be selected from monocyclic or bicyclic, and fused or bridged ring systems. The heteroatoms in the heterocycloalkyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocycloalkyl radical is partially or fully saturated. The heterocycloalkyl is attached to the rest of the molecule through any atom of the heterocycloalkyl, valence permitting, such as any carbon or nitrogen atoms of the heterocycloalkyl. Examples of heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2oxopiperazinyl, 2oxopiperidinyl, 2oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1oxothiomorpholinyl, and 1,1dioxothiomorpholinyl. Heterocycloalkyl may be optionally substituted by one or more substituents such as those substituents described herein.

[0036] The term “heteroaryl” refers to a radical derived from a 3 to 12 membered aromatic ring radical that comprises one to eleven carbon atoms and at least one heteroatom wherein each heteroatom may be selected from N, O, and S. In some embodiments, the heteroaryl comprises at least one heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof. In some embodiments, the heteroaryl comprises at least one heteroatom selected from oxygen, nitrogen, or any combination thereof. In some embodiments, the heteroaryl comprises at least one heteroatom selected from oxygen, sulfur, or any combination thereof. In some embodiments, the heteroaryl comprises at least one heteroatom selected from nitrogen, sulfur, or any combination thereof. As used herein, the heteroaryl ring may be selected from monocyclic or bicyclic and fused or bridged ring systems rings wherein at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) ^–electron system in accordance with the Hückel theory. The heteroatom(s) in the heteroaryl radical may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl may be attached to thenitrogen atom of the heteroaryl. Heteroaryl includes aromatic single ring structures, preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like. Heteroaryl may be optionally substituted by one or more substituents such as those substituents described herein. Heteroaryl also includes polycyclic ring systems having two or more rings in which two or more atoms are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other rings can be aromatic or non-aromatic carbocyclic, or heterocyclic. Heteroaryl may be optionally substituted by one or more substituents such as those substituents described herein.

[0037] An “X-membered heterocycle” refers to the number of endocylic atoms, i.e., X, in the ring. For example, a 5-membered heteroaryl ring or 5-membered aromatic heterocycle has 5 endocyclic atoms, e.g., triazole, oxazole, thiophene, etc.

[0038] "Alkoxy" refers to a radical bonded through an oxygen atom of the formula –O-alkyl, where alkyl is an alkyl chain as defined above.

[0039] "Halo" or "halogen" refers to halogen substituents such as bromo, chloro, fluoro and iodo substituents.

[0040] As used herein, the term "haloalkyl" or “haloalkane” refers to an alkyl radical, as defined above, that is substituted by one or more halogen radicals, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally further substituted. Examples of halogen substituted alkanes (“haloalkanes”) include halomethane (e.g., chloromethane, bromomethane, fluoromethane, iodomethane), di-and trihalomethane (e.g., trichloromethane, tribromomethane, trifluoromethane, triiodomethane), 1-haloethane, 2- haloethane, 1,2-dihaloethane, 1-halopropane, 2-halopropane, 3-halopropane, 1,2-dihalopropane, 1,3-dihalopropane, 2,3-dihalopropane, 1,2,3-trihalopropane, and any other suitable combinations of alkanes (or substituted alkanes) and halogens (e.g., Cl, Br, F, and I). When an alkyl group is substituted with more than one halogen radicals, each halogen may be independently selected for example, 1-chloro,2-fluoroethane.

[0041] The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons or substitutable heteroatoms, e.g., an NH or NH2of a compound. It will be understood that “substitution” or “substituted with” includes the implicit proviso that suchand that the substitution results in a stable compound, i.e., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. In certain embodiments, substituted refers to moieties having substituents replacing two hydrogen atoms on the same carbon atom, such as substituting the two hydrogen atoms on a single carbon with an oxo, imino or thioxo group. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds.

[0042] In some embodiments, substituents may include any substituents described herein, for example: halogen, hydroxy, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-OH), hydrazino (=N- NH2), -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N (Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2), and -Rb-S(O)tN(Ra)2 (where t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl any of which may be optionally substituted by alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo(=N-OH), hydrazine(=N- NH2), -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N (Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2 (where t is 1 or 2); wherein each Rais independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, wherein each Ra, valence permitting, may be optionally substituted with alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-OH), hydrazine(=N- NH2), -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N (Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2)direct bond or a straight or branched alkylene, alkenylene, or alkynylene chain, and each Rcis a straight or branched alkylene, alkenylene or alkynylene chain. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate.

[0043] The term “salt” or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0044] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0045] The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.

[0046] The terms "subject," "individual," and "patient" may be used interchangeably and refer to humans, the as well as non-human mammals (e.g., non-human primates, canines, equines, felines, porcines, bovines, ungulates, lagomorphs, and the like). In various embodiments, the subject can be a human (e.g., adult male, adult female, adolescent male, adolescent female, male child, female child) under the care of a physician or other health worker in a hospital, as an outpatient, or other clinical context. In certain embodiments, the subject may not be under the care or prescription of a physician or other health worker.

[0047] As used herein, the phrase "a subject in need thereof" refers to a subject, as described infra, that suffers from, or is at risk for, a pathology to be prophylactically or therapeutically treated with a compound or salt described herein.

[0048] The terms “administer”, “administered”, “administers” and “administering” are defined as providing a composition to a subject via a route known in the art, including but not limited to intravenous, intraarterial, oral, parenteral, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, transmucosal, or intraperitoneal routes of administration. In certain embodiments, oral routes of administering a composition can be used. The terms ““administer”,providing a compound of the invention or a prodrug of a compound of the invention to the individual in need.

[0049] As used herein, “treatment” or “treating” refers to an approach for obtaining beneficial or desired results with respect to a disease, disorder, or medical condition including, but not limited to, a therapeutic benefit and / or a prophylactic benefit. In certain embodiments, treatment or treating involves administering a compound or composition disclosed herein to a subject. A therapeutic benefit may include the eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit may be achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder, such as observing an improvement in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. In certain embodiments, for prophylactic benefit, the compositions are administered to a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made. Treating can include, for example, reducing, delaying or alleviating the severity of one or more symptoms of the disease or condition, or it can include reducing the frequency with which symptoms of a disease, defect, disorder, or adverse condition, and the like, are experienced by a patient. Treating can be used herein to refer to a method that results in some level of treatment or amelioration of the disease or condition, and can contemplate a range of results directed to that end, including but not restricted to prevention of the condition entirely.

[0050] In certain embodiments, the term “prevent” or “preventing” as related to a disease or disorder may refer to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.

[0051] A “therapeutic effect,” as that term is used herein, encompasses a therapeutic benefit and / or a prophylactic benefit as described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0052] Compoundsof Formula (I): I), or a pharmaceutically acce 1R is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; R2aand R2bare each independently selected from: hydrogen, halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -NO2, -CN; and C1-6alkyl, optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -NO2,and -CN; R3is selected from hydrogen and C1-6 alkyl; L is selected from a bond, -C(O)-, and -C(O)C(R12)2-; Ring A is selected from C3-12 carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from (i), (ii), and (iii): (i) halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -OC(O)N(R13)2, -N(R13)C(O)OR13, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, =S, =NR13, and -CN; (ii) C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, =S, =NR13, and -CN; C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, C1-6haloalkyl, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, =S, =NR13, and -CN; and (iii) C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13,C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, =S, =NR13, and -CN; Ring B is selected from C3-12 carbocycle, 3- to 6-membered heterocycle, and 7- to 12-membered heterocycle, the 3- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from: halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)OR14, -OC(O)R14, -OC(O)N(R14)2, -N(R14)C(O)OR14, -C(O)N(R14)2, -N(R14)C(O)R14, -NO2, =S, =NR14, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)OR14, -OC(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, -NO2, =O, =S, =NR14, and -CN; and C3-12 carbocycle and 3- to 12-membered heterocycle any of which is optionally substituted with one or more substituents independently selected from halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)OR14, -OC(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, -NO2, =O, =S, =NR14, -CN, and C1-6alky, wherein the C1-6alkyl is optionally substituted with one or more substituents independently selected from halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)OR14, -OC(O)R14, - C(O)N(R14)2, -N(R14)C(O)R14, -NO2, =O, =S, =NR14, and -CN; wherein, when the 3- to 6-membered heterocycle is pyridinyl, the pyridinyl is further optionally substituted with one oxo group; and the C3-12carbocycle and 7- to 12-membered heterocycle, are each optionally substituted with one or substituents independently selected from: halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)OR15, -OC(O)R15, -OC(O)N(R15)2, -N(R15)C(O)OR15, -C(O)N(R15)2, -N(R15)C(O)R15, -NO2, =O, =S, =NR15, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)OR15, -OC(O)R15,C3-12 carbocycle and 3- to 12-membered heterocycle any of which is optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)OR15, -OC(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -NO2, =O, =S, =NR15, -CN, and C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)OR15, -OC(O)R15, - C(O)N(R15)2, -N(R15)C(O)R15, -NO2, =O, =S, =NR15, and -CN; and R11, R12, R13, R14, and R15ahydrogen; C1-6alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, -CN, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10- membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O-C1-6haloalkyl, C1-6alkyl, C1-6 haloalkyl, -NH2, -NO2, =O, and -CN; and C3-10 carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O-C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2,-NO2, =O, and -CN.

[0054] In some embodiments of a compound or salt of Formula (I), R1is selected from hydrogen and C1-6alkyl. In some embodiments, R1is selected from hydrogen and C1-3alkyl. In some embodiments, R1is hydrogen. In some embodiments, R1is C1-3 alkyl. In some embodiments, R1is selected from methyl and ethyl. In some embodiments, R1is methyl.

[0055] In some embodiments of a compound or salt of Formula (I), R2aand R2bare each independently selected from hydrogen, halogen, C1-3alkyl, and C1-3haloalkyl. In some embodiments, R2aand R2bare each independently selected from hydrogen, halogen, and C1-3 alkyl. In some embodiments, R2aand R2bare each independently selected from hydrogen and halogen. In some embodiments, R2aand R2bare each hydrogen.

[0056] In some embodiments of a compound or salt of Formula (I), R3is selected from hydrogen and C1-3 alkyl. In some embodiments, R3is C1-3 alkyl. In some embodiments, R3is hydrogen.

[0057] In some embodiments of a compound or salt of Formula (I), L is -C(O)-. In some embodiments, L is a bond. In some embodiments, L is -C(O)C(R12)2-.substituted C3-12 carbocycle. In some embodiments, Ring A is optionally substituted saturated C3-12carbocycle. In some embodiments, Ring A is optionally substituted unsaturated C3-12carbocycle. In some embodiments, Ring A is selected from optionally substituted C3-4 carbocycle, optionally substituted C3-5carbocycle, optionally substituted C3-6carbocycle, optionally substituted C3-7 carbocycle, optionally substituted C3-8 carbocycle, optionally substituted C3-9carbocycle, optionally substituted C3-10carbocycle, optionally substituted C3-11carbocycle, and optionally substituted C3-12 carbocycle. In some embodiments, Ring A is selected from optionally substituted C3carbocycle, optionally substituted C4carbocycle, optionally substituted C5 carbocycle, optionally substituted C6 carbocycle, optionally substituted C7 carbocycle, optionally substituted C8carbocycle, optionally substituted C9carbocycle, optionally substituted C10 carbocycle, optionally substituted C11 carbocycle, and optionally substituted C12 carbocycle. In some embodiments, Ring A is selected from optionally substituted C3-8monocyclic carbocycle and optionally substituted C6-12 bicyclic carbocycle. In some embodiments, Ring A is optionally substituted C3-8monocyclic carbocycle. In some embodiments, Ring A is optionally substituted C6-12 bicyclic carbocycle. In some embodiments, Ring A is selected from optionally substituted C6-12 fused carbocycle, optionally substituted C6-12 bridged carbocycle, and optionally substituted C6-12spirocyclic carbocycle.

[0059] In some embodiments, for the compound or salt of Formula(I), Ring A is 3- to 12- membered heterocycle. In some embodiments, Ring A is 3- to 12-membered saturated heterocycle. In some embodiments, Ring A is 3- to 12-membered unsaturated heterocycle. In some embodiments, Ring A is selected from optionally substituted 3- to 4-membered heterocycle, optionally substituted 3- to 5-membered heterocycle, optionally substituted 3- to 6- membered heterocycle, optionally substituted 3- to 7-membered heterocycle, optionally substituted 3- to 8-membered heterocycle, optionally substituted 3- to 9-membered heterocycle, optionally substituted 3- to 10-membered heterocycle, optionally substituted 3- to 11-membered heterocycle, and optionally substituted 3- to 12-membered heterocycle. In some embodiments, Ring A is selected from optionally substituted 3-membered heterocycle, optionally substituted 4- membered heterocycle, optionally substituted 5-membered heterocycle, optionally substituted 6- membered heterocycle, optionally substituted 7-membered heterocycle, optionally substituted 8- membered heterocycle, optionally substituted 9-membered heterocycle, optionally substituted 10- membered heterocycle, optionally substituted 11-membered heterocycle, and optionally substituted 12-membered heterocycle.carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, -C(O)R13, - C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, and -CN; C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, - C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, -CN, C3-10 carbocycle and 3- to 10-membered heterocycle, wherein the C3-10carbocycle and 3- to 10- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, =O, -CN, C1-6 alkyl, and C1-6 haloalkyl; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -NO2, =O, -CN, and C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, =O, and -CN. In some embodiments, Ring A is selected from unsaturated C3-12carbocycle and saturated 3- to 12- membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, - C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)OR13, - OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, -CN, C3-10carbocycle and 3- to 10- membered heterocycle, wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, =O, -CN, C1-6 alkyl, and C1-6 haloalkyl; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -NO2, =O, -CN, and C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, =O, and -CN. In some embodiments, Ring A is selected from monocyclic C3-12carbocycle and monocyclic 3- to 12- membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, - C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, and -CN; C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)OR13, - OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, -CN, C3-10 carbocycle and 3- to 10-optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, =O, -CN, C1-6alkyl, and C1-6haloalkyl; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -NO2, =O, -CN, and C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, =O, and -CN. In some embodiments, Ring A is selected from unsaturated monocyclic C3-12 carbocycle and saturated monocyclic 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)OR13, - OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, - C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, -CN, C3-10carbocycle and 3- to 10-membered heterocycle, wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, =O, -CN, C1-6 alkyl, and C1-6 haloalkyl; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, - C(O)N(R13)2, -NO2, =O, -CN, and C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, =O, and -CN.

[0061] In some embodiments of a compound or salt of Formula (I), Ring A is selected from C3-9 carbocycle and 3- to 9-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)OR13, - OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, - C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, -CN, C3-10carbocycle and 3- to 10-membered heterocycle, wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, =O, -CN, C1-6alkyl, and C1-6haloalkyl; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -NO2, =O, -CN, and C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one or moreembodiments, Ring A is selected from unsaturated C3-9 carbocycle and saturated 3- to 9- membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, - C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)OR13, - OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, -CN, C3-10carbocycle and 3- to 10- membered heterocycle, wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, =O, -CN, C1-6 alkyl, and C1-6 haloalkyl; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -NO2, =O, -CN, and C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, =O, and -CN. In some embodiments, Ring A is selected from monocyclic C3-9carbocycle and monocyclic 3- to 9- membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, - C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)OR13, - OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, -CN, C3-10carbocycle and 3- to 10- membered heterocycle, wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, =O, -CN, C1-6 alkyl, and C1-6 haloalkyl; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -NO2, =O, -CN, and C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, =O, and -CN. In some embodiments, Ring A is selected from unsaturated monocylic C3-9carbocycle and saturated monocyclic 3- to 9-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)OR13, - OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, and -CN; C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, - C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, -CN, C3-10 carbocycle and 3-are each optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, =O, -CN, C1-6alkyl, and C1-6haloalkyl; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, - C(O)N(R13)2, -NO2, =O, -CN, and C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, =O, and -CN.

[0062] In some embodiments of a compound or salt of Formula (I), Ring A is selected from C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)OR13, - OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, - C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, -CN, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, =O, -CN, C1-6 alkyl, and C1-6 haloalkyl; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -NO2, =O,-CN, and C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, =O, and -CN. In some embodiments, Ring A is selected from unsaturated C3-6carbocycle and saturated 3- to 6- membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, - C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, and -CN; C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)OR13, - OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, -CN, C3-10 carbocycle, and 3- to 10- membered heterocycle, wherein the C3-10carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, =O, -CN, C1-6alkyl, and C1-6haloalkyl; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -NO2, =O,-CN, and C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one or moreembodiments, Ring A is selected from monocyclic C3-6 carbocycle and monocyclic 3- to 6- membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, - C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)OR13, - OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, -CN, C3-10carbocycle, and 3- to 10- membered heterocycle, wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, =O, -CN, C1-6 alkyl, and C1-6 haloalkyl; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -NO2, =O,-CN, and C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, =O, and -CN.

[0063] In some embodiments of a compound or salt of Formula (I), Ring A is selected from C5-6carbocycle and 5- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)OR13, - OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, - C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, -CN, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, =O, -CN, C1-6alkyl, and C1-6haloalkyl; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -NO2, =O,-CN, and C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, =O, and -CN. In some embodiments, Ring A is selected from unsaturated C5-6 carbocycle and saturated 5- to 6- membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, - C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)OR13, -membered heterocycle, wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, =O, -CN, C1-6 alkyl, and C1-6 haloalkyl; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -NO2, =O,-CN, and C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, =O, and -CN.

[0064] In some embodiments of a compound or salt of Formula (I), Ring A is selected from unsaturated C6 carbocycle and saturated 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, and -CN; C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, - OR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, - CN, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein the C3-10carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, =O, -CN, C1-6 alkyl, and C1-6 haloalkyl; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, - C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -NO2, =O,-CN, and C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, =O, and -CN. In some embodiments, Ring A is selected from phenyl and piperidinyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, - N(R13)C(O)R13, -NO2, =O, and -CN; C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)OR13, - OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, -CN, C3-10 carbocycle and 3- to 10- membered heterocycle, wherein the C3-10carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, =O, -CN, C1-6alkyl, and C1-6haloalkyl; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -NO2,substituents independently selected from halogen, -OR13, -N(R13)2, =O, and -CN.

[0065] In some embodiments of a compound or salt of Formula (I), Ring A is selected from C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, the C3-6carbocycle and 3- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments, Ring A is selected from unsaturated C6 carbocycle and saturated 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, and -CN; C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -CN; and C3-6carbocycle and 3- to 6- membered heterocycle, the C3-6 carbocycle and 3- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, and C1-6haloalkyl; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, and C1-6haloalkyl. In some embodiments, Ring A is selected from phenyl and piperidinyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -CN; and C3-6 carbocycle and 3- to 6-membered heterocycle, the C3-6carbocycle and 3- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, and C1-6haloalkyl; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, and C1-6haloalkyl.

[0066] In some embodiments of a compound or salt of Formula (I), Ring A is selected from phenyl and piperidinyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, - CN; and C3-6 carbocycle and 3- to 6-membered heterocycle, the C3-6 carbocycle and 3- to 6-independently selected from: halogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, Ring A is selected from phenyl and piperidinyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -N(R13)2; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, and 3- to 6- membered heterocycle, the 3- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments, Ring A is selected from phenyl and piperidinyl, each of which is optionally substituted with one or more substituents independently selected from fluoro, methyl, -N(CH3)2, and . nts of a compound or salt of Formula (I), Ring A is selected fromphenyl and piperidinyl, each of which is optionally substituted with one or more substituents independently selected from C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, and C1-6haloalkyl. In some embodiments, Ring A is selected from phenyl and piperidinyl, each of which is optionally substituted with one or more substituents independently selected from 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, Ring A is selected from phenyl and piperidinyl, each of which is optionally substituted with one or more substituents independently selected from 5- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, Ring A is selected from phenyl and piperidinyl, each of which is optionally substituted with one or more substituents independently selected from morpholinyl, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments, Ring A is selected from phenyl and piperidinyl, each of which is optionally substituted with one or more substituents independently selected from morpholinyl, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, Ring A is selected from phenyl and piperidinyl, each of which is optionally substitute .phenyl and piperidinyl, each of which is optionally substituted with one or more substituents independently selected from: fluoro, methyl .

[0069] In some embodiments of a compoun,e is independently selected from hydrogen, C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, R13at each occurrence is independently selected from hydrogen and methyl. In some embodiments, R13is methyl. In some embodiments, R13is hydrogen.

[0071] In some embodiments, for the compound or salt of Formula (I), Ring B is optionally substituted C3-12 carbocycle. In some embodiments, Ring B is optionally substituted saturated C3- 12 carbocycle. In some embodiments, Ring B is optionally substituted unsaturated C3-12 carbocycle. In some embodiments, Ring B is selected from optionally substituted C3-4carbocycle, optionally substituted C3-5 carbocycle, optionally substituted C3-6 carbocycle, optionally substituted C3-7carbocycle, optionally substituted C3-8carbocycle, optionally substituted C3-9 carbocycle, optionally substituted C3-10 carbocycle, optionally substituted C3-11 carbocycle, and optionally substituted C3-12carbocycle. In some embodiments, Ring B is selected from optionally substituted C3 carbocycle, optionally substituted C4 carbocycle, optionally substituted C5carbocycle, optionally substituted C6carbocycle, optionally substituted C7carbocycle, optionally substituted C8 carbocycle, optionally substituted C9 carbocycle, optionally substituted C10carbocycle, optionally substituted C11carbocycle, and optionally substituted C12carbocycle. In some embodiments, Ring B is selected from optionally substituted C3-8embodiments, Ring B is optionally substituted C3-8 monocyclic carbocycle. In some embodiments, Ring B is optionally substituted C6-12bicyclic carbocycle. In some embodiments, Ring B is selected from optionally substituted C6-12 fused carbocycle, optionally substituted C6-12 bridged carbocycle, and optionally substituted C6-12spirocyclic carbocycle.

[0072] In some embodiments, for the compound or salt of Formula(I), Ring B is 3- to 12- membered heterocycle. In some embodiments, Ring B is 3- to 12-membered saturated heterocycle. In some embodiments, Ring B is 3- to 12-membered unsaturated heterocycle. In some embodiments, Ring B is selected from optionally substituted 3- to 4-membered heterocycle, optionally substituted 3- to 5-membered heterocycle, optionally substituted 3- to 6-membered heterocycle, optionally substituted 3- to 7-membered heterocycle, optionally substituted 3- to 8- membered heterocycle, optionally substituted 3- to 9-membered heterocycle, optionally substituted 3- to 10-membered heterocycle, optionally substituted 3- to 11-membered heterocycle, and optionally substituted 3- to 12-membered heterocycle. In some embodiments, Ring B is selected from optionally substituted 3-membered heterocycle, optionally substituted 4- membered heterocycle, optionally substituted 5-membered heterocycle, optionally substituted 6- membered heterocycle, optionally substituted 7-membered heterocycle, optionally substituted 8- membered heterocycle, optionally substituted 9-membered heterocycle, optionally substituted 10- membered heterocycle, optionally substituted 11-membered heterocycle, and optionally substituted 12-membered heterocycle.

[0073] In some embodiments of a compound or salt of Formula (I), Ring B is 3-to 6-membered heterocycle optionally substituted with one or more substituents selected from: halogen, -OR14, - N(R14)2, -C(O)R14, -C(O)OR14, -OC(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, -NO2, =O, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR14, -N(R14)2, -C(O)R14, -C(O)OR14, -OC(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, - NO2, =O, and -CN, C3-12carbocycle and 3- to 12-membered heterocycle, wherein the C3-12carbocycle and 3- to 12-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR14, -N(R14)2, =O, -CN, C1-6alkyl, and C1-6haloalkyl; and wherein, when the 3- to 6-membered heterocycle is pyridinyl, the pyridinyl is further optionally substituted with one oxo group. In some embodiments, Ring B is unsaturated 3-to 6-membered heterocycle optionally substituted with one or more substituents selected from: halogen, -OR14, -N(R14)2, -C(O)R14, -C(O)OR14, -OC(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, - NO2, =O, and -CN; and C1-6 alkyl optionally substituted with one or more substituentsC(O)N(R14)2, -N(R14)C(O)R14, -NO2, =O, and -CN, C3-12 carbocycle and 3- to 12-membered heterocycle, wherein the C3-12carbocycle and 3- to 12-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR14, -N(R14)2, =O, -CN, C1-6alkyl, and C1-6haloalkyl; and wherein, when the 3- to 6-membered heterocycle is pyridinyl, the pyridinyl is further optionally substituted with one oxo group. In some embodiments, Ring B is unsaturated monocyclic 3-to 6-membered heterocycle optionally substituted with one or more substituents selected from: halogen, -OR14, -N(R14)2, -C(O)R14, - C(O)OR14, -OC(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, -NO2, =O, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR14, -N(R14)2, -C(O)R14, -C(O)OR14, -OC(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, -NO2, =O, and -CN, C3-12 carbocycle and 3- to 12-membered heterocycle, wherein the C3-12 carbocycle and 3- to 12- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR14, -N(R14)2, =O, -CN, C1-6 alkyl, and C1-6 haloalkyl; and wherein, when the 3- to 6-membered heterocycle is pyridinyl, the pyridinyl is further optionally substituted with one oxo group.

[0074] In some embodiments of a compound or salt of Formula (I), Ring B is 5-to 6-membered heterocycle optionally substituted with one or more substituents selected from: halogen, -OR14, - N(R14)2, -C(O)R14, -C(O)OR14, -OC(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, -NO2, =O, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR14, -N(R14)2, -C(O)R14, -C(O)OR14, -OC(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, - NO2, =O, and -CN, C3-6carbocycle and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR14, -N(R14)2, =O, -CN, C1-6alkyl, and C1-6haloalkyl; and wherein, when the 3- to 6-membered heterocycle is pyridinyl, the pyridinyl is further optionally substituted with one oxo group. In some embodiments, Ring B is unsaturated 5-to 6-membered heterocycle optionally substituted with one or more substituents selected from: halogen, -OR14, -N(R14)2, -C(O)R14, -C(O)OR14, -OC(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, - NO2, =O, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR14, -N(R14)2, -C(O)R14, -C(O)OR14, -OC(O)R14, - C(O)N(R14)2, -N(R14)C(O)R14, -NO2, =O, and -CN, C3-6 carbocycle and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR14, -N(R14)2,pyridinyl, the pyridinyl is further optionally substituted with one oxo group. In some embodiments, Ring B is unsaturated monocyclic 5-to 6-membered heterocycle optionally substituted with one or more substituents selected from: halogen, -OR14, -N(R14)2, -C(O)R14, - C(O)OR14, -OC(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, -NO2, =O, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR14, -N(R14)2, -C(O)R14, -C(O)OR14, -OC(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, -NO2, =O, and -CN, C3-6 carbocycle and 3- to 6-membered heterocycle, wherein the C3-6 carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR14, -N(R14)2, =O, -CN, C1-6 alkyl, and C1-6 haloalkyl; and wherein, when the 3- to 6-membered heterocycle is pyridinyl, the pyridinyl is further optionally substituted with one oxo group.

[0075] In some embodiments of a compound or salt of Formula (I), Ring B is pyridinonyl optionally substituted with one or more substituents selected from: halogen, -OR14, -N(R14)2, - C(O)R14, -C(O)OR14, -OC(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, -NO2, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR14, -N(R14)2, -C(O)R14, -C(O)OR14, -OC(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, -NO2, =O, and -CN, C3-6carbocycle and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR14, -N(R14)2, =O, -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, Ring B is pyridinonyl optionally substituted with one or more substituents independently selected from: halogen, -OR14, -NR14, and -CN; and C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more substituents independently selected from halogen, -OR14, -N(R14)2, -CN, C3-6carbocycle and 3- to 6- membered heterocycle, wherein the C3-6 carbocycle and 3- to 6- membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl.

[0076] In some embodiments of a compound or salt of Formula (I), Ring B is pyridinonyl optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6 haloalkyl. In some embodiments, Ring B is pyridinonyl optionally substituted with one or more substituents independently selected from halogen, C1-3alkyl, and C1-3haloalkyl. In some embodiments, Ring B is pyridinonyl optionally substituted with one or more substituents independently selected from halogen, methyl, ethyl, and -CF3. In some embodiments, Ring B ismethyl and -CF3. In some embodiments, Rin .

[0077] In some embodiments of a compound a (I), Ring B is selected from C3-12carbocycle and 7- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents selected from: halogen, -OR15, -N(R15)2, -C(O)R15, -C(O)OR15, -OC(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -NO2, =O, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -C(O)R15, - C(O)OR15, -OC(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -NO2, =O, and -CN, C3-12carbocycle, and 3- to 12-membered heterocycle, wherein the C3-12 carbocycle and 3- to 12-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, =O, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, Ring B is selected from unsaturated C3-12 carbocycle and unsaturated 7- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents selected from: halogen, - OR15, -N(R15)2, -C(O)R15, -C(O)OR15, -OC(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -NO2, =O, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -C(O)R15, -C(O)OR15, -OC(O)R15, -C(O)N(R15)2, - N(R15)C(O)R15, -NO2, =O, and -CN, C3-12carbocycle, and 3- to 12-membered heterocycle, wherein the C3-12 carbocycle and 3- to 12-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, =O, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, Ring B is selected from unsaturated monocyclic C3-12carbocycle and unsaturated bicyclic 7- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents selected from: halogen, -OR15, - N(R15)2, -C(O)R15, -C(O)OR15, -OC(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -NO2, =O, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -C(O)R15, -C(O)OR15, -OC(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, - NO2, =O, and -CN, C3-12 carbocycle, and 3- to 12-membered heterocycle, wherein the C3-12 carbocycle and 3- to 12-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, =O, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, Ring B is selected from unsaturated monocyclic C3-12optionally substituted with one or more substituents selected from: halogen, -OR15, -N(R15)2, - C(O)R15, -C(O)OR15, -OC(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -NO2, =O, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, - OR15, -N(R15)2, -C(O)R15, -C(O)OR15, -OC(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -NO2, =O, and -CN, C3-12 carbocycle, and 3- to 12-membered heterocycle, wherein the C3-12 carbocycle and 3- to 12-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, =O, -CN, C1-6 alkyl, and C1-6 haloalkyl.

[0078] In some embodiments of a compound or salt of Formula (I), Ring B is selected from C3-6carbocycle and 7- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents selected from: halogen, -OR15, -N(R15)2, -C(O)R15, -C(O)OR15, -OC(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -NO2, =O, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -C(O)R15, - C(O)OR15, -OC(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -NO2, =O, and -CN, C3-6 carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, - OR15, -N(R15)2, =O, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, Ring B is selected from unsaturated C3-6carbocycle and unsaturated 7- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents selected from: halogen, -OR15, -N(R15)2, - C(O)R15, -C(O)OR15, -OC(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -NO2, =O, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, - OR15, -N(R15)2, -C(O)R15, -C(O)OR15, -OC(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -NO2, =O, and -CN, C3-6 carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6 carbocycle and 3- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, =O, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, Ring B is selected from unsaturated monocyclic C3-6carbocycle and unsaturated bicyclic 7- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents selected from: halogen, -OR15, -N(R15)2, -C(O)R15, -C(O)OR15, - OC(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -NO2, =O, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, - C(O)R15, -C(O)OR15, -OC(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -NO2, =O, and -CN, C3-6 carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituentssome embodiments, Ring B is selected from unsaturated monocyclic C3-6 carbocycle and unsaturated fused bicyclic 7- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents selected from: halogen, -OR15, -N(R15)2, -C(O)R15, - C(O)OR15, -OC(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -NO2, =O, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -C(O)R15, -C(O)OR15, -OC(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -NO2, =O, and -CN, C3-6 carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6 carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, =O, -CN, C1-6 alkyl, and C1-6 haloalkyl.

[0079] In some embodiments of a compound or salt of Formula (I), Ring B is selected from C5-6carbocycle and 9- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents selected from: halogen, -OR15, -N(R15)2, -C(O)R15, -C(O)OR15, -OC(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -NO2, =O, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -C(O)R15, - C(O)OR15, -OC(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -NO2, =O, and -CN, C3-6 carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6 carbocycle and 3- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, - OR15, -N(R15)2, =O, -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, Ring B is selected from unsaturated C5-6 carbocycle and unsaturated 9- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents selected from: halogen, -OR15, -N(R15)2, - C(O)R15, -C(O)OR15, -OC(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -NO2, =O, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, - OR15, -N(R15)2, -C(O)R15, -C(O)OR15, -OC(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -NO2, =O, and -CN, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, =O, -CN, C1-6alkyl, and C1-6haloalkyl. In some embodiments, Ring B is selected from unsaturated monocyclic C5-6 carbocycle and unsaturated bicyclic 9- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents selected from: halogen, -OR15, -N(R15)2, -C(O)R15, -C(O)OR15, - OC(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -NO2, =O, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6 carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, =O, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, Ring B is selected from unsaturated monocyclic C5-6carbocycle and unsaturated fused bicyclic 9- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents selected from: halogen, -OR15, -N(R15)2, -C(O)R15, - C(O)OR15, -OC(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -NO2, =O, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -C(O)R15, -C(O)OR15, -OC(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -NO2, =O, and -CN, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, =O, -CN, C1-6alkyl, and C1-6haloalkyl.

[0080] In some embodiments of a compound or salt of Formula (I), Ring B is selected from phenyl, quinolinonyl, and isoquinolinyl, each of which is optionally substituted with one or more substituents selected from: halogen, -OR15, -N(R15)2, -C(O)R15, -C(O)OR15, -OC(O)R15, - C(O)N(R15)2, -N(R15)C(O)R15, -NO2, =O, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -C(O)R15, - C(O)OR15, -OC(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -NO2, =O, and -CN, C3-6 carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, - OR15, -N(R15)2, =O, -CN, C1-6 alkyl, and C1-6 haloalkyl.

[0081] In some embodiments of a compound or salt of Formula (I), Ring B is selected from phenyl, quinolinonyl, and isoquinolinyl, each of which is optionally substituted with one or more substituents independently selected from: -OR15, -N(R15)2,=O, -CN, and C1-6alkyl, wherein the C1-6 alkyl is optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -CN, C3-6carbocycle and 3- to 6- membered heterocycle, wherein the C3-6 carbocycle and 3- to 6- membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments, Ring B is selected from phenyl, quinolinonyl, and isoquinolinyl, each of which is optionally substituted with one or more substituents independently selected from: -OR15, - N(R15)2, =O, -CN, and C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one orheterocycle, wherein the 3- to 6- membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments, Ring B is selected from phenyl, quinolinonyl, and isoquinolinyl, each of which is optionally substituted with one or more substituents independently selected from: methyl, -CF3, - OCH3, , , , , , is titutedwith one or more substituents independently selected from: methyl, -CF3, -OCH3,,d . In some embodiments, Ring B is selected from phenyl, quinolinonyl, which is optionally substituted with one or more substituents,cted from: F F F , ,, rrence isindependently selected from hydrogen, C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, R11at each occurrence is independently selected from hydrogen, methyl, and C1haloalkyl. In some embodiments, R11at each occurrence is independently selected from hydrogen and methyl.

[0084] In some embodiments of a compound or salt of Formula (I), R12at each occurrence is independently selected from hydrogen, C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, R12at each occurrence is independently selected from hydrogen, methyl, and C1haloalkyl. In some embodiments, R12at each occurrence is independently selected from hydrogen and methyl.

[0085] In some embodiments of a compound or salt of Formula (I), R13at each occurrence is independently selected from hydrogen, C1-3alkyl, and C1-3haloalkyl. In some embodiments, R13at each occurrence is independently selected from hydrogen, methyl, and C1 haloalkyl. In some embodiments, R13at each occurrence is independently selected from hydrogen and methyl.

[0086] In some embodiments of a compound or salt of Formula (I), R14at each occurrence is independently selected from hydrogen, C1-3alkyl, and C1-3haloalkyl. In some embodiments, R14at each occurrence is independently selected from hydrogen, methyl, and C1 haloalkyl. In some embodiments, R14at each occurrence is independently selected from hydrogen and methyl.

[0087] In some embodiments of a compound or salt of Formula (I), R15at each occurrence is independently selected from hydrogen, C1-3alkyl, and C1-3haloalkyl. In some embodiments, R15at each occurrence is independently selected from hydrogen, methyl, and C1 haloalkyl. In some embodiments, R15at each occurrence is independently selected from hydrogen and methyl. In some embodiments, R15is methyl.

[0088] In some embodiments of a compound or salt of Formula (I), the compound is selected from:,, , ,,,, , ,, andbed herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.may exist in Z- or E- form (or cis- or trans- form). Furthermore, some chemical entities may exist in various tautomeric forms. Unless otherwise specified, compounds or salts of Formula (I) are intended to include all Z-, E- and tautomeric forms as well.

[0091] “Isomers” are different compounds that have the same molecular formula. “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space. “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a “racemic” mixture. The term “(±)” is used to designate a racemic mixture where appropriate. “Diastereoisomers” or “diastereomers” are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) in which they rotate plane polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, the asymmetric centers of which can be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The present chemical entities, pharmaceutical compositions and methods are meant to include all such possible stereoisomers, including racemic mixtures, optically pure forms, mixtures of diastereomers and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. The optical activity of a compound can be analyzed via any suitable method, including but not limited to chiral chromatography and polarimetry, and the degree of predominance of one stereoisomer over the other isomer can be determined.

[0092] The compounds or salts for Formula (I), herein may in some cases exist as diastereomers, enantiomers, or other stereoisomeric forms. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the racemates, mixtures of diastereomers, and other mixtures thereof, to the extent they can be made by one of ordinary skill in the art by routine experimentation. Separation of stereoisomers may be performed by chromatography or by forming diastereomers and separating by recrystallization, or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981, hereinstereoselective synthesis. Furthermore, a mixture of two enantiomers enriched in one of the two can be purified to provide further optically enriched form of the major enantiomer by recrystallization and / or trituration.

[0093] In certain embodiments, compounds or salts for Formula (I), may comprise two or more enantiomers or diastereomers of a compound wherein a single enantiomer or diastereomer accounts for at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 98% by weight, or at least about 99% by weight or more of the total weight of all stereoisomers. Methods of producing substantially pure enantiomers are well known to those of skill in the art. For example, a single stereoisomer, e.g., an enantiomer, substantially free of its stereoisomer may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents (Stereochemistry of Carbon Compounds, (1962) by E. L. Eliel, McGraw Hill; Lochmuller (1975) J. Chromatogr., 113(3): 283-302). Racemic mixtures of chiral compounds can be separated and isolated by any suitable method, including, but not limited to: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions. Another approach for separation of the enantiomers is to use a Diacel chiral column and elution using an organic mobile phase such as done by Chiral Technologies (www.chiraltech.com) on a fee for service basis.

[0094] A "tautomer" refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. In certain embodiments, the compounds or salts for Formula (I), exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers may exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some non–limiting examples of tautomeric equilibrium include:ferent enrichedisotopic forms, e.g., enriched in the content of2H,3H,11C,13C and / or14C. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in U.S. Patent Nos.5,846,514 and 6,334,997. As described in U.S. Patent Nos.5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.

[0096] In certain embodiments, the compounds disclosed herein have some or all of the1H atoms replaced with2H atoms. The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0097] Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 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.

[0098] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.

[0099] Unless otherwise stated, compounds described herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by athe scope of the present disclosure.

[0100] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium (2H), tritium (3H), iodine-125 (125I) or carbon14 (14C). Isotopic substitution with2H,11C,13C,14C,15C,12N,13N,15N,16N,16O,17O,14F,15F,16F,17F,18F,33S,34S,35S,36S,35Cl,37Cl,79Br,81Br, and125I are all contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0101] Included in the present disclosure are salts, particularly pharmaceutically acceptable salts, of the compounds of Formula (I). The compounds of the present disclosure may possess a sufficiently acidic, a sufficiently basic, or both functional groups, can react with any of a number of inorganic bases, and inorganic and organic acids, to form a salt. Alternatively, compounds that are inherently charged, such as those with a quaternary nitrogen, can form a salt with an appropriate counterion, e.g., a halide such as bromide, chloride, or fluoride, particularly bromide.

[0102] The methods and compositions of Formula (I), include the use of amorphous forms as well as crystalline forms (also known as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. As well, in some embodiments, active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure. In addition, the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0103] Compounds of Formula (I), also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.

[0104] Included in the present disclosure are salts, particularly pharmaceutically acceptable salts, of compounds represented by Formula (I). The compounds of the present invention that possess a sufficiently acidic, a sufficiently basic, or both functional groups, can react with any of a number of inorganic bases, and inorganic and organic acids, to form a salt. Alternatively, compounds that are inherently charged, such as those with a quaternary nitrogen, can form a salt with an appropriate counterion, e.g., a halide such as bromide, chloride, or fluoride, particularly bromide.wherein a hydroxyl in the parent compound is presented as an ester or a carbonate, or carboxylic acid present in the parent compound is presented as an ester. The term “prodrug” is intended to encompass compounds which, under physiologic conditions, are converted into pharmaceutical agents of the present disclosure. One method for making a prodrug is to include one or more selected moieties which are hydrolyzed under physiologic conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal such as specific target cells in the host animal. For example, esters or carbonates (e.g., esters or carbonates of alcohols or carboxylic acids and esters of phosphonic acids) are preferred prodrugs of the present disclosure.

[0106] Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. Prodrugs may help enhance the cell permeability of a compound relative to the parent drug. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. Prodrugs may be designed as reversible drug derivatives, for use as modifiers to enhance drug transport to site-specific tissues or to increase drug residence inside of a cell.

[0107] In certain embodiments, the prodrug may be converted, e.g., enzymatically or chemically, to the parent compound under the conditions within a cell. In certain embodiments, the parent compound comprises an acidic moiety, e.g., resulting from the hydrolysis of the prodrug, which may be charged under the conditions within the cell. In particular embodiments, the prodrug is converted to the parent compound once it has passed through the cell membrane into a cell. In certain embodiments, the parent compound has diminished cell membrane permeability properties relative to the prodrug, such as decreased lipophilicity and increased hydrophilicity.

[0108] In some embodiments, the design of a prodrug increases the lipophilicity of the pharmaceutical agent. In some embodiments, the design of a prodrug increases the effective water solubility. See, e.g., Fedorak et al., Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J. Pharm. Sci., 64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol.14 of the A.C.S. Symposium Series; and Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, all incorporated herein for such disclosure). According to anothercompounds. The compounds may be synthesized using conventional techniques. Advantageously, these compounds are conveniently synthesized from readily available starting materials.

[0109] Synthetic chemistry transformations and methodologies useful in synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed. (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995).

[0110] Pharmaceutical Formulations

[0111] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound or salt of Formula (I) and at least one pharmaceutically acceptable excipient.

[0112] Pharmaceutical compositions can be formulated using one or more physiologically acceptable carriers comprising excipients and auxiliaries. Formulation can be modified depending upon the route of administration chosen. Pharmaceutical compositions comprising a compound, salt or conjugate can be manufactured, for example, by lyophilizing the compound, salt or conjugate, mixing, dissolving, emulsifying, encapsulating or entrapping the conjugate. The pharmaceutical compositions can also include the compounds, salts or conjugates in a free-base form or pharmaceutically acceptable salt form.

[0113] Methods for formulation of the conjugates can include formulating any of the compounds, salts or conjugates with one or more inert, pharmaceutically acceptable excipients or carriers to form a solid, semi-solid, or liquid composition. Solid compositions can include, for example, powders, tablets, dispersible granules and capsules, and in some aspects, the solid compositions further contain nontoxic, auxiliary substances, for example wetting or emulsifying agents, pH buffering agents, and other pharmaceutically acceptable additives. Alternatively, the compounds, salts or conjugates can be lyophilized or in powder form for re-constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0114] Pharmaceutical compositions can comprise at least one active ingredient (e.g., a compound, salt or conjugate). The active ingredients can be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization (e.g., hydroxymethylcellulose or gelatin microcapsules and poly-(methylmethacylate) microcapsules,microemulsions, nanoparticles and nanocapsules) or in macroemulsions.

[0115] Pharmaceutical compositions as often further can comprise more than one active compound (e.g., a compound, salt or conjugate and other agents) as necessary for the particular indication being treated. The active compounds can have complementary activities that do not adversely affect each other. For example, the composition can also comprise a chemotherapeutic agent, cytotoxic agent, cytokine, growth-inhibitory agent, anti-hormonal agent, anti-angiogenic agent, and / or cardioprotectant. Such molecules can be present in combination in amounts that are effective for the purpose intended.

[0116] The compositions and formulations can be sterilized. Sterilization can be accomplished by filtration through sterile filtration.

[0117] The compositions can be formulated for administration as an injection. Non-limiting examples of formulations for injection can include a sterile suspension, solution or emulsion in oily or aqueous vehicles. Suitable oily vehicles can include, but are not limited to, lipophilic solvents or vehicles such as fatty oils or synthetic fatty acid esters, or liposomes. Aqueous injection suspensions can contain substances which increase the viscosity of the suspension. The suspension can also contain suitable stabilizers. Injections can be formulated for bolus injection or continuous infusion. Alternatively, the compositions can be lyophilized or in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0118] For parenteral administration, the compounds, salts or conjugates can be formulated in a unit dosage injectable form (e.g., solution, suspension, emulsion) in association with a pharmaceutically acceptable parenteral vehicle. Such vehicles can be inherently non-toxic, and non-therapeutic. Vehicles can be water, saline, Ringer’s solution, dextrose solution, and 5% human serum albumin. Non-aqueous vehicles such as fixed oils and ethyl oleate can also be used. Liposomes can be used as carriers. The vehicle can contain minor amounts of additives such as substances that enhance isotonicity and chemical stability (e.g., buffers and preservatives).

[0119] Pharmaceutical formulations can be prepared for storage by mixing a compound, salt or conjugate with a pharmaceutically acceptable carrier, excipient, and / or a stabilizer. This formulation can be a lyophilized formulation or an aqueous solution. Acceptable carriers, excipients, and / or stabilizers can be nontoxic to recipients at the dosages and concentrations used. Acceptable carriers, excipients, and / or stabilizers can include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives, polypeptides; proteins, such as serum albumin or gelatin; hydrophilic polymers;mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes; and / or non-ionic surfactants or polyethylene glycol.

[0120] A compound or salt of any one of Formula (I) may be formulated in any suitable pharmaceutical formulation. A pharmaceutical formulation of the present disclosure typically contains an active ingredient (e.g., compound or salt of any one of Formula (I), and one or more pharmaceutically acceptable excipients or carriers, including but not limited to: inert solid diluents and fillers, diluents, sterile aqueous solution and various organic solvents, permeation enhancers, antioxidants, solubilizers, and adjuvants.

[0121] Pharmaceutical formulations may be provided in any suitable form, which may depend on the route of administration. In some embodiments, the pharmaceutical composition disclosed herein can be formulated in dosage form for administration to a subject. In some embodiments, the pharmaceutical composition is formulated for oral, intravenous, intraarterial, aerosol, parenteral, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, intranasal, intrapulmonary, transmucosal, inhalation, and / or intraperitoneal administration. In some embodiments, the dosage form is formulated for oral administration. For example, the pharmaceutical composition can be formulated in the form of a pill, a tablet, a capsule, an inhaler, a liquid suspension, a liquid emulsion, a gel, or a powder. In some embodiments, the pharmaceutical composition can be formulated as a unit dosage in liquid, gel, semi-liquid, semi- solid, or solid form.

[0122] The amount of compound or salt of Formula (I) will be dependent on the mammal being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound or salt of Formula (I) and the discretion of the prescribing physician.

[0123] In some embodiments, the disclosure provides a pharmaceutical composition for oral administration containing at least one compound or salt of Formula (I) and a pharmaceutical excipient suitable for oral administration. The composition may be in the form of a solid, liquid, gel, semi-liquid, or semi-solid. In some embodiments, the composition further comprises a second agent.

[0124] Pharmaceutical compositions of the disclosure suitable for oral administration can be presented as discrete dosage forms, such as hard or soft capsules, cachets, troches, lozenges, or tablets, or liquids or aerosol sprays each containing a predetermined amount of an active ingredient as a powder or in granules, a solution, or a suspension in an aqueous or non-aqueousgranules, or syrups or elixirs. Such dosage forms can be prepared by any of the methods of pharmacy, which typically include the step of bringing the active ingredient(s) into association with the carrier. In general, the composition are prepared by uniformly and intimately admixing the active ingredient(s) with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient(s) in a free-flowing form such as powder or granules, optionally mixed with an excipient such as, but not limited to, a binder, a lubricant, an inert diluent, and / or a surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound or salt of Formula (I)moistened with an inert liquid diluent.

[0125] In some embodiments, the disclosure provides a pharmaceutical composition for injection containing a compound or salt of Formula (I) disclosed herein and a pharmaceutical excipient suitable for injection. Components and amounts of agents in the composition are as described herein.

[0126] In certain embodiments, the compound or salt of Formula (I) may be formulated for injection as aqueous or oil suspensions, emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.

[0127] Aqueous solutions in saline are also conventionally used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, for the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

[0128] Pharmaceutical compositions may also be prepared from a compound or salt of Formula (I)and one or more pharmaceutically acceptable excipients suitable for transdermal, inhalative, sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal administration. Preparations for such pharmaceutical composition are well-known in the art. See, e.g., Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action,Pharmacology, Ninth Edition, McGraw Hill, 2003; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001; Remingtons Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999).

[0129] Methods of Treatment

[0130] The compounds described herein can be used in the preparation of medicaments for the prevention or treatment of diseases or conditions. In addition, a method for treating any of the diseases or conditions described herein in a subject in need of such treatment, involves administration of pharmaceutical compositions containing at least one compound described herein, or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said subject.

[0131] In some embodiments, a method of treating a subject in need thereof may comprise administering to the subject a therapeutically effective amount of a compound of the present disclosure. As used herein, the term “therapeutically effective amount” means the amount of an inhibitor that is sufficient to reduce the expression and / or activity of α4β7 integrin in a subject or in a cell.

[0132] A compound of the present disclosure may be administered to the subject using various different administration routes, including oral, rectal, transmucosal, topical, transdermal, inhalation, intravenous, subcutaneous, intradermal, intramuscular, intra-articular, intrathecal, intraventricular, intravenous, intraperitoneal, intranasal, or intraocular routes of administration.

[0133] The compositions containing the compound(s) described herein can be administered for prophylactic and / or therapeutic treatments. In therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition. Amounts effective for this use will depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician.

[0134] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a "prophylactically effective amount or dose." In this use, the precise amounts also depend on the patient's state of health, weight, and the like. Whendisease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.

[0135] In some embodiments, the present disclosure provides a method of modulating α4β7 integrin in a subject in need thereof, comprising administering to the subject a compound of Formula (I) or pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a method of modulating α4β7 integrin in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and an excipient.

[0136] In some embodiments, the present disclosure provides a method of treating an disease or condition comprising administering to a subject in need thereof a compound of Formula (I) or pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a method of treating a disease or condition comprising administering to a subject in need thereof a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and an excipient. In some embodiments, the disease or condition is an inflammatory disease or condition.

[0137] In some embodiments, the disease or condition is selected from: inflammatory bowel disease, ulcerative colitis, Crohn’s disease, graft-versus-host disease, type 1 diabetes, immune- mediated colitis, checkpoint inhibitor induced colitis, and primary sclerosing cholangitis. In some embodiments, the disease or condition is selected from: inflammatory bowel disease, ulcerative colitis, Crohn’s disease, graft-versus-host disease, type 1 diabetes, and primary sclerosing cholangitis. In some embodiments, the disease or condition is selected from: inflammatory bowel disease, ulcerative colitis, Crohn’s disease, graft-versus-host disease, immune-mediated colitis, checkpoint inhibitor induced colitis, and primary sclerosing cholangitis. In some embodiments, the disease or condition is selected from: inflammatory bowel disease, ulcerative colitis, Crohn’s disease, graft-versus-host disease, and primary sclerosing cholangitis. In some embodiments, the disease or condition is selected from: inflammatory bowel disease, ulcerative colitis, and Crohn’s disease. In some embodiments, the disease or condition is inflammatory bowel disease. In some embodiments, the disease or condition is ulcerative colitis. In some embodiments, the disease or condition is Crohn’s disease. In some embodiments, the disease or condition is graft-versus-host disease. In some embodiments, the disease or condition is type 1 diabetes. In some embodiments, the disease or condition is immune-mediated colitis. checkpointcholangitis.

[0138] EXAMPLES

[0139] The invention now being generally described, it will be more readily understood by reference to the following examples which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention in any way.

[0140] 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.

[0141] Examples 1 to 6 show general and exemplary procedures for the preparation of the claimed compounds of Formula (I). One of ordinary skill in the art will appreciate that variations on the following synthetic procedures may be necessary to obtain compounds of Formula (I), including changes in protecting group chemistry, reaction conditions, and / or order of synthetic steps. Such variations are within the ability of the ordinarily skilled artisan. As used in conjunction with a chemical structure, “*" denotes a stereocenter with an undetermined absolute stereochemistry of a single diastereomer. As provided in the Examples below “*" denotes a stereocenter with an undetermined absolute stereochemistry of a single diastereomer. EXAMPLE 1: Series B

[0142] Example 1-1: Series B1

[0143] General Scheme

[0145] Step 1: To a solution of compound B1-1 (10.0 g, 47.3 mmol, 1.00 eq) in DMF (50.0 mL) was added Pd2(dba)3(2.17 g, 2.37 mmol, 0.0500 eq) and SPhos (3.89 g, 9.48 mmol, 0.200 eq). Then a solution of compound B1-2-1 (37.4 g, 94.8 mmol, 2.00 eq) in DMF (100 mL) was added. The mixture was stirred at 85 °C for 12 hrs under N2. The reaction mixture was diluted with H2O (500 mL) and extracted with ethyl acetate (200 mL*3). The combined organic layers were washed with brine (100 mL*2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography. Compound B1-3278.0.

[0146] Step 2: To a solution of compound B1-3 (8.00 g, 17.6 mmol, 73.5% purity, 1.00 eq) in DCM (80.0 mL) was added HCl / dioxane (4.00 M, 40.0 mL, 9.07 eq) at 0 °C. The mixture was stirred at 20 °C for 2 hrs. The reaction mixture was filtered, and concentrated under reduced pressure to give a residue. Compound B1-4 (6.00 g, crude, HCl) was obtained as a yellow solid. LC-MS: (M+H)+: 234.0.

[0147] Step 3: To a solution of compound B1-4 (5.00 g, 18.5 mmol, 1.00 eq, HCl) and compound B1-5-1 (4.40 g, 27.8 mmol, 1.50 eq) in pyridine (60.0 mL) was added EDCI (10.6 g, 55.6 mmol, 3.00 eq). The mixture was stirred at 20 °C for 2 hrs. The reaction mixture was diluted with sat. aq. NaHCO3(200 mL) and extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with brine (50.0 mL*2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography. Compound B1-6-1 (3.00 g, 7.80 mmol, 42.0% yield, 97.1% purity) was obtained as a yellow solid. LC-MS: (M+H)+: 374.0.1H NMR: (400 MHz, CDCl3) δ 7.69 (d, J = 7.2 Hz, 1H), 7.42 - 7.33 (m, 3H), 6.95 (t, J = 8.4 Hz, 2H), 6.60 (d, J = 7.6 Hz, 1H), 5.18 (q, J = 6.0 Hz, 1H), 3.76 (s, 3H), 3.41 (dd, J1 = 14.4 Hz, J2 = 6.8 Hz, 1H), 3.28 (dd, J1 = 14.0 Hz, J2 = 6.8 Hz, 1H), 3.18 - 3.14 (m, 2H), 2.72 (t, J = 5.6 Hz, 2H).

[0148] Step 4: To a solution of compound B1-6-1 (600 mg, 1.56 mmol, 97.1% purity, 1.00 eq) in DCM (60.0 mL) was added Tf2O (2.64 g, 9.36 mmol, 1.54 mL, 6.00 eq) at -20 °C. The mixture was stirred at -20 °C for 1 hr. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC. Compound B1-7-1 (300 mg, 570 µmol, 36.5% yield, 96.1% purity) was obtained as a yellow oil. LC-MS: (M+H)+: 506.0.1H NMR: (400 MHz, CDCl3) δ 7.42 - 7.34 (m, 3H), 7.16 - 7.13 (m, 1H), 6.94 (t, J = 8.0 Hz, 2H), 6.56 (d, J = 7.2 Hz, 1H), 6.40 (s, 1H), 5.16 (q, J = 6.8 Hz, 1H), 3.75 (s, 3H), 3.51 (s, 2H), 3.43 - 3.31 (m, 2H).

[0149] Step 5: To a solution of compound B1-7-1 (200 mg, 384 µmol, 97.1% purity, 1.00 eq) and compound B1-8-1 (209 mg, 576 µmol, 97.2% purity, 1.50 eq) in dioxane (3.00 mL) and H2O (1.50 mL) was added Pd(dtbpf)Cl2 (25.0 mg, 38.4 µmol, 0.100 eq) and K3PO4 (244 mg, 1.15 mmol, 3.00 eq). The mixture was stirred at 20 °C for 1 hr under N2. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC. Compound B1-9-1 (180 mg, 302 µmol, 78.6% yield, 97.8% purity) was obtained as a yellow oil. LC-MS: (M+H)+: 583.1.1H NMR: (400 MHz, CDCl3) δ 8.01 (d, J = 7.6 Hz, 1H),6.92 (m, 4H), 6.65 - 6.54 (m, 1H), 6.47 (s, 1H), 5.23 - 5.16 (m, 1H), 3.80 (s, 3H), 3.72 (d, J = 5.2 Hz, 3H), 3.59 (d, J = 11.6 Hz, 2H), 3.42 - 3.40 (m, 2H).

[0150] Step 6: To a solution of compound B1-9-1 (200 mg, 343 µmol, 1.00 eq) in MeOH (3.00 mL) was added Pd / C (50.0 mg, 10.0% purity) under N2atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (15 Psi) at 20 °C for 12 hrs. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC. Compound B1-10-1 (130 mg, 221 µmol, 64.5% yield, 99.6% purity) was obtained as a yellow oil. LC-MS: (M+H)+: 585.2.1H NMR: (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.62 - 7.56 (m, 1H), 7.41 - 7.28 (m, 3H), 7.04 - 6.91 (m, 4H), 6.73 - 6.54 (m, 2H), 5.31 - 5.01 (m, 2H), 3.81 (s, 3H), 3.61 - 3.49 (m, 3H), 3.41 - 3.33 (m, 2H), 3.27 - 3.17 (m, 1H), 3.12 - 2.97 (m, 1H), 2.54 - 2.37 (m, 2H).

[0151] Step 7: To a solution of compound B1-10-1 (150 mg, 256 µmol, 1.00 eq) in H2O (2.00 mL) was added HCl / dioxane (4.00 M, 2.00 mL, 31.1 eq). The mixture was stirred at 60 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. Compound B1-11-1 (200 mg, crude) was obtained as white solid. LC-MS: (M+H)+: 571.1.

[0152] Step 8: The residue was purified by Prep-SFC. Compound 1 (46.72 mg, 80.4 µmol, 22.9% yield, 98.2% purity) was obtained as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 9.09 (s, 1H), 7.96 (s, 1H), 7.72 - 7.62 (m, 2H), 7.53 - 7.45 (m, 1H), 7.39 (t, J = 8.0 Hz, 1H), 7.13 (t, J = 8.0 Hz, 2H), 7.04 (d, J = 8.4 Hz, 1H), 6.94 (t, J = 6.8 Hz, 1H), 6.63 (d, J = 6.4 Hz, 1H), 4.90 (brs, 1H), 4.60 - 4.55 (m, 1H), 3.56 (s, 3H), 3.23 - 3.15 (m, 2H), 3.08 - 2.91 (m, 3H), 2.39 - 2.29 (m, 1H). LC-MS: (M+H)+: 571.1. Compound 2 (32.47 mg, 56.9 µmol, 16.2% yield, 100% purity) was obtained as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 12.74 (s, 1H), 9.13 (d, J = 8.0 Hz, 1H), 7.96 (s, 1H), 7.73 - 7.63 (m, 2H), 7.54 - 7.47 (m, 1H), 7.39 (t, J = 7.6 Hz, 1H), 7.14 (t, J = 8.0 Hz, 2H), 7.03 (d, J = 7.6 Hz, 1H), 6.97 (t, J = 7.2 Hz, 1H), 6.64 (d, J = 6.0 Hz, 1H), 4.89 (brs, 1H), 4.69 - 4.64 (m, 1H), 3.56 (s, 3H), 3.20 - 2.94 (m, 5H), 2.33 - 2.30 (m, 1H). LC-MS: (M+H)+: 571.2.

[0153] The compounds set forth in Table 1, were prepared using the synthetic procedures of Example 1-1, or analogous procedures as provided herein.

[0154] Table 1. Structure and Spectroscopic data for Compounds 3-14, 19, 203 m / z = 588.8 4 m / z = 588.8

[0155] Example 1-2: Series B2

[0156] Synthetic preparation of Series B2 compounds, Compound 48 and Compound 49added NaIO4 (12.6 g, 59.2 mmol, 3.28 mL, 2.00 eq). A solution of K2OsO4 (563 mg, 2.96 mmol, 0.100 eq) in H2O (30.0 mL) was added into the reaction mixture at 0 °C. The mixture was stirred at 25 °C for 1 hr. Water (10 mL) was added into rection mixture. The mixture was diluted with ethyl acetate (10.0 mL), and extracted with ethyl acetate (20.0 mL*3). The combined organic layers were washed with brine (20.0 mL*4), dried over Na2SO4filtered, and concentrated under reduced pressure to give a residue. Compound B2-2 (7.50 g, crude) was obtained as a white solid. LC-MS: (M+H)+: 256.0.1H NMR: (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.22 (d, J = 0.8 Hz, 1H), 7.97 (dd, J1 = 8.4 Hz, J2 = 1.6 Hz, 1H), 7.87 (dd, J1 = 8.4 Hz, J2 = 1.2 Hz, 1H), 7.28 (s, 1H), 3.75 (s, 3H).

[0158] Step 2: To a solution of compound B2-2 (7.50 g, 29.3 mmol, 1.00 eq) in DCE (100 mL) was added NaBH3CN (3.69 g, 58.7 mmol, 2.00 eq) and AcOH (1.76 g, 29.3 mmol, 1.68 mL, 1.00 eq) at 0 °C. The mixture was stirred at 25 °C for 1 hr. The reaction mixture was diluted with ethyl acetate (10.0 mL) and water (20 mL). The water layer was extracted with ethyl acetate (20.0 mL*3). The combined organic layers were washed with brine (20.0 mL*4), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Compound B2-3 (6.00 g, 23.3 mmol, 79.3% yield) was obtained as a yellow solid. LC-MS: (M+H)+: 257.9.1H NMR: (400 MHz, DMSO-d6) δ 7.74 (br dd, J1= 8.4 Hz, J2= 2.0 Hz, 1H), 7.62 (s, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.05 (s, 1H), 5.52 (t, J = 5.6 Hz, 1H), 4.69 (d, J = 5.6 Hz, 2H), 3.67 (s, 3H).

[0159] Step 3: To a solution of compound B2-3 (4.00 g, 15.5 mmol, 1.00 eq) in DCM (50.0 mL) was added imidazole (1.27 g, 18.6 mmol, 1.20 eq) and TBSCl (2.58 g, 17.1 mmol, 2.10 mL, 1.10 eq) at 0 °C. The mixture was stirred at 25°C for 1 hr. The reaction mixture was diluted with ethyl acetate (100 mL) and water (100 mL), and extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with brine (100 mL*3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography. Compound B2-4 (6.00 g, 16.1 mmol, 75.5% yield) was obtained as off-white solid. LC-MS: (M+H)+: 372.2.1H NMR: (400 MHz, DMSO-d6) δ 7.75 (br dd, J1= 8.0 Hz, J2= 2.0 Hz, 1H), 7.58 (s, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.04 (s, 1H), 4.89 (s, 2H), 3.64 (s, 3H), 0.93 (s, 9H), 0.11 (s, 6H).

[0160] Step 4: To a solution of compound B2-4 (5.00 g, 13.4 mmol, 1.00 eq) in THF (70.0 mL) was added TMP-MgLi (1.00 M, 40.3 mL, 3.00 eq) at -78 °C. The mixture was stirred at -78 °C for 0.5 hr. Br2(6.45 g, 40.3 mmol, 2.08 mL, 3.00 eq) was added into the mixture. Then the mixture was warmed to 25 °C for 2 hrs. The reaction mixture was quenched by addition aqueous solution ofextracted with ethyl acetate (100 mL*3). The combined organic layers were washed with brine (100 mL*2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. Compound B2-5 (8.30 g, crude) was obtained as brown gum.1H NMR: (400 MHz, DMSO-d6) δ 7.91 - 7.88 (m, 1H), 7.60 (s, 1H), 7.36 (d, J = 8.4 Hz, 1H), 4.88 (s, 2H), 3.75 (s, 3H), 0.94 (s, 9H), 0.12 (s, 6H).

[0161] Step 5: A mixture of compound B2-5 (8.30 g, 18.4 mmol, 1.00 eq), BPD (14.0 g, 55.3 mmol, 3.00 eq), KOAc (7.23 g, 73.7 mmol, 4.00 eq), Pd(dppf)Cl2•CH2Cl2 (1.51 g, 1.84 mmol, 0.100 eq) in dioxane (100 mL) was degassed and purged with N2 for 3 times. The mixture was stirred at 80 °C for 12 hrs under N2atmosphere. Water (100 mL) was added into reaction mixture. The resulting mixture was diluted with ethyl acetate (100 mL), and extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with brine (100 mL*3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography. Compound B2-6 (2.80 g, 5.63 mmol, 30.5% yield) was obtained as off-white solid. LC-MS: (M+H)+: 498.1.1H NMR: (400 MHz, DMSO-d6) δ 7.76 (br d, J = 6.4 Hz, 1H), 7.58 (br s, 1H), 7.34 (br d, J = 8.0 Hz, 1H), 4.90 (br s, 2H), 3.63 (br s, 3H), 1.31 (br s, 12H), 0.94 (br s, 9H), 0.12 (br s, 6H).

[0162] Step 6: A mixture of compound B2-6 (1.50 g, 3.02 mmol, 1.00 eq), compound B2-7 (1.89 g, 3.02 mmol, 1.00 eq), Pd(dtbpf)Cl2(196 mg, 301 μmol, 0.100 eq), K3PO4(1.92 g, 9.05 mmol, 3.00 eq) in dioxane (20.0 mL) and H2O (4.00 mL) was degassed and purged with N2for 3 times. The reaction mixture was stirred at 25 °C for 3 hrs under N2 atmosphere. The mixture was diluted with water (30 mL), extracted with ethyl acetate (50.0 mL*3). The combined organic layers were washed with brine (50.0 mL*3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography. Compound B2-8 (1.70 g, 2.01 mmol, 66.4% yield) was obtained as a yellow solid. LC-MS: (M+H)+: 848.4.

[0163] Step 7: To a solution of compound B2-8 (1.40 g, 1.65 mmol, 1.00 eq) in EtOH (5.00 mL) and methyltetrahydrofuran (30.0 mL) was added NaOAc (406 mg, 4.95 mmol, 3.00 eq) and Pd / C (351 mg, 330 μmol, 10.0% purity, 0.200 eq) under N2 atmosphere. The suspension was degassed and purged with H2for 3 times. The mixture was stirred under H2(50 Psi) at 40 °C for 10 hrs. After filtration via celite pad, the organic layer was concentrated under reduced pressure to dryness to give off-white solid. The reaction mixture was diluted by water (30p.0 mL) and extracted with ethylNa2SO4, filtered and concentrated under reduced pressure to give a residue. Compound B2-9 (1.30 g, crude) was obtained as yellow oil. LC-MS: (M+H)+: 850.4.

[0164] Step 8: To a solution of compound B2-9 (100 mg, 117 μmol, 1.00 eq) in THF (3.00 mL) was added TBAF (1.00 M, 176 μL, 1.50 eq). The mixture was stirred at 25 °C for 0.5 hr. The mixture was then diluted with water (10.0 mL), and extracted with ethyl acetate (10.0 mL*3). The combined organic layers were washed with brine (10.0 mL*3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC. Compound B2-10 (80.0 mg, 108 μmol, 92.4% yield) was obtained as a pink solid. LC-MS: (M+H)+: 736.2.

[0165] Step 9: To a solution of compound B2-10 (80.0 mg, 108 μmol, 1.00 eq) in DMSO (2.00 mL) was added IBX (60.9 mg, 217 μmol, 2.00 eq). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was quenched by aq. sodium sulfite (10.0 mL) and saturated NH4Cl (10.0 mL) aqueous solution at 0 °C. The resulting mixture was extracted with ethyl acetate (10.0 mL*3). The combined organic layers were washed with brine (10.0 mL*2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. Compound B2-11 (60.0 mg, 79.8 μmol, 73.4% yield, 97.6% purity) was obtained as a white solid. LC-MS: (M+H)+: 734.1.

[0166] Step 10: To a solution of compound B2-11 (60.0 mg, 79.8 μmol, 1.00 eq) in THF (2.00 mL) was added Me2NH / THF (2.00 M, 120 μL, 3.00 eq) stirred for 10 hrs. The mixture was added NaBH3CN (10.0 mg, 159 μmol, 2.00 eq) at 25°C. The reaction was stirred at 25 °C for 1 hr. The reaction mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (10.0 mL*3). The combined organic layers were washed with brine (10.0 mL*3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC. Compound B2-12 (55.0 mg, 72.1 μmol, 90.3% yield) was obtained as a white solid. LC-MS: (M+H)+: 763.2.

[0167] Step 11: The residue was purified by Prep-SFC. Compound B2-12_peak 1 (20.0 mg, 25.8 μmol, 32.9% yield, 98.7% purity) was obtained as a white solid. LC-MS:(M+H)+: 763.3. Compound B2-12_peak 2 (20.0 mg, 25.8 μmol, 32.8% yield, 98.5% purity) was obtained as a white solid. LC- MS: (M+H)+: 763.3.

[0168] Step 12: To a solution of compound B2-12_peak 1 (20.0 mg, 25.8 μmol, 1.00 eq) in dioxane (0.500 mL) was added HCl (6.00 M, 0.500 mL, 116 eq). The mixture was stirred at 60 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue wasobtained as a white solid. LC-MS: (M+H)+: 749.4.1H NMR: (400 MHz, DMSO-d6) δ 8.37 (br d, J = 8.0 Hz, 1H), 7.98 - 7.94 (m, 1H), 7.70 - 7.64 (m, 1H), 7.39 (br d, J = 8.8 Hz, 1H), 7.04 - 6.93 (m, 2H), 6.68 - 6.60 (m, 1H), 4.84 - 4.69 (m, 2H), 3.83 (br s, 2H), 3.55 (br s, 3H), 3.18 - 3.14 (m, 2H), 3.08 - 3.05 (m, 2H), 2.93 - 2.85 (m, 2H), 2.72 (br s, 2H), 2.64 - 2.62 (m, 2H), 2.37 - 2.26 (m, 8H), 2.04 - 1.99 (m, 1H), 1.72 - 1.54 (m, 3H).

[0169] Step 13: To a solution of compound B2-12_peak 2 (20.0 mg, 25.8 μmol, 1.00 eq) in dioxane (0.500 mL) was added HCl (6.00 M, 0.500 mL, 116 eq). The mixture was stirred at 60 °C for 1hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC. Compound 49 (11.09 mg, 14.7 μmol, 57.1% yield, 99.7% purity) was obtained as a white solid. LC-MS: (M+H)+: 749.5.1H NMR: (400 MHz, DMSO-d6) δ 8.38 (br d, J = 8.4 Hz, 1H), 7.96 (br d, J = 6.8 Hz, 1H), 7.71 (br s, 1H), 7.41 (br d, J = 8.4 Hz, 1H), 6.98 - 6.90 (m, 2H), 6.61 (br d, J = 6.8 Hz, 1H), 4.85 (br t, J = 7.6 Hz, 1H), 4.72 - 4.66 (m, 1H), 4.02 - 3.96 (m, 2H), 3.56 (br s, 3H), 3.23 - 3.15 (m, 3H), 3.09 - 3.00 (m, 2H), 2.92 - 2.85 (m, 2H), 2.77 (br d, J = 11.6 Hz, 1H), 2.63 (br d, J = 11.2 Hz, 1H), 2.44 (br s, 6H), 2.32 - 2.24 (m, 3H), 2.13 (br t, J = 11.6 Hz, 1H), 1.77 - 1.71 (m, 1H), 1.68 - 1.56 (m, 2H).

[0170] Example 1-3: Series B3

[0172] Synthetic preparation of Series B3 compounds, Compound 15 and Compound 21p p - . g, . , . q . ) was added a solution of Tf2O (1.43 g, 5.06 mmol, 834 µL, 5.00 eq) in DCM (3.00 mL) at - 20 °C,reduced pressure to give a residue. The residue was purified by Prep-TLC. Compound B3-2 (500 mg, crude) was obtained as a white solid. LC-MS: (M+H)+: 627.0.

[0174] Step 2: To a solution of compound B3-2 (50.0 mg, 79.8 µmol, 1.00 eq) and compound B3-3 (61.2 mg, 120 µmol, 1.50 eq) in dioxane (2.00 mL) and H2O (0.20 mL) was added K3PO4 (50.8 mg, 239 µmol, 3.00 eq) and Pd(dtbpf)Cl2(5.20 mg, 7.98 µmol, 0.100 eq) at 25 °C, then the mixture was stirred at 40 °C for 2 hrs. The residue was diluted with H2O (20.0 mL), and extracted with ethyl acetate (20.0 mL*2). The combined organic layers were washed with brine (20.0 mL*3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC. Compound B3-4-1 (220 mg, 255.25 µmol, 79.95% yield) was obtained as yellow oil. LC-MS: (M+H)+: 862.6.

[0175] Step 3: To a solution of compound B3-4-1 (200 mg, 232 µmol, 1.00 eq) in MeOH (3.00 mL) was added Pd / C (50.0 mg, 23.2 μmol, 10.0 % purity, 0.100 eq). The reaction mixture was stirred at 25 °C under H2(15 psi) for 6 hrs. The residue was filtered, and concentrated under reduced pressure to give a residue. The crude product was used into the next step without further purification. Compound B3-5-1 (180 mg, 208 μmol, 89.8% yield) was obtained as a white solid. LC-MS: (M+H)+: 864.5.

[0176] Step 4: A mixture of compound B3-5-1 (160 mg, 185 μmol, 1.00 eq), TBAF (1.00 M, 556 μL, 3.00 eq) in THF (4.00 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 25 °C for 1 hr under N2atmosphere. The reaction mixture was diluted with water (30.0 mL) and extracted with ethyl acetate (20.0 mL*3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. Compound B3-6-1 (140 mg, crude) was obtained as a yellow oil. LC-MS: (M+H)+: 750.1.1H NMR: (400 MHz, CDCl3) δ 7.89 (br s, 1H), 7.58 - 7.44 (m, 1H), 7.38 - 7.31 (m, 1H), 7.07 -8 (m, 1H), 6.93 - 6.89 (m, 1H), 6.73 (d, J = 7.6 Hz, 1H), 5.11 - 4.88 (m, 2H), 3.99 - 3.88 (m, 2H), 3.78 (s, 3H), 3.59 (br s, 3H), 3.40 - 3.30 (m, 2H), 3.04 - 2.96 (m, 3H), 2.93 - 2.79 (m, 4H), 2.60 - 2.49 (m, 1H), 2.46 - 2.34 (m, 2H), 2.25 - 2.14 (m, 2H), 1.98 - 1.89 (m, 2H), 1.29 - 1.24 (m, 2H), 1.05 - 1.00 (m, 2H).

[0177] Step 5: A mixture of compound B3-6-1 (140 mg, 187 μmol, 1.00 eq), TosCl (71.2 mg, 373 μmol, 2.00 eq), TEA (56.7 mg, 560 μmol, 78.0 μL, 3.00 eq) in DCM (3.00 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 25 °C for 24 hrs under N2. The reaction mixture was filtered, and concentrated under reduced pressure to give a residue. The residuewhite solid. LC-MS: (M+H)+: 904.5.

[0178] Step 6: A mixture of compound B3-7-1 (70.0 mg, 77.5 μmol, 1.00 eq), Me2NH (2.00 M, 1.00 mL, 25.8 eq) in THF (1.00 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 60 °C for 1 hr under N2. The reaction mixture was diluted with water (20.0 mL) and extracted with ethyl acetate (20.0 mL*3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. Compound B3-8 (80.0 mg, crude) was obtained as a yellow solid. LC-MS: (M+Na)+: 799.5.

[0179] Step 7: The residue was purified by Prep-SFC. Compound B3-8(peak 1) (30.0 mg, crude) was obtained as a white solid. LC-MS: (M+H)+: 777.6. Compound B3-8(peak 2) (30.0 mg, crude) was obtained as a white solid. LC-MS: (M+H)+: 777.4.

[0180] Step 8: To a solution of compound B3-8(peak 1) (30.0 mg, 38.6 μmol, 1.00 eq) in MeOH (1.00 mL), H2O (0.500 mL) was added LiOH.H2O (1.94 mg, 46.4 μmol, 1.20 eq). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC. Compound 15 (9.41 mg, 12.3 μmol, 31.9% yield, 99.8% purity) was obtained as a white solid. LC-MS: (M+H)+: 763.1.1H NMR: (400 MHz, DMSO- d6) δ 8.28 (d, J = 7.6 Hz, 1H), 7.78 (s, 1H), 7.65 - 7.51 (m, 2H), 7.01 - 6.86 (m, 2H), 6.66 - 6.52 (m, 1H), 4.85 - 4.81 (m, 1H), 4.63 - 4.60 (m, 1H), 3.53 (br s, 3H), 3.09 - 2.59 (m, 12H), 2.35 - 2.10 (m, 11H), 1.73 (br s, 1H), 1.67 - 1.54 (m, 2H).

[0181] Step 9: To a solution of compound B3-8(peak 2) (30.0 mg, 38.6 μmol, 1.00 eq) in H2O (0.500 mL), MeOH (1.00 mL) was added LiOH•H2O (1.94 mg, 46.4 μmol, 1.20 eq). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC. Compound 21 (9.47 mg, 12.2 μmol, 31.5% yield, 98.1% purity) was obtained as a white solid. LC-MS: (M+H)+: 763.3.1H NMR: (400 MHz, DMSO- d6) δ 8.27 (d, J = 7.2 Hz, 1H), 7.78 (s, 1H), 7.62 - 7.51 (m, 2H), 7.06 - 6.89 (m, 2H), 6.60 - 6.56 (m, 1H), 4.89 - 4.67 (m, 2H), 3.53 (s, 3H), 3.10 - 2.65 (m, 13H), 2.30 - 2.21 (m, 9H), 2.08 - 2.00 (m, 1H), 1.78 - 1.68 (m, 1H), 1.67 - 1.53 (m, 2H).

[0182] Synthetic preparation of Series B3 compounds, Compound 57L) was added HCl / dioxane (4.00 M, 1.00 mL, 21.0 eq). The mixture was stirred at 20 °C for 1 hr. The reaction mixture was diluted with water (10.0 mL) and extracted with DCM (10.0 mL*3). The combined organic layers were washed with brine (20.0 mL*3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC. Compound B3-6-1 (155 mg, crude) was obtained as a yellow oil. LC-MS: (M+H)+: 750.2.

[0184] Step 2: To a solution of compound B3-6-1 (30.0 mg, 40.0 μmol, 1.00 eq) in DMSO (1.00 mL) was added IBX (28.0 mg, 100 μmol, 2.50 eq). The mixture was stirred at 25 °C for 2 hrs. The reaction mixture was diluted with water (10.0 mL), and extracted with DCM (10.0 mL*3). The combined organic layers were washed with brine (20.0 mL*3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC. Compound B3-7-2 (20.0 mg, 26.7 μmol, 66.8% yield) was obtained as a yellow oil. LC-MS: (M+H)+: 748.3.

[0185] Step 3: To a solution of compound B3-7-2 (20.0 mg, 26.7 μmol, 1.00 eq), morpholine (6.99 mg, 80.2 μmol, 7.06 μL, 3.00 eq) and AcOH (1.61 mg, 26.7 μmol, 1.53 μL, 1.00 eq) in MeOH (1.00 mL) was stirred at 20 °C for 0.5 hr. NaBH3CN (3.36 mg, 53.5 μmol, 2.00 eq) was added into the mixture. The reaction mixture was stirred at 20 °C for 1.5 hrs. The reaction mixture was diluted with water (10.0 mL), and extracted with DCM (10.0 mL*3). The combined organic layers were washed with brine (30.0 mL*2), dried over Na2SO4, filtered, and concentrated under reduced pressure to82.2% yield) was obtained as a yellow oil. LC-MS: (M+H)+: 819.3.

[0186] Step 4: To a solution of compound B3-8-2 (18.0 mg, 21.9 μmol, 1.00 eq) in H2O (0.500 mL) was added HCl / dioxane (4.00 M, 225 μL, 40.9 eq). The mixture was stirred at 60 °C for 1 hr. The residue was concentrated under reduced pressure to give a residue. The residue was purified by Prep- HPLC. Compound 57 (11.16 mg, 13.2 μmol, 60.0% yield, 99.5% purity, HCl) was obtained as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 11.26 (s, 1H), 8.44 (d, J = 7.2 Hz, 1H), 7.83 (s, 1H), 7.64 (s, 2H), 7.05 - 6.89 (m, 2H), 6.59 (d, J = 6.8 Hz, 1H), 4.85 - 4.65 (m, 2H), 3.99 (d, J = 10.8 Hz, 2H), 3.83 (t, J = 11.6 Hz, 2H), 3.57 - 3.47 (m, 4H), 3.40 - 3.30 (m, 2H), 3.28 - 2.72 (m, 13H), 2.47 - 2.09 (m, 5H), 1.92 - 1.59 (m, 3H). LC-MS: (M+H)+: 805.4.

[0187] The compounds set forth in Table 2, were prepared using the synthetic procedures of Example 1-3 or analogous procedures as provided herein.

[0188] Table 2. Structure and Spectroscopic data for Compounds 39, 40 No. Structure

[0189] Example 1-4: Series B4,-3-1 (201 mg, 415 µmol, 99.4% purity, 1.30 eq) in dioxane (8.00 mL) and H2O (2.00 mL) was added Pd(dtbpf)Cl2 (20.8 mg, 31.9 µmol, 0.100 eq) and K3PO4 (135 mg, 638 µmol, 2.00 eq) at 25 °C, then the mixture was stirred at 25 °C for 3 hrs. The residue was diluted with H2O (20.0 mL), and extracted with ethyl acetate (20.0 mL*3). The combined organic layers were washed with brine (20.0 mL*3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC. Compound B4-4-1 (0.390g, crude) was obtained as yellow oil. LC-MS: (M+H)+: 833.3.

[0193] Step 2: To a solution of compound B4-4-1 (360 mg, 332 µmol, 77.0% purity, 1.00 eq) in MeOH (5.00 mL) was added Pd / C (200 mg, 10.0% purity) under N2. The suspension was degassedfor 48 hours. The mixture was stirred under H2 (15 psi) at 25 °C for 24 hours. The reaction mixture was filtered and the filter was concentrated. The residue was purified by Prep-TLC. Compound B4- 5-1 (0.230 g, 247 µmol, 74.4% yield, 90.0% purity) was obtained as white solid. LC-MS: (M+H)+: 835.3.1H NMR: (400 MHz, DMSO_d6) δ 8.52 (d, J = 7.2 Hz, 1H), 7.83 (d, J = 1.2 Hz, 1H), 7.67 – 7.48 (m, 3H), 7.02 – 6.90 (m, 2H), 6.67 – 6.56 (m, 1H), 4.92 – 4.62 (m, 2H), 4.27 – 4.13 (m, 2H), 4.13 – 3.95 (m, 1H), 3.66 (s, 3H), 3.53 (br s, 3H), 3.20 – 2.88 (m, 6H), 2.82 – 2.63 (m, 3H), 2.35 – 2.22 (m, 3H), 1.82 – 1.71 (m, 1H), 1.69 – 1.57 (m, 2H), 1.44 – 1.37 (m, 9H).

[0194] Step 3: To a solution of compound B4-5-1 (200 mg, 239 µmol, 1.00 eq) in DCM (2.00 mL) was added HCl / dioxane (4.00 M, 3.00 mL, 50.0 eq), the mixture was stirred at 25 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. Compound B4-6-1 (180 mg, 233 µmol, 97.4% yield, HCl) was obtained as colorless oil. LC-MS: (M+H)+: 735.3.

[0195] Step 4: To a compound B4-6-1 (180 mg, 233 µmol, 1.00 eq, HCl) in MeCN (2.00 mL) was added HCHO (94.7 mg, 1.17 mmol, 86.8 µL, 37.0% purity, 5.00 eq) and AcOH (28.0 mg, 466 µmol, 26.7 µL, 2.00 eq), the mixture was stirred at 25°C for 4 hrs. NaBH3CN (22.0 mg, 350 µmol, 1.50 eq) was added, and the mixture was stirred at 25 °C for 1 hr. The residue was diluted with H2O (30.0 mL), and extracted with ethyl acetate (10.0 mL*3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC to give desired compound (150 mg) as yellow oil, which was further separated by SFC. Compound B4-7-1_peak 1 (40.0 mg, 50.0 µmol, 21.4% yield, 95.5% purity) was obtained as yellow oil. LC-MS: (M+H)+: 763.5. Compound B4-7-1_peak 2 (35.0 mg, 43.0 µmol, 18.4% yield, 93.8% purity) was obtained as yellow oil. LC-MS: (M+H)+: 763.2.

[0196] Step 5: To a solution of compound B4-7-1_peak 1 (35.0 mg, 43.8 µmol, 95.5% purity, 1.00 eq) in H2O (0.200 mL) was added HCl / dioxane (4.00 M, 1.05 mL, 95.8 eq), the mixture was stirred at 60 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC. Compound 25 (15.18 mg, 19.6 µmol, 44.8% yield, 96.9% purity) was obtained as orange solid. LC-MS: (M+H)+: 749.4.1H NMR: (400 MHz, DMSO_d6) δ 10.67 (s, 1H), 8.41 (d, J = 8.0 Hz, 1H), 8.12 (s, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.02 - 6.87 (m, 2H), 6.61 (d, J = 6.8 Hz, 1H), 4.86 (t, J = 7.6 Hz, 1H), 4.74 - 4.63 (m, 1H), 4.43 (d, J = 4.0 Hz, 2H), 3.56 (s, 3H), 3.26 - 3.12 (m, 3H), 3.12 - 2.86 (m, 5H), 2.81 (d, J = 10.4 Hz, 1H), 2.71 (d, J = 3.6 Hz, 6H), 2.38 - 2.13 (m, 4H), 1.90 - 1.72 (m, 1H), 1.70 - 1.55 (m, 2H).eq) in H2O (0.200 mL) was added HCl / dioxane (4.00 M, 1.05 mL, 97.5 eq), the mixture was stirred at 60 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC. Compound 26 (12.01 mg, 15.5 µmol, 36.1% yield, 97.0% purity) was obtained as white solid. LC-MS: (M+H)+: 749.6.1H NMR: (400 MHz, DMSO_d6) δ 8.33 (d, J = 8.0 Hz, 1H), 7.86 (s, 1H), 7.65 - 7.55 (m, 2H), 7.05 - 6.89 (m, 2H), 6.60 (d, J = 6.0 Hz, 1H), 4.92 - 4.67 (m, 2H), 3.82 - 3.74 (m, 1H), 3.54 (s, 3H), 3.16 - 3.00 (m, 5H), 2.95 - 2.82 (m, 2H), 2.78 - 2.63 (m, 3H), 2.28 (t, J = 12.4 Hz, 3H), 2.20 (s, 6H), 2.09 - 1.97 (m, 1H), 1.83 - 1.49 (m, 3H).

[0198] The compounds set forth in Table 3, were prepared using the synthetic procedures of Example 1-4 or analogous procedures as provided herein.

[0199] Table 3. Structure and Spectroscopic data for Compounds 27, 28 No. Structure

[0200] Example 1-5: Series B5

[0201] General Scheme,mol, 3.00 eq) in DMF (1000 mL) was added dropwise MeI (146g, 1.03 mol, 64.0 mL, 3.00 eq) at 0 °C over 0.5 hr. The mixture was stirred at 25°C for 3 hrs. The reaction mixture was diluted with water (2.00 L), and extracted with ethyl acetate (500 mL*3). The combined organic layer was washed with brine (2.00 L*2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude product was triturated with ethyl acetate (100 mL) at 25 °C for 30 mins. Compound B5-12 (91.0 g, 297 mmol, 86.8% yield) was obtained as a yellow solid. LC-MS: (M+H)+: 307.9.1H NMR: (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.75 (dd, J1 = 8.8 Hz, J2 = 2.0 Hz, 1H), 7.33 (d, J = 9.2 Hz, 1H), 7.13 (s, 1H), 3.73 (s, 3H).

[0204] Step 2: A mixture of compound B5-12 (20.0 g, 65.3 mmol, 1.00 eq), compound B5-13 (17.5 g, 131 mmol, 2.00 eq), K3PO4 (41.6 g, 196 mmol, 3.00 eq), Pd(dtbpf)Cl2 (2.13 g, 3.27 mmol, 0.05 eq) in dioxane (400 mL), H2O (100 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 60 °C for 12 hrs under N2atmosphere. The reaction mixture was diluted with water (600 mL), and extracted with ethyl acetate (300 mL*3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. Compound B5-14 (15.0 g, crude) was obtained as a brown solid. LC-MS: (M+H)+: 254.1.1H NMR: (400 MHz, CDCl3) δ 7.85 - 7.73 (m, 2H), 7.42 (d, J = 9.2 Hz, 1H), 7.12 (s, 1H), 6.79 (dd, J1= 17.2 Hz, J2= 11.2 Hz, 1H), 5.81 (d, J = 17.2 Hz, 1H), 5.36 (d, J = 11.2 Hz, 1H), 3.76 (s, 3H).

[0205] Step 3: To a solution of compound B5-14 (15.0 g, 59.2 mmol, 1.00 eq) in THF (200 mL), H2O (200 mL) was added NaIO4(25.3 g, 118 mmol, 6.56 mL, 2.00 eq) and K2OsO4•2H2O (1.09 g, 2.96 mmol, 0.05 eq) at 0°C for 1 hr. The mixture was stirred at 25°C for 2 hrs. The reaction mixture was quenched by aq. Na2SO4 (1 L) at 0 °C, and then extracted with ethyl acetate (300 mL*3). The combined organic layers were dried over NaSO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography. Compound B5-15 (5 g, crude) was obtained as a white solid. LC-MS: (M+H)+: 256.0.1H NMR: (400 MHz, CDCl3) δ 10.08 (s, 1H), 8.34 (t, J = 1.6 Hz, 1H), 8.19 (dd, J1= 8.8 Hz, J2= 1.6 Hz, 1H), 7.60 (d, J = 8.8 Hz, 1H), 7.20 (s, 1H), 3.81 (s, 3H).

[0206] Step 4: To a solution of compound B5-15 (4.50 g, 17.6 mmol, 1.00 eq) in MeOH (100 mL) was added dropwise NaBH4(3.34 g, 88.1 mmol, 5.00 eq) at 0 °C. The mixture was stirred at 25 °C for 1 hr. The reaction mixture was quenched by sat. aq. NH4Cl (300 mL) at 0 °C, and then extracted with ethyl acetate (150 mL*3). The combined organic layers were dried over Na2SO4, filtered andobtained as a white solid. LC-MS: (M+H)+: 258.1.1H NMR: (400 MHz, CDCl3) δ 7.82 (s, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.09 (s, 1H), 4.81 (s, 2H), 3.74 (s, 3H).

[0207] Step 5: To a solution of compound B5-16 (4.00 g, 15.6 mmol, 1.00 eq) in THF (50.0 mL) was added TBSCl (4.69 g, 31.1 mmol, 3.81 mL, 2.00 eq) and imidazole (4.23 g, 62.2 mmol, 4.00 eq). The mixture was stirred at 20 °C for 1 hr. The reaction mixture was diluted with water (200 mL), and extracted with ethyl acetate (100 mL*3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography. Compound B5-17 (5.30 g, 14.3 mmol, 91.7 % yield) was obtained as a white solid.1H NMR: (400 MHz, CDCl3) δ 7.86 (s, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.43 (d, J = 8.8 Hz, 1H), 7.12 (s, 1H), 4.84 (s, 2H), 3.76 (s, 3H), 0.97 (s, 9H), 0.13 (s, 6H).

[0208] Step 6: To a solution of compound B5-17 (5.30 g, 14.3 mmol, 1.00 eq) in THF (100 mL) was added dropwise TMP-MgLi (1.00 M, 49.9 mL, 3.50 eq) at -78°C. Br2(9.12 g, 57.1 mmol, 2.94 mL, 4.00 eq) was added dropwise at -78 °C. The resulting mixture was stirred at 0 °C for 1 hr. The reaction mixture was quenched by addition sat. Na2SO4 (300 mL) at 0 °C, and then extracted with DCM (300 mL*3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. Compound B5-18 (6.00 g, crude) was obtained as a yellow solid. LC-MS: (M+H)+: 452.1.

[0209] Step 7: A mixture of compound B5-18 (4.00 g, 8.88 mmol, 1.00 eq), Pd(dppf)Cl2•CH2Cl2(725 mg, 888 μmol, 0.100 eq), KOAc (2.62 g, 26.7 mmol, 3.00 eq), BPD (4.51 g, 17.8 mmol, 2.00 eq) in dioxane (60.0 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 12 hrs under N2 atmosphere. The reaction mixture was diluted with water (300 mL), and extracted with ethyl acetate (100 mL*3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography. Compound B5-19 (3.00 g, 2.41 mmol, 27.1% yield, 40.0% purity) was obtained as yellow solid. LC-MS: (M+H)+: 498.3.

[0210] Step 8: To a solution of compound B5-20 (5.00 g, 16.8 mmol, 1.00 eq), BnBr (3.16 g, 18.5 mmol, 2.20 mL, 1.10 eq) in DMF (50.0 mL) was added K2CO3 (4.65 g, 33.6 mmol, 2.00 eq). The mixture was stirred at 20 °C for 3 hr. The reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (100 mL*2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified bycolorless oil.1H NMR: (400 MHz, CDCl3) δ 7.42 - 7.32 (m, 5H), 5.26 (s, 2H), 4.15 - 4.09 (m, 2H), 2.75 - 2.65 (m, 2H), 2.32 (d, J = 12.0 Hz, 2H), 1.82 - 1.68 (m, 2H), 1.45 (s, 9H).

[0211] Step 9: To a solution of compound B5-21 (5.00 g, 12.9 mmol, 1.00 eq) in DCM (50.0 mL) was added HCl / dioxane (4.00 M, 20.0 mL, 6.20 eq). The mixture was stirred at 20 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. Compound B5-22 (4.00 g, crude, HCl) was obtained as a yellow oil. LC-MS: (M+H)+: 288.1.

[0212] Step 10: To a solution of compound B5-22 (4.00 g, 12.4 mmol, 1.00 eq, HCl), compound B5-23 (5.74 g, 24.71 mmol, 2.00 eq) in dioxane (50.0 mL) was added DIEA (4.79 g, 37.1 mmol, 6.46 mL, 3.00 eq). The mixture was stirred at 80 °C for 12 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography. Compound B5-24 (4.80 g, crude) was obtained as a yellow oil. LC-MS: (M+H)+: 370.3.1H NMR: (400 MHz, CDCl3) δ 7.43 - 7.31 (m, 5H), 5.26 (s, 2H), 2.93 - 2.87 (m, 4H), 2.35 - 2.28 (m, 4H), 1.96 - 1.93 (m, 2H).

[0213] Step 11: To a solution of compound B5-24 (4.80 g, 13.0 mmol, 1.00 eq) in MeOH (50.0 mL) was added Pd / C (1.00 g, 10.0% purity) under N2. The suspension was degassed under vacuum and purged with H2three times. The mixture was stirred under H2(15.0 psi) at 25 °C for 3 hrs. The reaction mixture was filtered, and concentrated under reduced pressure to give a residue. Compound B5-25 (2.90 g, 10.4 mmol, 79.9% yield) was obtained as a white solid.1H NMR: (400 MHz, DMSO- d6) δ 3.24 - 3.10 (m, 2H), 2.92 (d, J = 12.0 Hz, 2H), 2.33 (t, J = 11.6 Hz, 2H), 2.14 (d, J = 12.0 Hz, 2H), 1.78 - 1.64 (m, 2H).

[0214] Step 12: Zn (20.9 g, 319 mmol, 3.00 eq) was added to a three necked flask, and heated at 110 °C under vacuum for 10 minutes. The flask was then cooled to 20 °C. A solution of TMSCl (2.31 g, 21.2 mmol, 2.70 mL, 0.200 eq) in DMF (50.0 mL) was added into the flask. The mixture was stirred at 20 °C for 20 minutes. And the supernatant liquor was removed by syringe. A mixture of compound B5-26 (35.0 g, 106 mmol, 1.00 eq) in DMF (100 mL) was added to the precipitate. The inner temperature was rapidly rose from 20 °C to 45 °C. The resulting mixture was stirred at 20 °C for 1 hr under N2. The solution of compound B5-27 was used in the next step.

[0215] Step 13: To a solution of compound B5-28 (10.0 g, 47.3 mmol, 1.00 eq) in DMF (50.0 mL) was added Pd2(dba)3(2.17 g, 2.37 mmol, 0.0500 eq) and SPhos (3.89 g, 9.48 mmol, 0.200 eq). A solution of compound B5-27 (37.4 g, 94.8 mmol, 2.00 eq) in DMF (100 mL) was added. ThemL), and extracted with ethyl acetate (200 mL*3). The combined organic layers were washed with brine (100 mL*2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography. Compound B5-29 (12.0 g, 26.4 mmol, 55.8% yield, 73.5% purity) was obtained as a yellow oil. LC-MS: (M-55)+: 278.0.

[0216] Step 14: To a solution of compound B5-29 (8.00 g, 17.6 mmol, 73.5% purity, 1.00 eq) in DCM (80.0 mL) was added HCl / dioxane (4.00 M, 40.0 mL, 9.07 eq) at 0 °C. The mixture was stirred at 20 °C for 2 hrs. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. Compound B5-30 (6.00 g, crude, HCl) was obtained as a yellow solid. LC-MS: (M+H)+: 234.0.

[0217] Step 15: To a solution of compound B5-30 (2.00 g, 7.16 mmol, 1.00 eq), compound B5-25 (2.00 g, 7.42 mmol, 1.04 eq, HCl) in DMF (40.0 mL) was added EDCI (2.75 g, 14.3 mmol, 2.00 eq), TEA (3.62 g, 35.8 mmol, 4.99 mL, 5.00 eq) and HOBt (1.94 g, 14.33 mmol, 2 eq). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was diluted with water (200 mL), and extracted with ethyl acetate (50.0 mL*3). The combined organic layers were washed with brine (100 mL*3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography. Compound B5-31 (2.50 g, 5.06 mmol, 70.5% yield) was obtained as a yellow solid. LC-MS: (M+H)+: 495.2.

[0218] Step 16: To a solution of compound B5-31 (1.00 g, 2.02 mmol, 1.00 eq) in DCM (6.00 mL) was added a solution of Tf2O (2.85 g, 10.1 mmol, 1.67 mL, 5.00 eq) in DCM (4.00 mL) at -20 °C. The mixture was stirred at -20 °C for 2 hrs. The residue was purified by Prep-TLC. Compound B5- 32 (720 mg, 1.10 mmol, 54.2% yield, 95.4% purity) was obtained as a yellow oil. LC-MS: (M+H)+: 627.4.1H NMR: (400 MHz, DMSO-d6) δ 8.49 (d, J = 8.4 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.25 - 7.23 (m, 2H), 6.68 (s, 1H), 4.96 - 4.90 (m, 1H), 3.67 (s, 3H), 3.64 - 3.60 (m, 2H), 3.21 - 3.15 (m, 1H), 2.93 - 2.70 (m, 4H), 2.68 - 2.55 (m, 1H), 2.21 - 2.14 (m, 2H), 1.91 - 1.86 (m, 1H), 1.59 - 1.53 (m, 3H).

[0219] Step 17: To a solution of compound B5-32 (720 mg, 1.10 mmol, 1.00 eq) and compound B5- 19 (545 mg, 1.10 mmol, 1.00 eq) in dioxane (8.00 mL) and H2O (2.00 mL) was added Pd(dtbpf)Cl2 (71.4 mg, 109 μmol, 0.100 eq) and K3PO4(581 mg, 2.74 mmol, 2.50 eq). The mixture was degassed and purged with N2for 3 times, and then stirred at 25 °C for 12 hrs under N2atmosphere. The reaction mixture was diluted with water (20.0 mL), and extracted with ethyl acetate (20.0 mL*3).pressure to give a residue. The residue was purified by Prep-TLC. Compound B5-33 (620 mg, 731 μmol, 66.6% yield, 100% purity) was obtained as a yellow solid. LC-MS: (M+H)+: 848.5.1H NMR: (400 MHz, DMSO-d6) δ 8.54 (t, J = 7.6 Hz, 1H), 7.91 (s, 1H), 7.70 - 7.64 (m, 2H), 7.17 - 7.05 (m, 2H), 3.89 (d, J = 7.2 Hz, 1H), 6.49 - 6.48 (m, 1H), 5.04 - 4.94 (m, 1H), 4.85 (s, 2H), 3.68 (s, 5H), 3.57 - 3.49 (m, 2H), 2.97 - 2.61 (m, 4H), 2.24 - 2.19 (m, 2H), 2.09 - 2.04 (m, 1H), 1.82 (t, J = 12.0 Hz, 1H), 1.67 - 1.48 (m, 3H), 0.91 (s, 9H), 0.09 (s, 6H).

[0220] Step 18: To a solution of compound B5-33 (420 mg, 495 μmol, 1.00 eq) in methyltetrahydrofuran (4.00 mL) and EtOH (0.500 mL) was added NaOAc (121 mg, 1.49 mmol, 3.00 eq), Pd / C (150 mg, 10.0% purity) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (15 psi) at 50 °C for 5 hrs. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC. Compound B5-34 (280 mg, 315 μmol, 63.7% yield, 95.8% purity) was obtained as a yellow solid. LC-MS: (M+H)+: 851.0.1H NMR: (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H), 7.03 - 6.99 (m, 1H), 6.90 (t, J = 6.4 Hz, 1H), 6.73 (d, J = 7.2 Hz, 1H), 6.35 (d, J = 6.4 Hz, 0.5H), 6.22 (d, J = 7.6 Hz, 0.5H), 5.02 - 4.96 (m, 1H), 4.84 (s, 2H), 3.80 (d, J = 6.4 Hz, 3H), 3.60 (s, 3H), 3.45 - 3.00 (m, 5H), 2.99 - 2.91 (m, 3H), 2.81 - 2.80 (m, 1H), 2.59 - 2.10 (m, 7H), 0.98 (s, 9H), 0.14 (s, 6H).

[0221] Step 19: To a solution of compound B5-34 (280 mg, 315 μmol, 1.00 eq) in DCM (3.00 mL) was added HCl / dioxane (4.00 M, 0.50 mL, 6.34 eq). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was diluted with water (10.0 mL), and extracted with DCM (10.0 mL*3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Compound B5-35 (250 mg, 300 μmol, 95.1% yield, 88.4% purity) was obtained as a yellow oil. LC-MS: (M+H)+: 736.1.

[0222] Step 20: To a solution of compound B5-35 (250 mg, 300 μmol, 1.00 eq) in DCM (3.00 mL) was added MnO2(261 mg, 3.00 mmol, 10.0 eq). The mixture was stirred at 40 °C for 72 hrs. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC. Compound B5-36 (140 mg, 186 μmol, 62.0% yield, 97.6% purity) was obtained as a yellow oil. LC-MS: (M+H)+: 734.4.1H NMR: (400 MHz, CDCl3) δ 10.0 (s, 1H), 8.52 (s, 1H), 8.13 (dd, J1= 8.8 Hz, J2= 1.6 Hz, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.07 - 7.00 (m, 1H), 6.93 - 6.87 (m, 1H), 6.74(d, J = 7.2 Hz, 1H), 6.35 (d, J = 7.6 Hz, 0.5H), 6.24 (d, J =3.02 (m, 4H), 2.98 - 2.90 (m, 5H), 2.57 - 2.38 (m, 3H), 2.24 - 2.15 (m, 2H), 2.14 - 2.13 (m, 1H), 2.09 - 2.00 (m, 1H).

[0223] Step 21: A solution of compound B5-36 (130 mg, 172 μmol, 1.00 eq) and compound B5-37 (44.1 mg, 518 μmol, 51.2 μL, 3.00 eq) in DCE (2.00 mL) was stirred at 25 °C for 12 hr. NaBH3CN (21.7 mg, 345 μmol, 2.00 eq) was added at 0 °C. The mixture was stirred at 25 °C for 2 hrs. The reaction mixture was quenched by addition sat. aq. NH4Cl (10.0 mL) and extracted with DCM (10.0 mL*3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC. Compound B5-38 (110 mg, 131 μmol, 75.8% yield, 95.7% purity) was obtained as a yellow oil. LC-MS: (M+H)+: 803.5.1H NMR: (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.40 - 7.35 (m, 1H), 7.16 (t, J = 8.0 Hz, 1H), 7.07 - 7.00 (m, 1H), 6.90 (t, J = 5.6 Hz, 1H),6.74 - 6.69 (m, 1H), 6.42 - 6.38 (m, 0.5H), 6.25 (d, J = 7.6 Hz, 0.5H), 5.08 - 4.92 (m, 2H), 3.79 (d, J = 8.8 Hz, 3H), 3.60 (s, 3H), 3.41 - 3.38 (m, 1H), 3.31 - 3.18 (m, 2H), 3.09 - 2.99 (m, 2H), 2.97 - 2.83 (m, 3H), 2.53 - 2.36 (m, 2H), 2.53 - 2.36 (m, 7H), 2.21 - 2.17 (m, 3H), 1.97 - 1.90 (m, 4H), 1.51 - 1.46 (m, 4H).

[0224] Step 22: Compound B5-38 was purified by Prep-SFC. Compound B5-38_peak 1 (35.0 mg, 43.4 μmol, 66.3% yield, 99.7% purity) was obtained as a yellow solid. LC-MS: (M+H)+: 803.5. Compound B5-38_peak 2 (40.0 mg, 46.4 μmol, 70.8% yield, 93.2% purity) was obtained as a yellow solid. LC-MS: (M+H)+: 803.5.

[0225] Step 23: To a solution of compound B5-38_peak 1 (25.0 mg, 31.0 μmol, 1.00 eq) in H2O (0.500 mL) was added HCl / dioxane (4.00 M, 0.200 mL, 25.7 eq). The mixture was stirred at 60 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC. Compound 41 (22.86 mg, 28.5 μmol, 91.9% yield, 98.5% purity) was obtained as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 8.33 (d, J = 8.0 Hz, 1H), 7.87 (s, 1H), 7.62 - 7.60 (m, 2H), 7.00 - 6.93 (m, 2H), 6.60 (d, J = 6.8 Hz, 1H), 5.03 - 4.56 (m, 2H), 3.77 - 3.74 (m, 1H), 3.55 (d, J = 8.8 Hz, 4H), 3.17 (d, J = 4.8 Hz, 1H), 3.14 (d, J = 4.4 Hz, 1H), 3.10 - 3.04 (m, 2H), 3.02 - 2.82 (m, 2H), 2.79 - 2.63 (m, 3H), 2.36 (s, 4H), 2.36 - 2.25 (m, 3H), 2.05 - 1.97 (m, 1H), 1.77 - 1.56 (m, 3H), 1.50 (s, 4H), 1.40 (s, 2H). LC-MS: (M+H)+: 789.4.

[0226] Step 24: To a solution of compound B5-38_peak 2 (30.0 mg, 34.8 μmol, 1.00 eq) in H2O (0.500 mL) was added HCl / dioxane (4.00 M, 0.200 mL, 22.9 eq). The mixture was stirred at 60 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. Thepurity) was obtained as an off-white solid.1H NMR: (400 MHz, DMSO-d6) δ 8.30 (d, J = 7.2 Hz, 1H), 7.87 (s, 1H), 7.62 - 7.60 (m, 2H), 6.97 - 6.90 (m, 2H), 6.59 (d, J = 7.6 Hz, 1H), 4.84 (t, J = 8.0 Hz, 1H), 4.66 - 4.63 (m, 1H), 3.77 - 3.70 (m, 1H), 3.55 (d, J = 10.8 Hz, 4H), 3.23 (d, J = 4.0 Hz, 1H), 3.20 (d, J = 3.2 Hz, 1H), 3.15 (d, J = 9.2 Hz, 1H), 3.08 - 3.00 (m, 2H), 2.91 - 2.84 (m, 2H), 2.76 (d, J = 10.8 Hz, 1H), 2.62 (d, J = 10.8 Hz, 1H), 2.36 (s, 4H), 2.30 - 2.22 (m, 3H), 2.15 - 2.10 (m, 1H), 1.73 (t, J = 14.0 Hz, 1H), 1.63 - 1.58 (m, 2H), 1.50 (s, 4H), 1.40 (s, 2H). LC-MS: (M+H)+: 789.4.

[0227] The compounds set forth in Table 4, were prepared using the synthetic procedures of Example 1-5 or analogous procedures as provided herein.

[0228] Table 4. Structure and Spectroscopic data for Compounds 45-47, 50-56 #Structure#StructureF F F F F F F

[0229] EXAMPLE 2: Series C

[0230] Example 2-1: Series C1

[0231] General Scheme. , . , . . mL) was added PdCl2(MeCN)2(94.2 mg, 363 µmol, 0.100 eq), compound C1-3 (1.82 g, 3.63 mmol, 1.00 eq), Cs2CO3 (3.55 g, 10.9 mmol, 3.00 eq) and DPPF (402 mg, 726 µmol, 0.200 eq). The mixture was stirred at 100 °C for 2 hrs. The reaction mixture was diluted with water (30.0 mL), and extracted with EtOAc (30.0 mL*3). The combined organic layers were washed with brine (30.0residue was purified by column chromatography. Compound C1-4 (630 mg, 1.23 mmol, 33.9% yield) was obtained as yellow oil. LC-MS: (M+H)+: 512.3.1H NMR: (400 MHz, DMSO-d6) δ 7.17 (t, J = 7.6 Hz, 1H), 6.94 (t, J = 6.4 Hz, 2H), 6.67 (s, 2H), 6.52 (s, 1H), 5.05 (d, J = 8.0 Hz, 1H), 4.72 – 4.67 (m, 1H), 4.55 (s, 2H), 3.74 (s, 9H), 3.63 (q, J = 6.8 Hz, 2H), 3.52 (s, 2H), 3.30 – 3.13 (m, 2H), 1.42 (s, 9H), 1.31 (t, J = 6.8 Hz, 3H).

[0234] Step 2: To a solution of compound C1-4 (580 mg, 1.13 mmol, 1.00 eq) in MeOH (5.00 mL) was added Pd / C (100 mg, 10% purity) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (15 psi) at 20°C for 12 hrs. The reaction mixture was filtered, and concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC. The residue was purified by SFC. Compound C1-5_peak 1 (170 mg, 331 µmol, 29.2% yield) was obtained as a colorless oil.1H NMR: (400 MHz, DMSO-d6) δ 6.97 (t, J = 7.4 Hz, 1H), 6.82 (d, J = 7.2 Hz, 1H), 6.70 (d, J = 7.2 Hz, 1H), 6.56 (s, 2H), 5.03 – 4.95 (m, 2H), 4.64 – 4.59 (m, 1H), 4.47 (s, 2H), 3.73 – 3.50 (m, 11 H), 3.17 – 3.02 (m, 3H), 2.92 – 2.84 (m, 1H), 2.37 – 2.27 (m, 2H), 1.42 (s, 9H), 1.28 (s, 3H). Compound C1-5_peak 2 (120 mg, 234 µmol, 20.6% yield) was obtained as a colorless oil.1H NMR: (400 MHz, DMSO-d6) δ 6.96 (t, J = 7.2 Hz, 1H), 6.82 (d, J = 7.2 Hz, 1H), 6.69 (d, J = 7.6 Hz, 1H), 6.56 (s, 2H), 5.01 (t, J = 8.8 Hz, 2H), 4.62 – 4.59 (m, 1H), 4.47 (s, 2H), 3.76 – 3.50 (m, 11H), 3.16 – 3.01 (m, 3H), 2.96 – 2.88 (m, 1H), 2.37 – 2.26 (m, 2H), 1.44 (s, 9H), 1.28 (t, J = 7.2 Hz, 3H).

[0235] Step 3: To a solution of compound C1-5_peak 1 (60.0 mg, 117 µmol, 1.00 eq) in DCM (2.00 mL) was added HCl / dioxane (4.00 M, 1.00 mL). The mixture was stirred at 20 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. Compound C1- 6_peak 1 (50.0 mg, 111 µmol, 95.1% yield, HCl) was obtained as a white solid. LC-MS: (M+H)+: 414.4.

[0236] Step 4: To a solution of compound C1-7-Int1 (3.00 g, 12.1 mmol, 1.00 eq) in MeCN (20.0 mL) was added K2CO3(5.03 g, 36.4 mmol, 3.00 eq) and pyrrolidine (1.04 g, 14.6 mmol, 1.22 mL, 1.20 eq). The mixture was stirred at 20 °C for 2 hrs. The reaction mixture was diluted with water (60.0 mL), and extracted with EtOAc (30.0 mL*3). The combined organic layers were washed with brine (30.0 mL*3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography. Compound C1-7-Int2 (1.80 g, 7.49 mmol, 61.7% yield, 98.7% purity) was obtained as a yellow oil.1H NMR: (400 MHz, DMSO-d6) δ(m, 4H). LC-MS: (M+H)+: 238.1.

[0237] Step 5: To a solution of compound C1-7-Int2 (1.80 g, 7.59 mmol, 1.00 eq) in MeOH (10.0 mL) was added LiOH.H2O (382 mg, 9.10 mmol, 1.20 eq) and H2O (5.00 mL). The mixture was stirred at 60 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. Compound C1-7-1 (1.90 g, crude, Li) was obtained as a yellow solid. LC-MS: (M+H)+: 223.9.1H NMR: (400 MHz, DMSO-d6) δ 7.11 (d, J = 7.6 Hz, 1H), 7.03 – 6.98 (m, 1H), 6.79 ((t, J = 8.4 Hz, 1H), 3.17 (s, 2H), 2.44 – 2.40 (m, 4H), 1.70 – 1.66 (m, 4H).

[0238] Step 6: To a solution of compound C1-6_peak 1 (45.0 mg, 100 µmol, 1.00 eq, HCl) in pyridine (2.00 mL) was added EDCI (57.5 mg, 300 µmol, 3.00 eq) and compound C1-7-1 (29.9 mg, 130 µmol, 1.30 eq, Li). The mixture was stirred at 20 °C for 2 hrs. The reaction mixture was diluted with NH4Cl (20.0 mL), and extracted with EtOAc (20.0 mL*3). The combined organic layers were washed with brine (20.0 mL*3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC. Compound C1-8-1_peak 1 (50.0 mg, 80.8 µmol, 80.8% yield) was obtained as a yellow solid. LC-MS: (M+H)+: 619.5.1H NMR: (400 MHz, CDCl3) δ 9.85 (brs, 1H), 7.31 – 7.28 (m, 1H), 7.07 – 7.01 (m, 1H), 6.95 (t, J = 7.2 Hz, 1H), 6.89 – 6.88 (m, 1H), 6.70 (d, J = 7.6 Hz, 1H), 6.55 (s, 2H), 5.02 – 4.93 (m, 2H), 4.47 (s, 2H), 4.18 (d, J = 11.6 Hz, 1H), 3.73 – 3.50 (m, 11H), 3.46 – 3.26 (m, 2H), 3.23 – 3.14 (m, 2H), 3.04 – 2.92 (m, 2H), 2.70 – 2.48 (m, 4H), 2.38 – 2.26 (m, 2H), 1.84 (s, 4H), 1.27 (t, J = 7.2 Hz, 3H).

[0239] Step 7: To a compound C1-8-1_peak 1 (40.0 mg, 64.6 µmol, 1.00 eq) in H2O (1.00 mL) was added HCl / dioxane (4.00 M, 1.00 mL). The mixture was stirred at 60 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC. Compound 17 (30.51 mg, 50.1 µmol, 77.5% yield, 99.4% purity) was obtained as a white solid. LC-MS: (M+H)+: 605.3.1H NMR: (400 MHz, DMSO-d6) δ 9.04 (d, J = 8.0 Hz, 1H), 7.43 - 7.37 (m, 1H), 7.28 (d, J = 7.2 Hz, 1H), 7.14 (t, J = 8.8 Hz, 1H), 6.97 (d, J = 7.6 Hz, 1H), 6.91 (t, J = 7.6 Hz, 1H), 6.58 (s, 2H), 6.53 (d, J = 7.2 Hz, 1H), 4.90 (t, J = 8.4 Hz, 1H), 4.62 - 4.57 (m, 1H), 4.40 (s, 2H), 3.73 (d, J = 14.0 Hz, 2H), 3.49 (d, J = 6.8 Hz, 6H), 3.20 - 3.10 (m, 6H), 2.97 - 2.81 (m, 4H), 2.23 - 2.19 (m, 2H), 1.74 - 1.68 (m, 4H), 1.15 (d, J = 7.2 Hz, 3H).

[0240] Step 8: To a solution of compound C1-5_peak 2 (60.0 mg, 117 µmol, 1.00 eq) in DCM (2.00 mL) was added HCl / dioxane (4.00 M, 1.00 mL). The mixture was stirred at 20 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. Compound C1-414.3.

[0241] Step 9: To a solution of compound C1-6_peak 2 (45.0 mg, 100 µmol, 1.00 eq, HCl) in pyridine (2.00 mL) was added EDCI (57.5 mg, 300 µmol, 3.00 eq) and compound C1-7-1 (27.6 mg, 120.0 µmol, 1.20 eq, Li). The mixture was stirred at 20 °C for 2 hrs. The reaction mixture was diluted with water (20.0 mL), and extracted with EtOAc (20.0 mL*3). The combined organic layers were washed with brine (20.0 mL*3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Compound C1-8-1_peak 2 (60.0 mg, crude) was obtained as a yellow solid. LC-MS: (M+H)+: 619.5.

[0242] Step 10: To a solution of compound C1-8-1_peak 2 (50.0 mg, 80.8 µmol, 1.00 eq) in H2O (1.00 mL) was added HCl / dioxane (4.00 M, 1.00 mL). The mixture was stirred at 60 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC. Compound 23 (23.7 mg, 39.1 µmol, 48.4% yield, 99.6% purity) was obtained as a white solid. LC-MS: (M+H)+: 605.3.1H NMR: (400 MHz, DMSO-d6) δ 9.07 (d, J = 8.0 Hz, 1H), 7.43 - 7.37 (m, 1H), 7.27 (d, J = 7.6 Hz, 1H), 7.15 (t, J = 8.8 Hz, 1H), 6.97 - 6.89 (m, 2H), 6.59 (s, 2H), 6.50 (d, J = 7.2 Hz, 1H), 4.88 (t, J = 8.8 Hz, 1H), 4.59 - 4.53 (m, 1H), 4.41 (s, 2H), 3.78 (d, J = 13.6 Hz, 2H), 3.49 (d, J = 6.8 Hz, 6H), 3.22 (dd, J1= 14.4 Hz, J2= 4.4 Hz, 3H), 3.13 - 3.06 (m, 2H), 2.94 - 2.84 (m, 3H), 2.57 - 2.54 (m, 2H), 2.27 - 2.21 (m, 2H), 1.76 - 1.69 (m, 4H), 1.16 (t, J = 7.2 Hz, 3H).

[0243] Example 2-2: Series C2

[0244] General SchemeTosNHNH2 (5.36 g, 28.8 mmol, 0.960 eq), AcOH (180 mg, 3.00 mmol, 171 µL, 0.100 eq) in MeOH (200 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 70 °C for 12 hrs under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. Compound C2-2 (15.0 g, 29.9 mmol, 99.7% yield) was obtained as off-white solid. LC-MS: (M+H)+: 502.4.1H NMR: (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 7.81 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 6.0 Hz, 2H), 7.25 - 7.16 (m, 2H), 4.26 - 4.16 (m, 1H), 3.60 (s, 3H), 3.06 - 2.89 (m, 4H), 2.76 (br d, J = 5.6 Hz, 2H), 2.36 (s, 3H), 1.29 (s, 9H).

[0247] Step 2: A mixture of compound C2-1 (4.00 g, 18.4 mmol, 1.00 eq), compound C2-2 (10.1 g, 20.2 mmol, 1.10 eq), PdCl2(MeCN)2(478 mg, 1.84 mmol, 0.100 eq), Cs2CO3(12.0 g, 36.8 mmol, 2.00 eq) and DPPF (2.04 g, 3.69 mmol, 0.200 eq) in dioxane (60.0 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 5 hrs under N2 atmosphere. The reaction mixture was diluted with H2O (100 mL), and extracted with ethyl acetate (150 mL*3). The combined organic layers were washed with brine (300 mL*2), and concentrated under reduced(4.50 g, 9.92 mmol, 53.8% yield) was obtained as yellow oil. LC-MS: (M-99)+: 354.2.1H NMR: (400 MHz, DMSO-d6) δ 7.39 (d, J = 8.0 Hz, 1H), 7.33 (t, J = 8.4 Hz, 1H), 7.11 (t, J = 7.6 Hz, 1H), 7.03 (d, J = 7.2 Hz, 1H), 6.77 - 6.69 (m, 3H), 6.44 - 6.39 (m, 1H), 4.36 - 4.34 (m, 1H), 3.65- 3.64 (m, 9H), 3.50 (d, J = 1.2 Hz, 1H), 3.44 (d, J = 1.2 Hz, 1H), 3.15 (br dd, J1 = 14.4 Hz, J2 = 4.8 Hz, 1H), 2.99 (br dd, J1= 14.0 Hz, J2= 3.6 Hz, 1H), 1.33 (s, 9H).

[0248] Step 3: To a solution of compound C2-3 (5.50 g, 12.1 mmol, 1.00 eq) in MeOH (100 mL) was added Pd / C (1.00 g, 12.1 mmol, 10.0% purity) under N2. The suspension was degassed under vacuum and purged with H2 three times. The mixture was stirred under H2 (15 psi) at 25 °C for 12 hrs. The residue was filtered with MeOH (500 mL), and then concentrated under reduced pressure to give a residue. Compound C2-4 (5.50 g, 12.0 mmol, 99.5% yield) was obtained as yellow oil. LC- MS: (M-99)+: 356.3.1H NMR: (400 MHz, DMSO-d6) δ 7.32 (t, J = 8.4 Hz, 1H), 7.16 (m, 1H), 6.92 (br d, J = 3.6 Hz, 2H), 6.63 (br d, J = 6.4 Hz, 2H), 6.51 (br d, J = 4.0 Hz, 1H), 4.91 (br t, J = 8.8 Hz, 1H), 4.30 - 4.14 (m, 1H), 3.82 - 3.41 (m, 9H), 3.08 - 2.95 (m, 2H), 2.91 - 2.81 (m, 2H), 2.29 - 2.17 (m, 2H), 1.33 (s, 9H).

[0249] Step 4: To a solution of compound C2-4 (5.50 g, 12.0 mmol, 1.00 eq) in MeCN (80.0 mL) was added NBS (2.15 g, 12.0 mmol, 1.00 eq). The mixture was stirred at 25 °C for 3 hrs. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H2O (50.0 mL), and extracted with ethyl acetate (60.0 mL*3). The combined organic layers were washed with brine (150 mL), and concentrated under reduced pressure to give a residue. Compound C2-5 (6.40 g, crude) was obtained as off-white solid. LC-MS: (M-99)+: 434.1.

[0250] Step 5: A mixture of compound C2-5 (6.40 g, 11.9 mmol, 1.00 eq), compound C2-6 (8.02 g, 59.8 mmol, 5.00 eq), Pd(dtbpf)Cl2(780 mg, 1.20 mmol, 0.100 eq), K3PO4(5.08 g, 23.9 mmol, 2.00 eq) in dioxane (100 mL), H2O (20.0 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90 °C for 3 hrs under N2 atmosphere. The residue was diluted with H2O (100 mL). and extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with brine (200 mL*2), concentrated under reduced pressure to give a residue. The residue was purified by column chromatography. Compound C2-7 (4.55 g, 9.45 mmol, 78.9% yield) was obtained as a yellow solid. LC-MS: (M-99)+: 382.2.1H NMR: (400 MHz, DMSO-d6) δ 7.45 (dd, J1= 8.4 Hz , J2= 3.6 Hz, 1H), 7.38 - 7.29 (m, 1H), 6.99 - 6.91 (m, 2H), 6.78 (br d, J = 8.4 Hz, 2H), 6.58 (br s, 1H),3.48 (m, 9H), 3.11 - 2.83 (m, 4H), 2.41 - 2.18 (m, 2H), 1.33 (d, J = 4.0 Hz, 9H).

[0251] Step 6: A mixture of compound C2-7 (4.55 g, 9.45 mmol, 1.00 eq), NaIO4(6.06 g, 28.3 mmol, 1.57 mL, 3.00 eq) in THF (50.0 mL) was added K2OsO4•2H2O (348 mg, 944 µmol, 0.100 eq) in H2O (20.0 mL) slowly at 0 °C, then the mixture was stirred at 25 °C for 2 hrs. The reaction mixture was quenched with water (100 mL). Then mixture was extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with Na2SO3(250 mL*2) and brine (300 mL*2). The organic solvent was dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography. Compound C2-8 (2.40 g, 4.96 mmol, 52.5% yield) was obtained as yellow oil. LC-MS: (M-99)+: 384.1.1H NMR: (400 MHz, DMSO-d6) δ 10.11 (br s, 1H), 7.72 (dd, J1 = 8.8 Hz, J2 = 3.2 Hz, 1H), 7.35 - 7.32 (m, 1H), 7.00 - 6.94 (m, 3H), 6.59 (br s, 1H), 4.87 (br t, J = 7.2 Hz, 1H), 4.28 - 4.19 (m, 1H), 3.98 - 3.46 (m, 9H), 3.22 - 3.03 (m, 2H), 2.97 - 2.83 (m, 2H), 2.40 - 2.21 (m, 2H), 1.35 - 1.31 (d, J = 5.2 Hz, 9H).

[0252] Step 7: To a solution of compound C2-8 (632 mg, 1.31 mmol, 1.00 eq) in THF (10.0 mL) was added Me2NH (2.00 M, 1.31 mL, 2.00 eq) and AcOH (15.7 mg, 261 µmol, 14.9 µL, 0.200 eq). NaBH3CN (98.5 mg, 1.57 mmol, 1.20 eq) was added after 3 hrs. The mixture was stirred at 25 °C for 2 hrs. The reaction mixture was diluted with H2O (50.0 mL), and extracted with ethyl acetate (50.0 mL*5). The combined organic layers were washed with brine (200 mL*2), filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give (1.20 g) crude as yellow oil. The mixture was further purification by Prep-SFC. Compound C2- 9_peak1 (580 mg, 1.13 mmol, 28.8% yield) was obtained as a white solid. LC-MS: (M+H)+: 513.4.1H NMR: (400 MHz, CDCl3) δ 7.22 (d, J = 8.8 Hz, 1H), 7.03 - 6.95 (m, 1H), 6.85 (br d, J = 7.2 Hz, 1H), 6.71 (br d, J = 7.2 Hz, 1H), 6.64 (br d, J = 8.4 Hz, 1H), 5.01 - 4.83 (m, 2H), 4.69 - 4.57 (m, 1H), 3.91 - 3.59 (m, 6H), 3.49 - 3.45 (m, 5H), 3.20 - 3.10 (m, 2H), 3.07 - 3.04 (m, 1H), 2.94 - 2.92 (m, 1H), 2.44 - 2.37 (m, 2H), 2.29 (s, 6H), 1.42 (s, 9H). Compound C2-9_peak2 (360 mg, 702 µmol, 17.9%) was obtained as a white solid and directly used in next step.

[0253] Step 8: To a solution of compound C2-9_peak1 (560 mg, 1.09 mmol, 1.00 eq) in DCM (5.00 mL) was added HCl / dioxane (4 M, 6.00 mL, 21.9 eq). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. Compound C2- 10_peak1 (500 mg, crude, HCl) was obtained as a white solid. LC-MS: (M+H)+: 413.3.compound C2-11-1 (34.3 mg, 222 µmol, 1.00 eq) in pyridine (1.00 mL) was added EDCI (106 mg, 556 µmol, 2.50 eq). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to remove pyridine. The residue was diluted with H2O (5.00 mL), and extracted with ethyl acetate (5.00 mL*3). The combined organic layers were washed with brine (10.0 mL*2), filtered, and concentrated under reduced pressure to give a residue. Compound C2-12-1 (110 mg, crude) was obtained as a yellow solid. LC-MS: (M+H)+: 549.8.

[0255] Step 10: To a solution of compound C2-12-1 (100 mg, 182 µmol, 1.00 eq) in H2O (0.500 mL) was added HCl / dioxane (4 M, 1.50 mL, 33.0 eq). The mixture was stirred at 60 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC. Compound 35 (40.54 mg, 74.92 µmol, 41.1% yield, 98.8% purity) was obtained as a white solid. LC-MS: (M+H)+: 535.5.1H NMR: (400 MHz, DMSO-d6) δ 8.82 (br d, J = 8.4 Hz, 1H), 7.33 - 7.25 (m, 1H), 7.20 (d, J = 8.8 Hz, 1H), 7.06 - 6.97 (m, 3H), 6.97 - 6.91 (m, 1H), 6.73 (br d, J = 7.6 Hz, 1H), 6.56 (br d, J = 4.8 Hz, 1H), 4.86 - 4.74 (m, 1H), 4.73 - 4.63 (m, 1H), 3.77 - 3.70 (m, 2H), 3.45 (br d, J = 11.6 Hz, 6H), 3.19 - 3.13 (m, 2H), 2.99 - 2.89 (m, 2H), 2.38 - 2.27 (m, 2H), 2.20 (s, 6H), 2.07 (s, 3H).

[0256] Step 11: To a solution of compound C2-9_peak2 (360 mg, 702 µmol, 1.00 eq) in DCM (3.00 mL) was added HCl / dioxane (4.00 M, 1.00 mL, 5.70 eq) at 0 °C. The mixture was stirred at 25 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. Compound C2-10_peak2 (400 mg, crude, HCl) was obtained as a yellow solid. LC-MS: (M+H)+: 413.1.

[0257] Step 12: To a solution of compound C2-10_peak2 (90.0 mg, 200 µmol, 1.00 eq, HCl) and compound C2-11-1 (33.9 mg, 220 µmol, 1.1 eq) in Py (1.00 mL) was added EDCI (115 mg, 601 µmol, 3.00 eq). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was diluted with water (15.0 mL), and extracted with ethyl acetate (15.0 mL*3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC. Compound C2-13-1 (70.0 mg, 94.9 µmol, 47.3% yield, 74.4% purity) was obtained as a yellow oil. LC-MS: (M+H)+: 549.5.

[0258] Step13: To a solution of compound C2-13-1 (60.0 mg, 81.3 µmol, 74.4% purity, 1.00 eq) in H2O (0.500 mL) was added HCl / dioxane (4.00 M, 372 µL, 18.2 eq). The mixture was stirred at 60 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. Thepurity) was obtained as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 8.85 (d, J = 8.0 Hz, 1H), 7.31 - 7.25 (m, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.02 - 6.99 (m, 3H), 6.93 (t, J = 7.6 Hz, 1H), 6.74 (d, J = 8.0 Hz, 1H), 6.53 (d, J = 6.8 Hz, 1H), 4.78 - 4.76 (m, 1H), 4.68 - 4.63 (m, 1H), 3.73 - 3.64 (m, 3H), 3.43 - 3.40 (m, 4H), 3.20 - 3.13 (m, 2H), 3.13 - 3.11 (m, 1H), 2.97 - 2.93 (m, 2H), 2.35 - 2.30 (m, 2H), 2.19 (s, 6H), 2.08 (s, 3H). LC-MS: (M+H)+: 535.4.

[0259] The compounds set forth in Table 5, were prepared using the synthetic procedures of Example 2-2 or analogous procedures as provided herein.

[0260] Table 5. Structure and Spectroscopic data for Compounds 29-34, 37, 38 # Structure # Structure

[0261] Example 3: Series D

[0262] General Scheme

[0264] Synthetic preparation of Series D1 compounds, Compound 161-2 (1.18 g, 7.93 mmol, 1.07 eq) in toluene (20.0 mL) was added TEA (802 mg, 7.93 mmol, 1.10 mL, 1.07 eq) at 0 °C. The mixture was stirred at 130 °C for 5 hrs. The reaction mixture was diluted with H2O (60.0 mL), and extracted with ethyl acetate (60.0 mL*3). The organic layer was washed with brine (60.0 mL), dried over Na2SO4, and concentrated under reduced pressure to give residue. The residue was purified by column chromatography. Compound D1-3 (2.50 g, 6.29 mmol, 84.8% yield, 91.4% purity) was obtained as a yellow oil.1H NMR: (400 MHz, DMSO-d6) δ 7.86 (s, 4H), 7.44 - 7.37 (m, 2H), 7.23 (t, J = 7.6 Hz, 1H), 5.3dd, J1 = 10.4 Hz, J2 = 5.2 Hz, 1H), 3.71 (s, 3H), 3.63 - 3.56 (m, 1H), 3.45 - 3.38 (m, 1H), 3.24 - 3.14 (m, 1H), 3.07 - 2.97 (m, 1H), 2.62 - 2.58 (m, 2H). LC- MS: (M+H)+: 364.2.

[0266] Step 2: To a solution of compound D1-3 (500 mg, 1.26 mmol, 1.00 eq) in DCM (5.00 mL) was added Tf2O (1.77 g, 6.29 mmol, 1.04 mL, 5.00 eq) at -40 °C. The mixture was stirred at -40 °C for 3 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC. Compound D1-4 (400 mg, 744 μmol, 59.2% yield, 92.2% purity) was obtained as a yellow oil. LC-MS: (M+H)+: 496.0.mg, 893 μmol, 1.20 eq), PdCl2(dtbpf) (48.5 mg, 74.4 μmol, 0.100 eq), K3PO4 (474 mg, 2.23 mmol, 3.00 eq) in dioxane (3.00 mL) and H2O (0.800 mL) was degassed and purged with N2for 3 times. The mixture was stirred at 25 °C for 3 hrs under N2atmosphere. The reaction mixture was diluted with H2O (30.0 mL), and extracted with ethyl acetate (30.0 mL*3). The organic layer was washed with brine (30.0 mL), dried over Na2SO4and concentrated under reduced pressure to give residue. The residue was purified by Prep-TLC. Compound D1-6 (400 mg, 698 μmol, 93.8% yield) was obtained as a yellow oil. LC-MS: (M+H)+: 573.3.1H NMR: (400 MHz, DMSO-d6) δ 7.85 (s, 5H), 7.80 - 7.67 (m, 2H), 7.47 - 7.38 (m, 1H), 7.07 - 6.90 (m, 2H), 6.84 - 6.81 (m, 1H), 6.51 - 6.39 (m, 1H), 5.46 - 5.37 (m, 1H), 3.91 (s, 2H), 3.73 - 3.66 (m, 6H), 3.54 - 3.38 (m, 2H).

[0268] Step 4: To a solution of compound D1-6 (380 mg, 663 μmol, 1.00 eq) in MeOH (5.00 mL) was added Pd / C (50.0 mg, 10.0% purity) under N2 atmosphere. The suspension was degassed and purged with H2for 3 times. The mixture was stirred under H2(50 Psi) at 50 °C for 48 hrs. The reaction mixture was filtered, and the filtrate was concentrated under the vacuum. The residue was purified by Prep-TLC. Compound D1-7 (300 mg, 522 μmol, 78.6% yield) was obtained as white solid. LC-MS: (M+H)+: 575.1.1H NMR: (400 MHz, DMSO-d6) δ 7.97 - 7.81 (m, 5H), 7.71 - 7.57 (m, 2H), 7.38 - 7.34 (m, 1H), 7.07 - 6.76 (m, 2H), 6.55 (t, J = 6.0 Hz, 1H), 5.41 - 5.17 (m, 1H), 4.89 - 4.66 (m, 1H), 3.71 (d, J = 4.0 Hz, 3H), 3.61 - 3.34 (m, 5H), 3.26 - 2.74 (m, 3H), 2.38 - 2.24 (m, 1H).

[0269] Step 5: Compound D1-7 was purified by Prep-SFC. Compound D1-7_peak1 (120 mg, 208 μmol, 40.0% yield) was obtained as a white solid.1H NMR: (400 MHz, CDCl3) δ 8.01 (s, 1H), 7.82 - 7.78 (m, 2H), 7.73 - 7.66 (m, 2H), 7.58 (t, J = 7.6 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.31 - 7.29 (m, 1H), 6.83 (s, 2H), 6.61 - 6.59 (m, 1H), 5.23 (dd, J1= 11.6 Hz, J2= 5.2 Hz, 1H), 5.06 - 4.96 (m, 1H), 3.81 (s, 3H), 3.72 - 3.49 (m, 5H), 3.43 - 3.08 (m, 2H), 2.64 - 2.36 (m, 2H). LC-MS: (M+H)+: 575.3. Compound D1-7_peak2 (130 mg, 226 μmol, 43.3% yield) was obtained as a white solid.1H NMR: (400 MHz, CDCl3) δ 8.07 - 7.94 (m, 1H), 7.84 - 7.82 (m, 2H), 7.73 - 7.70 (m, 2H), 7.58 (t, J = 7.6 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.32 - 7.28 (m, 1H), 7.07 - 7.02 (m, 1H), 6.95 (t, J = 6.8 Hz, 1H), 6.64 (d, J = 7.2 Hz, 1H), 5.35 - 5.30 (m, 1H), 5.06 - 4.86 (m, 1H), 3.80 (s, 3H), 3.63 (s, 5H), 3.41 - 3.24 (m, 1H), 3.05 - 2.87 (m, 1H), 2.60 - 2.23 (m, 2H). LC-MS: (M+H)+: 575.3.

[0270] Step 6: To a solution of compound D1-7_peak1 (120 mg, 208 μmol, 1.00 eq) in MeOH (2.00 mL) was added NH2NH2•H2O (210 mg, 3.57 mmol, 203 μL, 85.0% purity, 17.1 eq). Theextracted with DCM (20.0 mL*3). The organic layer was washed with brine (20.0 mL), dried over Na2SO4,and concentrated under reduced pressure to give residue. The residue was purified by Prep- TLC. Compound D1-8 (45.0 mg, 101 μmol, 48.5% yield) was obtained as a yellow oil. LC-MS: (M+H)+: 445.1.1H NMR: (400 MHz, DMSO-d6) δ 7.96 - 7.95 (m, 1H), 7.77 - 7.59 (m, 2H), 7.39 (t, J = 7.6 Hz, 1H), 6.94 - 6.93 (m, 2H), 6.62 (s, 1H), 5.00 - 4.81 (m, 1H), 3.68 - 3.52 (m, 7H), 3.24 - 3.10 (m, 2H), 3.06 - 2.89 (m, 2H), 2.75 - 2.69 (m, 1H), 2.38 - 2.26 (m, 1H).

[0271] Step 7: To a solution of compound D1-8 (40.0 mg, 90.0 μmol, 1.00 eq), compound D1-9-1 (20.7 mg, 90.0 μmol, 1.00 eq, Li) in MeCN (1.00 mL) was added TCFH (75.7 mg, 270 μmol, 3.00 eq) and NMI (44.3 mg, 540 μmol, 43.0 μL, 6.00 eq). The mixture was stirred at 25 °C for 2 hrs. The reaction mixture was diluted with H2O (20.0 mL), and extracted with DCM (20.0 mL*3). The organic layer was washed with brine (20.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give residue. The residue was purified by Prep-TLC. Compound D1-10-1 (45.0 mg, 69.3 μmol, 76.9% yield) was obtained as a yellow oil. LC-MS: (M+H)+: 650.2.

[0272] Step 8: A solution of compound D1-10-1 (40.0 mg, 61.5 μmol, 1.00 eq) in HCl (4.00 M, 1.00 mL, 64.9 eq) stirred at 60 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC. Compound 16 (15.04 mg, 23.6 μmol, 38.3% yield, 99.8% purity) was obtained as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 9.08 (d, J = 7.2 Hz, 1H), 8.04 - 7.90 (m, 1H), 7.77 - 7.59 (m, 2H), 7.46 - 7.34 (m, 2H), 7.27 (d, J = 7.6 Hz, 1H), 7.16 (t, J = 8.8 Hz, 1H), 7.02 (d, J = 7.6 Hz, 1H), 6.98 - 6.90 (m, 1H), 6.64 - 6.61 (m, 1H), 5.01 - 4.79 (m, 1H), 4.59 - 4.50 (m, 1H), 3.77 (d, J = 13.6 Hz, 2H), 3.61 - 3.48 (m, 5H), 3.28 - 3.17 (m, 4H), 3.12 - 2.97 (m, 2H), 2.91 - 2.85 (m, 1H), 2.38 – 2.

[0273] Synthetic preparation of Series D1 compounds, Compound 22(3.00 mL) was added NH2NH2•H2O (210 mg, 3.57 mmol, 203 μL, 85.0% purity, 15.7 eq). The mixture was stirred at 25 °C for 2 hrs. The reaction mixture was diluted with H2O (20.0 mL), and extracted with DCM (20.0 mL*3). The organic layer was washed with brine (20.0 mL), dried over Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC. Compound D1-8-1 (40.0 mg, 90.0 μmol, 39.7% yield) was obtained as a yellow oil. LC- MS: (M+H)+: 445.2.

[0275] Step 2: To a solution of compound D1-8-1 (40.0 mg, 90.0 μmol, 1.00 eq), compound D1-9-1 (20.7 mg, 90.0 μmol, 1.00 eq, Li) in MeCN (1.00 mL) was added TCFH (75.6 mg, 270 μmol, 3.00 eq) and NMI (44.3 mg, 540 μmol, 43.0 μL, 6.00 eq). The mixture was stirred at 25 °C for 2 hrs. The reaction mixture was diluted with H2O (20.0 mL), and extracted with DCM (20.0 mL*3). The organic layer was washed with brine (20.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give residue. The residue was purified by Prep-TLC. Compound D1-10-2 (30.0 mg, 46.2 μmol, 51.3% yield) was obtained as a yellow oil. LC-MS: (M+H)+: 650.2.

[0276] Step 3: A solution of compound D1-10-2 (30.0 mg, 46.2 μmol, 1.00 eq) in HCl (4.00 M, 1.00 mL, 86.6 eq) was stirred at 60 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC. Compound 22 (10.44 mg, 16.3 μmol, 35.4% yield, 99.6% purity) was obtained as a white solid.1H NMR: (400 MHz, DMSO-d6) δ 9.02 (d, J = 8.0 Hz, 1H), 8.00 - 7.90 (m, 1H), 7.76 - 7.61 (m, 2H), 7.47 - 7.35 (m, 2H), 7.29 (d, J = 7.6 Hz, 1H), 7.16 (t, J = 8.8 Hz, 1H), 7.08 - 6.92 (m, 2H), 6.64 - 6.62 (m, 1H), 4.93 -6H), 2.36 - 2.23 (m, 1H), 1.72 (s, 4H). LC-MS: (M+H)+: 636.2.

[0277] Example 4: Series E

[0278] General Scheme

[0280] Synthetic preparation of Series E1 compounds, Compound 24, Compound 18, Compound 58, and Compound 59

[0281] Step 1: To a solution of compound E1-1 (20.0 g, 125 mmol, 1.00 eq) in DCM (300 mL) was added m-CPBA (34.1 g, 168 mmol, 85.0% purity, 1.34 eq) at 0 °C, the mixture was stirred at 25°C for 12 hrs. The reaction mixture was quenched by sat. Na2SO3(100 mL) at 0°C, and then extracted with DCM (100 mL*3). The combined organic layers were washed with sat. aq. NaHCO3 (100 mL*2) and brine (50.0 mL*2), dried over Na2SO4, filtered, and concentrated under reduced pressure176.0.

[0282] Step 2: To a solution of compound E1-2 (55.0 g, 313 mmol, 1.00 eq) in DCM (30.0 mL) was added HCl / MeOH (4.00 M, 85.6 mL) at 0 °C. The mixture was stirred at 20 °C for 12 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was triturated with DCM (40.0 mL) at 20 °C for 30 mins. The reaction mixture was filtered, and the filter cake was concentrated under reduced pressure to give a residue. Compound E1-2A (50.0 g, 285 mmol, 90.9% yield) was obtained yellow solid.1H NMR: (400 MHz, DMSO-d6) δ 12.1 (s, 1H), 9.65 (s, 1H), 8.54 - 8.51 (m, 1H), 8.30 (d, J = 7.2 Hz, 1H), 7.84 - 7.76 (m, 2H), 7.42 - 7.39 (m, 1H), 4.03 (s, 3H).

[0283] Step 3: To a solution of compound E1-2A (49.3 g, 281 mmol, 1.00 eq) in anisole (500 mL) was added POBr3 (323 g, 1.13 mol, 114 mL, 4.00 eq). The mixture was stirred at 100 °C for 2 hrs. The reaction mixture was quenched by sat. NaHCO3(1000 mL) at 0 °C, and extracted with ethyl acetate (1000 mL*3). The combined organic layers were washed with brine (500 mL*2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography. Compound E1-3 (20.0 g, 84.01 mmol, 29.8% yield) was obtained as white solid.1H NMR: (400 MHz, CDCl3) δ 8.24 (d, J = 5.6 Hz, 1H), 8.03 - 7.96 (m, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.57 (t, J = 11.2 Hz, 1H), 7.04 (d, J = 7.6 Hz, 1H), 4.01 (s, 3H).

[0284] Step 4: To a solution of compound E1-3 (5.00 g, 21.0 mmol, 1.00 eq) in THF (75.0 mL) was added n-BuLi (2.50 M, 11.7 mL, 1.40 eq) at -78 °C. The mixture was stirred at -78 °C for 0.5 hr. A solution of compound E1-4 (4.65 g, 22.0 mmol, 1.05 eq) in THF (75.0 mL) was added at -78 °C. The mixture was warmed to 0 °C, and stirred at 0 °C for 3 hrs. The reaction mixture was quenched by sat. NH4Cl (100 mL) at 0 °C, and then extracted with ethyl acetate (200 mL*3). The combined organic layers were washed with brine (200 mL*2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography. Compound E1-5 (6.00 g, crude) was obtained as yellow oil. LC-MS: (M+H)+: 369.8.1H NMR: (400 MHz, CDCl3) δ 8.53 (d, J = 5.6 Hz, 1H), 8.14 (d, J = 5.6 Hz, 1H), 7.53 (s, 1H), 7.47 (d, J = 7.8 Hz, 1H), 7.23 (d, J = 8.2 Hz, 1H), 6.98 - 6.94 (m, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.70 (d, J = 7.2 Hz, 1H), 4.01 (s, 3H), 3.55 - 3.47 (m, 1H), 3.31 - 3.24 (m, 1H), 2.94 - 2.84 (m, 1H), 2.50 - 2.44 (m, 1H).

[0285] Step 5: Compound E1-5 (8.00 g, 21.61 mmol, 1.00 eq) was dissolved in MeSO3H (50.0 mL). The mixture was stirred at 80 °C for 1 hr. The reaction mixture was diluted with sat. NaHCO3 (500brine (50.0 mL*2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. Compound E1-6 (7.50 g, crude) was obtained as red solid. LC-MS: (M+H)+: 354.0.

[0286] Step 6: Zn (17.8 g, 273 mmol, 3.00 eq) was added to a three necked flask, and heated at 110 °C under vacuum for 10 minutes, then cooled to 20 °C. To the flask was added a solution of TMSCl (1.98 g, 18.2 mmol, 2.31 mL, 0.200 eq) in DMF (100 mL). The mixture was stirred at 20 °C for 20 minutes. The supernatant liquor was removed by syringe. Then a mixture of compound E1-7 (30.0 g, 91.1 mmol, 1.00 eq) in DMF (100 mL) was added to the precipitate, and the inner temperature was rapidly rose from 20 °C to 45 °C. And the resulting mixture was stirred at 20 °C for 1 hr under N2. Compound [(2R)-2-(tert-butoxycarbonylamino)-3-methoxy-3-oxo-propyl]-iodo-zinc (35.9 g, crude) in DMF (100 mL) was used next step directly.

[0287] To a solution of compound E1-6 (8.30 g, 23.5 mmol, 1.00 eq) in DMF (10.0 mL) was added Pd2(dba)3(2.16 g, 2.36 mmol, 0.100 eq) and SPhos (1.93 g, 4.71 mmol, 0.200 eq). Then a solution of [(2R)-2-(tert-butoxycarbonylamino)-3-methoxy-3-oxo-propyl]-iodo-zinc (27.8 g, 70.6 mmol, 3.00 eq) in DMF (80.0 mL) was added under N2. The mixture was stirred at 90 °C for 12 hrs. The reaction mixture was diluted with H2O (500 mL), and extracted with ethyl acetate (500 mL*3). The combined organic layers were washed with brine (100 mL*2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography. The residue was further purified by Prep-HPLC. Compound E1-8 (420 mg, 858 μmol, 3.64% yield, 97.0% purity) was obtained as yellow oil. LC-MS: (M+H)+: 475.1.1H NMR: (400 MHz, CDCl3) δ 8.66 (d, J = 6.0 Hz, 1H), 8.13 (d, J = 6.0 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.23 - 7.15 (m, 2H), 7.06 - 7.02 (m, 2H), 6.90 (s, 1H), 5.09 (d, J = 7.6 Hz, 1H), 4.83 - 4.64 (m, 1H), 4.07 (s, 3H), 3.74 (s, 3H), 3.67 (s, 2H), 3.35 - 3.19 (m, 2H), 1.43 - 1.38 (m, 9H).

[0288] Step 7: To a solution of compound E1-8 (370 mg, 756 μmol, 1.00 eq) in MeOH (8.00 mL) was added Pd / C (150 mg, 140 μmol, 10.0% purity, 1.86 eq) under N2. The suspension was degassed under vacuum and purged with H2several times. The mixture was stirred under H2(1.52 mg, 756 μmol, 1.00 eq) (15 psi) at 20 °C for 2 hrs. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. Compound E1-9 (350 mg, 734 μmol, 97.1% yield) was obtained as yellow oil. LC-MS: (M+H)+: 477.2.was added HCl / dioxane (4.00 M, 4.00 mL, 21.7 eq) at 0 °C. The mixture was stirred at 20 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. Compound E1- 10 (350 mg, crude, HCl) was obtained as yellow solid. LC-MS: (M+H)+: 377.1.

[0290] Step 9: To a solution of compound E1-10 (340 mg, 823 μmol, 1.00 eq, HCl) and compound E1-11-1 (275 mg, 988 μmol, 1.20 eq) in ACN (5.00 mL) was added TCFH (693 mg, 2.47 mmol, 3.00 eq) and NMI (338 mg, 4.12 mmol, 328 μL, 5.00 eq). The mixture was stirred at 20 °C for 2 hrs. The reaction mixture was diluted with sat. NaHCO3 (20.0 mL), and extracted with ethyl acetate (20.0 mL*3). The combined organic layers were washed with brine (10.0 mL*2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography. Compound E1-12-1 (358 mg, 494 μmol, 60.0% yield, 88.0% purity) was obtained as yellow oil. LC-MS: (M+H)+: 638.3.

[0291] Step 10: To a solution of compound E1-12-1 (308 mg, 425 μmol, 1.00 eq) in DCM (8.00 mL) was added BBr3(532 mg, 2.13 mmol, 204 μL, 5.00 eq) at -40 °C. The mixture was stirred at 0 °C for 2 hrs. The reaction mixture was filtered, and the cake was concentrated under reduced pressure to give a residue. Compound E1-13-1 (260 mg, crude) was obtained as yellow oil. LC-MS: (M+H)+: 610.3.

[0292] Step 11: To a solution of compound E1-13-1 (260 mg, 426. μmol, 1.00 eq) in MeOH (5.00 mL) was added H2SO4(4.18 mg, 42.6 μmol, 2.27 μL, 0.100 eq). The mixture was stirred at 80 °C for 2 hrs. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC. Compound E1-14-1 (130 mg, 208 μmol, 48.8% yield) was obtained as yellow solid. LC-MS: (M+H)+: 624.4.1H NMR: (400 MHz, CDCl3) δ 8.47 - 8.44 (m, 1H), 7.90 (d, J = 5.6 Hz, 1H), 7.82 - 7.80 (m, 1H), 7.43 (t, J = 8.4 Hz, 1H), 7.04 - 6.99 (m, 2H), 6.94 - 6.91 (m, 1H), 6.82 - 6.79 (m, 1H), 6.35 - 6.23 (m, 1H), 5.99 (brs, 1H), 5.37 (t, J = 8.4 Hz, 1H), 5.03 - 4.94 (m, 1H), 3.79 - 3.77 (m, 3H), 3.35 - 2.97 (m, 4H), 2.88 - 2.64 (m, 6H), 2.40 - 2.30 (m, 1H), 2.24 - 2.11 (m, 2H), 2.03 - 1.89 (m, 3H).

[0293] Step 12: To a solution of compound E1-14-1 (130 mg, 208 μmol, 1.00 eq) in DCM (10.0 mL) was added pyridine (65.9 mg, 833 μmol, 67.3 μL, 4.00 eq) and Tf2O (117 mg, 416 μmol, 68.7 μL, 2.00 eq) at 0 °C. The mixture was stirred at 20 °C for 12 hrs. The reaction mixture was diluted with H2O (10.0 mL), and extracted with ethyl acetate (10.0 mL*3). The combined organic layers were washed with brine (10.0 mL*2), dried over Na2SO4, filtered, and concentrated under reducedμmol, 88.8% yield) was obtained as yellow oil. LC-MS: (M+H)+:756.4.1H NMR: (400 MHz, CDCl3) δ 8.60 (d, J = 5.6 Hz, 1H), 8.30 (t, J = 6.0 Hz, 1H), 7.77 (d, J = 4.8 Hz, 1H), 7.72 - 7.62 (m, 2H), 7.07 - 7.02 (m, 1H), 6.98 - 6.95 (m, 1H), 6.78 (t, J = 6.0 Hz, 1H), 6.35 - 6.25 (m, 1 H), 5.42 - 5.36 (m, 1H), 5.02 - 4.97 (m, 1H), 3.80 - 3.78 (m, 3H), 3.37 - 3.13 (m, 3H), 3.07 - 3.01 (m, 1H), 2.89 - 2.78 (m, 4H), 2.71 - 2.64 (m, 2H), 2.41 - 2.22 (m, 2H), 2.15 - 2.09 (m, 2H), 2.01 - 1.92 (m, 2H).

[0294] Step 13: To a solution of compound E1-15-1 (140 mg, 185 μmol, 1.00 eq) and compound E1-15 (305 mg, 1.85 mmol, 10.0 eq) in THF (4.00 mL) and H2O (1.00 mL) was added Cs2CO3 (181 mg, 555 μmol, 3.00 eq), Pd(OAc)2 (24.9 mg, 111 μmol, 0.600 eq) and XPhos (44.1 mg, 92.6 μmol, 0.500 eq) under N2. The mixture was stirred at 80 °C for 12 hrs. The reaction mixture was diluted with H2O (10.0 mL), and extracted with ethyl acetate (10.0 mL*3). The combined organic layers were washed with brine (10.0 mL*2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC. Compound E1-17 (100 mg, 150 μmol, 81.2% yield) was obtained as yellow oil. LC-MS: (M+H)+: 665.5.1H NMR: (400 MHz, DMSOd-6) δ 8.57 - 8.53 (m, 1H), 8.38 - 8.35 (m, 2H), 7.98 - 7.95 (m, 1H), 7.70 - 7.60 (m, 2H), 7.00 - 6.91 (m, 2H), 6.65 - 6.57 (m, 1H), 5.45 (q, J = 7.6 Hz, 1H), 4.79 - 4.75 (m, 1H), 3.83 - 3.72 (m, 2H), 3.68 - 3.66 (m, 3H), 3.27 - 3.00 (m, 4H), 2.85 - 2.76 (m, 2H), 2.71 - 2.58 (m, 4H), 2.34 - 2.27 (m, 3H), 2.19 (s, 6H), 1.83 - 1.76 (m, 1H), 1.66 - 1.59 (m, 2H).

[0295] Step 14: Compound E1-17 (100 mg, 150 μmol, 1.00 eq) was separated by Prep-SFC. Two fractions of E1-17_peak 1 / E1-17_peak 2 and E1-17_peak 3 / E1-17_peak 4 were obtained. The mixture of E1-17_peak 1 and E1-17_peak 2 was further purified by Prep-SFC. Compound E1- 17_peak 1 (27.0 mg, 39.8 μmol, 26.4% yield, 98.0% purity) was obtained as yellow solid. LC-MS: (M+H)+: 665.5. Compound E1-17_peak 2 (35.0 mg, 50.6 μmol, 33.6% yield, 96.2% purity) was obtained as yellow solid. LC-MS: (M+H)+: 665.4. The mixture of E1-17_peak 3 and E1-17_peak 4 was further purified by Prep-SFC. Compound E1-17_peak 3 (19.0 mg, 24.9 μmol, 16.5% yield, 87.1% purity) was obtained as yellow solid. LC-MS: (M+H)+: 665.4. Compound E1-17_peak 4 (17.0 mg, 25.1 μmol, 16.7% yield, 98.3% purity) was obtained as yellow solid. LC-MS: (M+H)+: 665.4.

[0296] Step 15: To a solution of compound E1-17__peak 1 (27.0 mg, 39.8 μmol, 1.00 eq) in H2O (1.00 mL) was added HCl / dioxane (4.00 M, 1.00 mL, 100 eq). The mixture was stirred at 60 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residueobtained as white solid. LC-MS: (M+H)+: 651.3.1H NMR: (400 MHz, DMSO_d6) δ 8.38 - 8.34 (m, 3H), 7.96 (d, J = 5.6 Hz, 1H), 7.68 (d, J = 6.8 Hz, 1H), 7.61 (t, J = 8.4 Hz, 1H), 6.99 (d, J = 7.2 Hz, 1H), 6.91 (t, J = 7.6 Hz, 1H), 6.61 (d, J = 7.2 Hz, 1H), 5.43 (t, J = 8.0 Hz, 1H), 4.70 (brs, 1H), 3.83 - 3.72 (m, 2H), 3.23 - 3.19 (m, 1H), 3.11 - 3.02 (m, 2H), 2.77 - 2.53 (m, 7H), 2.33 - 2.20 (m, 8H), 2.03 (t, J = 7.6 Hz, 1H), 1.74 (t, J = 7.6 Hz, 1H), 1.63 - 1.54 (m, 2H).

[0297] Step 16: To a solution of compound E1-17_peak 2 (30.0 mg, 43.4 μmol, 1.00 eq) in H2O (1.00 mL) was added HCl / dioxane (4.00 M, 1.00 mL, 92.1 eq). The mixture was stirred at 60 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC. Compound 18 (9.37 mg, 14.4 μmol, 33.2% yield, 100% purity) was obtained as white solid. LC-MS: (M+H)+: 651.4.1H NMR:(400 MHz, DMSO_d6) δ 8.37 (d, J = 6.0 Hz, 3H), 7.96 (d, J = 5.6 Hz, 1H), 7.70 - 7.60 (m, 2H), 7.00 - 6.89 (m, 2H), 6.56 (d, J = 7.6 Hz, 1H), 5.45 (t, J = 8.4 Hz, 1H), 4.71 (brs, 1H), 3.84 - 3.73 (m, 2H), 3.26 - 3.21 (m, 1H), 3.11 - 2.97 (m, 2H), 2.90 - 2.56 (m, 7H), 2.32 - 2.20 (m, 8H), 2.12 (t, J = 12.0 Hz, 1H), 1.72 (t, J = 10.4 Hz, 1H), 1.64 - 1.55 (m, 2H).

[0298] Step 17: To a solution of compound E1-17_peak 3 (19.0 mg, 24.9 μmol, 1.00 eq) in H2O (0.500 mL) was added HCl / dioxane (4.00 M, 1.27 mL, 203 eq). The mixture was stirred at 60 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC. Compound 58 (11.16 mg, 16.9 μmol, 67.9% yield, 98.7% purity) was obtained as yellow solid. LC-MS: (M+H)+: 651.4.1H NMR: (400 MHz, DMSO_d6) δ 8.39 - 8.34 (m, 3H), 7.96 (d, J = 6.0 Hz, 1H), 7.68 (d, J = 6.8 Hz, 1H), 7.61 (t, J = 8.4 Hz, 1H), 6.62 (d, J = 7.6 Hz, 1H), 5.43 (t, J = 8.0 Hz, 1H), 4.75 - 4.69 (m, 1H), 3.83 - 3.73 (m, 2H), 3.25 - 3.19 (m, 1H), 3.11 - 3.00 (m, 2H), 2.77 - 2.55 (m, 7H), 2.28 (d, J = 13.4 Hz, 2H), 2.20 (s, 6H), 2.03 (t, J = 12.0 Hz, 1H), 1.73 (t, J = 11.6 Hz, 1H), 1.64 - 1.53 (m, 2H).

[0299] Step 18: To a solution of compound E1-17_peak 4 (17.0 mg, 25.1 μmol, 1.00 eq) in H2O (0.500 mL) was added HCl / dioxane (4.00 M, 1.00 mL, 159 eq). The mixture was stirred at 60 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC. Compound 59 (6.73 mg, 10.1 μmol, 40.5% yield, 98.5% purity) was obtained as white solid. LC-MS: (M+H)+: 651.4.1H NMR: (400 MHz, DMSO_d6) δ 8.38 - 8.34 (m, 3H), 7.97 (d, J = 5.6 Hz, 1H), 7.69 (d, J = 6.8 Hz, 1H), 7.61 (t, J = 8.4 Hz, 1H), 6.99 (d, J = 7.6 Hz, 1H), 6.91 (t, J = 3.6 Hz, 1H), 6.56 (d, J = 7.6 Hz, 1H), 5.45 (t, J = 8.0 Hz, 1H), 4.74 - 4.67 (m, 1H),4H), 2.30 - 2.20 (m, 8H), 2.13 (t, J = 12.0 Hz, 1H), 1.73 (t, J = 11.2 Hz, 1H), 1.64 - 1.54 (m, 2H).

[0300] The compounds set forth in Table 6, were prepared using the synthetic procedures of Example 4-1, or analogous procedures as provided herein.

[0301] Table 6. Structure and Spectroscopic data for Compounds 43, 44 No. Structure

[0302] EXAMPLE 5: Inhibition of α4β7 and α4β1 Integrins

[0303] α4β7 and α4β1 inhibition was evaluated in vitro using at least one of Integrin Adhesion Assay: Protocol 1 to Protocol 3, described in detail below.

[0304] Integrin Adhesion Assay: Protocol 1

[0305] MAdCAM (R&D Systems, 0.1ug) was diluted in 50 µL PBS, added to each well of an opaque ELISA plate (Thermo), and incubated overnight at 4°C. Coated plates were washed once with PBS and then blocked with 200 µL of assay buffer (10mM HEPES, 150mM NaCl, 1mM MnCl2, 0.1mM CaCl2, 1% BSA) for 1 hour at 37°C and 5% CO2. After incubation, buffer was aspirated from the plates and 50 µL of fresh assay buffer is added. Compounds were added by a compound dispenser (Tecan) and DMSO concentration was normalized to 1% across each plate.50 µL of RPMI-8866 cells (2x106per mL) were added to each well and the plates were incubated for 1 hour at 37°C and 5% CO2. After incubation, plates were allowed to cool to RT for 10 minutes before being washed four times in assay buffer by an automated plate washer (BioTek). After washing, 100well. Plates were mixed for 2 minutes at 1000rpm and then allowed to incubate an additional 10 minutes before reading out luminescence on a Tecan Spark plate reader. Raw data was converted to percent inhibition based on DMSO only and control compound wells, and curves were analyzed by 4-parameter fit within Dotmatics software.

[0306] EXAMPLE 6: Integrin Adhesion Assay Using Genetically Modified Cells

[0307] Generating Stable Cell Lines with ITGB1 or ITGB7 Knockout

[0308] To obtain subclones of the RPMI-8866 cell line (Sigma-Aldrich, St. Louis, MO) that were individually deficient in either integrin β1 or integrin β 7, CRISPR / Cas9 technology was employed (PMID: 30108345). Specifically, a Neon™ Transfection System System 10 µL Kit and the Neon™ Transfection device (both from ThermoFisher Scientific) were used.

[0309] The protocol was performed following the manufacturer instructions, described in https: / / www.thermofisher.com / document-connect / document- connect.html?url=https%3A%2F%2Fassets.thermofisher.com%2FTFS- Assets%2FLSG%2Fmanuals%2FMAN0017066_TrueCut_Cas9_Protein_v2_UG.pdf, which is incorporated by reference herein in its entirety.

[0310] RPMI-8866 cells were transferred to a flask the day before transfection, at a confluence of 5x105cells / mL. The cells were washed with PBS and resuspended in buffer R (Neon™ Transfection System, Invitrogen) to 2x105cells / 10uL for each reaction. The TrueCut™ HiFi Cas9 Protein (1250ng per reaction) was mixed with TrueGuide™ sgRNA (7.5 pmoles each / pool of 3 sequences, table 7) (ThermoFisher Scientific). This mix was combined with the RPMI-8866 cells and electroporated on the Neon system at 1700V / 20ms / 1 pulse. Transfected cells were allowed to recover in 500 µL pre- warmed cRMPI media (RPMI-1640 media with 10% FBS, 100 U / ml Penicillin-Streptomycin) at 37oC, 5% CO2 for 24 hours. At that time, an extra 500 µL of pre- warmed cRMPI media was added, and cells were incubated for another 24 hours.

[0311] For flow cytometry analysis, 100 µL of the transfected cells were collected and stained with anti-itga4 (Clone: 9F10, PE, BD Pharmingen™), anti-itgb1(Clone: (TS2 / 16), Super Bright 436, eBioscience), anti-itgb7 (Clone: FIB504, Brilliant Violet 650, BD Pharmingen™) and viability dye (LIVE / DEAD™ Fixable Green Dead Cell Stain, Invitrogen™). An Attune NxT Flow Cytometer was used to analyze the CRISPR-transfected cells. The flow cytometry results were analyzed usingto select appropriate gates for data analysis.

[0312] To generate an individual clones of cells deficient in either ITGB7 or ITGB1 by limiting dilution assay, the transfected cells were resuspended at 5 cells / mL and seeded in 384 well plates. Outgrowth of clones was monitored using a microscope, and 24 clones were transferred for expansion. Expression of either integrin was verified by flow cytometry in each of the clones. One clone of each integrin b7 or the integrin b1 knockout was chosen, expanded and aliquots were frozen in vapor phase liquid nitrogen.

[0313] Table 7: Single guided RNAs (ThermoFisher Scientific) pools itgb7 pool TrueGuide™ Synthetic sgRNA CRISPR646260_SGM ITGB7

[0314] Integrin Adhesion Assay: Protocol 2

[0315] MAdCAM (R&D Systems, 0.1ug) was diluted in 50 µL PBS, added to each well of an opaque ELISA plate (Thermo), and incubated overnight at 4^C. Coated plates were washed once with PBS and then blocked with 200 µL of assay buffer (10mM HEPES, 150mM NaCl, 1mM MnCl2, 0.1mM CaCl2, 1% BSA) for 1 hour at 37^C and 5% CO2. After incubation, buffer was aspirated from the plates and 50 µL of fresh assay buffer was added. Compounds were added using a compounds dispenser (Tecan), and DMSO concentration was normalized to 1% across each plate.50mL) were added to each well and the plates were incubated for 1 hour at 37^C at a CO2concentration of 5%. After incubation, plates were allowed to cool to RT for 10 minutes before being washed four times in assay buffer by an automated plate washer (BioTek). After washing, 100 µL of a 1:1 mixture of assay buffer and CellTiter GLO 2.0 reagent (Promega) were added to each well. Plates were mixed for 2 minutes at 1000rpm and then allowed to incubate an additional 10 minutes before reading out luminescence on a Tecan Spark plate reader. Raw data was converted to percent inhibition based on DMSO only and control compound conditions, and curves were fitted by 4-parameter curves within Dotmatics software.

[0316] Integrin Adhesion Assay: Protocol 3

[0317] VCAM (R&D Systems, 0.1ug) was diluted in 50 µL PBS, added to each well of an opaque ELISA plate (Thermo), and incubated overnight at 4^C. Coated plates were washed once with PBS and then blocked with 200 µL of assay buffer (10mM HEPES, 150mM NaCl, 1mM MnCl2, 0.1mM CaCl2, 1% BSA) for 1 hour at 37^C and 5% CO2. After incubation, buffer was aspirated from the plates and 50 µL of fresh assay buffer was added. Compounds were added by compounds dispenser (Tecan) and DMSO concentration was normalized to 1% across each plate.50 µL of RPMI-8866 cells with a stable LOF mutation of the ITGB7 gene (2x106per mL) were added to each well and the plates were incubated for 1 hour at 37^C and 5% CO2. After incubation, plates were allowed to cool to RT for 10 minutes before being washed four times in assay buffer by an automated plate washer (BioTek). After washing, 100 µL of a 1:1 mixture of assay buffer and CellTiter GLO 2.0 reagent (Promega) were added to each well. Plates were mixed for 2 minutes at 1000rpm and then allowed to incubate an additional 10 minutes before reading out luminescence on a Tecan Spark plate reader. Raw data was converted to percent inhibition based on DMSO only and control compound conditions, and curves were fitted by 4-parameter curves within Dotmatics software.

[0318] Table 8 below, provides pIC50values for the inhibition data for compounds of the present disclosure as determined by at least one of the assays described above. As disclosed herein, pIC50 equals -log10[IC50], wherein the IC50is expressed as a molar concentration. Accordingly, a high pIC50value, as provided in Table 8, denotes a compound with a high inhibitory activity against α4β7, α4β1, or both.

[0319] Table 8. α4β7 and α4β1 inhibition data (pIC50) for select compounds.No. pIC50apIC50bNo. pIC50apIC50ba

[0320] l 1 or Protocol 2.

[0321] bData obtained using Protocol 3.

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula (I): I), or a pharmaceutically accept 1R is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; R2aand R2bare each independently selected from: hydrogen, halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -NO2, -CN; and C1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, - OR11, -SR11, -N(R11)2, -C(O)R11, -NO2, and -CN; R3is selected from hydrogen and C1-6 alkyl; L is selected from a bond, -C(O)-, and -C(O)C(R12)2-; Ring A is selected from C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from (i), (ii), and (iii): (i) halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -OC(O)N(R13)2, -N(R13)C(O)OR13, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, =S, =NR13, and -CN; (ii) C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, =S, =NR13, and -CN; C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, C1-6haloalkyl, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13,(iii) C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -NO2, =O, =S, =NR13, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, =S, =NR13, and - CN; Ring B is selected from C3-12carbocycle, 3- to 6-membered heterocycle, and 7- to 12-membered heterocycle, the 3- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from: halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)OR14, -OC(O)R14, -OC(O)N(R14)2, -N(R14)C(O)OR14, -C(O)N(R14)2, -N(R14)C(O)R14, -NO2, =S, =NR14, and - CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)OR14, -OC(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, -NO2, =O, =S, =NR14, and -CN; and C3-12 carbocycle and 3- to 12-membered heterocycle any of which is optionally substituted with one or more substituents independently selected from halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)OR14, -OC(O)R14, -C(O)N(R14)2, - N(R14)C(O)R14, -NO2, =O, =S, =NR14, -CN, and C1-6 alky, wherein the C1-6 alkyl is optionally substituted with one or more substituents independently selected from halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)OR14, -OC(O)R14, -C(O)N(R14)2, - N(R14)C(O)R14, -NO2, =O, =S, =NR14, and -CN; wherein, when the 3- to 6-membered heterocycle is pyridinyl, the pyridinyl is further optionally substituted with one oxo group; and the C3-12carbocycle and 7- to 12-membered heterocycle, are each optionally substituted with one or substituents independently selected from:-OC(O)N(R15)2, -N(R15)C(O)OR15, -C(O)N(R15)2, -N(R15)C(O)R15, -NO2, =O, =S, =NR15, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)OR15, -OC(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -NO2, =O, =S, =NR15, and -CN; and C3-12 carbocycle and 3- to 12-membered heterocycle any of which is optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)OR15, -OC(O)R15, -C(O)N(R15)2, - N(R15)C(O)R15, -NO2, =O, =S, =NR15, -CN, and C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)OR15, -OC(O)R15, -C(O)N(R15)2, - N(R15)C(O)R15, -NO2, =O, =S, =NR15, and -CN; and R11, R12, R13, R14, and R15at each occurrence are independently selected from: hydrogen; C1-6alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, -CN, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6 alkyl, -O-C1-6 haloalkyl, C1-6 alkyl, C1-6 haloalkyl, -NH2, -NO2, =O, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6 alkyl, -O-C1-6 haloalkyl, C1-6 alkyl, C1-6 haloalkyl, -NH2, -NO2, =O, and -CN.

2. The compound or salt of claim 1, wherein R1is selected from hydrogen and C1-3alkyl.

3. The compound or salt of claim 2, wherein R1is hydrogen.

4. The compound or salt of any one of claims 1 to 3, wherein R2aand R2bare each independently selected from hydrogen, halogen, C1-3alkyl, and C1-3haloalkyl.

6. The compound or salt of any one of claims 1 to 5, wherein R3is selected from hydrogen and C1-3alkyl.

7. The compound or salt of claim 6, wherein R3is hydrogen.

8. The compound or salt of any one of claims 1 to 7, wherein L is -C(O)-.

9. The compound or salt of any one of claims 1 to 8, wherein Ring A is selected from C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, and -CN; C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, - N(R13)C(O)R13, -NO2, =O, -CN, C3-10carbocycle and 3- to 10-membered heterocycle, wherein the C3-10carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, =O, -CN, C1-6alkyl, and C1-6haloalkyl; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -NO2, =O, -CN, and C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, =O, and -CN.

10. The compound or salt of claim 9, wherein Ring A is selected from C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, - N(R13)C(O)R13, -NO2, =O, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, =O, -CN, C1-6alkyl, and C1-6haloalkyl; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -NO2, =O,-CN, and C1-6alkyl, wherein the C1-6 alkyl is optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, =O, and -CN.

11. The compound or salt of claim 10, wherein Ring A is selected from phenyl and piperidinyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, - N(R13)C(O)R13ocycle, wherein the C3-10carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, =O, -CN, C1-6alkyl, and C1-6haloalkyl; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -NO2, =O, -CN; and C1-6 alkyl, wherein the C1-6alkyl is optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, =O, and -CN.

12. The compound or salt of claim 11, wherein Ring A is selected from phenyl and piperidinyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, and -CN; C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -CN; and C3-6carbocycle and 3- to 6-membered heterocycle,one or more substituents independently selected from: halogen, C1-6 alkyl, and C1-6 haloalkyl; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, and C1-6haloalkyl.

13. The compound or salt of claim 12, wherein Ring A is selected from phenyl and piperidinyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -CN; and C3-6 carbocycle and 3- to 6-membered heterocycle, the C3-6 carbocycle and 3- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl.

14. The compound or salt of claim 13, wherein Ring A is selected from phenyl and piperidinyl, each of which is optionally substituted with one or more substituents independently selected from fluoro, methyl, .

15. The compound or salt of claim 12, wherein Ring A is selected from phenyl and piperidinyl, each of which is optionally substituted with one or more substituents independently selected from C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, and C1-6 haloalkyl.

16. The compound or salt of claim 15, wherein Ring A is selected from phenyl and piperidinyl, each of which is optionally substitute .each of which is optionally substituted with one or more substituents independently selected from: fluoro, methyl, .

18. The comein Ring A is selected from , 19. The compound of any one of claims 1 to 13, wherein R at each occurrence is independently selected from hydrogen, C1-3 alkyl, and C1-3 haloalkyl.

20. The compound of claim 19, wherein R13at each occurrence is independently selected from hydrogen and methyl.

21. The compound or salt of claim 20, wherein R13is methyl.

22. The compound or salt of any one of claims 1 to 21, wherein Ring B is 3-to 6-membered heterocycle optionally substituted with one or more substituents selected from: halogen, -OR14, -N(R14)2, -C(O)R14, -C(O)OR14, -OC(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, -NO2, =O, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR14, -N(R14)2, -C(O)R14, -C(O)OR14, -OC(O)R14, -C(O)N(R14)2, - N(R14)C(O)R14, -NO2, =O, and -CN, C3-12 carbocycle and 3- to 12-membered heterocycle,substituted with one or more substituents independently selected from halogen, -OR14, - N(R14)2, =O, -CN, C1-6alkyl, and C1-6haloalkyl; and wherein, when the 3- to 6-membered heterocycle is pyridinyl, the pyridinyl is further optionally substituted with one oxo group.

23. The compound or salt of claim 22, wherein Ring B is 5-to 6-membered heterocycle optionally substituted with one or more substituents selected from: halogen, -OR14, -N(R14)2, -C(O)R14, -C(O)OR14, -OC(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, -NO2, =O, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR14, -N(R14)2, -C(O)R14, -C(O)OR14, -OC(O)R14, -C(O)N(R14)2, - N(R14)C(O)R14, -NO2, =O, and -CN, C3-6 carbocycle and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR14, -N(R14)2, =O, -CN, C1-6 alkyl, and C1-6 haloalkyl; and wherein, when the 3- to 6-membered heterocycle is pyridinyl, the pyridinyl is further optionally substituted with one oxo group.

24. The compound or salt of claim 23, wherein Ring B is pyridinonyl optionally substituted with one or more substituents selected from: halogen, -OR14, -N(R14)2, -C(O)R14, -C(O)OR14, -OC(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, -NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR14, -N(R14)2, -C(O)R14, -C(O)OR14, -OC(O)R14, -C(O)N(R14)2, - N(R14)C(O)R14, -NO2, =O, and -CN, C3-6 carbocycle and 3- to 6-membered heterocycle, wherein the C3-6 carbocycle and 3- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR14, -N(R14)2, =O, -CN, C1-6alkyl, and C1-6haloalkyl.

25. The compound or salt of claim 24, wherein Ring B is pyridinonyl optionally substituted with one or more substituents independently selected from:C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one or more substituents independently selected from halogen, -OR14, -N(R14)2, -CN, C3-6carbocycle and 3- to 6- membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl.

26. The compound or salt of claim 25, wherein Ring B is pyridinonyl optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, and C1-6 haloalkyl.

27. The compound or salt of claim 26, wherein Ring B is pyridinonyl optionally substituted with one or more substituents independently selected from methyl and -CF3.

28. The compound or salt of claim of any one of claims 1 to 27, wherein Ring B is .

29. The compound or salt of any one of claims 1 to 21, wherein Ring B is selected from C3-12carbocycle and 7- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents selected from: halogen, -OR15, -N(R15)2, -C(O)R15, -C(O)OR15, -OC(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -NO2, =O, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -C(O)R15, -C(O)OR15, -OC(O)R15, -C(O)N(R15)2, - N(R15)C(O)R15, -NO2, =O, and -CN, C3-12carbocycle, and 3- to 12-membered heterocycle, wherein the C3-12 carbocycle and 3- to 12-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR15, - N(R15)2, =O, -CN, C1-6alkyl, and C1-6haloalkyl.10-membered heterocycle, each of which is optionally substituted with one or more substituents selected from: halogen, -OR15, -N(R15)2, -C(O)R15, -C(O)OR15, -OC(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -NO2, =O, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -C(O)R15, -C(O)OR15, -OC(O)R15, -C(O)N(R15)2, - N(R15)C(O)R15, -NO2, =O, and -CN, C3-6 carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6 carbocycle and 3- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, =O, - CN, C1-6 alkyl, and C1-6 haloalkyl.

31. The compound or salt of claim 30, wherein Ring B is selected from C5-6 carbocycle and 9- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents selected from: halogen, -OR15, -N(R15)2, -C(O)R15, -C(O)OR15, -OC(O)R15, -C(O)N(R15)2, - N(R15)C(O)R15, -NO2, =O, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -C(O)R15, -C(O)OR15, -OC(O)R15, -C(O)N(R15)2, - N(R15)C(O)R15, -NO2, =O, and -CN, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, =O, -CN, C1-6 alkyl, and C1-6 haloalkyl.

32. The compound or salt of claim 31, wherein Ring B is selected from phenyl, quinolinonyl, and isoquinolinyl, each of which is optionally substituted with one or more substituents selected from: halogen, -OR15, -N(R15)2, -C(O)R15, -C(O)OR15, -OC(O)R15, -C(O)N(R15)2, -N(R15)C(O)R15, -NO2, =O, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -C(O)R15, -C(O)OR15, -OC(O)R15, -C(O)N(R15)2, - N(R15)C(O)R15, -NO2, =O, and -CN, C3-6carbocycle, and 3- to 6-membered heterocycle,with one or more substituents independently selected from halogen, -OR15, -N(R15)2, =O, -CN, C1-6alkyl, and C1-6haloalkyl.

33. The compound or salt of claim 32, wherein Ring B is selected from phenyl, quinolinonyl, and isoquinolinyl, each of which is optionally substituted with one or more substituents independently selected from: -OR15, -N(R15)2,=O, -CN, and C1-6alkyl, wherein the C1-6 alkyl is optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -CN, C3-6 carbocycle and 3- to 6- membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, and C1-6 haloalkyl.

34. The compound or salt of claim 33, wherein Ring B is selected from phenyl, quinolinonyl, and isoquinolinyl, each of which is optionally substituted with one or more substituents independently ,35. The compound or salt of any one of claims 1 to 21 or 29 to 34, wherein Ring B is selected from: ,,. e compoun or sa t o any one o c a ms to , w ere n at eac occurrence is independently selected from hydrogen, C1-3alkyl, and C1-3haloalkyl.

37. The compound or salt of claim 36, wherein R14at each occurrence is independently selected from hydrogen and methyl.

38. The compound or salt of any one of claims 1 to 21 or 29 to 33, wherein R15at each occurrence is independently selected from hydrogen, C1-3 alkyl, and C1-3 haloalkyl.

39. The compound or salt of claim 38, wherein R15at each occurrence is independently selected from hydrogen and methyl.

40. The compound or salt of claim 39, wherein R15is methyl.,, , ,,,, ,, ,nd42. A pharmaceutical composition comprising pharmaceutically acceptable excipient and a compound or salt of any one of claims 1 to 41.

43. A method of modulating alpha 4 beta 7 integrin in a subject in need thereof, comprising administering to the subject a compound or salt of any one of claims 1 to 41 or a pharmaceutical composition of claim 42.

44. A method of treating an inflammatory disease or condition comprising administering to a subject in need thereof a compound or salt of any one of claims 1 to 41or a pharmaceutical composition of claim 42.

45. The method of claim 44, wherein the inflammatory disease or condition is selected from: inflammatory bowel disease, ulcerative colitis, Crohn’s disease, graft-versus-host disease, type 1cholangitis.

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