Inhibiting catechol-o-methyltransferase (COMT)

Abstract

Provided herein are compounds for inhibiting catechol-O-methyltransferase (COMT), and related methods of making and using the compounds.

Description

INHIBITING CATECHOL-O-METHYLTRANSFERASE (COMT)CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This patent application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Patent Application No. 63 / 650,745 filed May 22, 2024, and U.S. Provisional Patent Application No. 63 / 714,938, filed November 1, 2024, each of which is incorporated herein by reference in its entirety.TECHNICAL FIELD

[0002] The present disclosure relates to compounds and methods for inhibiting catechol-O- methyltransferase (COMT). Some COMT inhibitor compounds have been approved for the treatment of Parkinson’s disease.BACKGROUND

[0003] The enzyme catechol-O-methyltransferase (COMT) acts on physiological catechol substrates such as dopa, dopamine, norepinephrine and epinephrine and related hydroxylated metabolites, by catalyzing the transfer of the methyl group of S-adenosyl-L-methionine to the phenolic group of these substrates to form corresponding methyl ethers, leading to the elimination of biologically active catechols and some other hydroxylated metabolites. COMT is a magnesium dependent enzyme involved in the degradation of neurotransmitters in the brain, that exists in two forms; a soluble form (S-COMT) and a membrane bound form (MB-COMT).

[0004] As a key enzyme in dopamine metabolism, catechol-O-methyl transferase (COMT) has emerged as an attractive target for the treatment of various central and peripheral nervous systems disorders, including MDD, Parkinson’s disease, and other dopamine-related disorders. Two forms of COMT exist, a soluble form (S-COMT) in peripheral tissues, and a membranebound form (MB-COMT), mainly expressed in the brain. Current COMT inhibitors in the clinic contain a nitrocatechol moiety that is associated with poor brain penetration and toxicity.

[0005] Co-administration of a COMT inhibitor with Levodopa (L-DOPA), a precursor of dopamine, and an aromatic amino acid decarboxylase (AADC) inhibitor, increases the half-life of L-DOPA in vivo. Levodopa (L-DOPA) is administered to Parkinson's disease patients to boost the levels of dopamine in the brain. Since dopamine cannot cross the blood-brain barrier, L- DOPA is administered in its place and is transported into the brain and subsequently processed to dopamine. In the presence of a decarboxylase inhibitor, COMT becomes the majormetabolizing enzyme for L-DOPA, catalyzing the metabolism to 3-methoxy-4-hydroxy-L phenylalanine (3-OMD) in the brain and periphery. COMT plays a role in the metabolism of dopamine precursor levodopa (1-3 ,4-di hydroxyphenylalanine, or L-DOPA). A COMT inhibitor can alter the plasma pharmacokinetics of L-DOPA. When a COMT inhibitor is administered to a patient in need thereof in combination with levodopa, plasma levels of levodopa can be more sustained than after administration of levodopa and an aromatic amino acid decarboxylase inhibitor alone. It is believed that at a given frequency of levodopa administration, these more sustained plasma levels of levodopa result in more constant dopaminergic stimulation in the brain, leading to greater effects on the signs and symptoms of Parkinson’s disease.

[0006] Therapies for inhibiting COMT are believed to be useful for the treatment of certain diseases including Major Depressive Disorder (MDD). MDD is a debilitating often recurring disorder with a substantial lifetime risk and a high societal cost. Depressed patients frequently display a variety of co-morbid symptoms, and depression is often a feature of other neuropsychiatric disorders. The heterogeneity of MDD is well -documented and the multiple central mechanisms implicated in the control of mood and motivation underlie the need for multiple therapeutic approaches. Currently available drugs display limited efficacy and a slow onset of action, and are hampered by unwanted side effects. Traditional antidepressant drugs act through serotonergic and noradrenergic systems, and although newer drugs acting through glutamatergic systems show some promise, there remains considerable unmet need for improved medications. Central dopaminergic systems are an attractive alternative target, considering the involvement of dopamine in reward, anhedonia, and related functions. COMT is a key dopamine metabolizing enzyme, and elevated COMT activity may be associated with MDD. Notably, the COMT inhibitor (COMTi) tolcapone improved Hamilton Rating Scale for Depression scores in patients with MDD, despite poor brain penetration. The nitrocatechol group present in all currently available COMTis likely contributes to toxicity and poor brain penetration that severely limits their use. Novel compounds that are potent, selective, brain-penetrant, and safer are needed to fully exploit the benefits of COMTis as alternative treatments for MDD.

[0007] Major depressive disorder (MDD) is a serious, debilitating, and often recurring disorder with a substantial lifetime risk and a high societal cost. Depressed patients frequently display a variety of co-morbid symptoms, including depressed moods, loss of motivation and / or reductions in the ability to experience pleasure(anhedonia), loss of interest and energy, combined withpsychological and vegetative changes such as sleep and / or appetite disturbances, fatigue, feelings of guilt and despair, difficulties in maintaining mental focus, and recurrent thoughts of suicide. MDD often occurs together with other common illnesses, including both physical and psychiatric disorders. Currently available antidepressant drugs display limited efficacy, slow onset of action, and are hampered by unwanted side effects. Traditional antidepressant drugs act through serotonergic and noradrenergic systems. Although newer drugs acting through glutamatergic systems show some promise, there remains considerable unmet need for improved medications. Central dopaminergic systems have been identified as an alternative target, particularly through the involvement of dopamine in reward, anhedonia, and related functions. Indeed, several clinical studies demonstrate benefit with direct and indirect dopamine agonists in MDD.

[0008] While multiple inhibitors of COMT such as tolcapone and entacapone have been developed and approved for treatment of Parkinson's disease, entacapone has negligible brain penetration and tolcapone has been associated with liver injury and requires liver function monitoring. New COMT inhibiting compounds with improved brain penetration should have greater efficacy for Parkinson's disease, as well as have utility for other psychiatric and neurological conditions such as cognitive impairment in schizophrenia.

[0009] Accordingly, there remains a need for brain penetrating inhibitors of COMT and methods of using the same to treat central nervous system disorders.SUMMARY

[0010] In some embodiments, the present invention provides compounds for inhibiting the COMT enzyme. In some embodiments, the COMT inhibiting compounds have improved brain penetration. In some embodiments, the present invention provides methods of inhibiting the COMT enzyme. In some embodiments, the methods include administration of COMT inhibiting compounds having desired levels of brain penetration for the treatment of conditions of the central nervous system. In some embodiments, methods of treating Parkinson’s Disease (PD) comprise the therapeutic administration of a COMT inhibiting compound disclosed herein in combination with one or more other therapeutic agents such as L-DOPA, or as an adjunct to levodopa / carbidopa therapy. In some embodiments, methods of treating depression or anxiety comprise the therapeutic administration of a COMT inhibiting compound disclosed herein without L-DOPA. In some embodiments, methods of treating Major Depressive Disorder(MDD) comprise the therapeutic administration of a COMT inhibiting compound disclosed herein alone, as a monotherapy.

[0011] In some embodiments, the compound l-[( l,3-dimethyl-2-oxo-2,3-dihydro-lH-l,3- benzodiazol-5-yl)methyl]-2-(4-hydroxy-3-methoxyphenyl)-N-methyl-lH-l,3-benzodiazole-5- carb oxami de, or a pharmaceutically acceptable salt thereof, can be used to inhibit COMT using the methods provided herein.

[0012] In some embodiments, the disclosure provides certain compounds of Formula (I) that are COMT Inhibitor Compounds as defined herein, or methods of inhibiting COMT comprising administering a compound of Formula (I), or a pharmaceutically acceptable salt, enantiomer, or racemate thereof: wherein,R« and Rb are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, or halogen; or R, and Rb together form an alkenyl, carbonyl (=0), or a spirocyclic cycloalkyl optionally substituted with one or more R30;A1and A2are each independently N, NH, or CRr,A3is N or C; provided that at least one of A1, A2and A3is N;Bi is C( Rc1Rc2), NRc3or oxygen;Rc1, Rc2, Rc3and Rdare each independently hydrogen or methyl;R1and R2 are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, amine, amide, carboxyl, alkyl-acetate or alkyl-amide; or one of R1and R2together form a fused 6-member aryl ring or fused 6-member heteroaryl ring optionally substituted with R20;R12 is hydrogen or halogen;R20 is carboxyl, alkyl-acetate, amide or alkyl-amide;R30 is halogen, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl; provided the compound of Formula (I) is not l-[(l,3-dimethyl-2-oxo-2,3-dihydro-lH- 1 ,3-benzodiazol-5-yl)methyl]-2-(4-hydroxy-3-methoxyphenyl)-N-methyl-lH- 1 ,3- benzodiazole-5-carboxamide.

[0013] In some embodiments, the disclosure provides certain compounds of Formula (I-A-l) that are COMT Inhibitor Compounds as defined herein, methods of inhibiting COMT comprising administering a compound of Formula (I-A-l), or a pharmaceutically acceptable salt, enantiomer, or racemate thereof:Formula (I-A-l); wherein,Raand Rb are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, or halogen; or Ra and Rb together form a spirocyclic cycloalkyl optionally substituted with one or more R30;A1isNH; A2is C;A3is C;Bi is C(Rc1Rc2), NRc3or oxygen;Rc1, Rc2, Rc3and Rdare each independently hydrogen or methyl;R1is hydrogen, C1-4alkyl. C1-4haloalkyl, amine, amide, carboxyl, alkyl-acetate or alkyl-amide;R12 is hydrogen or halogen;R20 is carboxyl, alkyl-acetate or alkyl-amide; andR30 is halogen, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl; provided the compound of Formula (I-A-l) is not l-[(l,3-dimethyl-2-oxo-2,3-dihydro- lH-l,3-benzodiazol-5-yl)methyl]-2-(4-hydroxy-3-methoxyphenyl)-N-methyl-lH-l,3- benzodiazole-5-carboxamide.

[0014] In some embodiments, the disclosure provides certain compounds of Formula (I-B) that are COMT Inhibitor Compounds as defined herein, methods of inhibiting COMT comprising administering a compound of Formula (I-B), or a pharmaceutically acceptable salt, enantiomer, or racemate thereof: wherein,Ra and Rb are each independently hydrogen, C1-4alkyl, CIM haloalkyl, or halogen; or R« and Rb together form a spirocyclic cycloalkyl optionally substituted with one or more R30;A1is C; A2is N, NH, or CR1;A3 is N or C; provided that at least one of A2and A3 is N, or provided A2is NH if A3 is C;Bi is C(Rc1Rc2), NRc3or oxygen;Rc1, Rc2, Rc3and Rdare each independently hydrogen or methyl;R1is hydrogen, C1-4alkyl, C1-4haloalkyl, amine, amide, carboxyl, alkyl-acetate or alkyl-amide;R12 is hydrogen or halogen;R20 is carboxyl, alkyl-acetate or alkyl-amide; andR30 is halogen, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl;provided the compound of Formula (l-B) is not l-[(l,3-dimethyl-2-oxo-2,3-dihydro- lH-l,3-benzodiazol-5-yl)methyl]-2-(4-hydroxy-3-methoxyphenyl)-N-methyl-lH-l,3- benzodiazole-5-carboxamide.

[0015] In some embodiments, the compound is selected from the group consisting of:or a pharmaceutically acceptable salt thereof.

[0016] In some embodiments, a compound is a COMT Inhibitor Compound of Formula (I), wherein A1is N or CH and Aa is N or CH provided that no more than one of A1and Aa are N; Bi is oxygen or NRc3 and Rc3 is methyl; and one of Ra and Rb is hydrogen.

[0017] In some embodiments, a compound is a COMT Inhibitor Compound of Formula (I) wherein Bi is NRc.3; R.3 is methyl; Rdis methyl and Ra is hydrogen.

[0018] In some embodiments, the compound is a compound of Formula (II), or methods of inhibiting COMT comprising administering a compound of Formula (II), or a pharmaceutically acceptable salt, enantiomer, or racemate thereof:wherein,Ra and Rb are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, or halogen; or R» and Rb together form a spirocyclic C3-6 cycloalkyl;A1and ki are each independently CH or N; and R12 is hydrogen or halogen.

[0019] In some embodiments, the compound is a compound of Formula (II) wherein no more than one of A1and A2is N. In some embodiments, the compound is a compound of Formula (II) wherein no more than one of A1and A2is N, and R« and Rb are each independently hydrogen, fluorine, chlorine, or methyl or ethyl each optionally substituted with one or more fluoro; or R» and Rb together form a spirocyclic cyclopropyl. In some embodiments, the compound is a compound of Formula (II) wherein A1and A2are both N; R» is hydrogen; Rb is hydrogen, or methyl or ethyl each optionally substituted with one or more fluoro; and R12 is hydrogen or fluoro. In some embodiments, Ra and Rb are each independently hydrogen, halogen, or C1-4alkyl optionally substituted with one or more halogen.

[0020] In some embodiments, the compound is selected from the group consisting of:an or a pharmaceutically acceptable salt, enantiomer, or racemate thereof.

[0021] In some embodiments, a compound is a COMT Inhibitor Compound of Formula (I) that is not l-[(l,3-dimethyl-2-oxo-2,3-dihydro-lH-l,3-benzodiazol-5-yl)methyl]-2-(4-hydroxy-3- methoxyphenyl)-N-methyl-lH-l,3-benzodiazole-5-carboxamide, wherein A1is CR1, Aa is N or CH, and R1and Ra together form a fused 6-member aryl ring optionally substituted with Rao.

[0022] In some embodiments, a compound is a COMT Inhibitor Compounds of Formula (I) wherein Bi is NRc?; R«3 is methyl; Rdis methyl and R1and Ra together form a fused 6-member aryl ring optionally substituted with Rao; and Rao is carboxyl, alkyl-acetate or alkyl-amide.

[0023] In some embodiments, a compound is a COMT Inhibitor Compounds of Formula (IV) or methods of inhibiting COMT comprising administering a compound of Formula (IV), or a pharmaceutically acceptable salt, enantiomer, or racemate thereof:Formula (IV)wherein,Ra and Rb are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, or halogen; or Ra and Rb together form a spirocyclic cyclopropyl;Re is hydrogen or methyl; and R12 is hydrogen or halogen.

[0024] In some embodiments, the compound is a compound of Formula (IV) wherein Ra and Rb are each independently hydrogen, halogen, methyl or ethyl each optionally substituted with one or more halogen; or Ra and Rb together form a spirocyclic cyclopropyl; Re is hydrogen or methyl; and R12 is hydrogen or halogen. In some embodiments, the compound is a compound of Formula (IV) wherein Ra is hydrogen. In some embodiments, the compound is a compound of Formula (TV) wherein Ra is hydrogen; Rb is hydrogen, methyl or ethyl each optionally substituted with one or more fluoro, or halogen; Re is hydrogen or methyl; and R12 is hydrogen or fluoro. In some embodiments, the compound is a compound of Formula (IV) wherein Ra is hydrogen; Rb is hydrogen, methyl, ethyl, -CF3, or halogen; Re is hydrogen or methyl; and R12 is hydrogen or fluoro. In some embodiments, the compound is a compound of the formula:, or a pharmaceutically acceptable salt thereof.

[0025] In some embodiments, the disclosure provides a compound of Formula (V-A-l) or (V-A-2), and methods of inhibiting COMT comprising administering a compound of Formula (V-A-l) or (V-A-2), or a pharmaceutically acceptable salt, enantiomer, or racemate thereof, in an amount effective to inhibit COMT :wherein,R» and Rb are each independently hydrogen, C1-4alkyl, C1-4baloalkyl, or halogen; or Ra and Rb together form an alkenyl, carbonyl (=0), or a spirocyclic cycloalkyl optionally substituted with one or more R30;A1and A2are each independently N, NH or CR1;A3 is N or C; provided that at least one of A1, A2and A3is N;Bi is C(Rc1Rc2), NRc3or oxygen;Rc1, Rc2, Rc3and Rdare each independently hydrogen, C1-4alkyl or C3-6 cycloalkyl;R1and R2are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, amine, amide, carboxyl, alkyl-acetate or alkyl-amide; or one of R1and R2together form a fused 6-member aryl ring or fused 6-member heteroaryl ring optionally substituted with R20; each of R12a, R12b, R12c, R12d, and R12e, is independently hydrogen, nitro, alkoxy, hydroxy or halogen;R20 is caiboxyl, alkyl-acetate or alkyl-amide; andR30 is halogen, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl.

[0026] In some embodiments, the disclosure provides a compound of Formula (V-A-l) or (V-A-2), and methods of inhibiting COMT comprising administering a compound of Formula (V-A-l) or (V-A-2), or a pharmaceutically acceptable salt, enantiomer, or racemate thereof, in an amount effective to inhibit COMT:Formula (V-A-l),wherein,Raand Rbare each independently hydrogen, C1-4alkyl, C1-4haloalkyl, or halogen; or Raand Rb together form an alkenyl, carbonyl (=0), or a spirocyclic cycloalkyl optionally substituted with one or more R30; orRb and R12eare together alkyl;A1and A2are each independently N, NH or CR1;A3 is N or C; provided that at least one of A1, A2and A3 is N;Bi is C(RCIRc2), NRc3or oxygen;Rc1, Rc2, Rc3and Rdare each independently hydrogen, C1-4alkyl or C3-6 cycloalkyl;R1and R2are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, amine, amide, carboxyl, alkyl-acetate or alkyl-amide; or one of R1and R2 together form a fused 6-member aryl ring or fused 6-member heteroaryl ring optionally substituted with R20; each of R12a, R12b, R12c, and R12d, is independently hydrogen, nitro, alkoxy, hydroxy or halogen; R12eis hydrogen, nitro, alkoxy, hydroxy or halogen; or R12eand Rb are together alkyl;R20 is carboxyl, alkyl-acetate, or alkyl-amide; andR30 is halogen, C3-6cycloalkyl, or 3-6 member heterocycloalkyl.

[0027] In some embodiments, the disclosure provides a compound of Formula (V-A-l) or (V-A-2), and methods of inhibiting COMT comprising administering a compound of Formula (V-A-l) or (V-A-2), or a pharmaceutically acceptable salt, enantiomer, or racemate thereof, in an amount effective to inhibit COMT:wherein,Ra and Rb are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, or halogen; or Ra and Rb together form an alkenyl, carbonyl (=0), or a spirocyclic cycloalkyl optionally substituted with one or more R30;A1and A2are each independently N, NH or CR1;As is N or C; provided that at least one of A1, A2and A3 is N;Bi is C(Rc1Rc2), NRc3or oxygen;Rc1, Rc2, K.-3 and Rdare each independently hydrogen, C1-4alkyl or C3-6 cycloalkyl;R1and R2 are each independently hydrogen, CH alkyl, C1-4haloalkyl, amine, amide, carboxyl, alkyl-acetate or alkyl-amide; or one of R1and R2 together form a fused 6-member aryl ring or fused 6-member heteroaryl ring optionally substituted with R20; each of R12a, R12b, R12c, and R12d, is independently hydrogen, nitro, alkoxy, hydroxy or halogen; R12eis hydrogen, nitro, alkoxy, hydroxy or halogen;R20 is carboxyl, alkyl-acetate or alkyl-amide; andR30 is halogen, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl.

[0028] In some embodiments, the disclosure provides a compound of Formula (V-A-l) or (V-A-2), and methods of inhibiting COMT comprising administering a compound of Formula (V-A-l) or (V-A-2), or a pharmaceutically acceptable salt, enantiomer, or racemate thereof, in an amount effective to inhibit COMT:Formula (V-A-l),RizbR12CFormula (V-A-2) wherein,Rais hydrogen, CH alkyl, C1-4 haloalkyl, or halogen;Rb and Rue are together alkyl, forming a fused Cs-Ce cycloalkyl or 5-6 member heterocycloalkyl ring;A1and Aj are each independently N, NH or CR1;A? is N or C, provided that at least one of A1, A2and A3 is N;Bi is C(Rc1Rc2), NR«3 or oxygen;Rc1, Rc2, Rc3and Rdare each independently hydrogen, C1-4 alkyl or C3-6 cycloalkyl;R1and R2 are each independently hydrogen, C1-4 alkyl, C1-4haloalkyl, amine, amide, carboxyl, alkyl-acetate or alkyl-amide; or one of R1and R2 together form a fused 6-member aryl ring or fused 6-member heteroaryl ring optionally substituted with R20; each of Rna, R12b, R12c, and Rna, is independently hydrogen, nitro, alkoxy, hydroxy or halogen; R12eis hydrogen, nitro, alkoxy, hydroxy or halogen;R20 is carboxyl, alkyl-acetate or alkyl-amide; andRio is halogen, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl.

[0029] In some embodiments, the disclosure provides a compound of Formula (V-B), and methods of inhibiting COMT comprising administering a compound of Formula (V-B), or apharmaceutically acceptable salt, enantiomer, or racemate thereof, in an amount effective to inhibit COMT:wherein,Ra and Rb are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, or halogen; or Ra and Rb together form a spirocyclic cycloalkyl optionally substituted with one or more R30;Ai is NH; A2is C;As is C;Bi is C(Rc1Rc2), NRc3or oxygen;Rc1, Rc2, Rc3and Rdare each independently hydrogen, C1-4alkyl or C3-6 cycloalkyl,R1is hydrogen. C1-4alkyl, C1-4haloalkyl, amine, amide, carboxyl, alkyl-acetate or alkyl-amide; each of Rna, R12b, R12c, and Rna, is independently hydrogen, nitro, alkoxy, hydroxy or halogen;Rue is hydrogen, nitro, alkoxy, hydroxy or halogen; or R1zeand Rb are together alkyl;R20 is carboxyl, alkyl-acetate or alkyl-amide; andR30 is halogen, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl.

[0030] In some embodiments, the disclosure provides a compound of Formula (V-B), and methods of inhibiting COMT comprising administering a compound of Formula (V-B), or a pharmaceutically acceptable salt, enantiomer, or racemate thereof, in an amount effective to inhibit COMT:Formula (V-B), wherein,Raand Rb are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, or halogen; or R« and Rb together form a spirocyclic cycloalkyl optionally substituted with one or more R30; or R12eand Rb are together alkyl;A1is NH; A2is C;A3 is C;Bi is C(RtiiRc2), NRc3 or oxygen;Rc1, Rc2, Rc3and Rdare each independently hydrogen, C1-4alkyl or C3-6 cycloalkyl;R1is hydrogen, C1-4alkyl, C1-4haloalkyl, amine, amide, carboxyl, alkyl-acetate or alkyl-amide; each of R12a, R12b, R12c, and R12d, is independently hydrogen, nitro, alkoxy, hydroxy or halogen; R12eis hydrogen, nitro, alkoxy, hydroxy or halogen; or R12eand Rb are together alkyl;R20 is carboxyl, alkyl-acetate or alkyl-amide; andR30 is halogen, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl.

[0031] In some embodiments, the disclosure provides a compound of Formula (V-B), and methods of inhibiting COMT comprising administering a compound of Formula (V-B), or a pharmaceutically acceptable salt, enantiomer, or racemate thereof, in an amount effective to inhibit COMT:Formula (V-B), wherein,R» and Rb are each independently hydrogen, C1-4alkyl, C1-4baloalkyl, or halogen; or Ra and Rb together form a spirocyclic cycloalkyl optionally substituted with one or more R30;A1is NH, A2is C;A3 is C;Bi is C(Rc1Rc2), NRc3or oxygen;Rc1, Rc2, Rc3and Rdare each independently hydrogen, C1-4alkyl or C3-6 cycloalkyl;R1is hydrogen, C1-4alkyl, C1-4haloalkyl, amine, amide, carboxyl, alkyl-acetate or alkyl-amide; each of R12a, R12b, R12c, and R1za, is independently hydrogen, nitro, alkoxy, hydroxy or halogen; R12eis hydrogen, nitro, alkoxy, hydroxy or halogen;R20 is carboxyl, alkyl-acetate or alkyl-amide; andR30 is halogen, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl.

[0032] In some embodiments, the disclosure provides a compound of Formula (V-B), and methods of inhibiting COMT comprising administering a compound of Formula (V-B), or a pharmaceutically acceptable salt, enantiomer, or racemate thereof, in an amount effective to inhibit COMT:Formula (V-B), wherein,Ra is hydrogen, C1-4alkyl, C1-4haloalkyl, or halogen;Rb and Rue are together alkyl, forming a fused Cs-Ce cycloalkyl or 5-6 member heterocycloalkyl ring;A1is NH; A2is C;A3is C;Bi is C(Rc1Rc2), NRc3or oxygen;Rc1, Rc2, R<3 and Rdare each independently hydrogen, C1-4alkyl or C3-6 cycloalkyl;R1is hydrogen, C1-4alkyl, C1-4haloalkyl, amine, amide, carboxyl, alkyl-acetate or alkyl-amide;each of Rna, R12b, R12c, and Rna, is independently hydrogen, nitro, alkoxy, hydroxy or halogen; R12eis hydrogen, nitro, alkoxy, hydroxy or halogen;R20 is carboxyl, alkyl-acetate or alkyl-amide; andR30 is halogen, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl.

[0033] In some embodiments, the disclosure provides a compound of Formula (V-B-l), and methods of inhibiting COMT comprising administering a compound of Formula (V-B-l), or a pharmaceutically acceptable salt, enantiomer, or racemate thereof, in an amount effective to inhibit COMT:Formula (V-B-l) wherein A1, A2, A3, Bi, Rd, R20, R12a, R1ib, Rue, Rua, and R12eare as defined in Formula (V- B).

[0034] In some embodiments, the disclosure provides a compound of Formula (V-B-l), and methods of inhibiting COMT comprising administering a compound of Formula (V-B-l), or a pharmaceutically acceptable salt, enantiomer, or racemate thereof, in an amount effective to inhibit COMT:Formula (V-B-l) wherein A1, A1, A3, Bi, Rd, R20, R12a, R12b, Rue, Rua, and Rue are as defined in Formula (V- B).

[0035] In some embodiments, the disclosure provides compounds of Formula (V-C), methods of inhibiting COMT comprising administering a compound of Formula (V-C), or a pharmaceutically acceptable salt, enantiomer, or racemate thereof, in an amount effective to inhibit COMT:Formula (V-C) wherein,R« and Rb are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, or halogen; or Ri> and Rh together form a spirocyclic cycloalkyl optionally substituted with one or more R»;At is C;A2is N, NH or CR1;A3 is N or C; provided that at least one of A2and A3 is N, or provided A2is NH if A3 is C;Bi is C(Rc1Rc2), NR«3 or oxygen;Rc1, Rc2, Rc3and Rdare each independently hydrogen, CH alkyl or C3-6 cycloalkyl;R1is hydrogen, C1-4alkyl, C1-4haloalkyl, amine, amide, carboxyl, alkyl-acetate or alkyl-amide; each of R12a, Rnb, R12c, and Rna, is independently hydrogen, nitro, alkoxy, hydroxy or halogen; R12eis hydrogen, nitro, alkoxy, hydroxy or halogen; or Rue and Rb are together alkyl;R20 is carboxyl, alkyl-acetate or alkyl-amide; andR30 is halogen, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl.

[0036] In some embodiments, the disclosure provides compounds of Formula (V -C), methods of inhibiting COMT comprising administering a compound of Formula (V-C), or a pharmaceutically acceptable salt, enantiomer, or racemate thereof, in an amount effective to inhibit COMT:Formula (V-C) wherein,Ra and Rb are each independently hydrogen, C1-4alkyl, Ci-4 haloalkyl, or halogen; or R« and Rb together form a spirocyclic cycloalkyl optionally substituted with one or more R30; or R12eand Rb are together alkyl;A1is C;A2is N, NH or CR1;A3 is N or C; provided that at least one of A2and As is N, or provided A2is NH if As is C;Bi is C(Rc1Rc2), NRc3or oxygen;Rc1, Rc2, Rc3and Rdare each independently hydrogen, C1-4alkyl or Cs-e cycloalkyl;R1is hydrogen, C1-4alkyl, C1-4haloalkyl, amine, amide, carboxyl, alkyl-acetate or alkyl-amide; each of R12a, R1a, R1a, and RIM, is independently hydrogen, nitro, alkoxy, hydroxy or halogen;R12eis hydrogen, nitro, alkoxy, hydroxy or halogen; or R12eand Rb are together alkyl;R.20 is carboxyl, alkyl-acetate or alkyl-amide; andRso is halogen, Cs-6 cycloalkyl, or 3-6 member heterocycloalkyl.

[0037] In some embodiments, the disclosure provides compounds of Formula (V-C), methods of inhibiting COMT comprising administering a compound of Formula (V-C), or a pharmaceutically acceptable salt, enantiomer, or racemate thereof, in an amount effective to inhibit COMT: wherein,R. is hydrogen, C1-4alkyl, C1-4haloalkyl, or halogen;Rb and Rneare together alkyl, forming a fused Cs-Ce cycloalkyl or 5-6 member heterocycloalkyl ring;A1is C;Aj is N, NH or CR1;A3 is N or C; provided that at least one of A2and A? is N, or provided A2is NH if A3 is C;Bi is C(Rc1Rc2), NRc3or oxygen;Rc1, Rc2, Rc3and Rdare each independently hydrogen, C1-4alkyl or C3-6 cycloalkyl;R1is hydrogen, C1-4 alkyl, C1-4haloalkyl, amine, amide, carboxyl, alkyl-acetate or alkyl-amide; each of Rna, Rub, R12c, and R12d, is independently hydrogen, nitro, alkoxy, hydroxy or halogen; R12eis hydrogen, nitro, alkoxy, hydroxy or halogen; or R12eand Rb are together alkyl; R20 is carboxyl, alkyl-acetate or alkyl-amide; andR30 is halogen, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl.

[0038] In some embodiments, a compound of Formula (V-C) that is not l-[(l,3-dimethyl-2- oxo-2,3-dihydro-lH-l,3-benzodiazol-5-yl)methyl]-2-(4-hydroxy-3-methoxyphenyl)-N-methyl- lH-l,3-benzodiazole-5-carboxamide. In some embodiments, the compound of Formula (I-B) is l-[(l,3-dimethyl-2-oxo-2,3-dihydro-lH-l,3-benzodiazol-5-yl)methyl]-2-(4-hydroxy-3- methoxyphenyl)-N-methyl-lH-l,3-benzodiazole-5-carboxamide.

[0039] In some embodiments, the disclosure provides compounds of formula (V-D), methods of inhibiting COMT comprising administering a compound of Formula (V-D), or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit COMT:Formula (V-D); wherein A1, A1, As, Bi, Rd, R20, Rua, Rub, Rue, Rua, and Rue are as defined in Formula (V- C), provided that at least one of A2and A1is N, or provided A2is NH if A3 is C.

[0040] In some embodiments, the disclosure provides compounds of formula (V-D), methods of inhibiting COMT comprising administering a compound of Formula (V-D), or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit COMT:Formula (V-D); wherein A1, A2, A, Bi, Rd, R20, Rua, Rub, Rue, Rua, and Rue are as defined in Formula (V- C), provided that at least one of A2and A is N, or provided A2is NH if A is C.

[0041] In some embodiments, a compound is a COMT Inhibitor Compound of Formula (V- A-l), (V-A-2), (V-B^ (V-B-l), (V-C) or (V-D), wherein A is N or CH and A2is N or CH provided that no more than one of A1and A2are N; Bi is oxygen or NRc3 and Rc is methyl; and one of R» and Rb is hydrogen.

[0042] In some embodiments, a compound is a COMT Inhibitor Compound of Formula (V- A-l), (V-A-2), (V-B , (V-B-l), (V-C) or (V-D), wherein Bi is NR^; Rc3 is methyl; Rdis methyl and R2 is hydrogen.

[0043] In some embodiments, the disclosure provides compounds of Formula (V-E), methods of inhibiting COMT comprising administering a compound of Formula (V-E), or a pharmaceutically acceptable salt, enantiomer, or racemate thereof, in an amount effective to inhibit COMT:Formula (V-E) wherein,Ra and Rb are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, or halogen; or Ra and Rb together form a spirocyclic C3-6 cycloalkyl;A1and A2are each independently CH or N; each of R12a, R12b, R1&, and Rua, is independently hydrogen, nitro, alkoxy, hydroxy or halogen; andRne is hydrogen, nitro, alkoxy, hydroxy or halogen; or Rneand Rb are together alkyl.

[0044] In some embodiments, the disclosure provides compounds of Formula (V-E), methods of inhibiting COMT comprising administering a compound of Formula (V-E), or a pharmaceutically acceptable salt, enantiomer, or racemate thereof, in an amount effective to inhibit COMT:Formula (V-E) wherein,Ra and Rb are each independently hydrogen, C1-4alkyl. C1-4haloalkyl, or halogen; or Ra and Rb together form a spirocyclic C3-6 cycloalkyl; or Rne and Rb are together alkyl;A1and A2are each independently CH or N, and each of R12a, R12b, R12c, and R12d, is independently hydrogen, nitro, alkoxy, hydroxy or halogen; and R12eis hydrogen, nitro, alkoxy, hydroxy or halogen; or R12eand Rb are together alkyl.

[0045] In some embodiments, the disclosure provides certain compounds of Formula (I) that are COMT Inhibitor Compounds as defined herein, or methods of inhibiting COMT comprising administering a compound of Formula (VI), or a pharmaceutically acceptable salt, enantiomer, or racemate thereof:Formula (VI) wherein,R. is hydrogen. C1-4alkyl. C1-4haloalkyl, or halogen;A1and A2are each independently N, NH or CR1;A3 is N or C; provided that at least one of A1, A2and A1is N;Bi is C(R;iRc2), NR«3 or oxygen;Rc1, Rc2, Rc3and Rdare each independently hydrogen, C1-4alkyl or C3-6 cycloalkyl;R1and R2 are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, amine, amide, carboxyl, alkyl-acetate or alkyl-amide; or one of R1and R2 together form a fused 6-member aryl ring or fused 6-member heteroaryl ring optionally substituted with R20; each of R12a, R12b, R12c, and Rnd, is independently hydrogen, nitro, alkoxy, hydroxy or halogen;R20 is carboxyl, alkyl-acetate or alkyl-amide; andR30 is halogen, C3.6 cycloalkyl, or 3-6 member heterocycloalkyl.

[0046] In some embodiments, the compound is a compound of Formula (V-E) wherein no more than one of A1and A2is N. In some embodiments, the compound is a compound of Formula (V-E) wherein no more than one of A1and A2is N, and Ra and Rb are each independently hydrogen,fluorine, chlorine, or methyl or ethyl each optionally substituted with one or more fluoro; or R, and Rb together form a spirocyclic cyclopropyl. In some embodiments, the compound is a compound of Formula (II) wherein A1and A2are both N; R» is hydrogen; Rb is hydrogen, or methyl or ethyl each optionally substituted with one or more fluoro; and R12 is hydrogen or fluoro. In some embodiments, Ra and Rb are each independently hydrogen, halogen, or C1-4alkyl optionally substituted with one or more halogen.

[0047] In some embodiments, the disclosure provides compound of Formula (V-A-l ), (V-A- 2), (V-B), (V-B-l), (V-C), (V-D), (V-E) or (VI) and methods of inhibiting COMT comprising administering a compound of Formula (V-A-l), (V-A-2), (V-B), (V-B-l), (V-C), (V-D), (V-E) or (VI) or a pharmaceutically acceptable salt, enantiomer, or racemate thereof, in an amount effective to inhibit COMT, wherein each of Rm, Rnb, RIM, RIM, and RIM, is hydrogen, nitro, methoxy, hydroxy or F. In some embodiments, the disclosure provides compounds of Formula (V-A-l), (V-A-2), (V-B), (V-B-l), (V-C), (V-D), (V-E) or (VI) and methods of inhibiting COMT comprising administering a compound of Formula (V-A-l), (V-A-2), (V-B), (V-B-l), (V-C), (V-D), or (V-E), or a pharmaceutically acceptable salt, enantiomer, or racemate thereof, in an amount effective to inhibit COMT, wherein Rm is hydrogen or halogen, Rm is hydrogen, halogen or nitro, RIM is hydroxyl, RIM is hydroxyl or alkoxy and RIM is hydrogen. In some embodiments, the disclosure provides compounds of Formula (V-A-l), (V-A-2), (V-B), (V-B-l), (V-C), (V-D), or (V-E) and methods of inhibiting COMT comprising administering a compound of Formula (V-A-l), (V-A-2), (V-B), (V-B-l), (V-C), (V-D), or (V-E), or a pharmaceutically acceptable salt, enantiomer, or racemate thereof, in an amount effective to inhibit COMT, wherein Rm is hydrogen or F, Rm is hydrogen, F or nitro, Rm is hydroxyl, Rm is hydroxyl or methoxy and RIM is hydrogen.

[0048] In some embodiments, the method comprises administering a compound selected from the group consisting of:529 528 527435 434 433

[0049] In some embodiments, the compound is selected from the group consisting of:and or a pharmaceutically acceptable salt thereof.[000501 In some embodiments, the compound is selected from the group consisting of:or , or a pharmaceutically acceptable salt thereof.

[0051] In some embodiments, the compound is selected from the group consisting of, wherein R is H, C1-4alkyl (e.g., methyl), or C3-6 cycloalkyl (e.g., cyclopropyl).or a pharmaceutically acceptable salt thereof.

[0052] The inventors have discovered inter alia compounds of Formula (I), Formula (I-A), Formula (I-A-l), Formula (I-A-2), Formula (I-B), Formula (I-B-l), Formula (II), Formula (III), Formula (IV) and Formula (IV-A) or Formula (V-A-l), (V-A-2), (V-B), (V-B-l), (V-C), (V-D), (V-E) or (VI) can modulate, e.g., inhibit, the catechol-O-methyltransferase enzyme.Accordingly, in another aspect, the disclosure provides a method for inhibiting catechol-O- methyltransferase (COMT). Generally, the method comprises administering a compound of Formula (I), Formula (I-A), Formula (I-A-l), Formula (I-A-2), Formula (I-B), Formula (I-B-l), Formula (II), Formula (III), Formula (IV) and / or Formula (IV-A), or Formula (V-A-1), (V-A-2),(V-B), (V-B-l ), (V-C), (V-D), (V-E) or (VI) to a cell. Without limitations, administering to the cell can be in vitro or in vivo. For example, an effective amount of a compound of Formula (I), Formula (I-A), Formula (I-A-l), Formula (I-A-2), Formula (I-B), Formula (1-B-l), Formula (II), Formula (HI), Formula (IV) and Formula (IV- A) or Formula (V-A-l), (V-A-2), (V-B), (V-B-l), (V-C), (V-D), (V-E) or (VI) can be administered to a subject for inhibiting COMT.

[0053] In still another aspect, the disclosure provides a method for treating a COMT mediated disease or disorder-. Generally, the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I), Formula (I-A), Formula (I-A-l), Formula (I-A-2), Formula (I-B), Formula (I-B- 1), Formula (II), Formula (III), Formula (IV) and Formula (IV-A) or Formula (V-A-l), (V-A-2), (V-B), (V-B-l), (V-C), (V-D), or (V-E).

[0054] The disclosure also provides a pharmaceutical composition comprising a compound defined herein as a COMT Inhibitor Compound and / or a compound of Formula (I), Formula (I- A), Formula (I-A-l), Formula (I-A-2), Formula (I-B), Formula (I-B-l), Formula (II), Formula (in), Formula (IV) or Formula (IV-A) or Formula (V-A-l), (V-A-2), (V-B), (V-B-l), (V-C), (V- D), (V-E) or (VI) disclosed herein, and a pharmaceutically acceptable carrier or excipient.

[0055] In some embodiments, a method of treating Parkinson’s disease as an adjunct to levodopa / carbidopa therapy is provided, the method comprising administering to a subject a therapeutically effective amount of a compound disclosed herein. In some embodiments, the method is a method of prolonging effective treatment of Parkinson's disease, comprising administering to a patient in need thereof a compound, pharmaceutically acceptable salt thereof or pharmaceutical composition disclosed herein, in an amount effective to delay the patient's need for add-on L-DOPA therapy, wherein the patient currently receives L-DOPA therapy. In some embodiments, the method is a method of treating a neurological or psychiatric disorder for which inhibiting COMT provides a therapeutic effect, or treating symptoms associated with the neurological or psychiatric disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound, pharmaceutically acceptable salt thereof or pharmaceutical composition disclosed herein.

[0056] In some embodiments, a method for reducing the number or intensity of one or more symptoms of a psychiatric or neurological disorder for which inhibiting COMT provides a therapeutic effect in a patient in need thereof, the method comprising administering atherapeutically effective amount of a compound, pharmaceutically acceptable salt thereof or pharmaceutical composition disclosed herein. In some embodiments, the psychiatric disorder is selected from major depressive disorder (MDD), ADHD, obsessive-compulsive disorder, alcoholism and other addictions, depression, bipolar disorder, age-associated cognitive symptoms, impulse control disorders and schizophrenia. In some embodiments, the psychiatric disorder is Major Depressive Disorder (MDD).BRIEF DESCRIPTION OF THE FIGURES

[0057] No Figures are included in the disclosure.DETAILED DESCRIPTION

[0058] Applicants have discovered chemical compounds that are COMT Inhibitor Compounds. In some embodiments, the compound is a reversible COMT Inhibitor Compound that is not l-[(l,3-dimethyl-2-oxo-2,3-dihydro-1H-l,3-benzodiazol-5-yl)methyl]-2-(4-hydroxy- 3-methoxyphenyl)-N-methyl-lH-l,3-benzodiazole-5-carboxamide.

[0059] Compounds disclosed herein are usefule for methods of treating or preventing a neurological or psychiatric disorders or conditions, or treating symptoms associated with a neurological or psychiatric disorder, and in particular such disorders for which inhibiting COMT provides a therapeutic effect. Ln a particular embodiment, the invention provides a method of inhibiting COMT enzyme in a subject by administering compounds according to formula I, or a pharmaceutically acceptable salt thereof:Compounds

[0060] In some embodiments, the disclosure provides certain compounds of Formula (I) that are COMT Inhibitor Compounds as defined herein, or a pharmaceutically acceptable salt, enantiomer, or racemate thereof:Formula (I) wherein,Ra and Rb are each independentiy hydrogen, C1-4alkyl, C1-4haloalkyl, or halogen; or Raand Rb together form an alkenyl, carbonyl (=0), or spirocyclic cycloalkyl optionally substituted with one or more Rao;At and A2are each independentiy N, NH, or CRr,Aa is N or C; provided that at least one of A1, A2and Aa is N;Bi is C(Rc1Rc2), NRca or oxygen;Rc1, Rc2, R<3 and Ra are each independentiy hydrogen or methyl;R1and R2are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, amine, amide, carboxyl, alkyl-acetate or alkyl-amide; or one of R1and R2together form a fused 6-member aryl ring or fused 6-member heteroaryl ring optionally substituted with R2o;R1z is hydrogen or halogen; R2o is carboxyl, alkyl-acetate or alkyl-amide; andRao is halogen, Ca-s cycloalkyl, or 3-6 member heterocycloalkyl; provided the compound of Formula (I) is not l-[(l,3-dimethyl-2-oxo-2,3-dihydro-lH- l,3-benzodiazol-5-yl)methyl]-2-(4-hydroxy-3-methoxyphenyl)-N-methyl-lH-l,3- benzodiazole-5-carboxamide.

[0061] In some embodiments, the disclosure provides certain compounds of Formula (I) that are COMT Inhibitor Compounds as defined herein, or a pharmaceutically acceptable salt thereof:Formula (I) wherein,Ra and Rb are each independentiy hydrogen, C1-4alkyl, C1-4haloalkyl, or halogen; or Raand Rb together form an alkenyl, carbonyl (=0), or spirocyclic cycloalkyl optionally substituted with one or more Rao;At and A2are each independentiy N, NH, or CRr,Aa is N or C; provided that at least one of A1, A2and Aa is N;Bi is C(Rc1Rc2), NRca or oxygen;Rc1, Rc2, R<3 and Ra are each independentiy hydrogen or methyl;R1and R2are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, amine, amide, carboxyl, alkyl-acetate or alkyl-amide; or one of R1and R2together form a fused 6-member aryl ring or fused 6-member heteroaryl ring optionally substituted with R2o;R1z is hydrogen or halogen; R2o is carboxyl, alkyl-acetate or alkyl-amide; andRao is halogen, Ca-s cycloalkyl, or 3-6 member heterocycloalkyl; provided the compound of Formula (I) is not l-[(l,3-dimethyl-2-oxo-2,3-dihydro-lH- l,3-benzodiazol-5-yl)methyl]-2-(4-hydroxy-3-methoxyphenyl)-N-methyl-lH-l,3- benzodiazole-5-carboxamide.

[0062] In some embodiments, the disclosure provides certain compounds of Formula (I) that are COMT Inhibitor Compounds as defined herein.wherein,Ra and Rb are each independentiy hydrogen, C1-4alkyl, C1-4haloalkyl, or halogen; or Raand Rb together form an alkenyl, carbonyl (=0), or spirocyclic cycloalkyl optionally substituted with one or more Rao;At and A2are each independentiy N, NH, or CRr, Aa is N or C; provided that at least one of A1, A2and Aa is N;Bi is C(Rc1Rc2), NRca or oxygen;Rc1, Rc2, R<3 and Ra are each independentiy hydrogen or methyl;R1and R2are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, amine, amide, carboxyl, alkyl-acetate or alkyl-amide; or one of R1and R2together form a fused 6-member aryl ring or fused 6-member heteroaryl ring optionally substituted with R2o;R1z is hydrogen or halogen; R2o is carboxyl, alkyl-acetate or alkyl-amide; andRao is halogen, Ca-s cycloalkyl, or 3-6 member heterocycloalkyl; provided the compound of Formula (I) is not l-[(l,3-dimethyl-2-oxo-2,3-dihydro-lH-l,3- benzodiazol-5-yl)methyl]-2-(4-hydroxy-3-methoxyphenyl)-N-methyl-lH-l,3-benzodiazole-5- carb oxami de.

[0063] In some embodiments, the disclosure provides certain compounds of Formula (I) that are COMT Inhibitor Compounds as defined herein, or methods of inhibiting COMT comprising administering a compound of Formula (I), or a pharmaceutically acceptable salt, enantiomer, or racemate thereof:Formula (I) wherein,Ra and Rb are each independentiy hydrogen, C1-4alkyl, C1-4haloalkyl, or halogen; or Raand Rb together form an alkenyl, carbonyl (=0), or a spirocyclic cycloalkyl optionally substituted with one or more Rao;At and A2are each independentiy N, NH, or CRr,Aa is N or C; provided that at least one of A1, A2and Aa is N;Bi is C(Rc1Rc2), NRca or oxygen;Rc1, Rcz, Rea and Rdare each independentiy hydrogen, C1-4alkyl, Ca-6 cycloalkyl, or 3- 6 member heterocycloalkyl;R1and R2are each independentiy hydrogen, C1-4alkyl, C1-4haloalkyl, amine, amide, carboxyl, alkyl-acetate or alkyl-amide; or one of R1and R2together form a fused 6-member aryl ring or fused 6-member heteroaryl ring optionally substituted with R2o;R1z is hydrogen or halogen; R2o is carboxyl, alkyl-acetate, amide, or alkyl-amide;Rao is halogen, Ca-e cycloalkyl, or 3-6 member heterocycloalkyl; provided the compound of Formula (I) is not l-[(l,3-dimethyl-2-oxo-2,3-dihydro-lH- l,3-benzodiazol-5-yl)methyl]-2-(4-hydroxy-3-metboxyphenyl)-N-methyl-lH-l,3- benzodiazole-5-carboxamide.

[0064] In some embodiments, the disclosure provides certain compounds of Formula (I) that are COMT Inhibitor Compounds as defined herein, or methods of inhibiting COMT comprisingadministering a compound of Formula (I), or a pharmaceutically acceptable salt, enantiomer, or racemate thereof:Formula (I) wherein,Ra and Rb are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, or halogen; or R* and Rb together form an alkenyl, carbonyl (=0), or a spirocyclic cycloalkyl optionally substituted with one or more R30;A1and A2are each independently N, NH, or CR1;A3 is N or C; provided that at least one of A1, A2and A3 is N;Bi is C(Rc1Rc2), NRc3or oxygen,Rc1, Rc2, Rc3and Rdare each independently hydrogen, C1-4alkyl, C3-6 cycloalkyl optionally substituted with halo, C1-4alkyl or C1-4haloalkyl, 3-6 member heterocycloalkyl optionally substituted with halo, C1-4alkyl or C1-4haloalkyl, C1-4alkyl substituted with C3-6 cycloalkyl optionally substituted with halo, C1-4alkyl or C1-4haloalkyl or C1-4alkyl substituted with 3-6 member heterocycloalkyl optionally substituted with halo, C1-4alkyl or C1-4haloalkyl, wherein one or both of Ki and Rc2 is hydrogen, C1-4alkyl, or C1-4haloalkyl;R1and R2 are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, amine, amide, carboxyl, alkyl-acetate or alkyl-amide; or one of R1and R2 together form a fused 6-member aryl ring or fused 6-member heteroaryl ring optionally substituted with R20;R12 is hydrogen or halogen;R20 is carboxyl, alkyl-acetate, amide or alkyl-amide;R30 is halogen, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl;provided the compound of Formula (I) is not 1 -[(1 ,3-dimethyl-2-oxo-2,3-dihydro-l H- l,3-benzodiazol-5-yl)methyl]-2-(4-hydroxy-3-methoxyphenyl)-N-methyl-lH-l,3- benzodiazole-5-carboxamide.

[0065] In some embodiments, a compound is a compound of Formula (I) wherein KL Rc2, Rc3, and Rdare each independently methyl. In some embodiments, a compound is a compound of Formula (I) wherein Rc1, Rc2, and R<3 are each methyl. In some embodiments, a compound is a compound of Formula (I) wherein Rdis methyl.

[0066] In some embodiments, a compound is a compound of Formula (I) wherein A1is N or CR1; and A2is N or CH, provided that no more than one of A1and A2is N. In some embodiments, a compound is a compound of Formula (I) wherein A1is N; and A2is CH. In some embodiments, a compound is a compound of Formula (I) wherein A1is CR1; and A2is N or CH. In some embodiments, a compound is a compound of Formula (I) wherein A1is CR1; and A2is N. In some embodiments, a compound is a compound of Formula (I) wherein A1is CR1; and A2is CH. In some embodiments, a compound is a compound of Formula (I) whereinA1is CH; and A2is N. In some embodiments, a compound is a compound of Formula (I) wherein A1is CH; and A2is CH.

[0067] In some embodiments, A1is N, A2is NH, and A1is C.

[0068] In some embodiments, A1is N, A2is CR1, and A3 is N.

[0069] In some embodiments, Aj is N, A2is N, and A3 is N.

[0070] In some embodiments, A1is CR1, A2is N, and A3 is N.

[0071] In some embodiments, A1is N, NH, or CRL

[0072] In some embodiments, A1is N. In some embodiments, A, is NH. In some embodiments, A1is CRL In some embodiments A1is N or NH. In some embodiments, A1is N or CRL In some embodiments, A1is NH or CRL

[0073] In some embodiments, A2is N. In some embodiments, A2is NH. In some embodiments, A2is CRL In some embodiments Az is N or NH. In some embodiments, A2is N or CRL In some embodiments, A2is NH or CRL

[0074] In some embodiments, A3 is N or C. In some embodiments, A3 is N. In some embodiments, Ai is C.

[0075] In some embodiments, a compound is a compound of Formula (I) wherein R* and Rb are each independently hydrogen. In some embodiments, a compound is a compound of Formula(I) wherein Rais hydrogen and Rb is hydrogen. C1-4alkyl, C1-4haloalkyl, or halogen. In some embodiments, a compound is a compound of Formula (I) wherein Ra is hydrogen and Rb is C1-4alkyl. In some embodiments, a compound is a compound of Formula (I) wherein Rais hydrogen and Rb is methyl. In some embodiments, a compound is a compound of Formula (I) wherein R» is hydrogen and Rb is ethyl. In some embodiments, a compound is a compound of Formula (I) wherein Ra is hydrogen and Rb is C1-4haloalkyl. In some embodiments, a compound is a compound of Formula (I) wherein R, is hydrogen and Rb is methyl optionally substituted with one or more fluoro. In some embodiments, a compound is a compound of Formula (I) wherein Ra is hydrogen and Rb is -CF3. In some embodiments, a compound is a compound of Formula (I) wherein Ra is hydrogen and Rb is ethyl optionally substituted with one or more fluoro. In some embodiments, a compound is a compound of Formula (I) wherein R, is hydrogen and Rb is fluoro. In some embodiments, a compound is a compound of Formula (I) wherein Ra is fluoro and Rb is fluoro. In some embodiments, a compound is a compound of Formula (I) wherein Ra and Rb together form a spirocyclic cycloalkyl optionally substituted with one or more R30. In some embodiments, a compound is a compound of Formula (I) wherein Ra and Rb together form an unsubstituted spirocyclic cycloalkyl. In some embodiments, a compound is a compound of Formula (I) wherein R, and Rb together form an unsubstituted spirocyclic cyclopropyl.

[0076] In some embodiments, a compound is a compound of Formula (I) wherein A1is CR1and R1is hydrogen. In some embodiments, a compound is a compound of Formula (I) wherein A1is CR1, R1is hydrogen and Ra is hydrogen. In some embodiments, a compound is a compound of Formula (I) wherein A1is CR1and R1is methyl. In some embodiments, a compound is a compound of Formula (I) wherein A1is CR1and R1is an amide. In some embodiments, a compound is a compound of Formula (I) wherein A1is CR1and R1is a carboxyl. In some embodiments, a compound is a compound of Formula (I) wherein A1is CR1and R1is an alkylacetate. In some embodiments, a compound is a compound of Formula (I) wherein A1is CR1andR1is a methyl -acetate. In some embodiments, a compound is a compound of Formula (I) whereinA1is CR1and R1is an alkyl-amide.

[0077] In some embodiments, a compound is a compound of Formula (I) wherein Ra is hydrogen. In some embodiments, a compound is a compound of Formula (I) wherein Ra is methyl. In some embodiments, a compound is a compound of Formula (I) wherein Ra is an amide. In some embodiments, a compound is a compound of Formula (I) wherein Ra is a carboxyl. In someembodiments, a compound is a compound of Formula (I) wherein R2 is an alkyl-acetate. In some embodiments, a compound is a compound of Formula (I) wherein R2 is a methyl-acetate. In some embodiments, a compound is a compound of Formula (I) wherein R2 is an alkyl-amide.

[0078] In some embodiments, a compound is a compound of Formula (I) wherein R1and R2 together form a fused 6-member aryl ring optionally substituted with R20. In some embodiments, a compound is a compound of Formula (I) wherein R1and R2 together form a fused 6-member aryl ring optionally substituted with one R20. In some embodiments, a compound is a compound of Formula (I) wherein R1and R2 together form a fused 6-member aryl ring having the following chemical structure:, wherein * indicates the chemical bond to R1and ** indicates the chemical bond to R2. In some embodiments, a compound is a compound ofFormula (I) wherein R1and R2 together formwherein * indicates the chemical bond to R1and ** indicates the chemical bond to R2. In some embodiments, a compound is a compound of Formula (I) wherein R1and Rj together formwherein * indicates the chemical bond to R1and ** indicates the chemical bond to R? In some embodiments, a compound is a compound of Formula (I) wherein R1and R2 together formwherein * indicates the chemical bond to R1and ** indicates the chemical bond to R2. In some embodiments, a compound is a compound of Formula (I) wherein R1and R2 together form wherein * indicates the chemical bond to R1and ** indicates thechemical bond to R2.

[0079] In some embodiments, a compound is a compound of Formula (I) wherein R1and R2 together form a fused 6-member heteroaryl ring optionally substituted with R20. In some embodiments, a compound is a compound of Formula (I) wherein R1and R2 together form a fused 6-member heteroaryl ring comprising at least one nitrogen heteroatom, and optionally substituted with R20. In some embodiments, a compound is a compound of Formula (I) whereinR1and R2 together form a fused 6-member heteroaryl ring comprising at least one nitrogen heteroatom, and optionally substituted with one R20 at the meta substitution position with respect to the chemical bond to R2.

[0080] In some embodiments, a compound is a compound of Formula (I) wherein R20 is carboxyl. In some embodiments, a compound is a compound of Formula (I) wherein R20 is - COOH. In some embodiments, a compound is a compound of Formula (I) wherein R20 is - COO(CHs). In some embodiments, a compound is a compound of Formula (I) wherein R20 is - CONH2.

[0081] In some embodiments, a compound is a compound of Formula (I) wherein R12 is hydrogen. In some embodiments, a compound is a compound of Formula (I) wherein R12 is halogen. In some embodiments, a compound is a compound of Formula (I) wherein R12 is fluoro.

[0082] In some embodiments, a compound is a compound of Formula (I) wherein R20 is carboxyl, alkyl-acetate, amide or alkyl -ami de. In some embodiments, a compound is a compound of Formula (I) wherein R20 is carboxyl, alkyl-acetate, or alkyl-amide. In some embodiments, a compound is a compound of Formula (I) wherein R20 is carboxyl. In some embodiments, a compound is a compound of Formula (I) wherein R20 is alkyl-acetate. In some embodiments, a compound is a compound of Formula (I) wherein R20 is amide. In some embodiments, a compound is a compound of Formula (I) wherein R20 is alkyl-amide.

[0083] In some embodiments, the disclosure provides a compound of Formula (V-A-l), (V- A-2), and methods of inhibiting COMT comprising administering a compound of Formula (V-A- 1), (V-A-2), or a pharmaceutically acceptable salt, enantiomer, or racemate thereof, in an amount effective to inhibit COMT:Formula (V-A), wherein,Ri and Rb are each independently hydrogen, C j-4 alkyl, C1-4haloalkyl, or halogen; or R« and Rb together form an alkenyl, carbonyl (=0), or a spirocyclic cycloalkyl optionally substituted with one or more RJO;At and A1are each independently N, NH or CR1;A3 is N or C; provided that at least one of A1, A2and A3 is N;Bi is C(RCIRc2), NRc3or oxygen;Rc1, Rc2, Rc3and Rdare each independently hydrogen, C1-4alkyl or C3-6 cycloalkyl;R1and R2 are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, amine, amide, carboxyl, alkyl-acetate or alkyl-amide; or one of R1and R2 together form a fused 6-member aryl ring or fused 6-member heteroaryl ring optionally substituted with R20; each of Rna, R12b, R12c, R12d, and Rne, is independently hydrogen, nitro, alkoxy, hydroxy or halogen;R20 is carboxyl, alkyl-acetate or alkyl-amide; andR30 is halogen, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl.

[0084] In some embodiments, the disclosure provides certain compounds of Formula (V-A-l) selected from the compounds described in the table below:

[0085] In some embodiments, the disclosure provides certain compounds of Formula (V-A-l) selected from the compounds described in the table below:

[0086] In some embodiments, the disclosure provides certain compounds of Formula (V-A-l) selected from the compounds described in the table below:

[0087] In some embodiments, the disclosure provides certain compounds of Formula (V-A-l) selected from the compounds described in the table below:-OH H-OCH, H-OCH: H-OH H-OCH- H-OH H-OCH: H-OH H-OCH, H-OH H-OH H

[0088] In some embodiments, the disclosure provides certain compounds of Formula (I-A) that are COMT Inhibitor Compounds as defined herein, or a pharmaceutically acceptable salt, enantiomer, or racemate thereof:Formula (I-A) wherein R», Rb, A1, A2, Bi, Rd, R2 and R12 are each as defined with respect to Formula (I) above, provided the compound of Formula (I-A) is not l-[(l,3-dimethyl-2-oxo-2,3-dihydro- 1 H-l ,3-benzodiazol-5-yl)methyl]-2-(4-hydroxy-3-methoxyphenyl)-N-methyl-lH-l ,3- benzodiazole-5-carboxamide.

[0089] In some embodiments, the disclosure provides certain compounds of Formula (I-A) that are COMT Inhibitor Compounds as defined herein, or a pharmaceutically acceptable salt thereof:Formula (I-A) wherein Ra, Rb, A1, A2, Bj, Rd, R2 and R12 are each as defined with respect to Formula (I) above, provided the compound of Formula (I-A) is not l-[(l,3-dimethyl-2-oxo-2,3-dihydro-lH-l,3- benzodiazol-5-yl)methyl]-2-(4-hydroxy-3-methoxyphenyl)-N-methyl-lH-l,3-benzodiazole-5- carboxamide.

[0090] In some embodiments, the disclosure provides certain compounds of Formula (I-A) that are COMT Inhibitor Compounds as defined herein:Formula (I-A) wherein R», Rb, A1, A2, Bi, Rd, R2 and R12 are each as defined with respect to Formula (I) above, provided the compound of Formula (I-A) is not l-[(l,3-dimethyl-2-oxo-2,3-dihydro-lH-l,3- benzodiazol-5-yl)methyl]-2-(4-hydroxy-3-methoxyphenyl)-N-methyl-lH-l,3-benzodiazole-5- carboxamide.

[0091] In some embodiments, the disclosure provides certain compounds of Formula (I-A-l) that are COMT Inhibitor Compounds as defined herein, or a pharmaceutically acceptable salt, enantiomer, or racemate thereof:Formula (I-A-l ); wherein,Ri and Rb are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, or halogen; or Ra and Rb together form a spirocyclic cycloalkyl optionally substituted with one or more R30;A1is NH,A2is C;A3 is C;Bi is C(RtiiRti2), NR«3 or oxygen;Rc1, Rc2, Rc3and Rdare each independently hydrogen or methyl;R1is hydrogen, C1-4alkyl, C1-4haloalkyl, amine, amide, carboxyl, alkyl-acetate or alkyl-amide;R12 is hydrogen or halogen;R20 is carboxyl, alkyl-acetate or alkyl-amide;R30 is halogen, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl; provided the compound of Formula (I-A-l ) is not l-[(l,3-dimethyl-2-oxo-2,3-dihydro- lH-l,3-benzodiazol-5-yl)methyl]-2-(4-hydroxy-3-methoxyphenyl)-N-methyl-1H-l,3- benzodiazole-5-carboxamide.

[0092] In some embodiments, the disclosure provides certain compounds of Formula (I-A-l) that are COMT Inhibitor Compounds as defined herein, or a pharmaceutically acceptable salt thereof:Formula (I-A-l); wherein,R» and Rb are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, or halogen; or Ra and Rb together form a spirocyclic cycloalkyl optionally substituted with one or more R30;A1isNH;A2is C;A3 is C;Bi is C(Rc1Rc2), NRc3or oxygen;Rc1, Rc2, Rc3and Rdare each independently hydrogen or methyl;R1is hydrogen. C1-4alkyl, C1-4haloalkyl, amine, amide, carboxyl, alkyl-acetate or alkyl-amide;R12 is hydrogen or halogen,R20 is carboxyl, alkyl-acetate or alkyl-amide;R30 is halogen, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl; provided the compound of Formula (I-A-l ) is not l-[(l,3-dimethyl-2-oxo-2,3-dihydro- lH-l,3-benzodiazol-5-yl)methyl]-2-(4-hydroxy-3-methoxyphenyl)-N-methyl-lH-l,3- benzodiazole-5-carboxamide.

[0093] In some embodiments, the disclosure provides certain compounds of Formula (I-A-l) or Formula (V-A-2) that are COMT Inhibitor Compounds as defined herein:Formula (I-A-l); wherein,R» and Rb are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, or halogen; or Ra and Rb together form a spirocyclic cycloalkyl optionally substituted with one or more R30;A1isNH;A2is C;A3 is C;Bi is C(Rc1Rc2), NRc3or oxygen;Rc1, Rc2, Rc3and Rdare each independently hydrogen or methyl;R1is hydrogen. C1-4alkyl, C1-4haloalkyl, amine, amide, carboxyl, alkyl-acetate or alkyl-amide;R12 is hydrogen or halogen,R20 is carboxyl, alkyl-acetate or alkyl-amide;R30 is halogen, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl; provided the compound of Formula (I-A-l ) is not l-[(l,3-dimethyl-2-oxo-2,3-dihydro- lH-l,3-benzodiazol-5-yl)methyl]-2-(4-hydroxy-3-methoxyphenyl)-N-methyl-lH-l,3- benzodiazole-5-carboxamide.

[0094] In some embodiments, the disclosure provides certain compounds of Formula (I-A-l) or Formula (V-A-2) wherein R20 is carboxyl, alkyl-acetate, amide or alkyl-amide. In some embodiments, the disclosure provides certain compounds of Formula (I-A-l) or Formula (V-A- 2) wherein R20 is carboxyl, alkyl-acetate, or alkyl-amide. In some embodiments, the disclosure provides certain compounds of Formula (I-A-l) or Formula (V-A-2) wherein R20 is carboxyl. In some embodiments, the disclosure provides certain compounds of Formula (I-A-l) or Formula (V-A-2) wherein R20 is alkyl-acetate. In some embodiments, the disclosure provides certaincompounds of Formula (I-A-l) or Formula (V-A-2) wherein R20 is amide. In some embodiments, the disclosure provides certain compounds of Formula (I-A-l) or Formula (V-A- 2) wherein R20 is alkyl-amide.

[0095] In some embodiments, the disclosure provides a compound of Formula (V-B), and methods of inhibiting COMT comprising administering a compound of Formula (V-B), or a pharmaceutically acceptable salt, enantiomer, or racemate thereof, in an amount effective to inhibit COMT:Formula (V-B), wherein,Ra and Rb are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, or halogen; or R« and Rb together form a spirocyclic cycloalkyl optionally substituted with one or more R30;Ai is NH; A2is C;A3 is C;Bi is C(Rc1Rc2), NRc3or oxygen;Rc1, Rc2, Rc3and Rdare each independently hydrogen, C1-4alkyl or C3-6 cycloalkyl,R1is hydrogen, C1-4alkyl, C1-4haloalkyl, amine, amide, carboxyl, alkyl-acetate or alkyl-amide; each of R1ia, R12b, R12c, and R12d, is independently hydrogen, nitro, alkoxy, hydroxy or halogen;Rne is hydrogen, nitro, alkoxy, hydroxy or halogen; or Rue and Rb are together alkyl; R20 is carboxyl, alkyl-acetate or alkyl-amide; andR30 is halogen, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl.

[0096] In some embodiments, the disclosure provides certain compounds of Formula (I-A-2) that are COMT Inhibitor Compounds as defined herein, or a pharmaceutically acceptable salt thereof:Formula (I-A-2); wherein A1, A2, A3, Bi, Rd, R20, and R12 are as defined in Formula (I-A-l).

[0097] In some embodiments, the disclosure provides certain compounds of Formula (I-A-2) that are COMT Inhibitor Compounds as defined herein:Formula (I-A-2); wherein A1, A2, A1, Bi, Rd, R20, and R12 are as defined in Formula (I-A-l).

[0098] In some embodiments, the disclosure provides a compound of Formula (V-B-l), and methods of inhibiting COMT comprising administering a compound of Formula (V-B-l ), or a pharmaceutically acceptable salt, enantiomer, or racemate thereof, in an amount effective to inhibit COMT:Formula (V-B-l) wherein A1, Aj, A3, Bi, Rd, R20, R12a, Rub, R12c, R12d, and R12eare as defined in Formula (V- B).

[0099] In some embodiments, the disclosure provides certain compounds of Formula (I-A-2) or Formula (V-B) wherein R20 is carboxyl, alkyl-acetate, amide or alkyl-amide. In some embodiments, the disclosure provides certain compounds of Formula (I-A-2) or Formula (V-B) wherein R20 is carboxyl, alkyl-acetate, or alkyl-amide. In some embodiments, the disclosure provides certain compounds of Formula (I-A-2) or Formula (V-B) wherein R20 is carboxyl. In some embodiments, the disclosure provides certain compounds of Formula (I-A-2) or Formula (V-B) wherein R20 is alkyl-acetate. In some embodiments, the disclosure provides certain compounds of Formula (I-A-2) or Formula (V-B) wherein R20 is amide. In some embodiments, the disclosure provides certain compounds of Formula (I-A-2) or Formula (V-B) wherein R20 is alkyl-amide.[000100] In some embodiments, the compound is a compound of Formula (II), or a pharmaceutically acceptable salt, enantiomer, or racemate thereof:Formula (II) wherein,Raand Rb are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, or halogen; or Ra and Rb together form a spirocyclic C3-6 cycloalkyl;A1and A2are each independently CH or N; and R12 is hydrogen or halogen.[000101] In some embodiments, the compound is a compound of Formula (II), or a pharmaceutically acceptable salt thereof:wherein,Ra and Rb are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, or halogen; or Ra and Rb together form a spirocyclic C3-6 cycloalkyl;A1and Aj are each independently CH or N; andR12 is hydrogen or halogen.[000102] In some embodiments, the compound is a compound of Formula (11): wherein,Raand Rb are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, or halogen; or Ra and Rb together form a spirocyclic C3-6 cycloalkyl;A1and A2are each independently CH or N; and R12 is hydrogen or halogen.[000103] In some embodiments, the disclosure provides certain compounds of Formula (II) that are COMT Inhibitor Compounds as defined herein, or a pharmaceutically acceptable salt, or enantiomer, or racemate thereof:wherein A1and Aj are each independently CH or N, and Ra, Rb, and R12 are each as defined with respect to Formula (I) above.[000104] In some embodiments, the disclosure provides certain compounds of Formula (II) that are COMT Inhibitor Compounds as defined herein, or a pharmaceutically acceptable salt thereof:Formula (II) wherein A1and A2are each independently CH or N, and Ra, Rb, and R12 are each as defined with respect to Formula (I) above.[000105] In some embodiments, the disclosure provides certain compounds of Formula (II) that are COMT Inhibitor Compounds as defined herein:wherein A1and A2are each independently CH or N, and Ra, Rb, and R12 are each as defined with respect to Formula (I) above.[000106] In some embodiments, A1is CH and A2is N. In some embodiments, A1is N and A2is CH. In some embodiments, A1is N and A2is N. In some embodiments, A1is CH and A2is CH. [000107] In some embodiments, the compound of Formula (II) is not l-[(l,3-dimethyl-2-oxo-2.3-dihydro-lH-l,3-benzodiazol-5-yl)methyl]-2-(4-hydroxy-3-methoxyphenyl)-N-methyl-lH-1.3-benzodi azole-5-carboxamide.[000108] In some embodiments, the disclosure provides certain compounds of Formula (II) wherein R20 is carboxyl, alkyl-acetate, amide or alkyl-amide. In some embodiments, the disclosure provides certain compounds of Formula (II) wherein R20 is carboxyl, alkyl-acetate, or alkyl-amide. In some embodiments, the disclosure provides certain compounds of Formula (II) wherein R20 is carboxyl. In some embodiments, the disclosure provides certain compounds of Formula (II) wherein R20 is alkyl-acetate. In some embodiments, the disclosure provides certain compounds of Formula (II) wherein R20 is amide. In some embodiments, the disclosure provides certain compounds of Formula (II) wherein R20 is alkyl-amide.[000109] In some embodiments, the disclosure provides certain compounds of Formula (II) selected from the compounds described in the table below:[000110] In some embodiments, the disclosure provides certain compounds of Formula (HI) that are COMT Inhibitor Compounds as defined herein, or a pharmaceutically acceptable salt, enantiomer, or racemate thereof:Formula (ID) wherein,R» and Rb are each independently hydrogen, C1-4alkyl, or C1-4halo alkyl; or Ra and Rb together form a spirocyclic cyclopropyl;A1is CH orN;R12 is hydrogen or halogen; andR20 is hydrogen, -C(O)OH, -C(O)O(CH3), -C(O)NH2or -C(0)NH(CH3); provided the compound of Formula (III) is not l-[(l,3-dimethyl-2-oxo-2,3-dihydro-lH-l,3- benzodiazol-5-yl)methyl]-2-(4-hydroxy-3-methoxyphenyl)-N-methyl-lH-l,3-benzodiazole-5- carboxamide.[000111] In some embodiments, the disclosure provides certain compounds of Formula (III) that are COMT Inhibitor Compounds as defined herein, or a pharmaceutically acceptable salt thereof:wherein,Ra and Rb are each independently hydrogen, C1-4alkyl, or C1-4halo alkyl; or Raand Rb together form a spirocyclic cyclopropyl;A1is CH or N;R12 is hydrogen or halogen; andR20 is hydrogen, -C(O)OH, -C(O)O(CH3), -C(O)NH2or -C(O)NH(CH3); provided the compound of Formula (III ) is not 1 -[( 1 ,3-dimethyl-2-oxo-2,3-dihydro- lH-l,3-benzodiazol-5-yl)methyl]-2-(4-hydroxy-3-methoxyphenyl)-N-methyl-lH-l,3- benzodiazole-5-carboxamide.[0001121 In some embodiments, the disclosure provides certain compounds of Formula (III) that are COMT Inhibitor Compounds as defined herein: wherein,Raand Rb are each independently hydrogen, C1-4alkyl, or C1-4halo alkyl; or R, and Rb together form a spirocyclic cyclopropyl;A1is CH or N;R12 is hydrogen or halogen; andR20 is hydrogen, -C(O)OH, -C(O)O(CH3), -C(O)NH2or -C(0)NH(CH3); provided the compound of Formula (HI) is not l-[(l,3-dimethyl-2-oxo-2,3-dihydro- lH-l,3-benzodiazol-5-yl)methyl]-2-(4-hydroxy-3-methoxyphenyl)-N-methyl-1H-l,3- benzodiazole-5-cafboxamide.[000113] In some embodiments, the disclosure provides certain compounds of Formula (HI) that are COMT Inhibitor Compounds as defined herein, or a pharmaceutically acceptable salt, enantiomer, or racemate thereof:Formula (III) wherein Ra, Rb, A1, R20 and R12 are each as defined with respect to Formula (I) above, provided the compound of Formula (HI) is not l-[(l,3-dimethyl-2-oxo-2,3-dihydro-lH-l,3- benzodiazol-5-yl)methyl]-2-(4-hydroxy-3-methoxyphenyl)-N-methyl-lH-l,3-benzodiazole- 5-catboxamide.[000114] In some embodiments, the disclosure provides certain compounds of Formula (III) that are COMT Inhibitor Compounds as defined herein, or a pharmaceutically acceptable salt thereof:Rf»wherein Ra, Rb, A1, R20 and R12 are each as defined with respect to Formula (I) above, provided the compound of Formula (TH) is not l-[(l,3-dimethyl-2-oxo-2,3-dihydro-lH-l,3-benzodiazol-5- yl)methyl]-2-(4-hydroxy-3-methoxyphenyl)-N-methyl-lH-l,3-benzodiazole-5-carboxamide.[000115] In some embodiments, the disclosure provides certain compounds of Formula (III) that are COMT Inhibitor Compounds as defined herein:wherein Ra, Rb, A], R20 and Rn are each as defined with respect to Formula (I) above, provided the compound of Formula (III) is not l-[(l,3-dimethyl-2-oxo-2,3-dihydro-lH-l,3-benzodiazol-5- yl)metbyl]-2-(4-hydroxy-3-methoxyphenyl)-N-methyl-lH-l,3-benzodiazole-5-carboxamide. [000116] In some embodiments, the compound is a compound of Formula (III) that is not 1- [( 1 ,3-dimethyl-2-oxo-2,3-dihydro- 1H- 1 ,3 -benzodi azol-5-yl)methyl]-2-(4-hydroxy-3- methoxyphenyl)-N-methyl-l H-l,3-benzodiazole-5-carboxamide, or methods of inhibiting COMT comprising administering a compound of Formula (m) that is not l-[(l,3-dimethyl-2- oxo-2, 3-dihydro- 1H- 1 ,3-benzodiazol-5-yl)methyl]-2-(4-hydroxy-3-methoxyphenyl)-N-methyl- lH-l,3-benzodiazole-5-carboxamide, or a pharmaceutically acceptable salt, enantiomer, or racemate thereof:Formula (IH) wherein,Ra and Rb are each independently hydrogen, C1-4alkyl, or C1-4halo alkyl; or Ra and Rb together form a spirocyclic cyclopropyl;A1is CH or N;R12 is hydrogen or halogen; andR20 is hydrogen, -C(O)OH, -C(O)O(CH3), -C(O)NH2or -C(O)NH(CH3).[000117] In some embodiments, the compound is a compound of Formula (HI) wherein A1is N and R20 is hydrogen. In some embodiments, the compound is a compound of Formula (III) wherein A1is N and R20 is -C(O)OH. In some embodiments, the compound is a compound of Formula (HI) wherein A1is N and R20 is -C(O)O(CH3). In some embodiments, the compound is a compound of Formula (HI) wherein A1is N and R20 is -C(O)NH2. In some embodiments, the compound is a compound of Formula (III) wherein A1is N and R20 is -C(O)NH(CH3), provided that the compound of Formula (HI) is not l-[(l,3-dimethyl-2-oxo-2,3-dihydro-lH-l,3- benzodiazol-5-yl)methyl]-2-(4-hydroxy-3-methoxyphenyl)-N-methyl-lH-l,3-benzodiazole-5- carboxamide.[000118] In some embodiments, the disclosure provides certain compounds of Formula (HI) wherein R20 is carboxyl, alkyl-acetate, amide or alkyl-amide. In some embodiments, the disclosure provides certain compounds of Formula (HI) wherein R20 is carboxyl, alkyl-acetate, or alkyl-amide. In some embodiments, the disclosure provides certain compounds of Formula (HI) wherein R20 is carboxyl. In some embodiments, the disclosure provides certain compounds of Formula (HI) wherein R20 is alkyl-acetate. In some embodiments, the disclosure provides certaincompounds of Formula (III) wherein R20 is amide. In some embodiments, the disclosure provides certain compounds of Formula (HI) wherein R20 is alkyl-amide.[000119] In some embodiments, the disclosure provides certain compounds of Formula (III) selected from the compounds described in the table below:[000120] In some embodiments, the disclosure provides certain compounds of Formula (I-B) that are COMT Inhibitor Compounds as defined herein, or a pharmaceutically acceptable salt, enantiomer, or racemate thereof:wherein,Ra and Rb are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, or halogen; or Ra and Rb together form a spirocyclic cycloalkyl optionally substituted with one or more R30;A1is C; A2is N, NH, or CRj;A3 is N or C; provided that at least one of A2and A3 is N, or provided A2is NH if Ai is C;Bi is C(Rc1Rcz), NRc3or oxygen;Rc1, Rc2, R.-3 and Rdare each independently hydrogen or methyl;R1is hydrogen, C1-4alkyl, C1-4haloalkyl, amine, amide, carboxyl, alkyl-acetate or alkyl-amide;R1z is hydrogen or halogen; R2o is carboxyl, alkyl-acetate or alkyl-amide;R30 is halogen, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl; provided the compound of Formula (I-B) is not 1 -[(1,3 -dimethyl -2-oxo-2, 3 -dihydro- lH-l,3-benzodiazol-5-yl)methyl]-2-(4-hydroxy-3-methoxyphenyl)-N-methyl-lH-l,3- benzodiazole-5-carboxami de.[000121] In some embodiments, the disclosure provides certain compounds of Formula (I-B) that are COMT Inhibitor Compounds as defined herein, or a pharmaceutically acceptable salt thereof:Formula (I-B) wherein,Ra and Rb are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, or halogen; orRa and Rb together form a spirocyclic cycloalkyl optionally substituted with one or more R30;A1is C;A2is N, NH, or CR1;A3 is N or C; provided that at least one of A2and A3 is N, or provided A2is NH if A3 is C;Bi is C(Rc1Rc2), NR«3 or oxygen;Rc1, Rc2, Rc3and Rdare each independently hydrogen or methyl;R1is hydrogen, C1-4alkyl, C1-4haloalkyl, amine, amide, carboxyl, alkyl-acetate or alkyl-amide;R12 is hydrogen or halogen;R20 is carboxyl, alkyl-acetate or alkyl-amide;R30 is halogen, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl; provided the compound of Formula (I-B) is not l-[(l,3-dimethyl-2-oxo-2,3-dihydro- 1 H-l ,3-benzodiazol-5-yl)methyl]-2-(4-hydroxy-3-methoxyphenyl)-N-methyl-lH-l ,3- benzodiazole-5-carboxamide.[0001221 In some embodiments, the disclosure provides certain compounds of Formula (I-B) that are COMT Inhibitor Compounds as defined herein:Formula (I-B) wherein,Ra and Rb are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, or halogen; or Rfl and Rb together form a spirocyclic cycloalkyl optionally substituted with one or more R30;At is C;A2is N, NH, or CR1,A3 is N or C; provided that at least one of A2and A3 is N, or provided A2is NH if A3 is C;Bi is C(Rc1Rc2), NRc3or oxygen;Rd, Rcz, Rc3and Rdare each independently hydrogen or methyl;R1is hydrogen, C1-4alkyl, C1-4haloalkyl, amine, amide, carboxyl, alkyl-acetate or alkyl-amide;R1z is hydrogen or halogen;R20 is carboxyl, alkyl-acetate or alkyl-amide;R30 is halogen, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl; provided the compound of Formula (I-B) is not l-[(l,3-dimethyl-2-oxo-2,3-dihydro- lH-l,3-benzodiazol-5-yl)methyl]-2-(4-hydroxy-3-methoxyphenyl)-N-methyl-lH-l,3- benzodiazole-5-carboxamide.[000123] In some embodiments, the disclosure provides certain compounds of Formula (I-B) that are COMT Inhibitor Compounds as defined herein, methods of inhibiting COMT comprising administering a compound of Formula (I-B), or a pharmaceutically acceptable salt, enantiomer, or racemate thereof:wherein,Ra and Rt> are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, or halogen; or Raand Rb together form a spirocyclic cycloalkyl optionally substituted with one or more R30;A1is C;A2is N, NH, or CRj;A3 is N or C; provided that at least one of A2and A3 is N, or provided A2is NH if Ai is C;Bi is C(Rc1Rc2), NRc3or oxygen;Rc1, Rc2, Rc3and Rdare each independently hydrogen, C1-4alkyl, C3-6 cycloalkyl, or 3- 6 member heterocycloalkyl;R1is hydrogen, C1-4alkyl, C1-4haloalkyl, amine, amide, carboxyl, alkyl-acetate or alkyl-amide;R12 is hydrogen or halogen; R2o is carboxyl, alkyl-acetate or alkyl-amide; andR30 is halogen, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl; provided the compound of Formula (I-B) is not 1 -[(1,3 -dimethyl -2-oxo-2, 3 -dihydro- lH-l,3-benzodiazol-5-yl)methyl]-2-(4-hydroxy-3-methoxyphenyl)-N-methyl-lH-l,3- benzodiazole-5-carboxamide.[000124] In some embodiments, the disclosure provides certain compounds of Formula (I-B) that are COMT Inhibitor Compounds as defined herein, methods of inhibiting COMT comprising administering a compound of Formula (I-B), or a pharmaceutically acceptable salt, enantiomer, or racemate thereof: wherein,Ra and Rt> are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, or halogen; or Raand Rb together form a spirocyclic cycloalkyl optionally substituted with one or more R30;A1is C;A2is N, NH, or CRj;A3 is N or C; provided that at least one of A2and A3 is N, or provided A2is NH if Ai is C;Bi is C(Rc1Rc2), NRc3or oxygen;Rc1, Rc2, RV3 and Rdare each independently hydrogen, C1-4alkyl, C3-6 cycloalkyl optionally substituted with halo, C1-4alkyl or C1-4haloalkyl, 3-6 member heterocycloalkyloptionally substituted with halo, C1-4alkyl or C1-4haloalkyl, C1-4alkyl substituted with C3-6 cycloalkyl optionally substituted with halo, C1-4alkyl or C1-4haloalkyl or C1-4alkyl substituted with 3-6 member heterocycloalkyl optionally substituted with halo, C1-4alkyl or C1-4haloalkyl, wherein one or both of Ki and K2 is hydrogen, C1-4alkyl, or C1-4haloalkyl;R1is hydrogen, C1-4alkyl, C1-4haloalkyl, amine, amide, carboxyl, alkyl-acetate or alkyl-amide;R12 is hydrogen or halogen; R2o is carboxyl, alkyl-acetate, amide or alkyl-amide; andR30 is halogen, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl; provided the compound of Formula (I-B) is not l-[(l,3-dimethyl-2-oxo-2,3-dihydro- lH-l,3-benzodiazol-5-yl)methyl]-2-(4-hydroxy-3-methoxyphenyl)-N-methyl-lH-l,3- benzodiazole-5-carboxamide.[000125] In some embodiments, the disclosure provides certain compounds of Formula (I-B) that are COMT Inhibitor Compounds as defined herein, or a pharmaceutically acceptable salt, enantiomer, or racemate thereof:wherein Ra, Rb, A1, A2, R2and R12 are each as defined with respect to Formula (I) above, provided the compound of Formula (I-B) is not l-[(l,3-dimethyl-2-oxo-2,3-dihydro-lH-l,3- benzodiazol-5-yl)methyl]-2-(4-hydroxy-3-methoxyphenyl)-N-methyl-lH-l,3-benzodiazole- 5 -carboxamide.[000126] In some embodiments, the disclosure provides certain compounds of Formula (I-B) that are COMT Inhibitor Compounds as defined herein, or a pharmaceutically acceptable salt thereof:Formula (I-B) wherein Ra, Rb, A1, As, Rj and R12 are each as defined with respect to Formula (I) above, provided the compound of Formula (T-B) is not 1-[(1 ,3-dimethyl-2-oxo-2,3-dihydro-lH-l,3-benzodiazol-5- yl)methyl]-2-(4-hydroxy-3-methoxyphenyl)-N-methyl-lH-l,3-benzodiazole-5-carboxamide.[000127] In some embodiments, the disclosure provides certain compounds of Formula (I-B) that are COMT Inhibitor Compounds as defined herein:Formula (I-B) wherein Ra, Rb, A1, A2, R2 and Rn are each as defined with respect to Formula (I) above, provided the compound of Formula (I-B) is not l-[(l,3-dimethyl-2-oxo-2,3-dihydro-lH-l,3-benzodiazol-5- yl)metbyl]-2-(4-hydroxy-3-methoxyphenyl)-N-methyl-lH-l,3-benzodiazole-5-carboxamide. [000128] In some embodiments, the disclosure provides certain compounds of Formula (I-B) wherein R20 is carboxyl, alkyl-acetate, amide or alkyl-amide. In some embodiments, the disclosure provides certain compounds of Formula (I-B) wherein R20 is carboxyl, alkyl-acetate, or alkyl-amide. In some embodiments, the disclosure provides certain compounds of Formula (I- B) wherein R20 is carboxyl. In some embodiments, the disclosure provides certain compounds of Formula (I-B) wherein R20 is alkyl-acetate. In some embodiments, the disclosure providescertain compounds of Formula (I-B) wherein R20 is amide. In some embodiments, the disclosure provides certain compounds of Formula (I-B) wherein R20 is alkyl-amide.[000129] In some embodiments, the disclosure provides certain compounds of Formula (I-B) selected from the compounds described in the table below:[000130] In some embodiments, the disclosure provides compounds of Formula (V-C), methods of inhibiting COMT comprising administering a compound of Formula (V-C), or a pharmaceutically acceptable salt, enantiomer, or racemate thereof, in an amount effective to inhibit COMT:Formula (V-C) wherein,Raand Rb are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, or halogen; or Ra and Rb together form a spirocyclic cycloalkyl optionally substituted with one or more R30;A1is C; A2is N, NH or CR1;A3 is N or C; provided that at least one of A2and A? is N, or provided A2is NH if A3 is C;Bi is C(Rc1Rc2), NRc3or oxygen;Rc1, Rc2, Rc3and Rdare each independently hydrogen, C1-4alkyl or C3-6 cycloalkyl;R1is hydrogen, C1-4alkyl, C1-4haloalkyl, amine, amide, carboxyl, alkyl-acetate or alkyl-amide; each of Rna, Rub, R12c, and R12d, is independently hydrogen, nitro, alkoxy, hydroxy or halogen; R12eis hydrogen, nitro, alkoxy, hydroxy or halogen; or R12eand Rb are together alkyl;R20 is carboxy), alkyl-acetate or alkyl-amide; andR30 is halogen, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl.[000131] In some embodiments, the disclosure provides compounds of Formula (V-C), methods of inhibiting COMT comprising administering a compound of Formula (V-C), or a pharmaceutically acceptable salt, enantiomer, or racemate thereof, in an amount effective to inhibit COMT;wherein,Raand Rb are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, or halogen; or Ra and Rb together form a spirocyclic cycloalkyl optionally substituted with one or more R30;A1is C; A2is N, NH or CR1;A3 is N or C; provided that at least one of A2and A? is N, or provided A2is NH if A3 is C;Bi is C(Rc1Rc2), NRc3or oxygen;Rc1, Rc2, Rc3and Rdare each independently hydrogen, C1-4alkyl or C3-6 cycloalkyl;R1is hydrogen, C1-4alkyl, C1-4haloalkyl, amine, amide, carboxyl, alkyl-acetate or alkyl-amide; each of Rna, Rub, R12c, and R12d, is independently hydrogen, nitro, alkoxy, hydroxy or halogen; R12eis hydrogen, nitro, alkoxy, hydroxy or halogen; or R12eand Rb are together alkyl; R20 is carboxy), alkyl-acetate, amide or alkyl-amide; and R30 is halogen, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl.[000132] In some embodiments, the disclosure provides certain compounds of Formula (V-C) wherein R20 is carboxyl, alkyl-acetate, amide or alkyl-amide. In some embodiments, the disclosure provides certain compounds of Formula (V-C) wherein R20 is carboxyl, alkyl-acetate, or alkyl-amide. In some embodiments, the disclosure provides certain compounds of Formula (V-C) wherein R20 is carboxyl. In some embodiments, the disclosure provides certain compounds of Formula (V-C) wherein R20 is alkyl-acetate. In some embodiments, the disclosure provides certain compounds of Formula (V-C) wherein R20 is amide. In some embodiments, the disclosure provides certain compounds of Formula (V-C) wherein R20 is alkyl-amide.[000133] In some embodiments, the disclosure provides certain compounds of Formula (I-B-l) that are COMT Inhibitor Compounds as defined herein, or a pharmaceutically acceptable salt thereof:Formula (I-B-l); wherein Aj, A1, A3, Bi, Rd, R20, and Rn are as defined in Formula (I-B), provided that at least one of A2and A3 is N, or provided A2is NH if A3 is C.[000134] In some embodiments, the disclosure provides certain compounds of Formula (I-B-l) that are COMT Inhibitor Compounds as defined herein:Formula (1-B-l); wherein A1, A1, A3, Bi, Rd, R20, and R12 are as defined in Formula (I-B), provided that at least one of A2and A3 is N, or provided A2is NH if A3 is C.[000135J In some embodiments, the disclosure provides compounds of formula (V-D), methods of inhibiting COMT comprising administering a compound of Formula (V-D), or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit COMT;wherein A1, A2, A3, Bi, Rd, R20, and R12 are as defined in Formula (T-B-l), provided that at least one of A2and A3 is N, or provided A2is NH if A3 is C.[000136] In some embodiments, a compound is a COMT Inhibitor Compounds of Formula (IV) or methods of inhibiting COMT comprising administering a compound of Formula (IV), or a pharmaceutically acceptable salt, enantiomer, or racemate thereof:wherein, Raand Rb are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, or halogen; or R» and Rb together form a spirocyclic cyclopropyl;Re is hydrogen or methyl; and R12 is hydrogen or halogen.[000137] In some embodiments, the compound is a compound of Formula (IV) wherein Ra and Rb are each independently hydrogen, halogen, methyl or ethyl each optionally substituted with one or more halogen; or Ra and Rb together form a spirocyclic cyclopropyl; Re is hydrogen or methyl; and R12 is hydrogen or halogen. In some embodiments, the compound is a compound of Formula (IV) wherein Ra is hydrogen. In some embodiments, the compound is a compound of Formula (IV) wherein R, is hydrogen; Rb is hydrogen, methyl or ethyl each optionallysubstituted with one or more fluoro, or halogen; Re is hydrogen or methyl; and R12 is hydrogen or fluoro. In some embodiments, the compound is a compound of Formula (IV) wherein Ra is hydrogen; Rb is hydrogen, methyl, ethyl, -CF3, or halogen; Re is hydrogen or methyl; and R12 is hydrogen or fluoro. In some embodiments, the compound is a compound of the formula:, or a pharmaceutically acceptable salt thereof.[000138] In some embodiments, a compound is a COMT Inhibitor Compounds of Formula(IV) or a pharmaceutically acceptable salt, enantiomer, or racemate thereof:whereinRaand Rb are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, or halogen; or Ra and Rb together form a spirocyclic cyclopropyl;Re is hydrogen or methyl; andR12 is hydrogen or halogen.[000139] In some embodiments, a compound is a COMT Inhibitor Compounds of Formula(IV) or a pharmaceutically acceptable salt thereof:whereinRa and Rb are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, or halogen; or Ra and Rb together form a spirocyclic cyclopropyl;Re is hydrogen or methyl; andR12 is hydrogen or halogen.[000140] In some embodiments, a compound is a COMT Inhibitor Compounds of Formula(IV):whereinR« and Rb are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, or halogen; or Raand Rb together form a spirocyclic cyclopropyl;Re is hydrogen or methyl; and R12 is hydrogen or halogen.[000141] In some embodiments, a compound is a compound of Formula (IV) wherein R» and Rb are each independently hydrogen. In some embodiments, a compound is a compound of Formula (IV) wherein Ra is hydrogen and Rb is hydrogen, C1-4alkyl, C1-4haloalkyl, or halogen. In some embodiments, a compound is a compound of Formula (IV) wherein Ra is hydrogen and Rb is C1-4alkyl. In some embodiments, a compound is a compound of Formula (IV) wherein Ra is hydrogen and Rb is methyl. In some embodiments, a compound is a compound of Formula (IV) wherein Ra is hydrogen and Rb is ethyl. In some embodiments, a compound is a compound of Formula (IV) wherein Ra is hydrogen and Rb is C1-4haloalkyl. In some embodiments, a compound is a compound of Formula (IV) wherein Rais hydrogen and Rb is methyl optionally substituted with one or more fluoro. In some embodiments, a compound is a compound of Formula (IV) wherein R« is hydrogen and Rb is -CF3. In some embodiments, a compound is a compound of Formula (IV) wherein Ra is hydrogen and Rb is ethyl optionally substituted with one or more fluoro. In some embodiments, a compound is a compound of Formula (IV) wherein R, is hydrogen and Rb isfluoro. Tn some embodiments, a compound is a compound of Formula (IV) wherein R, is fluoro and Rb is fluoro. In some embodiments, a compound is a compound of Formula (IV) wherein R» and Rb together form a spirocyclic cycloalkyl optionally substituted with one or more R30. In some embodiments, a compound is a compound of Formula (TV) wherein Ra and Rb together form an unsubstituted spirocyclic cycloalkyl. In some embodiments, a compound is a compound of Formula (IV) wherein R, and Rb together form an unsubstituted spirocyclic cyclopropyl.[000142] In some embodiments, the disclosure provides certain compounds of Formula (IV) wherein R< is methyl. In some embodiments, the disclosure provides certain compounds of Formula (IV) wherein Re is hydrogen.[000143] In some embodiments, a compound is a compound of Formula (IV) wherein R12 is hydrogen. In some embodiments, a compound is a compound of Formula (IV) wherein R12 is halogen. In some embodiments, a compound is a compound of Formula (TV) wherein R12 is fluoro.[000144] In some embodiments, the disclosure provides certain compounds of Formula (IV) selected from the compounds described in the table below:[000145] In some embodiments, a compound i s a COMT Inhibitor Compounds of Formula (IV- A) or a pharmaceutically acceptable salt, enantiomer, or racemate thereof:whereinRa and Rb are each independently hydrogen, Cm alkyl, Cm haloalkyl, or halogen; or Ra and Rb together form an alkenyl, or a spirocyclic cycloalkyl optionally substituted with one or more Rao;Bi is C(KIRc2), NK3 or oxygen;Rc1, Rc2, Rea and Rdare each independently hydrogen or methyl;Reis hydrogen or methyl;R12 is hydrogen or halogen; andRao is halogen, C3.6 cycloalkyl, or 3-6 member heterocycloalkyl.[000146] In some embodiments, a compound is a COMT Inhibitor Compounds of Formula (IV-A) or a pharmaceutically acceptable salt thereof:whereinRa and Rb are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, or halogen; or Ra and Rb together form an alkenyl, or a spirocyclic cycloalkyl optionally substituted with one or more Rao;Bi is C(Rc1Rc2), NRca or oxygen;Rc1, Rc2, Rea and Rdare each independently hydrogen or methyl;Re is hydrogen or methyl;R12 is hydrogen or halogen; andRao is halogen, Ca-6 cycloalkyl, or 3-6 member heterocycloalkyl.[000147] In some embodiments, a compound is a COMT Inhibitor Compounds of Formula (IV-A):whereinRa and Rb are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, or halogen; or Ra and Rb together form an alkenyl, or a spirocyclic cycloalkyl optionally substituted with one or more R30;Bi is C(Rc1Rc2), NRS or oxygen;Rc1, Rc2, Rc3and Rdare each independently hydrogen or methyl; Re is hydrogen or methyl;Rn is hydrogen or halogen; andR30 is halogen, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl.[000148] In some embodiments, a compound is a compound of Formula (IV-A) wherein R« and Rb are each independently hydrogen, F, methyl, or ethyl; or Ra and Rb together form a cyclopropyl or ethynyl. In some embodiments, a compound is a compound of Formula (IV-A) wherein Ra and Rb together form a cyclopropyl or ethynyl. In some embodiments, a compound is a compound of Formula (IV-A) wherein Ra is H and Rb is hydrogen, F, methyl, ethyl or cyclopropyl. In some embodiments, a compound is a compound of Formula (IV-A) wherein Ra is H and Rb is hydrogen. F, or methyl. In some embodiments, a compound is a compound of Formula (I V-A) wherein Rn is hydrogen or F. In some embodiments, a compound is a compound of Formula (TV-A) wherein R30 is F or cyclopropyl. In some embodiments, a compound is a compound of Formula (IV-A) wherein R30 is 3-6 member heterocycloalkyl comprising a nitrogen or oxygen heteroatom. In some embodiments, a compound is a compound of Formula (IV-A) wherein Rc1, Rc1, Rc3 and Rdare each independently methyl. In some embodiments, a compound is a compound of Formula (IV-A) wherein R, and Rb are each independently hydrogen, F, Cl, methyl optionally substituted with one or more F; or Ra and Rb together form an alkenyl or a spirocyclic cyclopropyl, the alkenyl or spirocyclic cyclopropyl being optionally substituted with one or more F, Cl, cyclopropyl or 3-6 member heterocycloalkyl comprising a nitrogen or oxygen heteroatom; Bi is C(Rc1Rc2) , NRc3 or oxygen and Rc1, Rc1, Rc3 and Rdare each independently hydrogen or methyl; Rn is hydrogen or F or Cl. In some embodiments, a compound is a compound of Formula (IV-A) wherein Ra and Rb are each independently hydrogen, F, or methyl optionally substituted with one or more F; Bi is C(Rc1Rc2), NRc? or oxygen and Rc1, Rc2, Rc3 and Rdare each independently hydrogen or methyl; Rn is hydrogen or F.[000149] In some embodiments, the disclosure provides certain compounds of Formula (I) that are COMT Inhibitor Compounds as defined herein, or methods of inhibiting COMT comprising administering a compound of Formula (VI), or a pharmaceutically acceptable salt, enantiomer, or racemate thereof:Formula (VI) wherein,R. is hydrogen. C1-4alkyl. C1-4haloalkyl, or halogen;A1and A2are each independently N, NH or CR1;A3 is N or C; provided that at least one of A1, A2and A1is N;Bi is C(R;iRc2), NR«3 or oxygen;Rc1, Rc2, Rc3and Rdare each independently hydrogen, C1-4alkyl or C3-6 cycloalkyl;R1and R2are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, amine, amide, carboxyl, alkyl-acetate or alkyl-amide; or one of R1and R2together form a fused 6-member aryl ring or fused 6-member heteroaryl ring optionally substituted with R2Q; each of RIM, R12b, R12c, and RIM, is independently hydrogen, nitro, alkoxy, hydroxy or halogen;R20 is carboxyl, alkyl-acetate, amide or alkyl-amide; andR30 is halogen, C3.6 cycloalkyl, or 3-6 member heterocycloalkyl.[000150] In some embodiments, a compound is a COMT Inhibitor Compound of Formula (V- A-l), (V-A-2), (V-B), (V-B-l), (V-C), (V-D), (V-E) or (VI) wherein A1is N or CH and A2is N or CH provided that no more than one of A1and A2are N; Bi is oxygen or NRc3 and K is methyl;and one of R. and Rb is hydrogen. In some embodiments, a compound is a COMT Inhibitor Compound of Formula (V-A-l), (V-A-2), (V-B), (V-B-l), (V-C), (V-D), or (VI) wherein Bi is NRcs; Rc3is methyl; Rdis methyl and R2 is hydrogen.[000151] In some emnbodiments, the compound is a compound of Formula (V-A-l), (V-A-2), (V-B), (V-B-l), (V-C), (V-D), (V-E) or (VI) wherein R12ais II or F, Rub is -NCh, or F, Rucis hydroxyl, Rud is methoxy or hydroxy and Rue is H.[000152] In some embodiments, the compound is a compound of Formula (V-A-l), (V-A-2), (V- B), (V-B-l), (V-C), (V-D), (V-E) or (VI), wherein Ra is F, or methyl optionally substituted with one or more F, and Rb is hydrogen or F. In some embodiments, the compound is a compound of Formula (V-A-l), (V-A-2), (V-B), (V-B-l), (V-C) , (V-D), (V-E) or (VI), wherein R. is methyl, and Rb is hydrogen. In some embodiments, the compound is a compound of Formula (V-A-l), (V-A-2), (V-B), (V-B-l), (V-C) , (V-D), (V-E) or (VI), wherein R. is hydrogen, and Rb is hydrogen. In some embodiments, the compound is a compound of Formula (V-A-l), (V -A-2), (V-B), (V-B-l), (V-C) , (V-D), (V-E) or (VI), wherein Ra is -CF3 and Rb is hydrogen. In some embodiments, the compound is a compound of Formula (V-A-l), (V-A-2), (V-B), (V-B-l), (V-C), (V-D) or (V-E) wherein Ra and Rb together corm carbonyl (C==O) or C=CH2.[000153] In some embodiments, the compound is selected from the group consisting of:pharmaceutically acceptable salt thereof.[000154] In some embodiments, the compound is selected from the group consisting of:or a pharmaceutically acceptable salt thereof.[000155] In some embodiments, the compound is selected from the group consisting of:or a pharmaceutically acceptable salt thereof.[000156] In some embodiments, the compound is, or a pharmaceutically acceptable salt thereof.[000157] In some embodiments, the compound is selected from the group consisting of:, or a pharmaceutically acceptable salt thereof.and or a pharmaceutically acceptable salt thereof.[000158] In some embodiments, the compound is selected from the group consisting of:or a pharmaceutically acceptable salt thereof.[000159] In some embodiments, the compound is selected from the group consisting of:, or a pharmaceutically acceptable salt thereof.[000160] In some embodiments, the compound is selected from the group consisting of:or a pharmaceutically acceptable salt thereof.[000161] The compounds described herein can exist as salts, such as with pharmaceutically acceptable acids. Accordingly, such salts of the compounds described herein are included. The term '‘pharmaceutically acceptable salt” is meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein When compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the presentinvention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monobydrogencarbonic. phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, oxalic, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see. for example, Berge et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.[000162] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solventsPharmaceutical Compositions[000163] In certain embodiments, the present application is directed to a pharmaceutical composition comprising an active pharmaceutical ingredient. In certain embodiments, the pharmaceutical composition comprises a compound as disclosed herein as the active pharmaceutical ingredient (API) and a pharmaceutically acceptable carrier comprising one or more excipients. In some embodiments, the pharmaceutical composition optionally further comprises an additional therapeutic compound (i.e., agent) with the pharmaceutically acceptable carrier. The pharmaceutical composition can be a medicament.[000164] Pharmaceutically acceptable carriers include those known in the art. The choice of a pharmaceutically acceptable carrier can depend, for example, on the desired route of administration of the composition. A pharmaceutical composition (preparation) can be administered to a subject by any of a number of routes of administration including, for example, parenteral administration (e.g. intravenously, subcutaneously, or intramuscularly), oraladministration (for example, tablets, and capsules); absorption through the oral mucosa (e g., sublingually) or transdermally (for example as a patch applied to the skin) or topically (for example, as a cream, ointment or spray applied to the skin).[000165] In some embodiments, pharmaceutical compositions comprising compounds of Formula (I), Formula (I-A), Formula (I-A-l), Formula (I-A-2), Formula (I-B), Formula (I-B-l), Formula (II), Formula (III), Formula (IV), Formula (IV-A), Formula (V), Formula (V-A-l), Formula (V-A-2), Formula (V-B), Formula (V-B-l), Formula (V-C), Formula (V-D), Formula (V-E), Formula (VI) or pharmaceutically acceptable salts thereof can be formulated for oral administration. For example, a compound provided herein can be combined with suitable compendial excipients to form an oral unit dosage form, such as a capsule or tablet, containing a target dose of a compound of Formula (I), Formula (I-A), Formula (I-A-l), Formula (I-A-2), Formula (I-B), Formula (I-B-l), Formula (II), Formula (III), Formula (IV), Formula (IV-A), Formula (V), Formula (V-A-l), Formula (V-A-2), Formula (V-B), Formula (V-B-l), Formula (V-C), Formula (V-D), Formula (V-E), or Formula (VI). The drug product can be prepared by first manufacturing the compound of Formula (I), Formula (I-A), Formula (I-A-l), Formula (I- A-2), Formula (I-B), Formula (I-B-l), Formula (II), Formula (HI), Formula (IV), Formula (IV- A), Formula (V), Formula (V-A-l), Formula (V-A-2), Formula (V-B), Formula (V-B-l), Formula (V-C), Formula (V-D), Formula (V-E), or Formula (VI)as an active pharmaceutical ingredient (API), followed by roller compaction / milling with intragranular excipients and blending with extra granular excipients. A Drug Product can contain the selected compound of Formula (I), Formula (I-A), Formula (I-A-l), Formula (I-A-2), Formula (I-B), Formula (I-B-l), Formula (II), Formula (III), Formula (IV), Formula (IV-A), Formula (V), Formula (V-A-l), Formula (V-A-2), Formula (V-B), Formula (V-B-l), Formula (V-C), Formula (V-D), Formula (V-E), or Formula (VI)as the API and excipient components in a tablet in a desired dosage strength. The blended material can be compressed to form tablets and then film coated. The excipients can be selected from materials appropriate for inclusion in a pharmaceutical composition for an intended purpose and route of delivery including providing a desired manufacturing and stability properties and / or desired in vivo characteristics or other properties to the pharmaceutical composition. In some embodiments, the pharmaceutical composition can include a compound of Formula (I), Formula (I-A), Formula (I-A-l), Formula (I-A-2), Formula (I-B), Formula (I-B-l), Formula (II), Formula (HI), Formula (IV), Formula (IV-A), Formula (V),Formula (V-A-l), Formula (V-A-2), Formula (V-B), Formula (V-B-l), Formula (V-C), Formula (V-D), Formula (V-E), or Formula (VI)as the API in combination with a filler (e.g., a form of microcrystalline cellulose), a dry binder or disintegrant (e.g., a cross-linked polymer), a glidant (e g., colloidal silicon dioxide) and / or a lubricant (e.g., magnesium stearate). In some embodiments, the pharmaceutical composition can comprise a material such as an extended release or disintegrant involved in carrying or transporting the API pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body of a subject, including materials to desirable control the absorption of the API in the intestine.[000166] The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. For use in the methods of this invention, active compounds can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.[000167] Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the invention, with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.[000168] To prepare solid dosage forms for oral administration, the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, (2) binders, (3) humectants, (4) disintegrating agents, (5) solution retarding agents, (6) absorption accelerators, (7) wetting agents, (8) absorbents, (9) lubricants, (10) complexing agents, and (11) coloring agents. In the case of capsules (including sprinkle capsules and gelatin capsules), tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using suitableexcipients. The pharmaceutical compositions according to the present invention may contain conventional pharmaceutical carriers and / or auxiliary agents. In some embodiments, he pharmaceutical compositions according to the present invention may contain conventional carrier agents including a binder, a lubricant and / or a glidant selected from those products and materials generally used in pharmaceutical industiy for preparation of pharmaceutical compositions for an intended route of administration.[000169] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.[000170] Liquid dosage forms useful for oral administration include pharmaceutically acceptable carriers and the active ingredient provided as a solid form for reconstitution prior to administration or as a liquid (e.g., solutions, suspensions, or emulsions). In addition to the active ingredient, a liquid dosage forms may contain inert diluents commonly used in the art. For example, formulations of pharmaceutically acceptable compositions for injection can include aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles suitable for the intended route of administration. In some embodiments, the pharmaceutical composition is formulated for parenteral administration.[000171] The therapeutically effective amount of a pharmaceutical composition can be determined by human clinical trials to determine the safe and effective dose for a patient with a relevant diagnosis. It is generally understood that the effective amount of the compound may vary according to the weight, sex, age, and medical history of the subject. Other factors which influence the effective amount may include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent being administered with the compound of the invention. A larger total dose can be delivered by multiple administrations of the pharmaceutical composition at a dose and dose interval determined to be safe and effective for the patient.[000172] The present disclosure includes the use of pharmaceutically acceptable salts of compounds of the invention in the compositions and methods of the present invention.Pharmaceutical ly-acceptable salts include, for example, acid-addition salts and baseaddition salts. The acid that is added to a compound to form an acid-addition salt can be an organic acid or an inorganic acid. A base that is added to a compound to form a baseaddition salt can be an organic base or an inorganic base. In some embodiments, a pharmaceutically-acceptable salt is a metal salt, in some embodiments, a pharmaceutically - acceptable salt is an ammonium salt. For example, a pharmaceutically acceptable acid addition salt can exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates can also be prepared. The source of such solvate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent.[000173] A method of preparing a pharmaceutical composition can comprise: providing a first mixture comprising a pharmaceutically effective amount of a COMT inhibitor, or a pharmaceutically acceptable salt thereof, and starch or a starch derivative; granulating the first mixture using an aqueous solution of a wetting agent; isolating and drying the resulting granules; and a) encapsulating the dried granules to form a capsule; or b) mixing the dried granules with a lubricant, glidant or mixture thereof, compressing into a tablet and optionally coating the tablet. [000174] In some embodiments, a wet granulation method is employed that comprises the steps of mixing the active ingredient and excipients, and suspending in a liquid such as water containing a dissolved binder (e.g. lactose or microcrystalline cellulose). The wet mass is then sieved and the resulting granules are dried. The granules are mixed with a lubricant, e.g. magnesium stearate, and compressed into tablets or incorporated into capsules.[000175] In some embodiments, a pharmaceutical composition comprises a COMT Inhibitor Compound in a microparticulate formulation. As used herein, a “microparticulate formulation” means a pharmaceutical composition comprising opicapone, in a microparticulate form, such as can be formed by ball milling or by micronization through spiral jet mills. In some embodiments, a “microparticulate formulation” means a pharmaceutical composition comprising opicapone, wherein the opicapone is in a microparticulate form, such as can be formed by ball milling opicapone or by micronization of opicapone through spiral jet mills. Suitable micronization may be carried out with MC JETMILL type 200 milling equipment. In some embodiments, the D10 (EDC (equivalent circle diameter)) of the opicapone microparticles is not less than 3, 4, 5 or 6 pm (for example not less than 4 pm), the D50 (EDC) of the opicapone microparticles is 5-50, 10-45, 15-30 or 20-25 pm (for example 10-45 pm) and the D95 (EDC) of the opicapone microparticles is not more than 60, 70, 80 or 90 pm (for example not more than 90 pm). In some embodiments, the D10 (EDC) of the opicapone microparticles is not less than 4 or 5 pm (for example not less than 5 pm), the D50 (EDC) of the opicapone microparticles is 10-45 or 15-30 pm (for example 15-30 pm) and the D95 (EDC) of the opicapone microparticles is not more than 60 or 70 pm (for example not more than 60 pm). In some embodiments, the microparticles of opicapone comply with the following particle size specification (particle size determined by optical microscopy): D10 (EDC) is not less than 4 or 5 pm (for example not less than 5 pm), the D50 (EDC) is 10-45 or 15-30 pm (for example 15-30 pm) and the D95 (EDC) is not more than 60 or 70 pm (for example not more than 60 pm). In some embodiments, the microparticulate formulation also comprises the following excipients: lactose monohydrate; sodium starch glycolate, such as Type A; maize starch, such as pregelatinized; and magnesium stearate.[000176] In some embodiments, the pharmaceutical composition comprises a COMT Inhibitor Compound and a pharmaceutically acceptable excipient carrier. The carrier typically may be of polysaccharide type, and, for example, be selected from cellulose, methyl cellulose (MC), ethyl cellulose, carboxy methyl cellulose (CMC) and salts thereof, xanthan gum, carrageenan, and combinations thereof the carrier may also be a synthetic polymer, such as polyvinylpyrrolidone (PVP; Povidon) or polyacrylic acid (PAA; Carbomer). An exemplary carrier is the sodium salt of carboxymethyl cellulose (NaCMC).[000177] Suitable exemplary pharmaceutical COMT Inhibitor pharmaceutical compositions are prepared according to the following specifications:Methods of use[000178] In some embodiments, methods of treating or preventing a neurological or psychiatric disorders, or treating symptoms associated with a neurological or psychiatric disorder, are provided including treatment of disorders for which inhibiting COMT provides a therapeutic effect. Without being bound by theory, the mechanism of action of compounds disclosed herein can provide therapeutic effect by inhibiting the metabolism of catecholamines by COMT. Accordingly, in some embodiments, the disclosure provides methods of treating and / or preventing disease for which inhibiting degradation of catecholamines such as, for example, dopamine, norepinephrine or L-dihydroxyphenylalanine (I, -DOPA) provides a beneficial therapeutic effect.[000179] In some embodiments, a method of inhibiting COMT enzy me using compounds disclosed herein. These methods can comprise administering to a subject in need thereof an effective amount of a COMT -inhibiting compound in accordance with formula (I) or other compound disclosed herein, or a pharmaceutically acceptable salt thereof.[000180] The compounds described herein can modulate activity of COMT. For example, the compounds described herein can inhibit COMT. Accordingly, in one aspect the disclosure provides a method for inhibiting COMT. Generally, the method comprises administering to the cell a compound of Formula (I), Formula (I-A), Formula (I-A-l), Formula (I-A-2), Formula (I- B), Formula (I-B-l), Formula (II), Formula (HI), Formula (IV) or Formula (IV-A), or Formula (V), (V-A-l), (V-A-2), (V-B), (V-B-l), (V-C), (V-D), (V-E) or Formula (VI), as described herein. It is noted that the inhibition can be reversible or irreversible In some embodiments, the compounds are capable of inhibiting COMT.[000181] The compound can be administered to the cell in vitro or ex vivo. As used herein, administering the compound to the cell means contacting the cell with the compound so that the compound is taken up by the cell. Generally, the cell can be contacted with die compound in a cell culture e.g., in vitro or ex vivo, or die compound can be administrated to a subject, e.g., in vivo. Theterm “contacting” or “contact” as used herein in connection with contacting a cell includes subjecting die cells to an appropriate culture media, which comprises a compound of Formula (I), Formula (I- A), Formula (I-A-l), Formula (I-A-2), Formula (I-B), Formula (I-B-l), Formula (II), Formula (III), Formula (IV), Formula (IV- A), Formula (V), Formula (V-A-1), Formula (V-A-2), Formula (V-B), Formula (V-B-l), Formula (V-C), Formula (V-D), Formula (V-E), or Formula (VI).. Where the cell is in vivo, “contacting” or “contact” includes administering die compound, e.g., in a pharmaceutical composition to a subject via an appropriate administration route such that the compound contacts the cell in vivo.[000182] The COMT Inhibitor Compound can be contacted with a cell in vitro or ex vivo. As used herein, administering the COMT Inhibitor Compound to the cell includes contacting a cell with the COMT Inhibitor Compound so that the compound inhibits COMT within the cell. Generally, the cell can be contacted with the compound in a cell culture e.g., in vitro or ex vivo, or the compound can be administrated to a subject, e.g., in vivo. The term “contacting” or “contact” as used herein in connection with contacting a cell includes subjecting the cells to an appropriate culture media, which comprises a compound of Formula (I), Formula (I- A). Formula (I-A-l), Formula (I- A-2), Formula (1-B), Formula (I-B-l), Formula (II), Formula (III), Formula (IV), Formula (IV- A), Formula (V), Formula (V-A-1), Formula (V-A-2), Formula (V-B), Formula (V-B-l), Formula (V-C), Formula (V-D), Formula (V-E), or Formula (VI). Where the cell is in vivo, “contacting” or “contact” includes administering the compound, e.g., in a pharmaceutical composition to a subject via an appropriate administration route such that the compound contacts the cell in vivo.[000183] As described herein, the compound of Formula (I) can be administered to a cell in vivo for modulating COMT, e.g., inhibiting COMT. Accordingly, in some embodiments, a therapeutically effective amount of a compound of Formula (I), Formula (I-A), Formula (I-A-l), Formula (I-A-2), Formula (I-B), Formula (I-B-l), Formula (II), Formula (III), Formula (IV), Formula (IV-A), Formula (V), Formula (V-A-1), Formula (V-A-2), Formula (V-B), Formula (V- B-l), Formula (V-C), Formula (V-D), Formula (V-E), or Formula (Vl)can be administered to a subject for inhibiting COMT. For example, a therapeutically effective amount of a compound of Formula (I), Formula (I-A), Formula (I-A-l), Formula (I-A-2), Formula (I-B), Formula (I-B-l), Formula (II), Formula (III), Formula (IV), Formula (IV-A), Formula (V), Formula (V-A-1), Formula (V-A-2), Formula (V-B), Formula (V-B-l), Formula (V-C), Formula (V-D), Formula (V-E), or Formula (VI)can be administrated to a subject for treating a COMT mediated disease ordisorder. In some embodiments, the compound used to inhibit COMT is l-[(l,3-dimethyl-2-oxo-2.3-dihydro- 1H- 1 ,3 -benzodiazol-5-yl)methyl]-2-(4-hydroxy-3-methoxyphenyl)-N-methyl- 1H-1.3-benzodiazole-5-carboxamide. In some embodiments, the compound used to inhibit COMT is not l-[(l,3-dimethyl-2-oxo-2,3-dihydro-lH-l,3-benzodiazol-5-yl)methyl]-2-(4-hydroxy-3- methoxyphenyl)-N-methyl-lH-l,3-benzodiazole-5-carboxamide.The compounds described herein can be used for the treatment of a COMT-mediated disease or disorder, including the development of drug candidate compounds for these conditions, where a COMT-mediated disease or disorder is a disease or disorder wherein activity of COMT is related to treatment of the disease or disorder. Non-limiting examples of COMT mediated diseases or disorders include conditions of the central nervous system such as Parkinson’s disease (PD) in combination with L-DOPA, or diseases characterized by anxiety or depression such as major depressive disorder (MDD) neurodegenerative diseases, neuropsychiatric disorders, and other conditions that can be treated with a compound of Formula (I), Formula (I-A), Formula (I-A-l), Formula (I-A-2), Formula (I-B), Formula (I-B-l), Formula (II), Formula (III), Formula (IV), Formula (IV-A), Formula (V), Formula (V-A-l), Formula (V-A-2), Formula (V-B), Formula (V- B-l), Formula (V-C), Formula (V-D), Formula (V-E), Formula (VI).[000184] As described herein, the compound of Formula (I) can be administered to a cell in vivo for modulating COMT, e.g., inhibiting COMT. Accordingly, in some embodiments, a therapeutically effective amount of a compound of Formula (I), Formula (I-A), Formula (I-A-l), Formula (I-A-2), Formula (I-B), Formula (I-B-l), Formula (II), Formula (III), Formula (IV), Formula (IV-A), Formula (V), Formula (V-A-l), Formula (V-A-2), Formula (V-B), Formula (V- B-l), Formula (V-C), Formula (V-D), Formula (V-E), or Formula (Vl)can be administered to a subject for inhibiting COMT. For example, a therapeutically effective amount of a compound of Formula (I), Formula (I-A), Formula (I-A-l), Formula (I-A-2), Formula (I-B), Formula (I-B-l), Formula (II), Formula (III), Formula (IV), Formula (IV-A), Formula (V), Formula (V-A-l), Formula (V-A-2), Formula (V-B), Formula (V-B-l), Formula (V-C), Formula (V-D), Formula (V-E), or Formula (VI)can be administrated to a subject for treating a monoglycerol lipase mediated disease or disorder.[000185] By a COMT-mediated disease or disorder is meant a disease or disorder wherein activity of COMT is a cause of the disease or disorder. Non-limiting example, of COMT mediated diseases or disorders include neurodegenerative diseases, neuropsychiatric disorders,pain and chronic inflammatory diseases, cancer and other conditions that can be treated with a COMT inhibitor of Formula (I), Formula (I-A), Formula (I-A-l), Formula (I-A-2), Formula (I- B), Formula (I-B-l), Formula (II), Formula (III), Formula (IV), Formula (IV-A), Formula (V), Formula (V-A-l), Formula (V-A-2), Formula (V-B), Formula (V-B-l), Formula (V-C), Formula (V-D), Formula (V-E), or Formula (VI).[000186] In some embodiments, a compound of Formula (I), Formula (I-A), Formula (I-A-l), Formula (I-A-2), Formula (I-B), Formula (I-B-l), Formula (II), Formula (HI), Formula (IV), Formula (IV-A), Formula (V), Formula (V-A-l), Formula (V-A-2), Formula (V-B), Formula (V- B-l), Formula (V-C), Formula (V-D), Formula (V-E), or Formula (VI)is useful for evaluation as a drag candidate for the treatment of neurodegenerative diseases such as Parkinson’s disease. In some embodiments, a compound of Formula (I), Formula (I-A), Formula (I-A-l), Formula (I-A- 2), Formula (I-B), Formula (I-B-l), Formula (II), Formula (III), Formula (IV), Formula (IV-A), Formula (V), Formula (V-A-l), Formula (V-A-2), Formula (V-B), Formula (V-B-l), Formula (V-C), Formula (V-D), Formula (V-E), or Formula (VI)is useful for evaluation as a drug candidate for the treatment of Parkinson’s Disease (PD), in combination with administration of L-DOPA.[000187] A subject can be one who has been previously diagnosed with or identified as suffering from or having a condition in need of treatment a COMT-mediated disease or disorder or one or more complications related to such a condition, and optionally, have already undergone treatment for such a disease or disorder. Alternatively, a subject can also be one who has not been previously diagnosed as having a COMT-mediated disease or disorder or one or more complications related to such a disease or disorder. A “subject in need” of treatment for a particular condition can be a subject having that condition, diagnosed as having that condition, or at risk of developing that condition.[000188] In one embodiment, the subject is human. In another embodiment, the subject is an experimental animal or animal substitute as a disease model.[000189] It is noted that the terms “administered” and “subjected” are used interchangeably in the context of treatment of a disease or disorder. In jurisdictions that forbid the patenting of methods that are practiced on the human body, the meaning of “administering” of a composition to a human subject shall be restricted to prescribing a controlled substance that a human subject will be administer to the subject by any technique (e g., orally, inhalation, topical application,injection, insertion, etc ). The broadest reasonable interpretation that is consistent with laws or regulations defining patentable subject matter is intended. In jurisdictions that do not forbid the patenting of methods that are practiced on the human body, the “administering” of compositions includes both methods practiced on the human body and also the foregoing activities.[000190] As used herein, the term “administer” refers to the placement of a composition into a subject by a method or route which results in at least partial localization of the composition at a desired site such that desired effect is produced. A compound or composition described herein can be administered by any appropriate route known in the art including, but not limited to, oral or parenteral routes, including intravenous, intramuscular, subcutaneous, transdermal, airway (aerosol), pulmonary, nasal, rectal, and topical (including buccal and sublingual) administration. [000191] Exemplary modes of administration include, but are not limited to, injection, infusion, instillation, inhalation, or ingestion. “Injection” includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intraventricular, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, sub capsular, subarachnoid, intraspinal, intracerebro spinal, and intrastemal injection and infusion. In some embodiments, administration will generally be local rather than systemic.[000192] In preferred embodiments, the compositions are orally administered. Without limitations, oral administration can be in the form of solutions, suspensions, tablets, pills, capsules, sustained-release formulations, oral rinses, powders and the like.[000193] The phrase “therapeutically-effective amount” as used herein means that amount of a compound, material, or composition comprising a compound described herein which is effective for producing some desired therapeutic effect in at least a sub-population of cells, e.g., modulate or inhibit activity of COMT in a subject at a reasonable benefit / risk ratio applicable to any medical treatment. Thus, “therapeutically effective amount” means that amount which, when administered to a subject for treating a disease, is sufficient to affect such treatment for the disease.[000194] Depending on the route of administration, effective doses can be calculated according to the body weight, body surface area, or organ size of the subject to be treated. Optimization of the appropriate dosages can readily be made by one skilled in the art in light of pharmacokinetic data observed in human clinical trials. Alteratively, or additionally, the dosage to be administered can be determined from studies using animal models for the particular type ofcondition to be treated, and / or from animal or human data obtained from agents which are known to exhibit similar pharmacological activities. The final dosage regimen will be determined by the attending surgeon or physician, considering various factors which modify the action of active agent, e.g., the agent’s specific activity, the agent’s specific half-life in vivo, the severity of the condition and the responsiveness of the patient, the age, condition, body weight, sex and diet of the patient, the severity of any present infection, time of administration, the use (or not) of other concomitant therapies, and other clinical factors.[000195] The data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds lies preferably within a range of circulating concentrations that include the IC50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of use or administration utilized. The effective dose can be estimated initially from cell culture assays. A dose can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC«o (i.e., the concentration of the therapeutic which achieves a half-maximal inhibition of symptoms) as determined in cell culture. Levels in plasma can be measured, for example, by high performance liquid chromatography. The effects of any particular dosage can be monitored by a suitable bioassay.[000196] It will be appreciated that methods of treatment of the present invention can be employed in combination with additional therapies. For example, a treatment according to the present disclosure can be co-administered with one or more desired therapeutics or medical procedures for treating a COMT-mediated disease or disorder.Administration of COMT Inhibitor to a Patient Receiving L-DOPA[000197] In some embodiments, a method of treatment comprises administering a compound of Formula (I), Formula (I-A), Formula (I-A-l), Formula (I-A-2), Formula (I-B), Formula (I-B-l), Formula (II), Formula (III), Formula (IV), Formula (IV-A), Formula (V), Formula (V-A-l), Formula (V-A-2), Formula (V-B), Formula (V-B-l), Formula (V-C), Formula (V-D), Formula (V-E), or Formula (VI) to a patient in need thereof as an adjunct to levodopa and carbidopa for the treatment of the signs and symptoms of idiopathic Parkinson’s disease.[000198] In some embodiments, a method of treatment comprises administering a compound of Formula (I), Formula (I-A), Formula (I-A-l), Formula (I-A-2), Formula (I-B), Formula (I_B-1),Formula (II), Formula (III), Formula (IV), Formula (IV-A), Formula (V), Formula (V-A-l), Formula (V-A-2), Formula (V-B), Formula (V-B-l), Formula (V-C), Formula (V-D), Formula (V-E), or Formula (VI)to a patient in need thereof receiving concomitant levodopa therapy with carbidopa or another aromatic amino acid decarboxylase inhibitor who experienced end of dose wearing-off phenomena as well as in patients who did not experience such phenomena. In some embodiments, a method of treatment comprises administering a compound of Formula (I), Formula (I-A), Formula (I-A-l), Formula (I-A-2), Formula (I-B), Formula (I-B-1), Formula (II), Formula (III), Formula (IV), Formula (IV-A), Formula (V), Formula (V-A-l), Formula (V-A-2), Formula (V-B), Formula (V-B-l), Formula (V-C), Formula (V-D), Formula (V-E), or Formula (VI)to a patient in need thereof receiving concomitant levodopa therapy with benserazide. [000199] In some embodiments, a method of treatment comprises administering a compound of Formula (I), Formula (I-A), Formula (I-A-l), Formula (I-A-2), Formula (I-B), Formula (I-B-1), Formula (II), Formula (III), Formula (IV), Formula (IV-A), Formula (V), Formula (V-A-l), Formula (V-A-2), Formula (V-B), Formula (V-B-l), Formula (V-C), Formula (V-D), Formula (V-E), or Formula (VI)to a patient taking concomitant carbidopa levodopa therapy. In some embodiments, a method of treatment comprises administering a compound of Formula (I), Formula (l-A), Formula (I-A-l), Formula (I-A-2), Formula (I-B), Formula (l-B-1), Formula (II), Formula (HI), Formula (IV), Formula (IV-A), Formula (V), Formula (V-A-l), Formula (V-A-2), Formula (V-B), Formula (V-B-l), Formula (V-C), Formula (V-D), Formula (V-E), or Formula (VI) to a patient taking concomitant carbidopa levodopa therapy for a total of 3 weeks of treatment. In some embodiments, a compound of Formula (I), Formula (I-A), Formula (I-A-l), Formula (I-A-2), Formula (I-B), Formula (I-B-1), Formula (H), Formula (III), Formula (IV), Formula (IV-A), Formula (V), Formula (V-A-l), Formula (V-A-2), Formula (V-B), Formula (V- B-l), Formula (V-C), Formula (V-D), Formula (V-E), or Formula (VI)is administered together with the first dose of the day of levodopa / carbidopa administered to a patient diagnosed with Parkinson’s disease.[000200] In some embodiments, a COMT Inhibitor Compound of Formula (I), Formula (I-A), Formula (I-A-l), Formula (I-A-2), Formula (I-B), Formula (I-B-1), Formula (II), Formula (III), Formula (TV), Formula (IV-A), Formula (V), Formula (V-A-l), Formula (V-A-2), Formula (V- B), Formula (V-B-l), Formula (V-C), Formula (V-D), Formula (V-E), or Formula (VI)is administered to a patient with a reduction in the daily dose of over 600 mg of levodopa, or ifpatients have moderate or severe dyskinesias before beginning treatment with the COMT Inhibitor Compound. In some embodiments, the daily levodopa dose of a patient can be reduced by about 30% in a patient with or after the administration of a compound of Formula (I), Formula (I-A), Formula (I-A-l), Formula (I-A-2), Formula (I-B), Formula (I-B-l), Formula (II), Formula (HI), Formula (IV), Formula (IV-A), Formula (V), Formula (V-A-l), Formula (V-A-2), Formula (V-B), Formula (V-B-l), Formula (V-C), Formula (V-D), Formula (V-E), or Formula (VI).[000201] In some embodiments, a compound of Formula (I), Formula (I-A), Formula (I-A-l), Formula (I-A-2), Formula (I-B), Formula (I-B-l), Formula (II), Formula (III), Formula (IV), Formula (IV-A), Formula (V), Formula (V-A-l), Formula (V-A-2), Formula (V-B), Formula (V- B-l), Formula (V-C), Formula (V-D), Formula (V-E), or Formula (VI), is useful for evaluation as a drug candidate for the treatment of neurodegenerative diseases such as Parkinson’s disease in combination with L-DOPA. In some embodiments, a compound of Formula (I), Formula (I- A), Formula (I-A-l), Formula (I-A-2), Formula (I-B), Formula (I-B-l), Formula (II), Formula (III), Formula (IV), Formula (IV-A), Formula (V), Formula (V-A-l), Formula (V-A-2), Formula (V-B), Formula (V-B-l), Formula (V-C), Formula (V-D), Formula (V-E), Formula (VI), is useful for evaluation as a drug candidate for the treatment of Parkinson’s Disease (PD), in combination with administration of L-DOPA.[000202] Ln some embodiments, a compound of Formula (I), Formula (I-A), Formula (I-A-l), Formula (I-A-2), Formula (I-B), Formula (I-B-l), Formula (II), Formula (III), Formula (IV), Formula (IV-A), Formula (V), Formula (V-A-l), Formula (V-A-2), Formula (V-B), Formula (V- B-l), Formula (V-C), Formula (V-D), Formula (V-E), or Formula (VI)is used in the treatment of Parkinson’s disease as an adjunct to levodopa / carbidopa therapy.[000203] In mammals, COMT is distributed throughout various organs. The highest activities are in the liver and kidney. COMT also occurs in the heart, lung, smooth and skeletal muscles, intestinal tract, reproductive organs, various glands, adipose tissue, skin, blood cells and neuronal tissues, especially in glial cells. COMT catalyzes the transfer of the methyl group of S- adenosyl-L-methionine to the phenolic group of substrates that contain a catechol structure. Physiological substrates of COMT include dopa, catecholamines (dopamine, norepinephrine, epinephrine) and their hydroxylated metabolites. The function of COMT is the elimination of biologically active catechols and some other hydroxylated metabolites. In the presence of adecarboxylase inhibitor, COMT becomes the major metabolizing enzyme for levodopa catalyzing the metabolism to 3-methoxy-4 hydroxy-L-phenylalanine (3-OMD) in the brain and periphery.[000204] In some embodiments, a compound of Formula (I), Formula (I- A), Formula (I-A-l), Formula (I-A-2), Formula (I-B), Formula (I-B-l), Formula (II), Formula (HI), Formula (IV), Formula (IV-A), Formula (V), Formula (V-A-l), Formula (V-A-2), Formula (V-B), Formula (V- B-l), Formula (V-C), Formula (V-D), Formula (V-E), or Formula (VI)is administered together with levodopa / carbidopa, to increase the relative bioavailability (AUC) of levodopa (e.g., by decreasing levodopa clearance resulting in a prolongation of the terminal elimination half-life of levodopa). In some embodiments, administration of a COMT Inhibitor Compound of Formula(I), Formula (I-A), Formula (I-A-l), Formula (I-A-2), Formula (I-B), Formula (I-B-l), Formula(II), Formula (III), Formula QV), Formula (IV-A), Formula (V), Formula (V-A-l), Formula (V- A-2), Formula (V-B), Formula (V-B-l), Formula (V-C), Formula (V-D), Formula (V-E), or Formula (VI)can decrease plasma levels of 3-OMD when the COMT Inhibitor compound is given with levodopa / carbidopa.[000205] In some embodiments, methods of treatment comprise the administration of a COMT Inhibitor Compound disclosed herein as an adjunct to levodopa in the treatment of Parkinson’s disease. In some embodiments, methods of treatment comprise the administration of a COMT Inhibitor Compound to patients whose Parkinson’s disease was characterized by deterioration in their response to levodopa at the end of a dosing interval (“Fluctuating Patients” with wearing- off phenomena). In some embodiments, methods of treatment comprise the administration of a COMT Inhibitor Compound to patients whose response to levodopa was relatively stable (so- called non fluctuators). In some embodiments, a compound of Formula (I), Formula (I-A), Formula (I-A-l), Formula (I-A-2), Formula (I-B), Formula (I-B-l), Formula (II), Formula (III), Formula (IV), Formula (IV-A), Formula (V), Formula (V-A-l), Formula (V-A-2), Formula (V- B), Formula (V-B-l), Formula (V-C), Formula (V-D), Formula (V-E), or Formula (VI)is administered to a Fluctuating Patient with documented episodes of wearing-off phenomena, despite optimum levodopa therapy.[000206] In some methods of treatment, a compound of Formula (I), Formula (I-A), Formula (I-A-l), Formula (I-A-2), Formula (I-B), Formula (I-B-l), Formula (II), Formula (III), Formula (IV), Formula (IV-A), Formula (V), Formula (V-A-l), Formula (V-A-2), Formula (V-B),Formula (V-B-l), Formula (V-C), Formula (V-D), Formula (V-E), or Formula (VI)is administered to a patient receiving L-DOPA for the treatment of Paridnson’s Disease. In some embodiments, a method of treatment comprises a comparison between treatments in the change from baseline in the amount of time spent “On” (a period of relatively good functioning) and “Off” (a period of relatively poor functioning). Patients recorded periodically, throughout the duration of the treatment period, the time spent in each of these states.[000207] In some methods of treatment, patients can also be assessed using sub-parts of the Unified Parkinson’s Disease Rating Scale (UPDRS), a frequently used multi-item rating scale intended to evaluate mentation (Part I), activities of daily living (Part II), motor function (Part III), complications of therapy (Part IV), and disease staging (Parts V and VI); an Investigator’s Global Assessment of Change (IGA), a subjective scale designed to assess global functioning in 5 areas of Parkinson’s disease; the Sickness Impact Profile (SIP), a multi-item scale in 12 domains designed to assess the patient’s functioning in multiple areas; and the change in daily levodopa / carbidopa dose.Administration of COMT Inhibitor to Treat MDD[000208] In some embodiments, a method of treating MDD comprises administering a therapeutically effective amount of a compound of Formula (I), Formula (I-A), Formula (I-A-l), Formula (I-A-2), Formula (I-B), Formula (I-B-l), Formula (II), Formula (III), Formula (IV), Formula (IV-A), Formula (V), Formula (V-A-l), Formula (V-A-2), Formula (V-B), Formula (V- B-l), Formula (V-C), Formula (V-D), Formula (V-E), or Formula (VI)to a patient in need thereof. Major depressive disorder (MDD) is a serious, debilitating, and often recurring disorder with a substantial lifetime risk and a high societal cost. Depressed patients frequently display a variety of co-morbid symptoms, including depressed moods, loss of motivation and / or reductions in the ability to experience pleasure (anhedonia), loss of interest and energy, combined with psychological and vegetative changes such as sleep and / or appetite disturbances, fatigue, feelings of guilt and despair, difficulties in maintaining mental focus, and recurrent thoughts of suicide. MDD often occurs together with other common illnesses, including both physical and psychiatric disorders. Currently available antidepressant drugs display limited efficacy, slow onset of action, and are hampered by unwanted side effects. Traditional antidepressant drugs act through serotonergic and noradrenergic systems. Although newer drugs acting through glutamatergicsystems show some promise, there remains considerable unmet need for improved medications. Central dopaminergic systems have been identified as an alternative target, particularly through the involvement of dopamine in reward, anhedonia, and related functions.[000209] Elevated COMT activity has been reported in patients with MDD. A functional polymorphism in COMT gene (Val508 / 158Met) produces a high activity enzyme (Vai), which has been linked to lower cognitive function. The Vai 108 / 158Met polymorphism has also been associated with depression, with the low activity Met allele increased in depressive patients. However, these findings have been contested by others. It is now well-established that the Val / Val genotype is associated with early onset of MDD, and conferred a significant risk of poorer response to treatment with antidepressants in MDD. In contrast, the Met allele has [000210] been associated with a faster therapeutic effect of milnacipran (serotonin / noradrenaline uptake inhibitor).40 For non-motor, cognitive enhancing effects, there is evidence suggesting that a brain-penetrant COMT inhibitor might be beneficial. Tolcapone — the only brain-penetrant nitrocatechol — has been found to improve the attend onal task, auditory verbal short-term memory, visuo-spatial recall, constructional praxia and motor symptoms in PD patients. Tolcapone was also evaluated in patients with MDD, as diagnosed using the Structured Clinical Interview for DSM-IV and a 316 score in the Hamilton Rating Scale for Depression (HAM-D-17). After 8 weeks of treatment, there was significant decrease at endpoint in HAM-D- 17 scores. While this preliminary study suggests that tolcapone may be a promising agent for the treatment of MDD, current COMT inhibitors, all of which contain a disadvantageous nitrocatechol group, have poor brain penetration and may induce toxicity, which can severely limit their use. Therefore, potent, brain-penetrant, and safer compounds are needed to fully exploit the benefits of COMT inhibitors as alternative therapies, particularly lacking the problematic nitrocatechol scaffold. Given that tolcapone is equally active at S- and MB-COMT, and that MB-COMT selective inhibitors do not potentiate DA to the same extent, preferred compounds of Formula (I), Formula (I-A), Formula (I-A-l), Formula (I-A-2), Formula (I-B), Formula (I-B-l), Formula (II), Formula (III), Formula (IV), Formula (IV-A), Formula (V), Formula (V- A- 1), Formula (V-A-2), Formula (V-B), Formula (V-B-l ), Formula (V-C), Formula (V-D), Formula (V-E), or Formula (Vl)are those with equivalent activity at both subtypes. [000211] The methods of treatment provided herein may be used to treat or prevent a neurological or psychiatric disorder. In particular, exemplary embodiments of the inventioninclude methods of treating or preventing schizophrenia, major depression, a depressive phase of bipolar disorder, attention deficit disorder, attention deficit / hyperactivity disorder, sub stance dependency, or increased appetite associated with smoking cessation or antipsychotic use Other significant indications include age-associated cognitive symptoms, impulse control disorders, including compulsive gambling, sexual behavior, and other compulsive destructive behaviors. [000212] In addition to the psychiatric indications, the methods of the invention may also be used to treat neurological disorders. In one embodiment, the method of the present invention comprises administering an effective amount of a compound described herein above in combination with L-DOPA for treatment of Parkinson's disease. The compound can be administered in combination with L-DOPA, concurrently or separately, with or without an aromatic L-amino acid decarboxylase inhibitor (AADC) such as carbidopa, to prevent or inhibit COMT-mediated metabolism of L-DOPA.Therapeutic Administration of COMT Inhibitor for Other Conditions[000213] In some embodiments, a method of treatment comprises administering a compound of Formula (I), Formula (I-A), Formula (I-A-l), Formula (I-A-2), Formula (I-B), Formula (I-B-l), Formula (II), Formula (III), Formula (IV), Formula (IV-A), Formula (V), Formula (V-A-l), Formula (V-A-2), Formula (V-B), Formula (V-B-l), Formula (V-C), Formula (V-D), Formula (V-E), or Formula (VI) to a patient in need thereof for the treatment of psychological disorders such as depression. In some embodiments, a method of treatment comprises administering a compound of Formula (I), Formula (I-A), Formula (I-A-l), Formula (I-A-2), Formula (I-B), Formula (I-B-l), Formula (II), Formula (HI), Formula (IV), Formula (IV-A), Formula (V), Formula (V-A-l), Formula (V-A-2), Formula (V-B), Formula (V-B-l), Formula (V-C), Formula (V-D), Formula (V-E), or Formula (VI)to a patient in need thereof who is not receiving L- DOPA. In some embodiments, a method of treatment comprises administering a compound of Formula (I), Formula (I-A), Formula (I-A-l), Formula (I-A-2), Formula (I-B), Formula (I-B-l), Formula (II), Formula (HI), Formula (IV), Formula (IV-A), Formula (V), Formula (V-A-l). Formula (V-A-2), Formula (V-B), Formula (V-B-l), Formula (V-C), Formula (V-D), Formula (V-E), or Formula (VI)to a patient in need thereof as a monotherapy for the treatment of psychological disorders such as depression.[000214] In some embodiments, a method of treatment comprises administering a compound of Formula (I), Formula (I-A), Formula (I-A-l), Formula (I-A-2), Formula (I-B), Formula (I-B-l), Formula (II), Formula (III), Formula (IV), Formula (IV-A), Formula (V), Formula (V-A-l), Formula (V-A-2), Formula (V-B), Formula (V-B-l), Formula (V-C), Formula (V-D), Formula (V-E), or Formula (VI)to a patient in need thereof for the treatment of Major Depressive Disorder (MDD). In some embodiments, a method of treatment comprises administering a compound of Formula (I), Formula (I-A), Formula (I-A-l), Formula (I-A-2), Formula (I-B), Formula (I-B-l), Formula (II), Formula (HI), Formula (IV), Formula (IV-A), Formula (V), Formula (V-A-l), Formula (V-A-2), Formula (V-B), Formula (V-B-l), Formula (V-C), Formula (V-D), Formula (V-E), or Formula (VI) to a patient in need thereof, where the patient has been diagnosed with MDD using the Structured Clinical Interview for DSM-IV, [9] and with an initial 17-item Hamilton Rating Scale for Depression (HAM-D-17) score of >or=tol6. In some embodiments, a method of treatment comprises administering a compound of Formula (I), Formula (I-A), Formula (I-A-l), Formula (I-A-2), Formula (I-B), Formula (I-B-l), Formula (II), Formula (DI), Formula (IV), Formula (IV-A), Formula (V), Formula (V-A-l), Formula (V-A-2), Formula (V-B), Formula (V-B-l), Formula (V-C), Formula (V-D), Formula (V-E), or Formula (VI)to a patient having HAM-D-17 scores >or=tol6 at screen and baseline visits, and the HAM- D-17 score could not decrease by 20% or more between the screen and base-line visits.[000215] Ln some embodiments, a method of treatment comprises administering a compound of Formula (I), Formula (I-A), Formula (I-A-l), Formula (I-A-2), Formula (I-B), Formula (I-B- 1), Formula (II), Formula (III), Formula (IV), Formula (IV-A), Formula (V), Formula (V-A-l), Formula (V-A-2), Formula (V-B), Formula (V-B-l), Formula (V-C), Formula (V-D), Formula (V-E), or Formula (VI)to a patient in need thereof for the treatment of Major Depressive Disorder (MDD), wherein the patient is not characterized by any of the following Exclusion Criteria: pregnant women or women of child-bearing potential who were not using a medically accepted means of contraception; patients who, in the investigator's judgment, posed a current and serious suicidal or homicidal risk; those with a serious or unstable medical illness including cardiovascular, hepatic, renal, respiratory, endocrine, neurologic, or hematologic disease; those with a history of seizure disorder; those with multiple adverse drug reactions or allergy to the study drug, mood congruent or incongruent psychotic features, current use of other psychotropic drugs, clinical or laboratory evidence of hypothyroidism, failure to respond during the course oftheir current major depressive episode to at least one adequate antidepressant trial (defined as 6 weeks or more of treatment with either >or=tol50 mg of imipramine [or its tricyclic equivalent], >or=to60 mg of phenelzine [or its monoamine oxidase inhibitor equivalent], or >or=to20 mg of fluoxetine [or its selective serotonin reuptake inhibitor equivalent]), electroconvulsive therapy within the 6 months preceding baseline, or exposure to either an investigational psychotropic drug or fluoxetine within 40 days of the base-line visit or to any other psychotropic drug within 21 days of baseline; and the following DSM-TV diagnoses: organic mental disorders; substance use disorders, including alcohol, active within the last year; schizophrenia; delusional disorder; psychotic disorders not elsewhere classified; bipolar disorder; and significant antisocial personality disorder.[000216] In some embodiments, a method of treatment further comprises administering the following instruments at every visit of a clinical study (screen, baseline, and visits 1-6): the 28- item Hamilton Rating Scale for Depression (HAM-D), which allows scoring of the 17-, 21-, 25-, and 28-item scales and is completed by the clinician on the basis of his or her assessment of the patient's depressive symptoms; the Clinical Global Impressions Severity (CGI-S) and Improvement (CGI-I) scales, which is completed by the study clinician on the basis of his or her assessment of severity of the patient's disorder and improvement in the patient's symptoms of depression compared with baseline; and the Beck Depression Inventory (BDI), which is completed by the patient on the basis of his or her assessment of the severity of depression. The clinicians involved in the study can be appropriately trained in the use of the Structured Clinical Interview for DSM-IV Axis I Disorders-Patient Edition with videotaped and live interviews of patients, as well as in the use of a structured version of the HAM-D-28 with videotaped and live interviews of patients.[000217] In some embodiments, a method of treatment further comprises obtaining a signed informed consent document from each patient prior to treatment, performing the following laboratory tests at the screen visit and at week 8: complete blood cell count with differential and urinalysis, clinical chemistry (Chem-20), electrocardiogram, and SAMe and homocysteine blood levels. In addition, the Chem-20 tests are performed at week 4. The routine laboratory tests are performed by the clinical laboratories. Whole blood SAMe levels (in nanograms per milliliter) can be measured by high-performance liquid chromatography and ultraviolet detection at 254 nm[000218] In some embodiments, medication management sessions can be conducted according to the method described by Fawcett and colleagues [Fawcett J, Epstein P, Fiester SI, Elkin I, Autry JH. Clinical Management-Imipramine / Placebo Administration Manual: NIMH Treatment of Depression Collaborative Research Program. Psychopharmacol Bull 1987;23:309-24], In addition, the presence of any side effect or adverse event is carefully documented. Documentation of the presence of any side effect or adverse event is completed at every visit. Adverse events are classified as mild, moderate, or severe: "mild" indicated a noted change in patient condition that does not affect activity; "moderate" indicated a mild disruption in usual activity; and "severe" indicated a major disruption in usual activity. Vital signs are recorded at each visit, and a physical examination is performed at screen and endpoint (either discontinuation or completion). Patients are allowed to take prescribed nonpsychotropic drugs and over-the-counter medications such as aspirin, cold preparations, and vitamins and are not allowed to take any concomitant psychotropic medications (including antidepressants, antipsychotic agents, barbiturates, benzodiazepines, buspirone, zolpidem, psychostimulants, anorexics, and anticonvulsants), steroids, insulin, or anticoagulants during the study.[000219] COMT has emerged as an attractive target for the treatment of various central and peripheral nervous systems disorders, including MDD, PD, schizophrenia, and other dopamine- related disorders. COMT is a ubiquitous enzyme that exists in two forms: a soluble form (S- COMT), present in central and peripheral tissues (abundant in liver and kidney), and a membrane-bound form (MB-COMT), mainly expressed in the brain, which differ in 50 extra amino acids at the amino end of MB-COMT. Inhibition of S-COMT by second (entacapone, tolcapone) and third generation (opicapone) COMT inhibitors of the nitrocatechol family has been crucial for enhancing the efficacy of levodopa, which is the most efficacious drug for the treatment of motor symptoms of PD, by blocking COMT -dependent degradation of L-DOPA in peripheral tissuesDefinitions[000220] Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings that are commonly understood by those of ordinary skill in the art.[000221] For convenience, certain terms employed herein, in the specification, examples and appended claims are collected herein. Unless stated otherwise, or implicit from context, the following terms and phrases include the meanings provided below. Unless explicitly stated otherwise, or apparent from context, the terms and phrases below do not exclude the meaning that the term or phrase has acquired in the art to which it pertains. The definitions are provided to aid in describing particular embodiments, and are not intended to limit the claimed invention, because the scope of the invention is limited only by the claims. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.[000222] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as those commonly understood to one of ordinary skill in the art to which this invention pertains. Although any known methods, devices, and materials may be used in the practice or testing of the invention, the methods, devices, and materials in this regard are described herein. [000223] As used herein, the term “COMT Inhibitor Compound” refers to a compound that inhibits COMT with an ICso that is less than 10 micromolar using the potency assay of Example Al.[000224] As used herein, the term “alkyl” refers to an aliphatic hydrocarbon group which can be straight or branched having 1 to about 10 carbon atoms in the chain, and which preferably have about 1 to about 6 carbons in the chain. “Lower alkyl” refers to an alkyl group having 1 to about 4 carbon atoms. “Higher alkyl” refers to an alkyl group having about 5 to about 10 carbon atoms. The alkyl group can be optionally substituted with one or more alkyl group substituents which can be the same or different, where “alkyl group substituent” includes halo, amino, aryl, hydroxy, alkoxy, aryloxy, alkyloxy, alkylthio, arylthio, aralkyloxy, aralkylthio, carboxy, alkoxycarbonyl, oxo and cycloalkyl. “Branched” refers to an alkyl group in which a lower alkyl group, such as methyl, ethyl or propyl, is attached to a linear alkyl chain. Exemplary alkyl groups include methyl, ethyl, i-propyl, n-butyl, t-butyl, n-pentyl, heptyl, octyl, decyl, dodecyl, tridecyl, tetradecyl, pentadecyl and hexadecyl. Useful alkyl groups include branched or straight chainalkyl groups of 6 to 50 carbon, and also include the lower alkyl groups of 1 to about 4 carbons and the higher alkyl groups of about 12 to about 16 carbons.[000225| As used herein, the term “cycloalkyl” refers to a non-aromatic mono- or multicyclic ring system of about 3 to about 12 carbon atoms. Representative monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, and cyclohexyl. Useful multicyclic cycloalkyl rings include adamantyl. “Lower cycloalkyl” refers to an alkyl group having 3 to about 6 carbon atoms in the cycloalkyl ring, optionally substituted with halogen, alkyl, alkoxy' or other substituents disclosed herein. “Higher alkyl” refers to an alkyl group having about 5 to about 10 carbon atoms.[000226] “Aryl” refers to an aromatic carbocyclic radical containing about 3 to about 10 carbon atoms. The aryl group can be optionally substituted with one or more substituents, which can be the same or different, where “aryl group substituent” includes alkyl, alkenyl, alkynyl, hydroxy, alkoxy, carboxy, halo, nitro, trihalomethyl, cyano, alkoxycaibonyl, aryloxycarbonyl, aralkoxycarbonyl, acyloxy, acylamino, aroylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, arylthio, alkylthio, and alkylene. Exemplary aryl groups include substituted or unsubstituted phenyl.[000227] “Heterocyclyl” refers to a nonaromatic 3-8 membered monocyclic, or 8-12 membered bicyclic ring systems having 1-3 heteroatoms if monocyclic, or 1 -6 heteroatoms if bicyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, or 1-6 heteroatoms of N, O, or S if monocyclic, or bicyclic, respectively). Cxheterocyclyl and Cx-Cyheterocyclyl are typically used where X and Y indicate the number of carbon atoms in the ring system. In some embodiments, 1, 2 or 3 hydrogen atoms of each ring can be substituted by a substituent.Exemplary heterocyclyl groups include, but are not limited to piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, piperidyl, 4-morpholyl, 4-piperazinyl, pyrrolidinyl, perhydropyrrolizinyl, 1,4-diazaperhydroepinyl, 1,3-dioxanyl, 1,4-dioxanyland the like.[000228] “Heteroaryl” refers to an aromatic 3-8 membered monocyclic, or 8-12 membered fused bicyclic ring system having 1-3 heteroatoms if monocyclic, or 1-6 heteroatoms if bicyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively.[000229] Exemplary aryls and heteroaryls include, but are not limited to, phenyl, pyridinyl, pyrimidinyl, furanyl, thienyl, imidazolyl, thiazolyl, pyrazolyl, pyridazinyl, pyrazinyl, triazinyl, tetrazolyl, indolyl, benzyl, naphthyl, anthracenyl, azulenyl, fluorenyl, indanyl, indenyl, naphthyl,tetrahydronaphthyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-l,5,2-dithiazinyl, dihydrofuro[2,3 b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, IH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedi oxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3- oxadiazolyl, 1,2,4-oxadiazolyl, 1,2, 5 -oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-l,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4- thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thi enoimidazolyl, thiophenyl or xanthenyl, each of which can be optionally substituted.[000230] As used herein, the term “halogen” or “halo” refers to an atom selected from fluorine, chlorine, bromine and iodine. The term “halogen radioisotope” or “halo isotope” refers to a radionuclide of an atom selected from fluorine, chlorine, bromine and iodine[000231] A “halogen-substituted moiety” or “halo-substituted moiety”, as an isolated group or part of a larger group, means an aliphatic, alicyclic, or aromatic moiety, as described herein, substituted by one or more “halo” atoms, as such terms are defined in this application.[000232] The term “haloalkyl” as used herein refers to an alkyl structure with at least one substituent of fluorine, chorine, bromine or iodine, or with combinations thereof. Exemplary halo-substituted alkyl includes haloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl and the like (e.g. halosubstituted (Ci-C3)alkyl includes chloromethyl, dichloromethyl, difluoromethyl, trifluoromethyl (CFj), perfluoroethyl, 2,2,2-trifluoroethyl, 2,2,2-trifluoro-l,l-dichloroethyl, and the like).[000233] As used herein, the term “amino” means -NHz or -NH3 where one or more hydrogens are optionally substituted with alkyl, and the alkyl is optionally further substituted with one or more halogen or other substituents disclosed herein. The term “alkylamino” means a nitrogen moiety having one straight or branched unsaturated aliphatic, cyclyl, or heterocyclyl radicals attached to the nitrogen, e.g., -NH(alkyl). The term “dialkylamino” means a nitrogen moiety having at two straight or branched unsaturated aliphatic, cyclyl, or heterocyclyl radicals attached to the nitrogen, e g., -N(alkyl)(alkyl). The term “alkylamino” includes “alkenylamino,” “alkynylamino,” “cyclylamino,” and “heterocyclylamino.” The term “arylamino” means a nitrogen moiety having at least one aryl radical attached to the nitrogen. For example, -NHaryl, and — N(aryl)z. The term “heteroarylamino” means a nitrogen moiety having at least one heteroaryl radical attached to the nitrogen. For example — NHheteroaryl, and — N(heteroaryl)2. Optionally, two substituents together with the nitrogen can also form a ring. Unless indicated otherwise, the compounds described herein containing amino moieties can include protected derivatives thereof. Suitable protecting groups for amino moieties include acetyl, tertbutoxycarbonyl, benzyloxycarbonyl, and the like. Exemplary alkylamino includes, but is not limited to, NH(Ci-Cioalkyl), such as — NHCH3, — NHCH2CH3, — NHCH2CH2CH3, and — NHCH(CHI)2. Exemplary dialkylamino includes, but is not limited to, — N(Ci-Cioalkyl)2, such as N(CH3)2, — N(CH2CH3)2, — N(CH2CH2CH3)2, and — N(CH(CH3)2)2.[000234] The term “aminoalkyl” means an alkyl, alkenyl, and alkynyl as defined above, except where one or more substituted or unsubstituted nitrogen atoms ( — N — ) are positioned between carbon atoms of the alkyl, alkenyl, or alkynyl. For example, an (C2-Ce) aminoalkyl refers to a chain comprising between 2 and 6 carbons and one or more nitrogen atoms positioned between the carbon atoms.[000235] The terms “hydroxy” and “hydroxyl” mean the radical — OH.[000236] The terms “alkoxyl” or “alkoxy” as used herein refers to an alkyl group, as defined above, having an oxygen radical attached thereto, and can be represented by one of -O-alkyl, -O- alkenyl, and -O-alkynyl. Aroxy can be represented by -O-aryl or O-heteroaryl, wherein aryl and heteroaryl are as defined herein. The alkoxy and aroxy groups can be substituted as described above for alkyl. Exemplary alkoxy groups include, but are not limited to O-methyl, O-ethyl, O- w-propyl, O-isopropyl, O-n-butyl, O-isobutyl, O-sec-butyl, O-fert-butyl, O-pentyl, O- hexyl, O- cyclopropyl, O-cyclobutyl, O-cyclopentyl, O-cyclohexyl and the like.[000237] As used herein, the term “carbonyl” means the radical — C(O) — . Ft is noted that the carbonyl radical can be further substituted with a variety of substituents to form different carbonyl groups including acids, acid halides, amides, esters, ketones, and the like.[000238] The term “carboxy” means the radical — C(O)O — . It is noted that compounds described herein containing carboxy moieties can include protected derivatives thereof, i.e., where the oxygen is substituted with a protecting group. Suitable protecting groups for carboxy moieties include benzyl, tert-butyl, and the like. As used herein, a carboxy' group includes - COOH, i.e., carboxyl group.[000239] The term “cyano” means the radical — CN.[000240] The term “nitro” means the radical — NO2.[000241] The term, “heteroatom” refers to an atom that is not a carbon atom. Particular examples of heteroatoms include, but are not limited to nitrogen, oxygen, sulfur and halogens. A “heteroatom moiety” includes a moiety where the atom by which the moiety is attached is not a carbon. Examples of heteroatom moieties include — N=, — NRN— , — N'(O')=, — O — , — S — or — S(O)2 — , — OS(O)2 — , and — SS — , wherein RNis H or a further substituent.[000242] “Acyl” refers to an alkyl-CO — group, wherein alkyl is as previously described. Exemplary acyl groups comprise alkyl of 1 to about 30 carbon atoms. Exemplary acyl groups also include acetyl, propanoyl, 2-methylpropanoyl, butanoyl and palmitoyl.[000243] “Alkoxycarbonyl” refers to an alkyl-0 — CO — group. Exemplary alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, butyloxycarbonyl, and t-butyloxy carbonyl. [000244] “Carbamoyl” refers to an H2N — CO — group.[000245] “Alkylcarbamoyl” refers to a R’RN — CO — group, wherein one of R and R* is hydrogen and the other of R and R* is alkyl as previously described.[000246] “Dialkylcarbamoyl” refers to R'RN — CO — group, wherein each of R and R* is independently alkyl as previously described.[000247] The term “optionally substituted” means that the specified group or moiety is unsubstituted or is substituted with one or more (typically 1, 2, 3, 4, 5 or 6 substituents) independently selected from the group of substituents listed below in the definition for “substituents” or otherwise specified. The term “substituents” refers to a group “substituted” on a substituted group at any atom of the substituted group. Suitable substituents include, without limitation, halogen, hydroxy, caboxy, oxo, nitro, haloalkyl, alkyl, alkenyl, alkynyl, alkaiyl, aryl,heteroaryl, cyclyl, heterocyclyl, aralkyl, alkoxy, aryloxy, amino, acylamino, alkylcarbanoyl, arylcarbanoyl, aminoalkyl, alkoxycarbonyl, carboxy, hydroxyalkyl, alkanesulfonyl, arenesulfonyl, alkanesulfonamido, arenesulfonamido, aralkylsulfonamido, alkylcarbonyl, acyloxy, cyano or ureido. In some cases, two substituents, together with the carbons to which they are attached to can form a ring.[000248] For example, any alkyl, alkenyl, cycloalkyl, heterocyclyl, heteroaryl or aryl is optionally substituted with 1, 2, 3, 4 or 5 groups selected from OH, CN, SH, SO2NH2, SO2(Ci- C4)alkyl, SO2NH(Ci-C4)alkyl, halogen, carbonyl, thiol, cyano, NH2, NH(Ci-C4)alkyl, N[(Ci- C4)alkyl]2, C(O)NH2, COOH, COOMe, acetyl, (Ci-Cg)alkyl, O(Ci-Cg)alkyl, O(Ci-Cg)haloalkyl, (C2-Cg)alkenyl, (C2-Cg)alkynyl, haloalkyl, thioalkyl, cyanomethylene, alkylaminyl, aryl, heteroaryl, substituted aryl, NH2— C(O)-alkylene, NH(Me)-C(O)-alkylene, C.H2— C(O)- alkyl, C(O)- alkyl, alkylcarbonylaminyl, CH2— [CH(OH)]m— (CH2)p— OH, CH2— [CH(OH)]m— (CH2)p — NH2or CHz-aryl-alkoxy; or wherein any alkyl, cycloalkyl or heterocyclyl is optionally substituted with oxo, “m” and “p” are independently 1, 2, 3, 4, 5 or 6.[000249] In some embodiments, an optionally substituted group is substituted with 1 substituent. In some other embodiments, an optionally substituted group is substituted with 2 independently selected substituents, which can be same or different. In some other embodiments, an optionally substituted group is substituted with 3 independently selected substituents, which can be same, different or any combination of same and different. In still some other embodiments, an optionally substituted group is substituted with 4 independently selected substituents, which can be same, different or any combination of same and different. In yet some other embodiments, an optionally substituted group is substituted with 5 independently selected substituents, which can be same, different or any combination of same and different.[000250] In some embodiments, the compound is selected from the group consisting of:and or a pharmaceutically acceptable salt, enantiomer, or racemate thereof.[000251] In some embodiments, the compound is selected from the group consisting of:or a pharmaceutically acceptable salt thereof.[000252] In some embodiments, the compound is selected from the group consisting of:and[000253] In some embodiments, the compound is selected from the group consisting of:, , and[000254] In some embodiments, the compound is selected from the group consisting of:and or a pharmaceutically acceptable salt thereof.[000255] In some embodiments, the compound is a compound of the formula:, or a pharmaceutically acceptable salt thereof.[000256] In some embodiments, the compound is a compound of the formula:[000257] In some embodiments, the compound is selected from the group consisting of:and or a pharmaceutically acceptable salt thereof.[000258] In some embodiments, the compound is selected from the group consisting of:or , or a pharmaceutically acceptable salt thereof.[000259] Some embodiments of the present invention can be defined as any of the following numbered paragraphs;1. A compound of Formula (I):OHFormula (I) or a pharmaceutically acceptable salt, enantiomer, or racemate thereof, wherein:Ra and Rb are each independently hydrogen. C1-4alkyl, C1-4baloalkyl, or halogen; or Ra and Rb together form an alkenyl, carbonyl (=0), or a spirocyclic cycloalkyl optionally substituted with one or more R30;A1and A2are each independently N, NH, or CR1;A3 is N or C; provided that at least one of A1, A2and A3 is N;Bi is C(Rc1Rc2), NRc3or oxygen;Rc1, Rc2, Rc3and Rdare each independently hydrogen or methyl,R1and R2 are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, amine, amide, carboxyl, alkyl-acetate, or alkyl-amide; orone of R1and R2together form a fused 6-member aryl ring or fused 6-member heteroaryl ring optionally substituted with R2o;R12 is hydrogen or halogen;R20 is carboxyl, alkyl-acetate, or alkyl-amide; andR30 is halogen, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl; provided the compound of Formula (I) is not l-[(l,3-dimethyl-2-oxo-2,3-dihydro-lH- l,3-benzodiazol-5-yl)methyl]-2-(4-hydroxy-3-methoxyphenyl)-N-methyl-lH-1,3-benzodi azole- 5-carboxamide.2. The compound of paragraph 1, wherein the compound is a compound of Formula QI):Formula (II) or a pharmaceutically acceptable salt, enantiomer, or racemate thereof, wherein:Ra and Rb are each independently hydrogen, halogen, or C1-4alkyl optionally substituted with one or more halogen; or R» and Rb together form a spirocyclic cyclopropyl;A1and A2are each independently CH or N;R1o is methyl; andR12 is hydrogen or halogen.3. The compound of paragraph 2, wherein only one of A1and A2is N.4. The compound of any one of paragraphs 2-3, wherein Ra and Rb are each independently hydrogen, methyl or ethyl, wherein the methyl or ethyl are optionally substituted with one or more fluoro.5. The compound of paragraph 4, wherein at least one of Ra and Rb is hydrogen.6. The compound of any one of paragraphs 2-5, wherein A] is N.7. The compound of any one of paragraphs 2-5. wherein A1is CH.8. The compound of any one of paragraphs 2-7, wherein R1o is methyl.9. The compound of any one of paragraphs 2-8, wherein R12 is fluoro.10. The compound of any one of paragraphs 2-8, wherein R12 is hydrogen.11. The compound of paragraph 2, wherein R1o is methyl.12. The compound of paragraph 11, wherein only one of A1and A2is N.13. The compound of paragraph 12, wherein Ra and Rb are each independently hydrogen, methyl, -CF3, or ethyl, and at least one of Ra and Rb is hydrogen.14. The compound of paragraph 13, wherein R12 is hydrogen or fluoro.15. The compound of paragraph 14, wherein A1is CH.16. The compound of paragraph 14, wherein A1is N.17. The compound of paragraph 15, wherein R12 is fluoro.18. The compound of paragraph 16, wherein Ra and Rb are each hydrogen.19. The compound of paragraph 1, wherein the compound is a compound of Formula (HI):Formula (ID) or a pharmaceutically acceptable salt, enantiomer, or racemate thereof, wherein:Ra and Rb are each independently hydrogen, or C1-4 alkyl; or Ra and Rb together form a spirocyclic cyclopropyl;A1is CH or N;R1o is methyl;R12 is hydrogen or halogen; andR20 is hydrogen, -C(O)OH, -C(O)O(CH.3), -C(O)NH2or C(O)NH(CH3)20. The compound of paragraph 19, wherein R1o is methyl.21. The compound of any one of paragraphs 19-20, wherein R12 is hydrogen or fluoro.22. The compound of any one of paragraphs 19-21 , wherein Raand Rb are each independently hydrogen, methyl or ethyl.23. The compound of any one of paragraphs 19-21, wherein Raand Rb are each independently hydrogen, or methyl.24. The compound of any one of paragraphs 19-23, wherein R2o is -C(O)OH, -C(O)O(CH3) or C(O)NH(CH3).25. The compound of any one of paragraphs 19-24, wherein A1is N.26. The compound of paragraph 25, wherein at least one of Ra and Rb is hydrogen.27. The compound of any one of paragraphs 19-22, wherein R20 is hydrogen.28. The compound of any one of paragraph 27, wherein R12 is hydrogen or fluorine.29. The compound of any one of paragraphs 26-28, wherein Ra and Rb are each hydrogen.30. The compound of any one of paragraphs 26-28, wherein Rn is hydrogen.31. The compound of any one of paragraphs 19-30, wherein Ra and Rb are both hydrogen.32. The compound of paragraph 20, wherein R, and Rb are each independently hydrogen, R12 is hydrogen or fluoro, and R20 is hydrogen.33. The compound of paragraph 32, wherein A1is N.34. The compound of paragraph 33, wherein R12 is hydrogen.35. The compound of paragraph 33, wherein R12 is fluoro.36. The compound of paragraph 32, wherein A1is CH.37. The compound of paragraph 36, wherein R12 is hydrogen.38. The compound of paragraph 36, wherein R12 is fluoro.39. A compound of Formula (IV):or a pharmaceutically acceptable salt, enantiomer, or racemate thereof, wherein:Raand Rb are each independently hydrogen, C1-4alkyl, or halogen; or Raand Rb together form a spirocyclic cyclopropyl;Re is hydrogen or methyl; andR12 is hydrogen or halogen.40. The compound of paragraph 39, wherein Re is methyl.41. The compound of any one of paragraphs 39-40, wherein Raand Rb are each independently hydrogen, methyl, ethyl, fluoro, or together form a spirocyclic cyclopropyl .42. The compound of any one of paragraphs 39-40, wherein Ra and Rb are each independently hydrogen, methyl, fluoro, or together form a spirocyclic cyclopropyl.43. The compound of any one of paragraphs 39-42, wherein R12 is hydrogen or fluoro.44. The compound of any one of paragraphs 39-43, wherein R, and Rb together form a spirocyclic cyclopropyl .45. The compound of any one of paragraphs 39-43, wherein at least one of R» and Rb is hydrogen.46. The compound of any one of paragraphs 39-43, wherein R» is methyl and Rb is hydrogen.47. The compound of any one of paragraphs 39-43, wherein Ra and Rb are each hydrogen.48. The compound of paragraph 40, wherein R, and Rb together form a spirocyclic cyclopropyl and R12 is hydrogen or fluoro.49. The compound of paragraph 40, wherein Ra is methyl, Rb is hydrogen and R12 is hydrogen or fluoro.50. The compound of paragraph 40, wherein R, is hydrogen, Rb is hydrogen and R12 is hydrogen or fluoro.51. A compound selected from the group consisting of: a. 5-[(lS)-l-[2-(3-fluoro-4-hydroxy-5-methoxyphenyl)-lH-pyrrol-l-yl]ethyl]-l,3- dimethyl-2,3-dihydro-l H-l ,3-benzodiazol-2-one; b. 5-[(lR)-l-[2-(4-hydroxy-3-methoxyphenyl)-lH-pyrrol-l-yl]ethyl]-l,3-dimethyl-2.3-dihydro-l H-l ,3-benzodiazol-2-one; c. 5- { [2-(3 -fluoro-4-hydroxy-5-methoxyphenyl)- 1H- 1 ,3-benzodiazol-l -yl]methyl }-1.3-dimethyl-2,3 -dihydro- 1 H- 1 ,3 -benzodiazol -2-one;d. 5-[(I S)-l-[2-(3-fluoro-4-hydroxy-5-methoxyphenyl)-lH-pyrrol-l-yl]propyl]-l,3- dimethyl-2,3-dihydro- 1H- 1 ,3-benzodiazol -2-one; and e. 1 -[( 1 ,3-dimethyl-2-oxo-2,3-dihydro-l H-l ,3-benzodiazol-5-yl)methyl]-2-(4- hydroxy-3-methoxyphenyl)-lH-l,3-benzodiazole-5-carboxylic acid; or a pharmaceutically acceptable salt thereof.53. The compound of paragraph 51, or a pharmaceutically acceptable salt thereof, wherein the compound is 5-[(l S)-l-[2-(3-fluoro-4-hydroxy-5-methoxyphenyl)-lH-pyrrol-l-yl]ethyl]-l,3- dimethyl-2,3 -dihy dro- 1H- 1 ,3 -benzodi azol -2-one.54. The compound of paragraph 51, or a pharmaceutically acceptable salt thereof, wherein the compound is 5-[(lR)-l-[2-(4-hydroxy-3-methoxyphenyl)-lH-pyrrol-l-yl]ethyl]-l,3-dimethyl-2.3-dihydro- 1H- 1 ,3-benzodiazol -2-one.55. The compound of paragraph 51, or a pharmaceutically acceptable salt thereof, wherein the compound is 5-{[2-(3-fluoro-4-hydroxy-5-methoxyphenyl)-lH-l,3-benzodiazol-l-yl]methyl} -1.3-dimethyl-2,3-dihydro- 1 H- 1 ,3-benzodiazol-2-one.56. The compound of paragraph 51, or a pharmaceutically acceptable salt thereof, wherein the compound is 5-[(l S)-l-[2-(3-fluoro-4-hydroxy-5-methoxyphenyl)-lH-pyrrol-l-yl]propyl]-l,3- dim ethyl-2,3 -di hydro- 1 H- 1 ,3 -benzodiazol -2-one.57. The compound of paragraph 51, or a pharmaceutically acceptable salt thereof, wherein the compound is l-[(l,3-dimethyl-2-oxo-2,3-dihydro-lH-l,3-benzodiazol-5-yl)methyl]-2-(4- hy droxy-3 -methoxyphenyl)- 1 H- 1 ,3 -benzodiazole-5-carboxylic acid.58. A compound selected from the group consisting of: a. methyl l-[(l,3-dimethyl-2-oxo-2,3-dihydro-lH-l,3-benzodiazol-5-yl)methyl]- 2-(4-hydroxy-3-methoxyphenyl)-lH-l, 3 -benzodiazol e-5-carboxylate; b. N-[l-(l,3-dimethyl-2-oxo-2,3-dihydro-lH-l,3-benzodiazol-5-yl)cyclopropyl]-4-hydroxy-3-methoxy-N-methylbenzamide; c. 5-{[2-(4-hydroxy-3-methoxyphenyl)-lH-l,3-benzodiazol-l-yl]methyl}-1,3- dimethyl-2,3-dihydro- 1H- l,3-benzodiazol-2-one; or a pharmaceutically acceptable salt thereof.59. The compound of paragraph 57, wherein the compound is methyl l-[(l,3-dimethyl-2-oxo- 2,3-dihydro- 1H- 1 ,3 -benzodiazol-5-yl)methyl]-2-(4-hydroxy-3-methoxyphenyl)- 1H-1 ,3 - benzodiazol e-5-carboxylate.60. The compound of paragraph 57, wherein the compound is N-[l-(l,3-dimethyl-2-oxo-2,3- dihydro-lH-l,3-benzodiazol-5-yl)cyclopropyl]-4-hydroxy-3-methoxy-N-methylbenzamide.61. The compound of paragraph 57, wherein the compound is 5-{[2-(4-hydroxy-3- methoxyphenyl)- 1 H- 1 ,3 -benzodiazol - 1 -yl]m ethyl } - 1 ,3 -dimethyl -2, 3 -dihydro- 1 H- 1 ,3 - benzodiazol-2-one.62. A pharmaceutical composition comprising the compound:, or a pharmaceutically acceptable salt thereof.63. A pharmaceutical composition comprising the compound:, or a pharmaceutically acceptable salt thereof.64. A pharmaceutical composition comprising the compound:, or a pharmaceutically acceptable salt thereof.65. A pharmaceutical composition comprising the compound:, or a pharmaceutically acceptable salt thereof.66. A pharmaceutical composition comprising the compound:, or a pharmaceutically acceptable salt thereof.67. A pharmaceutical composition comprising the compound:, or a pharmaceutically acceptable salt thereof.68. A pharmaceutical composition comprising the compound:, or a pharmaceutically acceptable salt thereof.69. A pharmaceutical composition comprising the compound:or a pharmaceutically acceptable salt thereof.70. A pharmaceutical composition comprising the compound:, or a pharmaceutically acceptable salt thereof.71. A pharmaceutical composition comprising the compound:, or a pharmaceutically acceptable salt thereof.72. A pharmaceutical composition comprising the compound:, or a pharmaceutically acceptable salt, enantiomer, or racematethereof.73. A pharmaceutical composition comprising the compound:, or a pharmaceutically acceptable salt, enantiomer, or racemate thereof.74. A pharmaceutical composition comprising the compound:, or a pharmaceutically acceptable salt, enantiomer, or racemate thereof.75. A pharmaceutical composition comprising the compound:, or a pharmaceutically acceptable salt, enantiomer, or racemate thereof.76. A pharmaceutical composition comprising the compound:or a pharmaceutically acceptable salt, enantiomer, orracemate thereof.77. A pharmaceutical composition comprising the compound:, or a pharmaceutically acceptable salt thereof.78. A pharmaceutical composition comprising the compound:, or a pharmaceutically acceptable salt thereof.79. A pharmaceutical composition comprising the compound:, or a pharmaceutically acceptable salt, enantiomer, or racemate thereof.80. A pharmaceutical composition comprising the compound:, or a pharmaceutically acceptable salt thereof.81. A pharmaceutical composition comprising the compound:or a pharmaceutically acceptable salt thereof.82. A pharmaceutical composition of any one of paragraphs 61-81, formulated in combination with one or more excipients for oral administration.83. A compound of Formula (I-A-l):Formula (I-A-l) or a pharmaceutically acceptable salt, enantiomer, or racemate thereof, wherein:Ra and Rb are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, halogen, or together form a spirocyclic cycloalkyl optionally substituted with one or more R30;A1is NH;A2is C;A3 is C;Bi is C(RtiiRti2), NKd or oxygen;Rc1, Rc2, Rc3and Rdare each independently hydrogen or methyl;R12 is hydrogen or halogen;R20 is caiboxyl, alkyl-acetate or alkyl-amide; andR30 is halogen, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl;84. The compound of paragraph 83, or a pharmaceutically acceptable salt, enantiomer, or racemate thereof, wherein the compound has the chemical structure:85. The compound of paragraph 83, or a pharmaceutically acceptable salt, enantiomer, or racemate thereof, wherein the compound has the chemical structure:86. A compound of Formula (I-A-2):or a pharmaceutically acceptable salt thereof, wherein:A1is NH;A2is C;A3is C;Bi is C(Rc1Rcz), NRc3or oxygen;Rc1, Rcz, R<3 and Rdare each independently hydrogen or methyl;R1z is hydrogen or halogen; andR20 is carboxyl, alkyl-acetate or alkyl-amide.87. The compound of paragraph 86, or a pharmaceutically acceptable salt thereof, wherein the compound has the chemical structure:88. A compound of Formulaor a pharmaceutically acceptable salt, enantiomer, or racemate thereof, wherein:Ra and Rb are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, halogen, or together form a spirocyclic cycloalkyl optionally substituted with one or more R30;A1is C;Aj is N, CR1, or NH;A3 is N or C; provided that at least one of A2and A? is N;Bi is C(Rc1Rc2), NRc3or oxygen;Rc1, Rc2, Rc3and Rdare each independently hydrogen or methyl;R1is hydrogen, C1-4alkyl, C1-4haloalkyl, amine, amide, carboxyl, alkyl-acetate or alkyl-amide;R12 is hydrogen or halogen;Rao is carboxyl, alkyl-acetate or alkyl-amide;Rjo is halogen, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl; provided the compound of Formula (I-B) is not l-[(l,3-dimethyl-2-oxo-2,3-dihydro- lH-l,3-benzodiazol-5-yl)methyl]-2-(4-hydroxy-3-methoxyphenyl)-N-methyl-lH-l,3- benzodiazole-5-carboxamide.89. The compound of paragraph 88, or a pharmaceutically acceptable salt, enantiomer, or racemate thereof, wherein the compound has the chemical structure:.H„90. The compound of paragraph 88, or a pharmaceutically acceptable salt, enantiomer, or racemate thereof, wherein the compound has the chemical structure:91. A compound of FormulaFormula (I-B-l) or a pharmaceutically acceptable salt thereof, wherein:A1is C;Aj is N, CR1, or NH;As is N or C; provided that at least one of M and A? is N;Bi is C(Rc1Rc2), NRc3or oxygen;Rc1, Rc2, Rc3and Rdare each independently hydrogen or methyl;R12 is hydrogen or halogen; andR20 is carboxyl, alkyl-acetate or alkyl-amide.92. The compound of paragraph 91, or a pharmaceutically acceptable salt thereof, wherein the compound has the chemical structure:OH[000260] Some embodiments of the present invention can be defined as any of the following numbered paragraphs:1. A compound of Formula (I):Formula (I) or a pharmaceutically acceptable salt thereof, wherein:Ra and Rb are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, or halogen; or R* and Rb together form an alkenyl, carbonyl (=0), or a spirocyclic cycloalkyl optionally substituted with one or more R30;A1and A2are each independently N, NH, or CR1;A3 is N or C; provided that at least one of A1, A2and A3 is N;Bi is C(Rc1Rc2), NRc3or oxygen,Rc1, Rc2, Rc3and Rdare each independently hydrogen or methyl;R1and R2 are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, amine, amide, carboxyl, alkyl-acetate, or alkyl-amide; or one of R1and R2 together form a fused 6-member aryl ring or fused 6-member heteroaryl ring optionally substituted with R20;R12 is hydrogen or halogen;R20 is carboxyl, alkyl-acetate, or alkyl-amide; andR30 is halogen, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl; provided the compound of Formula (I) is not l-[(l,3-dimethyl-2-oxo-2,3-dihydro-lH- 1 ,3-benzodiazol-5-y l)methyl]-2-(4-hydroxy-3-methoxyphenyl)-N-methyl-l H- 1 ,3 -benzodi azole- 5-carboxamide.2. The compound of paragraph 1, wherein the compound is a compound of Formula (II):Formula (II) or a pharmaceutically acceptable salt thereof, wherein:Ra and Rb are each independently hydrogen, halogen, or Ci-4 alkyl optionally substituted with one or more halogen; or Raand Rb together form a spirocyclic cyclopropyl;A1and A2are each independently CH or N;R1o is methyl; andR12 is hydrogen or halogen.3. The compound of paragraph 2, wherein only one of A1and A2is N.4. The compound of any one of paragraphs 2-3, wherein Raand Rb are each independently hydrogen, methyl or ethyl, wherein the methyl or ethyl are optionally substituted with one or more fluoro.5. The compound of paragraph 4, wherein at least one of Ra and Rb is hydrogen.6. The compound of any one of paragraphs 2-5, wherein A1is N.7. The compound of any one of paragraphs 2-5, wherein A1is CH.8. The compound of any one of paragraphs 2-7, wherein R1o is methyl.9. The compound of any one of paragraphs 2-8, wherein R12 is fluoro.10. The compound of any one of paragraphs 2-8, wherein R12 is hydrogen.11 The compound of paragraph 2, wherein R1o is methyl.12. The compound of paragraph 11, wherein only one of A1and A2is N.13 The compound of paragraph 12, wherein Ra and Rb are each independently hydrogen, methyl, -CF3, or ethyl, and at least one of Ra and Rb is hydrogen.14. The compound of paragraph 13, wherein R12 is hydrogen or fluoro.15. The compound of paragraph 14, wherein A1is CH16. The compound of paragraph 14, wherein A1is N.17. The compound of paragraph 15, wherein Rn is fluoro.18. The compound of paragraph 16, wherein Ra and Rb are each hydrogen.19. The compound of paragraph 1, wherein the compound is a compound of Formula (III):Formula (III) or a pharmaceutically acceptable salt thereof, wherein:Ra and Rb are each independently hydrogen, or C1-4alkyl; or Ra and Rb together form a spirocyclic cyclopropyl;A1is CH or N;R1o is methyl;R12 is hydrogen or halogen; andR20 is hydrogen, -C(O)OH, -C(O)O(CH3), -C(O)NH2or C(O)NH(CH3).20. The compound of paragraph 19, wherein R1o is methyl.21. The compound of any one of paragraphs 19-20, wherein R12 is hydrogen or fluoro.22. The compound of any one of paragraphs 19-21, wherein R» and Rb are each independently hydrogen, methyl or ethyl.23. The compound of any one of paragraphs 19-21, wherein Ra and Rb are each independently hydrogen, or methyl.24. The compound of any one of paragraphs 19-23, wherein R20 is -C(O)OH, -C(O)O(CH3) or C(O)NH(CH3).25. The compound of any one of paragraphs 19-24, wherein A1is N.26. The compound of paragraph 25, wherein at least one of Ra and Rb is hydrogen.27. The compound of any one of paragraphs 19-22, wherein R20 is hydrogen.28. The compound of any one of paragraph 27, wherein R12 is hydrogen or fluorine.29. The compound of any one of paragraphs 26-28, wherein Ra and Rb are each hydrogen.30. The compound of any one of paragraphs 26-28, wherein Rn is hydrogen.31. The compound of any one of paragraphs 19-30, wherein Raand Rb are both hydrogen.32. The compound of paragraph 20, wherein Ra and Rb are each independently hydrogen, Rn is hydrogen or fluoro, and R20 is hydrogen.33. The compound of paragraph 32, wherein A1is N.34. The compound of paragraph 33, wherein Rn is hydrogen.35. The compound of paragraph 33, wherein Rn is fluoro.36. The compound of paragraph 32, wherein A1is CH.37. The compound of paragraph 36, wherein Rn is hydrogen.38. The compound of paragraph 36, wherein Rn is fluoro.39. A compound of Formula (IV).or a pharmaceutically acceptable salt thereof, wherein:Raand Rb are each independently hydrogen, C1-4alkyl, or halogen; or R» and Rb together form a spirocyclic cyclopropyl;Re is hydrogen or methyl; andR12 is hydrogen or halogen.40. The compound of paragraph 39, wherein Re is methyl.41. The compound of any one of paragraphs 39-40, wherein Ra and Rb are each independently hydrogen, methyl, ethyl, fluoro, or together form a spirocyclic cyclopropyl.42. The compound of any one of paragraphs 39-40, wherein Ra and Rb are each independently hydrogen, methyl, fluoro, or together form a spirocyclic cyclopropyl.43. The compound of any one of paragraphs 39-42, wherein Rn is hydrogen or fluoro.44. The compound of any one of paragraphs 39-43, wherein Ra and Rb together form a spirocyclic cyclopropyl.45. The compound of any one of paragraphs 39-43, wherein at least one of Ra and Rb is hydrogen.46. The compound of any one of paragraphs 39-43, wherein Ra is methyl and Rb is hydrogen.47. The compound of any one of paragraphs 39-43, wherein Ra and Rb are each hydrogen.48. The compound of paragraph 40, wherein Ra and Rb together form a spirocyclic cyclopropyl and R12 is hydrogen or fluoro.49. The compound of paragraph 40, wherein Ra is methyl, Rb is hydrogen and R12 is hydrogen or fluoro.50. The compound of paragraph 40, wherein Ra is hydrogen, Rb is hydrogen and R12 is hydrogen or fluoro.51. A compound selected from the group consisting of: a. 5-[( 1 S)- 1 -[2-(3 -fluoro-4-hydroxy-5-methoxyphenyl>- IH-pyrrol- 1 - yl]ethyl]-l,3-dimethyl-2,3-dihydro-lH-l,3-benzodiazol-2-one; b. 5-[(lR)-l-[2-(4-hydroxy-3-methoxyphenyl)-lH-pyrrol-l-yl]ethyl]-l,3- dimethyl-2,3-dihydro-1 H-l ,3-benzodiazol-2-one; c. 5- { [2-(3 -fluoro-4-hydroxy-5-methoxyphenyl)- 1H- 1 , 3 -benzodiazol- 1 - y 1 ]methyl } - 1 ,3 -dimethyl -2, 3 -dihydro- 1 H- 1 ,3 -benzodiazol -2-one; d. 5-[( 1 S)- 1 - [2-(3 -fluoro-4-hydroxy-5-methoxyphenyl)-lH-pyrrol- 1 - yl]propyl]- 1 ,3-dimethyl -2,3-dihy dro- 1H- 1 ,3 -benzodiazol-2-one; and e. 1 -[( 1 ,3-dimethyl-2-oxo-2,3-dihydro- 1H- 1 ,3-benzodiazol-5-yl)methyl]- 2-(4-hydroxy-3-methoxyphenyl)-lH-l, 3 -benzodi azole-5-carboxylic acid; or a pharmaceutically acceptable salt thereof.53. The compound of paragraph 51, or a pharmaceutically acceptable salt thereof, wherein the compound is 5-[(lS)-l-[2-(3-fluoro-4-hydroxy-5-methoxyphenyl)-lH-pyrrol-l-yl]ethyl]-l,3- dimethy I -2,3 -dihydro- 1 H- 1 ,3 -benzodiazol -2-one.54. The compound of paragraph 51, or a pharmaceutically acceptable salt thereof, wherein the compound is 5-[(lR)-l-[2-(4-hydroxy-3-methoxyphenyl)-lH-pyrrol-l-yl]ethyl]-l,3-dimethyl- 2,3-dihydro- 1H- 1 ,3-benzodiazol -2-one.55. The compound of paragraph 51 , or a pharmaceutically acceptable salt thereof, wherein the compound is 5-{[2-(3-fluoro-4-hydroxy-5-methoxyphenyl)-lH-l,3-benzodiazol-l-yl]methyl}- l,3-dimethyl-2,3-dihydro-lH-l,3-benzodiazol-2-one.56. The compound of paragraph 51, or a pharmaceutically acceptable salt thereof, wherein the compound is 5-[(lS)-l-[2-(3-fluoro-4-hydroxy-5-methoxyphenyl)-lH-pyrrol-l-yl]propyl]-l,3- dimethyl-2,3-dihydro- 1H- 1 ,3-benzodiazol-2-one.57. The compound of paragraph 51, or a pharmaceutically acceptable salt thereof, wherein the compound is 1 -[(1 ,3-dimethyl-2-oxo-2,3-dihydro- 1H- 1 ,3-benzodiazol-5-yl)methyl]-2-(4- hydroxy-3 -methoxyphenyl)- 1 H- 1 ,3 -benzodi azole-5-carboxylic acid .58. A compound selected from the group consisting of: a. methyl l-[(l,3-dimethyl-2-oxo-2,3-dihydro-lH-l,3-benzodiazol-5- yl)methyl]-2-(4-hydroxy-3-methoxyphenyl)-lH-l,3-benzodiazole- 5-carboxylate; b. N-[l-(l,3-dimethyl-2-oxo-2,3-dihydro-lH-l,3-benzodiazol-5- yl)cyclopropyl]-4-hydroxy-3-methoxy-N-methylbenzamide; c. 5- { [2-(4-hy droxy-3 -m ethoxyphenyl)- 1H- 1 ,3 -benzodiazol- 1 - yljmethylj-l ,3-dimethyl-2,3-dihydro-l H-l,3-benzodiazol-2-one; or a pharmaceutically acceptable salt thereof.59. The compound of paragraph 57, wherein the compound is methyl l-[(l,3-dimethyl-2-oxo- 2,3-dihydro- III- 1 ,3 -benzodiazol-5-yl)methyl]-2-(4-hydroxy-3-methoxy phenyl)- 1H-1 ,3 - benzodiazol e-5-carboxylate.60. The compound of paragraph 57, wherein the compound isN-[l-(l,3-dimethyl-2-oxo-2,3- dihydro-lH-l,3-benzodiazol-5-yl)cyclopropyl]-4-hydroxy-3-methoxy-N-methylbenzamide.61. The compound of paragraph 57, wherein the compound is 5-{[2-(4-hydroxy-3- methoxypheny I)- 1 H- 1 ,3 -benzodiazol - 1 -yljmethyl } - 1 ,3 -dimethyl -2,3 -dihydro- 1 H- 1 ,3 - benzodiazol-2-one.62. A pharmaceutical composition comprising the compound:, or a pharmaceutically acceptable salt thereof.63. A pharmaceutical composition comprising the compound:, or a pharmaceutically acceptable salt thereof.64. A pharmaceutical composition comprising the compound:, or a pharmaceutically acceptable salt thereof.65. A pharmaceutical composition comprising the compound:, or a pharmaceutically acceptable salt thereof.66. A pharmaceutical composition comprising the compound:, or a pharmaceutically acceptable salt thereof.67. A pharmaceutical composition comprising the compound:, or a pharmaceutically acceptable salt thereof.68. A pharmaceutical composition comprising the compound:, or a pharmaceutically acceptable salt thereof.69. A pharmaceutical composition comprising the compound:or a pharmaceutically acceptable salt thereof.70. A pharmaceutical composition comprising the compound:, or a pharmaceutically acceptable salt thereof.71. A pharmaceutical composition comprising the compound:, or a pharmaceutically acceptable salt thereof.72. A pharmaceutical composition comprising the compound:, or a pharmaceutically acceptable salt thereof.73. A pharmaceutical composition comprising the compound:, or a pharmaceutically acceptable salt thereof.74. A pharmaceutical composition comprising the compound:, or a pharmaceutically acceptable salt thereof.75. A pharmaceutical composition comprising the compound:, or a pharmaceutically acceptable salt thereof.76. A pharmaceutical composition comprising the compound:, or a pharmaceutically acceptable salt thereof.77. A pharmaceutical composition comprising the compound:, or a pharmaceutically acceptable salt thereof.78. A pharmaceutical composition comprising the compound:, or a pharmaceutically acceptable salt thereof.79. A pharmaceutical composition comprising the compound:pharmaceutically acceptable salt thereof.80. A pharmaceutical composition comprising the compound:or a pharmaceutically acceptable salt thereof.81. A pharmaceutical composition comprising the compound:or a pharmaceutically acceptable salt thereof.82. A pharmaceutical composition of any one of paragraphs 61-81, formulated in combination with one or more excipients for oral administration.83. A compound of Formula (I-A-l):Formula (I- A-l) or a pharmaceutically acceptable salt thereof, wherein:Raand Rb are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, halogen, or together form a spirocyclic cycloalkyl optionally substituted with one or more Rso;A1is NH, A2is C;A3 is C;Bi is C(Rc1Rc2), NRc3or oxygen;Rc1, Rc2, Rc3and Rdare each independently hydrogen or methyl,R12 is hydrogen or halogen;R20 is carboxyl, alkyl-acetate or alkyl-amide; andR30 is halogen, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl;84. The compound of paragraph 83, or a pharmaceutically acceptable salt thereof, wherein the compound has the chemical structure:85. The compound of paragraph 83, or a pharmaceutically acceptable salt thereof, wherein the compound has the chemical structure:86. A compound of Formulaor a pharmaceutically acceptable salt thereof, wherein:A1is NH,A2is C;A3 is C;Bi is C(Rc1Rc2), NRc3or oxygen,Rc1, Rc2. Rc3and Rdare each independently hydrogen or methyl;R12 is hydrogen or halogen; andR20 is carboxyl, alkyl-acetate or alkyl-amide.87. The compound of paragraph 86, or a pharmaceutically acceptable salt thereof, wherein the compound has the chemical structure:88. A compound of Formula (I-B):or a pharmaceutically acceptable salt thereof, wherein:Ra and Rb are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, halogen, or together form a spirocyclic cycloalkyl optionally substituted with one or more R30;A1is C;A2isN, CR1, orNH;A3 is N or C; provided that at least one of Aa and A3 is N;Bi is C(Rc1Rc2), NRc3or oxygen;Rc1, Rc2, Rc3and Rdare each independently hydrogen or methyl;R1is hydrogen, C1-4alkyl, C1-4haloalkyl, amine, amide, carboxyl, alkyl-acetate or alkyl-amide;R12 is hydrogen or halogen;R20 is carboxyl, alkyl-acetate or alkyl-amide;R30 is halogen, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl; provided the compound of Formula (I-B) is not l-[(l,3-dimethyl-2-oxo-2,3-dihydro- lH-l,3-benzodiazol-5-yl)methyl]-2-(4-hydroxy-3-methoxyphenyl)-N-methyl-lH-l,3- benzodiazole-5-carboxamide.89. The compound of paragraph 88, or a pharmaceutically acceptable salt thereof, wherein the compound has the chemical structure:90. The compound of paragraph 88, or a pharmaceutically acceptable salt thereof, wherein the compound has the chemical structure:91. A compound of Formula (Formula (I-B-l) or a pharmaceutically acceptable salt thereof, wherein:A1is C;A2isN, CR1, orNH;A? is N or C; provided that at least one of A2and A3 is N;Bi is C(Rc1Rc2), NRc3or oxygen;Rc1, Rcz, Rc3and Rdare each independently hydrogen or methyl;R1z is hydrogen or halogen; and R2o is carboxyl, alkyl-acetate or alkyl-amide.92. The compound of paragraph 91, or a pharmaceutically acceptable salt thereof, wherein the compound has the chemical structure:[000261] Some embodiments of the present invention can be defined as any of the following numbered paragraphs:1. A compound of Formula (I):Formula (I) wherein:Ra and Rb are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, or halogen; or Ra and Rb together form an alkenyl, carbonyl (=0), or a spirocyclic cycloalkyl optionally substituted with one or more R1o;A1and A2are each independently N, NH, or CR1; A2is N or C;provided that at least one of A1, A2and A3 is N;Bi is C(Rc1K;2), NRc3or oxygen;Rc1, Rc2, Rc3and Rdare each independently hydrogen or methyl;R1and R2 are each independently hydrogen, C1-4 alkyl, C1-4haloalkyl, amine, amide, carboxyl, alkyl-acetate, or alkyl-amide; or one of R1and R2 together form a fused 6-member aryl ring or fused 6-member heteroaryl ring optionally substituted with R20;R12 is hydrogen or halogen;R20 is carboxyl, alkyl-acetate, or alkyl-amide; andR30 is halogen, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl; provided the compound of Formula (I) is not l-[(l,3-dimethyl-2-oxo-2,3-dihydro-lH- l,3-benzodiazol-5-yl)methyl]-2-(4-hydroxy-3-methoxyphenyl)-N-methyl-lH-1,3-benzodiazole- 5-carboxamide.2. The compound of paragraph 1, wherein the compound is a compound of Formula (IT):Formula (II) wherein:Ra and Rb are each independently hydrogen, halogen, or C1-4alkyl optionally substituted with one or more halogen, or Raand Rb together form a spirocyclic cyclopropyl;A1and A2are each independently CH or N;R1o is methyl; andR12 is hydrogen or halogen.3. The compound of paragraph 2, wherein only one of A1and A2is N.4. The compound of any one of paragraphs 2-3, wherein R, and Rb are each independently hydrogen, methyl or ethyl, wherein the methyl or ethyl are optionally substituted with one or more fluoro.5. The compound of paragraph 4, wherein at least one of Ra and Rb is hydrogen.6. The compound of any one of paragraphs 2-5, wherein A1is N.7. The compound of any one of paragraphs 2-5, wherein A1is CH.8. The compound of any one of paragraphs 2-7, wherein R1o is methyl.9. The compound of any one of paragraphs 2-8, wherein R12 is fluoro.10. The compound of any one of paragraphs 2-8, wherein R12 is hydrogen.11 The compound of paragraph 2, wherein R1o is methyl.12. The compound of paragraph 11, wherein only one of A1and A2is N.13 The compound of paragraph 12, wherein Ra and Rb are each independently hydrogen, methyl, -CF3, or ethyl, and at least one of Ra and Rb is hydrogen.14. The compound of paragraph 13, wherein R12 is hydrogen or fluoro.15. The compound of paragraph 14, wherein A1is CH.16. The compound of paragraph 14, wherein A1is N.17. The compound of paragraph 15, wherein R12 is fluoro.18. The compound of paragraph 16, wherein R, and Rb are each hydrogen.19. The compound of paragraph 1, wherein the compound is a compound of Formula (111):Formula (III) wherein:Ra and Rb are each independently hydrogen, or C1-4 alkyl; or Ra and Rb together form a spirocyclic cyclopropyl;A1is CH or N;R1o is methyl;R12 is hydrogen or halogen; andRM is hydrogen, -C(O)OH, -C(O)O(CH.3), -C(O)NH2or C(O)NH(CH3).20. The compound of paragraph 19, wherein R1o is methyl.21. The compound of any one of paragraphs 19-20, wherein R1z is hydrogen or fluoro.22. The compound of any one of paragraphs 19-21, wherein Raand Rb are each independently hydrogen, methyl or ethyl.23. The compound of any one of paragraphs 19-21, wherein Ra and Rb are each independently hydrogen, or methyl.24. The compound of any one of paragraphs 19-23, wherein R20 is -C(O)OH, -C(O)O(CH3) or C(O)NH(CH3).25. The compound of any one of paragraphs 19-24, wherein A1is N.26. The compound of paragraph 25, wherein at least one of Ra and Rb is hydrogen.27. The compound of any one of paragraphs 19-22, wherein R2o is hydrogen.28. The compound of any one of paragraph 27, wherein R12 is hydrogen or fluorine.29. The compound of any one of paragraphs 26-28, wherein Ra and Rb are each hydrogen.30. The compound of any one of paragraphs 26-28, wherein R12 is hydrogen.31. The compound of any one of paragraphs 19-30, wherein R» and Rb are both hydrogen.32. The compound of paragraph 20, wherein Ra and Rb are each independently hydrogen, R12 is hydrogen or fluoro, and R20 is hydrogen.33. The compound of paragraph 32, wherein Ai is N.34. The compound of paragraph 33, wherein R12 is hydrogen.35. The compound of paragraph 33, wherein R12 is fluoro.36. The compound of paragraph 32, wherein At is CH.37. The compound of paragraph 36, wherein R12 is hydrogen.38. The compound of paragraph 36, wherein R12 is fluoro.39. A compound of Formula (IV):Formula (IV) wherein:Ra and Rb are each independently hydrogen, C1-4alkyl, or halogen; or Ra and Rb together form a spirocyclic cyclopropyl;Re is hydrogen or methyl; andR12 is hydrogen or halogen.40. The compound of paragraph 39, wherein R» is methyl.41. The compound of any one of paragraphs 39-40, wherein Raand Rb are each independently hydrogen, methyl, ethyl, fluoro, or together form a spirocyclic cyclopropyl.42. The compound of any one of paragraphs 39-40, wherein R, and Rb are each independently hydrogen, methyl, fluoro, or together form a spirocyclic cyclopropyl.43. The compound of any one of paragraphs 39-42, wherein R12 is hydrogen or fluoro.44. The compound of any one of paragraphs 39-43, wherein Ra and Rb together form a spirocyclic cyclopropyl.45. The compound of any one of paragraphs 39-43, wherein at least one of Ra and Rb is hydrogen.46. The compound of any one of paragraphs 39-43, wherein Ra is methyl and Rb is hydrogen.47. The compound of any one of paragraphs 39-43, wherein Ra and Rb are each hydrogen.48. The compound of paragraph 40, wherein Ra and Rb together form a spirocyclic cyclopropyl and R12 is hydrogen or fluoro.49. The compound of paragraph 40, wherein R, is methyl, Rb is hydrogen and R12 is hydrogen or fluoro.50. The compound of paragraph 40, wherein Ra is hydrogen, Rb is hydrogen and R12 is hydrogen or fluoro.51. A compound selected from the group consisting of:5-[(lS)-l-[2-(3-fluoro-4-hydroxy-5- methoxyphenyl)-lH-pyrrol-l-yl]ethyl]-l,3-dimethyl-2,3-dihydro-lH-l,3-benzodiazol-2-one;5-[(lR)-l-[2-(4-hydroxy-3-methoxyphenyl)-lH-pyrrol-l-yl]ethyl]-l,3-dimethyl-2,3-dihydro-lH- 1 ,3-benzodiazol-2-one;5-{[2-(3-fluoro-4-hydroxy-5-methoxyphenyl)-lH-l,3-benzodiazol-1-yl]methyl}-l,3-dimethyl- 2,3-dihydro- 1H- 1 ,3 -benzodiazol -2-one;5-[(l S)- 1 -[2-(3-fluoro-4-hydroxy-5-methoxyphenyl)- IH-pyrrol- 1 -yljpropyl]- 1 ,3-dimethyl-2, 3- dihydro-lH-l,3-benzodiazol-2-one; and l-[(l,3-dimethyl-2-oxo-2,3-dihydro-lH-l,3-benzodiazol-5-yl)methyl]-2-(4-hydroxy-3- methoxyphenyl)- 1H-1 ,3-benzodiazole-5-carboxylic acid.53. The compound of paragraph 51, wherein the compound is 5-[(lS)-l-[2-(3-fluoro-4-hydroxy- 5-methoxyphenyl)-lH-pyrrol-l-yl]ethyl]-l,3-dimethyl-2,3-dihydro-lH-l,3-benzodiazol-2-one.54. The compound of paragraph 51, wherein the compound is 5-[(lR)-l-[2-(4-hydroxy-3- methoxyphenyl)-lH-pyrrol-l-yl]ethyl]-l,3-dimethyl-2,3-dihydro-lH-l,3-benzodiazol-2-one.55. The compound of paragraph 51, wherein the compound is 5-{[2-(3-fluoro-4-hydroxy-5- methoxyphenyl)-lH-l,3-benzodiazol-l-yl]methyl}-l,3-dimethyl-2,3-dihydro-1H-l,3- benzodiazol-2-one.56. The compound of paragraph 51, wherein the compound is 5-[(lS)-l-[2-(3-fluoro-4-hydroxy- 5-methoxyphenyl)- IH-pyrrol- 1 -yljpropyl]- 1 ,3-dimethyl-2,3-dihydro- 1 H-l ,3 -benzodiazol -2-one.57. The compound of paragraph 51, wherein the compound is l-[(l,3-dimethyl-2-oxo-2,3- dihydro-lH-l,3-benzodiazol-5-yl)methyl]-2-(4-hydroxy-3-methoxyphenyl)-lH-l,3- benzodiazole-5-carboxylic acid.58. A compound selected from the group consisting of: a. methyl l-[(l,3-dimethyl-2-oxo-2,3-dihydro-lH-l,3-benzodiazol-5-yl)methyl]-2-(4-hydroxy- 3 -methoxyphenyl)- 1H- 1 ,3 -benzodi azole-5-carboxylate; b. N-[l-(l,3-dimethyl-2-oxo-2,3-dihydro-lH-l,3-benzodiazol-5-yl)cyclopropyl]-4-hydroxy-3- m ethoxy-N-methylbenzami de; c. 5- { [2-(4-hydroxy-3 -methoxyphenyl)- 1H- 1 ,3 -benzodiazol- 1 -yl]methyl } - 1 ,3 -dimethyl-2,3 - dihydro-lH-l,3-benzodiazol-2-one.59. The compound of paragraph 57, wherein the compound is methyl l-[(l,3-dimethyl-2-oxo- 2,3-dihydro- 1 H- 1 ,3 -benzodiazol-5-y l)methyl]-2-(4-hydroxy-3-methoxyphenyl)- 1 H- 1 ,3 - benzodiazole-5-carboxylate.60. The compound of paragraph 57, wherein the compound is N-[l-(l,3-dimethyl-2-oxo-2,3- dihydro-lH-l,3-benzodiazol-5-yl)cyclopropyl]-4-hydroxy-3-methoxy-N-methylbenzamide.61. The compound of paragraph 57, wherein the compound is 5-{[2-(4-hydroxy-3- methoxyphenyl)- 1H- 1 ,3 -benzodiazol- 1 -yljmethyl } - 1 ,3 -dimethyl-2, 3 -dihydro- 1H- 1,3- benzodiazol-2-one.62. A pharmaceutical composition comprising the compound:63. A pharmaceutical composition comprising the compound:64. A pharmaceutical composition comprising the compound:65. A pharmaceutical composition comprising the compound:66. A pharmaceutical composition comprising the compound:67. A pharmaceutical composition comprising the compound:68. A pharmaceutical composition comprising the compound:o / / O —■OHO69. A pharmaceutical composition comprising the compound: o / / o —70. A pharmaceutical composition comprising the compound: o w.o.■OHF71. A pharmaceutical composition comprising the compound:72. A pharmaceutical composition comprising the compound:73. A pharmaceutical composition comprising the compound:74. A pharmaceutical composition comprising the compound:o"3[ / 75. A pharmaceutical composition comprising the compound: o"3[IF76. A pharmaceutical composition comprising the compound: oNN -N N,0.‘OHF77. A pharmaceutical composition comprising the compound:78. A pharmaceutical composition comprising the compound:79. A pharmaceutical composition comprising the compound:80. A pharmaceutical composition comprising the compound:81. A pharmaceutical composition comprising the compound:82. A pharmaceutical composition of any one of paragraphs 61-81, formulated in combination with one or more excipients for oral administration.83. A compound of Formula (I-A-l):Formula (I- A-l) wherein:Ra and Rb are each independently hydrogen, C1-4 alkyl, C1-4haloalkyl, halogen, or together form a spirocyclic cycloalkyl optionally substituted with one or more R30;A1is NH;A2is C;A3is C;Bi is C(Rc1Rc2), NRc3or oxygen;Rc1, Rc2, Rc3and Rdare each independently hydrogen or methyl;R12 is hydrogen or halogen;R20 is carboxyl, alkyl-acetate or alkyl-amide; andR30 is halogen, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl;84. The compound of paragraph 83, wherein the compound has the chemical structure: OH85. The compound of paragraph 83, wherein the compound has the chemical structure:Formula (I-A-2) wherein:A1is NH;A2is C;A3 is C;Bi is C(Rc1Rc2), NRc3or oxygen;Rc1, Rc2, Rc3and Rdare each independently hydrogen or methyl;R12 is hydrogen or halogen; andR20 is carboxyl, alkyl-acetate or alkyl-amide.87. The compound of paragraph 86, wherein the compound has the chemical structure:88. A compound of FormulaFormula (I-B) wherein:R, and Rb are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, halogen, or together form a spirocyclic cycloalkyl optionally substituted with one or more R30,A1is C;A2is N, CR1, orNH;A3 is N or C; provided that at least one of A2and A3 is N;Bi is C(Rc1Rc2), NRc3or oxygen;Rc1, Rc2, Rc3and Rdare each independently hydrogen or methyl;R1is hydrogen, C1-4alkyl, C1-4haloalkyl, amine, amide, carboxyl, alkyl-acetate or alkyl-amide;R12 is hydrogen or halogen;R20 is carboxyl, alkyl-acetate or alkyl-amide;R30 is halogen, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl; provided the compound of Formula (I-B) is not l-[(l,3-dimethyl-2-oxo-2,3-dihydro- 1 H-l ,3-benzodiazol-5-yl)methyl]-2-(4-hydroxy-3-methoxyphenyl)-N-methyl-lH-l ,3- benzodiazole-5-carboxamide.89. The compound of paragraph 88, wherein the compound has the chemical structure:90. The compound of paragraph 88, wherein the compound has the chemical structure:91. A compound of FormulaFormula (I-B-l) wherein:At is C;A2isN, CR1, orNH;As is N or C; provided that at least one of A2and As is N;Bi is C(Rc1Rc2), NRCS or oxygen;Rc1, Rc2, Rc3and Rdare each independently hydrogen or methyl;R12 is hydrogen or halogen; andR20 is carboxyl, alkyl-acetate or alkyl-amide.92. The compound of paragraph 91, wherein the compound has the chemical structure:93. A compound having the chemical structure:or a pharmaceutically acceptable salt thereof.94. A compound having the chemical structure:O or a pharmaceutically acceptable salt thereof.[000262] Some embodiments of the present invention can be defined as any of the following numbered paragraphs:1. A method of inhibiting COMT in a subject in need thereof, the method comprising administering to the subject a COMT Inhibitor Compound of Formula (I):or a pharmaceutically acceptable salt, enantiomer, or racemate thereof, wherein:Ra and Rb are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, or halogen; or R* and Rb together form an alkenyl, carbonyl (=0), or a spirocyclic cycloalkyl optionally substituted with one or more R30;A1and A2are each independently N, NH, or CR1;A3 is N or C; provided that at least one of A1, A2and A3 is N;Bi is C(Rc1Rc2), NRc3or oxygen,Rc1, Rc2, Rc3and Rdare each independently hydrogen or methyl;R1and R2 are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, amine, amide, carboxyl, alkyl-acetate, or alkyl-amide; or one of R1and R2 together form a fused 6-member aryl ring or fused 6-member heteroaryl ring optionally substituted with R20;R12 is hydrogen or halogen;R20 is carboxyl, alkyl-acetate, or alkyl-amide; andR30 is halogen, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl.2. The method of paragraph 1, wherein the compound is a compound of Formula (II):Formula (H) or a pharmaceutically acceptable salt, enantiomer, or racemate thereof, wherein:Ra and Rb are each independently hydrogen, halogen, or Ci-4 alkyl optionally substituted with one or more halogen; or Ra and Rb together form a spirocyclic cyclopropyl;A1and A2are each independently CH or N;R1o is methyl; andRn is hydrogen or halogen.3. The method of paragraph 2, wherein only one of A1and Aj is N.4. The method of any one of paragraphs 2-3, wherein R» and Rj> are each independently hydrogen, methyl or ethyl, wherein the methyl or ethyl are optionally substituted with one or more fluoro.5. The method of paragraph 4, wherein at least one of Ra and Rb is hydrogen.6. The method of any one of paragraphs 2-5, wherein A1is N.7. The method of any one of paragraphs 2-5, wherein A1is CH.8. The method of any one of paragraphs 2-7, wherein R1o is methyl.9. The method of any one of paragraphs 2-8, wherein Rn is fluoro.10. The method of any one of paragraphs 2-8, wherein Rn is hydrogen.11. The method of paragraph 2, wherein R1o is methyl.12. The method of paragraph 11, wherein only one of A1and A2is N.13. The method of paragraph 12, wherein Ra and Rb are each independently hydrogen, methyl, - CF3, or ethyl, and at least one of Ra and Rb is hydrogen.14. The method of paragraph 13, wherein Rn is hydrogen or fluoro.15. The method of paragraph 14, wherein A1is CH.16. The method of paragraph 14, wherein A1is N.17. The method of paragraph 15, wherein Rn is fluoro.18. The method of paragraph 16, wherein Ra and Rb are each hydrogen.19. The method of paragraph 1, wherein the compound is a compound of Formula (III):Formula (III) or a pharmaceutically acceptable salt, enantiomer, or racemate thereof, wherein:Ra and Rb are each independently hydrogen, C1-4alkyl, or C1-4halo alkyl; or Ra and Rb together form a spirocyclic cyclopropyl;A1is CH orN;R1o is methyl;R12 is hydrogen or halogen; andR20 is hydrogen, -C(O)OH, -C(O)O(CH3), -C(O)NH2or C(O)NH(CH3).20. The method of paragraph 19, wherein R1o is methyl.21. The method of any one of paragraphs 19-20, wherein Rn is hydrogen or fluoro.22. The method of any one of paragraphs 19-21, wherein Ra and Rb are each independently hydrogen, methyl or ethyl.23. The method of any one of paragraphs 19-21, wherein Raand Rb are each independently hydrogen, or methyl.24. The method of any one of paragraphs 19-23, wherein R20 is -C(O)OH, -C(O)O(CH,3) or C(O)NH(CH3).25. The method of any one of paragraphs 19-24, wherein A1is N.26. The method of paragraph 25, wherein at least one of Raand Rb is hydrogen.27. The method of any one of paragraphs 19-22, wherein R20 is hydrogen.28. The method of any one of paragraphs 27, wherein R12 is hydrogen or fluorine.29. The method of any one of paragraphs 26-28, wherein Ra and Rb are each hydrogen.30. The method of any one of paragraphs 26-28, wherein R12 is hydrogen.31. The method of any one of paragraphs 19-30, wherein Ra and Rb are both hydrogen.32. The method of paragraph 20, wherein R» and Rb are each independently hydrogen, R12 is hydrogen or fluoro, and R20 is hydrogen.33. The method of paragraph 32, wherein A1is N.34. The method of paragraph 33, wherein R12 is hydrogen.35. The method of paragraph 33, wherein R12 is fluoro.36. The method of paragraph 32, wherein A1is CH.37. The method of paragraph 36, wherein R12 is hydrogen.38. The method of paragraph 36, wherein R12 is fluoro.39. A method of inhibiting COMT in a subject in need thereof, the method comprising administering to the subject a compound of Formula (IV):or a pharmaceutically acceptable salt, enantiomer, or racemate thereof, wherein:Ra and Rb are each independently hydrogen. C1-4alkyl, or halogen; or Ra and Rb together form a spirocyclic cyclopropyl;Re is hydrogen or methyl; andR12 is hydrogen or halogen.40. The method of paragraph 39, wherein Reis methyl.41. The method of any one of paragraphs 39-40, wherein Ra and Rb are each independently hydrogen, methyl, ethyl, fluoro, or together form a spirocyclic cyclopropyl.42. The method of any one of paragraphs 39-40, wherein Ra and Rb are each independently hydrogen, methyl, fluoro, or together form a spirocyclic cyclopropyl.43. The method of any one of paragraphs 39-42, wherein Rn is hydrogen or fluoro.44. The method of any one of paragraphs 39-43, wherein Ra and Rb together form a spirocyclic cyclopropyl.45. The method of any one of paragraphs 39-43, wherein at least one of Ra and Rb is hydrogen46. The method of any one of paragraphs 39-43, wherein Ra is methyl and Rb is hydrogen.47. The method of any one of paragraphs 39-43, wherein Ra and Rb are each hydrogen.48. The method of paragraph 40, wherein Ra and Rb together form a spirocyclic cyclopropyl andR12 is hydrogen or fluoro.49. The method of paragraph 40, wherein Ra is methyl, Rb is hydrogen and R12 is hydrogen or fluoro.50. The method of paragraph 40, wherein Ra is hydrogen, Rb is hydrogen and R12 is hydrogen or fluoro.51. A method of inhibiting COMT in a subject in need thereof, the method comprising administering to the subject a compound selected from the group consisting of: o 5-[( 1 S)-l - [2-(3 -fluoro-4-hydroxy-5-methoxyphenyl)- 1 H-pyrrol- 1 -yl] ethyl ] - 1 ,3- dimethyl-2,3-dihydro- 1H- 1 ,3-benzodiazol-2-one; o 5-[(lR)-l-[2-(4-hydroxy-3-methoxyphenyl)-lH-pyrrol-l-yl]ethyl]-l,3-dimethyl-2.3-dihydro-l H-l ,3-benzodiazol-2-one; o 5- { [2-(3 -fluoro-4-hydroxy-5-methoxyphenyl)- 1 H- 1 ,3-benzodiazol- 1 -yljmethyl } -1.3-dimethyl-2,3-dihydro-l H-l ,3-benzodiazol -2-one; o 5-[( 1 S)-l -[2-(3 -fluoro-4-hydroxy-5-methoxyphenyl)- IH-pyrrol- 1 -yljpropyl]- 1,3- dimethyl-2,3-dihydro-lH-l,3-benzodiazol-2-one; and o l-[(l,3-dimethyl-2-oxo-2,3-dihydro-lH-l,3-benzodiazol-5-yl)methyl]-2-(4- hydroxy-3-methoxyphenyl)-lH-l,3-benzodiazole-5-carboxylic acid; or a pharmaceutically acceptable salt thereof.52. The method of paragraph 51, or a pharmaceutically acceptable salt thereof, wherein the compound is 5-[(l S)-l-[2-(3-fluoro-4-hydroxy-5-methoxyphenyl)-lH-pyrrol-l-yl]ethyl]-l,3- dimethyl-2,3-dihydro-lH-l,3-benzodiazol-2-one.53. The method of paragraph 51, or a pharmaceutically acceptable salt thereof, wherein the compound is 5-[(lR)-l-[2-(4-hydroxy-3-methoxyphenyl)-lH-pyrrol-l-yl]ethyl]-l,3-dimethyl- 2, 3-dihydro- 1H- 1 ,3-benzodiazol -2-one.54. The method of paragraph 51, or a pharmaceutically acceptable salt thereof, wherein the compound is 5-{[2-(3-fluoro-4-hydroxy-5-methoxyphenyl)-lH-l,3-benzodiazol-l-yl]methyl}- 1 ,3-dimethyl -2, 3-dihydro- 1 H- 1 ,3-benzodiazol -2-one.55. The method of paragraph 51, or a pharmaceutically acceptable salt thereof, wherein the compound is 5-[( 1 S)- 1 -[2-(3-fluoro-4-hydroxy-5-methoxyphenyl)- 1 H-pyrrol- 1 -yljpropyl]- 1,3- dimethyl-2,3-dihydro-lH-l,3-benzodiazol-2-one.56. The method of paragraph 51, or a pharmaceutically acceptable salt thereof, wherein the compound is 1 -[(1 ,3-dimethyl-2-oxo-2, 3-dihydro- 1H- 1 ,3-benzodiazol-5-yl)methyl]-2-(4- hydroxy-3-methoxyphenyl)-l H-l ,3-benzodiazole-5-carboxylic acid.57. A method of inhibiting COMT in a subject in need thereof, the method comprising administering to the subject a compound selected from the group consisting of: a. methyl l-[(l,3-dimethyl-2-oxo-2,3-dihydro-lH-l,3-benzodiazol-5-yl)methyl]-2-(4-hydroxy-3-methoxyphenyl)-l H-l ,3-benzodiazole-5-carboxylate; b. N-[l-(l,3-dimethyl-2-oxo-2,3-dihydro-lH-l,3-benzodiazol-5-yl)cyclopropylJ- 4-hydroxy-3-methoxy-N-methylbenzamide; and c. 5- { [2-(4-hy droxy-3 -methoxy phenyl)- 1 H- 1 ,3 -benzodi azol- 1 -yljmethy I } - 1 ,3 - dimethyl -2, 3-dihydro- 1H- 1 ,3-benzodiazol-2-one; or a pharmaceutically acceptable salt thereof.58. The method of paragraph 57, wherein the compound is methyl 1 -[(1,3 -dimethyl -2-oxo-2, 3- dihydro-lH-l,3-benzodiazol-5-yl)methyl]-2-(4-hydroxy-3-methoxyphenyl)-lH-l,3- benzodiazole-5-carboxylate.59. The method of paragraph 57, wherein the compound is N-[l-(l,3-dimethyl-2-oxo-2,3- dihydro-lH-l,3-benzodiazol-5-yl)cyclopropyl]-4-hydroxy-3-methoxy-N-methylbenzamide.60. The method of paragraph 57, wherein the compound is 5-{[2-(4-hydroxy-3-methoxyphenyl)- 1 H- 1 ,3 -benzodiazol - 1 -yl ]m ethyl } - 1 ,3 -dimethyl -2, 3 -dihydro- 1 H- 1 ,3-benzodiazol -2-one.61. A method of inhibiting COMT in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a compound:, or a pharmaceutically acceptable salt thereof.62. A method of inhibiting COMT in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a compound:, or a pharmaceutically acceptable salt thereof.63. A method of inhibiting COMT in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a compound:, or a pharmaceutically acceptable salt thereof.64. A method of inhibiting COMT in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a compound:, or a pharmaceutically acceptable salt thereof.65. A method of inhibiting COMT in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a compound:, or a pharmaceutically acceptable salt thereof.66. A method of inhibiting COMT in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a compound:, or a pharmaceutically acceptable salt thereof.67. A method of inhibiting COMT in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a compound:, or a pharmaceutically acceptable salt thereof.68. A method of inhibiting COMT in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a compound:, or a pharmaceutically acceptable salt thereof.69. The method of any one of paragraphs 61-68, wherein the administration is an oral administration of a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof.70. A method of inhibiting COMT in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a compound:, or a pharmaceutically acceptable salt thereof.71. A method of inhibiting COMT in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a compound., or a pharmaceutically acceptable salt thereof.72. A method of inhibiting COMT in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a compound:, or a pharmaceutically acceptable salt thereof.73. A method of inhibiting COMT in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a compound. o, or a pharmaceutically acceptable salt, enantiomer, or racemate thereof.74. A method of inhibiting COMT in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a compound:, or a pharmaceutically acceptable salt, enantiomer, or racemate thereof.75. A method of inhibiting COMT in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a compound:, or a pharmaceutically acceptable salt, enantiomer, or racemate thereof.76. A method of inhibiting COMT in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a compound:, or a pharmaceutically acceptable salt, enantiomer, or racemate thereof.77. A method of inhibiting COMT in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a compound:, or a pharmaceutically acceptable salt, enantiomer, or racemate thereof.78. A method of inhibiting COMT in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a compound:, or a pharmaceutically acceptable salt thereof.79. A method of inhibiting COMT in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a compound:, or a pharmaceutically acceptable salt thereof.80. A method of inhibiting COMT in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a compound., or a pharmaceutically acceptable salt, enantiomer, or racemate thereof.SL A method of inhibiting COMT in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a compound:, or a pharmaceutically acceptable salt thereof.82. A method of inhibiting COMT in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a compound:, or a pharmaceutically acceptable salt thereof.83. A method of inhibiting COMT in a subject in need thereof, the method comprising administering to the subject a COMT inhibitor compound: l-[(l,3-dimethyl-2-oxo-2,3-dihydro- lH-l,3-benzodiazol-5-yl)methyl]-2-(4-hydroxy-3-methoxyphenyl)-N-methyl-1H-l,3- benzodiazole-5-carboxamide, or a pharmaceutically acceptable salt thereof.84. The method of any one of paragraphs 1-83, 98 or 99, wherein the compound is administered in combination with L-DOPA, and wherein the subject is diagnosed with Parkinson’s disease.85. The method of any one of paragraphs 1-83, 98 or 99, wherein administration of the compound is for the treatment of Parkinson’s disease as an adjunct to levodopa / carbidopa therapy.86. The method of any one of paragraphs 1-83, 98 or 99, wherein the compound is administered in conjunction with levodopa and an aromatic amino acid decarboxylase inhibitor.87. The method of any one of paragraphs 1-83, 98 or 99, wherein the compound is administered in conjunction with levodopa and carbidopa.88. The method of any one of paragraphs 84-87, wherein administration of the compound to the subject diagnosed with Parkinson’s disease increases the relative bioavailability of levodopa in the subject.89. The method of any one of paragraphs 84-88, wherein the method further comprises assessing the patient using at least one or more sub-parts of the Unified Parkinson’s Disease Rating Scale (UPDRS).90. The method of any one of paragraphs 84-89, wherein the method further comprises reducing a dose of L-DOPA administered to the subject to less than about 600 mg per day.91. The method of paragraph 90, wherein the method further comprises reducing the dose of L- DOPA administered to the subject by about 30% or more per day after administration of the COMT inhibitor compound.92. The method of any one of paragraphs 1-83, wherein the subject is not receiving L-DOPA.93. The method of paragraph 92, wherein the subject is diagnosed with depression prior to administration of the compound.94. The method of any one of paragraphs 92-93, wherein the subject is diagnosed with Major Depressive Disorder (MDD).95. The method of any one of paragraphs 92-93, wherein the COMT Inhibitor Compound is administered to the subject for treatment of Major Depressive Disorder (MDD).96. The method of any one of paragraphs 92-95, wherein the subject is diagnosed with MDD using the Structured Clinical Interview for DSM-IV, and an initial score of greater than or equal to 16 on the 17-item Hamilton Rating Scale for Depression (HAM-D-17).97. The method of paragraph 96, further comprising assessing the subject with one or more of the HAM-D-17, the Clinical Global Impressions Severity (CGI-S) scale, or the Beck Depression Inventory (BDI).98. A method of inhibiting COMT in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a compound:pharmaceutically acceptable salt thereof.99. A method of inhibiting COMT in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a compound:pharmaceutically acceptable salt thereof.[000263] Some embodiments of the present invention can be defined as any of the following numbered paragraphs:1. A compound of Formula (I):Formula (I) or a pharmaceutically acceptable salt, enantiomer, or racemate thereof, wherein:Ra and Rb are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, or halogen; or R* and Rb together form an alkenyl, carbonyl (=0), or a spirocyclic cycloalkyl optionally substituted with one or more R30;A1and A2are each independently N, NH, or CR1;A3 is N or C; provided that at least one of A1, A2and A3 is N;Bi is C(Rc1Rc2), NRc3or oxygen,Rc1, Rc2, Rc3and Rdare each independently hydrogen or methyl;R1and R2 are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, amine, amide, carboxyl, alkyl-acetate, or alkyl-amide; or one of R1and R2 together form a fused 6-member aryl ring or fused 6-member heteroaryl ring optionally substituted with R20;R12 is hydrogen or halogen;R20 is carboxyl, alkyl-acetate, or alkyl-amide; andR30 is halogen, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl; provided the compound of Formula (I) is not 1 -[(l,3-dimethyl-2-oxo-2,3-dihydro-lH- l,3-benzodiazol-5-yl)methyl]-2-(4-hydroxy-3-methoxyphenyl)-N-methyl-lH-l,3- benzodiazole-5-carboxamide.2. The compound of claim 1, wherein the compound is a compound of Formula (II):Formula (II) or a pharmaceutically acceptable salt, enantiomer, or racemate thereof, wherein:Ra and Rb are each independently hydrogen, halogen, or Ci-4 alkyl optionally substituted with one or more halogen; or R, and Rb together form a spirocyclic cyclopropyl;A1and A2are each independently CH or N;R1o is methyl; andR12 is hydrogen or halogen.3. The compound of claim 2, wherein only one of A1and A2is N.4. The compound of any one of claims 2-3, wherein Ra and Rb are each independently hydrogen, methyl or ethyl, wherein the methyl or ethyl are optionally substituted with one or more fluoro.5. The compound of claim 4, wherein at least one of Ra and Rb is hydrogen.6. The compound of any one of claims 2-5, wherein A1is N.7. The compound of any one of claims 2-5, wherein A1is CH.8. The compound of any one of claims 2-7, wherein R1o is methyl .9. The compound of any one of claims 2-8, wherein R12 is fluoro.10. The compound of any one of claims 2-8, wherein R12 is hydrogen.11. The compound of claim 2, wherein R1o is methyl.12. The compound of claim 11, wherein only one of A1and A2is N.13. The compound of claim 12, wherein R, and Rb are each independently hydrogen, methyl, -CF3, or ethyl, and at least one of Ra and Rb is hydrogen.14. The compound of claim 13, wherein R12 is hydrogen or fluoro.15. The compound of claim 14, wherein A1is CH.16. The compound of claim 14, wherein A1is N.17. The compound of claim 15, wherein R12 is fluoro.18. The compound of claim 16, wherein Raand Rb are each hydrogen.19. The compound of claim 1, wherein the compound is a compound of Formula (III):Formula (III) or a pharmaceutically acceptable salt, enantiomer, or racemate thereof, wherein:Ra and Rb are each independently hydrogen, or C1-4alkyl; or Ra and Rb together form a spirocyclic cyclopropyl;A1is CH or N;R1o is methyl;R12 is hydrogen or halogen; andR20 is hydrogen, -C(O)OH, -C(O)O(CH3), -C(O)NH2or C(O)NH(CH3).20. The compound of claim 19, wherein R1o is methyl.21. The compound of any one of claims 19-20, wherein R12 is hydrogen or fluoro.22. The compound of any one of claims 19-21, wherein Ra and Rb are each independently hydrogen, methyl or ethyl.23. The compound of any one of claims 19-21, wherein Ra and Rb are each independently hydrogen, or methyl.24. The compound of any one of claims 19-23, wherein R20 is -C(O)OH, -C(O)O(CH3) or C(O)NH(CH3).25. The compound of any one of claims 19-24, wherein Aj is N.26. The compound of claim 25, wherein at least one of Ra and Rb is hydrogen.27. The compound of any one of claims 19-22, wherein R20 is hydrogen.28. The compound of any one of claims 27, wherein R12 is hydrogen or fluorine.29. The compound of any one of claims 26-28, wherein Ra and Rb are each hydrogen.30. The compound of any one of claims 26-28, wherein R12 is hydrogen.31 The compound of any one of claims 19-30, wherein Ra and Rb are both hydrogen.32. The compound of claim 20, wherein Ra and Rb are each independently hydrogen, R12 is hydrogen or fluoro, and R20 is hydrogen.33. The compound of claim 32, wherein A1is N.34. The compound of claim 33, wherein R12 is hydrogen.35. The compound of claim 33, wherein R12 is fluoro.36. The compound of claim 32, wherein A1is CH.37. The compound of claim 36, wherein R12 is hydrogen.38. The compound of claim 36, wherein R12 is fluoro.39. A compound of Formula (TV):Formula (IV) or a pharmaceutically acceptable salt, enantiomer, or racemate thereof, wherein:Ra and Rb are each independently hydrogen, C1-4alkyl, or halogen; or Ra and Rb together form a spirocyclic cyclopropyl;Re is hydrogen or methyl; andR12 is hydrogen or halogen.40. The compound of claim 39, wherein Re is methyl.41. The compound of any one of claims 39-40, wherein R» and Rb are each independently hydrogen, methyl, ethyl, fluoro, or together form a spirocyclic cyclopropyl.42. The compound of any one of claims 39-40, wherein Ra and Rb are each independently hydrogen, methyl, fluoro, or together form a spirocyclic cyclopropyl .43. The compound of any one of claims 39-42, wherein R12 is hydrogen or fluoro.44. The compound of any one of claims 39-43, wherein Ra and Rb together form a spirocyclic cyclopropyl.45. The compound of any one of claims 39-43, wherein at least one of Ra and Rb is hydrogen.46. The compound of any one of claims 39-43, wherein Ra is methyl and Rb is hydrogen.47. The compound of any one of claims 39-43, wherein Ra and Rb are each hydrogen.48. The compound of claim 40, wherein Ra and Rb together form a spirocyclic cyclopropyl and R12 is hydrogen or fluoro.49. The compound of claim 40, wherein Ra is methyl, Rb is hydrogen and R12 is hydrogen or fluoro.50. The compound of claim 40, wherein Rais hydrogen, Rb is hydrogen and R12 is hydrogen or fluoro.51. A compound selected from the group consisting of: a. 5-[(lS)-l-[2-(3-fluoro-4-hydroxy-5-methoxyphenyl)-lH-pyrrol-l-yl]ethyl]-l,3- dimethyl -2, 3 -dihydro- 1 H- 1 , 3 -benzodi azol -2-one; b. 5-[(lR)-l-[2-(4-hydroxy-3-methoxyphenyl)-lH-pyrrol-l-yl]ethyl]-l,3-dimethyl-2.3-dihydro- 1H-1 ,3 -benzodiazol-2-one; c. 5-{ [2-(3 -fluoro-4-hydroxy-5-methoxyphenyl)- 1H- 1 ,3-benzodiazol- 1 -yljmethyl }-1.3-dimethyl-2,3-dihydro-lH-l,3-benzodiazol-2-one; d. 5-[(l S)-l-[2-(3-fluoro-4-hydroxy-5-methoxyphenyl)-lH-pyrrol-l-yl]propyl]-1,3- dimethyl-2,3-dihydro-lH-l,3-benzodiazol-2-one; and e. l-[(l,3-dimethyl-2-oxo-2,3-dihydro-lH-l,3-benzodiazol-5-yl)methyl]-2-(4- hydroxy-3-methoxyphenyl)-lH-l,3-benzodiazole-5-carboxylic acid; or a pharmaceutically acceptable salt thereof.52. The compound of claim 51, or a pharmaceutically acceptable salt thereof, wherein the compound is 5-[(l S)- 1 -[2-(3-fluoro-4-hydroxy-5-methoxyphenyl)- IH-pyrrol- 1 -yljethyl]-1 ,3-dimethy I -2,3-dihydro- 1 H- 1 ,3-benzodiazol-2-one.53. The compound of claim 51, or a pharmaceutically acceptable salt thereof, wherein the compound is 5-[(lR)-l-[2-(4-hydroxy-3-methoxyphenyl)-lH-pyrrol-l-yl]ethyl]-l,3- dimethyl-2, 3 -dihydro- 1H- 1 ,3 -benzodi azol-2-one.54. The compound of claim 51, or a pharmaceutically acceptable salt thereof, wherein the compound is 5- { [2-(3-fluoro-4-hydroxy-5-methoxyphenyl)- 1H-1 ,3-benzodiazol- 1 - yljmethyl } - 1 ,3-dimethy 1-2,3 -dihydro- 1 H- 1 ,3 -benzodiazol-2-one.55. The compound of claim 51, or a pharmaceutically acceptable salt thereof, wherein the compound is 5-[( 1 S)- 1 -[2-(3-fluoro-4-hydroxy-5-methoxyphenyl)- lH-pyrrol- 1 - yljpropy 1J-1 ,3-dimethyl-2,3-dihydro-l H-l,3-benzodiazol-2-one.56. The compound of claim 51, or a pharmaceutically acceptable salt thereof, wherein the compound is l-[(l,3-dimethyl-2-oxo-2,3-dihydro-lH-l,3-benzodiazol-5-yl)methyl]-2-(4- hydroxy-3 -methoxyphenyl)- 1H-1 ,3-benzodiazole-5-carboxylic acid.57. A compound selected from the group consisting of: a. methyl l-[(l,3-dimethyl-2-oxo-2,3-dihydro-lH-l,3-benzodiazol-5-yl)methyl]-2- (4-hydroxy-3 -methoxyphenyl)- 1 H- 1 ,3-benzodiazole-5-carboxylate; b. N-[l-(l,3-dimethyl-2-oxo-2,3-dihydro-lH-l,3-benzodiazol-5-yl)cyclopropylJ-4- hy droxy-3 -methoxy- N -methylbenzamide; c. 5-{ [2-(4-hydroxy-3-methoxyphenyl)- 1H- 1 ,3 -benzodiazol- 1 -yl Jmethyl }- 1 ,3 - dimethyl-2,3-dihydro-lH-l,3-benzodiazol-2-one; or a pharmaceutically acceptable salt thereof.58. The compound of claim 57, wherein the compound is methyl l-[(l,3-dimethyl-2-oxo-2,3- dihydro-1H-l,3-benzodiazol-5-yl)methyl]-2-(4-hydroxy-3-methoxyphenyl)-lH-l,3- benzodiazol e-5-carboxyl ate.59. The compound of claim 57, wherein the compound is N-[l-(l,3-dimethyl-2-oxo-2,3- dihydro-lH-l,3-benzodiazol-5-yl)cyclopropyl]-4-hydroxy-3-methoxy-N- methylbenzamide.60. The compound of claim 57, wherein the compound is 5-{[2-(4-hydroxy-3- methoxyphenyl)- 1H- 1 ,3 -benzodiazol- 1 -yljmethyl } - l,3-dimethyl-2,3-dihydro- 1 H- 1,3- benzodiazol-2-one.61. A pharmaceutical composition comprising the compound:F, or a pharmaceutically acceptable salt thereof.62. A pharmaceutical composition comprising the compound:, or a pharmaceutically acceptable salt thereof.63. A pharmaceutical composition comprising the compound:, or a pharmaceutically acceptable salt thereof.64. A pharmaceutical composition comprising the compound:, or a pharmaceutically acceptable salt thereof.65. A pharmaceutical composition comprising the compound:, or a pharmaceutically acceptable salt thereof.66. A pharmaceutical composition comprising the compound:, or a pharmaceutically acceptable salt thereof.67. A pharmaceutical composition comprising the compound:, or a pharmaceutically acceptable salt thereof.68. A pharmaceutical composition comprising the compound:, or a pharmaceutically acceptable salt thereof.69. A pharmaceutical composition comprising the compound:, or a pharmaceutically acceptable salt thereof.70. A pharmaceutical composition comprising the compound:, or a pharmaceutically acceptable salt thereof.71. A pharmaceutical composition comprising the compound:, or a pharmaceutically acceptable salt thereof.72. A pharmaceutical composition comprising the compound:, or a pharmaceutically acceptable salt, enantiomer, or racematethereof.73. A pharmaceutical composition comprising the compound:, or a pharmaceutically acceptable salt, enantiomer, or racemate thereof.74. A pharmaceutical composition comprising the compound:, or a pharmaceutically acceptable salt, enantiomer, or racemate thereof.75. A pharmaceutical composition comprising the compound:, or a pharmaceutically acceptable salt, enantiomer, or racemate thereof.76. A pharmaceutical composition comprising the compound:, or a pharmaceutically acceptable salt, enantiomer, or racemate thereof.77. A pharmaceutical composition comprising the compound:, or a pharmaceutically acceptable salt thereof.78. A pharmaceutical composition comprising the compound:, or a pharmaceutically acceptable salt thereof.79. A pharmaceutical composition comprising the compound:pharmaceutically acceptable salt, enantiomer, or racemate thereof.80. A pharmaceutical composition comprising the compound:or a pharmaceutically acceptable salt thereof.81. A pharmaceutical composition comprising the compound:or a pharmaceutically acceptable salt thereof.82. A pharmaceutical composition of any one of claims 61-81, formulated in combination with one or more excipients for oral administration.83. A compound of Formula (I-A-l):or a pharmaceutically acceptable salt, enantiomer, or racemate thereof, wherein:R« and Rb are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, halogen, or together form a spirocyclic cycloalkyl optionally substituted with one or more R30;A1is NH, A2is C;A1is C;Bi is C(Rc1Rc2), NRc3or oxygen;Rc1, Rc2, Rc3and Rdare each independently hydrogen or methyl,R12 is hydrogen or halogen;R20 is carboxyl, alkyl-acetate or alkyl-amide; andR30 is halogen, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl;84. The compound of claim 83, or a pharmaceutically acceptable salt, enantiomer, or racemate thereof, wherein the compound has the chemical structure:OH.85. The compound of claim 83, or a pharmaceutically acceptable salt, enantiomer, or racemate thereof, wherein the compound has the chemical structure:Formula (I-A-2) or a pharmaceutically acceptable salt thereof, wherein:A1is NH; A2is C;A3 is C;Bi is C(Rc1K;2), NRc3or oxygen;Rc1, Rc2, Rc3and Rdare each independently hydrogen or methyl;R12 is hydrogen or halogen; andR20 is carboxyl, alkyl-acetate or alkyl-amide.87. The compound of claim 86, or a pharmaceutically acceptable salt thereof, wherein the compound has the chemical structure:88. A compound of Formula (I-B):or a pharmaceutically acceptable salt, enantiomer, or racemate thereof, wherein:Ra and Rb are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, halogen, or together form a spirocyclic cycloalkyl optionally substituted with one or more R30;A1is C; A2is N, CR1, or NH;A? is N or C; provided that at least one of A2and A? is N;Bi is C(Rc1Rc2), NRc3or oxygen;Rc1, Rc2, Rc3and Rdare each independently hydrogen or methyl;R1is hydrogen, C1-4 alkyl, C1-4haloalkyl, amine, amide, carboxyl, alkyl-acetate or alkyl-amide;R12 is hydrogen or halogen;R20 is carboxyl, alkyl-acetate or alkyl-amide;R30 is halogen, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl; provided the compound of Formula (I-B) is not l-[(l,3-dimethyl-2-oxo-2,3-dihydro- lH-l,3-benzodiazol-5-yl)methyl]-2-(4-hydroxy-3-methoxyphenyl)-N-methyl-lH-l,3- benzodiazole-5-carboxamide.89. The compound of claim 88, or a pharmaceutically acceptable salt, enantiomer, or racemate thereof, wherein the compound has the chemical structure:90. The compound of claim 88, or a pharmaceutically acceptable salt, enantiomer, or racemate thereof, wherein the compound has the chemical structure:91. A compound of FormulaFormula (I-B-l) or a pharmaceutically acceptable salt thereof, wherein:A1is C; A2isN, CR1, orNH;A3 is N or C; provided that at least one of A2and A3 is N;Bi is C(Rc1Rcz), NRc3or oxygen;Rc1, Rc2, Rc3and Rdare each independently hydrogen or methyl,R12 is hydrogen or halogen; andR20 is carboxyl, alkyl -acetate or alkyl -amide.92. The compound of claim 91, or a pharmaceutically acceptable salt thereof, wherein the compound has the chemical structure:93. A compound having the chemical structure:or a pharmaceutically acceptable salt thereof.94. A compound having the chemical structure:or a pharmaceutically acceptable salt thereof.95. A compound of Formula (V-A-l) or Formula (V-A-2) or a pharmaceutically acceptable salt thereof:wherein,Ra and Rb are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, or halogen; or R« and Rb together form an alkenyl, carbonyl (=0), or a spirocyclic cycloalkyl optionally substituted with one or more R30;A1and A2are each independently N, NH or CR1;At is N or C; provided that at least one of A1, A2and A3 is N;Bi is C(Rc1Rc2), NRc3or oxygen;Rc1, Rc2, R<3 and Rdare each independently hydrogen, C1-4alkyl or C3-6 cycloalkyl;R1and R2are each independently hydrogen. C1-4alkyl, C1-4haloalkyl, amine, amide, carboxyl, alkyl-acetate or alkyl-amide; or one of R1and R2together form a fused 6-member aryl ring or fused 6-member heteroaryl ring optionally substituted with R2o; each of R12a, R12b, R12c, R12d, and R12e, is independently hydrogen, nitro, alkoxy, hydroxy or halogen; R2o is carboxyl, alkyl-acetate or alkyl-amide; andR30 is halogen, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl.96. A compound of Formula (V-B) or a pharmaceutically acceptable salt thereof:wherein,Ri and Rb are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, or halogen; or Raand Rb together form a spirocyclic cycloalkyl optionally substituted with one or more R30;A1is NH; A2is C;A3is C;Bi is C(Rc1Rc2), NRc3or oxygen;Rc1, Rc2, R<3 and Rdare each independently hydrogen, C1-4alkyl or C3-6 cycloalkyl;R1is hydrogen, C1-4alkyl, C1-4haloalkyl, amine, amide, carboxyl, alkyl-acetate or alkyl-amide;each of R12a, R12b, R12c, and Rna, is independently hydrogen, nitro, alkoxy, hydroxy or halogen; R12eis hydrogen, nitro, alkoxy, hydroxy or halogen; or R1zeand Rb are together alkyl;R20 is carboxyl, alkyl-acetate or alkyl-amide; andR30 is halogen, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl.97. The compound of claim 96, wherein the compound is a compound of Formula (V-B-1), or a pharmaceutically acceptable salt thereof:Formula (V-B-l).98. A compound of Formula (V-C) or a pharmaceutically acceptable salt thereof:wherein,Ra and Rb are each independently hydrogen, C1-4 alkyl, C1-4haloalkyl, or halogen; orRa and Rb together form a spirocyclic cycloalkyl optionally substituted with one or more R30;A1is C; A2is N, NH or CR1;A3 is N or C; provided that at least one of Aa and A3 is N, or provided Aa is NH if A3 is C;Bi is C(Rc1Rc2), NRc3or oxygen;Rc1, Rc2, R<3 and Ra are each independently hydrogen, C1-4alkyl or C3-6 cycloalkyl;R1is hydrogen, C1-4alkyl, C1-4haloalkyl, amine, amide, carboxyl, alkyl-acetate or alkyl-amide; each of Rua, R12b, R12c, and R1ad, is independently hydrogen, nitro, alkoxy, hydroxy or halogen; R12eis hydrogen, nitro, alkoxy, hydroxy or halogen; or R1?e and Rb are together alkyl;R20 is carboxyl, alkyl-acetate or alkyl-amide; andR30 is halogen, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl.99. The compound of claim 98, wherein the compound is a compound of Formula (V-D) or a pharmaceutically acceptable salt thereof:100. The compound of any one of claims 95-96, or 98, wherein Ra and Rb are each independently hydrogen, methyl optionally substituted with one or more fluoro, or fluoro, or Ra and Rb together form a spirocyclic cyclopropyl.101. The compound of claim 100, wherein R, is hydrogen and Rb is methyl.102. The compound of claim 100, wherein R» is hydrogen and Rb is -CF3.103. The method of claim 100, wherein Ra is hydrogen and Rb is fluoro.104. The method of claim 100, wherein Ra is fluoro and Rb is fluoro.105. The method of claim 100, wherein Ra and Rb together form carbonyl (C=O).106. The method of claim 100, wherein Raand Rb together form alkenyl (C=CH2).107. The compound of any one of claims 95-99, whereinR12* is hydrogen or fluoro;R12bis hydrogen, nitro or fluoro;R12C is hydroxyl;R12d is hydroxyl, or methoxy; and R12e, is hydrogen.108. The compound of any one of claims 95-99, whereinR12a is hydrogen;R12bis fluoro;R12c is hydroxyl;R12d is methoxy; and R12e, is hydrogen.109. The compound of any one of claims 95-99, whereinR12a is hydrogen;R12bis nitro;R12c is hydroxyl;R12d is methoxy; and R12e, is hydrogen.110. The compound of any one of claims 95-99, whereinR12a is hydrogen;R12bis nitro; R12eis hydroxyl;Rud is hydroxyl; and R12e, is hydrogen.111. The compound of any one of claims 95-99, whereinR12a is fluoro;R12bis fluoro;R12c is hydroxyl;R12d is hydroxyl; and R12e, is hydrogen.112. The compound of any one of claims 95-99, whereinRua is hydrogen;R12bis fluoro,R12c is hydroxyl;R12d is hydroxyl; and R12e, is hydrogen.113. The compound of any one of claims 95-112, wherein Bi is NRc3.114. The compound of claim 113, wherein R.3 is methyl.115. The compound of claim 113, wherein RC3 is hydrogen.116. The compound of any one of claims 95-112, wherein Bi is oxygen.117. The compound of any one of claims 95-116, wherein Rdis methyl.118. The compound of any one of claims 95-116, wherein Rdis cyclopropyl.119. The compound of any one of claims 95-116, wherein Rdis isopropyl.120. The compound of any one of claims 95-116, wherein Rdis hydrogen.121. The compound of any one of claims 95 or 100-120, wherein A1is CH, A2is CH andA1is N.122. The compound of any one of claims 95 or 100-120, wherein A1is N, A2is CH and A3 is N.123. The compound of any one of claims 95 or 100-120, wherein the compound is a compound of Formula (V-A-2) and A1and A3 are each N and A2is CH.124. The compound of any one of claims 95-123, wherein R1and R2 are each hydrogen.125. A compound selected from the group consisting of:529 528 527or a pharmaceutically acceptable salt thereof.[000264] Further, although preferred embodiments have been depicted and described in detail herein, it will be apparent to those skilled in the relevant art that various modifications, additions, substitutions, and the like can be made without departing from the spirit of the invention and these are therefore considered to be within the scope of the invention as defined in the claims which follow. Further, to the extent not already indicated, it will be understood by those of ordinary skill in the art that any one of the various embodiments herein described and illustrated can be further modified to incorporate features shown in any of the other embodiments disclosed herein.EXAMPLES[000265] The following examples illustrate some embodiments and aspects of the invention. It will be apparent to those skilled in the relevant art that various modifications, additions, substitutions, and the like can be performed without altering the spirit or scope of the invention, and such modifications and variations are encompassed within the scope of the invention as defined in the claims which follow. The following examples do not in any way limit the invention.Example 1: Preparation of Compounds 001, 015 and 016.(1-((1.3-dimethyl-2-oxo-2, 3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)-2-( 4-hydroxy-3- methoxypheT^l)-N-methyl-lH-benzo[d]imidazole-5-carboxamide) [Compound 001 or PSY-01- OOOOlj; methyl 1-[(1, 3-dimethyl-2-oxo-2, 3-dihydro-lH-l, 3-benzodiazol-5-yl)methyl]-2-(4-hydroxy-3- methoxyphenyl)-lH-l,3-benzodiazole-5-carboxylate[Compound 015, or PSY-01-0015 j and l-[(l,3-dimethyl-2-oxo-2,3-dihydro-lH-l,3-benzodiazol-5-yl)methyd]-2-(4-hydroxy’-3- methoxyphenyl)- lH-l,3-benzodiazole-5-carboxylic acid [Compound 016, or PSY-01-00016]Step-1: methyl 4-(((l,3-dimethyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5- yI)methyl)amino)-3-nitrobenzoate (Int-3).To a stirred solution of methyl 4-fluoro-3-nitrobenzoate (0.5 g, 2.51 mmol, 1.0 eq.) in dichloromethane (5 mL) was added 5-(aminomethyl)-l,3-dimethyl-l,3-dihydro-2H- benzo[d]imidazol-2-one hydrochloride (0.576 g, 3.012 mmol, 1.2 eq.) followed by addition of 1,8- Diazabicyclo[5.4.0]undec-7-ene (DBU) (0.764 g, 5.02 mmol, 2.0 eq.) at 0 °C. The reaction was allowed to warm to rt and stirred for 16h. After completion of reaction as monitored by TLC, the reaction mixture was diluted with di chloromethane (50 mL) and washed with water (20 mL), brine, dried over Na?SO4 and concentrated under reduced pressure to get crude material. The crude was purified by combiflash using 3% MeOH in dichloromethane as eluent to afford methyl 4-(((l,3- dimethyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)amino)-3-nitrobenzoate (0.69 g, Yield: 74%).Step-2: mmeetthhyyll 3-amino-4-(((l,3-diniethyl-2-oxo-2,3-dihydro-l H-benzo[d]imidazol-5- yl)methyl)amino)benzoate (Int-4).To a stirred solution of methyl 4-(((l,3-dimethyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5- yl)methyl)amino)-3-nitrobenzoate (0.67 g, 1.8 mmol, 1.0 eq.) in methanol (6.7 mL) was added ammonium formate (0.568 g, 9.02 mmol, 5.0 eq.) followed by addition of zinc dust (1.76 g, 27.08 mmol, 15.0 eq.) at room temperature and stirred for 2h. After completion of reaction as monitored by TLC, the reaction mixture was concentrated under reduce pressure to get crude product. The residue was purified by combiflash using 2-5% MeOH in dichloromethane as eluent to get methyl 3-amino-4-(((l,3-dimethyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5- yl)methy1)amino)benzoate (0.4 g, Yield: 65%).Step-3: Methyl l-((13-dimethyl-2-oxo-2,3-dihydro-lH-benzo|d]imidazol-5-yl)methyl)-2-(4- hydroxy-3-methoxyphenyl)-lH-benzo[d]imidazole-5-carboxylate (PSY-01-00015).To a stirred solution of methyl 3-amino-4-(((l,3-dimethyl-2-oxo-2,3-dihydro-lH- benzo[d]imidazol-5-yl)methyl)amino)benzoate (0.35 g, 1.03 mmol, 1.0 eq.) in ethanol (21 mL) was added 4-hydroxy-3-methoxybenzaldehyde (0.172 g, 1.13 mmol, 1.1 eq.) followed by addition of acetic acid (0.1 mL) at room temperature. The reaction was heated to 100 °C and stirred at this temperature for 8h. After completion of reaction as monitored by TLC, the reactionmixture was concentrated to get crude material. The crude material was dissolved in N,N- Dimethylformamide (1 mL) and the desired product was precipitated by adding in to water (20 mL). The solid compound was filtered and dried under vacuum which was further purified by combiflash using 2-3% MeOH in dichloromethane as eluent to afford methyl l-((l,3-dimethyl-2- oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)-2-(4-hydroxy-3-methoxyphenyl)-lH- benzo[d]imidazole-5-carboxylate (PSY-01-00015) (0.2 g, Yield: 45%).Step-4: l-((13-dimethyl-2-oxo-2r3-dihydro-lH-benzo[d|imidazol-5-yl)methyl)-2-(4- hydroxy-3-methoxyphenyl)-N-methyl-lH-benzo[d]imidazole-5-carboxamide (PSY-01- 00001).To a stirred solution of PSY-01-00015 (0.1 g, 0.212 mmol, 1.0 eq.) in Tetrahydrofuran (1 mL) were added solution of 2 M methylamine in Tetrahydrofuran (0.32 mL, 0.636 mmol, 3.0 eq.) followed by dropwise addition of IM solution of LiHMDS in Tetrahydrofuran (1.5 mL, 1.483 mmol, 7.0 eq.) at 0 °C. The resulting reaction mixture was stirred at 30 °C for 2h. After completion of reaction as monitored by TLC, the reaction mixture was quenched by adding MeOH (1 mL) and concentrated under vacuum to get crude material, which was purified by combiflash using 2-3% MeOH in Dichloromethane as eluent. The compound was further purified by Prep-HPLC purification. The fractions were lyophilized to get l-((l,3-dimethyl-2- oxo-2, 3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)-2-(4-hydroxy-3-methoxyphenyl)-N-methyl- lH-benzo[d]imidazole-5-carboxamide (PSY-01-00001) (0.025 g, Yield: 25%) as white solid.Step-5: l-((13-dimethyl-2-oxo-2y3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)-2-(4- hydroxy-3-methoxyphenyl)-lH-benzo|d]imidazoIe-5-carboxylic acid (PSY-01-00016).To a stirred solution of PSY-01-00015 (0.4 g, 0.847 mmol, 1.0 eq.) in water (2 mL) and methanol (0.5 mL) was added lithium hydroxide (0.213 g, 5.08 mmol, 6.0 eq.) at 30 °C. The reaction was stirred at 30 °C for 16h. After completion of reaction as monitored by TLC, the reaction mixture was concentrated to half volume and diluted with water (5 mL), ethyl acetate (10 mL) was added and filtered. The organic layer was separated. The pH of aqueous layer was adjusted to acidic (—4-5) using citric acid. The compound was filtered and washed with water. The crude compound was triturated with methanol (0.5 mL) and dried under vacuum to get 1-((l,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2-(4-hydroxy-3-m ethoxy phenyl)- lH-benzo[d]imidazole-5-carboxylic acid (PSY-01-00016) (0.35 g, Yield: 90 %).Example 2: Synthesis of (5-((2-(4-hydroxy-3-methoxyphenyl)-lH-benzo[d]imidazol-l- yl)methyl)-l,3-dimelhyl-l,3-dihydro-2H-betizo[d]imidazol-2-one. [Compound 004, or P SY-01- 00004]Synthetic scheme:Step-1: 1, 3-dimethyl-5-(((2-nitrophenyl) amino) methyl)-!, 3-dihydro-2H-benzo[d]imidazol- 2-one. (Int-3)To a stirred solution of methyl l-fluoro-2-nitrobenzene (0.15 g, 1.06 mmol) in N,N-Dimethyl formamide (1.5 mL) was added 5-(aminomethyl)-l,3-dimethyl-l,3-dihydro-2H- benzo[d]imidazol-2-one hydrochloride (0.242 g, 1.06 mmol) followed by addition of Potassium carbonate (K2CO3) (0.44 g, 3.18 mmol) at room temperature. The reaction was heated to 70 °C and stirred for 16h. After completion of reaction as monitored by TLC, the reaction mixture was poured in ice-cold water (50 mL). The yellow solid thus obtained was filtered and washed with water (10 mL). The yellow solid was dried under vacuum. The crude was purified by combiflashusing 2-3% MeOH in Dichloromethane as eluent to afford 1,3-dimethyl-5-(((2- nitrophenyl)amino)methyl)-l,3-dihydro-2H-benzo[d]imidazol-2-one (Int-3) (0.12 g, Yield: 36%).Step-2: 5-(((2-aminophenyl)amino)methyl)-l,3-dimethyl-l,3-dihydro-2H-benzo[d]imidazol- 2-one (Int-4)To a stirred solution of l,3-dimethyl-5-(((2-nitrophenyl)amino)methyl)-l,3-dihydro-2H- benzo[d]imidazol-2-one (0.2 g, 0.64 mmol) in methanol (2 mL) was added ammonium formate (0.201 g, 3.2 mmol) followed by addition of zinc dust (0.624 g, 9.6 mmol) at room temperature. The reaction was stirred at rt for 4h. After completion of reaction as monitored by TLC, the reaction mixture was filtered through celite pad and the filtrate was concentrated under reduce pressure to get crude material. The crude material was purified by combiflash using 3% MeOH in Dichloromethane as eluent to get 5-(((2-aminophenyl)amino)methyl)-1, 3-dimethyl-l,3-dihydro- 2H-benzo[d]imidazol-2-one (Int-4) (0.14 g, Yield: 77%).Step-3: 5-((2-(4-hydroxy-3-methoxyphenyl)-lH-benzo[d]imidazol-l-yl)methyl)-13- dimethyl-l,3-dihydro-2H-benzo[d]imidazol-2-one (PSY-01-00004).To a stirred solution of 5-(((2-aminophenyl)amino)methyl)-l,3-dimethyl-l,3-dihydro-2H- benzo[d]imidazol-2-one (0.13 g, 0.46 mmol) in ethanol (7.8 mL) was added 4-hydroxy-3- methoxybenzaldehyde (0.084 g, 0.55 mmol) followed by addition of acetic acid (0.05 mL) at room temperature. The reaction was heated to 90 °C and stirred at this temperature for 12 h. After completion of reaction as monitored by TLC, the reaction mixture was concentrated to get crude material. The crude material was dissolved in N,N-Dimethyl formamide (0.5 mL) and the desired product was precipitated by adding in to water (20 mL) which was further purified by combiflash using 2-3% MeOH in Dichloromethane as eluent to afford 5-((2-(4-hydroxy-3-methoxyphenyl)- lH-benzo[d]imidazol-l-yl)methyl)-L3-dimethyl-l,3-dihydro-2H-benzo[d] imidazol-2-one (PSY- 01-00004-001) (0.08 g, Yield: 42%).Example 3: Synthesis of l-((l,3-dimelhyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)- 2-(4-hydroxy-3-methoxyphenyl)-lH-benzo[d]imidazole-5-carboxamide [Compound 008]Synthetic scheme:Step-1: l-((l,3-dimethyl-2-oxo-2,3-dihydro-lH-benzo[d]iinidazol-5-yl)methyl)-2-(4- hydroxy-3-methoxy phenyl)-lH-benzo[d]imidazole-5-carboxainide (PSY-01-00008).To a stirred solution of l-((l,3-dimethyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)-2- (4-hydroxy-3-methoxyphenyl)-lH-benzo[d]imidazole-5-carboxylic acid (PSY-01-00018) (0.18 g, 0.393 mmol) in N,N-Dimethyl formamide (2 mL) were added ammonium chloride (0.21 g, 3.93 mmol), TBTU (0.252 g, 0.186 mmol) and N,N-Diisopropylethylamine (0.253 g, 1.965 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 16h. After completion of reaction as monitored by TLC, the reaction mixture was diluted with water (15 mL) and extracted with dichloromethane (3*50 mL). The organic layer was dried over sodium sulphate and concentrated under vacuum to get crude material which was purified by combiflash using 3% MeOH in dichloromethane as eluent. The solid triturated with mixture of MeOH and diethyl ether (5 mL, 1:9) and dried under vacuum to get l-((l,3-dimethyl-2-oxo-2,3-dihydro-lH- benzo[d]imidazol-5-yl)methyl)-2-(4-hydroxy-3-methoxy phenyl)-lH-benzo[d]imidazole-5- carboxamide PSY-01-00008 (0.06 g, 33%).Example 4: Synthesis of Compounds 131 and 176.[5-((2-(3-jluoro-4-hydroxy-5-melhoxyphenyl)-lH-benzo[d]imidazol-l-yl) methyl)-] ,3-dimethyl- l»3-dihydi*o-2H-benzo[d]iTnidazol-2-one] [Compound 131]; and[5-( (2-(2-fluoro-3-hydroxy-4-methoxyphenyl)-lH-benzo[d]imidazol-l-yl) methyl)-!, 3-dimethyl- l,3-dihydro-2H-benzo[d]imidazol-2-one] [Compound 176]Synthetic scheme:GDI, DIPEA. / ZnCNfrM(PPhi)t,DMF. 1OO°C, B hr DMF. nrr. 6 h DMFl130°Cl12 hr*** Br* \ •t*8M M InM,F H.MA Zn, MeOM,FVPd-C.MeOH, Z NH.COOH, Cone. HO. K«COS, DMF. AeOH (ColX eO"C, 2 hrRT, W hr 70%, 8 hr B0H. MFC^ hrHgN. I \ -OH**4 \ M Wtfr* NOj **• 1*7M 1*7MY4141S1IMA AeOH fC*), eenwc / ir II ’THmatfiMyeotm, AoOHWA, >> HecamfcWi -7CRD- RT. 12 hf TFM0*C.2 lr•MMl MUMPM1-B17IStep-A: Synthesis of 2-fluoro-6-methoxyphenol (Int-B)To a stirred solution of l-fluoro-3 -methoxybenzene (5.0 g, 39.68 mmol, 1.0 eq.) in Tetrahydrofuran (50 mL) were added dropwise / / -butyllithium (2.6 M, 18 mL, 39.68 mmol, 1.0 eq.) at -78°C, over a period of 30 min. and stirred the reaction mixture at same temperature for next 2 hr. Trimethoxyborane (4.4 g, 43.65 mmol, 1.1 eq.) was added dropwise to that reaction mixture (diluted in 10 mL of THF), stirred for 30 min. Reaction were warmed to room temperature then slow addition of acetic acid (3.5 mL, 59.52 mmol, 1.5 eq.) fallowed by Hydrogen peroxide (1.4 g, 39.68 mmol, 1.0 eq.) were added, stirred reaction mixture at room temperature for next 12 hr. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was diluted with water (20 mL) and extracted with Ethyl acetate (3*50 mL). The organic layer was washed with brine, dried over sodium sulphate and concentrated under vacuum to get crude material; which was purified by combi-flash by using 10% Ethyl acetate in n-hexane as mobile phase to give desired product as 2-fluoro-6-methoxyphenol (Int-B) 1.1 g (Yield: 20%).Step-B: Synthesis of 3-fluoro-4-hydroxy-5-methoxybenzaldehyde (Int-8) and 2-fluoro-3- hydroxy-4-methoxybenzaldehyde (Int-8A)To a stirred solution of TEA (8.0 mL), Hexamine (2.2 g, 15.49 mmol, 2.0 eq.) was added dropwise at 80°C over a period of 30 min, and stirred the reaction mixture for 1 hr. 2-fluoro-6- methoxyphenol [Int-B] (1.1 g, 7.746 mmol, 1.0 eq.) in TFA (5.0 mL) were added to that reaction mixture for 1 hr. and stirred the reaction at 80°C for 1 hr. the progress of the reaction of the was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with 20% Aq. NajCCh (PH-8) and again acidify with 2N HC1 (PH-4); then extracted with ethyl acetate (3 X 30 mL). The combined organic layer was dried over anhydrous sodium sulphate, filtered and concentrated to get crude compound; which was purified by combi-flash by using 10% ethyl acetate in n-hexane as mobile phase to give desired products as 3-fluoro- 4-hydroxy-5-methoxybenzaldehyde [Int-8] 0.4 gm (Yield: 31%) as a white solid and 2-fluoro-3- hydroxy-4-methoxybenzaldehyde [Int-8 A] 0.35 (Yield: 27%) as brownish solid.Step-1: Synthesis of 5-bromo-13-dihydro-2Z / -benzo[<Z]iniidazol-2-one (Int-2)To a stirred solution of 4-bromobenzene-l,2-diamine [Int-1] (8.0 g, 42.78 mmol, 1.0 eq.) in Dimethylformamide (80 mL), Carbonyldiimidazole (CDI) (20.7 g, 128.34 mmol, 3.0 eq.) was added followed by slow addition of N,N-Diisopropylethylamine (14.6 mL, 85.5612 mmol, 2.0 eq.), stirred reaction mixture at 100°C for 8 hr. The reaction was monitored on TLC. After completion of the reaction, it was diluted with water and was extracted with Ethyl acetate (3*100 mL), combined organic layer was washed with brine; dried over anhydrous sodium sulphate, concentrated to get crude compound which was purified by column chromatography using EtOAC: n-Hexane as solvent system to give the desired product as 5-bromo-l,3-dihydro-2 / 7- benzo[<7]imidazol-2-one (Int-2) 5.0 gm (Yield: 55.55%).Step-2: Synthesis of 5-bromo-l,3-dimethyl-lr3-dihydro-2H-benzo[< / ]imidazol-2-one (Int-3)To a stirred solution of 5-bromo-l,3-dihydro-27 / -benzo[< / |imidazol-2-one [Int-2] (4.0 g, 18.867 mmol, 1 eq.) in Dimethylformamide (40 mL), Potassium carbonate (10 g, 75.471 mmol, 4.0 eq.) and Methyl Iodide (8.0 g, 56.6034 mmol, 3.0 eq.) were added stirred reaction mixture at room temperature for 6 hr. Reaction was monitored on TLC. After completion of the reaction it was diluted with water and extracted with ethyl acetate (3*50 mL), combined organic layer was washed with water and brine; dried over anhydrous sodium sulphate concentrated to get crude compound which was purified by column chromatography using EtOAC : n-Hexanes as solvent system to give the desired product as 5-bromo-l,3-dimethyl-l,3-dihydro-2 / / -benzo[i / ]imidazol-2- one [Int-3] 4.1 g (Solid) (Yield: 91 .11%);Step-3: Synthesis of l,3-dimethyI-2-oxo-2,3-dihydro-LH-benzo[f / ]imidazole-5-carbonitrileTo a stirred solution of 5-bromo-l,3-dimethyl-l,3-dihydro-2 / 7-benzo[<7]imidazol-2-one [Int-3] (1.0 g, 4.166 mmol, 1.0 eq.) was dissolved in Dimethylformamide (10 mL). Zinc cyanide (0.97 g, 8.3332 mmol, 2.0 eq.) was added to that reaction mixture, reaction mixture was degassed under Ni for 15 min. fallowed by the addition of Tetrakis Pd(PPh3)4 (0.48 g, 0.4166 mmol, 0.1 eq.), stirred reaction mixture at 130°C for 12 hr. Reaction was monitored on TLC. After completion of the reaction, the reaction mixture was diluted with water was extracted with ethyl acetate (3*50 mL). Combined organic layer was washed with and brine dried over sodium sulfate and concentrated to obtain crude product which was purified by column chromatography using EtOAc: n-Hexanes as solvent system to get desired product as 1,3 -dimethyl -2-oxo-2, 3 -dihydro- 1H- benzo[tf]imidazole-5-carbonitrile (Int-4) 0.6 g (Solid) (Yield: 77.92%).Step-4: Synthesis of 5-(aminomethyl)-l,3-dimethyl-l,3-dihydro-27f-benzo[r / ]imidazol-2-one (Int-5)To a stirred solution of l,3-dimethyl-2-oxo-2,3-dihydro-l / Z-benzo[< / ]imidazole-5-carbonitrile (Int-4) 0.5 g in Methanol (10 mL); 2 drops of Conc.HCI was added followed by Palladium carbon (10% Pd / C 50% moisture) 0.15 g, stirred reaction mixture at room temperature for 10 hr. Reaction was monitored on TLC. After completion of the reaction, it was fdtered through cellite pad was washed with methanol, filtrate was concentrated under reduced pressure to get crude compound, it was purified by column chromatography using MeOH: DCM as solvent system to get desired product as 5-(aminomethyl)-l,3-dimethyl-l,3-dihydro-2 / / -benzo[t7]imidazol-2-one (Int-5) 0.25 g (Yield: 31.25%).Step-5: Synthesis of l,3-dimethyl-5-(((2-nitrophenyl) amino) methyl)-!, 3-dihydro-2fl- benzo[d]imidazol-2-one (Int-6)To a stirred solution of 5-(aminomethyl)-l,3-dimethyl-l,3-dihydro-2 / 7-benzo[<7]imidazol-2-one [Int-5] (0.3 g, 1.5706 mmol, 1.0 eq.) was dissolved in Dimethylformamide (3 mL), Potassium carbonate (065 g, 4.71204 mmol, 3.0 eq.) was added to reaction, followed by l-fluoro-2- nitrobenzene [Int-A] (0.26 g, 1.8848 mmol, 1.2 eq.), stirred reaction mixture at 70°C for 6 hr. The progress of the reaction was monitored on TLC. After completion of the reaction, it diluted with water was extracted with ethyl acetate (3*20 mL). combined organic was washed with brine; dried over sodium sulphate concentrated to get crude compound, which was purified by column chromatography using EtOAC : Hexanes as solvent system to get desired product as 1,3-dimethyl- 5-(((2-nitrophenyl) amino) methyl)- 1,3 -di hydro-2 / / -benzo[< / ]i mi dazol -2-one (Int-6) 0.3 g (Yield: 61.22%).Step-6: Synthesis of 5-(((2-Aminophenyl) amino) methyl)-13-dimethyl-l^-dihydro-2ff- benzo[rf|imidazol-2-one (Int-7).To a stirred solution of l,3-dimethyl-5-(((2-nitrophenyl) amino) m ethyl) -1,3 -dihy dro-277- benzo[<Z]imidazol-2-one [Int-6] (0.2 g, 0.64 mmol, 1.0 eq.) in methanol (10 mL) was added ammonium formate (0.201 g, 3.2 mmol, 5.0 eq.) followed by addition of zinc dust (0.624 g, 9.6 mmol, 15.0 eq.) at room temperature. The reaction was stirred at 60°C for 2 hr, the progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was filtered through cellite pad and the filtrate was concentrated under reduce pressure to get 5-(((2- Aminophenyl) amino) methyl)- l,3-dimethyl-l,3-dihydro-22 / -benzo[t / ]imidazol -2-one (Int-7) 0.160 g (Yield: 88%) as crude material, which was used as it is without further purification.Step-7: Synthesis of 5-((2-(3-fluoro-4-hydroxy-5-methoxyphenyl)-lH-benzo[d]iniidazol-l-yl) methyl)-13-dimethyl-13-dihydro-2H-benzo[d]imidazol-2-one (PSY-01-0131)To a stirred solution of 5-(((2-Aminophenyl) amino) methyl)- 1,3 -dimethyl- 1,3 -dihydro-2 / / - benzo[<Z]imidazol -2-one (Int-7) (0.15 g, 0.53 mmol, 1.0 eq.) in ethanol (10 mL) was added 3- fluoro-4-hydroxy-5-methoxybenzaldehyde [Int-8] (0.09 g, 0.53 mmol, 1 eq.) followed by addition of acetic acid (0.05 mL) at room temperature. The reaction was heated to 80 °C and stirred at this temperature for 6 hr. After completion of reaction as monitored by TLC, the reaction mixture was concentrated to get crude material, which was diluted with water (10 mL) and extracted with ethyl acetate (3 X 30 mL), washed with brine. The combined organic layer was dried over anhydrous sodium sulphate, filtered and concentrated to get crude compound; which was purified by combi- flash by using ethyl acetate as mobile phase to give desired product as 5-((2-(3-fluoro-4-hydroxy- 5-methoxyphenyl)- l / / -benzo[c / ]imidazol- 1 -yl) methyl)- 1 ,3-dimethyl- 1 ,3-dihydro-2 / 7- benzoMimidazol-2-one (PSY-01-0131) 0.080 g (Yield: 36%)Step-7A: Synthesis of 5-((2-(2-fluoro-3-hydroxy-4-methoxyphenyl)-l£7-benzo[<f]imidazol-1- yl) methyl)-13-dimethyl-l^-dihydro-2fl-benzo[i / |imidazol-2-one (PSY-01-0176)To a stirred solution of 5-(((2-Aminophenyl) amino) methyl)- 1 ,3-dimethyl- 1, 3-dihydro-2Z / - benzo[t / ]imidazol-2-one (Int-7) (0.16 g, 0.56 mmol, 1.0 eq.) in ethanol (10 mL) was added 2- fluoro-3-hydroxy-4-methoxybenzaldehyde [Int-8A] (0.096 g, 0.56 mmol, 1.0 eq.) followed by addition of acetic acid (0.05 mL ) at room temperature. The reaction was heated to 80 °C and stirred at this temperature for 6 hr. After completion of reaction as monitored by TLC, the reaction mixture was concentrated to get crude material, which was diluted with water (10 mL) and extracted with ethyl acetate (3 X 30 mL), washed with brine. The combined organic layer was dried overanhydrous sodium sulphate, filtered and concentrated to get crude compound; which was purified by combi -flash by using ethyl acetate as mobile phase to give desired product as 5-((2-(2-fluoro- 3-hydroxy-4-methoxyphenyl)-l / / -benzo[d]imidazol-l-yl) methyl)-!, 3-dimethyl-l,3-dihydro- 2 / 7- benzo[<7]imidazol-2-one (PSY-01-0176) 0.016 g (Yield: 7%).Example 5: Synthesis of Compounds 137 and 138(R)-5-(l-(2-(4-hydroxy-3-methoxyphenyl)-lH-pyrrol-l-yl) ethyl)- 1,3-dimethy -l,3-dihydro-2H- benzo[d]imidazol-2-one (Compound 137, or PSY-01-00137-001), and(S)-5-(l-(2-(4-hydroxy-3-methoxyphenyl)-lH-pyrrol-l-yl) ethyl)- 1, 3-dimethyl -1, 3-dihydro-2H- benzo[d]imidazol-2-one (Compound 138, or PSY-01-00138-001)Synthetic scheme:Step-1: Synthesis of methyl 2-oxo-2,3-dihydro-lH-benzo[d]imidazole-5-carboxylate (Int-2)To a stirred solution of Methyl 3,4-diaminobenzoate (Int-1) (20.0 g, 120.35 mmol, 1.0 eq.) in N,N-Dimethylformamide (200 mL) , added Carbonyldiimidazole (CDI) (29.27 g, 180.51 mmol, 1.5 eq.), then the resulting reaction mixture was stirred at 100° C for next 15 to 16 hr. The progress of the reaction was monitored by TLC; after completion of reaction, the reaction mixture was cooled to room temperature and diluted with DM water (600 mL) and extracted with Ethyl acetate (3*100 mL). The organic layer was washed with brine, dried over sodium sulphate and concentrated under vacuum to get crude material; which was purified by Combi flash column chromatography. The product was eluted in 30-35% in Ethyl acetate in n-hexane as a mobile phase to give desired compound as methyl 2-oxo-2,3-dihydro-lH-benzo[d]imidazole-5-caiboxylate (Int-2) 23.0 g(Yield: 99.48%)Step-2: Synthesis of methyl 13-dimethyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazole-5- carboxylate (lnt-3)To a stirred solution of methyl 2-oxo-2,3-dihydro-lH-benzo[d]imidazole-5-carboxylate (Int-2) (23.0 g, 119.68 mmol, 1.0 eq.) in N,N-Dimethylformamide (200 mL) were added potassium carbonate (49.69 g, 359.55 mmol, 3.0 eq.), followed by Methyl iodide (50.96 g, 359.55 mmol, 3.0 eq.) was added to that reaction mixture at room temperature. Reaction mixture was stirred at room temperature for next 10 to 12 hr.; the progress of the reaction was monitored by TLC. After completion of the reaction; mixture was pour in 600 mL DM water. Crude compound was extracted with ethyl acetate (3*150 mL); the organic layer was washed with brine; dried over sodium sulphate and concentrated under vacuum to get crude material; which was purified by Combi-flash column chromatography. The product was eluted in 15-20% in Ethyl acetate in n-hexane as a mobile phase to give desired compound as methyl l,3-dimethyl-2-oxo-2,3-dihydro-lH- benzo[d]imidazole-5-carboxylate (Int-3) 26.0 g (Yield: 98.67 %).Step-3: Synthesis of 5-(hydroxymethyl)-l,3-dimethyl-l,3-dihydro-2H-benzo[d]iinidazol-2- one (Int-4)To a stirred solution of Methyl l,3-dimethyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazole-5- carboxylate (lnt-3) (26.0 g, 118.05 mmol, 1.0 eq.) in Tetrahydrofuran (1200 mL) and Methanol (25 mL) were added Lithium borohydride (103 g, 472.82 mmol, 4.0 eq ), to that reaction mixture at room temperature. Reaction mixture was heated at 60°-65°C for next 22 to 24 hr; the progress of the reaction was monitored by TLC. After completion of the reaction; mixture was cooled to Room temperature and quench with ethyl acetate and pour in 1000 mL DM water. Crude compound was extracted with ethyl acetate (3 X 300 mL); The organic layer was washed with brine; dried over sodium sulphate and concentrated under vacuum to get crude material; which was purified by Combi flash column chromatography. The product was eluted in 60-65% in Ethyl acetate in n-hexane as a mobile phase to give desired compound as 5-(hydroxymethyl)-l,3- dimethyl-l,3-dihydro-2H-benzo[d]imidazol-2-one (Int-4) 15.0 g (Yield: 66.10 %).Step-4: Synthesis of l,3-dimethyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazole-5-carbaldehyde (Int-5)To a stirred solution of 5-(hydroxymethyl)-l,3-dimethyl-l,3-dihydro-2H-benzo[d]imidazol-2-one (Int-4) (3.5 g, 18.2 mmol, 1.0 eq.) in Dichloromethane (35 mL) was cooled to 0° - 5° C, added Pyridinium Chlorochromate (PCC) (5.89 g, 27.3 mmol, 1.5 eq.), then the resulting reaction mixture was stirred at room temperature for next 2 to 3 hr. The progress of the reaction was monitored by TLC; after completion of reaction, the reaction mixture was diluted with water (50 mL) and extracted with Dichloromethane (3*20 mL). The organic layer was washed with brine, dried over sodium sulphate and concentrated under vacuum to get crude material; which was purified by Combi flash column chromatography. The product was eluted in 15-20% in Ethyl acetate in n- hexane as a mobile phase to give desired compound as l,3-dimethyl-2-oxo-2,3-dihydro-lH- benzo[d]imidazole-5-carbaldebyde (Int-5) 3.0 g (Yield: 86.70%).Step-5: Synthesis of (E)-N-((13-dimethyl-2-oxo-2,3-dihydro-lH-benzofd]imidazol-5-yl) methylene)-2-methylpropane-2-sulfinamide (Int-6)To a stirred solution of l,3-dimethyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazole-5-carbaldehyde (Int-5) (3.0 g, 15.7 mmol, 1.0 eq.) in Tetrahydrofuran (30 mL) were added 2-Methyl-2 propane sulfinamide (5.74 g, 47.3 mmol, 3.0 eq.), followed by Titanium(iv) iso-propoxide (17.95 g, 63.1 mmol, 4.0 eq.) was added to that reaction mixture at room temperature. Reaction mixture was heated at 50° - 55°C for next 4 to 5 hr.; the progress of the reaction was monitored by TLC. After completion of the reaction; mixture was cooled to Room temperature and pour in 100 mL DM water. Crude compound was extracted with ethyl acetate (3*30 mL); the organic layer was washed with brine; dried over sodium sulphate and concentrated under vacuum to get crude material;which was purified by Combi flash column chromatography. The product was eluted in 40-50% in Ethyl acetate in n-hexane as a mobile phase to give desired compound as (E)-N-((l,3-dimethyl- 2-oxo-2?3-dihydro-l H-benzo[d]imidazol-5-yl) methylene)-2-methylpropane-2-sulfinamide (Int- 6) 2.75 g (Yield: 89.14 %).Step-6: Synthesis of N-(l-(l,3-diniethyl-2-oxo-2,3-dihydro-lH-benzo|d]imidazol-5-yl) ethyl)-2-methylpropane-2-sulfinamide (Int-7)To a stirred solution of (E)-N-((l,3-dimethyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl) methylene)-2-methylpropane-2-sulfinamide (lnt-6) (2.7 g, 9.18 mmol, 1.0 eq.) in Tetrahydrofuran (30 mL) was added Methyl magnesium bromide 1.0 M sol” in THF (22.9 mL, 22.9 mmol, 2.5 eq.) to reaction mixture at room temperature. Reaction mixture was stirred at 20° - 25°C for next 2 to 3 hr.; the progress of the reaction was monitored by TLC. After completion of the reaction; mixture was quench with 100 mL ammonium chloride solution. Crude compound was extracted with ethyl acetate (3*30 mL); Organic layer was washed with brine; dried over sodium sulphate and concentrated under vacuum to get crude material; which was purified by Combi flash column chromatography. The product was eluted in 60-70% in Ethyl acetate in n-hexane as a mobile phase to give desired compound as N-(l-(l,3-dimethyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl) ethyl)-2-methylpropane-2-sulfinamide (Int-7) 2.4 g (Yield: 84.50 %).Step-7: Synthesis of 5-(l-aminoethyl)-13-dimethyl-l^-dihydro-2H-benzo[d]iniidazoI-2-one (Int-8)To a stirred solution N-(l-(l,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl) ethyl)-2- methylpropane-2-sulfinamide (Int-7) (2.4 g, 8.06 mmol, 1.0 eq.) in 1-4 Dioxane (10 mL) was cooled to 0° - 5° C, added 4M HC1 in 1-4 Dioxane (5 mL), then the resulting reaction mixture was stirred at room temperature for next 5 to 6 hr. The progress of the reaction was monitored by TLC; After completion of reaction, the reaction mixture was filter on Buckner funnel and crude product was washed with Hexane (2*10 mL) and dried on vacuum pump to get crude material as 5-(l- aminoethyl)-l,3-dimethyl-l,3-dihydro-2H-benzo[d]imidazol-2-one (Int-8) 1.32 g (Yield: 83.01%).Step-8: Synthesis of 5-(l-(lH-pyrrol-l-yI) ethyl)-l,3-diniethyl-l,3-dihydro-2H- benzo[d]imidazol-2-one (Int-9)To a stirred solution of 2,5 Dimethoxy tetrahydrofuran (0.84 g, 6.40 mmol, 1.0 eq ) in DM water (20 mL), stirred reaction mixture at 100° C for 2 to 3 hr. Allowed the reaction mixture to cool at room temperature, were added solution of 5 -(1 -aminoethyl)- 1,3 -dimethyl- 1,3 -dihydro-2H- benzo[d]imidazol-2-one (lnt-8) (1 .32 g, 6.40 mmol, 1.0 eq.) in Dichloromethane (30 mL) followed by Sodium acetate (1.05 g, 12.8 mmol, 2.0 eq.) was added to reaction mixture at room temperature. Reaction mixture was allowed to stirre at room temperature for next 14 to 15 hr. under light protection; the progress of the reaction was monitored by TLC. After completion of the reaction; reaction mixture pour in 100 mL saturated Sodium carbonate solution. Crude compound was extracted with Dichloromethane (3 X 20 mL); The organic layer was washed with brine; dried over sodium sulphate and concentrated under vacuum to get crude material; which was purified by Combi flash column chromatography. The product was eluted in 30-40% in Ethyl acetate in n- hexane as a mobile phase to give desired compound as 5-(l-(lH-pyrrol-l-yl) ethyl)-! ,3-dimethyl- l,3-dihydro-2H-benzo[d]imidazol-2-one (Int-9) 0.620 g (Yield: 37.80 %).Step-9: Synthesis of 5-(l-(2-bromo-lH-pyrrol-l-yl) ethyl)-l,3-dimethyl-l,3-dihydro-2H- benzo[d]imidazol-2-one (Int-10)To a stirred solution of 5-(l-(lH-pyrrol-l-yl) ethyl)-l,3-dimethyl-l,3-dihydro-2H- benzo[d]imidazol-2-one (Int-9) (0.500 g, 1.96 mmol, 1.0 eq.) in Tetrahydrofuran (20 mL) was cooled to (-78°) C .added N-bromosuccinimide (0.35 g, 1.96 mmol, 1.0 eq ), then the resulting reaction mixture was stirred at (-78° ) C for next 2 to 3 hr. The progress of the reaction was monitored by TLC; after completion of reaction, the reaction mixture was quench with saturated sodium bicarbonate solution (20 mL) and extracted with Ethyl acetate (3*10 mL). The organic layer was washed with brine, dried over sodium sulphate and concentrated under vacuum to get crude material; which was purified by Combi flash column chromatography. The product was eluted in 40-45% in Ethyl acetate in n-hexane as a mobile phase to give desired compound as 5- (1 -(2-bromo-l H-pyrrol-1 -yl) ethyl)- 1 ,3-dimethyl-l ,3-dihydro-2H-benzo[d]imidazol-2-one (Int- 10) 0.324 g (Yield: 49.54%).Step-10: Synthesis of 5-(l-(2-(4-((tert-butyl diphenyl silyl) oxy)-3-methoxyphenyl)-lH- pyrrol-l-yl) ethyl)-l,3-dimethyl-l,3-dihydro-2H-benzo[d]imidazol-2-one (Int-11)To a stirred solution of 5-(l-(2-bromo-lH-pyrrol-l-yl)ethyl)-l,3-dimethyl-l,3-dihydro-2H- benzo[d]imidazol-2-one (Int-10) (0.320 g, 0.958 mmol, 1.0 eq.) in 1-4 Dioxane (10 mL) and DM water (10 mL), were added (4-((tert-butyl diphenyl silyl)oxy)-3 -methoxyphenyl) boronic acid (0.607 g, 1.24 mmol, 1.3 eq.), and potassium carbonate (0.264 g, 1 .91 mmol, 2.0 eq.) were stirred at room temperature with continuous purging of nitrogen for next 20 min. Tetrakis (triphenylphosphine)palladium(O) (0.055 g, 0.05 mmol, 0.05 eq.) was added at room temperature, then the resulting reaction mixture was stirred at 100°C for next 12 hr. The progress of the reaction was monitored by TLC; after completion of reaction, the reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3*15 mL). The organic layer was washed with brine,dried over sodium sulphate and concentrated under vacuum to get crude material; which was purified by Combi flash column chromatography. The product was eluted in 25-30% in Ethyl acetate in n-hexane as a mobile phase to give desired product as 5-(l-(2-(4-((tert-butyl diphenyl silyl) oxy)-3-methoxyphenyl)-lH-pyrrol-l-yl) ethyl)-l,3-dimethyl-l,3-dihydro-2H- benzo[d]imidazol-2-one (Int-11) 0.193 g (Yield: 32.76%).Step-11: Synthesis of (R)-5-(l-(2-(4-hydroxy-3-methoxyphenyl)-lH-pyrrol-l-yl) ethyl)-l,3- dimethy -l,3-dihydro-2H-benzo[d]imidazol-2-one (PSY-01-00137-001). (S)-5-(l-(2-(4- hydroxy-3-methoxyphenyl)-lH-pyrrol-l-yl) ethyl)-l,3-dimethyl -13-dihydro-2H- benzo[d]imidazol-2-one (PSY-01-00138-00nTo a stirred solution 5-(l-(2-(4-((tert-butyl diphenyl silyl) oxy)-3 -methoxyphenyl)- IH-pyrrol- 1- yl) ethyl)-l,3-dimethyl-l,3-dihydro-2H-benzo[d]imidazol-2-one (Int-11) (0.190 g, 0.308 mmol, 1.0 eq.) in Tetrahydrofuran (5.0 mL) was cooled to 0° - 5° C, added IM solution of TBAF in THE (0.467 mL, 0.467 mmol, 1.5 eq.), then the resulting reaction mixture was stirred at room temperature for next 2 to 3 hr. The progress of the reaction was monitored by TLC; After completion of reaction, the reaction mixture was diluted with water (10 mL) and extracted with Ethyl acetate (3 X 10 mL). The organic layer was washed with brine, dried over sodium sulphate and concentrated under vacuum to get crude material; which was purified by Combi flash column chromatography. The product was eluted in 40-50% in Ethyl acetate in n-hexane as a mobile phase to give mixture of diastereomer compound 0.89 g that was separated by chiral chromatography as (R)-5-(l -(2-(4-hydroxy-3 -methoxyphenyl)- IH-pyrrol- 1 -yl)ethyl)- 1 ,3 -dimethyl- 1 ,3-dihydro-2H- benzo[d]imidazol-2-one (PSY-01-00137) 0.021 g (Yield: 18.10%) and (S)-5-(l-(2-(4-hydroxy-3- methoxyphenyl)- IH-pyrrol- 1 -yl)ethyl)- 1 , 3 -dimethyl- 1 ,3 -dihydro-2H-benzo[d]imidazol-2-one (PSY-01-00138) 0.032 g (Yield: 27.58%).Example 6: Synthesis of Compound 139.[N-(l-(l, 3-dimethyl-2-oxo-2, 3-dihydro-lH-benzo[d]imidazol-5-yl) cyclopropyl)-4-hydroxy-3- methoxy-N-melhylbenzamide] (Compound 139, or PSY-01-0139)Synthetic scheme:Synthesis of Int-C:Step- A: Synthesis of Allyl 4-(allyloxy)-3-methoxybenzoate (Int-B).To a stirred solution of 4-hydroxy-3-methoxybenzoic acid [Int-A] (1.0 g, 5.952 mmol, 1.0 eq.) inN,N-Dimethylformamide (10 mL) were added potassium carbonate (K2CO3) (3.3 g, 23.80 mmol,4.0 eq.) and allyl bromide (2.2 g, 17.84 mmol, 3.0 eq.) at 0°C and the resulting reaction mixture was stirred at room temperature for 12 hr. After completion of reaction as monitored by TLC, the reaction mixture was diluted with cold water and extracted with ethyl acetate (3*50 mL). The organic layer was washed sat. NallCOa solution and brine, dried over sodium sulphate and concentrated under vacuum to get crude material; which was purified by combi -flash by using30% ethyl acetate in hexane as mobile phase to give desired product as allyl 4 -(allyl oxy )-3- methoxybenzoate (Int-B) 1.35 g (Yield: 96%).Step-B: Synthesis of 4-(allyloxy)-3-methoxybenzoic acid (Int-C)To a solution of Allyl 4-(allyloxy)-3-methoxybenzoate [Int-B] (0.5 g, 2.016 mmol, 1.0 eq.) in Tetrahydrofuran: Water: MeOH (1 : 1 : 1 = 6 mL) was added NaOH (0.075 g, 1.1814 mmol, 0.9 eq.); the resulting reaction mixture was stirred at 50°C for 6 hr. After completion of reaction as monitored by TLC, the reaction mixture was evaporated on rotavapour up to dryness obtained a crude residue, which was diluted with water was extracted with ethyl acetate (2 X 20 mL); Aqueous layer was then acidified with 2 N HC1 (pH-2) obtained a white solid, which was filtered through filter paper, dried under vacuum to get crude material 4-(allyloxy)-3-methoxybenzoic acid [Int-C] 0.34 g (Yield: 35%) which was used as it is for the next reaction.Synthesis ofPSY-0l-0139:Step-IA: Synthesis of l-(4-fluorophenyl) cyclopropan-l-amine (Int-2A).To a stirred solution of 4-fluorobenzonitrile [Int-1 A] (2.0 g, 16.52 mmol, 1.0 eq.) was dissolved in Tetrahydrofuran (20 mL); Titanium isopropoxide (5.2 g, 18.16 mmol, 1.1 eq.) was added to that reaction at -70°C; fallowed by dropwise addition of ethyl magnesium bromide (IM, 36 mL, 36.33 mmol, 2.2 eq.) and stirred reaction mixture at same temperature for 1 hr. Boron trifluoride etherate (4.7 g, 33.02 mmol, 2.0 eq.) was added dropwise to that reaction mixture at room temperature; and stirred for next 1 hr; the progress of the reaction was monitored by TLC, after completion of the reaction, the reaction mixture was diluted with water was extracted with ethyl acetate (3 X 50 mL), combined organic layer was washed with and brine dried over sodium sulfate and concentrated to obtain crude product, which was purified by combi-flash by using 40% ethyl acetate in hexane as mobile phase to give desired product as l-(4-fluorophenyl) cyclopropan-1 -amine (Int-2A) 0.6 g (Yield: 25%).Step-2A: Synthesis of l-(4-fluoro-3-nitrophenyl) cyclopropan-l-amine (Int-3A)In a single neck round bottom flask, fuming HNO3 (0.5 mL, 11.92 mmol, 1.5 eq.) was added carefully to ice bath cooled concentrated H2SO4 (10 mL). To the mixture was added l-(4- fluorophenyl) cyclopropan-1 -amine [Int-2A] (1.2 g, 7.94 mmol, 1.0 eq.) dropwise. The reaction mixture was stirred with cooling for 60 minutes. The reaction mixture was poured into ice and basified with 3M NaOH solution (25 mL) to about pH 8.0. The alkaline solution was extracted with dichloromethane (3 X 30 mL); combined organic layer was washed with and brine dried over sodium sulfate and concentrated to obtain crude product, which was purified by combi -flash by using 70% ethyl acetate in hexane as mobile phase to give desired product as l-(4-fluoro-3- nitrophenyl) cyclopropan-1 -amine [Int-3A] 0.9 g (Yield: 60%).Step-3A: Synthesis of 4-( allyloxy )-A-(l-(4-fluoro-3-nitrophenyl) cyclopropyl )-3-methoxy benzamide (Int-4A)To a stirred solution of 4-(allyloxy)-3 -methoxybenzoic acid (Int-C) (1.01 g, 4.89 mmol, 1.2 eq.) was dissolved in Tetrahydrofuran (10 mL) to that N,N-Diisopropylethylamine (1.05 g, 8.155 mmol, 2.0 eq.) was added, followed by HATU (2.8 g, 7.34 mmol, 1.8 eq.) at 0°C and stirred reaction mixture for 20 min. l-(4-fluoro-3-nitrophenyl) cyclopropan-1 -amine (Int-3A) (0.8 g, 4.077 mmol, 1.0 eq.) dissolved in 5 mL of Tetrahydrofuran, was slowly added to that reaction mixture, The resulting reaction mixture was stirred at room temperature for next 12 hr. The progress of the reaction was monitored by TLC; After completion of reaction, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 X 30 mL), washed with sat. NaHCCh and brine. The organic layer was washed with brine, dried over sodium sulphate and concentrated under vacuum to get crude material; which was purified by combi-flash by using60% ethyl acetate in hexane as mobile phase to give desired product as 4-(allyloxy)-A / -(l-(4- fluoro-3 -nitrophenyl) cyclopropyl)-3-methoxybenzamide (Int-4A) 1.1 g (Yield: 73%);Step-4A: Synthesis of 4-(allyloxy)-3-methoxy-A-(l-(4-(methyl amino)-3-nitrophenyl) cyclopropyl) benzamide (Int-5A)To a stirred solution of 4-(allyloxy)-jV-( 1 -(4-fluoro-3 -nitrophenyl) cy clopropy l)-3 - methoxybenzamide [Int-4A] (1.1 g, 2.84 mmol, 1.0 eq.) was dissolved in ethanol (10 mL), Triethyl amine (0.3 mL, 4.274 mmol, 1.5 eq.) was added, followed by Methyl amine (0.37 g, 5.1129 mmol, 1.8 eq.) and stirred reaction mixture at 60°C for 12 hr. The progress of the reaction was monitored on TLC; the reaction mixture was concentrated to get crude material, which was diluted with water (10 mL) and extracted with ethyl acetate (3 X 30 mL), washed with brine. The combined organic layer was dried over anhydrous sodium sulphate, filtered and concentrated to get crude compound; which was purified by combi-flash by using 40% ethyl acetate in hexane as mobile phase to give desired product as 4-(allyloxy)-3-methoxy-Ar-(l-(4-(methyl amino)-3 -nitrophenyl) cyclopropyl) benzamine [Int-5A] 0.85 g (Yield: 77%); LCMS: m / z 398.34 [M+H]+.Step-5A: Synthesis of 4-(allyloxy)-Ar-(l-(3-amino-4-(methyl amino) phenyl) cyclopropyl)-3- m ethoxy benz amide (Int-6A)To a stirred solution of 4-(allyloxy)-3-methoxy- / V-(l-(4-(methyl amino)-3-nitrophenyl) cyclopropyl) benzamine [Int-5A] (0.85 g, 2.14 mmol, 1.0 eq.) in ethanol (10 mL) and water (2 mL) was added Fe powder (0.36 g, 6.42 mmol, 3.0 eq.) followed by addition of ammonium chloride (0.7 g, 12.84 mmol, 6.0 eq.) at room temperature. The reaction was stirred at 80°C for 2 hr, the progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was filtered through cellite pad and the filtrate was concentrated under reduce pressure toget 4-(allyloxy)-A-(1-(3-amino-4-(methyl amino) phenyl) cyclopropyl)-3-methoxybenzamide [Int-6A] 0.74 g (Yield: 94%) as erode material, which was used as it is without further purification.Step-6A: Synthesis of 4-(allyloxy)-3-methoxy-A-(l-(l-methyl-2-oxo-2,3-dihydro-lH- benzo[d] imidazol-5-yl) cyclopropyl) Benzamide (Int-7A)To a stirred solution of 4-(allyloxy)-A-(l-(3-amino-4-( methyl amino) phenyl) cyclopropyl)-3- methoxybenzamide [Tnt-6A] (0.74 g, 2.016 mmol, 1.0 eq.) in N,N-Dimethylformamide (10 mL), Carbonyldiimidazole (0.65 g, 4.032 mmol, 2.0 eq.) was added followed by slow addition of Di- isopropylethylamine (0.52 g, 4.032 mmol, 2.0 eq.), stirred reaction mixture at 80°C for 12 hr. The reaction was monitored on TLC. After completion of the reaction it was diluted with water and was extracted with ethyl acetate (3 X 50 mL), combined organic layer was washed with brine; dried over anhydrous sodium sulphate, concentrated to get crude compound which was purified by combi-flash by using 80% ethyl acetate in hexane as mobile phase to give desired product as 4-(allyl oxy )-3 -methoxy -A'-( 1 -(1 -methyl-2-oxo-2,3-dihydro- l / / -benzo[< / ]imidazol-5-yl) cyclopropyl) Benzamide (Int-7A) 0.7 g (Yield: 78%).Step-7A: Synthesis ooff 4-(allyloxy)-. / V-(l-(l,3-diinethyl-2-oxo-2,3-dihydro-l / 7- benzo[d]imidazol-5-yl) cyclopropyl)-3-methoxy-jV-methylbenzamide (Int-SA)To a stirred solution of 4-(allyloxy)-3-methoxy-jV-(l-(l-methyl-2-oxo-2,3-dihydro-l / / - benzo[«7]imidazol-5-yl) cyclopropyl) Benzamide (Int-7A) (0.5 g, 1.274 mmol, 1.0 eq.) in N,N- Dimethylformamide (10 mL), Potassium carbonate (1 05 g, 7.633 mmol, 6.0 eq ) and Methyl Iodide (0.9 g, 6.361 mmol, 5.0 eq.) were added stirred reaction mixture at room temperature for 12 hr. Reaction was monitored on TLC and LCMS. NaH (0090 g, 2.035 mmol, 1.6 eq.) was added to that reaction mixture; fallowed by Methyl iodide (0.3 g, 2.035 mmol, 1.6 eq.) and stirred the reaction mixture for next 2 hr, the progress of the reaction was monstered by TLC and LCMS;After completion of the reaction it was diluted with water and extracted with ethyl acetate (3 X 50 mL), combined organic layer was washed with water and brine; dried over anhydrous sodium sulphate concentrated to get crude compound which was used for the next reaction, purified by combi-flash by using 80% ethyl acetate in hexane as mobile phase to give desired product as 4- (allyloxy)-vV-(l-( 1 ,3-dimethyl-2-oxo-2,3-dihydro- l / 7-benzo[tZ]imidazol-5-yl) cyclopropyl)-3- methoxy-A-methylbenzamide (Int-8A) 0.35 g (Yield: 66%).Step-8A: Synthesis of Ar-(l-(13-dimethyl-2-oxo-23-dihydro-177-benzo[rZ]imidazol-5-yl) cyclopropyl)-4-hydroxy-3-methoxy-A-methylbenzamide [PSY-01-00139]To a stirred solution of 4-(allyloxy)-W-(l-(l,3-dimethyl-2-oxo-2,3-dihydro-177-benzo|V7]imidazol- 5-yl) cyclopropyl)-3-methoxy-A-methylbenzamide [Int-7A] (0.2 g, 0.4750 mmol, 1.0 eq.) in MeOH (10 mL) were added Nickel (If) chloride hexahydrate (0.17 g, 0.7125 mmol, 1.5 eq.) at 0°C, to that sodium borohydride (0.055 g, 1.425 mmol, 3.0 eq.) was added portion wise and the resulting reaction mixture was stirred at room temperature for 20 min. After completion of reaction as monitored by TLC, the reaction mixture was evaporated on rotavapour up to dryness obtained a crude residue, which was diluted with water was extracted with dichloromethane (3 X 30 ml); combined organic layer was washed with and brine dried over sodium sulfate and concentrated to obtain crude product, which was purified by combi-flash by using 10% MeOH in DCM as mobile phase to give desired product as A-(l-(l,3-dimethyl-2-oxo-2,3-dihydro-l / f-benzo[< / ]imidazol-5- yl)cyclopropyl)-4-hydroxy-3-methoxy-A-methyl benzamide (PSY-01-00139) 0.03 g (Yield: 17%).Example 7: Synthesis of Compounds 196 and 197.(R)-5-(l-(2-(3-fltioro-4-hydroxy-5-methoxyphenyl)-lH-pyrrol-l-yI)propyl)-l,3-dimelhyl-l,3- dihydro-2H-benzo[d]imidazol-2-one (Compound 196, or PSY-01-00196-001);(S)-5-(l-(2-(3-fluoro-4-hydroxy-5-melhoxyphenyl)-lH-pyrrol-l-yl)propyl)-l,3-dimelhyl-l,3- dihydro-2H-benzo[dlimidazol-2-one (Compound 197, or PSY-01-00197—001)Synthetic scheme:Step-6: Synthesis of N-(l -(13-dimethyl-2-oxo-23-dihydro-lH-benzo[d]imidazol-5- yl)propyl)-2-methylpropane-2-sulfinamide (Int-7)To a stirred solution of (E)-N-((l,3-dimethyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5- yl)methylene)-2-methylpropane-2-sulfmamide (Int-6) (0.5 g, 1.70 mmol, 1 eq.) in Tetrahydrofuran(10 mL) was added Ethyl magnesium bromide 1.0 M soP in Tetrahydrofuran ( 1.70 mL, 4.26 mmol,2.5 eq.) at-10°C. Reaction mixture was stirred at 10°C for next 2 to 3 hr.; the progress of the reaction was monitored by TLC. After completion of the reaction; mixture was quench with 10 mL ammonium chloride solution. Crude compound was extracted with ethyl acetate (3*10 mL);Organic layer was washed with brine; dried over sodium sulphate and concentrated under vacuum to get crude material; which was purified by Combi flash column chromatography. The product was eluted in 60-70% in Ethyl acetate in n-hexane as a mobile phase to give desired compound as N-(l-(l,3-dimethyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)propyl)-2-methylpropane-2- sulfinamide (Int-7) 0.35 g (Yield: 63.63 %).Step-2: Synthesis of 5-(l-aminopropyl)-13-diinethyl-13-dihydro-2H-benzo[d]imidazol-2- one (Int-8)To a stirred solution N-(l-(l,3-dimethyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)propyl)-2- methylpropane-2-sulfinamide (Int-7) (2.4 g, 7.43 mmol, 1.0 eq.) in 1-4 Dioxane (10 mL) was cooled to 0° - 5° C, added 4 molar HC1 in 1-4 Dioxane (5 mL), then the resulting reaction mixture was stirred at room temperature for next 5 to 6 hr. The progress of the reaction was monitored by TLC; After completion of reaction, the reaction mixture was filter on Buckner funnel and crude product was washed with Hexane (2*10 mL) and dried on vacuum pump to get crude material as 5-(l-aminopropyl)-l,3-dimethyl-l,3-dihydro-2H-benzo[d]imidazol-2-one (Int-8) 1.10 g (Yield: 67.90%).Step-3: Synthesis of 5-(l-(lH-pyrrol-l-yl)propyl)-l,3-diinethyl-l,3-dihydro-2H-benzo[d] imidazole-2-one (Int-9)To a stirred solution of 2,5 Dimethoxy tetrahydrofuran (0.57 g, 6.40 mmol, 1.0 eq.) in DM water (20 mL), stirred reaction mixture at 100° C for 2 to 3 hr. Allowed the reaction mixture to cool at room temperature, were added solution of 5-(l-aminopropyl)-l,3-dimethyl-l,3-dihydro-2H-benzo[d]imidazol-2-one (Int-8) (1 .0 g, 6.40 mmol, 1.0 eq.) in Dichloromethane (30 mL) followed by Sodium acetate (0.71 g, 8.69 mmol, 2.0 eq.) was added to reaction mixture at room temperature. Reaction mixture was allowed to stirre at room temperature for next 14 to 15 hr. under light protection; the progress of the reaction was monitored by TLC. After completion of the reaction; reaction mixture pour in 100 mL saturated Sodium carbonate solution. Crude compound was extracted with Dichloromethane (3 X 20 mL); The organic layer was washed with brine; dried over sodium sulphate and concentrated under vacuum to get crude material; which was purified by Combi flash column chromatography. The product was eluted in 30-40% in Ethyl acetate in n- hexane as a mobile phase to give desired compound as 5-(l-(lH-pyrrol-l-yl)propyl)-l,3-dimethyl- l,3-dihydro-2H-benzo[d]imidazol-2-one (Int-9) 0.92 g (Yield: 75.48 %).Step-4: Synthesis of 5-(l-(2-bromo-!H-pyrrol-l-yl) propyl)-! 3-dimethyl-13-dihydro-2H- benzo[d]imidazol-2-oneTo a stirred solution of 5-(l-(lH-pyrrol-l-yl)propyl)-l,3-dimethyl-l,3-dihydro-2H- benzo[d]imidazol-2-one (Int-9) (0.500 g, 1.85 mmol, 1.0 eq.) in Tetrahydrofuran (15 mL) was cooled to (-78° ) C , added N-bromosuccinimide (0.329 g, 1.85 mmol, 1.0 eq.), then the resulting reaction mixture was stirred at (-78° ) C for next 2 to 3 hr. The progress of the reaction was monitored by TLC; after completion of reaction, the reaction mixture was quench with saturated sodium bicarbonate solution (20 mL) and extracted with Ethyl acetate (3*10 mL). The organic layer was washed with brine, dried over sodium sulphate and concentrated under vacuum to get crude material; which was purified by Combi flash column chromatography. The product was eluted in 40-45% in Ethyl acetate in n-hexane as a mobile phase to give desired compound as 5- (l-(2-bromo-lH-pyrrol-l-yl)propyl)-l,3-dimethyl-l,3-dihydro-2H-benzo[d]imidazol-2-one (Int- 10) 0.550 g (Yield: 85.93%).Step-5: Synthesis of 5-(l-(2-(4-(benzyIoxy)-3-fluoro-5-methoxyphenyl)-lH-pyrrol-l-yl) propyl)-!, 3-dimethyl-13-dihydro-2H-benzo[dJimidazol-2-one (Int-11)To a stirred solution of 5-(l-(2-bromo-lH-pyrrol-l-yl)propyl)-l,3-dimethyl-l,3-dihydro-2H- benzo[d]imidazol-2-one (Int-10) (0.670 g, 1.91mmol, 1.0 eq.) in 1-4 Dioxane (15 mL) and DM water (10 mL), were added 2-(4-(benzyloxy)-3-fluoro-5-methoxyphenyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (0.895 g, 2.48 mmol, 1.3 eq.), and potassium carbonate (0.52 g, 3.82 mmol, 2.0 eq.) were stirred at room temperature with continuous purging of nitrogen for next 20 min. Tetrakis (triphenylphosphine)palladium(O) (0.110 g, 0.095 mmol, 0.05 eq.) was added at room temperature, then the resulting reaction mixture was stirred at 100°C for next 12 hr. The progress of the reaction was monitored by TLC; after completion of reaction, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3*20 mL). The organic layer was washed with brine, dried over sodium sulphate and concentrated under vacuum to get crude material; which was purified by Combi flash column chromatography. The product was eluted in 50% in Ethyl acetate in n-hexane as a mobile phase to give desired product as 5-(l-(2-(4- (ben2yloxy)-3-fluoro-5-methoxyphenyl)-lH-pyrrol-l-yl)propyl)-l,3-dimethyl-l,3-dihydro-2H- benzo[d]imidazol-2-one (Int-11) 0.690 g (Yield: 71.87%).Step-6: Synthesis of 5-(l-(2-(3-fluoro-4-hydroxy-5-methoxyphenyl)-l H-pyrrol-l-yl)propyl)- l,3-dimethyl-l,3-dihydro-2H-benzo[d]imidazol-2-one (Int-12)To a stirred solution of 5-(l-(2-(4-(benzyloxy)-3-fluoro-5-methoxyphenyl)-lH-pyrrol-l- yl)propyl)-l,3-dimethyl-l,3-dihydro-2H-benzo[d]imidazol-2-one (Int-11) 0.690 g, 1.38 mmol, 1.0 eq.) was dissolved in Methanol (20 mL). 10% Pd / C (with 50% moisture) 0.10 g was added at Room Temperature and Reaction mixture was allowed to stir for 3 hr. under Hydrogen atmosphere.Reaction was monitored by TLC. After completion of the reaction, Reaction mixture was filtered through celite bed, washed with Methanol (70 mL) and concentrated to get crude compound, which was purified by column chromatography us...

Claims

CLAIMSWhat is claimed is:

1. A compound of Formula (I):or a pharmaceutically acceptable salt, enantiomer, or racemate thereof, wherein:Ra and Rb are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, or halogen, or Raand Rb together form an alkenyl, carbonyl (=0), or a spirocyclic cycloalkyl optionally substituted with one or more R30;A1and A2are each independently N, NH, or CR1;A3 is N or C; provided that at least one of A1, A2and A3 is N;Bi is C(Rc1Rc2), NRc3or oxygen;Rc1, Rc2, R.3 and Rdare each independently hydrogen or methyl,R1and R2 are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, amine, amide, carboxyl, alkyl-acetate, or alkyl-amide; or one of R1and R2 together form a fused 6-member aryl ring or fused 6-member heteroaryl ring optionally substituted with R20;R12 is hydrogen or halogen;R20 is carboxyl, alkyl-acetate, amide or alkyl-amide; andRao is halogen, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl;provided the compound of Formula (1) is not (l-[(l,3-dimethyl-2-oxo-2,3-dihydro- lH-l,3-benzodiazol-5-yl)methyl]-2-(4-hydroxy-3-methoxyphenyl)-N-methyl-lH-l,3- benzodiazole-5-carboxamide.

2. The compound of claim 1, wherein the compound is a compound of Formula (U):Formula (II) or a pharmaceutically acceptable salt, enantiomer, or racemate thereof, wherein:Ra and Rb are each independently hydrogen, halogen, or C1-4alkyl optionally substituted with one or more halogen; or R, and Rb together form a spirocyclic cyclopropyl,A1and A2are each independently CH or N;R1o is methyl; andR12 is hydrogen or halogen.

3. The compound of claim 2, wherein only one of A1and Az is N.

4. The compound of claim 3, wherein Ra and Rb are each independently hydrogen, methyl or ethyl, wherein the methyl or ethyl are optionally substituted with one or more fluoro.

5. The compound of claim 4, wherein R1o is methyl and R12 is hydrogen or fluoro; and Ra is hydrogen.

6. The compound of claim 5, wherein A2is CH.

7. The compound of claim 6, wherein A1is N.

8. The compound of claim 6, wherein A1is CH.

9. The compound of claim 8, wherein the compound is:(Compound 192), or a pharmaceutically acceptable salt thereof.

10. The compound of claim 8, wherein the compound is:(Compound 528), or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1, wherein the compound is a compound of Formula (HI):Formula (III) or a pharmaceutically acceptable salt, enantiomer, or racemate thereof, wherein:Ra and Rb are each independently hydrogen, or C1-4alkyl; or Ra and Rb together form a spirocyclic cyclopropyl;A1is CH or N;R1o is methyl;R12 is hydrogen or halogen; andR20 is hydrogen, -C(O)OH, -C(O)O(CH3), -C(O)NH2or C(O)NH(CH3).

12. The compound of claim 11, wherein a. R12 is hydrogen or fluoro; b. Ra and Rb are each independently hydrogen, methyl or ethyl; and c. R20 is -C(O)OH, -C(O)O(CH3) or C(O)NH(CH3).

13. The compound of claim 12, wherein A1is N.

14. The compound of claim 13, wherein R, and Rb are each hydrogen.

15. The compound of claim 14, wherein R12 is hydrogen or fluorine.

16. The compound of claim 15, wherein R20 is hydrogen, -C(O)OH, -C(O)O(CH3) or C(O)NH(CH3).

17. The compound of claim 15, wherein R20 is hydrogen18. The compound of claim 17, wherein the compound is:(Compound 004), or a pharmaceutically acceptable salt thereof.

19. The compound of claim 16, wherein R20 is C(O)OH.

20. The compound of claim 19, wherein the compound is: (Compound 016), or a pharmaceutically acceptable salt thereof.

21. A compound of Formula (I-A-l), Formula (I-B), Formula (IQ, Formula (IV), Formula (V-A-l), Formula (V-A-2), Formula (V-B), Formula (V-B-l), Formula (V-C), Formula (V-D), Formula (V-E), or Formula (VI) wherein,Ra and Rb are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, or halogen; or Ra and Rb together form a spirocyclic cycloalkyl optionally substituted with one or more R30;A1isNH;A2is C;A3 is C;Bi is C(RtiiRc2), NRc3or oxygen;Rc1, Rc2, Rc3and Rdare each independently hydrogen or methyl;R1is hydrogen, C1-4alkyl, C1-4haloalkyl, amine, amide, carboxyl, alkyl-acetate or alkyl-amide;R12 is hydrogen or halogen;R20 is carboxyl, alkyl-acetate or alkyl-amide; andR30 is halogen, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl; or wherein,R» and Rb are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, or halogen; or Raand Rb together form a spirocyclic cycloalkyl optionally substituted with one or more Rao;A1is C;A2is N, NH, or CR1,A3 is N or C; provided that at least one of A2and A3 is N, or provided A2is NH if A3 is C;Bi is C(Rc1Rc2), NRc3or oxygen;Rc1, Rc2, Rc3and Ra are each independently hydrogen or methyl;R1is hydrogen, C1-4alkyl, C1-4haloalkyl, amine, amide, carboxyl, alkyl-acetate or alkyl-amide;R12 is hydrogen or halogen;R20 is carboxyl, alkyl-acetate or alkyl-amide; andR30 is halogen, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl; orFormula (I I) wherein,Ra and Rb are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, or halogen; or Ra and Rb together form a spirocyclic C3-6 cycloalkyl;A1and A2are each independently CH or N, andR12 is hydrogen or halogen; wherein,Ra and Rb are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, or halogen; or Raand Rb together form a spirocyclic cyclopropyl;Re is hydrogen or methyl; andR12 is hydrogen or halogen; orwherein,R» and Rb are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, or halogen; or Ra and Rb together form a spirocyclic cycloalkyl optionally substituted with one or more R30;A1is C;A2is N, NH or CRj;A3 is N or C; provided that at least one of A2and A? is N, or provided A2is NH if A3 is C;Bi is C(Rc1Rc2), NRc3or oxygen;Rc1, Rc2, Rc3and Rdare each independently hydrogen, C1-4alkyl or C3-6 cycloalkyl;R1is hydrogen, C1-4alkyl, C1-4haloalkyl, amine, amide, carboxyl, alkyl-acetate or alkyl-amide; each of R12a, R12b, R12c, and Rud, is independently hydrogen, nitro, alkoxy, hydroxy or halogen; R12eis hydrogen, nitro, alkoxy, hydroxy or halogen; or R12eand Rb are together alkyl; R2o is carboxyl, alkyl-acetate or alkyl-amide; andR30 is halogen, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl; orFormula (V-D); wherein A1, A1, As, Bi, Rd, R20, Rua, Rub, R12c, Rua, and Rue are as defined in Formula (V- C), provided that at least one of A2and A1is N, or provided A2is NH if A3 is C;RizbR12CFormula (V-A-2) wherein,Raand Rb are each independently hydrogen, C j-4 alkyl, C1-4haloalkyl, or halogen; or R» and Rb together form an alkenyl, carbonyl (=0), or a spirocyclic cycloalkyl optionally substituted with one or more R30;A1and A2are each independently N, NH or CR1;A3 is N or C, provided that at least one of A1, A2and A3 is N;Bi is C(Rc1Rc2), NR«3 or oxygen;Rc1, Rc2, Rc3and Rdare each independently hydrogen, C1-4alkyl or C3-6 cycloalkyl;R1and R2 are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, amine, amide, carboxyl, alkyl-acetate or alkyl-amide; or one of R1and R2 together form a fused 6-member aryl ring or fused 6-member heteroaiyl ring optionally substituted with R20; each of Rna, R12b, Rnc, R12d, and R12e, is independently hydrogen, nitro, alkoxy, hydroxy or halogen;R20 is carboxyl, alkyl-acetate or alkyl-amide; andR30 is halogen, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl; orFormula (V-B), wherein,Ri and Rb are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, or halogen; or Ra and Rb together form a spirocyclic cycloalkyl optionally substituted with one or more R30;A1is NH;A2is C;A3 is C;Bi is C(Rc1Rc2), NRS or oxygen;Rc1. Rc2, Rc3and Rdare each independently hydrogen, C1-4alkyl or C3-6 cycloalkyl;R1is hydrogen, C1-4alkyl, C1-4haloalkyl, amine, amide, carboxyl, alkyl-acetate or alkyl-amide; each of Rua, R12b, R12c, and Rna, is independently hydrogen, nitro, alkoxy, hydroxy or halogen; R12eis hydrogen, nitro, alkoxy, hydroxy or halogen; or Rue and Rb are together alkyl;R20 is carboxyl, alkyl-acetate or alkyl-amide; andR30 is halogen, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl; orFormula (V-B-l) wherein A1, A2, A3, Bi, Rd, R20, R12a, R12b, R12c, R12d, and R12eare as defined in Formula (V- B), orFormula (V-E) wherein,Ra and Rb are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, or halogen, or Ra and Rb together form a spirocyclic C3-6 cycloalkyl;A1and A2are each independently CH or N; each of R12a, R12b, R12c, and R12d, is independently hydrogen, nitro, alkoxy, hydroxy or halogen; and R12eis hydrogen, nitro, alkoxy, hydroxy or halogen; or Rue and Rb are together alkyl;Formula (VI) wherein,R. is hydrogen. C1-4alkyl. C1-4haloalkyl, or halogen;A1and A2are each independently N, NH or CR1;A3 is N or C; provided that at least one of A1, A2and A1is N;Bi is C(R;iRc2), NR«3 or oxygen;Rc1, Rc2, Rc3and Rdare each independently hydrogen, C1-4alkyl or C3-6 cycloalkyl;R1and R2 are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, amine, amide, carboxyl, alkyl-acetate or alkyl-amide; or one of R1and R2 together form a fused 6-member aryl ring or fused 6-member heteroaryl ring optionally substituted with R20; each of R12a, R12b, R12c, and Rnd, is independently hydrogen, nitro, alkoxy, hydroxy or halogen;R20 is carboxyl, alkyl-acetate or alkyl-amide; andR30 is halogen, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl; or a pharmaceutically acceptable salt, enantiomer, or racemate thereof.

22. A pharmaceutical composition comprising a compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, formulated in combination with one or more excipients for oral administration.

23. A method of treating treatment of Parkinson’s disease as an adjunct to levodopa / carbidopa therapy, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I):or a pharmaceutically acceptable salt, enantiomer, or racemate thereof, wherein;Ra and Rb are each independentiy hydrogen, C1-4alkyl, C1-4haloalkyl, or halogen; or R« and Rb together form an alkenyl, carbonyl (=0), or a spirocyclic cycloalkyl optionally substituted with one or more R30;A1and A2are each independently N, NH, or CR1;A3 is N or C; provided that at least one of A1, A2and A3 is N;Bi is C(Rc1Rc2), NRc3or oxygen;Rc1, Rc2, Rc3and Rdare each independently hydrogen or methyl;R1and R2 are each independently hydrogen, C1-4alkyl, C1-4haloalkyl, amine, amide, carboxyl, alkyl-acetate, or alkyl-amide; or one of R1and R2 together form a fused 6-member aryl ring or fused 6-member heteroaryl ring optionally substituted with R20;R12 is hydrogen or halogen;Rao is carboxyl, alkyl-acetate, or alkyl-amide; andR30 is halogen, C3-6 cycloalkyl, or 3-6 member heterocycloalkyl.

24. The method of claim 23, wherein the method is a method of prolonging effective treatment of Parkinson's disease, comprising administering to a patient in need thereof a compound of any one of claims 1-21 or the pharmaceutical composition of claim 22, in an amount effective to delay the patient's need for add-on L-DOPA therapy, wherein the patient currently receives L-DOPA therapy.

25. The method of claim 23, wherein the method is a method of treating a neurological or psychiatric disorder for which inhibiting COMT provides a therapeutic effect, or treating symptoms associated with die neurological or psychiatric disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claims 1-21 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 22.

26. A method for reducing the number or intensity of one or more symptoms of a psychiatric or neurological disorder for which inhibiting COMT provides a therapeutic effect in a patient in need thereof, the method comprising administering a therapeutically effective amount of a compound of claims 1-21 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 22.

27. The method of claim 26, wherein the psychiatric disorder is selected from major depressive disorder (MDD), ADHD, obsessive-compulsive disorder, alcoholism and other addictions, depression, bipolar disorder, age-associated cognitive symptoms, impulse control disorders and schizophrenia.

28. The method of claim 26, wherein the psychiatric disorder is Major Depressive Disorder (MDD).

29. A method of inhibiting COMT comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-21 or the pharmaceutical composition of claim 22.

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