1-heteroarylazetidine-3-heteroarylmethylcarboxamide 5-HT2b antagonists

Abstract

1-Heteroaroylazetidine-3-heteroarylmethylcarboxamides are 5-HT2B receptor antagonists and the compounds and their pharmaceutical compositions are useful in the treatment of disorders such as pulmonary arterial hypertension, aortic valve disease, and myocardial infarction.

Description

1-HETEROARYLAZETIDINE-3-HETEROARYLMETHYLCARBOXAMIDE 5-HT2B ANTAGONISTS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 706,488 (filed October 11, 2024), which is hereby incorporated by reference in its entirety. STATEMENT OF GOVERNMENT INTEREST

[0002] This invention was made with government support under grant HL172247 awarded by National Institutes of Health. The government has certain rights in the Invention. TECHNICAL FIELD

[0003] The present disclosure relates to compounds, compositions, and methods for treating disorders associated with the 5-hydroxytryptamine 2B receptor, such as pulmonary arterial hypertension. BACKGROUND

[0004] Potential new targets for vasculopathies, such as pulmonary arterial hypertension (PAH) and systemic sclerosis (SSc), are lacking. Yet, despite the existing need for disease- modifying therapeutics, the rational selection of targets is significantly hampered by the still poor understanding of the cellular and molecular mechanisms that mediate SSc and PAH pathogenesis. Small vessel remodeling, an active pathologic process that results in thickened, muscularized arteriole walls, vascular leakage, and obliteration of the vessel lumen, is ultimately responsible for the clinical symptoms associated with PAH and SSc.

[0005] Pulmonary arterial hypertension (PAH) is a progressive lethal disease characterized by widespread obstruction in the smallest arteries of the lungs. Pulmonary vascular obstruction leads to increased pulmonary vascular resistance, which subsequently causes right heart failure. Prevalence of PAH is 15 cases per million which represents more than 4500 PAH patients in the United States. Its notorious mortality continues in the current era, as a third of all patients die within 3 years. Understanding the cellular and molecular pathogenesis of PAH is a key barrier to progress in developing effective treatments in the future.

[0006] The current treatment strategy for PAH is vasodilators which do not alter thepathogenesis of the disease, but simply treat symptoms; however, vasodilators are effective in less than 10% of PAH patients. Vasodilators target one of three pathways – endothelin, nitric oxide, or prostacyclin – and include 13 FDA approved drugs within these pathways. Development in the last 15 years has been focused on “me-too” drugs that simply refine action within one of these pathways and do not address the underlying pathogenesis of PAH. Moreover, most of these drugs have serious side effects and 11 of the 13 cost over $100k per year.

[0007] Serotonin (5-HT) is the primary epidemiologic risk factor for PAH, but the mechanisms through which it causes PAH are still unknown. From 1965 to 1972, the first appetite suppressant-induced epidemic of PAH occurred in Europe following the release of aminorex. During the 1990s, French researchers reported increased incidence of PAH among a patient population that was administered derivatives of the medication fenfluramine. Dexfenfluramine, which is the active enantiomer of fenfluramine and used to treat obesity in patients, was considered to be the chief culprit behind the increase in cases of PAH. Dexfenfluramine acts as a substrate for the serotonin transporter (5-HTT), causing increased extracellular 5-HT by a mechanism involving exchange of drug molecules for intracellular 5-HT. Dexfenfluramine also causes overexpression of 5-HTT, but with the net effect of increased available 5-HT.

[0008] Signaling through 5-HT2B, responsible for mediating serotonergic diet drug-induced PAH in humans (Deng et al., Am J Hum Genet. 2000; 67:737-744), is also necessary for the myeloid contribution to experimental PAH in hypoxic mice (Lane et al., Nat Genet.2000;26:81- 84).

[0009] Several mouse models have been developed to examine serotonergic PAH. Both mice with a knockout for 5-HTT (5-HTT- / -) (Eddahibi et al., J Clin Invest.2000; 105:1555-1562; MacLean et al., Circulation. 2004; 109:2150-2155), and mice with knockout of the 2B serotonin receptor, 5-HT2B, are protected against Group III pulmonary hypertension (PAH is Group I pulmonary hypertension) (Launay et al., Nat Med.2002;8:1129-1135).

[0010] It was thought for quite a while that the effects of 5-HT2B agonists leading to PAH were likely occurring through resident fibroblasts in the lungs. However, it is now known that bone marrow-derived cells contribute significantly to PAH. Bone marrow (BM)-derived proangiogenic cells (PACs) are a subtype of myeloid cells believed to contribute directly to small vessel remodeling. Phenotypically heterogeneous and poorly characterized, PACs are generallydescribed as expressing some combination of endothelial, hematopoietic, or stem cell surface markers (such as VEGFR2, Tie2, CD31, CXCR4, CD34, CD133, and c-Kit). Their presence in peripheral blood has been well-correlated with PAH in a number of studies, and BM-derived cells with endothelial or progenitor cell markers have been identified in the walls of remodeled vessels from PAH patients. While PACs are not believed to proliferate and occlude pulmonary vessels themselves, they are hypothesized to promote pathologic vasculogenic-like processes in neighboring endovascular cells. However, their exact function remains obscure, and to date no study has definitively established their role in promoting (or abrogating) disease.

[0011] Previously, it has been shown that bone marrow (BM)-derived proangiogenic cells (PACs) are a subtype of myeloid cells that contribute directly to small vessel remodeling in the Sugen-Hypoxia mouse model of PAH through 5-HT2B dependent mechanism. (Bloodworth et al., Circ Res.2018;123:e51-e64). By selectively ablating PACs utilizing a transgenic mouse model, the development of elevated pulmonary pressures was successfully prevented and reversed. PAC ablation also reduced markers of small vessel remodeling and restored vessel wall compliance to normal levels. The effectiveness of 5-HT2Bantagonism in preventing experimental PAH was then demonstrated in the same disease model and, through lineage tracing of hematopoietic cells, show reduced recruitment and altered gene expression profiles of PACs in animals treated with a pharmacologic inhibitor of 5-HT2B.

[0012] In addition to PAH, 5-HT2B ablation has been found to prevent hallmarks of SSc in preclinical mouse models (Dees et al., The Journal of experimental medicine.2011;208:961- 972). Specifically, in the bleomycin insult model, 5-HT2Bgenetic deletion or antagonism with SB204741 prevents skin thickening and myofibroblast activation. Similarly, in tight skin-1 (Tsk1) genetic mutant mouse model, genetic deletion of 5-HT2Bor antagonism of the receptor prevented increases in hypodermal thickness, collagen protein, and myofibroblast cell activation. Recently, it was also discovered that antagonism of 5-HT2B after a myocardial infarction improves heart function and prevents the progression to heart failure (Snider et al., Circulation. 2021;143:1317-1330). It was initially speculated that this was related to altered recruitment of BM-derived cells as observed for PAH. However, this was not the case, and it was targeting of 5- HT2Bon the cardiac fibroblasts that led to the improvement. Therefore, this indicates that 5-HT2Bantagonism may serve as a “two-hit” strategy for the treatment of PAH and SSc by preventing recruitment of PACs from the circulation, but also by preventing the resident cardiac and dermalfibroblasts from excessive fibrotic remodeling, which leads to the end-stage fibrosis associated with both pathologies.

[0013] In addition to PAH, it has been shown that targeting 5-HT2B is an effective therapy for aortic valve disease and post myocardial infarction remodeling in mice. (Hutcheson et al., J Mol Cell Cardiol.2012;53:707-714; Joll et al., PLoS One.2020;15:e0238407; Snider et al., Circulation.2021;143:1317-1330).

[0014] The 5-HT2Breceptor belongs to the 5-HT2serotonin receptor family which consists of three members: 5-HT2A, 5-HT2B and 5-HT2C. For reported 5-HT2B ligands, a high degree of selectivity over the other two 5-HT2 family members has been an issue; moreover, for many therapeutic applications, a larger therapeutic window would be achieved if the 5-HT2B antagonist were peripherally restricted (i.e, non-CNS penetrant). Thus, the discovery of highly selective 5- HT2Bantagonists, with low CNS penetration, are highly desireable to address significant unmet medical needs. SUMMARY

[0015] One aspect of the invention provides compounds of formula (I), or a pharmaceutically acceptable salt thereof,wherein: X1is nitrogen or C-H; R1and R2, together with the atoms to which they are attached, form a 5- to 8-membered partially unsaturated carbocycle, a 6-membered arene, or a 6-membered heteroarene containing 1-2 nitrogen atoms, each optionally substituted with R10and further optionally substituted with 1- 5 R11; or, alternatively, R1is hydrogen, R2is hydrogen,R10is C1-4alkyl, C1-2fluoroalkyl, halogen, cyano, oxo, G10, –OR10a, –C(O)R10a, or –C(O)OR10a; R10ais hydrogen, C1-4alkyl, C1-2fluoroalkyl, or C3-4cycloalkyl;R11, at each occurrence, is independently C1-4alkyl, halogen, or oxo; G1, G2, and G10are independently a C3-4cycloalkyl, wherein the cycloalkyl is optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, C1-4alkyl, C1-2fluoroalkyl, and –OC1-4alkyl; n is 0, 1, 2, 3, or 4; R3, at each occurrence, is independently selected from the group consisting of halogen, C1-4alkyl, and C1-2fluoroalkyl; L1is C1-3alkylene; m is 0, 1, 2, 3, or 4; and R4, at each occurrence, is independently C1-4alkyl, C1-2fluoroalkyl, halogen, –OH, –OC1-4alkyl, or C3-4cycloalkyl; with the proviso that the compound is not N-((1H-benzo[d]imidazol-2-yl)methyl)-1-(1H-indole- 3-carbonyl)azetidine-3-carboxamide.

[0016] In another aspect, the invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0017] In another aspect, the invention provides a method of treating a disorder in a subject, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof.

[0018] In another aspect, the invention provides a method for antagonizing the 5-HT2B receptor in a subject, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof.

[0019] In another aspect, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof, for use in the treatment of a disorder selected from the group consisting of pulmonary arterial hypertension, aortic valve disease, myocardial infarction, and systemic sclerosis.

[0020] In another aspect, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof, for use in antagonizing the 5-HT2Breceptor in a subject.

[0021] In another aspect, the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof, in the manufacture of a medicament forthe treatment of a disorder selected from the group consisting of pulmonary arterial hypertension, aortic valve disease, myocardial infarction, and system sclerosis.

[0022] In another aspect, the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof, in the manufacture of a medicament for antagonizing the 5-HT2Breceptor in a subject.

[0023] In another aspect, the invention provides a kit comprising a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof, and instructions for use.

[0024] 5-HT2B receptor antagonists of the invention may have selectivity for the 5-HT2B receptor over the 5-HT2A and 5-HT2C receptor subtypes. DETAILED DESCRIPTION

[0025] Disclosed herein are antagonists of the 5-HT2B receptor of formula (I). Compounds of formula (I) may exhibit selectivity for the 5-HT2B receptor over the 5-HT2A and / or 5-HT2C receptor subtypes. Compounds of formula (I) may be used to treat or prevent diseases and disorders associated with the 5-HT2B receptor, such as pulmonary arterial hypertension, aortic valve disease, and myocardial infarction. Compounds of formula (I) may be substrates for P- glycoprotein (P-gp), have limited penetration into the central nervous system, and / or have reduced potential for untoward central nervous system side-effects. 1. Definitions

[0026] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In case of conflict, the present document, including definitions, will control. Preferred methods and materials are described below, although methods and materials similar or equivalent to those described herein can be used in practice or testing of the present invention. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. The materials, methods, and examples disclosed herein are illustrative only and not intended to be limiting.

[0027] The terms “comprise(s),” “include(s),” “having,” “has,” “can,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that do not preclude the possibility of additional acts or structures. The singular forms “a,” “an” and “the” include plural references unless the context clearly dictates otherwise. Thepresent disclosure also contemplates other embodiments “comprising,” “consisting of” and “consisting essentially of,” the embodiments or elements presented herein, whether explicitly set forth or not.

[0028] The modifier “about” used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (for example, it includes at least the degree of error associated with the measurement of the particular quantity). The modifier “about” should also be considered as disclosing the range defined by the absolute values of the two endpoints. For example, the expression “from about 2 to about 4” also discloses the range “from 2 to 4.” The term “about” may refer to plus or minus 10% of the indicated number. For example, “about 10%” may indicate a range of 9% to 11%, and “about 1” may mean from 0.9-1.1. Other meanings of “about” may be apparent from the context, such as rounding off, so, for example “about 1” may also mean from 0.5 to 1.4.

[0029] Definitions of specific functional groups and chemical terms are described in more detail below. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March March's Advanced Organic Chemistry, 5thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987; the entire contents of each of which are incorporated herein by reference.

[0030] The term “alkoxy,” as used herein, refers to a group –O–alkyl. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy and tert-butoxy.

[0031] The term “alkyl,” as used herein, means a straight or branched, saturated hydrocarbon chain. The term “lower alkyl” or “C1-6alkyl” means a straight or branched chain hydrocarbon containing from 1 to 6 carbon atoms. The term “C1-4alkyl” means a straight or branched chain hydrocarbon containing from 1 to 4 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n- heptyl, n-octyl, n-nonyl, and n-decyl.

[0032] The term “alkenyl,” as used herein, means a straight or branched, hydrocarbon chain containing at least one carbon-carbon double bond.

[0033] The term “alkylene,” as used herein, refers to a divalent group derived from a straight or branched chain saturated hydrocarbon. Representative examples of alkylene include, but are not limited to, -CH2-, -CD2-, -CH2CH2-, -C(CH3)(H)-, -C(CH3)(D)-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and -CH2CH2CH2CH2CH2-.

[0034] The term “amide,” as used herein, means -C(O)NR- or -NRC(O)-, wherein R may be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroalkyl.

[0035] The term “amino,” as used herein, means –NRxRy, wherein Rx and Ry may be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroalkyl. In the case of an aminoalkyl group or any other moiety where amino appends together two other moieties, amino may be –NRx–, wherein Rxmay be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroalkyl.

[0036] The term “aryl,” as used herein, refers to a phenyl or a phenyl appended to the parent molecular moiety and fused to a cycloalkane group (e.g., the aryl may be indan-4-yl), fused to a 6-membered arene group (i.e., the aryl is naphthyl), or fused to a non-aromatic heterocycle (e.g., the aryl may be benzo[d][1,3]dioxol-5-yl). The term “phenyl” is used when referring to a substituent and the term 6-membered arene is used when referring to a fused ring. The 6- membered arene is monocyclic (e.g., benzene or benzo). The aryl may be monocyclic (phenyl) or bicyclic (e.g., a 9- to 12-membered fused bicyclic system).

[0037] The term “cycloalkyl” or “cycloalkane,” as used herein, refers to a saturated ring system containing all carbon atoms as ring members and zero double bonds. The term “cycloalkyl” is used herein to refer to a cycloalkane when present as a substituent. A cycloalkyl may be a monocyclic cycloalkyl (e.g., cyclopropyl), a fused bicyclic cycloalkyl (e.g., decahydronaphthalenyl), or a bridged cycloalkyl in which two non-adjacent atoms of a ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms (e.g., bicyclo[2.2.1]heptanyl). Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantyl, and bicyclo[1.1.1]pentanyl.

[0038] The term “cycloalkenyl” or “cycloalkene,” as used herein, means a non-aromatic monocyclic or multicyclic ring system containing all carbon atoms as ring members and at least one carbon-carbon double bond and preferably having from 5-10 carbon atoms per ring. The term “cycloalkenyl” is used herein to refer to a cycloalkene when present as a substituent. A cycloalkenyl may be a monocyclic cycloalkenyl (e.g., cyclopentenyl), a fused bicyclic cycloalkenyl (e.g., octahydronaphthalenyl), or a bridged cycloalkenyl in which two non-adjacent atoms of a ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms (e.g., bicyclo[2.2.1]heptenyl). Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl.

[0039] The term “carbocyclyl” means a “cycloalkyl” or a “cycloalkenyl.” The term “carbocycle” means a “cycloalkane” or a “cycloalkene.” The term “carbocyclyl” refers to a “carbocycle” when present as a substituent.

[0040] The term “1,1-carbocyclylene” means a geminal divalent group derived from a cycloalkyl. A representative example is 1,1-C3-6cycloalkylene (i.e.,A further example is 1,1-cyclopropylene (i.e.,

[0041] The term “fluoroalkyl,” as used herein, means an alkyl group, as defined herein, in which one, two, three, four, five, six, seven or eight hydrogen atoms are replaced by fluorine. Representative examples of fluoroalkyl include, but are not limited to, 2-fluoroethyl, 2,2,2- trifluoroethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl, and trifluoropropyl such as 3,3,3-trifluoropropyl.

[0042] The term “difluoroalkyl,” as used herein, means an alkyl group, as defined herein, in which two hydrogen atoms are replaced by fluorine. Representative examples of difluoroalkyl include difluoromethyl and difluoroethyl.

[0043] The term “halogen” or “halo,” as used herein, means Cl, Br, I, or F.

[0044] The term “haloalkyl,” as used herein, means an alkyl group, as defined herein, in which one, two, three, four, five, six, seven or eight hydrogen atoms are replaced by a halogen.

[0045] The term “heteroaryl,” as used herein, refers to an aromatic monocyclic heteroatom- containing ring (monocyclic heteroaryl) or a bicyclic ring system containing at least onemonocyclic heteroaromatic ring (bicyclic heteroaryl). The term “heteroaryl” is used herein to refer to a heteroarene when present as a substituent. The monocyclic heteroaryl are five or six membered rings containing at least one heteroatom independently selected from the group consisting of N, O and S (e.g.1, 2, 3, or 4 heteroatoms independently selected from O, S, and N). The five membered aromatic monocyclic rings have two double bonds and the six membered aromatic monocyclic rings have three double bonds. The bicyclic heteroaryl is an 8- to 12- membered ring system and includes a fused bicyclic heteroaromatic ring system (i.e., 10π electron system) such as a monocyclic heteroaryl ring fused to a 6-membered arene (e.g., quinolin-4-yl, indol-1-yl), a monocyclic heteroaryl ring fused to a monocyclic heteroarene (e.g., naphthyridinyl), and a phenyl fused to a monocyclic heteroarene (e.g., quinolin-5-yl, indol-4-yl). A bicyclic heteroaryl / heteroarene group includes a 9-membered fused bicyclic heteroaromatic ring system having four double bonds and at least one heteroatom contributing a lone electron pair to a fully aromatic 10π electron system, such as ring systems with a nitrogen atom at the ring junction (e.g., imidazopyridine) or a benzoxadiazolyl. A bicyclic heteroaryl also includes a fused bicyclic ring system composed of one heteroaromatic ring and one non-aromatic ring such as a monocyclic heteroaryl ring fused to a monocyclic carbocyclic ring (e.g., 6,7-dihydro-5H- cyclopenta[b]pyridinyl), or a monocyclic heteroaryl ring fused to a monocyclic heterocycle (e.g., 2,3-dihydrofuro[3,2-b]pyridinyl). The bicyclic heteroaryl is attached to the parent molecular moiety at an aromatic ring atom. Other representative examples of heteroaryl include, but are not limited to, indolyl (e.g., indol-1-yl, indol-2-yl, indol-4-yl), pyridinyl (including pyridin-2-yl, pyridin-3-yl, pyridin-4-yl), pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl (e.g., pyrazol-4-yl), pyrrolyl, benzopyrazolyl, 1,2,3-triazolyl (e.g., triazol-4-yl), 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, imidazolyl, thiazolyl (e.g., thiazol-4-yl), isothiazolyl, thienyl, benzimidazolyl (e.g., benzimidazol-5-yl), benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzothienyl, benzofuranyl, isobenzofuranyl, furanyl, oxazolyl, isoxazolyl, purinyl, isoindolyl, quinoxalinyl, indazolyl (e.g., indazol-4-yl, indazol-5-yl), quinazolinyl, 1,2,4- triazinyl, 1,3,5-triazinyl, isoquinolinyl, quinolinyl, imidazo[1,2-a]pyridinyl (e.g., imidazo[1,2- a]pyridin-6-yl), naphthyridinyl, pyridoimidazolyl, thiazolo[5,4-b]pyridin-2-yl, and thiazolo[5,4- d]pyrimidin-2-yl.

[0046] The term “heterocycle” or “heterocyclic,” as used herein, means a monocyclic heterocycle, a bicyclic heterocycle, or a tricyclic heterocycle. The term “heterocyclyl” is usedherein to refer to a heterocycle when present as a substituent. The monocyclic heterocycle is a three-, four-, five-, six-, seven-, or eight-membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S. The three- or four-membered ring contains zero or one double bond, and one heteroatom selected from the group consisting of O, N, and S. The five-membered ring contains zero or one double bond and one, two or three heteroatoms selected from the group consisting of O, N and S. The six-membered ring contains zero, one or two double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. The seven- and eight-membered rings contains zero, one, two, or three double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. Representative examples of monocyclic heterocyclyls include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, 1,3- dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, 2-oxo-3-piperidinyl, 2-oxoazepan-3-yl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxetanyl, oxepanyl, oxocanyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydrothienyl, tetrahydrothiopyranyl, thiadiazolinyl, thiadiazolidinyl, 1,2-thiazinanyl, 1,3-thiazinanyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1- dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl. The bicyclic heterocycle is a monocyclic heterocycle fused to a 6-membered arene, or a monocyclic heterocycle fused to a monocyclic cycloalkane (e.g., 7- to 12-membered fused bicyclic heterocyclyl ring system such as hexahydro-2H-cyclopenta[b]furanyl, octahydro-3aH- cyclohepta[b]furanyl, or 3-oxabicyclo[3.1.0]hexanyl), or a monocyclic heterocycle fused to a monocyclic cycloalkene, or a monocyclic heterocycle fused to a monocyclic heterocycle, or a monocyclic heterocycle fused to a monocyclic heteroarene, or a spiro heterocycle group (e.g., a 7- to 12-membered spiro heterocyclyl ring system such as 2-oxaspiro[3.3]heptanyl, 3- oxaspiro[5.5]undecanyl, 6-oxaspiro[2.5]octanyl, or 5-oxaspiro[2.4]heptanyl), or a bridged heterocycle ring system in which two non-adjacent atoms of the ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms (e.g., a 6- to 10-membered bridged bicyclic heterocyclyl ring system such as 7-oxabicyclo[2.2.1]heptanyl or 2-oxabicyclo[2.1.1]hexanyl), or an alkenylene bridge of two, three, or four carbon atoms. The bicyclic heterocyclyl is attached to the parent molecular moiety at a non-aromatic ring atom (e.g., indolin-1-yl). Representative examples ofbicyclic heterocyclyls include, but are not limited to, chroman-4-yl, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzothien-2-yl, 1,2,3,4-tetrahydroisoquinolin-2-yl, 2-azaspiro[3.3]heptan-2-yl, 2- oxa-6-azaspiro[3.3]heptan-6-yl, azabicyclo[2.2.1]heptyl (including 2-azabicyclo[2.2.1]hept-2- yl), azabicyclo[3.1.0]hexanyl (including 3-azabicyclo[3.1.0]hexan-3-yl), 2,3-dihydro-1H-indol- 1-yl, isoindolin-2-yl, octahydrocyclopenta[c]pyrrolyl, octahydropyrrolopyridinyl, tetrahydroisoquinolinyl, 7-oxabicyclo[2.2.1]heptanyl, hexahydro-2H-cyclopenta[b]furanyl, 2- oxaspiro[3.3]heptanyl, 3-oxaspiro[5.5]undecanyl, 6-oxaspiro[2.5]octan-1-yl, and 3- oxabicyclo[3.1.0]hexan-6-yl. Tricyclic heterocycles are exemplified by a bicyclic heterocycle fused to a 6-membered arene, or a bicyclic heterocycle fused to a monocyclic cycloalkane, or a bicyclic heterocycle fused to a monocyclic cycloalkene, or a bicyclic heterocycle fused to a monocyclic heterocycle, or a bicyclic heterocycle in which two non-adjacent atoms of the bicyclic ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, or an alkenylene bridge of two, three, or four carbon atoms. Examples of tricyclic heterocycles include, but are not limited to, octahydro-2,5-epoxypentalene, hexahydro-2H-2,5-methanocyclopenta[b]furan, hexahydro-1H-1,4-methanocyclopenta[c]furan, aza-adamantane (1- azatricyclo[3.3.1.13,7]decane), and oxa-adamantane (2-oxatricyclo[3.3.1.13,7]decane). The monocyclic, bicyclic, and tricyclic heterocyclyls are connected to the parent molecular moiety at a non-aromatic ring atom.

[0047] The term “hydroxyl” or “hydroxy,” as used herein, means an -OH group.

[0048] The term “hydroxyalkyl,” as used herein, means at least one -OH group, is appended to the parent molecular moiety through an alkylene group, as defined herein.

[0049] Terms such as "alkyl," "cycloalkyl," "alkylene," etc. may be preceded by a designation indicating the number of atoms present in the group in a particular instance ( e.g., "C1-4alkyl," "C3-6cycloalkyl," "C1-4alkylene"). These designations are used as generally understood by those skilled in the art. For example, the representation "C" followed by a subscripted number indicates the number of carbon atoms present in the group that follows. Thus, "C3alkyl" is an alkyl group with three carbon atoms (i.e., n-propyl, isopropyl). Where a range is given, as in "C1-4," the members of the group that follows may have any number of carbon atoms falling within the recited range. A "C1-4alkyl," for example, is an alkyl group having from 1 to 4 carbon atoms, however arranged (i.e., straight chain or branched).

[0050] The term “substituted” refers to a group that may be further substituted with one or more non-hydrogen substituent groups. Substituent groups include, but are not limited to, halogen, =O (oxo), =S (thioxo), cyano, nitro, fluoroalkyl, alkoxyfluoroalkyl, fluoroalkoxy, alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, heteroalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycle, cycloalkylalkyl, heteroarylalkyl, arylalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkylene, aryloxy, phenoxy, benzyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, -COOH, ketone, amide, carbamate, and acyl.

[0051] For compounds described herein, groups and substituents thereof may be selected in accordance with permitted valence of the atoms and the substituents, such that the selections and substitutions result in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.

[0052] For the recitation of numeric ranges herein, each intervening number there between with the same degree of precision is explicitly contemplated. For example, for the range of 6-9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0-7.0, the number 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly contemplated.

[0053] Abbreviations: DCM is dichloromethane; DIPEA is N,N-diisopropylethylamine; Dulbecco's Modified Eagle Medium (DMEM); DMF is N,N-dimethylformamide; DMSO is dimethylsulfoxide; eq, eq., or equiv is equivalent(s); EtOAc is ethyl acetate; Et3N is triethylamine; HATU is 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate; HEPES is (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid); h or h. is hour(s); hex is hexane; IPA is isopropyl alcohol; LCMS is liquid chromatography mass spectrometry;MeCN is acetonitrile; MeOH is methanol; MeOD is deuterated methanol; min or min. is minute(s); RP-HPLC is reverse phase high-performance liquid chromatography; ES-MS is electrospray mass spectrometry; rt, RT, or r.t. is room temperature; sat. is saturated; soln. is solution; TFA is trifluoroacetic acid; THF is tetrahydrofuran. 2. Compounds

[0054] In one aspect, the invention provides compounds of formula (I), wherein X1, L1, R1, R2, R3, R4, m, and n are as defined herein.

[0055] Optionally substituted cyclic groups (i.e., unsubstituted or substituted cyclic groups), such as optionally substituted aryl, heteroaryl, etc., are composed of a ring system and the ring system's optional substitution. Accordingly, a “ring system” refers to the base molecular structure formed by the constituent ring atoms, including any hydrogens required to satisfy the valency of the ring atoms. A ring system may be defined independently of its substituents. Thus, where only the ring system of an optionally substituted cyclic group is redefined with a more specific definition, any optional substitution of the original optionally substituted cyclic group remains for the new more specifically defined ring system. For example, an optionally substituted 5- to 12-membered heteroaryl may be further defined by specifying the ring system of the optionally substituted 5- to 12-membered heteroaryl is a 5- to 6-membered heteroaryl (i.e., 5- to 6-membered heteroaryl ring system), in which case the optional substitution of the original optionally substituted 5- to 12-membered heteroaryl continues to apply to the 5- to 6-membered heteroaryl ring system, unless otherwise expressly indicated.

[0056] Where heterocyclic and heteroaromatic ring systems are defined to "contain" or as "containing" specified heteroatoms (e.g., 1-3 heteroatoms independently selected from the groupconsisting of O, N, and S), any ring atoms of the heterocyclic and heteroaromatic ring systems that are not one of the specified heteroatoms are carbon atoms.

[0057] In the following, numbered embodiments of the invention are disclosed. The first embodiment is denoted E1, and subsequent embodiments are denoted E2, E3, E4, E5, E5.1, E6, E6.1, E6.2, etc.

[0058] E1. A compound of formula (I), or a pharmaceutically acceptable salt thereof,wherein: X1is nitrogen or C-H; R1and R2, together with the atoms to which they are attached, form a 5- to 8-membered partially unsaturated carbocycle, a 6-membered arene, or a 6-membered heteroarene containing 1-2 nitrogen atoms, each optionally substituted with R10and further optionally substituted with 1- 5 R11; or, alternatively, R1is hydrogen, C1-4alkyl, C1-2fluoroalkyl, or G1; R2is hydrogen, C1-4alkyl, C1-2fluoroalkyl, or G2; R10is C1-4alkyl, C1-2fluoroalkyl, halogen, cyano, oxo, G10, –OR10a, –C(O)R10a, or –C(O)OR10a; R10ais hydrogen, C1-4alkyl, C1-2fluoroalkyl, or C3-4cycloalkyl; R11, at each occurrence, is independently C1-4alkyl, halogen, or oxo; G1, G2, and G10are independently a C3-4cycloalkyl, wherein the cycloalkyl is optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, C1-4alkyl, C1-2fluoroalkyl, and –OC1-4alkyl; n is 0, 1, 2, 3, or 4; R3, at each occurrence, is independently selected from the group consisting of halogen, C1-4alkyl, and C1-2fluoroalkyl; L1is C1-3alkylene; m is 0, 1, 2, 3, or 4; and R4, at each occurrence, is independently C1-4alkyl, C1-2fluoroalkyl, halogen, –OH, –OC1-4alkyl, or C3-4cycloalkyl;with the proviso that the compound is not N-((1H-benzo[d]imidazol-2-yl)methyl)-1-(1H-indole- 3-carbonyl)azetidine-3-carboxamide.

[0059] E2. The compound of E1, or a pharmaceutically acceptable salt thereof, wherein X1is nitrogen.

[0060] E3. The compound of E1, or a pharmaceutically acceptable salt thereof, wherein X1is C-H.

[0061] E4. The compound of any of E1-E3, or a pharmaceutically acceptable salt thereof, wherein R1and R2, together with the atoms to which they are attached, form the optionally substituted 5- to 8-membered partially unsaturated carbocycle.

[0062] E5. The compound of any of E1-E4, or a pharmaceutically acceptable salt thereof, wherein the ring system of the optionally substituted 5- to 8-membered partially unsaturated carbocycle formed by R1and R2is a 6-membered partially unsaturated carbocycle. (i.e., R1and R2form a 6-membered partially unsaturated carbocycle with the optional substituents of E1).

[0063] E5.1. The compound of E5, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted 6-membered partially unsaturated carbocyclethe carbocycle is unsubstituted).

[0064] E6. The compound of any of E1-E3, or a pharmaceutically acceptable salt thereof, wherein R1and R2, together with the atoms to which they are attached, form the optionally substituted 6-membered arene.

[0065] E6.1. The compound of E6, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted 6-membered arene

[0066] E6.2. The compound of E6.1, or a pharmaceutically acceptable salt thereof, wherein.

[0067] E6.3. The compound of any of E6-E6.2, or a pharmaceutically acceptable salt thereof, wherein R10is C1-4alkyl, halogen, or –OC1-4alkyl.

[0068] E6.4. The compound of E6.2 or E6.3, or a pharmaceutically acceptable salt thereof, wherein R10is methyl, chloro, bromo, fluoro, or methoxy.

[0069] E6.5. The compound of any one of E6.2-E6.4, or a pharmaceutically acceptable

[0070] E6.6. The compound of E6.1, or a pharmaceutically acceptable salt thereof, wherein

[0071] E7. The compound of any of E1-E3, or a pharmaceutically acceptable salt thereof, wherein R1and R2, together with the atoms to which they are attached, form the optionally substituted 6-membered heteroarene containing 1-2 nitrogen atoms.

[0072] E7.1. The compound of E7, or a pharmaceutically acceptable salt thereof, wherein the 6-membered heteroarene containing 1-2 nitrogen atoms is unsubstituted.

[0073] E8. The compound of any of E1-E3 or E7-E7.1, or a pharmaceutically acceptable salt thereof, wherein the ring system of the optionally substituted 6-membered heteroarene formed by R1and R2is pyridine.

[0074] E8.1. The compound of any of E1-E3 or E7-E8, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted 6-membered heteroarene formed by R1and R2is

[0075] E9. The compound of any of E1-E8.1, or a pharmaceutically acceptable salt thereof, wherein R1andtogether with the atoms to which they are attached, form, ,

[0076] E10. The compound of any of E1-E3, or a pharmaceutically acceptable salt thereof, wherein R1is hydrogen.

[0077] E11. The compound of any of E1-E3 or E10, or a pharmaceutically acceptable salt thereof, wherein R2is C1-4alkyl.

[0078] E12. The compound of any of E1-E3 or E10-E11, or a pharmaceutically acceptable salt thereof, wherein R2is –CH3.

[0079] E13. The compound of any of E1-E12, or a pharmaceutically acceptable salt thereof, wherein n is 0.

[0080] E14. The compound of any of E1-E12, or a pharmaceutically acceptable salt thereof, wherein n is 1.

[0081] E15. The compound of any of E1-E12 or E14, or a pharmaceutically acceptable salt thereof, wherein R3is C1-4alkyl or halogen.

[0082] E16. The compound of any of E1-E12 or E14-E15, or a pharmaceutically acceptable salt thereof, wherein R3is –CH3or fluoro.

[0083] E17. The compound of any of E1-E12 or E14-E16, or a pharmaceutically acceptable salt thereof, wherein.

[0084] E18. The compound of E17, or a pharmaceutically acceptable salt thereof,.

[0085] E19. The compound of any of E1-E18, or a pharmaceutically acceptable salt thereof, wherein L1is –CH2–.

[0086] E20. The compound of any of E1-E19, or a pharmaceutically acceptable salt thereof, wherein m is 0.

[0087] E21. The compound of any of E1-E19, or a pharmaceutically acceptable salt thereof, wherein m is 1.

[0088] E22. The compound of any of E1-E19 or E21, or a pharmaceutically acceptable salt thereof, wherein R4is C1-4alkyl.

[0089] E23. The compound of any of E1-E19 or E21-E22, or a pharmaceutically acceptable salt thereof, wherein R4is –CH3.

[0090] E24. The compound of E1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: N-((1H-benzo[d]imidazol-2-yl)methyl)-1-(1H-indazole-3-carbonyl)azetidine-3-carboxamide; N-((1H-benzo[d]imidazol-2-yl)methyl)-1-(1H-indazole-3-carbonyl)-3-methylazetidine-3- carboxamide; N-((1H-benzo[d]imidazol-2-yl)methyl)-1-(4-methoxy-1H-indazole-3-carbonyl)-3- methylazetidine-3-carboxamide; N-((1H-benzo[d]imidazol-2-yl)methyl)-1-(4-chloro-1H-indazole-3-carbonyl)-3- methylazetidine-3-carboxamide; N-((1H-benzo[d]imidazol-2-yl)methyl)-1-(4-bromo-1H-indazole-3-carbonyl)-3- methylazetidine-3-carboxamide; N-((1H-benzo[d]imidazol-2-yl)methyl)-1-(5-fluoro-1H-indazole-3-carbonyl)-3- methylazetidine-3-carboxamide; N-((1H-benzo[d]imidazol-2-yl)methyl)-1-(5-chloro-1H-indazole-3-carbonyl)-3- methylazetidine-3-carboxamide; N-((1H-benzo[d]imidazol-2-yl)methyl)-3-methyl-1-(4-methyl-1H-pyrazole-3- carbonyl)azetidine-3-carboxamide; N-((1H-benzo[d]imidazol-2-yl)methyl)-3-methyl-1-(1H-pyrrolo[2,3-c]pyridine-3- carbonyl)azetidine-3-carboxamide; N-((1H-benzo[d]imidazol-2-yl)methyl)-3-methyl-1-(4,5,6,7-tetrahydro-1H-indazole-3- carbonyl)azetidine-3-carboxamide;N-((1H-benzo[d]imidazol-2-yl)methyl)-1-(6-fluoro-1H-indazole-3-carbonyl)-3- methylazetidine-3-carboxamide; (2S,3R)-N-((1H-benzo[d]imidazol-2-yl)methyl)-1-(1H-indazole-3-carbonyl)-2- methylazetidine-3-carboxamide; (2R,3S)-N-((1H-benzo[d]imidazol-2-yl)methyl)-1-(1H-indazole-3-carbonyl)-2- methylazetidine-3-carboxamide; N-((1H-benzo[d]imidazol-2-yl)methyl)-1-(5-chloro-1H-indazole-3-carbonyl)-3- fluoroazetidine-3-carboxamide; 1-(1H-indole-3-carbonyl)-N-((5-methyl-1H-benzo[d]imidazol-2-yl)methyl)azetidine-3- carboxamide; N-((1H-benzo[d]imidazol-2-yl)methyl)-1-(6-fluoro-1H-indole-3-carbonyl)azetidine-3- carboxamide; N-((1H-benzo[d]imidazol-2-yl)methyl)-1-(1H-pyrrolo[3,2-b]pyridine-3-carbonyl)azetidine-3- carboxamide; N-((1H-benzo[d]imidazol-2-yl)methyl)-1-(1H-pyrazolo[4,3-b]pyridine-3-carbonyl)azetidine- 3-carboxamide; N-((1H-benzo[d]imidazol-2-yl)methyl)-1-(5-methyl-1H-indole-3-carbonyl)azetidine-3- carboxamide; N-((1H-benzo[d]imidazol-2-yl)methyl)-1-(5-fluoro-1H-indole-3-carbonyl)azetidine-3- carboxamide; or a pharmaceutically acceptable salt thereof.

[0091] E24. The compound of E1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: N-((1H-benzo[d]imidazol-2-yl)methyl)-1-(1H-indole-3-carbonyl)azetidine-3-carboxamide N-((1H-benzo[d]imidazol-2-yl)methyl)-1-(1H-indazole-3-carbonyl)azetidine-3-carboxamide N-((1H-benzo[d]imidazol-2-yl)methyl)-1-(1H-indazole-3-carbonyl)-3-methylazetidine-3- carboxamide N-((1H-benzo[d]imidazol-2-yl)methyl)-1-(4-methoxy-1H-indazole-3-carbonyl)-3- methylazetidine-3-carboxamide N-((1H-benzo[d]imidazol-2-yl)methyl)-1-(4-chloro-1H-indazole-3-carbonyl)-3- methylazetidine-3-carboxamideN-((1H-benzo[d]imidazol-2-yl)methyl)-1-(4-bromo-1H-indazole-3-carbonyl)-3- methylazetidine-3-carboxamide N-((1H-benzo[d]imidazol-2-yl)methyl)-1-(5-fluoro-1H-indazole-3-carbonyl)-3- methylazetidine-3-carboxamide N-((1H-benzo[d]imidazol-2-yl)methyl)-1-(5-chloro-1H-indazole-3-carbonyl)-3- methylazetidine-3-carboxamide N-((1H-benzo[d]imidazol-2-yl)methyl)-3-methyl-1-(4-methyl-1H-pyrazole-3- carbonyl)azetidine-3-carboxamide N-((1H-benzo[d]imidazol-2-yl)methyl)-3-methyl-1-(1H-pyrrolo[2,3-c]pyridine-3- carbonyl)azetidine-3-carboxamide N-((1H-benzo[d]imidazol-2-yl)methyl)-3-methyl-1-(4,5,6,7-tetrahydro-1H-indazole-3- carbonyl)azetidine-3-carboxamide N-((1H-benzo[d]imidazol-2-yl)methyl)-1-(6-fluoro-1H-indazole-3-carbonyl)-3- methylazetidine-3-carboxamide (2S,3R)-N-((1H-benzo[d]imidazol-2-yl)methyl)-1-(1H-indazole-3-carbonyl)-2- methylazetidine-3-carboxamide (2R,3S)-N-((1H-benzo[d]imidazol-2-yl)methyl)-1-(1H-indazole-3-carbonyl)-2- methylazetidine-3-carboxamide N-((1H-benzo[d]imidazol-2-yl)methyl)-1-(5-chloro-1H-indazole-3-carbonyl)-3- fluoroazetidine-3-carboxamide 1-(1H-indole-3-carbonyl)-N-((5-methyl-1H-benzo[d]imidazol-2-yl)methyl)azetidine-3- carboxamide N-((1H-benzo[d]imidazol-2-yl)methyl)-1-(6-fluoro-1H-indole-3-carbonyl)azetidine-3- carboxamide N-((1H-benzo[d]imidazol-2-yl)methyl)-1-(1H-pyrrolo[3,2-b]pyridine-3-carbonyl)azetidine-3- carboxamide N-((1H-benzo[d]imidazol-2-yl)methyl)-1-(1H-pyrazolo[4,3-b]pyridine-3-carbonyl)azetidine- 3-carboxamide N-((1H-benzo[d]imidazol-2-yl)methyl)-3-fluoro-1-(1H-indazole-3-carbonyl)azetidine-3- carboxamide; N-((1H-benzo[d]imidazol-2-yl)methyl)-3-fluoro-1-(5-fluoro-1H-indazole-3-carbonyl)azetidine-3-carboxamide; N-((1H-benzo[d]imidazol-2-yl)methyl)-1-(4,6-difluoro-1H-indazole-3-carbonyl)-3- methylazetidine-3-carboxamide; N-((1H-benzo[d]imidazol-2-yl)methyl)-1-(4-fluoro-1H-indazole-3-carbonyl)-3- methylazetidine-3-carboxamide; N-((1H-indazol-5-yl)methyl)-1-(1H-indole-3-carbonyl)azetidine-3-carboxamide; N-((3H-imidazo[4,5-c]pyridin-2-yl)methyl)-1-(1H-indazole-3-carbonyl)-3-methylazetidine-3- carboxamide; N-((5-fluoro-1H-benzo[d]imidazol-2-yl)methyl)-1-(1H-indazole-3-carbonyl)-3- methylazetidine-3-carboxamide; (R)-N-(1-(1H-benzo[d]imidazol-2-yl)ethyl)-1-(1H-indazole-3-carbonyl)-3-methylazetidine-3- carboxamide; (S)-N-(1-(1H-benzo[d]imidazol-2-yl)ethyl)-1-(1H-indazole-3-carbonyl)-3-methylazetidine-3- carboxamide N-((5-chloro-1H-benzo[d]imidazol-2-yl)methyl)-1-(1H-indazole-3-carbonyl)-3- methylazetidine-3-carboxamide; N-((1H-benzo[d]imidazol-2-yl)methyl)-1-(1H-indazole-3-carbonyl)-N,3-dimethylazetidine-3- carboxamide; N-((3H-imidazo[4,5-b]pyridin-2-yl)methyl)-1-(1H-indazole-3-carbonyl)-3-methylazetidine-3- carboxamide; 1-(1H-indazole-3-carbonyl)-3-methyl-N-((5-(trifluoromethyl)-1H-benzo[d]imidazol-2- yl)methyl)azetidine-3-carboxamide; N-((5-butyl-1H-benzo[d]imidazol-2-yl)methyl)-1-(1H-indazole-3-carbonyl)-3- methylazetidine-3-carboxamide; 1-(1H-indazole-3-carbonyl)-N-((1-(4-methoxybenzyl)-1H-benzo[d]imidazol-2-yl)methyl)-3- methylazetidine-3-carboxamide; tert-butyl 3-(3-(((1-(tert-butoxycarbonyl)-1H-benzo[d]imidazol-2-yl)methyl)carbamoyl)-3- methylazetidine-1-carbonyl)-1H-indazole-1-carboxylate; or a pharmaceutically acceptable salt thereof.

[0092] E25. A pharmaceutical composition comprising the compound of any of E1-E24, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0093] E26. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof,wherein: X1is nitrogen or C-H; R1and R2, together with the atoms to which they are attached, form a 5- to 8-membered partially unsaturated carbocycle, a 6-membered arene, or a 6-membered heteroarene containing 1-2 nitrogen atoms, each optionally substituted with R10and further optionally substituted with 1- 5 R11; or, alternatively, R1is hydrogen, C1-4alkyl, C1-2fluoroalkyl, or G1; R2is hydrogen, C1-4alkyl, C1-2fluoroalkyl, or G2; R10is C1-4alkyl, C1-2fluoroalkyl, halogen, cyano, oxo, G10, –OR10a, –C(O)R10a, or –C(O)OR10a; R10ais hydrogen, C1-4alkyl, C1-2fluoroalkyl, or C3-4cycloalkyl; R11, at each occurrence, is independently C1-4alkyl, halogen, or oxo;G1, G2, and G10 are independently a C3-4cycloalkyl, wherein the cycloalkyl is optionallysubstituted with 1-5 substituents independently selected from the group consisting of halogen, C1-4alkyl, C1-2fluoroalkyl, and –OC1-4alkyl; n is 0, 1, 2, 3, or 4; R3, at each occurrence, is independently selected from the group consisting of halogen, C1-4alkyl, and C1-2fluoroalkyl; L1is C1-3alkylene; m is 0, 1, 2, 3, or 4; and R4, at each occurrence, is independently C1-4alkyl, C1-2fluoroalkyl, halogen, –OH, –OC1-4alkyl, or C3-4cycloalkyl; and a pharmaceutically acceptable carrier.

[0094] E26.1. The pharmaceutical composition of E26, wherein the compound of formula (I) is not N-((1H-benzo[d]imidazol-2-yl)methyl)-1-(1H-indole-3-carbonyl)azetidine-3- carboxamide.

[0095] E27. A method of antagonizing the 5-HT2B receptor in a subject comprising administering to the subject, an effective amount of the compound of any of E1-E24, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of E25- E26.1.

[0096] E28. A method of treating pulmonary arterial hypertension, aortic valve disease, myocardial infarction, or systemic sclerosis, comprising administering to a subject in need thereof, a therapeutically effective amount of the compound of any of E1-E24, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of E25- E26.1.

[0097] E29. A compound of any of E1-E24, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any of E25-E26.1, for use in a method of treating pulmonary arterial hypertension, aortic valve disease, myocardial infarction, or systemic sclerosis.

[0098] E30. Use of a compound of any of E1-E24, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any of E25-E26.1, in the manufacture of a medicament for treating pulmonary arterial hypertension, aortic valve disease, myocardial infarction, or systemic sclerosis.

[0099] Throughout the embodiments and description of the compounds of the invention, all instances of haloalkyl may be fluoroalkyl (e.g., any C1-4haloalkyl may be C1-4fluoroalkyl).

[0100] Compound names and / or structures can be assigned / determined by using the Struct=Name naming algorithm as part of CHEMDRAW® ULTRA.

[0101] The compound may exist as a stereoisomer wherein asymmetric or chiral centers are present. The stereoisomer is “R” or “S” depending on the configuration of substituents around the chiral carbon atom. The terms “R” and “S” used herein are configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, in Pure Appl. Chem., 1976, 45: 13-30. The disclosure contemplates various stereoisomers and mixtures thereof and these are specifically included within the scope of this invention. Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or diastereomers. In the compounds disclosed herein, a chiral atom depicted or described without a specific stereochemical configuration (e.g., a straight bond, not wedged or dashed bond, HC(OH)(CH3)(CH2CH3)) encompasses any stereochemical configuration at the chiral atom.

[0102] Individual stereoisomers of the compounds may be prepared synthetically from commercially available starting materials, which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by methods of resolution well-known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and optional liberation of the optically pure product from the auxiliary as described in Furniss, Hannaford, Smith, and Tatchell, “Vogel's Textbook of Practical Organic Chemistry,” 5th edition (1989), Longman Scientific & Technical, Essex CM20 2JE, England, or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns, or (3) fractional recrystallization methods.

[0103] It should be understood that the compound may possess tautomeric forms, as well as geometric isomers, and that these also constitute embodiments of the disclosure.

[0104] In the compounds of formula (I), and any subformulas, any "hydrogen" or "H," whether explicitly recited or implicit in the structure, encompasses hydrogen isotopes1H (protium) and2H (deuterium). Accordingly, any group comprising one or more hydrogen atoms encompasses corresponding deuterium-labeled versions of the group. For example,encompassesencompasses

[0105] The present disclosure also includes isotopically-labeled compounds (e.g., deuterium labeled), where an atom in the isotopically-labeled compound is specified as a particular isotope of the atom. Examples of isotopes suitable for inclusion in the compounds of the invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as, but not limited to2H,3H,13C,14C,15N,18O,17O,31P,32P,35S,18F, and36Cl, respectively. The compound may incorporate positron-emitting isotopes for medical imaging and positron-emitting tomography (PET) studies for determining the distribution of receptors. Suitable positron- emitting isotopes that can be incorporated in compounds of formula (I) are11C,13N,15O, and18F.

[0106] Isotopically-enriched forms of compounds of formula (I), or any subformulas, may generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using an appropriate isotopically-enriched reagent in place of a non-isotopically-enriched reagent. The extent ofisotopic enrichment can be characterized as a percent incorporation of a particular isotope at an isotopically-labeled atom (e.g., % deuterium incorporation at a deuterium label). a. Pharmaceutically Acceptable Salts

[0107] The disclosed compounds may exist as pharmaceutically acceptable salts. The term “pharmaceutically acceptable salt” refers to salts or zwitterions of the compounds which are water or oil-soluble or dispersible, suitable for treatment of disorders without undue toxicity, irritation, and allergic response, commensurate with a reasonable benefit / risk ratio and effective for their intended use. The salts may be prepared during the final isolation and purification of the compounds or separately by reacting an amino group of the compounds with a suitable acid. For example, a compound may be dissolved in a suitable solvent, such as but not limited to methanol and water and treated with at least one equivalent of an acid, like hydrochloric acid. The resulting salt may precipitate out and be isolated by filtration and dried under reduced pressure. Alternatively, the solvent and excess acid may be removed under reduced pressure to provide a salt. Representative salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, isethionate, fumarate, lactate, maleate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, oxalate, maleate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, glutamate, para-toluenesulfonate, undecanoate, hydrochloric, hydrobromic, sulfuric, phosphoric and the like. The amino groups of the compounds may also be quaternized with alkyl chlorides, bromides and iodides such as methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, stearyl and the like.

[0108] Basic addition salts may be prepared during the final isolation and purification of the disclosed compounds by reaction of a carboxyl group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation such as lithium, sodium, potassium, calcium, magnesium, or aluminum, or an organic primary, secondary, or tertiary amine. Quaternary amine salts can be prepared, such as those derived from methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N- methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine and N,N’-dibenzylethylenediamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like. b. General Synthesis

[0109] Compounds of formula (I) or any of its subformulas may be prepared by synthetic processes or by metabolic processes. Preparation of the compounds by metabolic processes includes those occurring in the human or animal body (in vivo) or processes occurring in vitro.

[0110] Compounds of formula (I) or any of its subformulas may be synthesized as shown in the following schemes. Scheme 1.

[0111] As shown in Scheme 1, carboxylic acids A’ may be reacted with amines B’ under suitable amide coupling conditions (e.g., HATU, Et3N, and DCM) to provide intermediate amides C’. Intermediate amides C’ may be subjected to suitable deprotection conditions (e.g., TFA) to provide intermediate amides D’. Intermediate amides D’ may be reacted with a 1H- pyrazole-3-carboxylic acid E’ under suitable amide coupling conditions (e.g., HATU, DIPEA, and DMF) to provide compounds F’. Scheme 2.

[0112] As shown in Scheme 2, carboxylic acids A” may be reacted with amines B” under suitable amide coupling conditions (e.g., HATU, DIPEA, and DMF) to provide intermediate compounds C”. Intermediate compounds C” may be subjected to suitable deprotection conditions to provide intermediate carboxylic acid compounds D”. The intermediate carboxylic acid compounds D” may be reacted with an amine compound E” under suitable amide coupling conditions to provide compounds F”.

[0113] Suitable reagents for coupling reactions described herein may be readily obtained from commerical sources or prepared by standard methods well known to those skilled in the art.

[0114] The compounds and intermediates may be isolated and purified by methods well- known to those skilled in the art of organic synthesis. Examples of conventional methods for isolating and purifying compounds can include, but are not limited to, chromatography on solid supports such as silica gel, alumina, or silica derivatized with alkylsilane groups, by recrystallization at high or low temperature with an optional pretreatment with activated carbon, thin-layer chromatography, distillation at various pressures, sublimation under vacuum, and trituration, as described for instance in “Vogel's Textbook of Practical Organic Chemistry,” 5th edition (1989), by Furniss, Hannaford, Smith, and Tatchell, pub. Longman Scientific & Technical, Essex CM202JE, England.

[0115] A disclosed compound may have at least one basic nitrogen whereby the compound can be treated with an acid to form a desired salt. For example, a compound may be reacted with an acid at or above room temperature to provide the desired salt, which is deposited, and collected by filtration after cooling. Examples of acids suitable for the reaction include, but are not limited to tartaric acid, lactic acid, succinic acid, as well as mandelic, atrolactic,methanesulfonic, ethanesulfonic, toluenesulfonic, naphthalenesulfonic, benzenesulfonic, carbonic, fumaric, maleic, gluconic, acetic, propionic, salicylic, hydrochloric, hydrobromic, phosphoric, sulfuric, citric, hydroxybutyric, camphorsulfonic, malic, phenylacetic, aspartic, or glutamic acid, and the like.

[0116] Reaction conditions and reaction times for each individual step can vary depending on the particular reactants employed and substituents present in the reactants used. Specific procedures are provided in the Examples section. Reactions can be worked up in the conventional manner, e.g. by eliminating the solvent from the residue and further purified according to methodologies generally known in the art such as, but not limited to, crystallization, distillation, extraction, trituration and chromatography. Unless otherwise described, the starting materials and reagents are either commercially available or can be prepared by one skilled in the art from commercially available materials using methods described in the chemical literature. Starting materials, if not commercially available, can be prepared by procedures selected from standard organic chemical techniques, techniques that are analogous to the synthesis of known, structurally similar compounds, or techniques that are analogous to the above described schemes or the procedures described in the synthetic examples section.

[0117] Routine experimentations, including appropriate manipulation of the reaction conditions, reagents and sequence of the synthetic route, protection of any chemical functionality that cannot be compatible with the reaction conditions, and deprotection at a suitable point in the reaction sequence of the method are included in the scope of the invention. Suitable protecting groups and the methods for protecting and deprotecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which can be found in PGM Wuts and TW Greene, in Greene’s book titled Protective Groups in Organic Synthesis (4thed.), John Wiley & Sons, NY (2006), which is incorporated herein by reference in its entirety. Synthesis of the compounds of the invention can be accomplished by methods analogous to those described in the synthetic schemes described hereinabove and in specific examples.

[0118] When an optically active form of a disclosed compound is required, it can be obtained by carrying out one of the procedures described herein using an optically active starting material (prepared, for example, by asymmetric induction of a suitable reaction step), or by resolution of a mixture of the stereoisomers of the compound or intermediates using a standard procedure (such as chromatographic separation, recrystallization or enzymatic resolution).

[0119] Similarly, when a pure geometric isomer of a compound is required, it can be obtained by carrying out one of the above procedures using a pure geometric isomer as a starting material, or by resolution of a mixture of the geometric isomers of the compound or intermediates using a standard procedure such as chromatographic separation.

[0120] It can be appreciated that the synthetic schemes and specific examples as described are illustrative and are not to be read as limiting the scope of the invention as it is defined in the appended claims. All alternatives, modifications, and equivalents of the synthetic methods and specific examples are included within the scope of the claims. 3. Pharmaceutical Compositions and Formulations

[0121] The disclosed compounds may be incorporated into pharmaceutical compositions suitable for administration to a subject (such as a patient, which may be a human or non-human). The disclosed compounds may also be provided as formulations, such as spray-dried dispersion formulations.

[0122] The pharmaceutical compositions and formulations may include a “therapeutically effective amount” or a “prophylactically effective amount” of the agent. A “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. A therapeutically effective amount of the composition may be determined by a person skilled in the art and may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the composition to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of a compound of the invention (e.g., a compound of formula (I) or any of its subformulas) are outweighed by the therapeutically beneficial effects. A “prophylactically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount.

[0123] For example, a therapeutically effective amount of a compound of formula (I) or any of its subformulas, may be about 1 mg / kg to about 1000 mg / kg, about 5 mg / kg to about 950 mg / kg, about 10 mg / kg to about 900 mg / kg, about 15 mg / kg to about 850 mg / kg, about 20 mg / kg to about 800 mg / kg, about 25 mg / kg to about 750 mg / kg, about 30 mg / kg to about 700 mg / kg,about 35 mg / kg to about 650 mg / kg, about 40 mg / kg to about 600 mg / kg, about 45 mg / kg to about 550 mg / kg, about 50 mg / kg to about 500 mg / kg, about 55 mg / kg to about 450 mg / kg, about 60 mg / kg to about 400 mg / kg, about 65 mg / kg to about 350 mg / kg, about 70 mg / kg to about 300 mg / kg, about 75 mg / kg to about 250 mg / kg, about 80 mg / kg to about 200 mg / kg, about 85 mg / kg to about 150 mg / kg, and about 90 mg / kg to about 100 mg / kg.

[0124] The pharmaceutical compositions and formulations may include pharmaceutically acceptable carriers. The term “pharmaceutically acceptable carrier,” as used herein, means a non- toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as, but not limited to, lactose, glucose and sucrose; starches such as, but not limited to, corn starch and potato starch; cellulose and its derivatives such as, but not limited to, sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as, but not limited to, cocoa butter and suppository waxes; oils such as, but not limited to, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols; such as propylene glycol; esters such as, but not limited to, ethyl oleate and ethyl laurate; agar; buffering agents such as, but not limited to, magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as, but not limited to, sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

[0125] Thus, the compounds and their physiologically acceptable salts may be formulated for administration by, for example, solid dosing, eye drop, in a topical oil-based formulation, injection, inhalation (either through the mouth or the nose), implants, or oral, buccal, parenteral, or rectal administration. Techniques and formulations may generally be found in “Remington's Pharmaceutical Sciences,” (Meade Publishing Co., Easton, Pa.). Therapeutic compositions must typically be sterile and stable under the conditions of manufacture and storage.

[0126] The route by which the disclosed compounds are administered and the form of the composition will dictate the type of carrier to be used. The composition may be in a variety of forms, suitable, for example, for systemic administration (e.g., oral, rectal, nasal, sublingual,buccal, implants, or parenteral) or topical administration (e.g., dermal, pulmonary, nasal, aural, ocular, liposome delivery systems, or iontophoresis).

[0127] Carriers for systemic administration typically include at least one of diluents, lubricants, binders, disintegrants, colorants, flavors, sweeteners, antioxidants, preservatives, glidants, solvents, suspending agents, wetting agents, surfactants, combinations thereof, and others. All carriers are optional in the compositions.

[0128] Suitable diluents include sugars such as glucose, lactose, dextrose, and sucrose; diols such as propylene glycol; calcium carbonate; sodium carbonate; sugar alcohols, such as glycerin; mannitol; and sorbitol. The amount of diluent(s) in a systemic or topical composition is typically about 50 to about 90%.

[0129] Suitable lubricants include silica, talc, stearic acid and its magnesium salts and calcium salts, calcium sulfate; and liquid lubricants such as polyethylene glycol and vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma. The amount of lubricant(s) in a systemic or topical composition is typically about 5 to about 10%.

[0130] Suitable binders include polyvinyl pyrrolidone; magnesium aluminum silicate; starches such as corn starch and potato starch; gelatin; tragacanth; and cellulose and its derivatives, such as sodium carboxymethylcellulose, ethyl cellulose, methylcellulose, microcrystalline cellulose, and sodium carboxymethylcellulose. The amount of binder(s) in a systemic composition is typically about 5 to about 50%.

[0131] Suitable disintegrants include agar, alginic acid and the sodium salt thereof, effervescent mixtures, croscarmellose, crospovidone, sodium carboxymethyl starch, sodium starch glycolate, clays, and ion exchange resins. The amount of disintegrant(s) in a systemic or topical composition is typically about 0.1 to about 10%.

[0132] Suitable colorants include a colorant such as an FD&C dye. When used, the amount of colorant in a systemic or topical composition is typically about 0.005 to about 0.1%.

[0133] Suitable flavors include menthol, peppermint, and fruit flavors. The amount of flavor(s), when used, in a systemic or topical composition is typically about 0.1 to about 1.0%.

[0134] Suitable sweeteners include aspartame and saccharin. The amount of sweetener(s) in a systemic or topical composition is typically about 0.001 to about 1%.

[0135] Suitable antioxidants include butylated hydroxyanisole (“BHA”), butylated hydroxytoluene (“BHT”), and vitamin E. The amount of antioxidant(s) in a systemic or topical composition is typically about 0.1 to about 5%.

[0136] Suitable preservatives include benzalkonium chloride, methyl paraben and sodium benzoate. The amount of preservative(s) in a systemic or topical composition is typically about 0.01 to about 5%.

[0137] Suitable glidants include silicon dioxide. The amount of glidant(s) in a systemic or topical composition is typically about 1 to about 5%.

[0138] Suitable solvents include water, isotonic saline, ethyl oleate, glycerine, hydroxylated castor oils, alcohols such as ethanol, and phosphate buffer solutions. The amount of solvent(s) in a systemic or topical composition is typically from about 0 to about 100%.

[0139] Suitable suspending agents include AVICEL RC-591 (from FMC Corporation of Philadelphia, PA) and sodium alginate. The amount of suspending agent(s) in a systemic or topical composition is typically about 1 to about 8%.

[0140] Suitable surfactants include lecithin, Polysorbate 80, and sodium lauryl sulfate, and the TWEENS from Atlas Powder Company of Wilmington, Delaware. Suitable surfactants include those disclosed in the C.T.F.A. Cosmetic Ingredient Handbook, 1992, pp.587-592; Remington's Pharmaceutical Sciences, 15th Ed.1975, pp. 335-337; and McCutcheon's Volume 1, Emulsifiers & Detergents, 1994, North American Edition, pp.236-239. The amount of surfactant(s) in the systemic or topical composition is typically about 0.1% to about 5%.

[0141] Although the amounts of components in the systemic compositions may vary depending on the type of systemic composition prepared, in general, systemic compositions include 0.01% to 50% of an active compound (e.g., a compound of formula (I) or any of its subformulas) and 50% to 99.99% of one or more carriers. Compositions for parenteral administration typically include 0.1% to 10% of actives and 90% to 99.9% of a carrier including a diluent and a solvent.

[0142] Compositions for oral administration can have various dosage forms. For example, solid forms include tablets, capsules, granules, and bulk powders. These oral dosage forms include a safe and effective amount, usually at least about 5%, and more particularly from about 25% to about 50% of actives. The oral dosage compositions include about 50% to about 95% of carriers, and more particularly, from about 50% to about 75%.

[0143] Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or multiple-compressed. Tablets typically include an active component, and a carrier comprising ingredients selected from diluents, lubricants, binders, disintegrants, colorants, flavors, sweeteners, glidants, and combinations thereof. Specific diluents include calcium carbonate, sodium carbonate, mannitol, lactose and cellulose. Specific binders include starch, gelatin, and sucrose. Specific disintegrants include alginic acid and croscarmellose. Specific lubricants include magnesium stearate, stearic acid, and talc. Specific colorants are the FD&C dyes, which can be added for appearance. Chewable tablets preferably contain sweeteners such as aspartame and saccharin, or flavors such as menthol, peppermint, fruit flavors, or a combination thereof.

[0144] Capsules (including implants, time release and sustained release formulations) typically include an active compound (e.g., a compound of formula (I) or any of its subformulas), and a carrier including one or more diluents disclosed above in a capsule comprising gelatin. Granules typically comprise a disclosed compound, and preferably glidants such as silicon dioxide to improve flow characteristics. Implants can be of the biodegradable or the non-biodegradable type.

[0145] The selection of ingredients in the carrier for oral compositions depends on secondary considerations like taste, cost, and shelf stability, which are not critical for the purposes of this invention.

[0146] Solid compositions may be coated by conventional methods, typically with pH or time-dependent coatings, such that a disclosed compound is released in the gastrointestinal tract in the vicinity of the desired application, or at various points and times to extend the desired action. The coatings typically include one or more components selected from the group consisting of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, EUDRAGIT® coatings (available from Evonik Industries of Essen, Germany), waxes and shellac.

[0147] Compositions for oral administration can have liquid forms. For example, suitable liquid forms include aqueous solutions, emulsions, suspensions, solutions reconstituted from non-effervescent granules, suspensions reconstituted from non-effervescent granules, effervescent preparations reconstituted from effervescent granules, elixirs, tinctures, syrups, and the like. Liquid orally administered compositions typically include a disclosed compound and a carrier, namely, a carrier selected from diluents, colorants, flavors, sweeteners, preservatives,solvents, suspending agents, and surfactants. Peroral liquid compositions preferably include one or more ingredients selected from colorants, flavors, and sweeteners.

[0148] Other compositions useful for attaining systemic delivery of the subject compounds include sublingual, buccal and nasal dosage forms. Such compositions typically include one or more of soluble filler substances such as diluents including sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose, and hydroxypropyl methylcellulose. Such compositions may further include lubricants, colorants, flavors, sweeteners, antioxidants, and glidants.

[0149] The disclosed compounds can be topically administered. Topical compositions that can be applied locally to the skin may be in any form including solids, solutions, oils, creams, ointments, gels, lotions, shampoos, leave-on and rinse-out hair conditioners, milks, cleansers, moisturizers, sprays, skin patches, and the like. Topical compositions include: a disclosed compound (e.g., a compound of formula (I) or any of its subformulas), and a carrier. The carrier of the topical composition preferably aids penetration of the compounds into the skin. The carrier may further include one or more optional components.

[0150] The amount of the carrier employed in conjunction with a disclosed compound is sufficient to provide a practical quantity of composition for administration per unit dose of the compound. Techniques and compositions for making dosage forms useful in the methods of this invention are described in the following references: Modern Pharmaceutics, Chapters 9 and 10, Banker & Rhodes, eds. (1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms, 2nd Ed., (1976).

[0151] A carrier may include a single ingredient or a combination of two or more ingredients. In the topical compositions, the carrier includes a topical carrier. Suitable topical carriers include one or more ingredients selected from phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols, symmetrical alcohols, aloe vera gel, allantoin, glycerin, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 myristyl propionate, dimethyl isosorbide, castor oil, combinations thereof, and the like. More particularly, carriers for skin applications include propylene glycol, dimethyl isosorbide, and water, and even more particularly, phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols, and symmetrical alcohols.

[0152] The carrier of a topical composition may further include one or more ingredients selected from emollients, propellants, solvents, humectants, thickeners, powders, fragrances, pigments, and preservatives, all of which are optional.

[0153] Suitable emollients include stearyl alcohol, glyceryl monoricinoleate, glyceryl monostearate, propane-1,2-diol, butane-1,3-diol, mink oil, cetyl alcohol, isopropyl isostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetyl alcohol, cetyl palmitate, di-n-butyl sebacate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, arachis oil, castor oil, acetylated lanolin alcohols, petroleum, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, myristyl myristate, and combinations thereof. Specific emollients for skin include stearyl alcohol and polydimethylsiloxane. The amount of emollient(s) in a skin-based topical composition is typically about 5% to about 95%.

[0154] Suitable propellants include propane, butane, isobutane, dimethyl ether, carbon dioxide, nitrous oxide, and combinations thereof. The amount of propellant(s) in a topical composition is typically about 0% to about 95%.

[0155] Suitable solvents include water, ethyl alcohol, methylene chloride, isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethylsulfoxide, dimethyl formamide, tetrahydrofuran, and combinations thereof. Specific solvents include ethyl alcohol and homotopic alcohols. The amount of solvent(s) in a topical composition is typically about 0% to about 95%.

[0156] Suitable humectants include glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate, gelatin, and combinations thereof. Specific humectants include glycerin. The amount of humectant(s) in a topical composition is typically 0% to 95%.

[0157] The amount of thickener(s) in a topical composition is typically about 0% to about 95%.

[0158] Suitable powders include beta-cyclodextrins, hydroxypropyl cyclodextrins, chalk, talc, fullers earth, kaolin, starch, gums, colloidal silicon dioxide, sodium polyacrylate, tetra alkyl ammonium smectites, trialkyl aryl ammonium smectites, chemically-modified magnesium aluminum silicate, organically-modified montmorillonite clay, hydrated aluminum silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethyl cellulose, ethylene glycolmonostearate, and combinations thereof. The amount of powder(s) in a topical composition is typically 0% to 95%.

[0159] The amount of fragrance in a topical composition is typically about 0% to about 0.5%, particularly, about 0.001% to about 0.1%.

[0160] Suitable pH adjusting additives include HCl or NaOH in amounts sufficient to adjust the pH of a topical pharmaceutical composition. 4. Methods of Use

[0161] The disclosed compounds, pharmaceutical compositions and formulations may be used in methods for treatment of disorders, such as pulmonary arterial hypertension, aortic valve disease, myocardial infarction, or systemic sclerosis. The disclosed compounds and pharmaceutical compositions may also be used in methods for decreasing 5-HT2B receptor activity in a mammal. The methods further include cotherapeutic methods for improving treatment outcomes. In the methods of use described herein, additional therapeutic agent(s) may be administered simultaneously or sequentially with the disclosed compounds and compositions. a. Treating Disorders

[0162] The disclosed compounds, pharmaceutical compositions and formulations may be used in methods for treating, preventing, ameliorating, controlling, reducing, or reducing the risk of a variety of disorders, or symptoms of the disorders, in which a patient may benefit from antagonism of the 5-HT2B receptor. Disorders include migraine, inflammatory pain, gastroesophageal reflux disease (GERD), constipation, diarrhea, functional gastrointestinal disorder, irritable bowel syndrome (IBS), osteoarthritis, rheumatoid arthritis, Crohn's disease, ulcerative colitis, glomerulonephritis, nephritis, dermatitis, hepatitis, vasculitis, renal ischemia, cerebral stroke, cerebral ischemia, asthma, reversible airway obstruction, adult respiratory disease syndrome, chronic obstructive pulmonary disease (COPD), pulmonary hypertension, pulmonary arterial hypertension, idiopathic interstitial pneumonia, bronchitis, liver fibrosis, lung fibrosis, cryptogenic fibrosing alveolitis, obesity, hepatocellular cancer, small intestinal neuroendocrine tumors, cardiovascular disorders such as chronic heart disease, congestive heart failure, aortic valve disease, myocardial infarction (Marsit et al., J Am Coll Cardiol. 2022 Aug, 80 (5) 500–510), valvular fibrotic remodeling, ischemic mitral regurgitation, and hypertension, benign prostatic hyperplasia, priapism, incontinence, bladder dysfunction, disorders of the uterus such as dysmenorrhoea, pre-term labour, and post-partum remodeling,restenosis, and systemic sclerosis. In some embodiments, the disorder may be pulmonary arterial hypertension, aortic valve disease, or myocardial infarction. The methods may comprise administering to a subject in need of such treatment a therapeutically effective amount of the compound of formula (I) or any of its subformulas or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or any of its subformulas or a pharmaceutically acceptable salt thereof.

[0163] The compounds and compositions may be further useful in a method for the prevention, treatment, control, amelioration, or reduction of risk of the diseases, disorders and conditions noted herein. The compounds and compositions may be further useful in a method for the prevention, treatment, control, amelioration, or reduction of risk of the aforementioned diseases, disorders and conditions, in combination with other agents.

[0164] In the treatment of conditions such as those that would benefit from antagonism of the 5-HT2Breceptor, an appropriate dosage level may be about 0.01 to 500 mg per kg patient body weight per day, which can be administered in single or multiple doses. The dosage level may be about 0.1 to about 250 mg / kg per day, or about 0.5 to about 100 mg / kg per day. A suitable dosage level can be about 0.01 to 250 mg / kg per day, about 0.05 to 100 mg / kg per day, or about 0.1 to 50 mg / kg per day. Within this range the dosage can be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg / kg per day. For oral administration, the compositions may be provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, or 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds can be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. This dosage regimen can be adjusted to provide the optimal therapeutic response. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient can be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy. b. Antagonism of the 5-HT2BReceptor

[0165] In some embodiments, the disclosure relates to a method for antagonizing the 5-HT2Breceptor receptor in at least one cell, comprising the step of contacting the at least one cell withat least one disclosed compound or at least one product of a disclosed method in an amount effective to antagonize the 5-HT2B receptor in the at least one cell. In some embodiments, the cell is mammalian, for example, human. In some embodiments, the cell has been isolated from a subject prior to the contacting step. In some embodiments, contacting is via administration to a subject.

[0166] In some embodiments, the invention relates to a method for antagonizing the 5-HT2Breceptor in a subject, comprising the step of administering to the subject at least one disclosed compound or at least one product of a disclosed method in a dosage and amount effective to antagonize the 5-HT2B receptor in the subject. In some embodiments, the subject is mammalian, for example, human. In some embodiments, the mammal has been diagnosed with a need for 5- HT2B receptor antagonism prior to the administering step. In some embodiments, the mammal has been diagnosed with a need for 5-HT2Breceptor antagonism prior to the administering step. In some embodiments, the method further comprises the step of identifying a subject in need of 5-HT2Breceptor antagonism.

[0167] In some embodiments, the disclosure relates to a method for antagonizing the 5-HT2Breceptor in a mammal, comprising the step of administering to the mammal an effective amount of at least one disclosed compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising at least one disclosed compound or pharmaceutically acceptable salt thereof.

[0168] In some embodiments, the compound administered antagonizes the 5-HT2B receptor with an IC50of less than about 10 μM, less than about 5 μM, less than about 1 μM, less than about 500 nM, or less than about 100 nM. In some embodiments, the compound administered antagonizes the 5-HT2Breceptor with an IC50of between about 10 μM and about 1 nM, about 1 μM and about 1 nM, about 100 nM and about 1 nM, or about 10 nM and about 1 nM.

[0169] Compounds of formula (I) may exhibit selectivity for the 5-HT2B receptor over the 5- HT2A and / or 5-HT2C receptor subtypes. For example, the compounds of formula (I) may have higher affinity for the 5-HT2B receptor over the 5-HT2A and / or 5-HT2C receptors. Compounds of formula (I) may have greater than or equal to 3-fold or higher affinity for the 5-HT2Breceptor over the 5-HT2Aand / or 5-HT2Creceptors, for example, from 3-1000 fold or more higher 5-HT2Baffinity. Relative binding affinities may be determined by comparison of IC50or Kivalues.

[0170] In some embodiments, the mammal is a human. In some embodiments, the mammal has been diagnosed with a need for reduction of 5-HT2B receptor activity prior to the administering step. In some embodiments, the method further comprises the step of identifying a mammal in need of reducing 5-HT2Breceptor activity. In some embodiments, the antagonism of the 5-HT2Breceptor treats a disorder associated with 5-HT2Breceptor activity in the mammal.

[0171] In some embodiments, antagonism of the 5-HT2Breceptor in a mammal is associated with the treatment of a disorder associated with the 5-HT2Breceptor, such as a disorder disclosed herein. c. Combination Therapies

[0172] In the methods of use described herein, additional therapeutic agent(s) may be administered simultaneously or sequentially with the disclosed compounds and compositions. Sequential administration includes administration before or after the disclosed compounds and compositions. In some embodiments, the additional therapeutic agent or agents may be administered in the same composition as the disclosed compounds. In other embodiments, there may be an interval of time between administration of the additional therapeutic agent and the disclosed compounds. In some embodiments, administration of an additional therapeutic agent with a disclosed compound may allow lower doses of the other therapeutic agents and / or administration at less frequent intervals. When used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of Formula (I) or any of its subformulas. The above combinations include combinations of a compound of the present invention not only with one other active compound, but also with two or more other active compounds.

[0173] The disclosed compounds can be used as single agents or in combination with one or more other drugs in the treatment, prevention, control, amelioration or reduction of risk of diseases, disorders and conditions for which the compound or the other drugs have utility, where the combination of drugs together are safer or more effective than either drug alone. The other drug(s) can be administered by a route and in an amount commonly used therefor, contemporaneously or sequentially with a disclosed compound. When a disclosed compound is used contemporaneously with one or more other drugs, a pharmaceutical composition in unitdosage form containing such drugs and the disclosed compound may be used. However, the combination therapy can also be administered on overlapping schedules. It is also envisioned that the combination of one or more active ingredients and a disclosed compound can be more efficacious than either as a single agent. Thus, when used in combination with one or more other active ingredients, the disclosed compounds and the other active ingredients can be used in lower doses than when each is used singly.

[0174] The pharmaceutical compositions and methods of the present invention can further comprise other therapeutically active compounds as noted herein which are usually applied in the treatment of the above mentioned pathological conditions.

[0175] The above combinations include combinations of a disclosed compound not only with one other active compound, but also with two or more other active compounds. Likewise, disclosed compounds can be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which disclosed compounds are useful. Such other drugs can be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present invention. When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to a disclosed compound is preferred. Accordingly, the pharmaceutical compositions include those that also contain one or more other active ingredients, in addition to a compound of the present invention.

[0176] The weight ratio of a disclosed compound to the second active ingredient can be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with another agent, the weight ratio of a disclosed compound to the other agent will generally range from about 1000:1 to about 1:1000, preferably about 200:1 to about 1:200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.

[0177] In such combinations a disclosed compound and other active agents can be administered separately or in conjunction. In addition, the administration of one element can be prior to, concurrent to, or subsequent to the administration of other agent(s).

[0178] Accordingly, the disclosed compounds can be used alone or in combination with other agents which are known to be beneficial in the subject indications or other drugs that affect receptors or enzymes that either increase the efficacy, safety, convenience, or reduce unwanted side effects or toxicity of the disclosed compounds. The subject compound and the other agent can be coadministered, either in concomitant therapy or in a fixed combination.

[0179] In some embodiments, the compound can be employed in combination with any other agent that is used to treat a disorder described herein, such as a standard of care therapy for a disorder that would benefit from5-HT2B receptor antagonism, such as a disorder described herein.

[0180] In some embodiments, the compound can be employed in combination with vasodilators that target endothelin, nitric oxide, and / or prostacyclin pathways in the treatment of PAH. For example, the compound can be used in combination with phophodiesterase-5 (PDE-5) inhibitors (e.g., tadalafil, sildenafil), soluble guanylate cyclase (sGC) stimulators (e.g., riociguat), endothelin receptor blockers (e.g., bosentan, ambrisentan, macitentan), or prostacyclins (e.g., epoprostenol, treprostinil, iloprost).

[0181] For the treatment of myocardial infarction, the compound can be used in combination with platelet aggregation inhibitors such as the P2Y12 receptors antagonists (e.g., ticagrelor, cangrelor, clopidogrel), angiotensin II receptor blockers (e.g., valsartan), diuretics (e.g., hydrochlorothiazide), non-steroidal mineralocorticoid receptor antagonists (e.g., finerenone), anti-coagulants (e.g., enoxaparin), or thrombolytics (e.g., reteplase). d. Modes of Administration

[0182] Methods of treatment may include any number of modes of administering a disclosed composition. Modes of administration may include tablets, pills, dragees, hard and soft gel capsules, granules, pellets, aqueous, lipid, oily or other solutions, emulsions such as oil-in-water emulsions, liposomes, aqueous or oily suspensions, syrups, elixirs, solid emulsions, solid dispersions or dispersible powders. For the preparation of pharmaceutical compositions for oral administration, the agent may be admixed with commonly known and used adjuvants and excipients such as for example, gum arabic, talcum, starch, sugars (such as, e.g., mannitose, methyl cellulose, lactose), gelatin, surface-active agents, magnesium stearate, aqueous or non- aqueous solvents, paraffin derivatives, cross-linking agents, dispersants, emulsifiers, lubricants, conserving agents, flavoring agents (e.g., ethereal oils), solubility enhancers (e.g., benzyl benzoate or benzyl alcohol) or bioavailability enhancers (e.g. Gelucire™). In the pharmaceuticalcomposition, the agent may also be dispersed in a microparticle, e.g. a nanoparticulate composition. For parenteral administration, the agent can be dissolved or suspended in a physiologically acceptable diluent, such as, e.g., water, buffer, oils with or without solubilizers, surface-active agents, dispersants or emulsifiers. As oils for example and without limitation, olive oil, peanut oil, cottonseed oil, soybean oil, castor oil and sesame oil may be used. More generally spoken, for parenteral administration, the agent can be in the form of an aqueous, lipid, oily or other kind of solution or suspension or even administered in the form of liposomes or nano-suspensions.

[0183] The term “parenterally,” as used herein, refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion. 5. Kits

[0184] In one aspect, the disclosure provides a kit comprising at least one disclosed compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising at least one disclosed compound or a pharmaceutically acceptable salt thereof and instructions for use thereof.

[0185] The kits may comprise information, instructions, or both that use of the kit will provide treatment for medical conditions in mammals (particularly humans). The information and instructions may be in the form of words, pictures, or both, and the like. In addition or in the alternative, the kit may include the compound, a composition, or both; and information, instructions, or both, regarding methods of application of compound, or of composition, preferably with the benefit of treating or preventing medical conditions in mammals (e.g., humans). 6. Examples

[0186] All NMR spectra were recorded on a 400 MHz AMX Bruker NMR spectrometer.1H chemical shifts are reported in values in ppm downfield with the deuterated solvent as the internal standard. Data are reported as follows: chemical shift, multiplicity (s = singlet, bs = broad singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, m = multiplet, ABq = AB quartet), coupling constant, integration. Reversed-phase LCMS analysis was performed using an Agilent 1200 system comprised of a binary pump with degasser, high-performance autosampler, thermostatted column compartment, C18 column, diode-array detector (DAD) andan Agilent 6150 MSD with the following parameters. The gradient conditions were 5% to 95% acetonitrile with the aqueous phase 0.1% TFA in water over 1.4 minutes. Samples were separated on a Waters Acquity UPLC BEH C18 column (1.7 μm, 1.0 x 50 mm) at 0.5 mL / min, with column and solvent temperatures maintained at 55 ºC. The DAD was set to scan from 190 to 300 nm, and the signals used were 220 nm and 254 nm (both with a band width of 4nm). The MS detector was configured with an electrospray ionization source, and the low-resolution mass spectra were acquired by scanning from 140 to 700 AMU with a step size of 0.2 AMU at 0.13 cycles / second, and peak width of 0.008 minutes. The drying gas flow was set to 13 liters per minute at 300 ºC and the nebulizer pressure was set to 30 psi. The capillary needle voltage was set at 3000 V, and the fragmentor voltage was set at 100V. Data acquisition was performed with Agilent Chemstation and Analytical Studio Reviewer software. EXAMPLE 1. N-((1H-Benzo[d]imidazol-2-yl)methyl)-1-(1H-indazole-3-carbonyl)-3- methylazetidine-3-carboxamide

[0187] tert-Butyl 3-(((1H-benzo[d]imidazol-2-yl)methyl)carbamoyl)-3-methylazetidine- 1-carboxylate. To a vial was added 1-(tert-butoxycarbonyl)-3-methylazetidine-3-carboxylic acid (100 mg, 0.47 mmol, 1 eq) and (1H-benzo[d]imidazol-2-yl)methanamine dihydrochloride (124mg, 0.56 mmol, 1.2 eq), which were suspended in DCM (5 mL). To the stirring mixture was added triethylamine (194 μL, 1.39 mmol, 3 eq), followed by HATU (213 mg, 0.56 mmol, 1.2 eq). The resulting mixture was stirred at r.t. for 3 h, then was quenched with H2O and extracted several times with 3:1 chloroform / IPA solution (v / v). The organic layers were combined and concentrated, and the crude material was purified via normal-phase column chromatography (0- 100% EtOAc in hexanes, then 0-15% MeOH in DCM) to give the title compound (130 mg, 81%). Some impurities were present, but the material was carried forward without additional purification.1H NMR (400 MHz, acetone-d6) 10.95 (s, 1H), 8.27 (t, J = 5.4 Hz, 1H), 7.61 – 7.53 (m, 2H), 7.25 – 7.18 (m, 2H), 4.79 (d, J = 5.7 Hz, 2H), 4.21 (d, J = 7.9 Hz, 2H), 3.59 (d, J = 8.0 Hz, 2H), 1.54 (s, 3H), 1.38 (s, 9H). ES-MS [M+H]+= 345.3.

[0188] N-((1H-Benzo[d]imidazol-2-yl)methyl)-3-methylazetidine-3-carboxamide trifluoroacetic acid. To a vial containing tert-butyl 3-(((1H-benzo[d]imidazol-2- yl)methyl)carbamoyl)-3-methylazetidine-1-carboxylate (130 mg, 0.38 mmol, 1 eq) was added DCM (3.5 mL), followed by trifluoroacetic acid (580 μL, 7.57 mmol, 20 eq). The resulting solution was stirred at r.t. for 16 h, then was concentrated to give the title compound (100%), which was taken directly to the next step without further purification. ES-MS [M+H]+= 245.2.

[0189] N-((1H-Benzo[d]imidazol-2-yl)methyl)-1-(1H-indazole-3-carbonyl)-3- methylazetidine-3-carboxamide. To a vial containing N-((1H-benzo[d]imidazol-2-yl)methyl)- 3-methylazetidine-3-carboxamide trifluoroacetic acid (65.9 mg, 0.18 mmol, 1 eq) was added DMF (1 mL), followed by 1H-indazole-3-carboxylic acid (35.0 mg, 0.22 mmol, 1.2 eq) and DIPEA (95 μL, 0.55 mmol, 3 eq). The mixture was stirred, and HATU (101 mg, 0.27 mmol, 1.4eq) was added. The resulting reaction mixture was stirred at r.t. for 3.5 h, then was quenched with H2O and purified via RP-HPLC (5-50% MeCN in 0.05% aqueous NH4OH solution) to give the title compound (12.0 mg, 17%).1H NMR (400 MHz, DMSO-d6) 8.66 (t, J = 5.6 Hz, 1H), 8.17 (d, J = 8.2 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.56 – 7.36 (m, 3H), 7.26 - 7.21 (m, 1H), 7.16 – 7.09 (m, 2H), 4.86 (d, J = 9.9 Hz, 1H), 4.60 - 4.48 (m, 2H), 4.42 - 4.31 (m, 2H), 3.84 (d, J = 9.6 Hz, 1H), 1.58 (s, 3H). ES-MS [M+H]+= 389.3. EXAMPLE 2. 1-(1H-Indole-3-carbonyl)-N-((5-methyl-1H-benzo[d]imidazol-2- yl)methyl)azetidine-3-carboxamide

[0190] Methyl 1-(1H-indole-3-carbonyl)azetidine-3-carboxylate. To a solution of 1H- indole-3-carboxylic acid (300 mg, 1.86 mmol, 1 eq) and methyl azetidine-3-carboxylate hydrochloride (339 mg, 2.23 mmol, 1.2 eq) in DMF (10 mL) was added DIPEA (0.97 mL, 5.58 mmol, 3 eq), followed by HATU (849 mg, 2.23 mmol, 1.2 eq). The resulting reaction mixture was stirred at r.t. for 2 h, after which time the reaction mixture was diluted with H2O and EtOAc.The organic layer was washed with H2O and brine, and dried over MgSO4. The solvents were filtered and concentrated, and the crude residue was purified by normal-phase column chromatography (3-100% EtOAc in hexanes, then 0-40% DCM in EtOAc) to give the title compound as a white solid (103 mg, 21%). ES-MS [M+H]+= 259.1.

[0191] 1-(1H-Indole-3-carbonyl)azetidine-3-carboxylic acid. To a suspension of methyl 1- (1H-indole-3-carbonyl)azetidine-3-carboxylate (226 mg, 0.88 mmol, 1 eq) in THF (3 mL) and H2O (3 mL) was added LiOH (63 mg, 2.63 mmol, 3 eq). The resulting reaction mixture was stirred at r.t. for 1 h, after which time the reaction mixture was brought to pH = 3 with 2M aqueous HCl solution and extracted with DCM and 3:1 chloroform / IPA solution (v / v). The combined organic extracts were filtered through a hydrophobic phase separator and concentrated to give the title compound as a white solid (133 mg, 62%). ES-MS [M+H]+= 245.1.

[0192] 1-(1H-Indole-3-carbonyl)-N-((5-methyl-1H-benzo[d]imidazol-2- yl)methyl)azetidine-3-carboxamide. To a mixture of 1-(1H-indole-3-carbonyl)azetidine-3- carboxylic acid (13 mg, 0.053 mmol, 1 eq) and (5-methyl-1H-benzo[d]imidazol-2- yl)methanamine (13 mg, 0.080 mmol, 1.5 eq) in DMF (1 mL) was added DIPEA (0.046 mL, 0.27 mmol, 5 eq), followed by HATU (30 mg, 0.080 mmol, 1.5 eq). The resulting reaction mixture was stirred at r.t. overnight, after which time the reaction mixture was purified directly by RP-HPLC (6-46% MeCN in 0.05% aqueous NH4OH solution over 5 min). The fractions containing product were concentrated to give the title compound as a white solid (9.7 mg, 47%).1H NMR (400 MHz, DMSO) 8.69 (t, J = 5.7 Hz, 1H), 8.09 – 8.07 (m, 1H), 7.74 (s, 1H), 7.40 –7.38 (m, 1H), 7.36 – 7.17 (m, 2H), 7.14 – 7.05 (m, 2H), 6.92 (d, J = 8.2 Hz, 1H), 4.47 (d, J = 5.6 Hz, 2H), 4.44 – 3.96 (m, 4H), 3.53 – 3.45 (m, 1H), 2.35 (s, 3H). ES-MS [M+H]+= 388.3.

[0193] The compounds shown in Table 1 may be prepared similarly to the compounds described above, with appropriate starting materials. Compound 1 was purchased from Life Chemicals. Compounds 2-15 and 17-25 were prepared according to Example 1 above, with appropriate starting materials. Compounds 16 and 26-35 were prepared according to Example 2. Table 1EXAMPLE 3. Preparation of 1-(1H-indazole-3-carbonyl)-N-((1-(4-methoxybenzyl)-1H- benzo[d]imidazol-2-yl)methyl)-3-methylazetidine-3-carboxamide

[0194] tert-Butyl 3-(((1-(4-methoxybenzyl)-1H-benzo[d]imidazol-2- yl)methyl)carbamoyl)-3-methylazetidine-1-carboxylate. To a suspension of tert-butyl 3- (((1H-benzo[d]imidazol-2-yl)methyl)carbamoyl)-3-methylazetidine-1-carboxylate (693 mg, 2.01 mmol, 1 eq) and potassium carbonate (423 mg, 3.02 mmol, 1.5 eq) in DMF (10 mL) was added 1-(chloromethyl)-4-methoxybenzene (0.33 mL, 2.41 mmol, 1.2 eq) dropwise. The resulting reaction mixture was stirred at 50 °C overnight, after which time the reaction mixture was cooled to r.t. and diluted with EtOAc and brine. The organic layer was washed with brine and dried over MgSO4. The solvents were filtered and concentrated, and crude residue was purified via normal phase column chromatography (3-100% EtOAc in hexanes, then 0-5% MeOH in DCM) to give the title compound as a white solid (827 mg, 89%).1H NMR (400 MHz, CDCl3) 7.77 – 7.72 (m, 1H), 7.33 – 7.26 (m, 3H), 7.01 – 6.98 (m, 2H), 6.86 – 6.79 (m, 3H), 5.34 (s, 2H), 4.66 (d, J = 4.8 Hz, 2H), 4.16 (d, J = 8.3 Hz, 2H), 3.76 (s, 3H), 3.64 (d, J = 8.4 Hz, 2H), 1.53 (s, 3H), 1.43 (s,

[0195] N-((1-(4-methoxybenzyl)-1H-benzo[d]imidazol-2-yl)methyl)-3-methylazetidine-3- carboxamide. To a stirring solution of tert-butyl 3-(((1-(4-methoxybenzyl)-1H- benzo[d]imidazol-2-yl)methyl)carbamoyl)-3-methylazetidine-1-carboxylate (821 mg, 1.77 mmol, 1 eq) in DCM (9 mL) was added TFA (3 mL). The resulting reaction mixture was stirredat r.t. for 30 min, after which time the reaction was slowly quenched with sat. NaHCO3 solution, and the aqueous layer was extracted with DCM and 3:1 chloroform / IPA (v / v). Combined organic extracts were dried over MgSO4, and solvents were filtered and concentrated to give the title compound as a tan solid, which was used without additional purification (644 mg, 100%). ES- MS [M+H]+= 365.3.

[0196] 1-(1H-Indazole-3-carbonyl)-N-((1-(4-methoxybenzyl)-1H-benzo[d]imidazol-2- yl)methyl)-3-methylazetidine-3-carboxamide (compound 36). To a stirring solution of N-((1- (4-methoxybenzyl)-1H-benzo[d]imidazol-2-yl)methyl)-3-methylazetidine-3-carboxamide (644 mg, 1.77 mmol, 1 eq) and indazole-3-carboxylic acid (315 mg, 1.94 mmol, 1.1 eq) in DCM (10 mL) was added DIPEA (0.92 mL, 5.3 mmol, 3 eq), followed by HATU (807 mg, 2.12 mmol, 1.2 eq). The resulting reaction mixture was stirred at r.t. for 1 h, after which time the reaction mixture was diluted with H2O and DCM. The aqueous layer was extracted with DCM, and combined organic extracts were filtered through a hydrophobic phase separator and concentrated. Crude residue was purified via normal phase column chromatography (3-100% EtOAc in hexanes, then 0-7% MeOH in DCM) to give the title compound as an off white solid (330 mg, 37%).1H NMR (400 MHz, DMSO) 8.71 (t, J = 5.7 Hz, 1H), 8.17 (d, J = 8.2 Hz, 1H), 7.62 – 7.57 (m, 2H), 7.43 – 7.38 (m, 2H), 7.23 (ddd, J = 7.9, 6.9, 0.9 Hz, 1H), 7.19 – 7.14 (m, 2H), 7.09 – 7.06 (m, 2H), 6.84 – 6.80 (m, 2H), 5.44 (s, 2H), 4.70 (d, J = 9.9 Hz, 1H), 4.65 (dd, J = 5.7, 1.7 Hz, 2H), 4.27 (d, J = 9.9 Hz, 1H), 4.22 (J = 9.8 Hz, 1H), 3.77 (d, J = 9.7 Hz, 1H), 3.60 (s, 3H), 1.48 (s, 3H). ES-MS [M+H]+= 509.2. EXAMPLE 4. Preparation of tert-butyl 3-(3-(((1-(tert-butoxycarbonyl)-1H- benzo[d]imidazol-2-yl)methyl)carbamoyl)-3-methylazetidine-1-carbonyl)-1H-indazole-1- carboxylate

[0197] tert-Butyl 3-(3-(((1-(tert-butoxycarbonyl)-1H-benzo[d]imidazol-2- yl)methyl)carbamoyl)-3-methylazetidine-1-carbonyl)-1H-indazole-1-carboxylate (compound 37). To a solution of N-((1H-benzo[d]imidazol-2-yl)methyl)-1-(1H-indazole-3- carbonyl)-3-methylazetidine-3-carboxamide (24 mg, 0.062 mmol, 1 eq) and DMAP (1.5 mg, 0.012 mmol, 0.2 eq) in DCM (1 mL) was added DIPEA (0.032 mL, 0.19 mmol, 3 eq), followed by a solution of Boc anhydride (40 mg, 0.19 mmol, 3 eq) in DCM (0.5 mL). The resulting reaction mixture was stirred at r.t. overnight, after which time solvents were concentrated. Crude residue was purified via normal phase column chromatography (3-100% EtOAc in hexanes) to give the title compound as a white solid (24.5 mg, 67%).1H NMR (400 MHz, CDCl3) 8.42 – 8.38 (m, 1H), 8.12 (d, J = 8.5 Hz, 1H), 7.98 – 7.92 (m, 1H), 7.71 – 7.67 (m, 1H), 7.54 (ddd, J = 8.5, 7.1, 1.2 Hz, 1H), 7.41 – 7.32 (m, 4H), 5.08 (d, J = 10.2 Hz, 1H), 4.99 – 4.88 (m, 2H), 4.65 (d, J = 10.1 Hz, 1H), 4.59 (d, J = 10.7 Hz, 1H), 4.08 (d, J = 11.0 Hz, 1H), 1.77 (s, 3H), 1.73 (s, 9H), 1.72 (s, 9H). ES-MS [M+H]+= 589.4. Biological Activity A. 5-HT2BCalcium Mobilization Assay

[0198] To determine the functional activity of compounds in a cellular assay, receptor- induced mobilization of intracellular calcium was measured in tetracycline (Tet)-inducible human 5-HT2Bin Flp-In 293 T-Rex (Invitrogen) cells (Kaplan A.L. et al. Nature 2022; 610:582- 591). The stable 5-HT2B- Flp-In 293 T-Rex cells were cultured in DMEM medium containing10% Tet-tested fetal bovine serum (R&D Systems), 2 mM glutamine, 1 mM sodium pyruvate, non-essential amino acid mixture, 20 mM HEPES, 100 units / mL antibiotics / antimycotic, 200 μg / mL hygromycin, and 20 μg / mL blasticidin. All reagents used were from Life Technologies (Carlsbad, CA) unless otherwise noted.

[0199] The day before the assay, the stable 5-HT2Bcells (20,000 cells / 20 L / well) were plated in black-walled, clear-bottomed, amine-treated 384 well plates (Corning) in the plating medium that contains 2 μg / mL Tet to induce the receptor expression. The plating medium was DMEM supplemented with 1% dialyzed fetal bovine serum, 2 mM glutamine, 1 mM sodium pyruvate, non-essential amino acid mixture, 20 mM HEPES, and 100 units / mLantibiotics / antimycotic. The cell plates were incubated overnight at 37 °C in the presence of 5% CO2. The next day, a calcium assay buffer (Hank’s balanced salt solution (HBSS), 20 mM HEPES, 2.5 mM Probenecid, 4.16 mM sodium bicarbonate (Sigma-Aldrich, St. Louis, MO)) was prepared to dilute compounds, agonists, and Fluo-4-acetomethoxyester (Fluo- 4-AM, Ion Biosciences), fluorescent calcium indicator dye. Compounds were serially diluted 1:3 into 10 point concentration response curves in DMSO using the Bravo Liquid Handler (Agilent, Santa Clara, CA), transferred to a 384 well daughter plates using an Echo acoustic liquid handler (Beckman Coulter, Indianapolis, Indiana), and diluted in assay Buffer to a 2X final concentration. The agonist plates were prepared using 5-HT (Tocris) concentrations for the EC20, EC80 and ECMAX responses by diluting in assay buffer to a 5X final concentration. The 2X dye solution (2.3 μM) was prepared by mixing a 2.3 mM Fluo-4-AM stock in DMSO with 10% (w / v) pluronic acid F-127 in a 1:1 ratio in assay buffer. Using a microplate washer (BioTek, Winooski, VT), cells were washed with assay buffer 3 times to remove medium. After the final wash, 20 L of assay buffer remained in the cell plates. Immediately, 20 L of the 2X dye solution (final 1.15 μM) was added to each well of the cell plate using a Multidrop Combi dispenser (Thermo Fisher, Waltham, MA). After cells were incubated with the dye solutions for 45 min at 37 °C in the presence of 5% CO2, the dye solutions were removed and replaced with assay buffer using a microplate washer, leaving 20 L of assay buffer in the cell plate. The compound, agonist, and cell plates were placed inside the Functional Drug Screening System (FDSS 7000 or uCell, Hamamatsu, Japan) to measure the calcium flux. The triple add protocol was used to measure Ca kinetics; Compound, 5-HT for EC20, 5-HT for EC80 / Maxadds in an order.

[0200] Briefly, after establishing a fluorescence baseline for 2 seconds (excitation, 480 nm;emission, 530 nm), a first add occurred by adding 20 μL of test compound to the cells, and the response was measured for 140 seconds. This was followed by a second add; 10 μL (5X) of an EC20 concentration of 5-HT agonist was added to the cells, and the response of the cells was measured for 125 seconds. Immediately after the second add, a third add occurred by adding 12 μL (5X) of an EC80concentration of 5-HT agonist, and the response of the cells was measured for 90 seconds. Vehicle (0.6 % DMSO) in assay buffer was added to the control wells at the first add to ensure 5-HT EC20, EC80,ECMaxresponse in the absence of testing compounds. Calcium fluorescence was recorded as fold over basal fluorescence and raw data were normalized to the maximal response to 5-HT agonist (ECMax). The compound-evoked decrease in calcium response in the presence of 5-HT EC80 agonist was determined as inhibition activity of antagonist, and potency (IC50), and the maximum inhibition response (% 5-HTMin) of compounds were determined using a four-parameter logistical equation using GraphPad Prism (La Jolla, CA) orthe Dotmatics software platform (Woburn, MA):where A is the molar concentration of the compound; bottom and top denote the lower and upper plateaus of the concentration-response curve; HillSlope is the Hill coefficient that describes the steepness of the curve; and EC50 is the molar concentration of compound required to generate a response halfway between the top and bottom.

[0201] IC50 values for selected compounds were determined as described above and are shown in Table 2. Table 2.B. 5-HT2ASelectivity Assay

[0202] Functional activities of the compounds at human 5-HT2A were assessed by measuring the receptor-induced mobilization of intracellular calcium. Chinese Hamster Ovary (CHO) stably expressing human 5-HT2A(5-HT2A-CHO) were cultured in F12 medium containing 10% fetal bovine serum, 20 mM HEPES, 100 units / mL antibiotics / antimycotic, 0.5 mg / mL G418. Calcium flux assay performed as exactly described above except that cells were plated in (15,000 cells / 20 L / well) in black-walled, clear-bottomed, 384 well plates (Greiner Bio-One, Monroe, NC) in F12 medium containing 10% dialyzed fetal bovine serum, 20 mM HEPES, and 100 units / mL antibiotics / antimycotic. IC50 values for compounds 1-16, 17-19, and 21 were >10,000 nM for the 5-HT2A receptor.

[0203] It is understood that the foregoing detailed description and accompanying examples are merely illustrative and are not to be taken as limitations upon the scope of the invention, which is defined solely by the appended claims and their equivalents.

[0204] Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including without limitation those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, compositions, formulations, or methods of use of the invention, may be made without departing from the spirit and scope thereof.

Claims

CLAIMS 1. A compound of formula (I), or a pharmaceutically acceptable salt thereof,wherein: X1is nitrogen or C-H; R1and R2, together with the atoms to which they are attached, form a 5- to 8-membered partially unsaturated carbocycle, a 6-membered arene, or a 6-membered heteroarene containing 1-2 nitrogen atoms, each optionally substituted with R10and further optionally substituted with 1- 5 R11; or, alternatively, R1is hydrogen, C1-4alkyl, C1-2fluoroalkyl, or G1; R2is hydrogen, C1-4alkyl, C1-2fluoroalkyl, or G2; R10is C1-4alkyl, C1-2fluoroalkyl, halogen, cyano, oxo, G10, –OR10a, –C(O)R10a, or –C(O)OR10a; R10ais hydrogen, C1-4alkyl, C1-2fluoroalkyl, or C3-4cycloalkyl; R11, at each occurrence, is independently C1-4alkyl, halogen, or oxo; G1, G2, and G10are independently a C3-4cycloalkyl, wherein the cycloalkyl is optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, C1-4alkyl, C1-2fluoroalkyl, and –OC1-4alkyl; n is 0, 1, 2, 3, or 4; R3, at each occurrence, is independently selected from the group consisting of halogen, C1-4alkyl, and C1-2fluoroalkyl; L1is C1-3alkylene; m is 0, 1, 2, 3, or 4; and R4at each occurrence, is independently C1-4alkyl, C1-2fluoroalkyl, halogen, –OH, –OC1-4alkyl, or C3-4cycloalkyl; with the proviso that the compound is not N-((1H-benzo[d]imidazol-2-yl)methyl)-1-(1H-indole- 3-carbonyl)azetidine-3-carboxamide.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X1is nitrogen.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X1is C-H.

4. The compound of any of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein R1and R2, together with the atoms to which they are attached, form the optionally substituted 5- to 8-membered partially unsaturated carbocycle.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein the ring system of the optionally substituted 5- to 8-membered partially unsaturated carbocycle formed by R1and R2is a 6-membered partially unsaturated carbocycle.

6. The compound of any of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein R1and R2, together with the atoms to which they are attached, form the optionally substituted 6-membered arene.

7. The compound of any of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein R1and R2, together with the atoms to which they are attached, form the optionally substituted 6-membered heteroarene containing 1-2 nitrogen atoms.

8. The compound of any of claims 1-3 or 7, or a pharmaceutically acceptable salt thereof, wherein the ring system of the optionally substituted 6-membered heteroarene formed by R1and R2is pyridine.

9. The compound of any of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein R1and R2, together with the atoms to which they are attached, form,, 10. The compound of any of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein R1is hydrogen.

11. The compound of any of claims 1-3 or 10, or a pharmaceutically acceptable salt thereof, wherein R2is C1-4alkyl.

12. The compound of any of claims 1-3 or 10-11, or a pharmaceutically acceptable salt thereof, wherein R2is –CH3.

13. The compound of any of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein n is 0.

14. The compound of any of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein n is 1.

15. The compound of any of claims 1-12 or 14, or a pharmaceutically acceptable salt thereof, wherein R3is C1-4alkyl or halogen.

16. The compound of any of claims 1-12 or 14-15, or a pharmaceutically acceptable salt thereof, wherein R3is –CH3or fluoro.

17. The compound of compound of any of claims 1-13 or 14-16, or a pharmaceutically acceptable salt thereof, wherein.

18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein.

19. The compound of any of claims 1-18, or a pharmaceutically acceptable salt thereof, wherein L1is –CH2–.

20. The compound of any of claims 1-19, or a pharmaceutically acceptable salt thereof, wherein m is 0.

21. The compound of any of claims 1-19, or a pharmaceutically acceptable salt thereof, wherein m is 1.

22. The compound of any of claims 1-19 or 21, or a pharmaceutically acceptable salt thereof, wherein R4is C1-4alkyl.

23. The compound of any of claims 1-19 or 21-22, or a pharmaceutically acceptable salt thereof, wherein R4is –CH3.

24. The compound of claim 1, selected from the group consisting of: N-((1H-benzo[d]imidazol-2-yl)methyl)-1-(1H-indazole-3-carbonyl)azetidine-3-carboxamide N-((1H-benzo[d]imidazol-2-yl)methyl)-1-(1H-indazole-3-carbonyl)-3-methylazetidine-3- carboxamide N-((1H-benzo[d]imidazol-2-yl)methyl)-1-(4-methoxy-1H-indazole-3-carbonyl)-3- methylazetidine-3-carboxamideN-((1H-benzo[d]imidazol-2-yl)methyl)-1-(4-chloro-1H-indazole-3-carbonyl)-3- methylazetidine-3-carboxamide N-((1H-benzo[d]imidazol-2-yl)methyl)-1-(4-bromo-1H-indazole-3-carbonyl)-3- methylazetidine-3-carboxamide N-((1H-benzo[d]imidazol-2-yl)methyl)-1-(5-fluoro-1H-indazole-3-carbonyl)-3- methylazetidine-3-carboxamide N-((1H-benzo[d]imidazol-2-yl)methyl)-1-(5-chloro-1H-indazole-3-carbonyl)-3- methylazetidine-3-carboxamide N-((1H-benzo[d]imidazol-2-yl)methyl)-3-methyl-1-(4-methyl-1H-pyrazole-3- carbonyl)azetidine-3-carboxamide N-((1H-benzo[d]imidazol-2-yl)methyl)-3-methyl-1-(1H-pyrrolo[2,3-c]pyridine-3- carbonyl)azetidine-3-carboxamide N-((1H-benzo[d]imidazol-2-yl)methyl)-3-methyl-1-(4,5,6,7-tetrahydro-1H-indazole-3- carbonyl)azetidine-3-carboxamide N-((1H-benzo[d]imidazol-2-yl)methyl)-1-(6-fluoro-1H-indazole-3-carbonyl)-3- methylazetidine-3-carboxamide (2S,3R)-N-((1H-benzo[d]imidazol-2-yl)methyl)-1-(1H-indazole-3-carbonyl)-2- methylazetidine-3-carboxamide (2R,3S)-N-((1H-benzo[d]imidazol-2-yl)methyl)-1-(1H-indazole-3-carbonyl)-2- methylazetidine-3-carboxamide N-((1H-benzo[d]imidazol-2-yl)methyl)-1-(5-chloro-1H-indazole-3-carbonyl)-3- fluoroazetidine-3-carboxamide 1-(1H-indole-3-carbonyl)-N-((5-methyl-1H-benzo[d]imidazol-2-yl)methyl)azetidine-3- carboxamide N-((1H-benzo[d]imidazol-2-yl)methyl)-1-(6-fluoro-1H-indole-3-carbonyl)azetidine-3- carboxamide N-((1H-benzo[d]imidazol-2-yl)methyl)-1-(1H-pyrrolo[3,2-b]pyridine-3-carbonyl)azetidine-3- carboxamide N-((1H-benzo[d]imidazol-2-yl)methyl)-1-(1H-pyrazolo[4,3-b]pyridine-3-carbonyl)azetidine-3- carboxamideN-((1H-benzo[d]imidazol-2-yl)methyl)-3-fluoro-1-(1H-indazole-3-carbonyl)azetidine-3- carboxamide; N-((1H-benzo[d]imidazol-2-yl)methyl)-3-fluoro-1-(5-fluoro-1H-indazole-3- carbonyl)azetidine-3-carboxamide; N-((1H-benzo[d]imidazol-2-yl)methyl)-1-(4,6-difluoro-1H-indazole-3-carbonyl)-3- methylazetidine-3-carboxamide; N-((1H-benzo[d]imidazol-2-yl)methyl)-1-(4-fluoro-1H-indazole-3-carbonyl)-3- methylazetidine-3-carboxamide; N-((1H-indazol-5-yl)methyl)-1-(1H-indole-3-carbonyl)azetidine-3-carboxamide; N-((3H-imidazo[4,5-c]pyridin-2-yl)methyl)-1-(1H-indazole-3-carbonyl)-3-methylazetidine-3- carboxamide; N-((5-fluoro-1H-benzo[d]imidazol-2-yl)methyl)-1-(1H-indazole-3-carbonyl)-3- methylazetidine-3-carboxamide; (R)-N-(1-(1H-benzo[d]imidazol-2-yl)ethyl)-1-(1H-indazole-3-carbonyl)-3-methylazetidine-3- carboxamide; (S)-N-(1-(1H-benzo[d]imidazol-2-yl)ethyl)-1-(1H-indazole-3-carbonyl)-3-methylazetidine-3- carboxamide N-((5-chloro-1H-benzo[d]imidazol-2-yl)methyl)-1-(1H-indazole-3-carbonyl)-3- methylazetidine-3-carboxamide; N-((1H-benzo[d]imidazol-2-yl)methyl)-1-(1H-indazole-3-carbonyl)-N,3-dimethylazetidine-3- carboxamide; N-((3H-imidazo[4,5-b]pyridin-2-yl)methyl)-1-(1H-indazole-3-carbonyl)-3-methylazetidine-3- carboxamide; 1-(1H-indazole-3-carbonyl)-3-methyl-N-((5-(trifluoromethyl)-1H-benzo[d]imidazol-2- yl)methyl)azetidine-3-carboxamide; N-((5-butyl-1H-benzo[d]imidazol-2-yl)methyl)-1-(1H-indazole-3-carbonyl)-3- methylazetidine-3-carboxamide; 1-(1H-indazole-3-carbonyl)-N-((1-(4-methoxybenzyl)-1H-benzo[d]imidazol-2-yl)methyl)-3- methylazetidine-3-carboxamide; tert-butyl 3-(3-(((1-(tert-butoxycarbonyl)-1H-benzo[d]imidazol-2-yl)methyl)carbamoyl)-3- methylazetidine-1-carbonyl)-1H-indazole-1-carboxylate;or a pharmaceutically acceptable salt thereof.

25. A pharmaceutical composition comprising the compound of any of claims 1-24, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

26. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof,wherein: X1is nitrogen or C-H; R1and R2, together with the atoms to which they are attached, form a 5- to 8-membered carbocycle, a 6-membered arene, or a 6-membered heteroarene containing 1-2 nitrogen atoms, each optionally substituted with R10and further optionally substituted with 1-5 R11; or, alternatively, R1is hydrogen, C1-4alkyl, C1-2fluoroalkyl, or G1; R2is hydrogen, C1-4alkyl, C1-2fluoroalkyl, or G2; R10is C1-4alkyl, C1-2fluoroalkyl, halogen, cyano, oxo, G10, –OR10a, –C(O)R10a, or –C(O)OR10a; R10ais hydrogen, C1-4alkyl, C1-2fluoroalkyl, or C3-4cycloalkyl; R11, at each occurrence, is independently C1-4alkyl, halogen, or oxo; G1, G2, and G10are independently a C3-4cycloalkyl, wherein the cycloalkyl is optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, C1-4alkyl, C1-2fluoroalkyl, and –OC1-4alkyl; n is 0, 1, 2, 3, or 4; R3, at each occurrence, is independently selected from the group consisting of halogen, C1-4alkyl, and C1-2fluoroalkyl; L1is C1-3alkylene; m is 0, 1, 2, 3, or 4; andR4, at each occurrence, is independently C1-4alkyl, C1-2fluoroalkyl, halogen, –OH, –OC1-4alkyl, and C3-4cycloalkyl; and a pharmaceutically acceptable carrier.

27. A method of antagonizing the 5-HT2Breceptor in a subject comprising administering to the subject, an effective amount of the compound of any of claims 1-24, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 25 or 26.

28. A method of treating pulmonary arterial hypertension, aortic valve disease, myocardial infarction, or systemic sclerosis, comprising administering to a subject in need thereof, a therapeutically effective amount of the compound of any of claims 1-24, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 25 or 26.

29. A compound of any of claims 1-24, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any of claim 25 or 26, for use in a method of treating pulmonary arterial hypertension, aortic valve disease, myocardial infarction, or systemic sclerosis.

30. Use of a compound of any of claims 1-24, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any of claims 25-26, in the manufacture of a medicament for treating pulmonary arterial hypertension, aortic valve disease, myocardial infarction, or systemic sclerosis.

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