Prostaglandin receptor EP2 antagonists, derivatives, and uses related thereto

Abstract

Disclosed herein are prostaglandin receptor EP2 antagonists, derivatives, compositions, and methods related thereto. In certain embodiments, the disclosure relates to methods of treating or preventing conditions and diseases in which EP2 receptor activation has a physiological role by administering a compound disclosed herein to a subject in need thereof.

Description

[0001] PROSTAGLANDIN RECEPTOR EP2 ANTAGONISTS, DERIVATIVES, AND USES

[0002] RELATED THERETO

[0003] CROSS-REFERENCE TO RELATED APPLICATIONS

[0004] This application claims the benefit of U.S. Provisional Application No. 63 / 695,328 filed September 16, 2024. The entirety of this application is hereby incorporated by reference for all purposes.

[0005] STATEMENT REGARDING FEDERALLY FUNDED RESEARCH

[0006] This invention was made with government support under -AG052460, NS127386, NS113879, and NS058158 awarded by the National Institutes of Health. The government has certain rights in the invention.

[0007] BACKGROUND

[0008] Cyclooxygenase-2 (COX-2) is a driver of inflammation in many diseases and disorders. These diseases include rheumatoid arthritis, osteoarthritis, endometriosis, postoperative pain, inflammatory bowel disorders, Alzheimer’s Disease, certain cancers, and epilepsy, among others. COX-2 is rapidly upregulated in damaged tissue, for example in the central nervous system (CNS) after a prolonged seizure or cerebral ischemia. Status epilepticus is a condition in which the brain is in a state of persistent seizure. Longer seizure duration, cerebral insult, and refractory convulsive status epilepticus were strongly associated with poor outcomes suggesting a role for early neuroprotective strategies. See Legriel et al., Critical Care Medicine, 2010, 38 (12):2295-2303. Thus, there is a need to identify improved methods for treating or preventing patients recovering from prolonged seizures.

[0009] In the CNS, COX-2 induction overall contributes to neuroinflammation and neurodegeneration by producing prostaglandins. Pharmacological inhibition of COX can provide relief from the symptoms of inflammation and pain. Prostaglandin E2 (PGE2), a dominant enzymatic product of COX- 2 in CNS, can activate four G protein-coupled receptors (GPCRs): EPl, EP2, EP3 and EP4. When activated by PGE2, EP2 stimulates adenylate cyclase (AC) resulting in elevation of cytoplasmic cyclic AMP (cAMP) concentration, which triggers multiple downstream events mediated by protein kinase A (PKA) and exchange protein activated by cAMP (Epac). PGE2 / EP2 signaling plays a variety of roles. For example, PGE2 is a major mediator of inflammation and pain. PGE2 is one of the major prostanoid species in inflammatory lesions such as arthritic joints and endometriotic lesions and shows pleiotropic proinflammatory actions in vitro.

[0010] PGE2 signaling through EP2 / EP4 exacerbates symptoms of inflammation by increasing IL-23 expression and reducing IL-12 / IL-27, which together causes T-cells to differentiate to Th 17 effectors both in inflammatory bowel disease (colitis) and arthritis. The PGE2 / EP2 system up-regulates a variety of inflammatory mediators including chemokines, cytokines, nitric oxide, and prostaglandins, to develop and maintain the inflammatory response.

[0011] In the brain, based on the phenotype of EP2 knockout mice, EP2 activation in microglia promotes inflammation and neurotoxicity in animal models of neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). See e.g., Liang et al. report deletion of the prostaglandin E2 EP2 receptor reduces oxidative damage and amyloid burden in a model of Alzheimer's disease. J Neurosci. 2005, 25(44): 10180-7.

[0012] Qiu et al. report small-molecule inhibition of prostaglandin E receptor 2 impairs cyclooxygenase-associated malignant glioma growth. Br J Pharmacol, 2019, 176(11): 1680-1699. Hou et al. report targeting EP2 receptor for neuroblastoma. Biomed Pharmacother, 2022, 156: 113966. Baryawno et al. report tumor-growth-promoting cyclooxygenase-2 prostaglandin E2 pathway provides medulloblastoma therapeutic targets. Neuro Oncol, 2008, 10(5): 661-674.

[0013] Because PGE2 / EP2 signaling mediates both peripheral and neural inflammation, pharmacological targeting of this pathway can have beneficial implications for the treatment of inflammatory diseases. Thus, there is a need to identify agents that can inhibit PGE2 / EP2 signaling.

[0014] Buchmann et al., (WO / 2008 / 152099) report compositions for the treatment of disorders connected with the EP2 receptor. See also U.S. Published Patent Applications 2014 / 0179750 2017 / 0042905, 2017 / 0081314, and 2018 / 0318315.

[0015] Rojas et al. report inhibition of the prostaglandin E2 receptor EP2 prevents status epilepticus- induced memory deficits. Neuropharmacology, 2016, 110(Pt A):419-430.

[0016] Ganesh et al. report an EP2 antagonist with anti-inflammatory properties, Mol Pharmaceutics, 2018, 15 (12), pp 5809-5817.

[0017] Aoki et al. report prostaglandin E2-EP2-NF-KB signaling in macrophages as a potential therapeutic target for intracranial aneurysms. Sci Signal, 2017, 10(465).

[0018] Amaradhi et al. report prostaglandin Receptor EP2 Antagonist, TG8-260. ACS Pharmacol Transl Sci, 2022, 5(2): 118-133. Jiang et al. report a role of prostaglandin receptor EP2 in the regulations of cancer cell proliferation, invasion, and inflammation. J Pharmacol Exp Ther, 2013, 344(2): 360-367.

[0019] References cited herein are not an admission of prior art.

[0020] SUMMARY

[0021] It has been discovered that certain compounds antagonize EP2 signaling. In some embodiments, this disclosure relates to compounds and methods of treating or preventing EP2 associated diseases or conditions comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein or derivatives, salts, and prodrug forms thereof.

[0022] In certain embodiments, the compound is l-methyl-N-(2-(2-methyl-lH-indol-3-yl)ethyl)-lH- pyrrolo[2,3-c]pyridine-2-carboxamide, derivative, prodrug, or salt thereof. In certain embodiments, the compound is 5-methoxy-l-methyl-N-(2-(2-methyl-lH-indol-3-yl)ethyl)-lH-pyrrolo[2,3-c]pyridine-2- carboxamide (BPN-37112), derivative, prodrug, or salt thereof. In certain embodiments, the compound is l,7-dimethyl-N-(2-(2-methyl-lH-indol-3-yl)ethyl)-lH-pyrrolo[2,3-c]pyridine-2-carboxamide (BPN-37440), derivative, prodrug, or salt thereof. In certain embodiments, the compounds can be combined with one or more pharmaceutically acceptable excipients to form a pharmaceutical composition. Example excipients include diluent, carrier, or filler.

[0023] In certain embodiments, the compounds described herein can be used to treat a variety of diseases or conditions related to an EP2 receptor including, but not limited to, cancer, brain cancer, glioma, glioblastoma, neuroblastoma, medulloblastoma, brain injury, neuropathic pain, hypertension, ischemic or hemorrhagic injury, neuroinflammation after a seizure, endometriosis, cancer, inflammatory bowel disease (colitis), arthritis / rheumatoid arthritis, skin inflammation, vascular inflammation, Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), kidney disease / transplant rejection, atherosclerosis, ischaemic heart disease, acne vulgaris, asthma, chronic prostatitis, glomerulonephritis, hypersensitivities, pelvic inflammatory disease, sarcoidosis, vasculitis, interstitial cystitis, preterm delivery, and autoimmune diseases.

[0024] In certain embodiments, the compounds described herein can be used to treat subarachnoid haemorrhage or to prevent rupture of intracranial aneurysms. In certain embodiments, the compounds described herein can be used to treat cancer or tumor growth. In certain embodiments, the compounds described herein can be used to treat colon cancer or colon tumor growth. In certain embodiments, compounds described herein can be used to treat or prevent pain, e.g., post-surgical pain. In certain embodiments, compounds described herein can be used to treat or prevent mechanical hyperalgesia or delayed-onset muscle soreness. In certain embodiments, compounds described herein can be used to treat or prevent diabetes mellitus-induced inflammation and microvascular dysfunction or diabetic retinopathy.

[0025] In certain embodiments, the disclosure relates to the use of a compound as described herein in the production of a medicament for the treatment of a disease or condition related to an EP2 receptor. Compounds disclosed here can be contained in pharmaceutical compositions and administered alone or in combination with one or more additional active agents. The active agents can be administered simultaneously in the same dosage form or in separate dosage forms. Alternatively, the active agents can be administered sequentially in different dosage forms.

[0026] In certain embodiments, the disclosure relates to method of making compounds disclosed herein by mixing starting materials and reagents disclosed herein under conditions such that the compounds are formed.

[0027] DETAILED DESCRIPTION

[0028] Before the present disclosure is described in greater detail, it is to be understood that this disclosure is not limited to particular embodiments, and as such may, of course, vary. An “embodiment” refers to an example, and the claims are not necessarily limited to such example. The scope of the present disclosure will be limited only by the appended claims or as amended during prosecution.

[0029] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, the preferred methods and materials are now described.

[0030] All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference and are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited. Further, the dates of publication provided could be different from the actual publication dates that may need to be independently confirmed.

[0031] As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described as illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present disclosure. Any recited method can be carried out in the order of events recited or in any other order that is logically possible.

[0032] Embodiments of the present disclosure will employ, unless otherwise indicated, techniques of medicine, organic chemistry, biochemistry, molecular biology, pharmacology, and the like, which are within the skill of the art. Such techniques are explained fully in the literature.

[0033] It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise.

[0034] For any element disclosed herein expressly, by chemical formula, by inference, or by a single letter designation, the element is contemplated to include that element in its natural abundance or versions accessible in enriched forms in excess of natural abundance using standard synthetic techniques. For example, “H” or “hydrogen” refers to the hydrogen element or versions accessible as enriched in excess of natural abundance for common isotopes thereof, e.g., deuterium,2H, or tritium3H. Similarly, enriched halogen isotopes are contemplated, e.g.,18F,19F, or76Br.

[0035] As used herein, “alkyl” means a noncyclic straight chain or branched, unsaturated or saturated hydrocarbon such as those containing from 1 to 10 carbon atoms, typically 1 to 6 carbon atoms. Within any embodiments, herein alkyl may refer to an alkyl with 1 to 6 carbons (Ci-ealkyl). Representative saturated straight chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-septyl, n- octyl, n-nonyl, and the like; while saturated branched alkyls include isopropyl, sec-butyl, isobutyl, tertbutyl, isopentyl, and the like. Unsaturated alkyls contain at least one double or triple bond between adjacent carbon atoms (referred to as an “alkenyl” or “alkynyl,” respectively). Representative straight chain and branched alkenyls include ethylenyl, propylenyl, 1-butenyl, 2-butenyl, isobutylenyl, 1- pentenyl, 2-pentenyl, 3 -methyl- 1-butenyl, 2-methyl-2-butenyl, 2,3- dimethyl-2-butenyl, and the like; while representative straight chain and branched alkynyls include acetylenyl, propynyl, 1-butynyl, 2- butynyl, 1 -pentynyl, 2-pentynyl, 3- methyl- 1-butynyl, and the like.

[0036] Non-aromatic mono or polycyclic alkyls are referred to herein as "carbocycles" or "carbocyclyl" groups. Representative saturated carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like; while unsaturated carbocycles include cyclopentenyl and cyclohexenyl, and the like.

[0037] "Heterocarbocycles" or heterocarbocyclyl" groups are carbocycles which contain from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur which may be saturated or unsaturated (but not aromatic), monocyclic or polycyclic, and wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quatemized. Heterocarbocycles include morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.

[0038] "Aryl" means an aromatic carbocyclic monocyclic or polycyclic ring such as phenyl or naphthyl. Polycyclic ring systems may, but are not required to, contain one or more non-aromatic rings, as long as one of the rings is aromatic.

[0039] As used herein, "heteroaryl" refers an aromatic heterocarbocycle having 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, and containing at least 1 carbon atom, including both mono- and polycyclic ring systems. Polycyclic ring systems may, but are not required to, contain one or more non-aromatic rings, as long as one of the rings is aromatic. Representative heteroaryls are furyl, benzofuranyl, thiophenyl, benzothiophenyl, pyrrolyl, indolyl, isoindolyl, azaindolyl, pyridyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, benzoxazolyl, pyrazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, and quinazolinyl. It is contemplated that the use of the term "heteroaryl" includes N- alkylated derivatives such as a 1-methylimidazol- 5-yl substituent.

[0040] As used herein, "heterocycle" or "heterocyclyl" refers to mono- and polycyclic ring systems having 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, and containing at least 1 carbon atom. The mono- and polycyclic ring systems may be aromatic, non-aromatic or mixtures of aromatic and non-aromatic rings. Heterocycle includes heterocarbocycles, heteroaryls, and the like.

[0041] "Alkylthio" refers to an alkyl group as defined above with the indicated number of carbon atoms attached through a sulfur bridge. An example of an alkylthio is methylthio, (i. e. , -S-CHs).

[0042] "Alkoxy" refers to an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n- pentoxy, and s-pentoxy. Preferred alkoxy groups are methoxy, ethoxy, n-propoxy, i- propoxy, n-butoxy, s-butoxy, t-butoxy.

[0043] "Alkylamino" refers an alkyl group as defined above attached through an amino bridge. An example of an alkylamino is methylamino, (i.e., -NH-CH-).

[0044] "Alkanoyl" refers to an alkyl as defined above attached through a carbonyl bride (i.e., - (C=O)alkyl).

[0045] “Alkyloxycarbonyl” refers to an alkyl as defined above attached through a carboxy bridge (i.e., -(C=O)Oalkyl.

[0046] “Alkylcarbamoyl” refers to an alkyl as defined above attached through a carbonyl bridge (i.e., -(C=O)NHalkyl). “Alkanoyl” refers to an alkyl as defined above attached through a carbonyl bridge (i.e., - (C=O)alkyl).

[0047] "Alkylsulfonyl" refers to an alkyl as defined above attached through a sulfonyl bridge (i.e., - S(=O)2alkyl) such as mesyl and the like, and "Arylsulfonyl" refers to an aryl attached through a sulfonyl bridge (i.e., - S(=O)2aryl).

[0048] "Alkylsulfonamide" refers to an alkyl as defined above attached through a sulfamoyl bridge (i.e., -S(=O)2NHalkyl), and an "Arylsulfonamide" refers to an alkyl attached through a sulfamoyl bridge (i.e., (i.e., - S(=O)2NHaryl).

[0049] "Alkylsulfinyl" refers to an alkyl as defined attached through a sulfinyl bridge (i.e. -S(=O)alkyl).

[0050] “Glycol” refers to an alkyl group substitute with terminal oxygen atoms, and the term is intended to include repeating glycol units, e.g., polyethylene glycol -O(CH2CH2O)nX, wherein X is typically an H, alkyl, alkoxy, halogenated alkoxy, or alkanoyl, and n is typically 1-50, 1-100, or 1- 1,000.

[0051] The terms “halogen” and “halo” refer to fluorine, chlorine, bromine, and iodine.

[0052] The term “halogenated alkyl” refers to an alkyl partially or entirely substituted with halogens, e.g., CF3.

[0053] The term "substituted" refers to a molecule wherein at least one hydrogen atom is replaced with a substituent. When substituted, one or more of the groups are "substituents." The molecule may be multiply substituted. In the case of an oxo substituent ("=O"), two hydrogen atoms are replaced. Example substituents within this context may include halogen, hydroxy, alkyl, alkoxy, halogenated alkoxy, nitro, cyano, oxo, carbocyclyl, carbocycloalkyl, heterocarbocyclyl, heterocarbocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -NRaRb, -NRaC(=O)Rb, -NR1C(=O)NRaNRb, -NRaC(=O)ORb, -NRaSChRb, -C(=O)Rl, -C(=O)ORl, -C(=O)NRaRb, -OC(=O)NRaRb, -ORa, -SRa, -SORa, -S(=O)2Ra, -OS(=O)2Ra and -S(=O)2ORa. Ra andRb in this context may be the same or different and independently hydrogen, halogen hydroxyl, alkyl, alkoxy, halogenated alkoxy, alkyl, amino, alkylamino, dialkylamino, carbocyclyl, carbocycloalkyl, heterocarbocyclyl, heterocarbocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl.

[0054] The term "optionally substituted," as used herein, means that substitution is optional and therefore it is possible for the designated atom to be unsubstituted.

[0055] As used herein, "salts" refer to derivatives of the disclosed compounds where the parent compound is modified making acid or base salts thereof. Examples of salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkylamines, or dialkylamines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. In certain embodiment the salts are conventional nontoxic pharmaceutically acceptable salts including the quaternary ammonium salts of the parent compound formed, and non-toxic inorganic or organic acids. Contemplated salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.

[0056] A "subject" refers any animal, preferably a human patient, livestock, or domestic pet.

[0057] The term “prodrug” refers to an agent that is converted into a biologically active form in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent compound. They may, for instance, be bioavailable by oral administration whereas the parent compound is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. A prodrug may be converted into the parent drug by various mechanisms, including enzymatic processes and metabolic hydrolysis. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of an alcohol or acetamide, formamide and benzamide derivatives of an amine functional group in the active compound and the like.

[0058] As used herein, the terms "prevent" and "preventing" include the prevention of the recurrence, spread or onset. It is not intended that the present disclosure be limited to complete prevention. In some embodiments, the onset is delayed, or the severity of the disease is reduced.

[0059] As used herein, the terms "treat" and "treating" are not limited to the case where the subject (e.g. patient) is cured and the disease is eradicated. Rather, embodiments, of the present disclosure also contemplate treatment that merely reduces symptoms, and / or delays disease progression.

[0060] The terms "co-administration" or "administered in combination with," and their grammatical equivalents, as used herein, encompass administration of two or more agents to a subject so that both agents and / or their metabolites are present in the subject at the same time. Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present.

[0061] Prostaglandin Receptor EP2 Antagonists / Inhibitors

[0062] Certain compounds were identified as antagonists of the human EP2 receptor. Although it is not intended that certain embodiments of the disclosure be limited by any specific mechanism, certain of these compounds have low cellular toxicity and represent competitive antagonists of the EP2 prostaglandin receptor.

[0063] In certain embodiments, compounds have Formula IA or Formula IB,

[0064] Formula IA Formula IB salt, or prodrug thereof, wherein: a dotted line represents a double or single bond; n is 1, 2, 3, or 4;

[0065] Q is CH, N, or NX6;

[0066] W is N or C;

[0067] Y1is CX1or N; Y2is CX2or N; Y3is CX3or N; and Y4is CX4or N;

[0068] Y5is CR3or N;

[0069] X1, X2, X3, and X4are each, the same or different, hydrogen, alkyl, halogen, halogenated alkyl, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, alkoxy, halogenated alkoxy, glycol, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein X1, X2, X3, and X4are optionally substituted with one or more, the same or different, X10;

[0070] X5and X6are each, the same or different, hydrogen, alkyl, or halogenated alkyl, wherein X5and X6are optionally substituted with one or more, the same or different, X10;

[0071] X10is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, alkoxy, halogenated alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein X10is optionally substituted with one or more, the same or different, X11;

[0072] X11is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, acetyloxy, N-methylcarbamoyl, acetylamino, acetyloxy, N-ethylcarbamoyl, acetylamino, acetyloxy, N,N-dimethylcarbamoyl, acetylamino, acetyloxy, N,N-diethylcarbamoyl, acetylamino, acetyloxy, N-methyl-N-ethylcarbamoyl, acetylamino, acetyloxy, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl, ethoxycarbonyl, N- methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N- ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl;

[0073] R1, R2, R3, R4and R5are each, the same or different, hydrogen, alkyl, halogenated alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, alkoxy, halogenated alkoxy, glycol, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R1, R2, R , R4andR5are optionally substituted with one or more, the same or different, R10;

[0074] R10is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, alkoxy, halogenated alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R10is optionally substituted with one or more, the same or different, R11;

[0075] R11is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, alkoxy, halogenated alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R11is optionally substituted with one or more, the same or different, R12; and

[0076] R12is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, acetyloxy, N-methylcarbamoyl, acetylamino, acetyloxy, N-ethylcarbamoyl, acetylamino, acetyloxy, N,N-dimethylcarbamoyl, acetylamino, acetyloxy, N,N-diethylcarbamoyl, acetylamino, acetyloxy, N-methyl-N-ethylcarbamoyl, acetylamino, acetyloxy, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl, ethoxycarbonyl, N- methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N- ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.

[0077] In certain embodiments, n is 2 or 3.

[0078] In certain embodiments, Q is NX6or NH, and W is C.

[0079] In certain embodiments, Q is CH and W is N.

[0080] In certain embodiments, Q is N and W is N.

[0081] In certain embodiments, R1is hydrogen, methyl, or alkyl, optionally substituted with one or more, the same or different, R10.

[0082] In certain embodiments, R2is hydrogen or halogen. In certain embodiments, R’ is hydrogen, alkyl, halogen, cyano, hydroxy, amino, or mercapto optionally substituted with one or more, the same or different, R10.

[0083] In certain embodiments, R4is hydrogen, alkyl, halogen, halogenated alkyl, nitro, cyano, hydroxy, amino, mercapto, alkoxy, halogenated alkoxy, glycol, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, alkoxy, halogenated alkoxy, alkylthio, alkylamino, or (alkyl)2amino, optionally substituted with one or more, the same or different, R10.

[0084] In certain embodiments, R4is hydrogen, hydroxy, alkyl, alkoxy or glycol, optionally substituted with one or more, the same or different, R10

[0085] In certain embodiments, R5is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, alkoxy, halogenated alkoxy, alkylthio, alkylamino, or (alkyl)2amino, optionally substituted with one or more, the same or different, R10.

[0086] In certain embodiments, R5is hydrogen, halogen, or alkyl.

[0087] In certain embodiments, n is 2.

[0088] In certain embodiments, X1is hydrogen, halogen, or F.

[0089] In certain embodiments, X2is hydrogen, halogen, or F.

[0090] In certain embodiments, X3, is hydrogen, halogen, or F.

[0091] In certain embodiments, X4is hydrogen, halogen, or F.

[0092] In certain embodiments, Y1is CH, N, or CF.

[0093] In certain embodiments, Y2is CH, N, or CF.

[0094] In certain embodiments, Y3is CH, N, or CF.

[0095] In certain embodiments, Y4is CH, N, or CF.

[0096] In certain embodiments, Y5is CH or N.

[0097] In certain embodiments, X5is H, alkyl, or halogenated alkyl.

[0098] In certain embodiments, R1is hydrogen methyl, ethyl, propyl, isopropyl, isobutyl, carbocyclyl, or heterocyclyl.

[0099] In certain embodiments, R4is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cycloalkyl, carbocyclyl, or heterocyclyl.

[0100] In certain embodiments, R2is hydrogen, halogen, methyl, ethyl, alkyl, cycloalkyl, alkylamino, alkyloxy, acetyl, or heterocyclyl.

[0101] In certain embodiments, R5is hydrogen, halogen, methyl, ethyl, propyl, isopropyl, alkyl, branched alkyl, cycloalkyl, or heterocyclyl.

[0102] In certain embodiments, compounds have Formula IC or Formula ID

[0103] Formula IC Formula ID or pharmaceutically acceptable salt or prodrug thereof, wherein: a dotted line represents a double or single bond; n is 2 or 3;

[0104] W is N or C;

[0105] Y1is CX1or N; Y2is CX2or N; Y3is CX3or N; Y4is CX4or N;

[0106] Y5is N or CR3;

[0107] X1, X2, X3, and X4are each, the same or different, hydrogen, alkyl, halogen, halogenated alkyl, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, alkoxy, halogenated alkoxy, glycol, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein X1, X2, X3, and X4are optionally substituted with one or more, the same or different, X10;

[0108] X5and X6are each, the same or different, hydrogen, alkyl, or halogenated alkyl, wherein X5and X6are optionally substituted with one or more, the same or different, X10;

[0109] X10is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, alkoxy, halogenated alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein X10is optionally substituted with one or more, the same or different, X11;

[0110] X11is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, acetyloxy, N-methylcarbamoyl, acetylamino, acetyloxy, N-ethylcarbamoyl, acetylamino, acetyloxy, N,N-dimethylcarbamoyl, acetylamino, acetyloxy, N,N-diethylcarbamoyl, acetylamino, acetyloxy, N-methyl-N-ethylcarbamoyl, acetylamino, acetyloxy, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N- methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N- ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl; R1, R2, R3, R4and R5are each, the same or different, hydrogen, alkyl, halogen, halogenated alkyl, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, alkoxy, halogenated alkoxy, glycol, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R1, R2, R4andR5are optionally substituted with one or more, the same or different, R10;

[0111] R10is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, alkoxy, halogenated alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R10is optionally substituted with one or more, the same or different, R11;

[0112] R11is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, alkoxy, halogenated alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R11is optionally substituted with one or more, the same or different, R12; and

[0113] R12is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, acetyloxy, N-methylcarbamoyl, acetylamino, acetyloxy, N-ethylcarbamoyl, acetylamino, acetyloxy, N,N-dimethylcarbamoyl, acetylamino, acetyloxy, N,N-diethylcarbamoyl, acetylamino, acetyloxy, N-methyl-N-ethylcarbamoyl, acetylamino, acetyloxy, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl, ethoxycarbonyl, N- methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N- ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.

[0114] In certain embodiments, n is 2 or 3.

[0115] In certain embodiments, W is C.

[0116] In certain embodiments, W is N.

[0117] In certain embodiments, R1is hydrogen, methyl, or alkyl, optionally substituted with one or more, the same or different, R10.

[0118] In certain embodiments, R2is hydrogen or halogen.

[0119] In certain embodiments, R3is hydrogen, alkyl, halogen, cyano, hydroxy, amino, or mercapto optionally substituted with one or more, the same or different, R10.

[0120] In certain embodiments, R4is hydrogen, alkyl, halogen, halogenated alkyl, nitro, cyano, hydroxy, amino, mercapto, alkoxy, halogenated alkoxy, glycol, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, alkoxy, halogenated alkoxy, alkylthio, alkylamino, or (alkyl)2amino, optionally substituted with one or more, the same or different, R10.

[0121] In certain embodiments, R5is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, alkoxy, halogenated alkoxy, alkylthio, alkylamino, or (alkyl)2amino, optionally substituted with one or more, the same or different, R10.

[0122] In certain embodiments, R5is hydrogen, halogen, or alkyl.

[0123] In certain embodiments, n is 2.

[0124] In certain embodiments, Y1is CH, N, or CF.

[0125] In certain embodiments, Y2is CH, N, or CF.

[0126] In certain embodiments, Y3is CH, N, or CF.

[0127] In certain embodiments, Y4is CH, N, or CF.

[0128] In certain embodiments, Y5is CH or N.

[0129] In certain embodiments, X5is hydrogen, alkyl, or halogenated alkyl.

[0130] In certain embodiments, X6is hydrogen.

[0131] In certain embodiments, R1is hydrogen methyl, ethyl, propyl, isopropyl, isobutyl, carbocyclyl, or heterocyclyl.

[0132] In certain embodiments, R4is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cycloalkyl, carbocyclyl, or heterocyclyl.

[0133] In certain embodiments, R2is hydrogen, halogen, methyl, ethyl, alkyl, cycloalkyl, alkylamino, alkyloxy, acetyl, or heterocyclyl.

[0134] In certain embodiments, R5is hydrogen, halogen, methyl, ethyl, propyl, isopropyl, alkyl, branched alkyl, cycloalkyl, or heterocyclyl.

[0135] In certain embodiments, compounds have Formula IE or Formula IF,

[0136] Formula IE Formula IF or salt or prodrug thereof, wherein: n is 2 or 3;

[0137] Y1is CX1or N; Y2is CX2or N; Y3is CX3or N; Y4is CX4or N;

[0138] Y5is N or CR3; X1, X2, X3, and X4are each, the same or different, hydrogen, alkyl, halogen, halogenated alkyl, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, alkoxy, halogenated alkoxy, glycol, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein X1, X2, X', and X4are optionally substituted with one or more, the same or different, X10;

[0139] X5and X6are each, the same or different, hydrogen, alkyl, or halogenated alkyl, wherein X5and X6are optionally substituted with one or more, the same or different, X10;

[0140] X10is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, alkoxy, halogenated alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein X10is optionally substituted with one or more, the same or different, X11;

[0141] X11is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, acetyloxy, N-methylcarbamoyl, acetylamino, acetyloxy, N-ethylcarbamoyl, acetylamino, acetyloxy, N,N-dimethylcarbamoyl, acetylamino, acetyloxy, N,N-diethylcarbamoyl, acetylamino, acetyloxy, N-methyl-N-ethylcarbamoyl, acetylamino, acetyloxy, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N- methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N- ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl;

[0142] R1, R2, R3, R4and R5are each, the same or different, hydrogen, alkyl, halogen, halogenated alkyl, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, alkoxy, halogenated alkoxy, glycol, alkylthio, alkylamino, (alkyl)2amino, alkylsulfmyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R1, R2, R3, R4and R5are optionally substituted with one or more, the same or different, R10;

[0143] R10is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, alkoxy, halogenated alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R10is optionally substituted with one or more, the same or different, R11;

[0144] R11is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, alkoxy, halogenated alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R11is optionally substituted with one or more, the same or different, R12; and R12is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, acetyloxy, N-methylcarbamoyl, acetylamino, acetyloxy, N-ethylcarbamoyl, acetylamino, acetyloxy, N,N-dimethylcarbamoyl, acetylamino, acetyloxy, N,N-diethylcarbamoyl, acetylamino, acetyloxy, N-methyl-N-ethylcarbamoyl, acetylamino, acetyloxy, methylthio, ethylthio, methylsulfmyl, ethylsulfmyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N- methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N- ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.

[0145] In certain embodiments, n is 2.

[0146] In certain embodiments, R1is hydrogen, methyl, or alkyl, optionally substituted with one or more, the same or different, R10.

[0147] In certain embodiments, R2is hydrogen or halogen.

[0148] In certain embodiments, R3is hydrogen, alkyl, halogen, cyano, hydroxy, amino, or mercapto optionally substituted with one or more, the same or different, R10.

[0149] In certain embodiments, R4is hydrogen, alkyl, halogen, halogenated alkyl, nitro, cyano, hydroxy, amino, mercapto, alkoxy, halogenated alkoxy, glycol, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, alkoxy, halogenated alkoxy, alkylthio, alkylamino, or (alkyl)2amino, optionally substituted with one or more, the same or different, R10.

[0150] In certain embodiments, R5is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, alkoxy, halogenated alkoxy, alkylthio, alkylamino, or (alkyl)2amino, optionally substituted with one or more, the same or different, R10.

[0151] In certain embodiments, R5is hydrogen, halogen, or alkyl.

[0152] In certain embodiments, n is 2.

[0153] In certain embodiments, Y1is CH, N, or C-F.

[0154] In certain embodiments, Y2is CH, N, or C-F.

[0155] In certain embodiments, Y3is CH, N, or C-F.

[0156] In certain embodiments, Y4is CH, N, or C-F.

[0157] In certain embodiments, X5is hydrogen, alkyl, or halogenated alkyl.

[0158] In certain embodiments, X6is hydrogen.

[0159] In certain embodiments, R1is hydrogen methyl, ethyl, propyl, isopropyl, isobutyl, carbocyclyl, or heterocyclyl. In certain embodiments, R2is hydrogen, halogen, methyl, ethyl, alkyl, cycloalkyl, alkylamino, alkyloxy, acetyl, or heterocyclyl.

[0160] In certain embodiments, R4is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cycloalkyl, carbocyclyl, or heterocyclyl.

[0161] In certain embodiments, R5is hydrogen, halogen, methyl, ethyl, propyl, isopropyl, alkyl, branched alkyl, cycloalkyl, or heterocyclyl.

[0162] In certain embodiments, compounds have Formula IG or Formula IH

[0163] Formula IG Formula IH or salts thereof wherein,

[0164] Y1is CH, N, or CF;

[0165] Y2is CH, N, or CF;

[0166] Y3is CH, N, or CF;

[0167] Y4is CH, N, or CF;

[0168] Y5is CH, or N;

[0169] Z is O, NH, S, CH2, PO2, or PO;

[0170] R1, R2, R4and R5are each, the same or different, hydrogen, alkyl, halogen, halogenated alkyl, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, alkoxy, halogenated alkoxy, glycol, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R1, R2, R\ R4and R5are optionally substituted with one or more, the same or different, R10;

[0171] In certain embodiments, R1is methyl, ethyl, propyl, isopropyl, isobutyl, isobutyl, carbocyclyl, or heterocyclic ring.

[0172] In certain embodiments, R2is hydrogen, halogen, methyl, ethyl, alkyl, alkylamino, alkyloxy, acetyloxy, acetylamino, cycloalkyl, or heterocyclyl.

[0173] In certain embodiments, R4is methyl, ethyl, isopropoxy, isobutyloxy, methoxyethyl, acetyl, or phenacyl.

[0174] In certain embodiments, R5is hydrogen, halogen, methyl, ethyl, alkyl, branched alkyl, cycloalkyl, or heterocyclyl. In certain embodiments, compounds have Formula IJ or Formula IK

[0175] Formula IJ Formula IK or salts thereof wherein,

[0176] Y1is CH, N, or CF;

[0177] Y2is CH, N, or CF;

[0178] Y3is CH, N, or CF;

[0179] Y4is CH, N, or CF;

[0180] Y5is CH, or N;

[0181] R2, R4and R5are each, the same or different, hydrogen, alkyl, halogen, halogenated alkyl, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, alkoxy, halogenated alkoxy, glycol, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R1, R2, R', R4and R5are optionally substituted with one or more, the same or different, R10;

[0182] In certain embodiments, R2is hydrogen, halogen, methyl, ethyl, alkyl, alkylamino, alkyloxy, acetyloxy, acetylamino, cycloalkyl, or heterocyclyl.

[0183] In certain embodiments, R4is methyl, ethyl, isopropyl, isobutyl, cyclopropyl, cyclobutyl, -OCH3, -OCH2CH3, -OCF3, OCHF2, isopropyloxy, isobutyoxy, methoxyethyloxy, methylamine, ethylamine, alkylamine, -O-carbocycyl, -O-heterocyclyl, -CH2-aryl; and

[0184] R5is hydrogen, halogen, methyl, ethyl, alkyl, branched alkyl, cycloalkyl, or heterocyclyl.

[0185] In certain embodiments, compounds have Formula IIA or Formula IIB, salt, or prodrug thereof, wherein: a dotted line represents a double or single bond; n is 1, 2, 3, or 4;

[0186] Q is CH, N, or NX6;

[0187] W is N or C;

[0188] Y1is CX1or N; Y2is CX2or N; Y3is CX3or N; Y4is CX4or N;

[0189] Y5is CR3or N;

[0190] X1, X2, X3, and X4are each, the same or different, hydrogen, alkyl, halogen, halogenated alkyl, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, alkoxy, halogenated alkoxy, glycol, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein X1, X2, X3, and X4are optionally substituted with one or more, the same or different, X10;

[0191] X5and X6are each, the same or different, hydrogen, alkyl, or halogenated alkyl, wherein X5and X6are optionally substituted with one or more, the same or different, X10;

[0192] X10is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, alkoxy, halogenated alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein X10is optionally substituted with one or more, the same or different, X11;

[0193] X11is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, acetyloxy, N-methylcarbamoyl, acetylamino, acetyloxy, N-ethylcarbamoyl, acetylamino, acetyloxy, N,N-dimethylcarbamoyl, acetylamino, acetyloxy, N,N-diethylcarbamoyl, acetylamino, acetyloxy, N-methyl-N-ethylcarbamoyl, acetylamino, acetyloxy, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl, ethoxycarbonyl, N- methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N- ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl;

[0194] R1, R2, R3, R4and R5are each, the same or different, hydrogen, alkyl, halogen, halogenated alkyl, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, alkoxy, halogenated alkoxy, glycol, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R1, R2, R3, R4and R5are optionally substituted with one or more, the same or different, R10;

[0195] R10is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, alkoxy, halogenated alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R10is optionally substituted with one or more, the same or different, R11;

[0196] R11is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, alkoxy, halogenated alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R11is optionally substituted with one or more, the same or different, R12; and

[0197] R12is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, acetyloxy, N-methylcarbamoyl, acetylamino, acetyloxy, N-ethylcarbamoyl, acetylamino, acetyloxy, N,N-dimethylcarbamoyl, acetylamino, acetyloxy, N,N-diethylcarbamoyl, acetylamino, acetyloxy, N-methyl-N-ethylcarbamoyl, acetylamino, acetyloxy, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N- methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N- ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.

[0198] In certain embodiments, n is 2 or 3.

[0199] In certain embodiments, Q is NX6and W is C.

[0200] In certain embodiments, Q is CH and W is N.

[0201] In certain embodiments, Q is N and W is N.

[0202] In certain embodiments, R1is hydrogen, methyl, or alkyl, optionally substituted with one or more, the same or different, R10.

[0203] In certain embodiments, R2is hydrogen or halogen.

[0204] In certain embodiments, R3is hydrogen, alkyl, halogen, cyano, hydroxy, amino, or mercapto optionally substituted with one or more, the same or different, R10.

[0205] In certain embodiments, R4is hydrogen, alkyl, halogen, halogenated alkyl, nitro, cyano, hydroxy, amino, mercapto, alkoxy, halogenated alkoxy, glycol, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, alkoxy, halogenated alkoxy, alkylthio, alkylamino, or (alkyl)2amino, optionally substituted with one or more, the same or different, R10.

[0206] In certain embodiments, R5is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, alkoxy, halogenated alkoxy, alkylthio, alkylamino, or (alkyl)2amino, optionally substituted with one or more, the same or different, R10.

[0207] In certain embodiments, R5is hydrogen, halogen, or alkyl.

[0208] In certain embodiments, n is 2. In certain embodiments, X1is hydrogen, halogen, or F.

[0209] In certain embodiments, X2is hydrogen, halogen, or F.

[0210] In certain embodiments, X", is hydrogen, halogen, or F.

[0211] In certain embodiments, X4is hydrogen, halogen, or F.

[0212] In certain embodiments, Y1is CH, N, or CF.

[0213] In certain embodiments, Y2is CH, N, or CF.

[0214] In certain embodiments, Y is CH, N, or CF.

[0215] In certain embodiments, Y4is CH, N, or CF.

[0216] In certain embodiments, Y5is CH or N.

[0217] In certain embodiments, R1is hydrogen methyl, ethyl, propyl, isopropyl, isobutyl, carbocyclyl, or heterocyclyl.

[0218] In certain embodiments, R4is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cycloalkyl, carbocyclyl, or heterocyclyl.

[0219] In certain embodiments, R2is hydrogen, halogen, methyl, ethyl, alkyl, cycloalkyl, alkylamino, alkyloxy, acetyl, or heterocyclyl.

[0220] In certain embodiments, R5is hydrogen, halogen, methyl, ethyl, propyl, isopropyl, alkyl, branched alkyl, cycloalkyl, or heterocyclyl.

[0221] In certain embodiments, compounds have Formula IIC or Formula IID, or pharmaceutically acceptable salt or prodrug thereof, wherein: a dotted line represents a double or single bond; n is 2 or 3;

[0222] W is N or C;

[0223] Y1is CX1or N; Y2is CX2or N; Y3is CX3or N; Y4is CX4or N;

[0224] Y5is CR3or N;

[0225] X1, X2, X3, and X4are each, the same or different, hydrogen, alkyl, halogen, halogenated alkyl, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, alkoxy, halogenated alkoxy, glycol, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein X1, X2, X3, and X4are optionally substituted with one or more, the same or different, X10;

[0226] X5and X6are each, the same or different, hydrogen, alkyl, or halogenated alkyl, wherein X5and X6are optionally substituted with one or more, the same or different, X10;

[0227] X10is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, alkoxy, halogenated alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein X10is optionally substituted with one or more, the same or different, X11;

[0228] X11is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, acetyloxy, N-methylcarbamoyl, acetylamino, acetyloxy, N-ethylcarbamoyl, acetylamino, acetyloxy, N,N-dimethylcarbamoyl, acetylamino, acetyloxy, N,N-diethylcarbamoyl, acetylamino, acetyloxy, N-methyl-N-ethylcarbamoyl, acetylamino, acetyloxy, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N- methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N- ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl;

[0229] R1, R2, R R4and R5are each, the same or different, hydrogen, alkyl, halogen, halogenated alkyl, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, alkoxy, halogenated alkoxy, glycol, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R1, R2, R3, R4and R5are optionally substituted with one or more, the same or different, R10;

[0230] R10is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, alkoxy, halogenated alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R10is optionally substituted with one or more, the same or different, R11;

[0231] R11is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, alkoxy, halogenated alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R11is optionally substituted with one or more, the same or different, R12; and

[0232] R12is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, acetyloxy, N-methylcarbamoyl, acetylamino, acetyloxy, N-ethylcarbamoyl, acetylamino, acetyloxy, N,N-dimethylcarbamoyl, acetylamino, acetyloxy, N,N-diethylcarbamoyl, acetylamino, acetyloxy, N-methyl-N-ethylcarbamoyl, acetylamino, acetyloxy, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N- methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N- ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.

[0233] In certain embodiments, n is 2 or 3.

[0234] In certain embodiments, W is C.

[0235] In certain embodiments, W is N.

[0236] In certain embodiments, R1is hydrogen, methyl, or alkyl, optionally substituted with one or more, the same or different, R10.

[0237] In certain embodiments, R2is hydrogen or halogen.

[0238] In certain embodiments, R’ is hydrogen, alkyl, halogen, cyano, hydroxy, amino, or mercapto optionally substituted with one or more, the same or different, R10.

[0239] In certain embodiments, R4is hydrogen, alkyl, halogen, halogenated alkyl, nitro, cyano, hydroxy, amino, mercapto, alkoxy, halogenated alkoxy, glycol, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, alkoxy, halogenated alkoxy, alkylthio, alkylamino, or (alkyl)2amino, optionally substituted with one or more, the same or different, R10.

[0240] In certain embodiments, R5is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, alkoxy, halogenated alkoxy, alkylthio, alkylamino, or (alkyl)2amino, optionally substituted with one or more, the same or different, R10.

[0241] In certain embodiments, R5is hydrogen, halogen, or alkyl.

[0242] In certain embodiments, n is 2.

[0243] In certain embodiments, Y1is CH, N, or CF.

[0244] In certain embodiments, Y2is CH, N, or CF.

[0245] In certain embodiments, Y3is CH, N, or CF.

[0246] In certain embodiments, Y4is CH, N, or CF.

[0247] In certain embodiments, Y5is CH or N.

[0248] In certain embodiments, R1is hydrogen methyl, ethyl, propyl, isopropyl, isobutyl, carbocyclyl, or heterocyclyl.

[0249] In certain embodiments, R4is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cycloalkyl, carbocyclyl, or heterocyclyl. In certain embodiments, R2is hydrogen, halogen, methyl, ethyl, alkyl, cycloalkyl, alkylamino, alkyloxy, acetyl, or heterocyclyl.

[0250] In certain embodiments, R5is hydrogen, halogen, methyl, ethyl, propyl, isopropyl, alkyl, branched alkyl, cycloalkyl, or heterocyclyl.

[0251] In certain embodiments, compounds have Formula IIE or Formula IIF, or salt or prodrug thereof, wherein: n is 2 or 3;

[0252] Y1is CX1or N; Y2is CX2or N; Y3is CX3or N; Y4is CX4or N;

[0253] Y5is CR3or N;

[0254] X1, X2, X3, and X4are each, the same or different, hydrogen, alkyl, halogen, halogenated alkyl, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, alkoxy, halogenated alkoxy, glycol, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein X1, X2, X', and X4are optionally substituted with one or more, the same or different, X10;

[0255] X5and X6are each, the same or different, hydrogen, alkyl, or halogenated alkyl, wherein X5and X6are optionally substituted with one or more, the same or different, X10;

[0256] X10is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, alkoxy, halogenated alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein X10is optionally substituted with one or more, the same or different, X11;

[0257] X11is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, acetyloxy, N-methylcarbamoyl, acetylamino, acetyloxy, N-ethylcarbamoyl, acetylamino, acetyloxy, N,N-dimethylcarbamoyl, acetylamino, acetyloxy, N,N-diethylcarbamoyl, acetylamino, acetyloxy, N-methyl-N-ethylcarbamoyl, acetylamino, acetyloxy, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N- methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N- ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl;

[0258] R1, R2, R R4and R5are each, the same or different, hydrogen, alkyl, halogen, halogenated alkyl, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, alkoxy, halogenated alkoxy, glycol, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R1, R2, R3, R4and R5are optionally substituted with one or more, the same or different, R10;

[0259] R10is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, alkoxy, halogenated alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R10is optionally substituted with one or more, the same or different, R11;

[0260] R11is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, alkoxy, halogenated alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R11is optionally substituted with one or more, the same or different, R12; and

[0261] R12is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, acetyloxy, N-methylcarbamoyl, acetylamino, acetyloxy, N-ethylcarbamoyl, acetylamino, acetyloxy, N,N-dimethylcarbamoyl, acetylamino, acetyloxy, N,N-diethylcarbamoyl, acetylamino, acetyloxy, N-methyl-N-ethylcarbamoyl, acetylamino, acetyloxy, methylthio, ethylthio, methylsulfinyl, ethylsulfmyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N- methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N- ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.

[0262] In certain embodiments, n is 2.

[0263] In certain embodiments, R1is hydrogen, methyl, or alkyl, optionally substituted with one or more, the same or different, R10.

[0264] In certain embodiments, R2is hydrogen or halogen.

[0265] In certain embodiments, R3is hydrogen, alkyl, halogen, cyano, hydroxy, amino, or mercapto optionally substituted with one or more, the same or different, R10.

[0266] In certain embodiments, R4is hydrogen, alkyl, halogen, halogenated alkyl, nitro, cyano, hydroxy, amino, mercapto, alkoxy, halogenated alkoxy, glycol, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, alkoxy, halogenated alkoxy, alkylthio, alkylamino, or (alkyl)2amino, optionally substituted with one or more, the same or different, R10.

[0267] In certain embodiments, R5is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, alkoxy, halogenated alkoxy, alkylthio, alkylamino, or (alkyl)2amino, optionally substituted with one or more, the same or different, R10.

[0268] In certain embodiments, R5is hydrogen, halogen, or alkyl.

[0269] In certain embodiments, n is 2.

[0270] In certain embodiments, Y1is CH, N, or CF.

[0271] In certain embodiments, Y2is CH, N, or CF.

[0272] In certain embodiments, Y3is CH, N, or CF.

[0273] In certain embodiments, Y4is CH, N, or CF.

[0274] In certain embodiments, Y5is CH or N.

[0275] In certain embodiments, R1is hydrogen methyl, ethyl, propyl, isopropyl, isobutyl, carbocyclyl, or heterocyclyl.

[0276] In certain embodiments, R4is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cycloalkyl, carbocyclyl, or heterocyclyl.

[0277] In certain embodiments, R2is hydrogen, halogen, methyl, ethyl, alkyl, cycloalkyl, alkylamino, alkyloxy, acetyl, or heterocyclyl.

[0278] In certain embodiments, R5is hydrogen, halogen, methyl, ethyl, propyl, isopropyl, alkyl, branched alkyl, cycloalkyl, or heterocyclyl.

[0279] Prostaglandin receptor EP2 related diseases and conditions

[0280] Prostaglandin EP2 receptor related diseases or conditions include neurological disorders, brain injury, neuropathic pain, hypertension, ischemic injury, neuroinflammation, e.g., after a seizure, rupture of cerebral aneurysms, endometriosis, cancer, inflammatory bowel disease (colitis), arthritis / rheumatoid arthritis, skin inflammation, vascular inflammation, Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), kidney disease / transplant rejection, atherosclerosis, ischaemic heart disease, acne vulgaris, asthma, chronic prostatitis, glomerulonephritis, hypersensitivities, inflammatory bowel diseases, pelvic inflammatory disease, sarcoidosis, vasculitis, interstitial cystitis, and other autoimmune diseases.

[0281] Neurological disorders, diseases, or conditions contemplated include, brain injury such as brain damage according to cerebral lobe, basal ganglia, cerebellum, brainstem, frontal lobe damage, parietal lobe damage, temporal lobe damage, occipital lobe damage, aphasia, dysarthria, apraxia, agnosia, amnesia, spinal cord disorders, peripheral nervous system disorders, cranial nerve disorders, autonomic nervous system disorders, seizure disorders such as epilepsy, movement disorders such as Parkinson's disease, sleep disorders, headaches (including migraine), lower back and neck pain, neuropathic pain, delirium and dementia such as in Alzheimer's disease, dizziness, vertigo, stupor, coma, stroke (CVA, cerebrovascular attack), multiple sclerosis (MS) and other demyelinating diseases, infections of the brain or spinal cord (including meningitis), prion diseases, complex regional pain syndrome (CRPS), glioblastoma, neuroblastoma and medulloblastoma and prostate cancer.

[0282] Status epilepticus refers to a potentially life-threatening condition in which the brain is in a state of persistent seizure or recurrent seizure typically lasting longer than about 20-30 minutes. It is not intended that time of the seizure be of any specific duration, but typically 30-60 minutes is sufficient to damage neurons and seizures are unlikely to self-terminate by that time. The mortality rate of status epilepticus is high in adults who experience at least 1 hour of status epilepticus (30-37% by 1 month).

[0283] In certain embodiments, the compounds or compositions are administered at about 0.5, 1, 2, 3, 4, or 5 hours after a subject has stopped having a seizure, e.g., because the subject was administered an anticonvulsant or an anaesthetic.

[0284] Examples of why one may experience such a seizure include because they have epilepsy and have stopped taking anticonvulsant medication, a stroke, hemorrhage, or as a result of intoxicants, adverse reactions to drugs, sudden withdrawal from chronic consumption of alcoholic beverages, fasting, trauma to the brain, brain disorders such as, but not limited to, meningitis, encephalitis, brain tumors, abscess. It is contemplated that in certain embodiments, the subject may be in a convulsive status epilepticus for any of the reasons provided herein.

[0285] Status epilepticus can be co-treated with midazolam, valproate, phenobarbital, thiopental pentobarbital, diazepam, or other benzodiazepines such as clonazepam, or lorazepam. If these compounds are ineffective, one may administer general anaesthetics such as propofol or an NMDA antagonist such as ketamine. In certain embodiments, the disclosure contemplates administering compounds disclosed herein after or in combination with being treated with anticonvulsive agents such as those describe above.

[0286] COX-2 and prostanoid products have a role in progression of tumors including lung, head and neck, prostate and colon, ovary and breast, hepatocellular carcinoma. Taking COX-2 inhibitor drugs regularly may reduce the rates of certain cancers and cancer related deaths. Upregulation of COX-2 in tumor tissues has been reported to be accompanied by high levels of PGE2. Moreover, EP2 activation by PGE2 can promote cancer cell growth and invasion by activating iNOS / guanylate cyclase (GC) and mitogen-activated protein kinase (MAPK)-ERKl / 2 via PKA-mediated epidermal growth factor (EGF) receptor activation. PGE2 / EP2 signaling in mammary epithelial cells triggers hyperplasia of mammary glands and EP2 receptor is an important element for PGE2 regulated vascular endothelial growth factor (VEGF) induction in mouse mammary tumor cells. EP2 signaling directly regulates tumor angiogenesis in endothelium by enhancing endothelial cell motility and cell survival, mediates epidermal hypertrophy and tumor aggression in response to ultraviolet (UV)-irradiation, and induces skin carcinogenesis.

[0287] Thus, within certain embodiments, it is contemplated that compounds disclosed herein may be used for the treatment of cancers and tumors of the nervous system including those subjects diagnosed with cancer, including, skin, blood vessel, lung, head and neck, prostate and colon, ovary and breast cancer and hepatocellular carcinoma. In certain embodiments, it is contemplated that compounds disclosed herein may be used for the treatment of cancer, cancer cell proliferation, glioblastoma, malignant glioma, neuroblastoma, medulloblastoma, peripheral and neural inflammation, intracranial aneurysms.

[0288] In certain embodiments, it is contemplated that compounds disclosed herein may be used for the treatment of rheumatoid arthritis, osteoarthritis, endometriosis, postoperative pain, inflammatory bowel disorders, cancer, cancer cell proliferation, epilepsy, seizure, persistent seizure, cerebral ischemia, cerebral insult, refractory convulsive status epilepticus, prolonged seizure, status epilepticus- induced memory deficits, inflammation, pain, inflammatory lesions, arthritic joints, endometriosis, endometriotic lesions, chronic inflammatory disease, arthritis, rheumatoid arthritis (RA) skin inflammation, vascular inflammation, inflammatory bowel disease (colitis), neurotoxicity, Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS), cancer, cancer cell proliferation, glioblastoma, malignant glioma, neuroblastoma, medulloblastoma, peripheral and neural inflammation, or intracranial aneurysms.

[0289] In certain embodiments, it is contemplated that compounds disclosed herein may be used for the treatment of autoimmune diseases, such as, but not limited to, encephalomyelitis, leukoencephalitis, Addison's disease, agammaglobulinemia, alopecia areata, amyotrophic lateral sclerosis, ankylosing spondylitis, anti-GBM / TBM nephritis, antiphospholipid syndrome, antisynthetase syndrome, atopic allergy, atopic dermatitis, aplastic anemia, cardiomyopathy, enteropathy, hemolytic anemia, hepatitis, inner ear disease, lymphoproliferative syndrome, peripheral neuropathy, pancreatitis, polyendocrine syndrome, progesterone dermatitis, thrombocytopenic purpura, urticaria, uveitis, concentric sclerosis, Behcet’s syndrome, Berger's disease, Bickerstaffs encephalitis, Blau syndrome, Bullous pemphigoid, Castleman's disease, celiac disease, inflammatory demyelinating polyneuropathy, multifocal osteomyelitis, Churg-Strauss syndrome, cicatricial pemphigoid, Cogan syndrome, cold agglutinin disease, complement component 2 deficiency, cranial arteritis, CREST syndrome, Crohn’s Disease, Cushing's Syndrome, cutaneous leukocytoclastic angiitis, Degos disease, Dercum's disease Suspected, dermatitis herpetiformis, dermatomyositis, diabetes mellitus type 1, diffuse cutaneous systemic sclerosis, Dressier's syndrome, Discoid lupus, erythematosus, eczema, enthesitis-related arthritis, eosinophilic fasciitis, eosinophilic, gastroenteritis, epidermolysis bullosa acquisita, erythema nodosum, cryoglobulinemia, Evan's syndrome, fibrodysplasia ossificans progressive, fibrosing alveolitis, gastritis, gastrointestinal pemphigoid, giant cell arteritis, glomerulonephritis, Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome (GBS), Hashimoto's encephalitis, Hashimoto's thyroiditis, haemolytic anaemia, hypogammaglobulinemia, demyelinating diseases, pulmonary fibrosis, thrombocytopenic purpura, nephropathy, inclusion body myositis, demyelinating polyneuropathy, interstitial cystitis, Kawasaki's Disease, Lambert-Eaton myasthenic syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosis, linear IgA disease (LAD), lupoid hepatitis, lupus erythematosus, Majeed syndrome, microscopic polyangiitis, Miller-Fisher syndrome, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, myositis, ocular cicatricial pemphigoid, palindromic rheumatism, PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcus), paraneoplastic cerebellar degeneration, paroxysmal nocturnal haemoglobinuria (PNH), Parry Romberg syndrome, pemphigus pernicious anaemia, perivenous encephalomyelitis, POEMS syndrome, polyarteritis nodosa, polymyalgia rheumatic, polymyositis, primary biliary cirrhosis, primary sclerosing cholangitis, progressive inflammatory neuropathy, psoriasis Accepted, psoriatic arthritis, pyoderma gangrenosum, pure red cell aplasia, Rasmussen's encephalitis, Raynaud phenomenon, relapsing polychondritis, Reiter's syndrome, Restless leg syndrome, retroperitoneal fibrosis, rheumatoid arthritis, rheumatoid fever, sarcoidosis, Schmidt syndrome, Schnitzler syndrome, scleritis, scleroderma, Sjogren's syndrome, spondyloarthropathy, Still's disease, stiff person syndrome, subacute bacterial endocarditis (SBE), Susac’s syndrome, Sweet's syndrome, Sydenham chorea, sympathetic ophthalmia, Takayasu's arteritis, temporal arteritis, Tolosa-Hunt syndrome, transverse myelitis, ulcerative colitis, undifferentiated connective tissue disease, undifferentiated spondyloarthropathy, vasculitis, vitiligo, and Wegener's granulomatosis.

[0290] EP2 receptor is widely expressed throughout the human body and brain. Studies suggest that EP2 mediates a majority of COX-2 driven inflammatory signaling following an initial acute brain injury, or during the chronic disease states. EP2 promotes cell signaling through G-protein coupled mechanism or G-protein independent cellular mechanisms to exacerbate the disease. The mechanistic details and various diseases impacted by the EP2 receptor activation have been extensively reviewed. The neurodegenerative diseases that are strongly exacerbated by the EP2 receptor function are status epilepticus, traumatic brain injury, epilepsy, Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Other CNS diseases such as stroke (hemorrhagic and ischemic), unruptured cerebral aneurysms are also exacerbated by EP2 function. Other diseases that are strongly exacerbated by EP2 receptor function are cancer types such as glioblastoma, neuroblastoma, medulloblastomas, and prostate cancer. Furthermore, EP2 was indicated to exacerbate inflammatory bowel disease, rheumatoid arthritis, skin inflammation, endometriosis, and preterm delivery. EP2 receptor antagonism with small molecule inhibitor reduces neuroinflammation and neurodegeneration in status epilepticus models, Alzheimer’s model, prevents cancer proliferation and metastasis, endometriosis-derived hyperalgesia, and a chronic spatial memory deficit caused by peripheral administration of lipopolysaccharide. Therefore, targeting EP2 receptors with small molecule antagonist is therapeutically beneficial for treating several of these diseases.

[0291] Pharmaceutical Formulations

[0292] In certain embodiments, this disclosure relates to pharmaceutical compositions comprising a compound disclosed herein derivative, ester, prodrug, or salt thereof, with or without a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition is in the form of a table, pill, capsule, powder, granules, gel, or gel capsule. In certain embodiments, the pharmaceutical composition is in the form of an aqueous liquid comprising pH buffering agents and optionally salts and / or saccharide or polysaccharide.

[0293] In certain embodiments, the pharmaceutically acceptable excipient is lactose, sucrose, mannitol, triethyl citrate, dextrose, cellulose, methyl cellulose, ethyl cellulose, hydroxyl propyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, croscarmellose sodium, polyvinyl N-pyrrolidone, crospovidone, ethyl cellulose, povidone, methyl and ethyl acrylate copolymer, polyethylene glycol (e.g., PEG of an average molecular weight or 400, 300, or 150), diethylene glycol monoethyl ether (Transcutol™ HP), fatty acid esters of sorbitol, lauryl sulfate, gelatin, glycerin, glyceryl monooleate, silicon dioxide, titanium dioxide, talc, com starch, carnauba wax, stearic acid, sorbic acid, magnesium stearate, calcium stearate, castor oil, mineral oil, calcium phosphate, starch, carboxymethyl ether of starch, iron oxide, triacetin, acacia gum, esters, or salts thereof.

[0294] Pharmaceutical compositions disclosed herein may be in the form of pharmaceutically acceptable salts, as generally described below. Some non-limiting examples of suitable pharmaceutically acceptable organic and / or inorganic acids are hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, acetic acid, and citric acid, as well as other pharmaceutically acceptable acids known per se (for which reference is made to the references referred to below).

[0295] When the compounds of the disclosure contain an acidic group as well as a basic group, the compounds of the disclosure may also form internal salts, and such compounds are within the scope of the disclosure. When a compound contains a hydrogen-donating heteroatom (e.g. NH), salts are contemplated to covers isomers formed by transfer of said hydrogen atom to a basic group or atom within the molecule.

[0296] Pharmaceutically acceptable salts of the compounds include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulphate / sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chlonde, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salts. Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts. For a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002), incorporated herein by reference.

[0297] The compounds described herein may be administered in the form of prodrugs. A prodrug can include a covalently bonded carrier which releases the active parent drug when administered to a mammalian subject. Prodrugs can be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Prodrugs include, for example, compounds wherein a hydroxyl group is bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl group. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol functional groups in the compounds. Methods of structuring a compound as prodrugs can be found in the book of Testa and Mayer, Hydrolysis in Drug and Prodrug Metabolism, Wiley (2006). Typical prodrugs form the active metabolite by transformation of the prodrug by hydrolytic enzymes, the hydrolysis of amide, lactams, peptides, carboxylic acid esters, epoxides, or the cleavage of esters of inorganic acids. Pharmaceutical compositions for use in the present disclosure typically comprise an effective amount of a compound and a suitable pharmaceutical acceptable carrier. The preparations may be prepared in a manner known per se, which usually involves mixing the at least one compound according to the disclosure with the one or more pharmaceutically acceptable carriers, and, if desired, in combination with other pharmaceutical active compounds, when necessary under aseptic conditions. Reference is again made to U.S. Pat. No. 6,372,778, U.S. Pat. No. 6,369,086, U.S. Pat. No. 6,369,087 and U.S. Pat. No. 6,372,733 and the further references mentioned above, as well as to the standard handbooks, such as the latest edition of Remington's Pharmaceutical Sciences.

[0298] Generally, for pharmaceutical use, the compounds may be formulated as a pharmaceutical preparation comprising at least one compound and at least one pharmaceutically acceptable carrier, diluent or excipient and / or adjuvant, and optionally one or more further pharmaceutically active compounds.

[0299] The pharmaceutical preparations of the disclosure are preferably in a unit dosage form, and may be suitably packaged, for example in a box, blister, vial, bottle, sachet, ampoule or in any other suitable single-dose or multi-dose holder or container (which may be properly labeled); optionally with one or more leaflets containing product information and / or instructions for use. Generally, such unit dosages will contain between 1 and 1000 mg, and usually between 5 and 500 mg, of the at least one compound of the disclosure, e.g. about 10, 25, 50, 100, 200, 300 or 400 mg per unit dosage.

[0300] The compositions can be formulated for enteral, parenteral, topical, transdermal, or pulmonary administration. The compounds can be formulated for immediate release, controlled release, and combinations thereof. Examples of controlled release formulations include delayed release, extended release, pulsatile release, and combinations thereof.

[0301] The compounds can be administered by a variety of routes including the oral, ocular, rectal, transdermal, subcutaneous, intravenous, intramuscular, or intranasal routes, depending on the specific preparation used. The compound will generally be administered in an “effective amount”, by which is meant any amount of a compound that, upon suitable administration, is sufficient to achieve the desired therapeutic or prophylactic effect in the subject to which it is administered. Usually, depending on the condition to be prevented or treated and the route of administration, such an effective amount will usually be between 0.01 to 1000 mg per kilogram body weight of the patient per day, more often between 0.1 and 500 mg, such as between 1 and 250 mg, for example about 5, 10, 20, 50, 100, 150, 200 or 250 mg, per kilogram body weight of the patient per day, which may be administered as a single daily dose, divided over one or more daily doses. The amount(s) to be administered, the route of administration and the further treatment regimen may be determined by the treating clinician, depending on factors such as the age, gender and general condition of the patient and the nature and severity of the disease / symptoms to be treated. Reference is again made to U.S. Pat. No. 6,372,778, U.S. Pat. No. 6,369,086, U.S. Pat. No. 6,369,087 and U.S. Pat. No. 6,372,733 and the further references mentioned above, as well as to the standard handbooks, such as the latest edition of Remington's Pharmaceutical Sciences.

[0302] Depending upon the manner of introduction, the compounds described herein may be formulated in a variety of ways. Formulations containing one or more inhibitors can be prepared in various pharmaceutical forms, such as granules, tablets, capsules, suppositories, powders, controlled release formulations, suspensions, emulsions, creams, gels, ointments, salves, lotions, or aerosols and the like. Preferably, these formulations are employed in solid dosage forms suitable for simple, and preferably oral, administration of precise dosages. Solid dosage forms for oral administration include, but are not limited to, tablets, soft or hard gelatin or non-gelatin capsules, and caplets. However, liquid dosage forms, such as solutions, syrups, suspension, shakes, can also be utilized. Suitable topical formulations include, but are not limited to, lotions, ointments, creams, and gels.

[0303] Formulations containing one or more of the compounds described herein may be prepared using a pharmaceutically acceptable carrier composed of materials that are considered safe and effective and may be administered to an individual without causing undesirable biological side effects or unwanted interactions. The carrier is all components present in the pharmaceutical formulation other than the active ingredient or ingredients. As generally used herein “carrier” includes, but is not limited to, diluents, binders, lubricants, disintegrators, fdlers, pH modifying agents, preservatives, antioxidants, solubility enhancers, and coating compositions.

[0304] Carrier also includes all components of the coating composition which may include plasticizers, pigments, colorants, stabilizing agents, and ghdants. Delayed release, extended release, and / or pulsatile release dosage formulations may be prepared as described in standard references such as “Pharmaceutical dosage form tablets”, eds. Liberman et. al. (New York, Marcel Dekker, Inc., 1989), “Remington - The science and practice of pharmacy”, 20th ed., Lippincott Williams & Wilkins, Baltimore, MD, 2000, and “Pharmaceutical dosage forms and drug delivery systems”, 6th Edition, Ansel et al., (Media, PA: Williams and Wilkins, 1995). These references provide information on carriers, materials, equipment, and process for preparing tablets and capsules and delayed release dosage forms of tablets, capsules, and granules.

[0305] Examples of suitable coating materials include, but are not limited to, cellulose polymers such as cellulose acetate phthalate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetate succinate; polyvinyl acetate phthalate, acrylic acid polymers and copolymers, and methacrylic resins, zein, shellac, and polysaccharides.

[0306] Additionally, the coating material may contain conventional carriers such as plasticizers, pigments, colorants, glidants, stabilization agents, pore formers and surfactants.

[0307] Optional pharmaceutically acceptable excipients present in the drug-containing tablets, beads, granules, or particles include, but are not limited to, diluents, binders, lubricants, disintegrants, colorants, stabilizers, and surfactants. Diluents, also referred to as “fillers,” are typically necessary to increase the bulk of a solid dosage form so that a practical size is provided for compression of tablets or formation of beads and granules. Suitable diluents include, but are not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose, sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, kaolin, sodium chloride, dry starch, hydrolysed starches, pregelatinized starch, silicone dioxide, titanium oxide, magnesium aluminum silicate and powdered sugar.

[0308] Binders are used to impart cohesive qualities to a solid dosage formulation, and thus ensure that a tablet, bead, or granule remains intact after the formation of the dosage forms. Suitable binder materials include, but are not limited to, starch, pregelatinized starch, gelatin, sugars (including sucrose, glucose, dextrose, lactose and sorbitol), polyethylene glycol, waxes, natural and synthetic gums such as acacia, tragacanth, sodium alginate, cellulose, including hydroxypropyl methylcellulose, hydroxypropylcellulose, ethylcellulose, and synthetic polymers such as acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid / polymethacrylic acid and polyvinylpyrrolidone.

[0309] Lubricants are used to facilitate tablet manufacture. Examples of suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, glycerol behenate, polyethylene glycol, talc, and mineral oil.

[0310] Disintegrants are used to facilitate dosage form disintegration or “breakup” after administration, and include, but are not limited to, starch, sodium starch glycolate, sodium carboxymethyl starch, sodium carboxymethylcellulose, hydroxypropyl cellulose, pregelatinized starch, clays, cellulose, arginine, gums, or cross-linked polymers.

[0311] Surfactants may be anionic, cationic, amphoteric, or non-ionic surface-active agents. Suitable anionic surfactants include, but are not limited to, those containing carboxylate, sulfonate and sulfate ions. Examples of anionic surfactants include sodium, potassium, ammonium of long chain alkyl sulfonates and alkyl aryl sulfonates such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium bis-(2-ethylthioxyl)-sulfosuccinate; and alkyl sulphates such as sodium lauryl sulfate. Cationic surfactants include, but are not limited to, quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride, cetrimonium bromide, stearyl dimethylbenzyl ammonium chloride, polyoxyethylene and coconut amine. Examples of non-ionic surfactants include ethylene glycol monostearate, propylene glycol myristate, glyceryl monostearate, glyceryl stearate, polyglyceryl-4- oleate, sorbitan acylate, sucrose acylate, PEG- 150 laurate, PEG-400 monolaurate, polyoxyethylene monolaurate, polysorbates, polyoxyethylene octylphenylether, PEG- 1000 cetyl ether, polyoxyethylene tri decyl ether, polypropylene glycol butyl ether, stearoyl monoisopropanol ami de, and polyoxyethylene hydrogenated tallow amide. Examples of amphoteric surfactants include sodium N-dodecyl-beta- alanine, sodium N-lauryl-beta-iminodipropionate, myristoamphoacetate, lauryl betaine and lauryl sulfobetaine.

[0312] If desired, the tablets, beads, granules, or particles may also contain minor amount of nontoxic auxiliary substances such as wetting or emulsifying agents, dyes, pH buffering agents, or preservatives.

[0313] The concentration of the inhibitor(s) to carrier and / or other substances may vary from about 0.5 to about 100 wt.% (weight percent). For oral use, the pharmaceutical formulation will generally contain from about 5 to about 100% by weight of the active material. For other uses, the pharmaceutical formulation will generally have from about 0.5 to about 50 wt. % of the active material.

[0314] The compositions described herein can be formulation for modified or controlled release. Examples of controlled release dosage forms include extended-release dosage forms, delayed release dosage forms, pulsatile release dosage forms, and combinations thereof.

[0315] In certain embodiments, controlled release forms contain a pharmaceutically acceptable acrylic polymer, including but not limited to, acrylic acid and methacrylic acid copolymers, methyl methacrylate, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacryhc acid), methacrylic acid alkylamine copolymer poly(methyl methacrylate), poly(methacrylic acid)(anhydride), polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers.

[0316] In certain embodiments, the acrylic polymer is comprised of one or more ammonio methacrylate copolymers. Alternatively, extended-release formulations can be prepared using osmotic systems or by applying a semi-permeable coating to the dosage form. In the latter case, the desired drug release profile can be achieved by combining low permeable and high permeable coating materials in suitable proportion. An immediate release portion can be added to the extended-release system by means of either applying an immediate release layer on top of the extended-release core using a coating or compression process or in a multiple unit system such as a capsule containing extended and immediate release beads.

[0317] Extended-release tablets containing hydrophilic polymers are prepared by techniques commonly known in the art such as direct compression, wet granulation, or dry granulation. Their formulations usually incorporate polymers, diluents, binders, and lubricants as well as the active pharmaceutical ingredient. The usual diluents include inert powdered substances such as starches, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, grain flours and similar edible powders. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride and powdered sugar. Powdered cellulose derivatives are also useful. Typical tablet binders include substances such as starch, gelatin, and sugars such as lactose, fructose, and glucose. Natural and synthetic gums, including acacia, alginates, methylcellulose, and polyvinylpyrrolidone can also be used. Polyethylene glycol, hydrophilic polymers, ethylcellulose and waxes can also serve as binders. A lubricant is necessary in a tablet formulation to prevent the tablet and punches from sticking in the die. The lubricant is chosen from such slippery solids as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils.

[0318] Preferred coating materials include bioerodible, gradually hydrolyzable, gradually water- soluble, and / or enzymatically degradable polymers, and may be conventional “enteric” polymers. Enteric polymers, as will be appreciated by those skilled in the art, become soluble in the higher pH environment of the lower gastrointestinal tract or slowly erode as the dosage form passes through the gastrointestinal tract, while enzymatically degradable polymers are degraded by bacterial enzymes present in the lower gastrointestinal tract, particularly in the colon. Suitable coating materials for effecting delayed release include, but are not limited to, cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropylmethyl cellulose phthalate, methylcellulose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate and carboxymethylcellulose sodium; acrylic acid polymers and copolymers, preferably formed from acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate and / or ethyl methacrylate.

[0319] The coating composition may include conventional additives, such as plasticizers, pigments, colorants, stabilizing agents, glidants, etc. Examples of typical plasticizers include polyethylene glycol, propylene glycol, triacetin, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, triethyl acetyl citrate, castor oil and acetylated monoglycerides. A stabilizing agent is preferably used to stabilize particles in the dispersion. Typical stabilizing agents are non-ionic emulsifiers such as sorbitan esters, polysorbates and polyvinylpyrrolidone. Glidants are typically used to reduce sticking effects during film formation and drying. One effective glidant is talc. Other glidants such as magnesium stearate and glycerol monostearates may also be used. Pigments such as titanium dioxide may also be used. Small quantities of an anti-foaming agent, such as a silicone (e.g., simethicone), may also be added to the coating composition.

[0320] The compounds described herein can be administered adjunctively with other active compounds. These compounds include but are not limited to analgesics, anti-inflammatory drugs, antipyretics, antidepressants, antiepileptics, antihistamines, antimigraine drugs, antimuscarinics, anxiolytics, sedatives, hypnotics, antipsychotics, bronchodilators, anti-asthma drugs, cardiovascular drugs, corticosteroids, dopaminergics, electrolytes, gastro-intestinal drugs, muscle relaxants, nutritional agents, vitamins, parasympathomimetics, stimulants, anorectics and anti-narcoleptics. “Adjunctive administration,” as used herein, means the inhibitors can be administered in the same dosage form or in separate dosage forms with one or more other active agents.

[0321] Specific examples of compounds that can be adjunctively administered with the compounds include, but are not limited to, aceclofenac, acetaminophen, atomoxetine, almotriptan, alprazolam, amantadine, amcinonide, aminocyclopropane, amitriptyline, amlodipine, amoxapine, amphetamine, aripiprazole, aspirin, atomoxetine, azasetron, azatadine, beclomethasone, benactyzine, benoxaprofen, bermoprofen, betamethasone, bicifadine, bromocriptine, budesonide, buprenorphine, bupropion, buspirone, butorphanol, butriptyline, caffeine, carbamazepine, carbidopa, carisoprodol, celecoxib, chlordiazepoxide, chlorpromazine, choline salicylate, citalopram, clomipramine, clonazepam, clomdine, clonitazene, clorazepate, clotiazepam, cloxazolam, clozapine, codeine, corticosterone, cortisone, cyclobenzaprine, cyproheptadine, demexiptiline, desipramine, desomorphine, dexamethasone, dexanabinol, dextroamphetamine sulfate, dextromoramide, dextropropoxyphene, dezocine, diazepam, dibenzepin, diclofenac sodium, diflunisal, dihydrocodeine, dihydroergotamine, dihydromorphine, dimetacrine, divalproex, dizatriptan, dolasetron, donepezil, dothiepin, doxepin, duloxetine, ergotamine, escitalopram, estazolam, ethosuximide, etodolac, femoxetine, fenamates, fenoprofen, fentanyl, fludiazepam, fluoxetine, fluphenazine, flurazepam, flurbiprofen, flutazolam, fluvoxamine, frovatriptan, gabapentin, galantamine, gepirone, granisetron, haloperidol, huperzine A, hydrocodone, hydrocortisone, hydromorphone, hydroxyzine, ibuprofen, imipramine, indiplon, indomethacin, indoprofen, iprindole, ipsapirone, ketanserin, ketoprofen, ketorolac, lesopitron, levodopa, lipase, lofepramine, lorazepam, loxapine, maprotiline, mazindol, mefenamic acid, melatonin, melitracen, memantine, meperidine, meprobamate, mesalamine, metapramine, metaxalone, methadone, methadone, methamphetamine, methocarbamol, methyldopa, methylphenidate, metoclopramide, mianserin, mifepristone, milnacipran, minaprine, mirtazapine, moclobemide, modafinil (an anti-narcoleptic), molindone, morphine, morphine hydrochloride, nabumetone, nadolol, naproxen, naratriptan, nefazodone, neurontin, nomifensine, nortriptyline, olanzapine, olsalazine, ondansetron, opipramol, orphenadrine, oxaflozane, oxaprozin, oxazepam, oxitriptan, oxycodone, oxymorphone, pancrelipase, parecoxib, paroxetine, pemoline, pentazocine, pepsin, perphenazine, phenacetin, phendimetrazine, phenmetrazine, phenylbutazone, phenytoin, phosphatidylserine, pimozide, pirlindole, piroxicam, pizotifen, pizotyline, pramipexole, prednisolone, prednisone, pregabalin, propranolol, propizepine, propoxyphene, protriptyline, quazepam, quinupramine, reboxetine, reserpine, risperidone, ritanserin, rivastigmine, rizatriptan, rofecoxib, ropinirole, rotigotine, salsalate, sertraline, sibutramine, sildenafil, sulfasalazine, sulindac, sumatriptan, tacrine, temazepam, tetrabenazine, thiazides, thioridazine, thiothixene, tiapride, tizanidine, tofenacin, tolmetin, toloxatone, topiramate, tramadol, trazodone, triazolam, trifluoperazine, trimethobenzamide, trimipramine, tropisetron, valdecoxib, valproic acid, venlafaxine, viloxazine, vitamin E, zimeldine, ziprasidone, zolmitriptan, zolpidem, zopiclone and isomers, salts, and combinations thereof.

[0322] EXPERIMENTAL

[0323] EP2 receptor properties of

[0324] The compound BPN-37112 was evaluated for potency against EP2 receptor, and selectivity against other prostanoid receptors in a cAMP-driven TR-FRET assays on EP2, EP4, DPI and IP receptor overexpressed C6-glioma cell lines. BPN-37112 displayed high EP2 potency with ICso of 15.6 nM, and a weak potency against DPI receptor with ICso of 2,424 nM, which is about 150-fold selectivity. This compound did not show any inhibition activity of EP4 and IP receptors, indicating its selectivity to EP2 vs. EP4 or IP receptor are greater that 660-fold.

[0325] BPN-37112 was tested in the Schild cAMP assay and dose-dependently inhibited the EP2 receptor activity by causing a rightward shift of EP2 agonist (PGE2) providing an ECso with a Schild KB value of 1.4 nM. The Schild slope of unity (1) derived from Log (dr-1) plotting against Log (M) of the compound indicates that it is a competitive binding inhibitor of the EP2 receptor. A second compound in the class, BPN-37440 has also shown a Schild potency of 5.65 nM with an average Schild slope of 1. Furthermore, another compound BPN-37590 has also shown a Schild potency of 12.5 nM with a Schild slope of 1.12, suggesting the competitive mechanism of inhibition is general within the class of molecules. Certain compounds were also tested for ADME properties including BPN-37112, BPN-37440, BPN-37590, BPN-37359, and BPN-37272. Several possessed suitable ADME criteria for preclinical and clinical evaluations. Compounds BPN-37112, and BPN-37440 displayed greater than 50 pM aqueous solubility and their solubility trended to increase as the pH of the solution decreased suggesting pH-dependency.

[0326] Synthesis of 5-methoxy- l-methyl-N-(2-(2-methyl- lH-indol-3-yl)ethyl)- IH-py rrolo [2,3- c]pyridine-2-carboxamide (BPN-37112)

[0327] The starting material, 5-methoxy-lH-pyrrolo[2,3-c]pyridine-2-carboxylic acid (A) was converted to intermediates B and C using synthetic methods shown. The compounds B and C were treated with lithium hydroxide hydrolysis to give the precursor 5-methoxy-l-methyl-lH-pyrrolo[2,3- c]pyridine-2-carboxylic acid (D), which on coupling with commercially available starting material 2- (2-methyl-lH-indol-3-yl)ethan-l -amine (E) provided compound BPN-37112 with an overall yield 53 % (over 3 steps). Step 1: To a stirred solution of compound A (1.00 g, 5.20 mmol, 1 equiv.) in DMSO (25 mL) at rt was added KOH (874 mg, 15.6 mmol, 3 equiv.), followed by Mel (1.62 g, 11.4 mmol, 2.2 equiv.). The reaction mixture was stirred at rt for 2 hours. After this time, the resulting reaction mixture was added water (200 mL). The solid formed was collected by vacuum filtration. The filter cake was rinsed with water (10 mL) and dried under high vacuum in a 50 °C oven to provide compound B as an off- white solid (784 mg, 57%): ESI MS m / z, 221 [M+H]+.

[0328] Step 2: To a stirred solution of compound B (360 mg, 1.64 mmol, 1 equiv.) in MeOH (15 mL), THE (15 mL), and water (5 mL) at rt was added LiOH»H2O (206 mg, 4.91 mmol, 3 equiv). The reaction mixture was stirred at 40 °C for overnight. After this time, the resulting reaction mixture was cooled to rt and concentrated under reduced pressure. The resulting residue was dissolved in water (10 mL) and adjusted pH to about 4 by addition of 2 N HC1 aqueous solution. The solid formed was collected by vacuum filtration. The filter cake was dried under high vacuum in a 50 °C oven to provide compound D as an off-white solid (321 mg, 95%): ESI MS m / z, = 207 [M+H]+.

[0329] Step 3: To a stirred solution of compound D (259 mg, 1.26 mmol, 1 equiv.) and Et-N (385 mg, 3.81 mmol, 3 equiv.) in DMF (10 mL) at rt was added compound E (328 mg, 1.89 mmol, 1.5 equiv.), followed by HATU (718 mg, 1.89 mmol, 1.5 equiv ). The reaction mixture was stirred at rt for overnight. After this time, the resulting reaction mixture was quenched with sat. aq. NaHCCh (50 mL). The resulting mixture was extracted with EtOAc (3 x). The combined extracts were washed with 10% LiCl aqueous solution (3 x), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel eluting with 50-80% EtOAc / CH2C12 to afford BPN-37112 as an off-white solid (416 mg, 91%).

[0330] 5-Methoxy-l-methyl-N-(2-(2-methyl-lH-indol-3-yl)ethyl)-lH-pyrrolo[2,3-c]pyridine-2- carboxamide: 'H NMR (500 MHz, DMSO-de) 5 10.71 (s, 1H), 8.77 (t, J = 5.3 Hz, 1H), 8.56 (s, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.23 (d, J = 7.7 Hz, 1H), 6.99-6.92 (m, 3H), 6.82 (s, 1H), 3.98 (s, 3H), 3.85 (s, 3H), 3.45-3.40 (m, 2H), 2.95-2.87 (m, 2H), 2.33 (s, 3H). ESI MS m / z, 363 [M+H]+

[0331] Synthesis of l,7-dimethyl-N-(2-(2-methyl-lH-indol-3-yl)ethyl)-lH-pyrrolo[2,3-c]pyridine-2- carboxamide (BPN-37440)

[0332] MeMgC!, NMP,

[0333] FetHQacetyiacetonate

[0334] Commercially available starting material I was methylated using methyl iodide in the presence of calcium carbonate to provide J. Then J was treated with methyl magnesium chloride in the presence of iron III catalyst providing an N-methylated product K in excellent yield. This intermediate K was hydrolysed with lithium hydroxide to acid which was coupled to amine precursor E to get the final product BPN-37440 in excellent yields. This synthetic method produced the material in 53% overall yield (4 steps), and it is amenable to scaling to multi-gram synthesis.

[0335] Step 1: To a stirred solution of compound I (16.8 g, 74.6 mmol, 1 equiv.) in DMF (200 mL) was added CS2CO3 (36.5 g, 112 mmol, 1.5 equiv.) followed by CH3I (13.7 g, 96.3 mmol, 1.3 equiv.) at rt. The reaction mixture was stirred at rt for 3 h. After this time, the reaction mixture was cooled with an ice / water bath and diluted with water (500 mL). The solid precipitated was collected by vacuum fdtration. The filter cake was rinsed with water (10 L), dried under high vacuum at 50 °C oven to afford compound J (16.7 g, 94%) as a light yellow solid: ESI MS m / z, 239 [M+H]+.

[0336] Step 2: An oven-dried flask was charged with compound J (8.00 g, 33.5 mmol, 1 equiv.) and dissolved in anhydrous THF (160 ml) at it. The resulting solution was added NMP (33.2 g, 335 mmol, 10 equiv.) followed by iron(lll) acetylacetonate (591 mg, 1.68 mmol, 0.05 equiv.) under nitrogen. The resulting dark-red solution was cooled to 0 °C and a solution of MeMgCl in THF (3 M, 12.3 mL, 36.9 mmol, 1.1 equiv.) was added dropwise and stirred at 0 °C for 5 min. After this time, the reaction mixture was quenched with water (20 ml) at 0 °C. The resulting suspension was warmed to rt, diluted with ethyl acetate (600 ml), washed with water (200 ml) and brine (100 ml). The organics were dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel eluting with 0%-50% EtOAc / hexane) to provide compound K (7.00 g, 95%) as a yellow solid: ESI MS m / z, 219 [M+H]+. Step 3: To a stirred solution of compound K (7.00 g, 32.1 mmol, 1 equiv.) in MeOH (14 mL), THF (14 mL), and water (4 mL) was added LiOTM O (4.04 g, 96.2 mmol, 3 equiv.) at rt. The reaction mixture was then heated at 40 °C for 2 h. After this time, the reaction mixture was cooled to 0 °C and adjusted pH to about 4 by addition of 6 N HC1 aqueous solution. The solid formed was collected by vacuum filtration. The filter cake was dried under high vacuum in a 50 °C oven to provide compound L (5.78 g, 95%) as a white solid: 'HNMR (500 MHz, DMSO-d6) 5 14.76 (br s, 1H), 8.15 (d, J = 6.3 Hz, 1H), 7.97 (d, J = 6.3 Hz, 1H), 7.42 (s, 1H), 4.40 (s, 3H), 3.21 (s, 3H). ESI MS m / z, 191 [M+H]+.

[0337] Step 4: To a stirred solution of compound L (360 mg, 1.90 mmol, 1 equiv.), compound E (495 mg, 2.84 mmol, 1.5 equiv.), and EtsN (726 mg, 7.19 mmol, 4 equiv.) in DMF (15 mL) was added HATU (1.08 g, 2.84 mmol, 1.5 equiv.) at rt. The reaction mixture was stirred at rt for 1 h. After this time, the reaction mixture was diluted with EtOAc (100 mL). The resulting solution was washed with saturated NaHCCE aqueous solution (50 mL), LiCl aqueous solution (10%, 3 x 30 mL), and brine (30 mL), dried over anhydrous Na2SO , filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel eluting with 0%-10% MeOH / EtOAc to afford compound BPN-37440 (412 mg, 63%) as a white solid. l,7-Dimethyl-N-(2-(2-methyl-lH-indol-3-yl)ethyl)-lH-pyrrolo[2,3-c]pyridine-2- carboxamide: 'H NMR (500 MHz, DMSO-de) 5 10.71(s, 1H), 8.77-8.73 (m, 1H), 7.96 (d, J = 5.0 Hz, 1H), 7.46 (d, J = 5.0 Hz, 1H), 7.40 (d, J = 7.0 Hz, 1H), 7.22 (d, J = 5.0 Hz, 1H), 6.99-6.91 (m, 2H), 6.89 (s, 1H), 4.20 (s, 3H), 3.44-3.40 (m, 2H), 2.93 (s, 3H), 2.91-2.87 (m, 2H), 2.33 (s, 3H). ESI MS, m / z, 347 [M+H]+

[0338] Synthesis of 5-methoxy- l-methyl-N-(2-(2-methyl- lH-indol-3-yl)ethyl)- IH-py rrolo [2,3- b]pyridine-2-carboxamide BPN-37272

[0339] Ester F was methylated with methyl iodide using a base, sodium hydride, to give G, which was subjected to hydrolysis with lithium hydroxide providing a precursor H, which was on further coupling with amine E which resulted in the final product.

[0340] 5-Methoxy-l-methyl-N-(2-(2-methyl-lH-indol-3-yl)ethyl)-lH-pyrrolo[2,3-b]pyridine-2- carboxamide 'H NMR (500 MHz, DMSO-de): 5 10.71 (s, 1H), 8.66 (t, J = 5.8 Hz, 1H), 8.14 (d, J = 2.75 Hz, 1H), 7.65 (d, J = 2.75 Hz, 1H), 7.49 (d, J = 7.7 Hz, 1H), 7.23 (d, J = 7.7 Hz, 1H), 6.99-6.92 (m, 3H), 3.99 (s, 3H), 3.84 (s, 3H), 3.45-3.39 (m, 2H), 2.93-2.89 (m, 2H), 2.34 (s, 3H). ESI MS m / z, 363 [M+H]+.

[0341] Additional compounds were prepared by substituting the appropriate starting materials.

[0342] BPN-37363: 5-Hy droxy- 1 -methyl-N-(2-(2-methyl- 1 H-indol-3 -y 1 ) ethyl ) - 1 H-py rrolo [2,3 - c]pyndine-2-carboxamide: *H NMR (500 MHz, DMSO-de) 5 10.72 (s, 1H), 9.98 (br s, 1H), 8.77 (t, J = 5.8 Hz, 1H), 8.38 (s, 1H), 7.47 (d, J = 7.7 Hz, 1H), 7.22 (d, J = 7.7 Hz, 1H), 6.99-6.91 (m, 2H), 6.72 (s, 1H), 6.34 (s, 1H), 3.93 (s, 3H), 3.42-3.38 (m, 2H), 2.91-2.88 (m, 2H), 2.33 (s, 3H). ESI MS m / z, 349 [M+H]+.

[0343] BPN-37501 : 5 -Methoxy- 1 ,3 -dimethyl-N-(2-(2-methy 1- 1 H-indol-3 -y 1) ethy 1)- 1 H-pyrrolo [2,3 - c] pyndme-2-carboxamide: 'H NMR (500 MHz, DMSO-de) 8 10.73 (s, 1H), 8.53 (t, J = 5.8 Hz, 1H), 8.44 (s, 1H), 7.48 (d, J = 7.7 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 6.99-6.86 (m, 2H), 6.86 (s, 1H), 3.85 (s, 3H), 3.70 (s, 3H), 3.51-3.46 (m, 2H), 2.95-2.92 (m, 2H), 2.35 (s, 3H), 2.19 (s, 3H). ESI MS m / z, 377 [M+H]+.

[0344] BPN-36814: N-(2-(2-Methyl-lH-indol-3-yl)ethyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbox amide: 'H NMR (500 MHz, DMSO-de) 8 12.57 (s, 1H), 10.71 (s, 1H), 9.12 (s, 1H), 8.82-8.77 (m, 2H), 7.49 (d, J = 7.7 Hz, 1H), 7.23 (d, J = 7.9 Hz, 1H), 7.18 (s, 1H), 6.99-6.95 (m, 1H), 6.95-6.90 (m, 1H), 3.49-3.42 (m, 2H), 2.94-2.89 (m, 2H), 2.31 (s, 3H). ESI MS m / z, 320 [M+H]+.

[0345] BPN-37524. 5-Cyclopropoxy-l-methyl-N-(2-(2-methyl-lH-indol-3-yl)ethyl)-lH-pyrrolo [2,3-c]pyndine-2-carboxamide: ’H NMR (500 MHz, DMSO-de) 8 10.71 (s, 1H), 8.76 (t, J = 7.5 Hz, 1H), 8.58 (s, 1H), 7.48 (d, J = 10.0 Hz, 1H), 7.25-7.21 (m, 1H), 7.04 (s, 1H), 7.00-6.95 (m, 2H), 6.85 (s, 1H), 4.11-4.06 (m, 1H), 3.99 (s, 3H), 3.45-3.40 (m, 2H), 2.93-2.89 (m, 2H), 2.33 (s, 3H), 0.79- 0.73 (m, 2H), 0.68-0.63 (m, 2H). ESI MS m / z, 389 [M+H]+.

[0346] BPN-37360. 5 -(2-(2 -Methoxy ethoxy )ethoxy )- 1 -methyl-N-(2-(2-methyl- 1 H-indol-3 -yl) ethyl)- lH-pyrrolo[2,3-c]pyridine-2-carboxamide:JH NMR (500 MHz, DMSO-de): 5 10.71 (s, 1H), 8.77 (t, J = 5.8 Hz, 1H), 8.55 (s, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 6.99-6.91 (m, 3H), 6.82 (s, 1H), 4.35-4.33 (m, 2H), 3.98 (s, 3H), 3.75-3.72 (m, 2H), 3.59-3.57 (m, 2H), 3.47-3.38 (m, 4H), 3.25 (s, 3H), 2.92-2.89 (m, 2H), 2.33 (s, 3H). ESI MS m / z, 451 [M+H]+

[0347] BPN-37359. 5-(Methoxy-d3)-l-methyl-N-(2-(2-methyl-lH-indol-3-yl)ethyl)-lH-pyrrolo [2,3-c]pyridine-2-carboxamide: 'H NMR (500 MHz, DMSO-de): 5 10.71 (s, 1H), 8.77 (t, J = 5.8 Hz, 1H), 8.56 (s, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 6.99-6.91 (m, 3H), 6.82 (s, 1H), 3.98 (s, 3H), 3.43-3.39 (m, 2H), 2.91-2.89 (m, 2H), 2.33 (s, 3H). ESI MS m / z, 366 [M+H]+.

[0348] BPN-37387. 5-Ethoxy-l-methyl-N-(2-(2-methyl-lH-indol-3-yl)ethyl)-lH-pyrrolo[2,3-c] pyndme-2-carboxamide: 'H NMR (500 MHz, DMSO-de): 5 10.71 (s, 1H), 8.76 (t, J = 5.7 Hz, 1H), 8.55 (s, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 6.99-6.90 (m, 3H), 6.82 (s, 1H), 4.27 (q, J = 7.0 Hz, 2H), 3.98 (s, 3H), 3.43-3.39 (m, 2H), 2.92-2.89 (m, 2H), 2.33 (s, 3H), 1.32 (t, J = 7.0 Hz, 3H). ESI MS m / z, 377 [M+H]+; UPLC purity: >99%.

[0349] BPN-37409. 5 -Isopropoxy- 1 -methyl-N-(2-(2-methyl- 1 H-indol-3 -yl)ethyl)- 1 H-py rrolo [2,3 - c]pyndine-2-carboxamide: 'H NMR (500 MHz, DMSO-de): 5 10.71 (s, 1H), 8.76 (t, J = 5.7 Hz, 1H), 8.54 (s, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 6.99-6.91 (m, 2H), 6.85 (s, 1H), 6.80 (s, 1H), 5.20-5.15 (m, 1H), 3.98 (s, 3H), 3.43-3.39 (m, 2H), 2.92-2.89 (m, 2H), 2.33 (s, 3H), 1.27 (d, J = 6.2 Hz, 6H). ESI MS m / z, 391 [M+H]+.

[0350] BPN-37313. 5 -Methoxy- 1 -methyl-N-(2-(2-methyl- 1 H-indol-3 -y l)ethy 1)- 1 H-indole-2- carboxamide: 'H NMR (500 MHz, DMSO-de) 5 10.70 (s, 1H), 8.51-8.48 (m, 1H), 7.49 (d, J = 10.0 Hz, 1H), 7.41 (d, J = 9.0 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.08 (d, J = 2.0 Hz, 1H), 6.99-6.93 (m, 2H), 6.91-6.89 (m, 2H), 3.95 (s, 3H), 3.77 (s, 3H), 3.42-3.38 (m, 2H), 2.93-2.87 (m, 2H), 2.00 (s, 3H). ESI MS, m / z = 362 [M+H]+

[0351] BPN-37362. 3 -Methy l-N-(2-(2-methyl- 1 H-indol-3 -y 1 )ethy 1 ) - 1 H-pyrrolo [2,3 -b]pyridine-2- carboxamide:1HNMR (500 MHz, DMSO-de) 5 11.54 (s, 1H), 10.72 (s, 1H), 8.32-8.31 (m, 1H), 8.07- 8.03 (m, 2H), 7.49 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.11-7.08 (m, 1H), 6.99-6.91 (m, 2H), 3.47-3.73 (m, 2H), 3.30 (s, 3H), 2.94-2.88 (m, 2H), 2.30 (s, 3H). ESI MS, m / z = 333 [M+H]+

[0352] BPN-37361. N-(2-(7-Fluoro-2-methyl- 1 H-indol-3 -yl)ethyl)-5 -methoxy- 1 -methyl- 1 H- pyrrolo[2,3-c]pyridine-2-carboxamide:1HNMR (500 MHz, DMSO-de) 8 11.16 (s, 1H), 8.77-8.74 (m, 1H), 8.55 (s,lH), 7.30 (d, J = 8.0 Hz, 1H), 6.92-6.87 (m, 2H), 6.81-6.78 (m, 2H), 3.97 (s, 3H), 3.84 (s, 3H), 3.43-3.39 (m, 2H), 2.92-2.88 (m, 2H), 2.34 (s, 3H). ESI MS, m / z = 381 [M+H]+

[0353] BPN-37408. 5-Methoxy-l-methyl-N-(2-(2-methyl-lH-pyrrolo[2,3-c]pyridin-3-yl)ethyl)-lH- pyrrolo[2,3-c]pyridine-2-carboxamide:1HNMR (500 MHz, DMSO-de) 8 11.24 (s, 1H), 8.77-8.73 (m, 1H), 8.55 (s, 2H), 8.01 (d, J = 6.0 Hz, 1H), 7.44 (d, J = 5.0 Hz, 1H), 6.92 (s, 1H), 6.79 (s, 1H), 3.94 (s, 3H), 3.84 (s, 3H), 3.45-3.39 (m, 2H), 2.92 - 2.88 (m,2H), 2.38 (s, 3H). ESI MS m / z, 364 [M+H]+

[0354] BPN-37442. N-(2-(5 -Fluoro-2-methy 1- lH-indol-3 -yl)ethyl)-5 -methoxy- 1 -methyl- 1 H- pyrrolo[2,3-c]pyridine-2-carboxamide: 'H NMR (500 MHz, DMSO-de) 3 10.82 (s, 1H), 8.77-8.73 (m, 2H), 8.55 (s, 1H), 7.22-7.18 (m, 2H), 6.93-6.90 (m, 2H), 3.97 (s, 3H), 3.84 (s, 3H), 3.72-3.38 (m, 2H), 2.89-2.85 (m, 2H), 2.32 (s, 3H). ESI MS m / z, 381 [M+H]+

[0355] BPN-37441. 5-Chloro- 1 -methy l-N-(2-(2-methyl- 1 H-indol-3 -yl)ethyl)- 1 H-py rrolo [2,3 -c] pyridme-2-carboxamide: 'H NMR (500 MHz, DMSO-de) 6 10.72 (s, 1H), 8.91-8.87 (m, 1H), 8.79 (s,lH), 7.73 (d, 1 = 1.0 Hz, 1H), 7.47 (d, J = 7.0 Hz, 1H), 7.22 (d, J = 5.0 Hz, 1H), 6.99-6.95 (m, 2H), 6.94-6.91 (m, 1H), 4.04 (s, 3H), 3.44-3.40 (m, 2H), 2.93-2.89 (m, 2H), 2.33 (s, 3H). ESI MS, m / z, 367 [M+H]+

[0356] BPN-37440. l,7-Dimethyl-N-(2-(2-methyl-lH-indol-3-yl)ethyl)-lH-pyrrolo[2,3-c]pyrid ine- 2-carboxamide: 'H NMR (500 MHz, DMSO-de) 8 10.71(s, 1H), 8.77-8.73 (m, 1H), 7.96 (d, J = 5.0 Hz, 1H), 7.46 (d, J = 5.0 Hz, 1H), 7.40 (d, J = 7.0 Hz, 1H), 7.22 (d, J = 5.0 Hz, 1H), 6.99-6.91 (m, 2H), 6.89 (s, 1H), 4.20 (s, 3H), 3.44-3.40 (m, 2H), 2.93 (s, 3H), 2.91-2.87 (m, 2H), 2.33 (s, 3H). ESI MS, m / z, 347 [M+H]+

[0357] BPN-37439. 1 -Ethy 1-5 -methoxy -N-(2-(2-methyl- lH-indol-3 -yl)ethyl)- 1 H-py rrolo [2,3 -c] pyridine-2-carboxamide:XH NMR (500 MHz, DMSO-de) 6 10.71 (s, 1H), 8.79-8.75 (m, 1H), 8.59 (s, 1H), 7.47(d, J = 8.0 Hz, 1H), 7.24-7.20 (m, 1H), 6.99-6.91(m, 3H), 6.82 (s, 1H), 4.56 (q, J = 7.0 Hz, 2H), 3.85 (s, 3H), 3.44-3.40 (m, 2H), 2.92-2.88 (m, 2H), 2.33 (s, 3H), 1.30 (t, J = 7.0 Hz, 3H). ESI MS m / z, 377 [M+H]+

[0358] BPN-37502. 5-Methoxy-l-methyl-N-(2-(2-methyl-lH-pyrrolo[2,3-b]pyridin-3-yl)ethyl)-lH- pyrrolo[2,3-c]pyridine-2-carboxamide: 1H NMR (500 MHz, DMSO-d6) 8 11.25 (s, 1H), 8.75 (s, 1H), 8.55 (s, 1H), 8.07-8.05 (m, 1H), 7.84-7.81 (m, 1H), 6.98-6.95 (m, 1H), 6.92 (d, J = 5.0 Hz, 1H), 6.79 (s, 1H), 3.95 (s, 3H), 3.84 (s, 3H), 3.45-3.41 (m, 2H), 2.92-2.88 (m, 2H), 2.31 (s, 3H). ESI MS m / z, 364 [M+H]+

[0359] BPN-36789. N-(2-(2-Methyl-lH-indol-3-yl)ethyl)-lH-pyrrolo[3,2-b]pyridine-2-carbox amide: ’H NMR (500 MHz, DMSO-de) 8 11.79 (s, 1H), 10.71 (s, 1H), 8.77-8.75 (m, 1H), 8.38-8.37 (m, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 7.0 Hz, 1H), 7.23-7.16 (m, 3H), 6.93-6.91 (m, 2H), 3.48-3.44 (m, 2H), 2.93-2.88 (m, 2H), 2.31 (s, 3H). ESI MS m / z, 319 [M+H]+

[0360] BPN-36841. N-(2-(2-Methyl-lH-indol-3-yl)ethyl)-lH-pyrrolo[2,3-b]pyridine-2-carbox amide: 'H NMR (500 MHz, DMSO-de) 8 12.00 (s, 1H), 10.70 (s, 1H), 8.59 (s, 1H), 8.29 (d, J = 4.0 Hz, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.08-7.05 (m, 2H), 6.99-6.89 (m, 3H), 3.45-3.41 (m, 2H), 2.92-2.88 (m, 2H), 2.31 (s, 3H). ESI MS m / z, 319 [M+H]+

[0361] BPN-36957. 5-Methoxy-N-(2-(2-methyl-lH-indol-3-yl)ethyl)-lH-indole-2-carboxamide: 'H NMR (500 MHz, DMSO-d6) 6 11.38 (s, 1H), 10.70 (s, 1H), 8.51 (t, J = 7.5 Hz, 1H), 7.50 (d, J = 10.0 Hz, 1H), 7.31 (d, J = 15.0 Hz, 1H), 7.23 (d, J = 10.0 Hz, 1H), 7.07 (d, J = 5.0 Hz, 1H), 6.99-6.95 (m, 2H), 6.94-6.91 (m, 1H), 6.82 (dd, J = 10.0, 5.0 Hz, 1H), 3.76 (s, 3H), 3.46-3.40 (m, 2H), 2.92-2.88 (m, 2H), 2.31 (s, 3H). ESI MS m / z, 348 [M+H]+

[0362] BPN-36958. 5 -Methyl-N-(2-(2-methyl- 1 H-indol-3 -yl)ethyl)- 1 H-pyrrolo [2,3 -c]pyridine-2- carboxamide: ’H NMR (500 MHz, DMSO-de) 8 12.64 (s, 1H), 10.72 (s, 1H), 9.02 (t, J = 5.0 Hz, 1H), 8.80 (s, 1H), 7.79 (s, 1H), 7.48 (d, J = 10.0 Hz, 1H), 7.23 (d, J = 10.0 Hz, 1H), 7.19 (s, 1H), 6.99-6.89 (m, 2H), 3.50-3.44 (m, 2H), 2.94-2.90 (m, 2H), 2.60 (s, 3H), 2.31 (s, 3H). ESI MS m / z, 333 [M+H]+

[0363] BPN-37358. 5-Amino-l-methyl-N-(2-(2-methyl-lH-indol-3-yl)ethyl)-lH-pyrrolo[2,3-c] pyridine-2-carboxamide:JH NMR (500 MHz, DMSO-de): 8 10.71 (s, 1H), 8.67 (t, J = 5.8 Hz, 1H),

[0364] 8.39 (s, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.23 (d, J = 7.7 Hz, 1H), 6.99-6.91 (m, 2H), 6.65 (s, 1H), 6.56 (s, 1H), 5.56 (br s, 2H), 3.91 (s, 3H), 3.45-3.38 (m, 2H), 2.91-2.87 (m, 2H), 2.33 (s, 3H). ESI MS m / z, 348 [M+H]+

[0365] BPN-37273. 5-Acetamido- 1 -methyl-N-(2-(2-methyl- 1 H-indol-3 -yl)ethyl)- 1 H-pyrrolo [2,3 - c]pyridine-2-carboxamide: 'H NMR (500 MHz, DMSO-de): 8 10.71 (s, 1H), 10.29 (s, 1H), 8.79 (t, J = 5.8 Hz, 1H), 8.71 (s, 1H), 8.22 (s, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.23 (d, J = 7.7 Hz, 1H), 6.99-6.91 (m, 2H), 6.92 (s, 1H), 4.02 (s, 3H), 3.44-3.88 (m, 2H), 2.93-2.88 (m, 2H), 2.34 (s, 3H), 2.09 (s, 3H). ESI MS m / z, 390 [M+H]+

[0366] BPN-36793. 5 -Methoxy -N-(2-(2-methyl- 1 H-indol-3 -yl)ethyl)- 1 H-py rrolo[2,3 -c]pyridine-2- carboxamide: 'H NMR (500 MHz, DMSO-de): 8 11.76 (s, 1H), 10.70 (s, 1H), 8.78 (t, J = 5.8 Hz, 1H),

[0367] 8.40 (s, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.23 (d, J = 7.7 Hz, 1H), 6.99-6.91 (m, 4H), 3.84 (s, 3H), 3.46-

[0368] 3.40 (m, 2H), 2.93-2.89 (m, 2H), 2.31 (s, 3H). ESI MS m / z, 349 [M+H]+

[0369] BPN-36792. N-(2-(2-Methyl-lH-indol-3-yl)ethyl)-lH-pyrrolo[2,3-c]pyridine-2-carbox amide: 'H NMR (500 MHz, DMSO-de): 8 12.09 (s, 1H), 10.71 (s, 1H), 8.83 (t, J = 5.9 Hz, 1H), 8.79 (s, 1H), 8.13 (d, J = 5.5 Hz, 1H), 7.62 (d, J = 5.5 Hz, 1H), 7.49 (d, J = 7.7 Hz, 1H), 7.22 (d, J = 7.7 Hz, 1H), 7.10 (s, 1H), 6.99-6.91 (m, 2H), 3.49-3.43 (m, 2H), 2.94-2.90 (m, 2H), 2.31 (s, 3H). ESI MS m / z, 319 [M+H]+

[0370] BPN-36794. 6-Methoxy-N-(2-(2-methyl-lH-indol-3-yl)ethyl)-lH-pyrrolo[2,3-c]pyridine-2- carboxamide: ‘HNMR (500 MHz, DMSO-de): 8 11.82 (s, 1H), 10.70 (s, 1H), 8.38 (t, J = 5.8 Hz, 1H), 7.93 (d, J = 7.8 Hz, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 6.99-6.93 (m, 3H), 6.57 (d, J = 8.5 Hz, 1H), 3.89 (s, 3H), 3.45-3.39 (m, 2H), 2.91-2.87 (m, 2H), 2.31 (s, 3H). ESI MS m / z, 349 [M+H]+

[0371] BPN-36790. N-(2-(2-Methyl-lH-indol-3-yl)ethyl)-lH-pyrrolo[3,2-c]pyndine-2-carbox amide: 'H NMR (500 MHz, DMSO-de): 8 12.06 (s, 1H), 10.71 (s, 1H), 8.94 (s, 1H), 8.77 (t, J = 5.7 Hz, 1H), 8.23 (d, J = 5.8 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.39 (d, J = 5.8 Hz, 1H), 7.24-7.22 (m, 2H), 6.99-6.91 (m, 2H), 3.48-3.42 (m, 2H), 2.89-2.87 (m, 2H), 2.31 (s, 3H). ESIMS m / z, 319 [M+H]+ BPN-37092. 1 -Methyl-N-(2-(2-methyl- 1 H-indol-3 -yl)ethyl)- 1 H-pyrrolo [2,3 -c]pyridine-2- carboxamide: 'H NMR (500 MHz, DMSO-de) 8 10.72 (s, 1H), 9.16 (s, 1H), 8.95 (t, J = 5.8 Hz, 1H), 8.28-8.25 (m, 1H), 7.85 (d, J = 5.8 Hz, 1H), 7.48 (d, J = 7.7 Hz, 1H), 7.24-7.22 (m, 1H), 7.10 (s, 1H), 6.99-6.88 (m, 2H), 4.09 (s, 3H), 3.47-3.43 (m, 2H), 2.94-2.89 (m, 2H), 2.34 (s, 3H). ESI MS m / z, 333 [M+H]+

[0372] BPN-36791. N-(2-(2-Methyl- 1 H-indol-3 -yl)ethyl)-5H-py rrolo [3 ,2-d]pyrimidine-6-carbox amide: ’H NMR (500 MHz, DMSO-de) 8 12.35 (s, 1H), 10.72 (s, 1H), 8.99 (t, J = 5.8 Hz, 1H), 8.93 (s, 1H), 8.88 (s, 1H), 7.50 (d, J = 7.7 Hz, 1H), 7.24-7.20 (m, 2H), 6.99-6.90 (m, 2H), 3.50-3.45 (m, 2H), 2.95-2.92 (m, 2H), 2.31 (s, 3H). ESI MS m / z, 320 [M+H]+

[0373] BPN-37637. 5 -Cyano- 1 -methyl-N-(2-(2-methyl- lH-indol-3 -yl)ethyl)- 1 H-pyrrolo [2,3 -c] pyridine-2-carboxamide: 'H NMR (500 MHz, DMSO-de) 8 10.70 (s, 1H), 9.12 (s, 1H), 8.96 (t, J = 5.8 Hz, 1H), 8.40 (s, 1H), 7.47 (d, J = 7.8 Hz, 1H), 7.22 (d, J = 7.8 Hz, 1H), 7.15 (s, 1H), 6.99-6.91 (m, 2H), 4.11 (s, 3H), 3.46-3.42 (m, 2H), 2.93-2.88 (m, 2H), 2.33 (s, 3H). ESI MS m / z, 358 [M+H]+

[0374] BPN-37666. l-Methyl-N-(2-(2-methyl-lH-indol-3-yl)ethyl)-5-(methylsulfonyl)-lH- pyrrolo[2,3-c]pyridine-2-carboxamide: 'H NMR (500 MHz, DMSO-de) 8 10.72 (s, 1H), 9.13 (s, 1H), 8.98 (t, J = 5.8 Hz, 1H), 8.38 (s, 1H), 7.48 (d, J = 7.7 Hz, 1H), 7.24-7.22 (m, 2H), 6.99-6.91 (m, 2H), 4.14 (s, 3H), 3.46-3.42 (m, 2H), 3.23 (s, 3H), 2.94-2.90 (m, 2H), 2.30 (s, 3H). ESI MS m / z, 411 [M+H]+

[0375] BPN-37691. N-(2-(7-Fluoro-2-methyl-lH-indol-3-yl)ethyl)-l,5,7-trimethyl-lH-pyrrolo [2,3- c]pyndine-2-carboxamide: 'H NMR (500 MHz, DMSO-de) 8 11.17 (s, 1H), 8.73 (t, J = 5.4 Hz, 1H), 7.30 (d, J = 7.8 Hz, 1H), 7.22 (s, 1H), 6.92-6.78 (m, 2H), 6.74 (s, 1H), 4.17 (s, 3H), 3.43-3.39 (m, 2H), 2.91-2.88 (m, 5H), 2.44 (s, 3H), 2.34 (s, 3H). ESI MS m / z, 379 [M+H]+ BPN-37692. l,5,7-Trimethyl-N-(2-(2-methyl-lH-indol-3-yl)ethyl)-lH-pyrrolo[2,3-c]pyri dine-2-carboxamide:’H NMR (500 MHz, DMSO-de) 5 10.71 (s, 1H), 8.73 (t, J = 5.8 Hz, 1H), 7.47 (d, J = 7.7 Hz, 1H), 7.24-7.22 (m, 2H), 6.99-6.91 (m, 2H), 6.76 (s, 1H), 4.17 (s, 3H), 3.43-3.39 (m, 2H), 2.91-2.89 (m, 5H), 2.44 (s, 3H), 2.33 (s, 3H). ESI MS m / z, 361 [M+H]+

[0376] BPN-37703. N5, 1 -Dimethyl -N2-(2-(2-methyl- 1 H-indol-3 -yl)ethyl)- 1 H-pyrrolo [2,3 -c]pyri dine-2,5-dicarboxamide:XH NMR (500 MHz, DMSO-de) 5 10.72 (s, 1H), 8.96 (s, 1H), 8.88 (m, 1H), 8.66-8.63 (m, 1H), 8.35 (d, J = 1.0 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.12 (s, 1H), 6.99-6.91 (m, 2H), 4.11 (s, 3H), 3.45-3.41 (m, 2H), 2.93-2.89 (m, 2H), 2.84 ( d, J = 5.0 Hz, 3H), 2.34 (s, 3H). ESI MS m / z, 390 [M+H]+

[0377] BPN-37690. l-Methyl-N-(2-(2-methyl-lH-indol-3-yl)ethyl)-5-(methylamino)-lH-pyrrolo [2,3-c]pyndine-2-carboxamide: ’H NMR (500 MHz, DMSO-de) 8 10.70 (s, 1H), 8.64 (s, 1H), 8.43 (s, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 6.97-6.92 (m, 2H), 6.67 (s, 1H), 6.40 (d, J = 1.0 Hz, 1H), 5.70 (s, 1H), 3.92 (s, 3H), 3.41-3.37 (m, 2H), 2.91-2.87 (m, 2H), 2.74 (d, J = 5.0 Hz, 3H), 2.07 (s, 3H). ESI MS m / z, 362 [M+H]+

[0378] BPN-37669. 5-Amino-l-methyl-N-(2-(2-methyl-lH-indol-3-yl)ethyl)-lH-pyrrolo[2,3-b] pyridine-2-carboxamide: 'H NMR (500 MHz, DMSO-de) 8 10.70 (s, 1H), 8.51 (m, 1H), 7.90 (d, J = 3.0 Hz, 1H), 7.48 (d, I = 8.0 Hz, 1H), 7.23 (d, I = 8.0 Hz, 1H), 7.12 (d, J = 3.0 Hz, 1H), 6.99-6.91 (m, 2H), 6.74 (s, 1H), 4.84 (s, 2H), 3.94 (s, 3H), 3.41-3.37 (m, 2H), 2.91-2.87 (m, 2H), 2.07 (s, 3H). ESI MS m / z, 348 [M+H]+

[0379] BPN-37668. l,5-Dimethyl-N-(2-(2-methyl-lH-indol-3-yl)ethyl)-lH-pyrrolo[2,3-b]pyrid ine- 2-carboxamide: 'H NMR (500 MHz, DMSO-de) 8 10.70 (s, 1H), 8.66 (m, 1H), 8.23 (d, J = 2.0 Hz, 1H), 7.87-7.86 (m, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 6.99-6.91 (m, 3H), 3.99 (s, 3H), 3.43-3.39 (m, 2H), 2.92-2.88 (m, 2H), 2.39 (s, 3H), 2.33 (s, 3H). ESI MS m / z, 347 [M+H]+

[0380] BPN-37590. 5-(2 -Methoxy ethoxy)-! -methyl-N-(2-(2-methyl-lH-indol-3-yl)ethyl)-lH- pyrrolo[2,3-c]pyridine-2-carboxamide: 'll NMR (500 MHz, DMSO-de) 8 10.71 (s, 1H), 8.77 (d, J = 6.0 Hz, 1H), 8.54 (s, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.23 (s, 1H), 6.99-6.91 (m, 3H), 6.82 (s, 1H), 4.35- 4.33 (m, 2H), 3.97 (s, 3H), 3.65 (d, J = 5.0 Hz, 2H), 3.43-3.39 (m, 2H), 3.30 (s, 3H), 2.90 (m, 2H), 2.36 (s, 3H). ESI MS m / z, 407 [M+H]+

[0381] BPN-37559. l-Methyl-N-(2-(2-methyl-lH-indol-3-yl)ethyl)-5-(trifluoromethyl)-lH- pyrrolo[2,3-c]pyridine-2-carboxamide: 'H NMR (500 MHz, DMSO-de) 8 10.72 (s, 1H), 9.11 (s, 1H), 8.95 (s, 1H), 8.20 (s, 1H), 7.48 (d, J = 8.0 Hz,lH), 7.23 (d, J = 8.0 Hz, 1H), 7.16 (s, 1H), 6.99-6.91 (m, 2 H), 4.12 (s, 3H), 3.46-3.42 (m, 2H), 2.94-2.90 (m, 2H), 2.33 (s, 3H). ESI MS m / z ,401 [M+H]+ BPN-37547. 5-(Difluoromethoxy)-l-methyl-N-(2-(2-methyl-lH-indol-3-yl)ethyl)-lH- pyrrolo[2,3-c]pyridine-2-carboxamide:JH NMR (500 MHz, DMSO-de) 5 10.71 (s, 1H), 8.86 (m, 1H), 8.67 (s, 1H), 7.76 (s, 2H), 7.46 (m, 1H), 7.27-7.22 (m, 1H), 6.99-6.91 (m, 3H), 4.03 (s, 3H), 3.44- 3.40 (m, 2H), 2.93-2.89 (m, 2H), 2.33 (s, 3H). ESI MS m / z, 399 [M+H]+

[0382] BPN-37702. 5 -Methoxy- 1 ,7-dimethyl -N-(2-(2-methyl- 1 H-indol-3 -yl)ethyl)- 1 H-pyrrolo [2,3 - c]pyndine-2-carboxamide:JH NMR (500 MHz, DMSO-de): § 10.71 (s, 1H), 8.72 (t, J = 5.8 Hz, 1H), 7.47 (d, J = 7.7 Hz, 1H), 7.24-7.22 (m, 1H), 6.99-6.91 (m, 2H), 6.71 (s, 1H), 6.69 (s, 1H), 4.12 (s, 3H), 3.81 (s, 3H), 3.42-3.38 (m, 2H), 2.90-2.86 (m, 2H), 2.86 (s, 3H), 2.33 (s, 3H). ESI MS m / z, 377 [M+H]+

[0383] BPN-37667. 5-((2-(Dimethylamino)ethyl)(methyl)amino)-l-methyl-N-(2-(2-methyl-lH- indol-3-yl)ethyl)-lH-pyrrolo[2,3-c]pyridine-2-carboxamide: 'H NMR (500 MHz, DMSO-de): 8 10.78 (s, 1H), 8.79 (t, J = 5.8 Hz, 1H), 8.57 (s, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.23 (d, J = 7.7 Hz, 1H), 6.97- 6.92 (m, 2H), 6.80 (s, 1H), 6.73 (s, 1H), 3.97 (s, 3H), 3.86 (t, J = 6.6 Hz, 2H), 3.40 (q, J = 6.6 Hz, 2H), 3.11 (br s, 2H), 2.97 (s, 3H), 2.90 (t, J = 7.6 Hz, 2H), 2.70 (s, 6H), 2.33 (s, 3H). ESI MS m / z, 433 [M+H]+

[0384] BPN-37589. 7-Methoxy-l-methyl-N-(2-(2-methyl-lH-indol-3-yl)ethyl)-lH-pyrrolo[2,3- c]pyndine-2-carboxamide: 'H NMR (500 MHz, DMSO-de): 8 10.70 (s, 1H), 8.59 (t, J = 5.8 Hz, 1H), 7.46 (d, J = 7.7 Hz, 1H), 7.23-7.19 (m, 2H), 6.99-6.92 (m, 2H), 6.91 (s, 1H), 6.46 (d, J = 7.0 Hz, 1 H), 4.29 (s, 3H), 3.40 (s, 3H), 3.40-3.36 (m, 2H), 2.90-2.86 (m, 2H), 2.33 (s, 3H). ESI MS m / z, 363 [M+H]+

[0385] BPN-37546. 5-(2-(Dimethylamino)acetamido)-l-methyl-N-(2-(2-methyl-lH-indol-3- yl)ethyl)-lH-pyrrolo[2,3-c]pyridine-2-carboxamide: 'H NMR (500 MHz, DMSO-de): 8 10.72 (s, 1H), 9.76 (s, 1H), 8.79 (t, J = 5.8 Hz, 1H), 8.71 (s, 1H), 8.25 (s, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.23 (d, J = 7.7 Hz, 1H), 6.99-6.91 (m, 3H), 4.03 (s, 3H), 3.44-3.40 (m, 2H), 3.17 (s, 2H), 2.93-2.90 (m, 2H), 2.35 (s, 6H), 2.33 (s, 3H). ESI MS m / z, 433 [M+H]+

[0386] BPN-37545. l-Methyl-N-(2-(2-methyl-lH-indol-3-yl)ethyl)-5-(N-methylacetamido)-lH- pyrrolo[2,3-c]pyridine-2-carboxamide:1H NMR (500 MHz, DMSO-de): 8 10.72 (s, 1H), 8.87 (s, 1H), 8.84 (t, J = 5.8 Hz, 1H), 7.63 (s, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.23 (d, J = 7.7 Hz, 1H), 7.01 (s, 1H), 6.99-6.91 (m, 2H), 4.07 (s, 3H), 3.45-3.41 (m, 2H), 3.21 (s, 3H), 2.93-2.89 (m, 2H), 2.33 (s, 3H), 1.81 (s, 3H). ESI MS m / z, 404 [M+H]+

[0387] BPN-37681. N5,N’, 1 -T rimethyl-N2-(2-(2-methyl- 1 H-indol-3 -yl)ethyl)- 1 H-pyrrolo [2,3 - c]pyridine-2,5-dicarboxamide: ’H NMR (500 MHz, DMSO-de) 8 10.72 (s, 1H), 8.94 (s, 1H), 8.86 (t, J = 5.8 Hz, 1H), 7.85 (d, J = 1.1 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.24-7.22 (m, 1H), 7.06 (d, J = 0.6 Hz, 1H), 7.00-6.91 (m, 2H), 4.09 (s, 3H), 3.45-3.41 (m, 2H), 3.02 (s, 3H), 3.00 (s, 3H), 2.94-2.90 (m, 2H), 2.34 (s, 3H). ESI MS m / z, 404 [M+H]+

[0388] BPN-37664. l-Methyl-N-(2-(2-methyl-lH-indol-3-yl)ethyl)-5-(methylsulfonamido)-lH- pyrrolo[2,3-c]pyridine-2-carboxamide: ’H NMR (500 MHz, DMSO-de) 8 10.71 (s, 1H), 9.95 (s, 1H), 8.80 (t, J = 5.8 Hz, 1H), 8.74 (s, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.24-7.21 (m, 2H), 7.00-6.89 (m, 3H), 4.02 (s, 3H), 3.44-3.40 (m, 2H), 3.19 (s, 3H), 2.93-2.89 (m, 2H), 2.33 (s, 3H). ESI MS m / z, 426 [M+H]+

[0389] BPN-37652. N-(2-(7-Fluoro-2-methyl-lH-indol-3-yl)ethyl)-l,7-dimethyl-lH-pyrrolo[2,3- c]pyridine-2-carboxamide: *H NMR (500 MHz, DMSO-de) 8 11.17 (s, 1H), 8.76 (t, J = 5.8 Hz, 1H),

[0390] 7.97 (d, J = 5.4 Hz, 1H), 7.40 (d, J = 5.5 Hz, 1H), 7.31 (d, J = 7.8 Hz, 1H), 6.94-6.87 (m, 1H), 6.85- 6.77 (m, 2H), 4.20 (s, 3H), 3.44-3.40 (m, 2H), 2.94-2.88 (m, 5H), 2.35 (s, 3H). ESI MS m / z, 365 [M+H]+

[0391] BPN-37651. N-(2-(5-Fluoro-2-methyl-lH-indol-3-yl)ethyl)-l,7-dimethyl-lH-pyrrolo[2,3- c]pyndine-2-carboxamide: *H NMR (500 MHz, DMSO-de) 8 10.83 (s, 1H), 8.74 (t, J = 5.8 Hz, 1H),

[0392] 7.97 (d, J = 5.5 Hz, 1H), 7.39 (d, J = 5.4 Hz, 1H), 7.24-7.18 (m, 2H), 6.85-6.76 (m, 2H), 4.19 (s, 3H), 3.43-3.39 (m, 2H), 2.93 (s, 3H), 2.90-2.86 (m, 2H), 2.33 (s, 3H). ESI MS m / z, 365 [M+H]+

[0393] BPN-37638: 7-Isopropyl-l-methyl-N-(2-(2-methyl-lH-indol-3-yl)ethyl)-lH-pyrrolo[2,3- c]pyndine-2-carboxamide: *H NMR (500 MHz, DMSO-de) 8 10.72 (s, 1H), 8.76 (t, J = 5.8 Hz, 1H), 8.10 (d, J = 5.3 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.40 (d, J = 5.3 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 7.00-6.89 (m, 2H), 6.84 (s, 1H), 4.15 (s, 3H), 3.94-3.85 (m, 1H), 3.45-3.41 (m, 2H), 2.93-2.89 (m, 2H), 2.34 (s, 3H), 1.33 (d, J = 6.6 Hz, 6H). ESI MS m / z, 375 [M+H]+

[0394] BPN-37584. 7-Cyclopropyl-l-methyl-N-(2-(2-methyl-lH-indol-3-yl)ethyl)-lH-pyrrolo [2,3- c]pyndine-2-carboxamide: 'H NMR (500 MHz, DMSO-de) 8 10.72 (s, 1H), 8.77 (t, J = 5.8 Hz, 1H),

[0395] 7.97 (d, J = 5.3 Hz, 1H), 7.49 (d, J = 7.7 Hz, 1H), 7.35 (d, J = 5.4 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 7.00-6.91 (m, 2H), 6.85 (s, 1H), 4.32 (s, 3H), 3.45-3.41 (m, 2H), 2.94-2.90 (m, 2H), 2.81-2.74 (m, 1H), 2.34 (s, 3H), 1.16-1.12 (m, 2H), 1.02-0.97 (m, 2H). ESI MS m / z, 373 [M+H]+

[0396] BPN-37560. 5 -(Allyloxy)- 1 -methy l-N-(2-(2-methyl- 1 H-indol-3 -yl)ethyl)- 1 H-pyrrolo [2,3 - c]pyridine-2-carboxamide: ’H NMR (500 MHz, DMSO-de) 8 10.71 (s, 1H), 8.78 (t, J = 5.8 Hz, 1H), 8.55 (s, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 7.00-6.91 (m, 3H), 6.83 (s, 1H), 6.14- 6.03 (m, 1H), 5.40-5.34 (m, 1H), 5.24-5.17 (m, 1H), 4.81-4.77 (m, 2H), 3.98 (s, 3H), 3.44-3.40 (m, 2H), 2.93-2.89 (m, 2H), 2.33 (s, 3H). ESI MS m / z, 389 [M+H]+; UPLC purity: 97.8%.

[0397] BPN-37548. l-Methyl-N-(2-(2-methyl-lH-indol-3-yl)ethyl)-5-((tetrahydrofuran-2-yl) methoxy)-lH-pyrrolo[2,3-c]pyridine-2-carboxamide: ’H NMR (500 MHz, DMSO-de) 8 10.71 (s, 1H), 8.77 (t, J = 5.8 Hz, 1H), 8.54 (s, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 7.00-6.91 (m, 3H), 6.82 (s, 1H), 4.30-4.10 (m, 3H), 3.98 (s, 3H), 3.81-3.76 (m, 1H), 3.69-3.63 (m, 1H), 3.43-4.39 (m, 2H), 2.92-2.88 (m, 2H), 2.33 (s, 3H), 2.10-1.76 (m, 3H), 1.71-1.62 (m, 1H). ESI MS m / z, 433 [M+H]+

[0398] BPN-37544. 5-Isobutoxy-l-methyl-N-(2-(2-methyl-lH-indol-3-yl)ethyl)-lH-pyrrolo[2,3- c]pyridine-2-carboxamide: ’H NMR (500 MHz, DMSO-de) 5 10.71 (s, 1H), 8.77 (t, J = 5.7 Hz, 1H), 8.54 (s, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 7.00-6.90 (m, 3H), 6.82 (s, 1H), 4.01- 3.97 (m, 5H), 3.43-3.39 (m, 2H), 2.92-2.88 (m, 2H), 2.33 (s, 3H), 2.07-1.97 (m, 1H), 0.98 (d, J = 6.7 Hz, 6H). ESI MS m / z, 405 [M+H]+

[0399] BPN-37600. 7-Ethoxy- 1 -methyl-N-(2-(2-methyl- lH-indol-3 -yl)ethyl)- 1 H-py rrolo [2,3 -c] pyridine-2-carboxamide: *H NMR (500 MHz, DMSO-de) 5 10.71 (s, 1H), 8.70 (t, J = 5.8 Hz, 1H), 7.63 (d, J = 5.6 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 7.15 (d, J = 5.6 Hz, 1H), 7.00- 6.90 (m, 2H), 6.88 (s, 1H), 4.47 (q, J = 7.0 Hz, 2H), 4.21 (s, 3H), 3.43-3.39 (m, 2H), 2.92-2.88 (m, 2H), 2.33 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H). ESI MS m / z, 377 [M+H]+

[0400] BPN-37601. 7-Hy droxy- 1 -methy l-N-(2-(2-methyl- 1 H-indol-3 -yl)ethyl)- 1 H-py rrolo [2,3 - c]pyridine-2-carboxamide: 'H NMR (500 MHz, DMSO-de) 5 11.00-10.95 (m, 1H), 10.70 (s, 1H), 8.58 (t, J = 5.8 Hz, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 7.00-6.84 (m, 3H), 6.75 (s, 1H), 6.42 (d, J = 6.9 Hz, 1H), 4.29 (s, 3H), 3.40-3.36 (m, 2H), 2.90-2.86 (m, 2H), 2.33 (s, 3H). ESI MS m / z, 349 [M+H]+

[0401] BPN-37734. 5-((Dimethylamino)methyl)-l-methyl-N-(2-(2-methyl-lH-indol-3-yl)ethyl)-lH- pyrrolo[2,3-c]pyridine-2-carboxamide: ’H NMR (500 MHz, DMSO-de) § 10.70 (s, 1H), 8.88 (s, 1H), 8.79 (t, J = 5.8 Hz, 1H), 7.59 (s, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.26-7.21 (m, 1H), 7.00-6.91 (m, 3H), 4.06 (s, 3H), 3.71 (s, 2H), 3.44-3.40 (m, 2H), 2.93-2.89 (m, 2H), 2.34 (s, 3H), 2.28 (s, 6H). ESI MS m / z, 390 [M+H]+

[0402] BPN-37735. N-(2-(7-Fluoro-2-methyl-lH-indol-3-yl)ethyl)-5-methoxy-l,7-dimethyl-lH- pyrrolo[2,3-c]pyridine-2-carboxamide: 'H NMR (500 MHz, DMSO-de): 6 11.17 (s, 1H), 8.72 (t, J = 5.8 Hz, 1H), 7.30 (d, J = 7.7 Hz, 1H), 6.92-6.89 (m, 1H), 6.82-6.78 (m, 1H), 6.71 (s, 1H), 6.68 (s, 1H), 4.11 (s, 3H), 3.81 (s, 3H), 3.42-3.38 (m, 2H), 2.92-2.88 (m, 2H), 2.85 (s, 3H), 2.34 (s, 3H). ESI MS m / z, 395 [M+H]+ Table 1. Compound Properties

[0403]

Claims

CLAIMSWhat is claimed is:

1. A compound of Formula IA,Formula IA or salt or prodrug thereof, wherein: a dotted line represents a double or single bond, n is 1, 2, 3, or 4;Q is CH, N, or NX6;W is N or C;Y1is CX1or N; Y2is CX2or N; Y3is CX3or N; Y4is CX4or N;Y5is CR3or N;X1, X2, X-5, and X4are each, the same or different, hydrogen, alkyl, halogen, halogenated alkyl, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, alkoxy, halogenated alkoxy, glycol, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein X1, X2, X3, and X4are optionally substituted with one or more, the same or different, X10;X5and X6are each, the same or different, hydrogen, alkyl, or halogenated alkyl, wherein X5and X6are optionally substituted with one or more, the same or different, X10;X10is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, alkoxy, halogenated alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein X10is optionally substituted with one or more, the same or different, X11;X11is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, acetyloxy, N-methylcarbamoyl, acetylamino, acetyloxy, N-ethylcarbamoyl, acetylamino, acetyloxy, N,N-dimethylcarbamoyl, acetylamino, acetyloxy, N,N-diethylcarbamoyl, acetylamino, acetyloxy, N-methyl-N-ethylcarbamoyl, acetylamino, acetyloxy, methylthio, ethylthio,methylsulfinyl, ethylsulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl, ethoxycarbonyl, N- methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N- ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl;R1, R2, R3, R4and R5are each, the same or different, hydrogen, alkyl, halogenated alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, alkoxy, halogenated alkoxy, glycol, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R1, R2, R , R4andR5are optionally substituted with one or more, the same or different, R10;R10is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, alkoxy, halogenated alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R10is optionally substituted with one or more, the same or different, R11;R11is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, alkoxy, halogenated alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R11is optionally substituted with one or more, the same or different, R12; andR12is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, acetyloxy, N-methylcarbamoyl, acetylamino, acetyloxy, N-ethylcarbamoyl, acetylamino, acetyloxy, N,N-dimethylcarbamoyl, acetylamino, acetyloxy, N,N-diethylcarbamoyl, acetylamino, acetyloxy, N-methyl-N-ethylcarbamoyl, acetylamino, acetyloxy, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl, ethoxycarbonyl, N- methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N- ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.

2. The compound of claim 1, wherein Q is NH and W is C.

3. The compound of claims 1 or 2, wherein n is 2.

4. The compound of any of claims 1-3, wherein R1is methyl, or alkyl, optionally substituted with one or more, the same or different, R10.

5. The compound of any of claims 1-4, wherein R2is hydrogen or halogen.

6. The compound of any of claims 1-5, wherein R3is hydrogen, alkyl, halogen, cyano, hydroxy, amino, or mercapto optionally substituted with one or more, the same or different, R10.

7. The compound of any of claims 1-6, wherein R4is hydrogen, hydroxy, alkoxy or glycol, optionally substituted with one or more, the same or different, R10.

8. The compound of any of claims 1 -7, wherein R3is hydrogen, alkyl, halogen, halogenated alkyl, nitro, cyano, hydroxy, amino, mercapto, alkoxy, halogenated alkoxy, glycol, formyl, carboxy, carbamoyl, acetylamino, acetyloxy, alkoxy, halogenated alkoxy, alkylthio, alkylamino, or (alkyl)2amino, optionally substituted with one or more, the same or different, R10.

9. The compound of any of claims 1-8, wherein R5is hydrogen, halogen, or alkyl.

10. The compound of any of claims 1 -9, wherein X1is hydrogen, halogen, or F.

11. The compound of any of claims 1-9, wherein X" is hydrogen, halogen, or F.

12. The compound of claim 1, which is l,7-dimethyl-N-(2-(2-methyl-lH-indol-3-yl)ethyl)-lH- pyrrolo[2,3-c]pyridine-2-carboxamide (37440) or salt thereof.

13. The compound of claim 1, which is 5-methoxy-l-methyl-N-(2-(2-methyl-lH-indol-3- yl)ethyl)-lH-pyrrolo[2,3-c]pyridine-2-carboxamide (37112 ) or salt thereof.

14. The compound of claim 1, which is -(2-methoxy ethoxy)- 1 -methyl-N-(2-(2-methyl- IH-indol- 3-yl)ethyl)-lH-pyrrolo[2,3-c]pyridine-2-carboxamide (37590) or salt thereof.

15. A pharmaceutical composition comprising a compound as in any of claims 1-14 and a pharmaceutically acceptable excipient.

16. The pharmaceutical composition or claim 15 in the form of a table, pill, capsule, powder, granules, gel, or gel capsule.

17. The pharmaceutical composition or claim 15 in the form of an aqueous liquid comprising pH buffering agents and optionally salts and / or saccharide or polysaccharide.

18. A method of treating or preventing a prostaglandin receptor EP2 associated disease or condition comprising administering an effective amount of a compound as in claims 1-14 to a subject in need thereof.

19. The method of claim 18, wherein the EP2 receptor related disease or condition is cancer, brain cancer, glioma, glioblastoma, neuroblastoma, medulloblastoma, brain injury, neuropathic pain, hypertension, ischemic or hemorrhagic injury, neuroinflammation after a seizure, epilepsy, endometriosis, inflammatory bowel disease (colitis), arthritis / rheumatoid arthritis, skin inflammation, vascular inflammation, Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), kidney disease / transplant rejection, atherosclerosis, ischaemic heart disease, acne vulgaris, asthma, chronic prostatitis, glomerulonephritis, hypersensitivities, inflammatory bowel diseases, pelvic inflammatory disease, sarcoidosis, vasculitis, interstitial cystitis, post-surgical pain, and autoimmune diseases.

20. The use of a compound as described in any one of claims 1-13 in the production of a medicament for the treatment of an EP2 receptor associated disease or condition.

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