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for invention","granted":true,"earliest_filing_date":"2015-09-15","grant_date":"2019-09-24","anticipated_term_date":"2035-09-15","has_disclaimer":true,"patent_status":"ACTIVE","publication_count":2,"has_spc":false,"has_grant_event":true,"has_entry_into_national_phase":false,"has_intention_to_grant":true},"abstract":{"en":[{"text":"Disclosed are chemical entities of formula I: wherein X, Y, Z, R 1 , R 3 , R 4 , R 5 and R 6 are defined herein, as NR2B subtype selective receptor antagonists. Also disclosed are pharmaceutical compositions comprising a chemical entity of formula I, and methods of treating various diseases and disorders associated with NR2B antagonism, e.g., diseases and disorders of the CNS, such as depression, by administering a chemical entity of formula I.","lang":"en","source":"USPTO_FULLTEXT","data_format":"ORIGINAL"}]},"abstract_lang":["en"],"has_abstract":true,"claim":{"en":[{"text":"1. A chemical entity selected from the group consisting of: TABLE 1.CcompoundXR 1C-1HHC-2FHC-3ClHC-4CH 3HC-5CF 3HC-6CF 2 HHC-7CH 2 FHC-8CH 2 CH 3HC-9cyclopropylHC-10CH 3 OHC-11CF 3 OHC-12CHF 2 OHC-13SCH 3HC-14CNHC-15FFC-16ClFC-17CH 3FC-18CF 3FC-19CF 2 HFC-20CH 2 FFC-21CH 2 CH 3FC-22cyclopropylFC-23FClC-24ClClC-25CH 3ClC-26CF 3ClC-27cyclopropylClC-28FCH 3C-29ClCH 3C-30CH 3CH 3C-31CF 3CH 3C-32cyclopropylCH 3 TABLE 2.CcompoundXR 1R 4R 5C-33CF 3HCH 3HC-34ClHCH 3HC-35CH 3HCH 3HC-36CF 3HClHC-37ClHClHC-38CH 3HClHC-39CF 3FCH 3HC-40ClFCH 3HC-41CH 3FCH 3HC-42CF 3FClHC-43ClFClHC-44CH 3FClHC-45CF 3HHCH 3C-46ClHHCH 3C-47CH 3HHCH 3 TABLE 3.CcompoundXR 2R 3C-48FFHC-49ClFHC-50CH 3FHC-51CF 3FHC-52FCH 3HC-53ClCH 3HC-54CH 3CH 3HC-55CF 3CH 3HC-56FClHC-57ClClHC-58CH 3ClHC-59CF 3ClFC-60FHFC-61ClHFC-62CH 3HFC-63CF 3HClC-64FHClC-65ClHClC-66CH 3HClC-67CF 3HCH 3C-68FHCH 3C-69ClHCH 3C-70CH 3HCH 3 TABLE 4.CcompoundXR 1R 6C-71FHCH 3C-72ClHCH 3C-73CH 3HCH 3C-74CF 3HCH 3C-75CF 2 HHCH 3C-76CH 2 FHCH 3C-77OCF 3HCH 3C-78OCF 2 HHCH 3C-79CH 2 CH 3HCH 3C-80cyclopropylHCH 3C-81FHFC-82ClHFC-83CH 3HFC-84CF 3HFC-85CF 2 HHFC-86CH 2 FHFC-87OCF 3HFC-88OCF 2 HHFC-89CH 2 CH 3HFC-90cyclopropylHFC-91FFCH 3C-92ClFCH 3C-93CH 3FCH 3C-94CF 3FCH 3C-95FFFC-96ClFFC-97CH 3FFC-98CF 3FF TABLE 5.CcompoundXR 1R 6C-99FHCH 3C-100ClHCH 3C-101CH 3HCH 3C-102CF 3HCH 3C-103CF 2 HHCH 3C-104CH 2 FHCH 3C-105OCF 3HCH 3C-106OCF 2 HHCH 3C-107CH 2 CH 3HCH 3C-108cyclopropylHCH 3C-109FHFC-110ClHFC-111CH 3HFC-112CF 3HFC-113CF 2 HHFC-114CH 2 FHFC-115OCF 3HFC-116OCF 2 HHFC-117CH 2 CH 3HFC-118cyclopropylHFC-119FFCH 3C-120ClFCH 3C-121CH 3FCH 3C-122CF 3FCH 3C-123FFFC-124ClFFC-125CH 3FFC-126CF 3FF TABLE 6.CcompoundXR 1R 2R 3C-127CF 3HHHC-128CH 3HHHC-129FHHHC-130ClHHHC-131OCH 3HHHC-132OCF 3HHHC-133SCH 3HHHC-134CH 2 CH 3HHHC-135cyclopropylHHHC-136CF 3FHHC-137CF 3HFHC-138CF 3HHFC-139HCF 3HHC-140HHCF 3HC-141HHHCF 3 TABLE 7.CcompoundXR 4R 6C-142CF 3CH 3HC-143CH 3CH 3HC-144CF 3HFC-145CH 3HFC-146CH 2 CH 3HFC-147SCH 3HFC-148cyclopropylHFC-149OCF 3HFC-150OCH 3HFC-151CF 3HCH 3C-152CH 3HCH 3C-153CH 2 CH 3HCH 3C-154SCH 3HCH 3C-155cyclopropylHCH 3C-156OCF 3HCH 3C-157OCH 3HCH 3 TABLE 8.CcompoundXR 4R 6C-158CF 3ClHC-159CH 3ClHC-160CF 3HFC-161CH 3HFC-162CH 2 CH 3HFC-163SCH 3HFC-164cyclopropylHFC-165OCF 3HFC-166OCH 3HFC-167CF 3HCH 3C-168CH 3HCH 3C-169CH 2 CH 3HCH 3C-170SCH 3HCH 3C-171cyclopropylHCH 3C-172OCF 3HCH 3C-173OCH 3HCH 3 TABLE 9.CcompoundXR 1C-174HHC-175FHC-176ClHC-177CH 3HC-178CF 3HC-179CF 2 HHC-180CH 2 FHC-181CH 2 CH 3HC-182cyclopropylHC-183CH 3 OHC-184CF 3 OHC-185CHF 2 OHC-186SCH 3HC-187CNHC-188FFC-189ClFC-190CH 3FC-191CF 3FC-192CF 2 HFC-193CH 2 FFC-194CH 2 CH 3FC-195cyclopropylFC-196FClC-197ClClC-198CH 3ClC-199CF 3ClC-200cyclopropylClC-201FCH 3C-202ClCH 3C-203CH 3CH 3C-204CF 3CH 3C-205cyclopropylCH 3 TABLE 10.CcompoundXR 2R 3C-206FFHC-207ClFHC-208CH 3FHC-209CF 3FHC-210FCH 3HC-211ClCH 3HC-212CH 3CH 3HC-213CF 3CH 3HC-214FClHC-215ClClHC-216CH 3ClHC-217CF 3ClFC-218FHFC-219ClHFC-220CH 3HFC-221CF 3HClC-222FHClC-223ClHClC-224CH 3HClC-225CF 3HCH 3C-226FHCH 3C-227ClHCH 3C-228CH 3HCH 3 TABLE 11.CcompoundXR 4C-229CF 3HC-230CH 3HC-231ClHC-232FHC-233CF 2 HHC-234OCF 3HC-235OCF 2 HHC-236CH 2 CH 3HC-237cyclopropylHC-238isopropylHC-239CF 3CH 3C-240CH 3CH 3C-241CH 2 CH 3CH 3C-242cyclopropylCH 3C-243isopropylCH 3C-244OCF 3CH 3 or a pharmaceutically acceptable salt thereof.","lang":"en","source":"USPTO_FULLTEXT","data_format":"ORIGINAL"},{"text":"2. The chemical entity of claim 1 , wherein the chemical entity is C-179: or a pharmaceutically acceptable salt thereof.","lang":"en","source":"USPTO_FULLTEXT","data_format":"ORIGINAL"},{"text":"3. A pharmaceutical composition comprising the chemical entity of claim 1 and a pharmaceutically acceptable carrier.","lang":"en","source":"USPTO_FULLTEXT","data_format":"ORIGINAL"},{"text":"4. The pharmaceutical composition of claim 3 , which is suitable for oral administration.","lang":"en","source":"USPTO_FULLTEXT","data_format":"ORIGINAL"},{"text":"5. A method of treating a disease or disorder responsive to NR2B antagonism in a subject in need of such treatment, comprising administering an effective amount of the chemical entity of claim 1 , wherein the disease or disorder is depression, a seizure disorder, pain, a movement disorder, Huntington's disease, cerebral ischaemia, traumatic brain injury, or a substance abuse disorder.","lang":"en","source":"USPTO_FULLTEXT","data_format":"ORIGINAL"},{"text":"6. The method of claim 5 , wherein the disease or disorder is depression.","lang":"en","source":"USPTO_FULLTEXT","data_format":"ORIGINAL"},{"text":"7. A pharmaceutical composition comprising the chemical entity of claim 2 and a pharmaceutically acceptable carrier.","lang":"en","source":"USPTO_FULLTEXT","data_format":"ORIGINAL"},{"text":"8. The pharmaceutical composition of claim 7 , which is suitable for oral administration.","lang":"en","source":"USPTO_FULLTEXT","data_format":"ORIGINAL"},{"text":"9. A method of treating a disease or disorder responsive to NR2B antagonism in a subject in need of such treatment, comprising administering an effective amount of the chemical entity of claim 2 , wherein the disease or disorder is depression, a seizure disorder, pain, a movement disorder, Huntington's disease, cerebral ischaemia, traumatic brain injury, or a substance abuse disorder.","lang":"en","source":"USPTO_FULLTEXT","data_format":"ORIGINAL"},{"text":"10. The method of claim 9 , wherein the disease or disorder is depression.","lang":"en","source":"USPTO_FULLTEXT","data_format":"ORIGINAL"}]},"claim_lang":["en"],"has_claim":true,"description":{"en":{"text":"BACKGROUND Non-selective NMDA receptor antagonists, originally developed in stroke and head trauma, have more recently shown clinical efficacy in treating depression. The non-selective NMDA receptor antagonist, ketamine, has been shown to have rapid onset and efficacy in depression resistant to standard monoamine reuptake inhibitor therapy (Mathews and Zarate, 2013 , J. Clin. Psychiatry 74:516-158). However, non-selective NMDA receptor antagonists such as ketamine have a range of undesirable pharmacological activities which limit application in humans. In particular dissociative or psychogenic side effects are particularly prominent for non-selective NMDA receptor antagonists. More recently, NR2B subtype selective NMDA receptor antagonists have demonstrated potential in a wide range of clinical indications. In particular, NR2B antagonists have also demonstrated antidepressant activity in early stage clinical trials (Ibrahim et al., 2012 , J. Clin. Psychopharmacol. 32, 551-557; Preskorn et al., 2008 , J. Clin. Psychopharmacol. 28, 631-637). Furthermore, selective NR2B antagonists have advantages over unselective NMDA receptor antagonists such as ketamine due to greatly diminished dissociative side effects. However, NR2B antagonists described to date have generally exhibited drawbacks with regard to other drug properties which have limited potential use in human drug therapy. SUMMARY For broad scope of application and safe human use in a range of clinical indications including depression, improved NR2B subtype selective antagonists are needed. The present invention, among other things, addresses the need for NR2B receptor antagonists that are improved in one or more aspects exemplified by pharmacokinetic performance, oral activity, cardiovascular safety, and in vitro and in vivo therapeutic safety index measures. In some embodiments, the present invention encompasses the insight that chemical entities of formula I: wherein X, Y, Z, R 1 , R 3 , R 4 , R 5 and R 6 are defined herein, are NR2B subtype selective receptor antagonists. Chemical entities of formula I, and pharmaceutically acceptable compositions thereof, are useful for treating a variety of diseases and disorders associated with NR2B receptor antagonism. Such diseases and disorders include those described herein. BRIEF DESCRIPTION OF THE DRAWING FIG. 1 shows the results of compound C-178 in the forced swim test as described in Example 2.4.1. FIG. 2 shows the results of compound C-179 in the forced swim test as described in Example 2.4.2. FIG. 3 shows the results of compound C-6 in the haloperidol-induced catalepsy model as described in Example 2.5.1. FIG. 4 shows the results of compound C-12 in the haloperidol-induced catalepsy model as described in Example 2.5.2. FIG. 5 shows the results of compound C-5 in the haloperidol-induced catalepsy model as described in Example 2.5.3. FIG. 6 shows the results of compound C-11 in the electroconvulsive threshold test as described in Example 2.6.1. FIG. 7 shows the results of compound C-127 in the electroconvulsive threshold test as described in Example 2.6.2. FIG. 8 shows the results of compound C-179 in the electroconvulsive threshold test as described in Example 2.6.3. FIG. 9 shows the results of compound C-179 in the 6 Hz seizure test as described in Example 2.7.1. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS General Description of Chemical Entities In some embodiments, the present invention provides chemical entities of formula I: wherein: Y and Z are independently N or C(R 2 );X is —H; halo; C 1 -C 6 alkyl optionally substituted with 1 to 6 fluoro; C 3 -C 6 cycloalkyl;C 1 -C 4 alkoxy optionally substituted with 1 to 6 fluoro; —CN; —NO 2 ; —N(R 7 )(R 8 ); —SW; —S(O) 2 R 9 ; or —C(O)OR 7 ;R 1 is —H; halo; C 1 -C 4 alkyl optionally substituted with 1 to 3 fluoro; C 3 -C 6 cycloalkyl; C 1 -C 4 alkoxy optionally substituted with 1 to 3 fluoro; —CN; —NO 2 ; —N(R 7 )(R 8 ); —C(O)OR 7 ; or —C(O)N(R 7 )(R 8 );R 2 is —H; halo; C 1 -C 4 alkyl optionally substituted with 1 to 3 fluoro; cyclopropyl; or C 1 -C 4 alkoxy optionally substituted with 1 to 3 fluoro;R 3 is —H, —F, —Cl, —CH 3 , —CF 3 or —OCH 3 ;R 4 is —H; —F; —Cl; C 1 -C 3 alkyl optionally substituted with 1 to 3 fluoro; or cyclopropyl;R 5 is —H or —CH 3 ;R 6 is —H, —F or —CH 3 ;each instance of R 7 independently is C 1 -C 4 alkyl;each instance of R 8 independently is —H or C 1 -C 4 alkyl; andR 9 is C 1 -C 4 alkyl optionally substituted with 1 to 3 fluoro. Unless otherwise specified or clear from context, the term “chemical entity” refers to a compound having the indicated structure, whether in its “free” form (e.g., “free compound” or “free base” or “free acid” form, as applicable), or in a salt form, particularly a pharmaceutically acceptable salt form, and furthermore whether in solid state form or otherwise. Thus, in some embodiments the term “chemical entity” refers to a compound having the indicated structure, or a pharmaceutically acceptable salt thereof. In some embodiments, a solid state form is an amorphous (i.e., non-crystalline) form; in some embodiments, a solid state form is a crystalline form. In some embodiments, a crystalline form (e.g., a polymorph, pseudohydrate, or hydrate). Similarly, the term encompasses the compound whether provided in solid form or otherwise. Unless otherwise specified, all statements made herein regarding “compounds” apply to the associated chemical entities, as defined. Chemical Entities and Definitions Unless otherwise specified, the word “includes” (or any variation thereon, e.g., “include”, “including”, etc.) is intended to be open-ended. For example, “A includes 1, 2 and 3” means that A includes but is not limited to 1, 2 and 3. Unless otherwise specified, the phrase “such as” is intended to be open-ended. For example, “A can be a halogen, such as chlorine or bromine” means that A can be, but is not limited to, chlorine or bromine. Chemical entities of this invention include those described generally above, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5 th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations , VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987. The term “alkyl”, as by itself or as part of another substituent, means a substituted or unsubstituted, linear or branched, univalent hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation. Unless otherwise specified, alkyl groups contain 1 to 7 carbon atoms (“C 1 -C 7 alkyl”). In some embodiments, alkyl groups contain 1 to 6 carbon atoms (“C 1 -C 6 alkyl”). In some embodiments, alkyl groups contain 1 to 5 carbon atoms (“C 1 -C 5 alkyl”). In some embodiments, alkyl groups contain 1 to 4 carbon atoms (“C 1 -C 4 alkyl”). In some embodiments, alkyl groups contain 3 to 7 carbon atoms (“C 3 -C 7 alkyl”). Examples of saturated alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, s-butyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more carbon-carbon double bonds or carbon-carbon triple bonds. Examples of unsaturated alkyl groups include allyl, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the like. The term “lower alkyl” refers to alkyl groups having 1 to 4 (if saturated) or 2 to 4 (if unsaturated) carbon atoms. Exemplary lower alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl and the like. The term “alkenyl” refers to alkyl groups having at least two carbon atoms and at least one carbon-carbon double bond. The term “alkynyl” refers to alkyl groups having at least two carbon atoms and at least one carbon-carbon triple bond. The term “cycloalkyl”, by itself or as part of another substituent, refers to a monocyclic univalent hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. In some embodiments, cycloalkyl groups contain 3 to 8 ring carbon atoms (“C 3 -C 8 cycloalkyl”). Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. The term “alkoxy”, by itself or as part of another substituent, refers to the group —O-alkyl. The term “halogen” or “halo”, by itself or as part of another substituent, refers to fluorine, chlorine, bromine or iodine. As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66:1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate. Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement hydrogen, carbon, nitrogen, oxygen, chlorine or fluorine with 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 17 O, 18 O, 36 Cl or 18 F, respectively, are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention. Additionally, incorporation of heavier isotopes such as deuterium ( 2 H) can afford certain therapeutic advantages resulting from greater metabolic stability, for example, increase in vivo half-life, or reduced dosage requirements. Exemplary Embodiments of Chemical Entities In some embodiments, the present invention provides chemical entities of formula I: wherein: Y and Z are independently N or C(R 2 );X is —H; halo; C 1 -C 6 alkyl optionally substituted with 1 to 6 fluoro; C 3 -C 6 cycloalkyl; C 1 -C 4 alkoxy optionally substituted with 1 to 6 fluoro; —CN; —NO 2 ; —N(R 7 )(R 8 ); —SR 7 ; —S(O) 2 R 9 ; or —C(O)OR 7 ;R 1 is —H; halo; C 1 -C 4 alkyl optionally substituted with 1 to 3 fluoro; C 3 -C 6 cycloalkyl; C 1 -C 4 alkoxy optionally substituted with 1 to 3 fluoro; —CN; —NO 2 ; —N(R 7 )(R 8 ); —C(O)OR 7 ; or —C(O)N(R 7 )(R 8 );R 2 is —H; halo; C 1 -C 4 alkyl optionally substituted with 1 to 3 fluoro; cyclopropyl; or C 1 -C 4 alkoxy optionally substituted with 1 to 3 fluoro;R 3 is —H, —F, —Cl, —CH 3 , —CF 3 or —OCH 3 ;R 4 is —H; —F; —Cl; C 1 -C 3 alkyl optionally substituted with 1 to 3 fluoro; or cyclopropyl;R 5 is —H or —CH 3 ;R 6 is —H, —F or —CH 3 ;each instance of R 7 independently is C 1 -C 4 alkyl;each instance of R 8 independently is —H or C 1 -C 4 alkyl; andR 9 is C 1 -C 4 alkyl optionally substituted with 1 to 3 fluoro. In some such embodiments, at least one of Y and Z is N. In some embodiments, Y and Z are independently N or C(R 2 ); X is —H; halo; C 1 -C 4 alkyl optionally substituted with 1 to 6 fluoro; cyclopropyl; C 1 -C 2 alkoxy optionally substituted with 1 to 3 fluoro; —CN; —NO 2 ; —N(R 7 )(R 8 ); —SR 7 ; or —S(O) 2 R 9 ;R 1 is —H; halo; C 1 -C 4 alkyl optionally substituted with 1 to 3 fluoro; cyclopropyl; C 1 -C 2 alkoxy optionally substituted with 1 to 3 fluoro; —CN; —NO 2 ; —N(R 7 )(R 8 ); —C(O)OR 7 ; or —C(O)N(R 7 )(R 8 );R 2 is —H; halo; C 1 -C 4 alkyl optionally substituted with 1 to 3 fluoro; cyclopropyl; or C 1 -C 2 alkoxy optionally substituted with 1 to 3 fluoro;R 3 is —H, —F, —Cl, —CH 3 , —CF 3 or —OCH 3 ;R 4 is —H; —F; —Cl; C 1 -C 3 alkyl optionally substituted with 1 to 3 fluoro; or cyclopropyl;R 5 is —H or —CH 3 ;R 6 is —H, —F or —CH 3 ;each instance of R 7 independently is C 1 -C 2 alkyl;each instance of R 8 independently is —H or C 1 -C 2 alkyl; andR 9 is C 1 -C 2 alkyl optionally substituted with 1 to 3 fluoro. In some such embodiments, at least one of Y and Z is N. In some embodiments, Y and Z are independently N or C(R 2 ); X is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , —CHF 2 , —CH 2 F, —CF 2 CF 3 , —CH 2 CF 2 CF 3 , —CH(CF 3 ) 2 , cyclopropyl, —OCH 3 , —OCF 3 , —OCHF 2 , —OCFH 2 , —CN, —NO 2 , —NH(CH 3 ), —N(CH 3 ) 2 , —N(CH 3 )(CH 2 CH 3 ), —SCH 3 , —SCH 2 CH 3 , —SO 2 CH 3 , —SO 2 CH 2 CH 3 or —SO 2 CF 3 ;R 1 is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , cyclopropyl, —OCH 3 , —OCF 3 , —OCHF 2 , —OCFH 2 , —CN, —NO 2 , —CO 2 CH 3 , —CO 2 CH 2 CH 3 , —C(O)N(CH 3 ) 2 —C(O)NH(CH 3 ) or —C(O)N(CH 3 )(CH 2 CH 3 );R 2 is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , cyclopropyl, —OCH 3 , —OCF 3 , —OCHF 2 or —OCFH 2 ;R 3 is —H, —F, —Cl, —CH 3 , —CF 3 or —OCH 3 ;R 4 is —H, —F, —Cl, —CH 3 or cyclopropyl;R 5 is —H or —CH 3 ; andR 6 is —H, —F or —CH 3 . In some such embodiments, at least one of Y and Z is N. In some embodiments, Y and Z are independently N or C(R 2 ); X is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , —CHF 2 , —CH 2 F, —CF 2 CF 3 , —CH 2 CF 2 CF 3 , —CH(CF 3 ) 2 , cyclopropyl, —OCH 3 , —OCF 3 , —OCHF 2 , —OCFH 2 , —CN, —NO 2 , —N(CH 3 ) 2 , —SCH 3 , —SO 2 CH 3 or —SO 2 CF 3 ;R 1 is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , cyclopropyl, —OCH 3 , —OCF 3 , —OCHF 2 , —OCFH 2 , —CN, —NO 2 , —CO 2 CH 3 , —CO 2 CH 2 CH 3 , —C(O)N(CH 3 ) 2 or —C(O)NH(CH 3 );R 2 is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , cyclopropyl, —OCH 3 , —OCF 3 , —OCHF 2 or —OCFH 2 ;R 3 is —H, —F, —Cl, —CH 3 , —CF 3 or —OCH 3 ;R 4 is —H, —F, —Cl, —CH 3 or cyclopropyl;R 5 is —H or —CH 3 ; andR 6 is —H, —F or —CH 3 . In some such embodiments, at least one of Y and Z is N. In some embodiments, Y and Z are independently N or C(R 2 ); X is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , —CHF 2 , —CH 2 F, cyclopropyl, —OCH 3 , —OCF 3 , —OCHF 2 , —CN or —SCH 3 ;R 1 is —H, —F, —Cl, —CH 3 or —CF 3 ;R 2 is —H, —F, —Cl, —CH 3 or —CF 3 ;R 3 is —H, —F, —Cl, —CH 3 or —CF 3 ;R 4 is —H, —Cl or —CH 3 ;R 5 is —H or —CH 3 ; andR 6 is —H, —F or —CH 3 . In some such embodiments, at least one of Y and Z is N. In some embodiments, X is —H; halo; C 1 -C 4 alkyl optionally substituted with 1 to 6 fluoro; cyclopropyl; C 1 -C 2 alkoxy optionally substituted with 1 to 3 fluoro; —CN; —NO 2 ; —N(R 7 )(R 8 ); —SR 7 ; or —S(O) 2 R 9 . In some embodiments, X is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , —CHF 2 , —CH 2 F, —CF 2 CF 3 , —CH 2 CF 2 CF 3 , —CH(CF 3 ) 2 , cyclopropyl, —OCH 3 , —OCF 3 , —OCHF 2 , —OCFH 2 , —NO 2 , —NH(CH 3 ), —N(CH 3 ) 2 , —N(CH 3 )(CH 2 CH 3 ), —SCH 3 , —SCH 2 CH 3 , —SO 2 CH 3 , —SO 2 CH 2 CH 3 or —SO 2 CF 3 . In some embodiments, X is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , —CHF 2 , —CH 2 F, —CF 2 CF 3 , —CH 2 CF 2 CF 3 , —CH(CF 3 ) 2 , cyclopropyl, —OCH 3 , —OCF 3 , —OCHF 2 , —OCFH 2 , —NO 2 , —N(CH 3 ) 2 , —SCH 3 , —SO 2 CH 3 or —SO 2 CF 3 . In some embodiments, X is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , —CHF 2 , —CH 2 F, cyclopropyl, —OCH 3 , —OCF 3 , —OCHF 2 , —CN or —SCH 3 . In some embodiments, X is —H. In some embodiments, X is halo. In some embodiments, X is —F or —Cl. In some embodiments, X is C 1 -C 6 alkyl optionally substituted with 1 to 6 fluoro. In some embodiments, X is C 1 -C 4 alkyl optionally substituted with 1 to 6 fluoro. In some embodiments, X is —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , —CHF 2 , —CH 2 F, —CF 2 CF 3 , —CH 2 CF 2 CF 3 or —CH(CF 3 ) 2 . In some embodiments, X is-CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , —CHF 2 or —CH 2 F. In some embodiments, X is C 3 -C 6 cycloalkyl. In some embodiments X is cyclopropyl. In some embodiments, X is C 1 -C 4 alkoxy optionally substituted with 1 to 6 fluoro. In some embodiments, X is C 1 -C 2 alkoxy optionally substituted with 1 to 3 fluoro. In some embodiments, X is —OCH 3 , —OCF 3 , —OCHF 2 or —OCFH 2 . In some embodiments, X is —OCH 3 , —OCF 3 or —OCHF 2 , In some embodiments, X is —CN. In some embodiments, X is-NO 2 . In some embodiments, X is —N(R 7 )(R 8 ). In some embodiments, X is —NH(CH 3 ), —N(CH 3 ) 2 or —N(CH 3 )(CH 2 CH 3 ). In some embodiments, X is —N(CH 3 ) 2 . In some embodiments, X is —SR′. In some embodiments, X is —SCH 3 or —SCH 2 CH 3 . In some embodiments, X is —SCH 3 . In some embodiments, X is —S(O) 2 R 9 . In some embodiments, X is —SO 2 CH 3 , —SO 2 CH 2 CH 3 or —SO 2 CF 3 . In some embodiments, X is —SO 2 CH 3 or —SO 2 CF 3 . In some embodiments, R 1 is —H; halo; C 1 -C 4 alkyl optionally substituted with 1 to 3 fluoro; cyclopropyl; C 1 -C 2 alkoxy optionally substituted with 1 to 3 fluoro; —CN; —NO 2 ; —N(R 7 )(R 8 ); —C(O)OR 7 ; or —C(O)N(R 7 )(R 8 ). In some embodiments, R 1 is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , cyclopropyl, —OCH 3 , —OCF 3 , —OCHF 2 , —OCFH 2 , —CN, —NO 2 , —CO 2 CH 3 , —CO 2 CH 2 CH 3 , —C(O)N(CH 3 ) 2 , —C(O)NH(CH 3 ) or —C(O)N(CH 3 )(CH 2 CH 3 ). In some embodiments, R 1 is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , cyclopropyl, —OCH 3 , —OCF 3 , —OCHF 2 , —OCFH 2 , —CN, —NO 2 , —CO 2 CH 3 , —CO 2 CH 2 CH 3 , —C(O)N(CH 3 ) 2 or —C(O)NH(CH 3 ). In some embodiments, R 1 is —H, —F, —Cl, —CH 3 or —CF 3 . In some embodiments, R 1 is —H. In some embodiments, R 1 is halo. In some embodiments, R 1 is —F or —Cl. In some embodiments, R 1 is C 1 -C 4 alkyl optionally substituted with 1 to 3 fluoro. In some embodiments, R 1 is —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 or —CF 3 . In some embodiments, R 1 is —CH 3 or —CF 3 . In some embodiments, R 1 is C 3 -C 6 cycloalkyl. In some embodiments, R 1 is cyclopropyl. In some embodiments, R 1 is C 1 -C 4 alkoxy optionally substituted with 1 to 3 fluoro. In some embodiments, R 1 is C 1 -C 2 alkoxy optionally substituted with 1 to 3 fluoro. In some embodiments, R 1 is —OCH 3 , —OCF 3 , —OCHF 2 or —OCFH 2 . In some embodiments, R 1 is —CN. In some embodiments, R 1 is —NO 2 . In some embodiments, R 1 is —N(R 7 )(R 8 ). In some embodiments, R 1 is —C(O)OR 7 . In some embodiments, R 1 is —CO 2 CH 3 or —CO 2 CH 2 CH 3 . In some embodiments, R 1 is —C(O)N(R 7 )(R 8 ). In some embodiments, R 1 is —C(O)N(CH 3 ) 2 , —C(O)NH(CH 3 ) or —C(O)N(CH 3 )(CH 2 CH 3 ). In some embodiments, R 1 is —C(O)N(CH 3 ) 2 or —C(O)NH(CH 3 ). In some embodiments, R 2 is —H; halo; C 1 -C 4 alkyl optionally substituted with 1 to 3 fluoro; cyclopropyl; or C 1 -C 2 alkoxy optionally substituted with 1 to 3 fluoro. In some embodiments, R 2 is —H, —F, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , cyclopropyl, —OCH 3 , —OCF 3 , —OCHF 2 or —OCFH 2 . In some embodiments, R 2 is —H, —F, —Cl, —CH 3 or —CF 3 . In some embodiments, R 2 is —H. In some embodiments, R 2 is halo. In some embodiments, R 2 is —F or —Cl. In some embodiments, R 2 is C 1 -C 4 alkyl optionally substituted with 1 to 3 fluoro. In some embodiments, R 2 is —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 or —CF 3 . In some embodiments, R 2 is —CH 3 or —CF 3 . In some embodiments, R 2 is cyclopropyl. In some embodiments, R 2 is C 1 -C 4 alkoxy optionally substituted with 1 to 3 fluoro. In some embodiments, R 2 is C 1 -C 2 alkoxy optionally substituted with 1 to 3 fluoro. In some embodiments, R 2 is —OCH 3 , —OCF 3 , —OCHF 2 or —OCFH 2 . In some embodiments, R 3 is —H, —F, —Cl, —CH 3 , —CF 3 or —OCH 3 . In some embodiments, R 3 is —H, —F, —Cl, —CH 3 or —CF 3 . In some embodiments, R 3 is —H. In some embodiments, R 3 is —F or —Cl. In some embodiments, R 3 is —CH 3 or —CF 3 . In some embodiments, R 3 is —OCH 3 . In some embodiments, R 4 is —H; —F; —Cl; C 1 -C 3 alkyl optionally substituted with 1 to 3 fluoro; or cyclopropyl. In some embodiments, R 4 is —H, —F, —Cl, —CH 3 or cyclopropyl. In some embodiments, R 4 is —H, —Cl or —CH 3 . In some embodiments, R 4 is —H. In some embodiments, R 4 is —F or —Cl. In some embodiments, R 4 is C 1 -C 3 alkyl optionally substituted with 1 to 3 fluoro. In some embodiments, R 4 is —CH 3 . In some embodiments, R 4 is cyclopropyl. In some embodiments, R 5 is —H or —CH 3 . In some embodiments, R 5 is —H. In some embodiments, R 5 is —CH 3 . In some embodiments, R 6 is —H, —F or —CH 3 . In some embodiments, R 6 is —H. In some embodiments, R 6 is —F. In some embodiments, R 6 is —CH 3 . In some embodiments, a chemical entity of formula (I) is a chemical entity of formula (Ia): wherein each of R 1 , X, R 4 and R 5 is as described in embodiments of formula (I), supra, or described in embodiments herein, both singly and in combination. In some embodiments of formula (Ia): X is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , —CHF 2 , —CH 2 F, —CF 2 CF 3 , —CH 2 CF 2 CF 3 , —CH(CF 3 ) 2 , cyclopropyl, —OCH 3 , —OCF 3 , —OCHF 2 , —OCFH 2 , —CN, —NO 2 , —N(CH 3 ) 2 , —SCH 3 , —SO 2 CH 3 or —SO 2 CF 3 ;R 1 is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , cyclopropyl, —OCH 3 , —OCF 3 , —OCHF 2 , —OCFH 2 , —CN, —NO 2 , —CO 2 CH 3 , —CO 2 CH 2 CH 3 , —C(O)N(CH 3 ) 2 or —C(O)NH(CH 3 );R 4 is —H, —F, —Cl, —CH 3 or cyclopropyl; andR 5 is —H or —CH 3 . In some embodiments of formula (Ia): X is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , —CHF 2 , —CH 2 F, cyclopropyl, —OCH 3 , —OCF 3 , —OCHF 2 , —CN or —SCH 3 ;R 1 is —H, —F, —Cl, —CH 3 or —CF 3 ;R 4 is —H, —Cl or —CH 3 ; andR 5 is —H or —CH 3 . In some embodiments of formula (Ia): X is —Cl, —CH 3 or —CF 3 ;R 1 is —H or —F;R 4 is —Cl or —CH 3 ; andR 5 is —H. In some embodiments of formula (Ia): X is —Cl, —CH 3 or —CF 3 ;R 1 is —H;R 4 is —H; andR 5 is —CH 3 . In some embodiments, a chemical entity of formula (I) is a chemical entity of formula (II): wherein each of R 1 , R 2 , X and R 3 is as described in embodiments of formula (I), supra, or described in embodiments herein, both singly and in combination. In some embodiments of formula (II): X is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , —CHF 2 , —CH 2 F, —CF 2 CF 3 , —CH 2 CF 2 CF 3 , —CH(CF 3 ) 2 , cyclopropyl, —OCH 3 , —OCF 3 , —OCHF 2 , —OCFH 2 , —CN, —NO 2 , —N(CH 3 ) 2 , —SCH 3 , —SO 2 CH 3 or —SO 2 CF 3 ;R 1 is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , cyclopropyl, —OCH 3 , —OCF 3 , —OCHF 2 , —OCFH 2 , —CN, —NO 2 , —CO 2 CH 3 , —CO 2 CH 2 CH 3 , —C(O)N(CH 3 ) 2 or —C(O)NH(CH 3 );R 2 is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , cyclopropyl, —OCH 3 , —OCF 3 , —OCHF 2 or —OCFH 2 ; andR 3 is —H, —F, —Cl, —CH 3 , —CF 3 or —OCH 3 . In some embodiments of formula (II): X is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , —CHF 2 , —CH 2 F, cyclopropyl, —OCH 3 , —OCF 3 , —OCHF 2 , —CN or —SCH 3 ;R 1 is —H, —F, —Cl, —CH 3 or —CF 3 ;R 2 is —H, —F, —Cl, —CH3 or —CF 3 ; andR 3 is —H, —F, —Cl, —CH 3 or —CF 3 In some embodiments of formula (II): X is —F, —Cl, —CH 3 or —CF 3 ;R 1 is —H;R 2 is —H, —F, —Cl or —CH 3 ; andR 3 is —H, —F, —Cl, or —CH 3 . In some embodiments, a chemical entity of formula (I) is a chemical entity of formula (IIa): wherein each of R 1 and X is as described in embodiments of formula (I), supra, or described in embodiments herein, both singly and in combination. In some embodiments of formula (IIa): X is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , —CHF 2 , —CH 2 F, —CF 2 CF 3 , —CH 2 CF 2 CF 3 , —CH(CF 3 ) 2 , cyclopropyl, —OCH 3 , —OCF 3 , —OCHF 2 , —OCFH 2 , —CN, —NO 2 , —N(CH 3 ) 2 , —SCH 3 , —SO 2 CH 3 or —SO 2 CF 3 ; andR 1 is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , cyclopropyl, —OCH 3 , —OCF 3 , —OCHF 2 , —OCFH 2 , —CN, —NO 2 , —CO 2 CH 3 , —CO 2 CH 2 CH 3 , —C(O)N(CH 3 ) 2 or —C(O)NH(CH 3 ). In some embodiments of formula (IIa): X is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , —CHF 2 , —CH 2 F, cyclopropyl, —OCH 3 , —OCF 3 , —OCHF 2 , —CN or —SCH 3 ; andR 1 is —H, —F, —Cl, —CH 3 or —CF 3 . In some embodiments of formula (IIa): X is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CF 3 , —CHF 2 , —CH 2 F, cyclopropyl, —OCH 3 , —OCF 3 , —OCHF 2 , —CN or —SCH 3 ; andR 1 is —H, —F, —Cl, or —CH 3 . In some embodiments, a chemical entity of formula (I) is a chemical entity of formula (III): wherein each of R 1 , R 2 , X and R 3 is as described in embodiments of formula (I), supra, or described in embodiments herein, both singly and in combination. In some embodiments of formula (III): X is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , —CF 2 CF 3 , —CH 2 CF 2 CF 3 , —CH(CF 3 ) 2 , cyclopropyl, —OCH 3 , —OCHF 2 , —OCFH 2 , —CN, —NO 2 , —N(CH 3 ) 2 , —SCH 3 , —SO 2 CH 3 or —SO 2 CF 3 ;R 1 is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , cyclopropyl, —OCH 3 , —OCHF 2 , —OCFH 2 , —CN, —NO 2 , —CO 2 CH 3 , —CO 2 CH 2 CH 3 , —C(O)N(CH 3 ) 2 or —C(O)NH(CH 3 );R 2 is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , cyclopropyl, —OCH 3 , —OCHF 2 or —OCFH 2 ; andR 3 is —H, —F, —Cl, —CH 3 , —CF 3 or —OCH 3 . In some embodiments of formula (III): X is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , cyclopropyl, —OCH 3 , —OCHF 2 , —CN or —SCH 3 ;R 1 is —H, —F, —Cl, —CH 3 or —CF 3 ;R 2 is —H, —F, —Cl, —CH 3 or —CF 3 ; andR 3 is —H, —F, —Cl, —CH 3 or —CF 3 . In some embodiments, a chemical entity of formula (I) is a chemical entity of formula (Ma): wherein each of R 1 and X is as described in embodiments for formula (I), supra, or described in embodiments herein, both singly and in combination. In some embodiments of formula (Ma): X is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , —CHF 2 , —CH 2 F, —CF 2 CF 3 , —CH 2 CF 2 CF 3 , —CH(CF 3 ) 2 , cyclopropyl, —OCH 3 , —OCF 3 , —OCHF 2 , —OCFH 2 , —CN, —NO 2 , —N(CH 3 ) 2 , —SCH 3 , —SO 2 CH 3 or —SO 2 CF 3 ; andR 1 is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , cyclopropyl, —OCH 3 , —OCF 3 , —OCHF 2 , —OCFH 2 , —CN, —NO 2 , —CO 2 CH 3 , —CO 2 CH 2 CH 3 , —C(O)N(CH 3 ) 2 or —C(O)NH(CH 3 ). In some embodiments of formula (Ma): X is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , —CHF 2 , —CH 2 F, cyclopropyl, —OCH 3 , —OCF 3 , —OCHF 2 , —CN or —SCH 3 ; andR 1 is —H, —F, —Cl, —CH 3 or —CF 3 . In some embodiments of formula (Ma):X is —F, —Cl, —CH 3 , —CH 2 CH 3 , —CF 3 , —CHF 2 , —CH 2 F, cyclopropyl, —OCF 3 , —OCHF 2 ; andR 1 is —H or —F. In some embodiments, a chemical entity of formula (I) is a chemical entity of formula (IIIb): wherein each of R 1 and X is as described in embodiments for formula (I), supra, or described in embodiments herein, both singly and in combination. In some embodiments of formula (IIIb), X is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , —CHF 2 , —CH 2 F, —CF 2 CF 3 , —CH 2 CF 2 CF 3 , —CH(CF 3 ) 2 , cyclopropyl, —OCH 3 , —OCF 3 , —OCHF 2 , —OCFH 2 , —CN, —NO 2 , —N(CH 3 ) 2 , —SCH 3 , —SO 2 CH 3 or —SO 2 CF 3 ; and R 1 is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , cyclopropyl, —OCH 3 , —OCF 3 , —OCHF 2 , —OCFH 2 , —CN, —NO 2 , —CO 2 CH 3 , —CO 2 CH 2 CH 3 , —C(O)N(CH 3 ) 2 or —C(O)NH(CH 3 ). In some embodiments of formula (IIIb): X is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , —CHF 2 , —CH 2 F, cyclopropyl, —OCH 3 , —OCF 3 , —OCHF 2 , —CN or —SCH 3 ; andR 1 is —H, —F, —Cl, —CH 3 or —CF 3 . In some embodiments of formula (IIIb): X is —F, —Cl, —CH 3 , —CH 2 CH 3 , —CF 3 , —CHF 2 , —CH 2 F, cyclopropyl, —OCF 3 , —OCHF 2 ; andR 1 is —H or —F. In some embodiments, a chemical entity of formula (I) is a chemical entity of formula (IV): wherein each of R 1 , R 2 , X and R 3 is as described in embodiments of formula (I), supra, or described in embodiments herein, both singly and in combination. In some embodiments of formula (IV): X is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , —CF 2 CF 3 , —CH 2 CF 2 CF 3 , —CH(CF 3 ) 2 , cyclopropyl, —OCH 3 , —OCHF 2 , —OCFH 2 , —CN, —NO 2 , —N(CH 3 ) 2 , —SCH 3 , —SO 2 CH 3 or —SO 2 CF 3 ;R 1 is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , cyclopropyl, —OCH 3 , —OCHF 2 , —OCFH 2 , —CN, —NO 2 , —CO 2 CH 3 , —CO 2 CH 2 CH 3 , —C(O)N(CH 3 ) 2 or —C(O)NH(CH 3 );R 2 is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , cyclopropyl, —OCH 3 , —OCHF 2 or —OCFH 2 ; andR 3 is —H, —F, —Cl, —CH 3 , —CF 3 or —OCH 3 . In some embodiments of formula (IV): X is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , cyclopropyl, —OCH 3 , —OCHF 2 , —CN or —SCH 3 ;R 1 is —H, —F, —Cl, —CH 3 or —CF 3 ;R 2 is —H, —F, —Cl, —CH3 or —CF 3 ; andR 3 is —H, —F, —Cl, —CH 3 or —CF 3 . In some embodiments, a chemical entity of formula (I) is a chemical entity of formula (IVa): wherein each of R 1 and X is as described in embodiments for formula (I), supra, or described in embodiments herein, both singly and in combination. In some embodiments of formula (IVa): X is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , —CHF 2 , —CH 2 F, —CF 2 CF 3 , —CH 2 CF 2 CF 3 , —CH(CF 3 ) 2 , cyclopropyl, —OCH 3 , —OCF 3 , —OCHF 2 , —OCFH 2 , —CN, —NO 2 , —N(CH 3 ) 2 , —SCH 3 , —SO 2 CH 3 or —SO 2 CF 3 ; andR 1 is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , cyclopropyl, —OCH 3 , —OCF 3 , —OCHF 2 , —OCFH 2 , —CN, —NO 2 , —CO 2 CH 3 , —CO 2 CH 2 CH 3 , —C(O)N(CH 3 ) 2 or —C(O)NH(CH 3 ). In some embodiments of formula (IVa): X is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , —CHF 2 , —CH 2 F, cyclopropyl, —OCH 3 , —OCF 3 , —OCHF 2 , —CN or —SCH 3 ; andR 1 is —H, —F, —Cl, —CH 3 or —CF 3 . In some embodiments of formula (IVa): X is —F, —Cl, —CH 3 , —CH 2 CH 3 , —CF 3 , —CHF 2 , —CH 2 F, cyclopropyl, —OCF 3 , —OCHF 2 ; andR 1 is —H or —F. In some embodiments, a chemical entity of formula (I) is a chemical entity of formula (IVb): wherein each of R 1 and X is as described in embodiments for formula (I), supra, or described in embodiments herein, both singly and in combination. In some embodiments of formula (IVb): X is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , —CHF 2 , —CH 2 F, —CF 2 CF 3 , —CH 2 CF 2 CF 3 , —CH(CF 3 ) 2 , cyclopropyl, —OCH 3 , —OCF 3 , —OCHF 2 , —OCFH 2 , —CN, —NO 2 , —N(CH 3 ) 2 , —SCH 3 , —SO 2 CH 3 or —SO 2 CF 3 ; andR 1 is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , cyclopropyl, —OCH 3 , —OCF 3 , —OCHF 2 , —OCFH 2 , —CN, —NO 2 , —CO 2 CH 3 , —CO 2 CH 2 CH 3 , —C(O)N(CH 3 ) 2 or —C(O)NH(CH 3 ). In some embodiments of formula (IVb): X is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , —CHF 2 , —CH 2 F, cyclopropyl, —OCH 3 , —OCF 3 , —OCHF 2 , —CN or —SCH 3 ; andR 1 is —H, —F, —Cl, —CH 3 or —CF 3 . In some embodiments of formula (IVb): X is —F, —Cl, —CH 3 , —CH 2 CH 3 , —CF 3 , —CHF 2 , —CH 2 F, cyclopropyl, —OCF 3 , —OCHF 2 ; andR 1 is —H or —F. In some embodiments, a chemical entity of formula (I) is a chemical entity of formula (V): wherein each of R 1 , R 2 , X, R 3 and R 4 is as described in embodiments of formula (I), supra, or described in embodiments herein, both singly and in combination. In some embodiments of formula (V): X is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , —CF 2 CF 3 , —CH 2 CF 2 CF 3 , —CH(CF 3 ) 2 , cyclopropyl, —OCH 3 , —OCHF 2 , —OCFH 2 , —CN, —NO 2 , —N(CH 3 ) 2 , —SCH 3 , —SO 2 CH 3 or —SO 2 CF 3 ;R 1 is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , cyclopropyl, —OCH 3 , —OCHF 2 , —OCFH 2 , —CN, —NO 2 , —CO 2 CH 3 , —CO 2 CH 2 CH 3 , —C(O)N(CH 3 ) 2 or —C(O)NH(CH 3 );R 2 is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , cyclopropyl, —OCH 3 , —OCHF 2 or —OCFH 2 ;R 3 is —H, —F, —Cl, —CH 3 , —CF 3 or —OCH 3 ; andR 4 is —H, —F, —Cl, —CH 3 or cyclopropyl. In some embodiments of formula (V):X is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , cyclopropyl, —OCH 3 , —OCHF 2 , —CN or —SCH 3 ;R 1 is —H, —F, —Cl, —CH 3 or —CF 3 ;R 2 is —H, —F, —Cl, —CH 3 or —CF 3 ;R 3 is —H, —F, —Cl, —CH 3 or —CF 3 ; andR 4 is —H, —Cl or —CH 3 . In some embodiments of formula (V): X is —H, —CH 3 or —CF 3 ;R 1 is —H, —F or —CF 3 ;R 2 is —H;R 3 is —H or —CF 3 ; andR 4 is —Cl or —CH 3 . In some embodiments, a chemical entity of formula (I) is a chemical entity of formula (Va): wherein each of R 2 and X is as described in embodiments of formula (I), supra, or described in embodiments herein, both singly and in combination. In some embodiments of formula (Va): X is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , —CF 2 CF 3 , —CH 2 CF 2 CF 3 , —CH(CF 3 ) 2 , cyclopropyl, —OCH 3 , —OCF 3 , —OCHF 2 , —OCFH 2 , —CN, —NO 2 , —N(CH 3 ) 2 , —SCH 3 , —SO 2 CH 3 or —SO 2 CF 3 ; andR 2 is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , cyclopropyl, —OCH 3 , —OCF 3 , —OCHF 2 or —OCFH 2 . In some embodiments of formula (Va): X is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , cyclopropyl, —OCH 3 , —OCF 3 , —OCHF 2 , —CN or —SCH 3 ; andR 2 is —H, —F, —Cl, —CH 3 or —CF 3 . In some embodiments of formula (Va): X is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CF 3 , cyclopropyl, —OCH 3 , —OCF 3 or —SCH 3 ; andR 2 is —H, —F or —CF 3 . In some embodiments, a chemical entity of formula (I) is a chemical entity of formula (VI): wherein each of R 1 , R 2 , X and R 3 is as described in embodiments of formula (I), supra, or described in embodiments herein, both singly and in combination. In some embodiments of formula (VI): X is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , —CF 2 CF 3 , —CH 2 CF 2 CF 3 , —CH(CF 3 ) 2 , cyclopropyl, —OCH 3 , —OCHF 2 , —OCFH 2 , —CN, —NO 2 , —N(CH 3 ) 2 , —SCH 3 , —SO 2 CH 3 or —SO 2 CF 3 ;R 1 is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , cyclopropyl, —OCH 3 , —OCHF 2 , —OCFH 2 , —CN, —NO 2 , —CO 2 CH 3 , —CO 2 CH 2 CH 3 , —C(O)N(CH 3 ) 2 or —C(O)NH(CH 3 );R 2 is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , cyclopropyl, —OCH 3 , —OCHF 2 or —OCFH 2 ; andR 3 is —H, —F, —Cl, —CH 3 , —CF 3 or —OCH 3 . In some embodiments of formula (VI): X is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , cyclopropyl, —OCH 3 , —OCHF 2 , —CN or —SCH 3 ;R 1 is —H, —F, —Cl, —CH 3 or —CF 3 ;R 2 is —H, —F, —Cl, —CH3 or —CF 3 ; andR 3 is —H, —F, —Cl, —CH 3 or —CF 3 . In some embodiments, a chemical entity of formula (I) is a chemical entity of formula (VIa): wherein each of R 2 and X is as described in embodiments for formula (I), supra, or described in embodiments herein, both singly and in combination. In some embodiments of formula (VIa): X is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , —CHF 2 , —CH 2 F, —CF 2 CF 3 , —CH 2 CF 2 CF 3 , —CH(CF 3 ) 2 , cyclopropyl, —OCH 3 , —OCF 3 , —OCHF 2 , —OCFH 2 , —CN, —NO 2 , —N(CH 3 ) 2 , —SCH 3 , —SO 2 CH 3 or —SO 2 CF 3 ; andR 2 is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , cyclopropyl, —OCH 3 , —OCF 3 , —OCHF 2 or —OCFH 2 . In some embodiments of formula (VIa): X is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , —CHF 2 , —CH 2 F, cyclopropyl, —OCH 3 , —OCF 3 , —OCHF 2 , —CN or —SCH 3 ; andR 2 is —H, —F, —Cl, —CH 3 or —CF 3 . In some embodiments of formula (VIa): X is —CH 3 , —CH 2 CH 3 , —CF 3 , cyclopropyl, —OCH 3 , —OCF 3 or —SCH 3 ; andR 2 is —H. In some embodiments, a chemical entity of formula (I) is a chemical entity of formula (VIb): wherein each of R 2 and X is as described in embodiments for formula (I), supra, or described in embodiments herein, both singly and in combination. In some embodiments of formula (VIb): X is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , —CHF 2 , —CH 2 F, —CF 2 CF 3 , —CH 2 CF 2 CF 3 , —CH(CF 3 ) 2 , cyclopropyl, —OCH 3 , —OCHF 2 , —OCFH 2 , —CN, —NO 2 , —N(CH 3 ) 2 , —SCH 3 , —SO 2 CH 3 or —SO 2 CF 3 ; andR 2 is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , cyclopropyl, —OCH 3 , —OCHF 2 or —OCFH 2 . In some embodiments of formula (VIb): X is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , —CHF 2 , cyclopropyl, —OCH 3 , —OCHF 2 , —CN or —SCH 3 ; andR 2 is —H, —F, —Cl, —CH 3 or —CF 3 . In some embodiments of formula (VIb): X is —CH 3 , —CH 2 CH 3 , —CF 3 , cyclopropyl, —OCH 3 , —OCF 3 or —SCH 3 ; andR 2 is —H. In some embodiments, a chemical entity of formula (I) is a chemical entity of formula (VII): wherein each of R 1 , R 2 , X and R 3 is as described in embodiments of formula (I), supra, or described in embodiments herein, both singly and in combination. In some embodiments of formula (VII): X is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , —CF 2 CF 3 , —CH 2 CF 2 CF 3 , —CH(CF 3 ) 2 , cyclopropyl, —OCH 3 , —OCHF 2 , —OCFH 2 , —CN, —NO 2 , —N(CH 3 ) 2 , —SCH 3 , —SO 2 CH 3 or —SO 2 CF 3 ;R 1 is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , cyclopropyl, —OCH 3 , —OCHF 2 , —OCFH 2 , —CN, —NO 2 , —CO 2 CH 3 , —CO 2 CH 2 CH 3 , —C(O)N(CH 3 ) 2 or —C(O)NH(CH 3 );R 2 is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , cyclopropyl, —OCH 3 , —OCHF 2 or —OCFH 2 ; andR 3 is —H, —F, —Cl, —CH 3 , —CF 3 or —OCH 3 . In some embodiments of formula (VII): X is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , cyclopropyl, —OCH 3 , —OCHF 2 , —CN or —SCH 3 ;R 1 is —H, —F, —Cl, —CH 3 or —CF 3 ;R 2 is —H, —F, —Cl, —CH3 or —CF 3 ; andR 3 is —H, —F, —Cl, —CH 3 or —CF 3 . In some embodiments, a chemical entity of formula (I) is a chemical entity of formula (VIIa): wherein each of R 2 and X is as described in embodiments for formula (I), supra, or described in embodiments herein, both singly and in combination. In some embodiments of formula (VIIa): X is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , —CHF 2 , —CH 2 F, —CF 2 CF 3 , —CH 2 CF 2 CF 3 , —CH(CF 3 ) 2 , cyclopropyl, —OCH 3 , —OCF 3 , —OCHF 2 , —OCFH 2 , —CN, —NO 2 , —N(CH 3 ) 2 , —SCH 3 , —SO 2 CH 3 or —SO 2 CF 3 ; andR 2 is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , cyclopropyl, —OCH 3 , —OCF 3 , —OCHF 2 or —OCFH 2 . In some embodiments of formula (VIIa): X is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , —CHF 2 , —CH 2 F, cyclopropyl, —OCH 3 , —OCF 3 , —OCHF 2 , —CN or —SCH 3 ; andR 2 is —H, —F, —Cl, —CH 3 or —CF 3 . In some embodiments of formula (VIIa): X is —CH 3 , —CH 2 CH 3 , —CF 3 , cyclopropyl, —OCH 3 , —OCF 3 or —SCH 3 ; andR 2 is —H. In some embodiments, a chemical entity of formula (I) is a chemical entity of formula (VIIb): wherein each of R 2 and X is as described in embodiments for formula (I), supra, or described in embodiments herein, both singly and in combination. In some embodiments of formula (VIIb), X is —H, —F, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , —CF 2 CF 3 , —CH 2 CF 2 CF 3 , —CH(CF 3 ) 2 , cyclopropyl, —OCH 3 , —OCHF 2 , —OCFH 2 , —NO 2 , —N(CH 3 ) 2 , —SCH 3 , —SO 2 CH 3 or —SO 2 CF 3 ; andR 2 is —H, —F, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , cyclopropyl, —OCH 3 , —OCHF 2 or —OCFH 2 . In some embodiments of formula (VIIb): X is —H, —F, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , cyclopropyl, —OCH 3 , —OCHF 2 , —CN or —SCH 3 ; andR 2 is —H, —F, —Cl, —CH 3 or —CF 3 . In some embodiments of formula (VIIb): X is —CH 3 , —CH 2 CH 3 , —CF 3 , cyclopropyl, —OCH 3 , —OCF 3 or —SCH 3 ; andR 2 is —H. In some embodiments, a chemical entity of formula (I) is a chemical entity of formula (VIII): wherein each of R 1 , R 2 , X and R 3 is as described in embodiments of formula (I), supra, or described in embodiments herein, both singly and in combination. In some embodiments of formula (VIII): X is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , —CF 2 CF 3 , —CH 2 CF 2 CF 3 , —CH(CF 3 ) 2 , cyclopropyl, —OCH 3 , —OCHF 2 , —OCFH 2 , —CN, —NO 2 , —N(CH 3 ) 2 , —SCH 3 , —SO 2 CH 3 or —SO 2 CF 3 ;R 1 is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , cyclopropyl, —OCH 3 , —OCHF 2 , —OCFH 2 , —CN, —NO 2 , —CO 2 CH 3 , —CO 2 CH 2 CH 3 , —C(O)N(CH 3 ) 2 or —C(O)NH(CH 3 );R 2 is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , cyclopropyl, —OCH 3 , —OCHF 2 or —OCFH 2 ; andR 3 is —H, —F, —Cl, —CH 3 , —CF 3 or —OCH 3 . In some embodiments of formula (VIII): X is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , cyclopropyl, —OCH 3 , —OCHF 2 , —CN or —SCH 3 ;R 1 is —H, —F, —Cl, —CH 3 or —CF 3 ;R 2 is —H, —F, —Cl, —CH 3 or —CF 3 ; andR 3 is —H, —F, —Cl, —CH 3 or —CF 3 . In some embodiments of formula (VIII): X is —F, —Cl, —CH 3 or —CF 3 ;R 1 is —H;R 2 is —H, —F, —Cl or —CH 3 ; andR 3 is —H, —F, —Cl or —CH 3 . In some embodiments, a chemical entity of formula (I) is a chemical entity of formula (VIIIa): wherein each of R 1 and X is as described in embodiments of formula (I), supra, or described in embodiments herein, both singly and in combination. In some embodiments of formula (VIIIa): X is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , —CHF 2 , —CH 2 F, —CF 2 CF 3 , —CH 2 CF 2 CF 3 , —CH(CF 3 ) 2 , cyclopropyl, —OCH 3 , —OCF 3 , —OCHF 2 , —OCFH 2 , —CN, —NO 2 , —N(CH 3 ) 2 , —SCH 3 , —SO 2 CH 3 or —SO 2 CF 3 ; andR 1 is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , cyclopropyl, —OCH 3 , —OCF 3 , —OCHF 2 , —OCFH 2 , —CN, —NO 2 , —CO 2 CH 3 , —CO 2 CH 2 CH 3 , —C(O)N(CH 3 ) 2 or —C(O)NH(CH 3 ). In some embodiments of formula (VIIIa): X is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , —CHF 2 , —CH 2 F, cyclopropyl, —OCH 3 , —OCF 3 , —OCHF 2 , —CN or —SCH 3 ; andR 1 is —H, —F, —Cl, —CH 3 or —CF 3 . In some embodiments of formula (VIIIa): X is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CF 3 , —CHF 2 , —CH 2 F, cyclopropyl, —OCH 3 , —OCF 3 , —OCHF 2 , —CN or —SCH 3 ; andR 1 is —H, —F, —Cl or —CH 3 . In some embodiments, a chemical entity of formula (I) is a chemical entity of formula (IX): wherein each of X and R 4 is as described in embodiments of formula (I), supra, or described in embodiments herein, both singly and in combination. In some embodiments of formula (IX): X is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , —CHF 2 , —CH 2 F, —CF 2 CF 3 , —CH 2 CF 2 CF 3 , —CH(CF 3 ) 2 , cyclopropyl, —OCH 3 , —OCF 3 , —OCHF 2 , —OCFH 2 , —CN, —NO 2 , —N(CH 3 ) 2 , —SCH 3 , —SO 2 CH 3 or —SO 2 CF 3 ; andR 4 is —H, —F, —Cl, —CH 3 or cyclopropyl. In some embodiments of formula (IX): X is —H, —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , —CHF 2 , —CH 2 F, cyclopropyl, —OCH 3 , —OCF 3 , —OCHF 2 , —CN or —SCH 3 ; andR 4 is —H, —Cl or —CH 3 . In some embodiments of formula (IX): X is —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , —CHF 2 , cyclopropyl, —OCF 3 or —OCHF 2 ; andR 4 is —H or —CH 3 . Exemplary chemical entities of formula I are shown in Tables 1.C to 11.C, below. TABLE 1.CcompoundXR 1C-1HHC-2FHC-3ClHC-4CH 3HC-5CF 3HC-6CF 2 HHC-7CH 2 FHC-8CH 2 CH 3HC-9cyclopropylHC-10CH 3 OHC-11CF 3 OHC-12CHF 2 OHC-13SCH 3HC-14CNHC-15FFC-16ClFC-17CH 3FC-18CF 3FC-19CF 2 HFC-20CH 2 FFC-21CH 2 CH 3FC-22cyclopropylFC-23FClC-24ClClC-25CH 3ClC-26CF 3ClC-27cyclopropylClC-28FCH 3C-29ClCH 3C-30CH 3CH 3C-31CF 3CH 3C-32cyclopropylCH 3 TABLE 2.CcompoundXR 1R 4R 5C-33CF 3HCH 3HC-34ClHCH 3HC-35CH 3HCH 3HC-36CF 3HClHC-37ClHClHC-38CH 3HClHC-39CF 3FCH 3HC-40ClFCH 3HC-41CH 3FCH 3HC-42CF 3FClHC-43ClFClHC-44CH 3FClHC-45CF 3HHCH 3C-46ClHHCH 3C-47CH 3HHCH 3 TABLE 3.CcompoundXR 2R 3C-48FFHC-49ClFHC-50CH 3FHC-51CF 3FHC-52FCH 3HC-53ClCH 3HC-54CH 3CH 3HC-55CF 3CH 3HC-56FClHC-57ClClHC-58CH 3ClHC-59CF 3ClFC-60FHFC-61ClHFC-62CH 3HFC-63CF 3HClC-64FHClC-65ClHClC-66CH 3HClC-67CF 3HCH 3C-68FHCH 3C-69ClHCH 3C-70CH 3HCH 3 TABLE 4.CcompoundXR 1R 6C-71FHCH 3C-72ClHCH 3C-73CH 3HCH 3C-74CF 3HCH 3C-75CF 2 HHCH 3C-76CH 2 FHCH 3C-77OCF 3HCH 3C-78OCF 2 HHCH 3C-79CH 2 CH 3HCH 3C-80cyclopropylHCH 3C-81FHFC-82ClHFC-83CH 3HFC-84CF 3HFC-85CF 2 HHFC-86CH 2 FHFC-87OCF 3HFC-88OCF 2 HHFC-89CH 2 CH 3HFC-90cyclopropylHFC-91FFCH 3C-92ClFCH 3C-93CH 3FCH 3C-94CF 3FCH 3C-95FFFC-96ClFFC-97CH 3FFC-98CF 3FF TABLE 5.CcompoundXR 1R 6C-99FHCH 3C-100ClHCH 3C-101CH 3HCH 3C-102CF 3HCH 3C-103CF 2 HHCH 3C-104CH 2 FHCH 3C-105OCF 3HCH 3C-106OCF 2 HHCH 3C-107CH 2 CH 3HCH 3C-108cyclopropylHCH 3C-109FHFC-110ClHFC-111CH 3HFC-112CF 3HFC-113CF 2 HHFC-114CH 2 FHFC-115OCF 3HFC-116OCF 2 HHFC-117CH 2 CH 3HFC-118cyclopropylHFC-119FFCH 3C-120ClFCH 3C-121CH 3FCH 3C-122CF 3FCH 3C-123FFFC-124ClFFC-125CH 3FFC-126CF 3FF TABLE 6.CcompoundXR 1R 2R 3C-127CF 3HHHC-128CH 3HHHC-129FHHHC-130ClHHHC-131OCH 3HHHC-132OCF 3HHHC-133SCH 3HHHC-134CH 2 CH 3HHHC-135cyclopropylHHHC-136CF 3FHHC-137CF 3HFHC-138CF 3HHFC-139HCF 3HHC-140HHCF 3HC-141HHHCF 3 TABLE 7.CcompoundXR 4R 6C-142CF 3CH 3HC-143CH 3CH 3HC-144CF 3HFC-145CH 3HFC-146CH 2 CH 3HFC-147SCH 3HFC-148cyclopropylHFC-149OCF 3HFC-150OCH 3HFC-151CF 3HCH 3C-152CH 3HCH 3C-153CH 2 CH 3HCH 3C-154SCH 3HCH 3C-155cyclopropylHCH 3C-156OCF 3HCH 3C-157OCH 3HCH 3 TABLE 8.CcompoundXR 4R 6C-158CF 3ClHC-159CH 3ClHC-160CF 3HFC-161CH 3HFC-162CH 2 CH 3HFC-163SCH 3HFC-164cyclopropylHFC-165OCF 3HFC-166OCH 3HFC-167CF 3HCH 3C-168CH 3HCH 3C-169CH 2 CH 3HCH 3C-170SCH 3HCH 3C-171cyclopropylHCH 3C-172OCF 3HCH 3C-173OCH 3HCH 3 TABLE 9.CcompoundXR 1C-174HHC-175FHC-176ClHC-177CH 3HC-178CF 3HC-179CF 2 HHC-180CH 2 FHC-181CH 2 CH 3HC-182cyclopropylHC-183CH 3 OHC-184CF 3 OHC-185CHF 2 OHC-186SCH 3HC-187CNHC-188FFC-189ClFC-190CH 3FC-191CF 3FC-192CF 2 HFC-193CH 2 FFC-194CH 2 CH 3FC-195cyclopropylFC-196FClC-197ClClC-198CH 3ClC-199CF 3ClC-200cyclopropylClC-201FCH 3C-202ClCH 3C-203CH 3CH 3C-204CF 3CH 3C-205cyclopropylCH 3 TABLE 10.CcompoundXR 2R 3C-206FFHC-207ClFHC-208CH 3FHC-209CF 3FHC-210FCH 3HC-211ClCH 3HC-212CH 3CH 3HC-213CF 3CH 3HC-214FClHC-215ClClHC-216CH 3ClHC-217CF 3ClFC-218FHFC-219ClHFC-220CH 3HFC-221CF 3HClC-222FHClC-223ClHClC-224CH 3HClC-225CF 3HCH 3C-226FHCH 3C-227ClHCH 3C-228CH 3HCH 3 TABLE 11.CcompoundXR 4C-229CF 3HC-230CH 3HC-231ClHC-232FHC-233CF 2 HHC-234OCF 3HC-235OCF 2 HHC-236CH 2 CH 3HC-237cyclopropylHC-238isopropylHC-239CF 3CH 3C-240CH 3CH 3C-241CH 2 CH 3CH 3C-242cyclopropylCH 3C-243isopropylCH 3C-244OCF 3CH 3 Pharmacology Glutamate (GLU) is a fundamental excitatory neurotransmitter in the mammalian brain and central nervous system (CNS). The effects of this endogenous neurotransmitter are mediated through binding to and activation of GLU to glutamate receptors (GLURs), which are broadly classified into metabotropic G-protein coupled (mGluRs) and ligand gated ion channels or ionotropic GluRs. The ionotropic GLURs are pharmacologically classified into three main types based on the actions of selective receptor agonists: NMDA (N-methyl D-aspartate selective), KA (kainic acid selective) and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors whose structure and pharmacological function has been recently reviewed in detail (S. F. Traynelis et al. Pharmacology Reviews, 2010, 62, 405-496). Electrophysiology studies have demonstrated NMDARs to be cation ion channels that are subject to voltage-dependent channel block by endogenous Mg 2+ . Activation of NMDARs by glutamate in the presence of glycine as a co-agonist results in opening of the receptor ion channel. This in turn allows for the flow of Na + and Ca 2+ into the cell generating excitatory postsynaptic potentials (EPSPs) and Ca 2+ activated second messenger signaling pathways in neurons. By virtue of their permeability to Ca 2+ , activation of NMDA receptors regulates long-term changes in neuronal communication such as learning and memory and synaptic plasticity. Since the original pharmacological characterization with selective ligands, molecular biology and cloning studies have enabled detailed characterization of NMDARs at the molecular level (Paoletti et al., 2013 , Nat. Rev. Neurosci. 14:383-400). Thus, NMDARs are heterotetramers comprised of two NR1 subunits and two NR2 subunits. NR1 subunits contain the binding site for the glycine co-agonist while NR2 subunits contain the binding site for glutamate. The existence of multiple splice variants for NR1 and four isoforms of NR2 (NR2A, NR2B, NR2C and NR2D) from different genes results in a diverse molecular array and of NMDARs. The pharmacological and electrophysiological properties of NMDARs vary depending on the particular NR1 isoform and NR2 subtype composition. Furthermore, the NR2 subtype isoforms are differentially expressed across cell types and brain regions. Thus, compounds that interact selectivity with NR2 subunits can exert specific pharmacological effects in particular brain regions and have potential to treat CNS diseases with a high degree of specificity and selectivity (e.g. vz side effects). For example the low expression of the NR2B subtype in the cerebellum relative to other brain structures (Cull-Candy et al., 1998 , Neuropharmacol. 37:1369-1380) indicated lower motor side effects for this subtype. NMDA receptor antagonism has been extensively investigated for its potential to treat a variety of CNS diseases including stroke, epilepsy, pain, depression Parkinson's Disease and Alzheimer's disease (Paoletti et al., Nat. Rev. Neurosci 14:383-400; Sancora, 2008 , Nature Rev. Drug Disc., 7, 426-437). The NMDA receptor offers a number of pharmacological entry points for developing receptor inhibitors. Direct blockers of the NMDAR ion channel pore represent one family of antagonist compounds for which efficacy could be demonstrated in diverse in vitro and in vivo CNS disease models including, epilepsy, pain and neurodegeneration/stroke. However, compounds from this class, as exemplified by phencyclidine (PCP), MK-801, and ketamine, are generally categorized as unselective across the diversity of NMDA receptor subtypes. In humans unselective, high-affinity NMDAR antagonists have generally been associated with serious clinical side effects including hallucinations, dysphoria and lack of coordination. Nevertheless, ketamine, an intravenous drug originally approved for use in anesthesia (Haas et. al, 1992 , Anesthesia Prog., 39, 61-68) has more recently demonstrated clinical efficacy as an antidepressant therapy (Katalinic et al. 2013 , Aust. N. Z. J. Psychiatry, 47, 710-727). The antidepressant action of acute ketamine therapy has an essentially immediate onset compared to approximately six weeks required for standard serotonin reuptake inhibitor (S SRI) drug therapy. Thus, intravenous administration of the drug has shown rapid onset and prolonged efficacy that can be maintained with continued intermittent administrations (Zarate et al., 2006 , Arch. Gen. Psychiatry 63, 856-864). Finally, ketamine has been shown to be effective in cases of depression resistant to standard drug therapies (Murrough et al., 2013 , American J. Psychiatry, 170, 1134-1142) including bipolar depression (Zarate et al. 2012 , Biol. Psychiatry, 71, 939-946). However, as an intravenous drug with serious side effects (Gianni et. al 1985 , Psychiatric Medicine, 3, 197-217; Curran et al 2000 , Addiction, 95, 575-590) and potential chronic toxicity (Hardy et al., 2012 , J. Clin. Oncol. 30:3611-3617; Noppers et al., 2011 , Pain 152:2173-2178) ketamine therapy is of limited utility and restricted to acute or intermittent administration. To have broader scope of application and utility as a therapy for depression and other CNS diseases, orally active selective NMDA antagonists with reduced side effects are needed that can be administered chronically. Ifenprodil, a vasodilator α 1 -adrenergic antagonist drug, was determined to have a novel allosteric modulator mechanism of action at the NR2B NMDA receptor subtype (Reynolds et al. 1989 , Mol. Pharmacol., 36, 758-765). This new mechanism held promise for a new class of NMDA antagonist drugs having therapeutic efficacy without the limiting side effects of subtype unselective ion channel blockers. Following this discovery, NR2B selective antagonist analogs of ifenprodil (Borza et al., 2006 , Current Topics in Medicinal Chemistry, 6, 687-695; Layton et al. Current Topics in Medicinal Chemistry, 6, 697-709) optimized against the undesirable α 1 -adrenergic activity included Ro-25,6981 (Fischer et al. 1997 , J. Pharmacol. Exp. Ther., 283, 1285-1292) and CP-101,606 otherwise known as traxoprodil (Chenard et al. 1995 , Journal of Medicinal Chemistry, 38, 3138-3145; Menniti et al. 1998 , CNS Drug Reviews., 4, 307-322). In a clinical study, CP-101,606 evidenced antidepressant activity in humans after intravenous administration with a favorable dissociative side effect profile relative to unselective NMDA antagonists (Preskorn et al. 2008 , Journal of Clinical Psychopharmacology, 28, 631-637). However, CP-101,606 has suboptimal pharmacokinetic properties and requires limiting intravenous administration. For CP-101,606 a slow intravenous infusion protocol was required for optimal results in the aforementioned antidepressant clinical study (Preskorn et al. 2008 , Journal of Clinical Psychopharmacology, 28, 631-637). Other NR2B antagonists which have been described as reviewed by B. Ruppa et al. (K. B. Ruppa et al., Annual Reports in Medicinal Chemistry 2012, 47:89-103) include MK0657 (J. A. McCauley et al., 3 rd Anglo - Swedish Medicinal Chemistry Symposium , Åre, Sweden, Mar. 11-14, 2007; L. Mony et al., British J. of Pharmacology 2009, 157:1301-1317; see also Intl. Appl. Publ. No. WO 2004/108705; U.S. Pat. No. 7,592,360) and compounds of formula LX (Intl. Appl. Publ. No. WO 2006/113471), below, including the specific analog LX-1 depicted below. The difficulties presented by NR2B antagonists having basic amine moieties with regard to overcoming hERG and CYP2D6 safety liabilities while maintaining NR2B in vitro and in vivo potency are well established as noted by Kawai et al. (M. Kawai et al., Bioorganic and Medicinal Chem. Lett. 2007, v17:5533-5536) and Brown et al. (Brown et al., Bioorganic and Medicinal Chem. Lett. 2011, v21:3399-3403). Compound inhibition of hERG channels and associated QT prolongation in the electrocardiograph (ECG) represents a well recognized serious human cardiovascular safety risk (Hancox et al., Molecular Pharmacology 2008, 73:1592-1595). QT prolongation can lead to torsades de pointes (TdP) cardiac arrhythmia which can degenerate into ventricular tachycardia and sudden death. Compound inhibition of human metabolic cytochrome P-450 enzymes including CYP2D6 represents a risk with regard to human drug safety due to drug-drug interactions ( Drug Metabolism Handbook: Concepts and Applications , ed. Ala F. Nassar copyright 2009 Wiley & Sons, Hoboken, N.J.). Thus, the clearance of drugs that are substrates of CYP2D6 can be reduced by compounds that inhibit CYP2D6. The result can be toxic or side effect overload due to accumulation of the given CYP2D6 drug substrate. CNS drugs including antidepressant drugs feature prominently among the established CYP2D6 substrates. Therefore, CYP2D6 inhibition is highly undesirable for an NR2B antagonist drug especially given the common application of comedications or polypharmacy in CNS indications including depression. Examples of CY2D6 substrates include antidepressants from the SSRI class such as fluoxetine, paroxetine, and fluvoxamine, duloxetine, an antidepressants from the SSNI class, numerous antipsychotics including haloperidol, risperidone and aripiperazole, numerous beta-blocker antihypertensives including metaprolol, propranolol, timolol and alprenolol and the Alzheimer's disease anticholinesterase inhibitor drug donepezil (Flockhart D A (2007). “ Drug Interactions: Cytochrome P 450 Drug Interaction Table”, Indiana University School of Medicine, accessed at <
or a pharmaceutically acceptable salt thereof."],"number":1,"annotation":false,"claim":true,"title":false},{"lines":["The chemical entity of claim 1, wherein the chemical entity is C-179:\n
or a pharmaceutically acceptable salt thereof."],"number":2,"annotation":false,"claim":true,"title":false},{"lines":["A pharmaceutical composition comprising the chemical entity of claim 1 and a pharmaceutically acceptable carrier."],"number":3,"annotation":false,"claim":true,"title":false},{"lines":["The pharmaceutical composition of claim 3, which is suitable for oral administration."],"number":4,"annotation":false,"claim":true,"title":false},{"lines":["A method of treating a disease or disorder responsive to NR2B antagonism in a subject in need of such treatment, comprising administering an effective amount of the chemical entity of claim 1, wherein the disease or disorder is depression, a seizure disorder, pain, a movement disorder, Huntington's disease, cerebral ischaemia, traumatic brain injury, or a substance abuse disorder."],"number":5,"annotation":false,"claim":true,"title":false},{"lines":["The method of claim 5, wherein the disease or disorder is depression."],"number":6,"annotation":false,"claim":true,"title":false},{"lines":["A pharmaceutical composition comprising the chemical entity of claim 2 and a pharmaceutically acceptable carrier."],"number":7,"annotation":false,"claim":true,"title":false},{"lines":["The pharmaceutical composition of claim 7, which is suitable for oral administration."],"number":8,"annotation":false,"claim":true,"title":false},{"lines":["A method of treating a disease or disorder responsive to NR2B antagonism in a subject in need of such treatment, comprising administering an effective amount of the chemical entity of claim 2, wherein the disease or disorder is depression, a seizure disorder, pain, a movement disorder, Huntington's disease, cerebral ischaemia, traumatic brain injury, or a substance abuse disorder."],"number":9,"annotation":false,"claim":true,"title":false},{"lines":["The method of claim 9, wherein the disease or disorder is depression."],"number":10,"annotation":false,"claim":true,"title":false}]}},"filters":{"npl":[],"notNpl":[],"applicant":[],"notApplicant":[],"inventor":[],"notInventor":[],"owner":[],"notOwner":[],"tags":[],"dates":[],"types":[],"notTypes":[],"j":[],"notJ":[],"fj":[],"notFj":[],"classIpcr":[],"notClassIpcr":[],"classNat":[],"notClassNat":[],"classCpc":[],"notClassCpc":[],"so":[],"notSo":[],"sat":[]},"sequenceFilters":{"s":"SEQIDNO","d":"ASCENDING","p":0,"n":10,"sp":[],"si":[],"len":[],"t":[],"loc":[]}}