Substituted tetrahydropyrrolo-pyridinone compounds and their use in treating medical conditions

Abstract

The present invention provides substituted tetrahydropyrrolo-pyridinone compounds, pharmaceutical compositions, and their use in the treatment of muscarinic acetylcholine receptor-mediated disorders.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 433,156, filed December 16, 2022, the contents of which are incorporated herein by reference in their entirety.

[0002] The present invention provides substituted tetrahydropyrrolo-pyridinone compounds, pharmaceutical compositions, and their use in the treatment of muscarinic acetylcholine receptor-mediated disorders. [Background technology]

[0003] Muscarinic acetylcholine receptor-mediated disorders, such as major depressive disorder (MDD), bipolar disorder (BPD), and schizophrenia, are psychiatric disorders that continue to be significant public health issues. While currently available antidepressants, mood stabilizers, and antipsychotics can alleviate mood disorder symptoms in some patients, they are only partially effective for a significant number of patients, and many patients are resistant to treatment with currently available medications. Patients with major depressive disorder often experience at least two weeks of pervasive depressed mood, low self-esteem, and loss of interest or pleasure in activities that are usually found enjoyable. Patients with bipolar disorder often experience periods of depression and periods of abnormally elevated mood, each lasting several days to several weeks. Patients with schizophrenia often experience active social avoidance, passive social withdrawal, emotional withdrawal, and anxiety. Supportive care is used in some situations to alleviate symptoms of muscarinic acetylcholine receptor-mediated disorders, but supportive care does not directly treat the disorder and is not a good long-term solution to a patient's medical needs.

[0004] The compound that modulates muscarinic acetylcholine receptor can be used to treat diseases related to the activity of muscarinic acetylcholine receptor, such as major depressive disorder, bipolar disorder and schizophrenia.Muscarinic acetylcholine receptor is an acetylcholine receptor that forms a G protein-coupled receptor complex in the cell membrane of certain nerve cells and other cells.US Patent No. 10,604,519 describes that certain compounds are active against M4 muscarinic acetylcholine receptor.However, in order to treat disorders mediated by muscarinic acetylcholine receptor, new compounds with excellent drug-like properties are needed.

[0005] The present invention addresses the above-mentioned needs and provides other related advantages. Summary of the Invention

[0006] The present invention provides substituted tetrahydropyrrolo-pyridinone compounds, pharmaceutical compositions, and their use in the treatment of muscarinic acetylcholine receptor-mediated disorders. In particular, one aspect of the present invention provides a collection of substituted tetrahydropyrrolo-pyridinone compounds, such as those represented by Formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in the detailed description. Further description of additional collections of substituted tetrahydropyrrolo-pyridinone compounds is provided in the detailed description. The compound can be part of a pharmaceutical composition that includes a pharmaceutically acceptable carrier.

[0007] Another aspect of the present invention provides a method for treating a muscarinic acetylcholine receptor-mediated disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein, such as a compound of Formula I, to treat the muscarinic acetylcholine receptor-mediated disorder, as further described in the detailed description.

[0008] Another aspect of the present invention provides a method for activating a muscarinic acetylcholine receptor, comprising contacting the muscarinic acetylcholine receptor with an effective amount of a compound described herein, such as a compound of Formula I, to activate the muscarinic acetylcholine receptor, as further described in the detailed description. DETAILED DESCRIPTION OF THE INVENTION

[0009] The present invention provides substituted tetrahydropyrrolo-pyridinone compounds, pharmaceutical compositions, and their use in the treatment of muscarinic acetylcholine receptor-mediated disorders. The practice of the present invention utilizes, unless otherwise indicated, conventional techniques of organic chemistry, pharmacology, molecular biology (including recombinant techniques), cell biology, biochemistry, and immunology. Such techniques are described in such references as "Comprehensive Organic Synthesis" (B.M. Trost & I. Fleming, eds., 1991-1992); "Handbook of Experimental Immunology" (D.M. Weir & C.C. Blackwell, eds.); "Current Protocols in Molecular Biology" (F.M. Ausubel et al., eds., 1987 and periodic updates); and "Current Protocols in Immunology" (J.E. Coligan et al., eds., 1991), each of which is incorporated herein by reference in its entirety.

[0010] Various aspects of the invention are described in the following sections, but an aspect of the invention described in a particular section is not limited to any particular section. Further, if a variable is not accompanied by a definition, the preceding definition of that variable takes precedence.

[0011] definition Compounds of the present disclosure include those outlined herein and are further exemplified by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise specified. These definitions apply regardless of whether a term is used alone or in combination with other terms, unless otherwise specified. Thus, the definition of "alkyl" applies not only to "alkyl" but also to "alkyl" moieties such as "-O-alkyl." For purposes of this invention, chemical elements are defined as defined in the CAS version of the Periodic Table of the Elements (Handbook of Chemistry and Physics, 75 th Further, general principles of organic chemistry are specified in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5 th Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0012] The terms "aliphatic" or "aliphatic group," as used herein, mean a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that has one point of attachment to the rest of the molecule and that is fully saturated or contains one or more units of unsaturation, or a monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic (also referred to herein as "cycloaliphatic"). Unless otherwise specified, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In still other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in still other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "cycloaliphatic" refers to a monocyclic C3-C6 hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic, having one point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups, and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0013] As used herein, the term "bicyclic ring" or "bicyclic ring system" refers to any bicyclic ring system, i.e., a carbocyclic or heterocyclic ring system having saturated or one or more unsaturated units and having one or more atoms in common between the two rings of the ring system. Thus, the term includes any permissible ring fusion, such as ortho-fused or spiro-fused rings. As used herein, the term "heterobicyclic" is a subset of "bicyclic," which requires the presence of one or more heteroatoms in one or both of the two rings. Such heteroatoms may be present at the ring junction, are optionally substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, and the like. In some embodiments, bicyclic groups have 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. As used herein, the term "bridged bicyclic" refers to any bicyclic ring system, i.e., saturated or partially unsaturated carbocyclic or heterocyclic, having at least one bridge. According to the IUPAC definition, a "bridge" is an unbranched chain of atoms or a single atom or valence bond connecting two bridgeheads, and a "bridgehead" is an atom attached to three or more skeletal atoms (excluding hydrogen) of the ring system. In some embodiments, a bridged bicyclic group has 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include the groups described below, each group attached to the remainder of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, bridged bicyclic groups are optionally substituted with one or more substituents as described for aliphatic groups. Alternatively or additionally, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bicyclic rings include: [ka]

[0014] Exemplary bridged bicyclics include: [ka]

[0015] The term "lower alkyl" refers to a straight or branched chain C 1-4 refers to an alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0016] The term "lower haloalkyl" refers to a C substituted with one or more halogen atoms. 1-4 refers to a straight or branched chain alkyl group.

[0017] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocyclic ring, e.g., N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (including those in N-substituted pyrrolidinyl).

[0018] The term "unsaturated," as used herein, means that a moiety has one or more units of unsaturation.

[0019] As used herein, "C 1-8 (or C 1-6 The term "divalent saturated or unsaturated, straight or branched hydrocarbon chain of the formula (I)" refers to divalent alkylene, alkenylene, and alkynylene chains, which are straight or branched, as defined herein.

[0020] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2) n-, where n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms have been replaced with a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0021] The term "-(C alkylene)-" refers to a bond. 0-3 The term "alkylene)-" refers to a bond (i.e., C) and a -(C 1-3 alkylene)-groups.

[0022] The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms have been replaced with a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0023] The term "halogen" means F, Cl, Br, or I.

[0024] The term "aryl," used alone or as part of a larger moiety such as "aralkyl," "aralkoxy," or "aryloxyalkyl," refers to a monocyclic or bicyclic ring system having a total of 5 to 14 ring members, in which at least one ring in the system is aromatic and each ring in the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring." In certain embodiments of the present invention, "aryl" refers to an aromatic ring system, including, but not limited to, phenyl, biphenyl, naphthyl, anthracyl, and the like, which may bear one or more substituents. Also included within the scope of the term "aryl" as used herein are groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthymidyl, phenanthridinyl, or tetrahydronaphthyl. The term "phenylene" refers to a polyvalent phenyl group having the appropriate number of open valences, taking into account the groups to which it is attached.

[0025] The terms "heteroaryl" and "heteroa-," used alone or as part of a larger moiety, such as "heteroaralkyl" or "heteroaralkoxy," refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms, with 6, 10, or 14 pi electrons shared in the cyclic arrangement, and having 1 to 5 heteroatoms in addition to the carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms "heteroaryl" and "heteroa-," as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where, unless otherwise specified, the radical or point of attachment is on the heteroaromatic ring or on one of the rings to which the heteroaromatic ring is fused. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. Heteroaryl groups can be monocyclic or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," all of which terms include optionally substituted rings. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl group, where the alkyl and heteroaryl portions independently are optionally substituted.

[0026] The term "heteroarylene" refers to a polyvalent heteroarylene group having the appropriate number of open valences, taking into account the groups attached to it. For example, a "heteroarylene" is a divalent heteroaryl group when two groups are attached, and a "heteroarylene" is a trivalent heteroaryl group when three groups are attached.

[0027] As used herein, the terms "heterocycle," "heterocyclyl," "heterocyclic radical," and "heterocyclic ring" are used interchangeably and refer to a stable 5- to 7-membered monocyclic moiety or a 7- to 10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated and has, in addition to carbon atoms, one or more, preferably one to four, heteroatoms as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0 to 3 heteroatoms selected from oxygen, sulfur, and nitrogen, the nitrogen can be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or + It can be NR (as in N-substituted pyrrolidinyl).

[0028] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure, and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenylpyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, 2-oxa-6-azaspiro[3.3]heptane, and quinuclidinyl. The terms "heterocycle," "heterocyclyl," "heterocyclyl ring," "heterocyclic group," "heterocyclic moiety," and "heterocyclic radical" are used interchangeably herein and include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or alicyclic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. Heterocyclyl groups can be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions are independently optionally substituted. The term "oxo-heterocyclyl" refers to a heterocyclyl substituted with one or more oxo groups. The term "heterocyclylene" refers to a polyvalent heterocyclyl group having the appropriate number of open valences, taking into account the groups attached to it. For example, "heterocyclylene" is a divalent heterocyclyl group when two groups are attached, and "heterocyclylene" is a trivalent heterocyclyl group when three groups are attached. The term "oxo-heterocyclylene" refers to a polyvalent oxo-heterocyclyl group having the appropriate number of open valences taking into account the groups attached to it.

[0029] As used herein, the term "partially unsaturated" refers to a ring moiety that contains at least one double or triple bond. The term "partially unsaturated" is intended to include rings with multiple sites of unsaturation, but is not intended to include aryl and heteroaryl moieties as defined herein.

[0030] As described herein, the compounds of the present invention may contain "optionally substituted" moieties. In general, the term "substituted," whether preceded by the term "optionally," means that one or more hydrogens of the specified moiety have been replaced with a suitable substituent. Unless otherwise specified, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position of any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be the same or different at each position. Combinations of substituents envisioned by the present invention are preferably those that result in the formation of stable or chemically feasible compounds. The term "stable," as used herein, refers to a compound that remains substantially unchanged when subjected to conditions that allow for the compound's production, detection, and, in certain embodiments, its recovery, purification, and use for one or more of the purposes disclosed herein.

[0031] Each optional substituent on a substitutable carbon is a halogen; -(CH2) 0-4 R°;-(CH2) 0-4 OR°;-O(CH2) 0-4 R°, -O-(CH2) 0-4 C(O)OR°;-(CH2) 0-4 CH(OR°)2;-(CH2) 0-4 SR°;-(CH2) 0-4 Ph (can be substituted by R°); -(CH2) 0-4 O(CH2) 0-1 Ph (which may be substituted with R°); -CH=CHPh (which may be substituted with R°); -(CH2) 0-4 O(CH2) 0-1 -pyridyl (which may be substituted by R°); -NO2; -CN; -N3; ​​-(CH2)0-4 N(R°)2;-(CH2) 0-4 N(R°)C(O)R°;-N(R°)C(S)R°;-(CH2) 0-4 N(R°)C(O)NR°2;-N(R°)C(S)NR°2;-(CH2) 0-4 N(R°)C(O)OR°;-N(R°)N(R°)C(O)R°;-N(R°)N(R°)C(O)NR°2;-N(R°)N(R°)C(O)OR°;-(CH2) 0-4 C(O)R°;-C(S)R°;-(CH2) 0-4 C(O)OR°;-(CH2) 0-4 C(O)SR°;-(CH2) 0-4 C(O)OSiR°3;-(CH2) 0-4 OC(O)R°;-OC(O)(CH2) 0-4 SR-, SC(S)SR°;-(CH2) 0-4 SC(O)R°;-(CH2) 0-4 C(O)NR°2;-C(S)NR°2;-C(S)SR°;-SC(S)SR°, -(CH2) 0-4 OC(O)NR°2;-C(O)N(OR°)R°;-C(O)C(O)R°;-C(O)CH2C(O)R°;-C(NOR°)R°;-(CH2) 0-4 SSR°;-(CH2) 0-4 S(O)2R°;-(CH2) 0-4 S(O)2OR°;-(CH2) 0-4 OS(O)2R°;-S(O)2NR°2;-S(O)(NR°)R°;-S(O)2N=C(NR°2)2;-(CH2) 0-4 S(O)R°;-N(R°)S(O)2NR°2;-N(R°)S(O)2R°;-N(OR°)R°;-C(NH)NR°2;-P(O)2R°;-P(O)R°2;-OP(O)R°2;-OP(O)(OR°)2;SiR°3;-(C 1-4 straight or branched chain alkylene)ON(R°)2; or -(C 1-4 is a monovalent substituent independently selected from straight or branched chain alkylene)C(O)ON(R°)2.

[0032] Each R° is independently hydrogen, C 1-6Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, -CH2- (a 5- to 6-membered heteroaryl ring), or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or, notwithstanding the above definitions, two independent R°, taken together with the atom(s) between them, form a 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur and which may be substituted on a saturated carbon atom of R° by a divalent substituent selected from =O and =S; or each R° is selected from halogen, -(CH2) 0-2 R ● ,-(Halo R ● ), -(CH2) 0-2 OH, -(CH2) 0-2 OR ● , -(CH2) 0-2 CH(OR ● )2;-O(HaloR ● ), -CN, -N3, -(CH2) 0-2 C(O)R ● , -(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR ● , -(CH2) 0-2 SR ● , -(CH2) 0-2 SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR ● , -(CH2) 0-2 NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3. -C(O)SR ● , -(C 1-4 straight or branched chain alkylene)C(O)OR ● , or -SSR ● is optionally substituted with a monovalent substituent independently selected from

[0033] Each R ● is C 1-4Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each R ● is unsubstituted or, if preceded by halo, is substituted with one or more halogens only, or the optional substituents on the saturated carbon are ═O, ═S, ═NNR * 2, =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O)2R * , =NR * , =NOR * , -O(C(R * 2)) 2-3 O- or -S(C(R * 2)) 2-3 or a divalent substituent attached to a vicinal substitutable carbon of an "optionally substituted" group is -O(CR * 2) 2-3 O-, where each individual R * is hydrogen, C 1-6 It is selected from aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0034] R * C 1-6 If aliphatic, R * is halogen, -R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ● is C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each R ● is unsubstituted or, if preceded by halo, substituted with one or more halogens only.

[0035] The optional substituents on the substitutable nitrogen are independently -R † , -NR † 2. -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CHC(O)R † , -S(O)2R † , -S(O)NR † 2. -C(S)NR † 2. -C(NH)NR † 2, or -N(R † )S(O)2R † where each R † are independently hydrogen, C 1-6 an aliphatic, unsubstituted -OPh, or an unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or two independent R † together with the atom(s) therebetween to form an unsubstituted 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein R † C 1-6 If aliphatic, R † is halogen, -R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ● is C 1-4Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each R ● is unsubstituted or, if preceded by halo, substituted with one or more halogens only.

[0036] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, etc., and that is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, and 2-hydroxy-ethanesulfonate. Examples of suitable salts include benzoate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate.

[0037] Furthermore, acids generally considered suitable for forming pharmaceutically useful salts from basic pharmaceutical compounds are described, for example, in P. Stahl et al., Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al., Journal of Pharmaceutical Sciences (1977) 66(1)1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; and The Orange Book (Food & Drug Administration, Washington, DC website), the disclosures of which are incorporated herein by reference.

[0038] Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N + (C 1-4 Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, formed where appropriate using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0039] Unless otherwise specified, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational) isomeric) forms of the structure, including, for example, the R and S configurations of each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Thus, not only single stereochemical isomers of the present compounds, but also enantiomeric, diastereomeric, and geometric (or conformational) mixtures are within the scope of the invention. Unless otherwise specified, all tautomers of the compounds of the invention are within the scope of the invention. The invention includes compounds that differ only in the presence of one or more isotopically enriched atoms, for example, the replacement of hydrogen by deuterium or tritium, or 13 C or 14 Compounds having this structure including the replacement of a carbon with a C-enriched carbon are within the scope of this disclosure. Such compounds are useful, for example, as analytical tools, probes in biological assays, or as therapeutic agents according to the present invention.

[0040] Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known to those skilled in the art, such as, for example, chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting the individual diastereomers into the corresponding pure enantiomers (e.g., by hydrolysis). Alternatively, specific enantiomers of compounds of the present invention can be prepared by asymmetric synthesis. Furthermore, if the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxylic acid), diastereomeric salts can be formed with a suitable optically active acid or base, followed by resolution of the diastereomers so formed by fractional crystallization or chromatographic means well known in the art, followed by recovery of the pure enantiomers.

[0041] Individual stereoisomers of the compounds of the present invention may, for example, be substantially free of other isomers, or may be, for example, racemic or mixed with all other stereoisomers or other selected stereoisomers. The chiral center(s) of the compounds of the present invention may have the S or R configuration as defined by the IUPAC 1974 Recommendations. Furthermore, to the extent that the compounds described herein may exist as atropisomers (e.g., substituted biaryls), all forms of such atropisomers are considered to be part of the present invention.

[0042] Chemical names, common names, and chemical structures can be used interchangeably to describe the same structure. When a compound is referred to using both a chemical structure and a chemical name, and there is ambiguity between the structure and the name, the structure shall prevail. It should also be noted that in the text, schemes, examples, and tables of this specification, any carbon and heteroatom that does not have a valence is assumed to have a sufficient number of hydrogen atoms (or atoms) to satisfy the valence.

[0043] As used herein, the words "a" and "an" mean "one or more" and include the plural forms unless the context requires otherwise.

[0044] The term "alkyl" refers to a straight or branched chain saturated hydrocarbon, e.g., a straight or branched group of 1 to 12, 1 to 10, or 1 to 6 carbon atoms, and is defined herein as C1-C6, respectively. 12 Alkyl, C1-C 10alkyl, and C1-C6 alkyl. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, and the like.

[0045] The term "cycloalkyl" refers to a monovalent cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) saturated hydrocarbon group of 3 to 12, 3 to 8, 4 to 8, or 4 to 6 carbons, referred to herein as, for example, "C3-C6 cycloalkyl," which is derived from a cycloalkane. Exemplary cycloalkyl groups include cyclohexyl, cyclopentyl, cyclobutyl, and cyclopropyl. The term "cycloalkylene" refers to a divalent cycloalkyl group.

[0046] The term "haloalkyl" refers to an alkyl group substituted with at least one halogen. Exemplary haloalkyl groups include -CHF, -CHF, -CF, -CHCF, -CFCF, and the like. The term "haloalkylene" refers to a divalent haloalkyl group.

[0047] The term "hydroxyalkyl" refers to an alkyl group substituted with at least one hydroxyl. Exemplary hydroxyalkyl groups include -CHCHOH, -C(H)(OH)CH, -CHC(H)(OH)CHCHOH, and the like.

[0048] The terms "alkenyl" and "alkynyl" are art-recognized and refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively.

[0049] The terms "alkoxyl" or "alkoxy" are art-recognized and refer to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy, and the like. The term "haloalkoxyl" refers to an alkoxyl group substituted with at least one halogen. Exemplary haloalkoxyl groups include -OCHF, -OCHF, -OCF, -OCHCF, -OCFCF, and the like.

[0050] The term "oxo" is art-recognized and refers to an "=O" substituent. For example, a cyclopentane substituted with an oxo group is cyclopentanone.

[0051] [ka] The symbol indicates the point of attachment.

[0052] When any substituent or variable occurs more than one time in any constituent or compound of the present invention, its definition on each occurrence is independent of its definition at every other occurrence, unless otherwise stated.

[0053] One or more compounds of the present invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc., and the present invention is intended to encompass both solvated and unsolvated forms. "Solvate" refers to a physical association of a compound of the present invention with one or more solvent molecules. This physical association may involve varying degrees of ionic and covalent bonding, including hydrogen bonding. A solvate may be isolated in certain cases, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolate, methanolate, etc. A "hydrate" is a solvate in which the solvent molecule is HO.

[0054] As used herein, the terms "subject" and "patient" are used interchangeably and refer to an organism treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., murine, simian, equine, bovine, porcine, canine, feline, etc.), and most preferably, humans.

[0055] "EC 50 The term "maximum response" is art-recognized and refers to the concentration of a compound needed to achieve 50% of the maximum response.

[0056] As used herein, the term "effective amount" refers to an amount of a compound sufficient to produce a beneficial or desired result (e.g., a therapeutic, ameliorative, inhibitory, or preventative result). An effective amount may be administered in one or more administrations, applications, or dosages, and is not intended to be limited to a particular formulation or route of administration. As used herein, the term "treating" includes any effect that results in the improvement of a condition, disease, disorder, etc., e.g., alleviation, reduction, modulation, amelioration, or elimination, or amelioration of symptoms thereof.

[0057] As used herein, the term "pharmaceutical composition" refers to a combination of an active agent with an inert or active carrier, which makes the composition particularly suitable for in vivo or ex vivo diagnostic or therapeutic use.

[0058] As used herein, the term "pharmaceutically acceptable carrier" refers to any of the standard pharmaceutical carriers, such as phosphate-buffered saline, water, emulsions (e.g., oil / water or water / oil emulsions), and various types of wetting agents. The composition may also contain stabilizers and preservatives. For examples of carriers, stabilizers, and adjuvants, see, for example, Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA

[1975] .

[0059] For therapeutic uses, the salts of the compounds of the invention are contemplated as pharmaceutically acceptable. However, salts of acids and bases that are non-pharmaceutically acceptable may also be useful, for example, in the preparation or purification of a pharmaceutically acceptable compound.

[0060] In addition, when a compound of the present invention contains both a basic moiety (such as, but not limited to, pyridine or imidazole) and an acidic moiety (such as, but not limited to, a carboxylic acid), zwitterions ("internal salts") can be formed. Such acid and base salts used within the scope of the present invention are pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts. Such salts of compounds of the present invention can be formed, for example, by reacting a compound of the present invention with an amount, e.g., an equivalent amount, of acid or base in a medium such as an aqueous medium or a medium in which the salt precipitates, followed by lyophilization.

[0061] Throughout the description, when compositions are described as having, including, or comprising particular components, or when processes and methods are described as having, including, or comprising particular steps, it is further contemplated that there are compositions of the invention that consist essentially of, or consist of, the recited components, and that there are processes and methods of the invention that consist essentially of, or consist of, the recited processing steps.

[0062] As a general matter, compositions in which percentages are specified are by weight unless otherwise specified.

[0063] I. Substituted Tetrahydropyrrolo-pyridinone Compounds One aspect of the present invention provides substituted tetrahydropyrrolo-pyridinone compounds. The compounds can be used in the pharmaceutical compositions and methods of treatment described herein. Exemplary compounds are described in the following section, along with exemplary procedures for making the compounds.

[0064] One aspect of the present invention is a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, -(C 1-6 alkylene)-(C 3-6 cycloalkyl), or hydrogen; R 2 Ha, Halo, C 1-4 Alkyl, C 1-4 haloalkyl, or hydrogen; R 3 is C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxyl, -S-(C 1-4 alkyl), or halo; R 4 are each independently C 1-4 Alkyl, C 1-4 represents haloalkyl or halo, R 5 are each independently C 1-6 Alkyl, Halo, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, Hydroxyl, C 1-6 Alkoxyl, -(C 1-6 alkylene)-(C 1-6 alkoxyl), -(C 1-6 alkylene)-(C 3-6 cycloalkyl), -(C 1-6 haloalkylene)-(C 3-6 cycloalkyl), or -(C 1-6 alkylene)-(C 3-6 halocycloalkyl), or two R 5 together with the atoms therebetween to form a 4- to 7-membered ring containing one or two heteroatoms independently selected from oxygen, nitrogen, and sulfur; R 6 is (i)-(C 0-4 alkylene)-(3- to 7-membered saturated or unsaturated heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), (ii)-(C 0-4 alkylene)-(5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or (iii)-(C 0-4 alkylene)-phenyl, where heterocyclyl, heteroaryl, and phenyl are each independently selected from 0, 1, 2, or 3 R 7 is replaced by R 7 are each independently C 1-6 Alkyl, Halo, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, hydroxyl, or C 1-6 represents alkoxyl, A 1is a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or phenyl, wherein the heteroaryl and phenyl are selected from n R 5 and t R 6 is replaced by m is 0, 1, 2, or 3; n is 0, 1, or 2; t is 0 or 1.

[0065] The definitions of the variables in Formula I above encompass multiple chemical groups. The present application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from the chemical groups above, ii) the definition of a variable is a collection of two or more chemical groups selected from the chemical groups above, and iii) the compound is defined by a combination of variables, each variable being defined by (i) or (ii).

[0066] In certain embodiments, the compound is a compound of Formula I.

[0067] As roughly defined above, R 1 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, -(C 1-6 alkylene)-(C 3-6 cycloalkyl), or hydrogen. In certain embodiments, R 1 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, or -(C 1-6 alkylene)-(C 3-6 In certain embodiments, R 1 is C 1-6 Haloalkyl, C 3-6 Cycloalkyl, -(C 1-6 alkylene)-(C 3-6cycloalkyl), or hydrogen. In certain embodiments, R 1 is C 1-6 Alkyl, C 3-6 Cycloalkyl, -(C 1-6 alkylene)-(C 3-6 cycloalkyl), or hydrogen. In certain embodiments, R 1 is C 1-6 Alkyl, C 1-6 Haloalkyl, -(C 1-6 alkylene)-(C 3-6 cycloalkyl), or hydrogen. In certain embodiments, R 1 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, or hydrogen.

[0068] In certain embodiments, R 1 is C 3-6 Cycloalkyl, -(C 1-6 alkylene)-(C 3-6 cycloalkyl), or hydrogen. In certain embodiments, R 1 is C 1-6 Haloalkyl, -(C 1-6 alkylene)-(C 3-6 cycloalkyl), or hydrogen. In certain embodiments, R 1 is C 1-6 Haloalkyl, C 3-6 cycloalkyl, or hydrogen. In certain embodiments, R 1 is C 1-6 Haloalkyl, C 3-6 cycloalkyl, or -(C 1-6 alkylene)-(C 3-6 In certain embodiments, R 1 is C 1-6 Alkyl, -(C 1-6 alkylene)-(C 3-6 cycloalkyl), or hydrogen. In certain embodiments, R 1 is C 1-6 Alkyl, C 3-6 cycloalkyl, or hydrogen. In certain embodiments, R1 is C 1-6 Alkyl, C 3-6 cycloalkyl, or -(C 1-6 alkylene)-(C 3-6 In certain embodiments, R 1 is C 1-6 Alkyl, C 1-6 haloalkyl, or hydrogen. In certain embodiments, R 1 is C 1-6 Alkyl, C 1-6 haloalkyl, or -(C 1-6 alkylene)-(C 3-6 In certain embodiments, R 1 is C 1-6 Alkyl, C 1-6 Haloalkyl, or C 3-6 It is cycloalkyl.

[0069] In certain embodiments, R 1 is C 1-6 In certain embodiments, R 1 is C 1-4 In certain embodiments, R 1 is C 1-3 In certain embodiments, R 1 is C 2-6 In certain embodiments, R 1 is C 3-6 In certain embodiments, R 1 is methyl, ethyl, or propyl. In certain embodiments, R 1 is methyl. In certain embodiments, R 1 is ethyl.

[0070] In certain embodiments, R 1 is C 1-6 In certain embodiments, R 1 is C 1-4 In certain embodiments, R 1 is C 1-3 In certain embodiments, R 1 is C2-6 In certain embodiments, R 1 is C 3-6 In certain embodiments, R 1 is C 1-6 haloalkyl, where the halogen is F. In certain embodiments, R 1 is C 1-4 haloalkyl, where the halogen is F. In certain embodiments, R 1 is C 1-3 haloalkyl, where the halogen is F. In certain embodiments, R 1 is C 2-6 haloalkyl, where the halogen is F. In certain embodiments, R 1 is C 3-6 haloalkyl, where the halogen is F.

[0071] In certain embodiments, R 1 is CF. In some embodiments, R 1 is CHF2. In some embodiments, R 1 is —CH 2 CF 3 . In some embodiments, R 1 is -CH2CHF2.

[0072] In certain embodiments, R 1 is C 3-6 In certain embodiments, R 1 is C 4-6 In certain embodiments, R 1 is C 5-6 In certain embodiments, R 1 is cyclopropyl.

[0073] In certain embodiments, R 1 is -(C 1-6 alkylene)-(C 3-6 In certain embodiments, R 1 is -(C 1-4 alkylene)-(C 3-6In certain embodiments, R 1 is -(C 2-6 alkylene)-(C 3-6 In certain embodiments, R 1 is -(C 1-4 alkylene)-(C 5-6 In certain embodiments, R 1 is -(C 1-3 alkylene)-(C 4-6 In certain embodiments, R 1 is -(C 1-2 alkylene)-(C 3-5 In certain embodiments, R 1 is -CH2-cyclopropyl.

[0074] In certain embodiments, R 1 is hydrogen.

[0075] In certain embodiments, R 1 is selected from those listed in Table 1.

[0076] As roughly defined above, R 2 Ha, Halo, C 1-4 Alkyl, C 1-4 haloalkyl, or hydrogen. In certain embodiments, R 2 Ha, Halo, C 1-4 Alkyl, or C 1-4 In certain embodiments, R 2 is C 1-4 Alkyl, C 1-4 haloalkyl, or hydrogen. In certain embodiments, R 2 Ha, Halo, C 1-4 haloalkyl, or hydrogen. In certain embodiments, R 2 Ha, Halo, C 1-4 alkyl, or hydrogen. In certain embodiments, R 2 is C 1-4 haloalkyl or hydrogen. In certain embodiments, R 2 is C 1-4alkyl or hydrogen. In certain embodiments, R 2 is C 1-4 Alkyl or C 1-4 In certain embodiments, R 2 is halo or hydrogen. In certain embodiments, R 2 is a halo or C 1-4 In certain embodiments, R 2 is a halo or C 1-4 It is alkyl.

[0077] In certain embodiments, R 2 is halo. In certain embodiments, R 2 is selected from F, Cl, and Br. In certain embodiments, R 2 is selected from F and Cl. In certain embodiments, R 2 is F. In certain embodiments, R 2 is Cl.

[0078] In certain embodiments, R 2 is C 1-4 In certain embodiments, R 2 is C 1-3 In certain embodiments, R 2 is C 2-4 In certain embodiments, R 2 is C 3-4 In certain embodiments, R 2 is methyl, ethyl, or propyl. In certain embodiments, R 2 is methyl. In certain embodiments, R 2 is ethyl.

[0079] In certain embodiments, R 2 is C 1-4 In certain embodiments, R 2 is C 1-3 In certain embodiments, R 2 is C 2-4 In certain embodiments, R 2is C 3-4 In certain embodiments, R 2 is C 1-4 haloalkyl, where the halogen is F. In certain embodiments, R 2 is C 1-4 haloalkyl, where halogen is selected from F. In certain embodiments, R 2 is C 1-3 haloalkyl, where the halogen is F. In certain embodiments, R 2 is C 2-4 haloalkyl, where the halogen is F. In certain embodiments, R 2 is C 3-4 haloalkyl, where the halogen is F.

[0080] In certain embodiments, R 2 is CF. In some embodiments, R 2 is CHF2. In some embodiments, R 2 is —CH 2 CF 3 . In some embodiments, R 2 is —CH2CHF2. In certain embodiments, R 2 is hydrogen.

[0081] In certain embodiments, R 2 is selected from those listed in Table 1.

[0082] As roughly defined above, R 3 is C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxyl, -S-(C 1-4 alkyl), or halo. In certain embodiments, R 3 is C 1-4 Haloalkyl, C 1-4 Alkoxyl, -S-(C 1-4 alkyl), or halo. In certain embodiments, R 3 is C 1-4 Alkyl, C 1-4 Alkoxyl, -S-(C1-4 alkyl), or halo. In certain embodiments, R 3 is C 1-4 Alkyl, C 1-4 Haloalkyl, -S-(C 1-4 alkyl), or halo. In certain embodiments, R 3 is C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 In certain embodiments, R 3 is C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxyl, or -S-(C 1-4 alkyl).

[0083] In certain embodiments, R 3 is C 1-4 Alkoxyl, -S-(C 1-4 alkyl), or halo. In certain embodiments, R 3 is C 1-4 Haloalkyl, -S-(C 1-4 alkyl), or halo. In certain embodiments, R 3 is C 1-4 Haloalkyl, C 1-4 In certain embodiments, R 3 is C 1-4 Haloalkyl, C 1-4 Alkoxyl, or -S-(C 1-4 In certain embodiments, R 3 is C 1-4 Alkyl, -S-(C 1-4 alkyl), or halo. In certain embodiments, R 3 is C 1-4 Alkyl, C 1-4 In certain embodiments, R 3 is C 1-4 Alkyl, C 1-4 Alkoxyl, or -S-(C 1-4 In certain embodiments, R 3 is C 1-4Alkyl, C 1-4 haloalkyl, or halo. In certain embodiments, R 3 is C 1-4 Alkyl, C 1-4 Haloalkyl, or -S-(C 1-4 In certain embodiments, R 3 is C 1-4 Alkyl, C 1-4 Haloalkyl, or C 1-4 It is alkoxyl.

[0084] In certain embodiments, R 3 is C 1-4 In certain embodiments, R 3 is C 1-3 In certain embodiments, R 3 is C 2-4 In certain embodiments, R 3 is C 3-4 In certain embodiments, R 3 is methyl, ethyl, or propyl. In certain embodiments, R 3 is methyl. In certain embodiments, R 3 is ethyl.

[0085] In certain embodiments, R 3 is C 1-4 In certain embodiments, R 3 is C 1-3 In certain embodiments, R 3 is C 2-4 In certain embodiments, R 3 is C 3-4 In certain embodiments, R 3 is C 1-4 haloalkyl, where the halogen is F. In certain embodiments, R 3 is C 1-4 haloalkyl, where halogen is selected from F. In certain embodiments, R 3 is C 1-3haloalkyl, where the halogen is F. In certain embodiments, R 3 is C 2-4 haloalkyl, where the halogen is F. In certain embodiments, R 3 is C 3-4 haloalkyl, where the halogen is F.

[0086] In certain embodiments, R 3 is CF. In some embodiments, R 3 is CHF2. In some embodiments, R 3 is —CH 2 CF 3 . In some embodiments, R 3 is -CH2CHF2.

[0087] In certain embodiments, R 3 is C 1-4 In certain embodiments, R 3 is C 1-3 In certain embodiments, R 3 is C 2-4 In certain embodiments, R 3 is C 3-4 In certain embodiments, R 3 is —OCH, —OCHCH, —OCH(CH), or —OC(CH). In certain embodiments, R 3 is —OCH. In certain embodiments, R 3 is —OCH2CH3. In certain embodiments, R 3 is —OCH(CH). In certain embodiments, R 3 is —OC(CH). In certain embodiments, R 3 is -OCHF2.

[0088] In certain embodiments, R 3 is -S-(C 1-4 In certain embodiments, R 3 is -S-(C 1-3 In certain embodiments, R3 is -S-(C 2-4 In certain embodiments, R 3 is -S-(C 3-4 In certain embodiments, R 3 is -SCH3, -SCH2CH3, -SCH(CH3)2, or -SC(CH3)3.

[0089] In certain embodiments, R 3 is halo. In certain embodiments, R 3 is selected from Cl and Br. In certain embodiments, R 3 is selected from F and Cl. In certain embodiments, R 3 is F. In certain embodiments, R 3 is Cl.

[0090] In certain embodiments, R 3 is selected from those listed in Table 1.

[0091] As roughly defined above, R 4 are each independently C 1-4 Alkyl, C 1-4 In certain embodiments, R 4 are each independently C 1-4 In certain embodiments, R 4 are each independently C 1-4 In certain embodiments, R 4 are each independently C 1-4 Alkyl, or C 1-4 represents haloalkyl.

[0092] In certain embodiments, R 4 are each independently C 1-4 In certain embodiments, R 4 are each independently C 1-3 In certain embodiments, R 4 are each independently C 2-4 In certain embodiments, R4 are each independently C 3-4 In certain embodiments, R 4 each independently represents methyl, ethyl, or propyl. In certain embodiments, R 4 is methyl.

[0093] In certain embodiments, R 4 are each independently C 1-4 In certain embodiments, R 4 are each independently C 1-3 In certain embodiments, R 4 are each independently C 2-4 In certain embodiments, R 4 are each independently C 3-4 represents haloalkyl.

[0094] In certain embodiments, R 4 is C 1-4 haloalkyl, where the halogen is F. In certain embodiments, R 4 is C 1-3 haloalkyl, where the halogen is F. In certain embodiments, R 4 is C 2-4 haloalkyl, where the halogen is F. In certain embodiments, R 4 is C 3-4 haloalkyl, where the halogen is F. In certain embodiments, R 4 each independently represents halo. In certain embodiments, R 4 each independently represents Cl or F.

[0095] In certain embodiments, R 4 is C 1-4 Alkyl, C 1-4 haloalkyl, or halo. In certain embodiments, R 4 is C 1-4 haloalkyl or halo. In certain embodiments, R 4 is C 1-4alkyl or halo. In certain embodiments, R 4 is C 1-4 Alkyl or C 1-4 It is haloalkyl.

[0096] In certain embodiments, R 4 is CF. In some embodiments, R 4 is CHF2. In some embodiments, R 4 is —CH 2 CF 3 . In some embodiments, R 4 is -CH2CHF2.

[0097] In certain embodiments, R 4 is halo. In certain embodiments, R 4 is selected from F and Cl. In certain embodiments, R 4 is F. In certain embodiments, R 4 is Cl.

[0098] In certain embodiments, R 4 is selected from those listed in Table 1.

[0099] As roughly defined above, R 5 are each independently C 1-6 Alkyl, Halo, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, Hydroxyl, C 1-6 Alkoxyl, -(C 1-6 alkylene)-(C 1-6 alkoxyl), -(C 1-6 alkylene)-(C 3-6 cycloalkyl), -(C 1-6 haloalkylene)-(C 3-6 cycloalkyl), or -(C 1-6 alkylene)-(C 3-6 halocycloalkyl), or two R 5 together with the atoms therebetween to form a 4-7 membered ring containing one or two heteroatoms independently selected from oxygen, nitrogen, and sulfur.5 are each independently C 1-6 Alkyl, Halo, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, Hydroxyl, C 1-6 Alkoxyl, -(C 1-6 alkylene)-(C 1-6 alkoxyl), -(C 1-6 alkylene)-(C 3-6 cycloalkyl), or -(C 1-6 alkylene)-(C 3-6 halocycloalkyl), or two R 5 together with the atoms therebetween to form a 4-7 membered ring containing one or two heteroatoms independently selected from oxygen, nitrogen, and sulfur. 5 are each independently a halo, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, Hydroxyl, C 1-6 Alkoxyl, -(C 1-6 alkylene)-(C 1-6 alkoxyl), -(C 1-6 alkylene)-(C 3-6 cycloalkyl), or -(C 1-6 alkylene)-(C 3-6 halocycloalkyl), or two R 5 together with the atoms therebetween to form a 4- to 7-membered ring containing one or two heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0100] In certain embodiments, R 5 are each independently C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, Hydroxyl, C 1-6 Alkoxyl, -(C 1-6 alkylene)-(C 1-6 alkoxyl), -(C 1-6 alkylene)-(C 3-6 cycloalkyl), or -(C 1-6 alkylene)-(C 3-6halocycloalkyl), or two R 5 together with the atoms therebetween to form a 4-7 membered ring containing one or two heteroatoms independently selected from oxygen, nitrogen, and sulfur. 5 are each independently C 1-6 Alkyl, Halo, C 3-6 Cycloalkyl, Hydroxyl, C 1-6 Alkoxyl, -(C 1-6 alkylene)-(C 1-6 alkoxyl), -(C 1-6 alkylene)-(C 3-6 cycloalkyl), or -(C 1-6 alkylene)-(C 3-6 halocycloalkyl), or two R 5 together with the atoms therebetween to form a 4-7 membered ring containing one or two heteroatoms independently selected from oxygen, nitrogen, and sulfur. 5 are each independently C 1-6 Alkyl, Halo, C 1-6 Haloalkyl, Hydroxyl, C 1-6 Alkoxyl, -(C 1-6 alkylene)-(C 1-6 alkoxyl), -(C 1-6 alkylene)-(C 3-6 cycloalkyl), or -(C 1-6 alkylene)-(C 3-6 halocycloalkyl), or two R 5 together with the atoms therebetween to form a 4- to 7-membered ring containing one or two heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0101] In certain embodiments, R 5 are each independently C 1-6 Alkyl, Halo, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxyl, -(C 1-6 alkylene)-(C 1-6alkoxyl), -(C 1-6 alkylene)-(C 3-6 cycloalkyl), or -(C 1-6 alkylene)-(C 3-6 halocycloalkyl), or two R 5 together with the atoms therebetween to form a 4-7 membered ring containing one or two heteroatoms independently selected from oxygen, nitrogen, and sulfur. 5 are each independently C 1-6 Alkyl, Halo, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, hydroxyl, -(C 1-6 alkylene)-(C 1-6 alkoxyl), -(C 1-6 alkylene)-(C 3-6 cycloalkyl), or -(C 1-6 alkylene)-(C 3-6 halocycloalkyl), or two R 5 together with the atoms therebetween to form a 4-7 membered ring containing one or two heteroatoms independently selected from oxygen, nitrogen, and sulfur. 5 are each independently C 1-6 Alkyl, Halo, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, Hydroxyl, C 1-6 Alkoxyl, -(C 1-6 alkylene)-(C 3-6 cycloalkyl), or -(C 1-6 alkylene)-(C 3-6 halocycloalkyl), or two R 5 together with the atoms therebetween to form a 4- to 7-membered ring containing one or two heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0102] In certain embodiments, R 5 are each independently C 1-6 Alkyl, Halo, C 1-6 Haloalkyl, C3-6 Cycloalkyl, Hydroxyl, C 1-6 Alkoxyl, -(C 1-6 alkylene)-(C 1-6 alkoxyl), or -(C 1-6 alkylene)-(C 3-6 halocycloalkyl), or two R 5 together with the atoms therebetween to form a 4- to 7-membered ring containing one or two heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0103] In certain embodiments, R 5 are each independently C 1-6 Alkyl, Halo, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, Hydroxyl, C 1-6 Alkoxyl, -(C 1-6 alkylene)-(C 1-6 alkoxyl), or -(C 1-6 alkylene)-(C 3-6 cycloalkyl), or two R 5 together with the atoms therebetween to form a 4-7 membered ring containing one or two heteroatoms independently selected from oxygen, nitrogen, and sulfur. 5 are each independently C 1-6 Alkyl, Halo, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, Hydroxyl, C 1-6 Alkoxyl, -(C 1-6 alkylene)-(C 1-6 alkoxyl), -(C 1-6 alkylene)-(C 3-6 cycloalkyl), or -(C 1-6 alkylene)-(C 3-6 In certain embodiments, R 5 are each independently -(C 1-6 alkylene)-(C 1-6 alkoxyl), -(C 1-6 alkylene)-(C 3-6cycloalkyl), or -(C 1-6 alkylene)-(C 3-6 halocycloalkyl), or two R 5 together with the atoms therebetween to form a 4- to 7-membered ring containing one or two heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0104] In certain embodiments, R 5 are each independently C 1-6 Alkyl, Halo, C 1-6 Haloalkyl, C 3-6 cycloalkyl, or -(C 1-6 alkylene)-(C 3-6 cycloalkyl).

[0105] In certain embodiments, R 5 are each independently C 1-6 In certain embodiments, R 5 are each independently C 1-4 In certain embodiments, R 5 are each independently C 1-3 In certain embodiments, R 5 are each independently C 2-6 In certain embodiments, R 5 are each independently C 3-6 In certain embodiments, R 5 each independently represents methyl, ethyl, or propyl.

[0106] In certain embodiments, R 5 each independently represents halo. In certain embodiments, R 5 each independently represents F or Cl. In certain embodiments, R 5 each independently represents F or Cl.

[0107] In certain embodiments, R 5 are each independently C 1-6 In certain embodiments, R 5are each independently C 1-4 In certain embodiments, R 5 are each independently C 1-3 In certain embodiments, R 5 are each independently C 2-6 In certain embodiments, R 5 are each independently C 3-6 represents haloalkyl.

[0108] In certain embodiments, R 5 are each independently C 1-6 represents haloalkyl, where the halogen is F. In certain embodiments, R 5 are each independently C 1-4 represents haloalkyl, where each halogen is independently selected from F. In certain embodiments, R 5 are each independently C 1-3 represents haloalkyl, where the halogen is F. In certain embodiments, R 5 are each independently C 2-6 represents haloalkyl, where the halogen is F. In certain embodiments, R 5 are each independently C 3-6 Represents haloalkyl, where halogen is F.

[0109] In certain embodiments, R 5 each independently represents -CF, -CHF, -CHCF, or -CHCHF. In certain embodiments, R 5 is —CF. In certain embodiments, R 5 is -CHF2.

[0110] In certain embodiments, R 5 are each independently C 3-6 In certain embodiments, R 5 are each independently C 4-6 In certain embodiments, R 5 are each independently C 5-6 represents cycloalkyl.

[0111] In certain embodiments, R 5 each independently represents a C cycloalkyl. In certain embodiments, R 5 each independently represents a C4 cycloalkyl. In certain embodiments, R 5 each independently represents a C cycloalkyl. In certain embodiments, R 5 Each independently represents a C6 cycloalkyl.

[0112] In certain embodiments, R 5 each independently represents cyclopropyl or cyclopentyl.

[0113] In certain embodiments, R 5 are each independently C 1-6 In certain embodiments, R 5 are each independently C 1-3 In certain embodiments, R 5 are each independently C 2-6 In certain embodiments, R 5 are each independently C 4-6 In certain embodiments, R 5 each independently represents -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH2CH2CH2CH3, -O(CH2)4CH3, -OCH(CH3)2, -OCH2CH(CH3)2, -OCH2CH2CH(CH3)2, -O(CH2)3CH(CH3)2, -OC(CH3)3, -OCH2C(CH3)3, or -OCH2CH2C(CH3)3. In certain embodiments, R 5 each independently represents —OCH3 or —OCH2CH3.

[0114] In certain embodiments, R 5 are each independently -(C 1-6 alkylene)-(C 3-6 In certain embodiments, R 5 are each independently -(C 1-4alkylene)-(C 3-6 In certain embodiments, R 5 are each independently -(C 2-6 alkylene)-(C 3-6 In certain embodiments, R 5 are each independently -(C 1-4 alkylene)-(C 5-6 In certain embodiments, R 5 are each independently -(C 1-3 alkylene)-(C 4-6 In certain embodiments, R 5 are each independently -(C 1-2 alkylene)-(C 3-5 cycloalkyl).

[0115] In certain embodiments, R 5 are each independently -(C 1-6 alkylene)-(C 1-6 In certain embodiments, R 5 are each independently -(C 1-4 alkylene)-(C 3-6 In certain embodiments, R 5 are each independently -(C 2-6 alkylene)-(C 3-6 In certain embodiments, R 5 are each independently -(C 1-4 alkylene)-(C 5-6 In certain embodiments, R 5 are each independently -(C 1-3 alkylene)-(C 4-6 In certain embodiments, R 5 are each independently -(C 1-2 alkylene)-(C 3-5 alkoxyl).

[0116] In certain embodiments, R 5 are each independently -(C 1-6 alkylene)-(C3-6 In certain embodiments, R 5 are each independently -(C 1-4 alkylene)-(C 3-6 In certain embodiments, R 5 are each independently -(C 2-6 alkylene)-(C 3-6 In certain embodiments, R 5 are each independently -(C 1-4 alkylene)-(C 5-6 In certain embodiments, R 5 are each independently -(C 1-3 alkylene)-(C 4-6 In certain embodiments, R 5 are each independently -(C 1-2 alkylene)-(C 3-5 halocycloalkyl).

[0117] In certain embodiments, R 5 is C 1-6 In certain embodiments, R 5 is C 1-4 In certain embodiments, R 5 is C 1-3 In certain embodiments, R 5 is C 2-6 In certain embodiments, R 5 is C 3-6 In certain embodiments, R 5 is methyl, ethyl, or propyl.

[0118] In certain embodiments, R 5 is halo. In certain embodiments, R 5 is selected from F and Cl. In certain embodiments, R 5 is F. In certain embodiments, R 5 is Cl.

[0119] In certain embodiments, R5 is C 1-6 In certain embodiments, R 5 is C 1-4 In certain embodiments, R 5 is C 1-3 In certain embodiments, R 5 is C 2-6 In certain embodiments, R 5 is C 3-6 It is haloalkyl.

[0120] In certain embodiments, R 5 is C 1-6 haloalkyl, where the halogen is F. In certain embodiments, R 5 is C 1-4 haloalkyl, where halogen is selected from F. In certain embodiments, R 5 is C 1-3 haloalkyl, where the halogen is F. In certain embodiments, R 5 is C 2-6 haloalkyl, where the halogen is F. In certain embodiments, R 5 is C 3-6 haloalkyl, where the halogen is F.

[0121] In certain embodiments, R 5 is -CF3. In some embodiments, R 5 is -CHF. In some embodiments, R 5 is —CH 2 CF 3 . In some embodiments, R 5 is -CH2CHF2.

[0122] In certain embodiments, R 5 is C 3-6 In certain embodiments, R 5 is C 4-6 In certain embodiments, R 5 is C 5-6 In certain embodiments, R5 is C cycloalkyl. In certain embodiments, R 5 is C4 cycloalkyl. In certain embodiments, R 5 is C cycloalkyl. In certain embodiments, R 5 is Ccycloalkyl. In certain embodiments, R 5 is selected from cyclopropyl and cyclopentyl. In certain embodiments, R 5 is cyclopropyl.

[0123] In certain embodiments, R 5 is a hydroxyl.

[0124] In certain embodiments, R 5 is C 1-6 In certain embodiments, R 5 is C 1-3 In certain embodiments, R 5 is C 2-6 In certain embodiments, R 5 is C 4-6 In certain embodiments, R 5 is -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH2CH2CH2CH3, -O(CH2)4CH3, -OCH(CH3)2, -OCH2CH(CH3)2, -OCH2CH2CH(CH3)2, -O(CH2)3CH(CH3)2, -OC(CH3)3, -OCH2C(CH3)3, or -OCH2CH2C(CH3)3. In certain embodiments, R 5 is -OCH3 or -OCH2CH3.

[0125] In certain embodiments, R 5 is -(C 1-6 alkylene)-(C 3-6 In certain embodiments, R 5 is -(C 1-4 alkylene)-(C 3-6 In certain embodiments, R 5 is -(C2-6 alkylene)-(C 3-6 In certain embodiments, R 5 is -(C 1-4 alkylene)-(C 5-6 In certain embodiments, R 5 is -(C 1-3 alkylene)-(C 4-6 In certain embodiments, R 5 is -(C 1-2 alkylene)-(C 3-5 cycloalkyl).

[0126] In certain embodiments, R 5 is -(C 1-6 alkylene)-(C 1-6 In certain embodiments, R 5 is -(C 1-4 alkylene)-(C 3-6 In certain embodiments, R 5 is -(C 2-6 alkylene)-(C 3-6 In certain embodiments, R 5 is -(C 1-4 alkylene)-(C 5-6 In certain embodiments, R 5 is -(C 1-3 alkylene)-(C 4-6 In certain embodiments, R 5 is -(C 1-2 alkylene)-(C 3-5 alkoxyl).

[0127] In certain embodiments, R 5 is -(C 1-6 alkylene)-(C 3-6 halocycloalkyl). In certain embodiments, R 5 is -(C 1-4 alkylene)-(C 3-6 halocycloalkyl). In certain embodiments, R 5 is -(C 2-6alkylene)-(C 3-6 halocycloalkyl). In certain embodiments, R 5 is -(C 1-4 alkylene)-(C 5-6 halocycloalkyl). In certain embodiments, R 5 is -(C 1-3 alkylene)-(C 4-6 halocycloalkyl). In certain embodiments, R 5 is -(C 1-2 alkylene)-(C 3-5 halocycloalkyl).

[0128] In certain embodiments, two R 5 are taken together with the atoms between them to form a 4- to 7-membered ring containing one or two heteroatoms independently selected from oxygen, nitrogen, and sulfur. 5 are taken together with the atoms between them to form a 4-6 membered ring containing one or two heteroatoms independently selected from oxygen, nitrogen, and sulfur. 5 are taken together with the atoms between them to form a 4- to 7-membered ring containing one heteroatom independently selected from oxygen, nitrogen, and sulfur. 5 are taken together with the atoms between them to form a 4- to 7-membered ring containing two heteroatoms independently selected from oxygen, nitrogen, and sulfur. In certain embodiments, two R 5 together with the atoms therebetween to form a 5- to 6-membered ring containing two heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0129] In certain embodiments, R 5 is selected from those listed in Table 1.

[0130] As roughly defined above, R 6 is (i)-(C 0-4alkylene)-(3- to 7-membered saturated or unsaturated heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), (ii)-(C 0-4 alkylene)-(5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or (iii)-(C 0-4 alkylene)-phenyl, where heterocyclyl, heteroaryl, and phenyl are each independently selected from 0, 1, 2, or 3 R 7 is replaced by

[0131] In certain embodiments, R 6 is (i)-(C 0-4 alkylene)-(3- to 7-membered saturated or unsaturated heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), (ii)-(C 0-4 alkylene)-(5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or (iii)-(C 0-4 alkylene)-phenyl, where heterocyclyl, heteroaryl, and phenyl are each independently selected from one, two, or three R 7 is replaced by

[0132] In certain embodiments, R 6 is -(C 0-4 alkylene)-(5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or -(C 0-4 alkylene)-phenyl, where heteroaryl and phenyl are selected from 0, 1, 2, or 3 R 7 is replaced by

[0133] In certain embodiments, R 6 is -(C 0-4 alkylene)-(3- to 7-membered saturated or unsaturated heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or -(C 0-4alkylene)-phenyl, where heterocyclyl and phenyl are selected from 0, 1, 2, or 3 R 7 In certain embodiments, R 6 is -(C 0-4 alkylene)-(3- to 7-membered saturated or unsaturated heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or -(C 0-4 alkylene)-(5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur). 6 is -(C 0-4 alkylene)-(3- to 7-membered saturated or unsaturated heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), where the heterocyclyl is selected from 0, 1, 2, or 3 R 7 is replaced by

[0134] In certain embodiments, R 6 is -(C 0-4 alkylene)-(3- to 7-membered saturated or unsaturated heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), where the heterocyclyl is selected from 0, 1, 2, or 3 R 7 In certain embodiments, R 6 is -(C 1-4 alkylene)-(3- to 7-membered saturated or unsaturated heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), where the heterocyclyl is selected from 0, 1, 2, or 3 R 7 In certain embodiments, R 6 is -(C 2-4 alkylene)-(3- to 7-membered saturated or unsaturated heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), where the heterocyclyl is selected from 0, 1, 2, or 3 R 7 In certain embodiments, R 6 is -(C0-4 alkylene)-(3- to 6-membered saturated or unsaturated heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), where the heterocyclyl is selected from 0, 1, 2, or 3 R 7 In certain embodiments, R 6 is -(C 0-4 alkylene)-(3-5 membered saturated or unsaturated heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), where the heterocyclyl is selected from 0, 1, 2, or 3 R 7 In certain embodiments, R 6 is -(C 1-3 alkylene)-(3- to 6-membered saturated or unsaturated heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), where the heterocyclyl is selected from 0, 1, 2, or 3 R 7 is replaced by

[0135] In certain embodiments, R 6 is —CH— (a 3- to 7-membered saturated or unsaturated heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), where the heterocyclyl is selected from 0, 1, 2, or 3 R 7 In certain embodiments, R 6 is —CHCH— (a 3- to 7-membered saturated or unsaturated heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), where the heterocyclyl is selected from 0, 1, 2, or 3 R 7 In certain embodiments, R 6 is —CH—(4-6 membered saturated or unsaturated heterocyclyl containing one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur), where the heterocyclyl is selected from 0, 1, 2, or 3 R 7 In certain embodiments, R 6is —CH2CH2— (a 4-6 membered saturated or unsaturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), where the heterocyclyl is selected from 0, 1, 2, or 3 R 7 is replaced by

[0136] In certain embodiments, R 6 is -(C 0-4 alkylene)-(5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), where heteroaryl is selected from 0, 1, 2, or 3 R 7 is replaced by

[0137] In certain embodiments, R 6 is -(C 1-4 alkylene)-(5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), where heteroaryl is selected from 0, 1, 2, or 3 R 7 In certain embodiments, R 6 is -(C 2-4 alkylene)-(5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), where heteroaryl is selected from 0, 1, 2, or 3 R 7 In certain embodiments, R 6 is -(C 0-4 alkylene)-(5-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), where the heteroaryl is selected from 0, 1, 2, or 3 R 7 In certain embodiments, R 6 is -(C 0-4 alkylene)-(6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), where heteroaryl is selected from 0, 1, 2, or 3 R 7 In certain embodiments, R 6 is -(C0-2 alkylene)-(5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), where heteroaryl is selected from 0, 1, 2, or 3 R 7 is replaced by

[0138] In certain embodiments, R 6 is —CH—(5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), where heteroaryl is selected from 0, 1, 2, or 3 R 7 In certain embodiments, R 6 is —CHCH— (a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), where the heteroaryl is selected from 0, 1, 2, or 3 R 7 is replaced by

[0139] In certain embodiments, R 6 is -CH2-(phenyl), where phenyl is selected from 0, 1, 2, or 3 R 7 In certain embodiments, R 6 is -CH2CH2-(phenyl), where phenyl is selected from 0, 1, 2, or 3 R 7 In certain embodiments, R 6 is -CH2-(phenyl), where phenyl is selected from the group consisting of 1, 2, or 3 R 7 In certain embodiments, R 6 is -CH2CH2-(phenyl), where phenyl is selected from the group consisting of 1, 2, or 3 R 7 is replaced by

[0140] In certain embodiments, R 6 is -(C 0-4 alkylene)-phenyl, where phenyl is selected from 0, 1, 2, or 3 R 7 In certain embodiments, R 6 is -(C 1-4alkylene)-phenyl, where phenyl is selected from 0, 1, 2, or 3 R 7 In certain embodiments, R 6 is -(C 2-4 alkylene)-phenyl, where phenyl is selected from 0, 1, 2, or 3 R 7 In certain embodiments, R 6 is -(C 0-2 alkylene)-phenyl, where phenyl is selected from 0, 1, 2, or 3 R 7 In certain embodiments, R 6 is -(C 0-4 alkylene)-phenyl, where phenyl is selected from the group consisting of 1, 2, or 3 R 7 In certain embodiments, R 6 is -(C 1-4 alkylene)-phenyl, where phenyl is selected from the group consisting of 1, 2, or 3 R 7 In certain embodiments, R 6 is -CH2-(phenyl), where phenyl is selected from 0, 1, 2, or 3 R 7 In certain embodiments, R 6 is -CH2CH2-(phenyl), where phenyl is selected from 0, 1, 2, or 3 R 7 is replaced by

[0141] In certain embodiments, R 6 is selected from those listed in Table 1.

[0142] As roughly defined above, R 7 are each independently C 1-6 Alkyl, Halo, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, hydroxyl, or C 1-6 In certain embodiments, R 7 are each independently C 1-6 Alkyl, Halo, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, hydroxyl, or C1-6 In certain embodiments, R 7 are each independently a halo, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, hydroxyl, or C 1-6 In certain embodiments, R 7 are each independently C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, hydroxyl, or C 1-6 In certain embodiments, R 7 are each independently C 1-6 Alkyl, Halo, C 3-6 Cycloalkyl, hydroxyl, or C 1-6 In certain embodiments, R 7 are each independently C 1-6 Alkyl, Halo, C 1-6 Haloalkyl, hydroxyl, or C 1-6 In certain embodiments, R 7 are each independently C 1-6 Alkyl, Halo, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, or C 1-6 In certain embodiments, R 7 are each independently C 1-6 Alkyl, Halo, C 1-6 Haloalkyl, C 3-6 It represents cycloalkyl, or hydroxyl.

[0143] In certain embodiments, R 7 are each independently C 1-6 Haloalkyl, C 3-6 Cycloalkyl, hydroxyl, or C 1-6 In certain embodiments, R 7 are each independently a halo, C 3-6 Cycloalkyl, hydroxyl, or C 1-6 In certain embodiments, R 7 are each independently a halo, C1-6 Haloalkyl, hydroxyl, or C 1-6 In certain embodiments, R 7 are each independently a halo, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, or C 1-6 In certain embodiments, R 7 are each independently a halo, C 1-6 Haloalkyl, C 3-6 In certain embodiments, R represents cycloalkyl, cycloalkyl, or hydroxyl. 7 are each independently C 1-6 Alkyl, C 3-6 Cycloalkyl, hydroxyl, or C 1-6 In certain embodiments, R 7 are each independently C 1-6 Alkyl, C 1-6 Haloalkyl, hydroxyl, or C 1-6 In certain embodiments, R 7 are each independently C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, or C 1-6 In certain embodiments, R 7 are each independently C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 In certain embodiments, R represents cycloalkyl, cycloalkyl, or hydroxyl. 7 are each independently C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 In certain embodiments, R represents cycloalkyl, cycloalkyl, or hydroxyl. 7 are each independently C 1-6 Alkyl, halo, hydroxyl, or C 1-6 In certain embodiments, R 7 are each independently C 1-6 Alkyl, Halo, C 3-6 Cycloalkyl, or C 1-6In certain embodiments, R 7 are each independently C 1-6 Alkyl, Halo, C 3-6 In certain embodiments, R represents cycloalkyl, cycloalkyl, or hydroxyl. 7 are each independently C 1-6 Alkyl, Halo, C 1-6 Haloalkyl, or C 1-6 In certain embodiments, R 7 are each independently C 1-6 Alkyl, Halo, C 1-6 In certain embodiments, R 7 are each independently C 1-6 Alkyl, Halo, C 1-6 Haloalkyl, or C 3-6 represents cycloalkyl.

[0144] In certain embodiments, R 7 are each independently C 1-6 In certain embodiments, R 7 are each independently C 1-4 In certain embodiments, R 7 are each independently C 1-3 In certain embodiments, R 7 are each independently C 2-6 In certain embodiments, R 7 are each independently C 3-6 In certain embodiments, R 7 each independently represents methyl, ethyl, or propyl.

[0145] In certain embodiments, R 7 are each independently C 1-6 In certain embodiments, R 7 are each independently C 1-4 In certain embodiments, R 7 are each independently C 1-3 In certain embodiments, R 7are each independently C 2-6 In certain embodiments, R 7 are each independently C 3-6 represents haloalkyl.

[0146] In certain embodiments, R 7 are each independently C 1-6 represents haloalkyl, where the halogen is F. In certain embodiments, R 7 are each independently C 1-4 represents haloalkyl, where the halogen is F. In certain embodiments, R 7 are each independently C 1-3 represents haloalkyl, where the halogen is F. In certain embodiments, R 7 are each independently C 2-6 represents haloalkyl, where the halogen is F. In certain embodiments, R 7 are each independently C 3-6 represents haloalkyl, where the halogen is F. In certain embodiments, R 7 each independently represents -CF3, -CHF2, -CH2CF3, or -CH2CHF2.

[0147] In certain embodiments, R 7 are each independently C 3-6 In certain embodiments, R 7 are each independently C 4-6 In certain embodiments, R 7 are each independently C 5-6 In certain embodiments, R 7 each independently represents cyclopropyl or cyclopentyl.

[0148] In certain embodiments, R 7 are each independently C 1-6 In certain embodiments, R 7 are each independently C 1-3 In certain embodiments, R 7are each independently C 2-6 In certain embodiments, R 7 are each independently C 4-6 represents alkoxyl.

[0149] In certain embodiments, R 7 each independently represents -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH2CH2CH2CH3, -O(CH2)4CH3, -OCH(CH3)2, -OCH2CH(CH3)2, -OCH2CH2CH(CH3)2, -O(CH2)3CH(CH3)2, -OC(CH3)3, -OCH2C(CH3)3, or -OCH2CH2C(CH3)3. In certain embodiments, R 7 each independently represents —OCH3 or —OCH2CH3.

[0150] In certain embodiments, R 7 is C 1-6 In certain embodiments, R 7 is C 1-4 In certain embodiments, R 7 is C 1-3 In certain embodiments, R 7 is C 2-6 In certain embodiments, R 7 is C 3-6 In certain embodiments, R 7 is methyl, ethyl, or propyl.

[0151] In certain embodiments, R 7 is halo. In certain embodiments, R 7 is Cl or F. In certain embodiments, R 7 is F. In certain embodiments, R 7 is Cl.

[0152] In certain embodiments, R 7 is C 1-6 In certain embodiments, R 7 is C 1-4In certain embodiments, R 7 is C 1-3 In certain embodiments, R 7 is C 2-6 In certain embodiments, R 7 is C 3-6 It is haloalkyl.

[0153] In certain embodiments, R 7 is C 1-6 haloalkyl, where the halogen is F. In certain embodiments, R 7 is C 1-4 haloalkyl, where halogen is selected from F. In certain embodiments, R 7 is C 1-3 haloalkyl, where the halogen is F. In certain embodiments, R 7 is C 2-6 haloalkyl, where the halogen is F. In certain embodiments, R 7 is C 3-6 haloalkyl, where the halogen is F.

[0154] In certain embodiments, R 7 is -CF3. In some embodiments, R 7 is -CHF. In some embodiments, R 7 is —CH 2 CF 3 . In some embodiments, R 7 is —CH2CHF2. In certain embodiments, R 7 is C 3-6 In certain embodiments, R 7 is C 4-6 In certain embodiments, R 7 is C 5-6 In certain embodiments, R 7 is cyclopropyl, cyclobutyl, or cyclopentyl. In certain embodiments, R 7 is cyclopropyl. In certain embodiments, R 7 is a hydroxyl.

[0155] In certain embodiments, R 7 is C 1-6 In certain embodiments, R 7 is C 1-3 In certain embodiments, R 7 is C 2-6 In certain embodiments, R 7 is C 4-6 In certain embodiments, R 7 is -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH2CH2CH2CH3, -O(CH2)4CH3, -OCH(CH3)2, -OCH2CH(CH3)2, -OCH2CH2CH(CH3)2, -O(CH2)3CH(CH3)2, -OC(CH3)3, -OCH2C(CH3)3, or -OCH2CH2C(CH3)3. In certain embodiments, R 7 is -OCH3 or -OCH2CH3.

[0156] In certain embodiments, R 7 is selected from those listed in Table 1.

[0157] As roughly defined above, A 1 is a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or phenyl, wherein the heteroaryl and phenyl are selected from n R 5 and t R 6 is replaced by

[0158] In certain embodiments, A 1 is an 8-10 membered bicyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or phenyl, where the heteroaryl and phenyl are joined together by n R 5 and t R 6is replaced by

[0159] In certain embodiments, A 1 is a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or phenyl, where the heteroaryl and phenyl are joined together by n R 5 and t R 6 In certain embodiments, A 1 is a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is selected from n R 5 and t R 6 is replaced by

[0160] In certain embodiments, A 1 is a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, where the heteroaryl is selected from n R 5 and t R 6 In certain embodiments, A 1 is an 8-10 membered bicyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, where the heteroaryl is selected from n R 5 and t R 6 In certain embodiments, A 1 is phenyl, where phenyl is a group consisting of n R 5 and t R 6 In certain embodiments, A 1 is a 5-membered monocyclic heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heteroaryl is selected from n R 5 and t R 6 is replaced by

[0161] In certain embodiments, A 1 is pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyrrolyl, thiophenyl, or pyridinyl, each of which is selected from n R 5 and t R 6 In certain embodiments, A 1 is pyrazolyl, imidazolyl, oxazolyl, or isoxazolyl, each of which is selected from n R 5 and t R 6 In certain embodiments, A 1 n R 5 and t R 6 and pyrazolyl substituted with

[0162] In certain embodiments, A 1 is selected from those listed in Table 1.

[0163] As generally defined above, m is 0, 1, 2, or 3. In certain embodiments, m is 1, 2, or 3. In certain embodiments, m is 0, 2, or 3. In certain embodiments, m is 0, 1, or 3. In certain embodiments, m is 0, 1, or 2. In certain embodiments, m is 2 or 3. In certain embodiments, m is 0 or 1. In certain embodiments, m is 0 or 3. In certain embodiments, m is 0 or 2. In certain embodiments, m is 1 or 2. In certain embodiments, m is 1 or 3. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3.

[0164] As generally defined above, n is 0, 1, or 2. In certain embodiments, n is 1 or 2. In certain embodiments, n is 0 or 2. In certain embodiments, n is 0 or 1. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2.

[0165] As generally defined above, t is 0 or 1. In certain embodiments, t is 0. In certain embodiments, t is 1.

[0166] In certain embodiments, t is 1 and n is 0.

[0167] The above description describes multiple embodiments for compounds of Formula I. This patent application specifically contemplates all combinations of embodiments.

[0168] In certain embodiments, the compound of formula I is further defined by formula Ia, or a pharmaceutically acceptable salt thereof, wherein all indicated variables are as defined in the description of formula I above: [ka]

[0169] In certain embodiments, the compound of Formula I is further defined by Formula Ib, Formula Ic, Formula Id, or Formula Ie, or a pharmaceutically acceptable salt thereof, wherein all indicated variables are as defined in the description of Formula I above: [ka]

[0170] In certain embodiments, the compound of formula I is further defined by formula If or Ig, or a pharmaceutically acceptable salt thereof, wherein all indicated variables are as defined in the description of formula I above: [ka]

[0171] In certain embodiments, compounds of formula I are further defined by formula Ih, formula Ii, formula Ij, formula Ik, formula Il, and formula Im, or a pharmaceutically acceptable salt thereof, wherein all indicated variables are as defined in the description of formula I above: [ka]

[0172] In some embodiments, the present invention provides compounds of Formula I, wherein each of the variables, both alone and in combination, is as defined above and in the embodiments herein.

[0173] The above description describes multiple embodiments for compounds of Formula I. This patent application specifically contemplates all combinations of embodiments.

[0174] Exemplary Specific Compounds In certain embodiments, the compound is a compound of Table 1 or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Table 1. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16] [Table 1-17] [Table 1-18] [Table 1-19]

[0175] Synthesis method Methods for preparing the compounds described herein are illustrated in the following synthetic schemes. The schemes are provided to illustrate the invention and are not intended to limit the scope or spirit of the invention. Starting materials shown in the schemes may be obtained from commercial sources or may be prepared based on literature procedures.

[0176] Scheme 1 shows a general method for preparing tetrahydropyrrolo-pyridinone C. Tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one A is coupled to carboxylic acid B using amide bond forming conditions (e.g., acid-amine coupling via HATU) to afford tetrahydropyrrolo-pyridinone C. [ka]

[0177] It is understood by those skilled in the art of organic synthesis that the functional groups present on various portions of the molecule in the schemes must be compatible with the reagents and reactions proposed. Substituents that are incompatible with the reaction conditions will be apparent to those skilled in the art and, therefore, require alternative methods (e.g., the use of protecting groups or alternative reactions). Protecting group chemistry and strategies are well known in the art and are described, for example, in "Protecting Groups in Organic Synthesis," T.W. Greene and P.G.M. Buts, 3 rd edition, John Wiley & Sons, 1999, the entire contents of which are incorporated herein by reference. The modular synthetic route shown in Scheme 1 can also be readily modified by one skilled in the art by performing functional group transformations on the intermediates and final compounds to provide additional compounds. Such functional group transformations are well known in the art and are described, for example, in "Comprehensive Organic Synthesis" (B.M. Trost & I. Fleming, eds., 1991-1992).

[0178] Compounds useful in synthetic procedures Another aspect of the present invention provides compounds useful in synthetic procedures. For example, one aspect of the present invention provides a compound of formula II: [ka] or a salt thereof, wherein: R 1A is C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, -(C 1-6 alkylene)-(C 3-6 cycloalkyl), or hydrogen; R 2A Ha, Halo, C 1-4 Alkyl, C 1-4 haloalkyl, or hydrogen; R 3A is C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxyl, C 1-4 Haloalkoxyl, -S-(C 1-4 alkyl), or halo; R 4A and R 5A are independently hydrogen, C 1-4 Alkyl, C 1-4 haloalkyl, or halo; Z 1 is hydrogen or -C(O)2(C 1-6 alkyl).

[0179] The definitions of the variables in Formula II above encompass multiple chemical groups. The present application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from the chemical groups above, ii) the definition of a variable is a collection of two or more chemical groups selected from the chemical groups above, and iii) the compound is defined by a combination of variables, each variable being defined by (i) or (ii).

[0180] In certain embodiments, the compound is of formula II.

[0181] As roughly defined above, R 1A is C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, -(C 1-6 alkylene)-(C 3-6 cycloalkyl), or hydrogen. In certain embodiments, R 1A is hydrogen, methyl, or [ka] In certain embodiments, R 1A is hydrogen. In certain embodiments, R 1A is methyl. In certain embodiments, R 1A teeth, [ka] In certain embodiments, R 1A is C 1-6 In certain embodiments, R 1A is C 1-6 In certain embodiments, R 1A is C 3-6 In certain embodiments, R 1A is -(C 1-6 alkylene)-(C 3-6 In certain embodiments, R 1A is selected from the groups set forth in the compounds of Table 1-A below.

[0182] As roughly defined above, R 2A Ha, Halo, C 1-4 Alkyl, C 1-4 haloalkyl, or hydrogen. In certain embodiments, R 2A is hydrogen, fluoro, chloro, methyl, or —CF. In certain embodiments, R 2A is hydrogen. In certain embodiments, R 2A is fluoro. In certain embodiments, R 2A is chloro. In certain embodiments, R 2A is methyl. In certain embodiments, R 2A is —CF. In certain embodiments, R 2A is halo. In certain embodiments, R 2A is C 1-4 In certain embodiments, R 2A is C 1-4 In certain embodiments, R 2A is selected from the groups set forth in the compounds of Table 1-A below.

[0183] As roughly defined above, R 3A is C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxyl, C1-4 Haloalkoxyl, -S-(C 1-4 alkyl), or halo. In certain embodiments, R 3A is methyl, —OCH, —OCHCH, —OCHF, or —SCH. In certain embodiments, R 3A is methyl. In certain embodiments, R 3A is —OCH. In certain embodiments, R 3A is —OCH2CH3. In certain embodiments, R 3A is -OCHF. In certain embodiments, R 3A is -SCH3. In certain embodiments, R 3A is C 1-4 In certain embodiments, R 3A is C 1-4 In certain embodiments, R 3A is C 1-4 In certain embodiments, R 3A is C 1-4 In certain embodiments, R 3A is -S-(C 1-4 In certain embodiments, R 3A is halo. In certain embodiments, R 3A is selected from the groups set forth in the compounds of Table 1-A below.

[0184] As roughly defined above, R 4A and R 5A are independently hydrogen, C 1-4 Alkyl, C 1-4 haloalkyl, or halo. In certain embodiments, R 4A is hydrogen or methyl. In certain embodiments, R 4A is hydrogen. In certain embodiments, R 4A is methyl. In certain embodiments, R 4A is C 1-4 In certain embodiments, R 4A is C 1-4 In certain embodiments, R 4Ais halo. In certain embodiments, R 4A is selected from the groups set forth in the compounds of Table 1-A below. In certain embodiments, R 5A is hydrogen or methyl. In certain embodiments, R 5A is hydrogen. In certain embodiments, R 5A is methyl. In certain embodiments, R 5A is C 1-4 In certain embodiments, R 5A is C 1-4 In certain embodiments, R 5A is halo. In certain embodiments, R 5A is selected from the groups set forth in the compounds of Table 1-A below.

[0185] As roughly defined above, Z 1 is hydrogen or -C(O)2(C 1-6 In certain embodiments, Z 1 is hydrogen or tert-butoxycarbonyl. In certain embodiments, Z 1 is hydrogen. In certain embodiments, Z 1 is tert-butoxycarbonyl. In certain embodiments, Z 1 is -C(O)2(C 1-6 In certain embodiments, Z 1 is selected from the groups set forth in the compounds of Table 1-A below.

[0186] The above description describes multiple embodiments for compounds of Formula II, and this patent application specifically contemplates all combinations of embodiments.

[0187] Another aspect of the present invention provides the compounds of Table 1-A below. [Table 2]

[0188] In certain embodiments, R 1Ais hydrogen, methyl, or [ka] In certain embodiments, R 2A is hydrogen, fluoro, chloro, methyl, or —CF. In certain embodiments, R 3A is methyl, —OCH, —OCHCH, —OCHF, or —SCH. In certain embodiments, R 4A is hydrogen or methyl. In certain embodiments, R 5A is hydrogen or methyl. In certain embodiments, Z 1 is hydrogen or tert-butoxycarbonyl.

[0189] II. Therapeutic applications Another aspect of the present invention provides a method for treating a muscarinic acetylcholine receptor-mediated disorder, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound described herein, such as a compound of Formula I, to treat the muscarinic acetylcholine receptor-mediated disorder. In certain embodiments, the particular compound of Formula I is a compound defined by one of the embodiments described in Section I above.

[0190] The methods described herein can be further defined according to additional characteristics, such as the nature of the muscarinic acetylcholine receptor-mediated disorder and / or the subject.

[0191] Muscarinic acetylcholine receptor-mediated disorders can be treated or prevented by modulating the muscarinic system. Such diseases include those in which direct activation of the muscarinic acetylcholine receptor itself or inhibition of the cholinesterase enzyme provides a therapeutic effect. Exemplary muscarinic acetylcholine receptor-mediated disorders include schizophrenia, movement disorders, mood disorders, cognitive disorders, attention disorders, addictive disorders, and pain. In certain embodiments, the muscarinic acetylcholine receptor-mediated disorder is selected from schizophrenia, movement disorders, mood disorders, cognitive disorders, attention disorders, addictive disorders, and neurological disorders. In certain embodiments, the muscarinic acetylcholine receptor-mediated disorder is a movement disorder, mood disorder, or cognitive disorder. In certain embodiments, the muscarinic acetylcholine receptor-mediated disorder is selected from attention disorders and addictive disorders.

[0192] In certain embodiments, the muscarinic acetylcholine receptor-mediated disorder is schizophrenia or a related disorder. Schizophrenia-related disorders include schizoaffective disorder, psychotic disorder, psychosis associated with Alzheimer's disease, hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D), Creutzfeldt-Jakob disease, prion disorders, psychosis associated with Parkinson's disease, psychotic depression, bipolar disorder, bipolar disorder with psychosis, Huntington's disease, dementia with Lewy bodies, cerebral amyloid angiopathy, or any other disease with psychotic features.

[0193] In certain embodiments, the muscarinic acetylcholine receptor-mediated disorder is selected from schizoaffective disorder, psychosis, delusional disorder, psychosis associated with Alzheimer's disease, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch Type (HCHWA-D), Creutzfeldt-Jakob disease, prion disorders, psychosis associated with Parkinson's disease, psychotic depression, bipolar disorder, bipolar disorder with psychosis, Huntington's disease, cerebral amyloid angiopathy, and dementia with Lewy bodies. In certain embodiments, the muscarinic acetylcholine receptor-mediated disorder is selected from schizoaffective disorder, psychosis, psychosis associated with Alzheimer's disease, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch Type (HCHWA-D), Creutzfeldt-Jakob disease, prion disorders, psychosis associated with Parkinson's disease, psychotic depression, bipolar disorder, bipolar disorder with psychosis, Huntington's disease, cerebral amyloid angiopathy, and dementia with Lewy bodies.

[0194] In certain embodiments, the muscarinic acetylcholine receptor-mediated disorder is a movement disorder. Exemplary movement disorders include Gilles de la Tourette syndrome, Friedreich's ataxia, amyotrophic lateral sclerosis, progressive supranuclear palsy, Huntington's chorea, dyskinesia, restless legs syndrome, and other diseases or disorders whose symptoms include hyperkinesia, tics, and convulsions. In certain embodiments, the muscarinic acetylcholine receptor-mediated disorder is selected from Gilles de la Tourette syndrome, Friedreich's ataxia, amyotrophic lateral sclerosis, progressive supranuclear palsy, Huntington's chorea, dyskinesia, and restless legs syndrome.

[0195] In certain embodiments, the muscarinic acetylcholine receptor-mediated disorder is a mood disorder. Exemplary mood disorders include major depressive disorder, dysthymia, recurrent brief depressive disorder, minor depressive disorder, bipolar disorder, mania, and anxiety. In certain embodiments, the muscarinic acetylcholine receptor-mediated disorder is selected from major depressive disorder, dysthymia, recurrent brief depressive disorder, minor depressive disorder, bipolar disorder, mania, and anxiety.

[0196] In certain embodiments, the muscarinic acetylcholine receptor-mediated disorder is a cognitive disorder. Exemplary cognitive disorders include diseases or disorders characterized by cognitive deficits (e.g., working memory, problem-solving abilities, etc.), such as Alzheimer's disease, hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D), Creutzfeldt-Jakob disease, prion disorders, Parkinson's disease, Parkinson's disease-levodopa-induced dyskinesia, cerebral amyloid angiopathy, dementia (e.g., AIDS-related dementia, vascular dementia, age-related dementia, dementia associated with Lewy bodies, and idiopathic dementia), Pick's disease, tauopathy, synucleinopathy, confusion, mild cognitive impairment, cognitive deficits associated with fatigue, learning disabilities, traumatic brain injury, autism, age-related cognitive decline, and Cushing's disease, cognitive impairment associated with autoimmune diseases.

[0197] In certain embodiments, the muscarinic acetylcholine receptor-mediated disorder is selected from Alzheimer's disease, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch Type (HCHWA-D), Creutzfeldt-Jakob disease, prion disorders, Parkinson's disease, Parkinson's disease-levodopa-induced dyskinesia, cerebral amyloid angiopathy, dementia (e.g., AIDS-associated dementia, vascular dementia, age-related dementia, dementia associated with Lewy bodies, and idiopathic dementia), Pick's disease, tauopathy, synucleinopathy, confusion, mild cognitive impairment, cognitive deficits associated with fatigue, learning disabilities, traumatic brain injury, autism, age-associated cognitive decline, and Cushing's disease.

[0198] In certain embodiments, the disorder mediated by muscarinic acetylcholine receptor is attention disorder.Exemplary attention disorder is the disease or disorder characterized by abnormality or reduction in attention range, such as attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADD), Dubowitz syndrome, FG syndrome, Down syndrome, insulin-like growth factor I (IGF1) deficiency-induced growth retardation, hepatic encephalopathy syndrome and Strauss syndrome.

[0199] In certain embodiments, the muscarinic acetylcholine receptor-mediated disorder is selected from attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADD), Dubowitz syndrome, FG syndrome, Down syndrome, developmental delay due to insulin-like growth factor I (IGF1) deficiency, hepatic encephalopathy syndrome, and Strauss syndrome.

[0200] In certain embodiments, the muscarinic acetylcholine receptor-mediated disorder is an addictive disorder. Exemplary addictive disorders are diseases or conditions characterized by addiction or substance dependence as defined by the Diagnostic & Statistical Manual V (DSM-5). Such disorders are often characterized by physical dependence on the substance, withdrawal symptoms, and tolerance. Such substances include, but are not limited to, alcohol, cocaine, amphetamines, opioids, benzodiazepines, inhalants, nicotine, barbiturates, cocaine, and cannabis. Addictive disorders also include behaviors that patients engage in compulsively or persistently despite clear negative consequences. For example, lurdomania (gambling addiction or compulsive gambling) is recognized by those skilled in the art as an addictive behavior that often leads to destructive consequences. In certain embodiments, the addictive behavior can be internet gaming disorder (gaming addiction) as defined in DSM-5.

[0201] In certain embodiments, the muscarinic acetylcholine receptor-mediated disorder is addiction to one of the following substances: alcohol, cocaine, amphetamines, opioids, benzodiazepines, inhalants, nicotine, barbiturates, cocaine, or cannabis; uldomania; and internet gaming disorder.

[0202] In certain embodiments, the muscarinic acetylcholine receptor-mediated disorder is a neuropathy. Exemplary neuropathy is pain, physical suffering, or discomfort caused by disease or injury. Pain is a subjective experience, and pain perception occurs as part of the central nervous system (CNS). Although noxious (peripheral) stimuli are usually transmitted to the CNS beforehand, pain is not necessarily associated with nociception. Clinical pain is diverse and stems from different underlying pathophysiological mechanisms, requiring different treatment approaches. Several major types of clinical pain have been characterized: acute pain, chronic pain, neuropathic pain, inflammatory pain, and nociceptive pain.

[0203] In certain embodiments, the muscarinic acetylcholine receptor-mediated disorder is selected from acute pain, chronic pain, neuropathic pain, inflammatory pain, and nociceptive pain. In certain embodiments, the muscarinic acetylcholine receptor-mediated disorder is acute pain. In certain embodiments, the muscarinic acetylcholine receptor-mediated disorder is chronic pain. In certain embodiments, the muscarinic acetylcholine receptor-mediated disorder is neuropathic pain. In certain embodiments, the muscarinic acetylcholine receptor-mediated disorder is inflammatory pain. In certain embodiments, the muscarinic acetylcholine receptor-mediated disorder is nociceptive pain. In certain embodiments, the muscarinic acetylcholine receptor-mediated disorder is inflammatory pain or nociceptive pain.

[0204] In certain embodiments, the muscarinic acetylcholine receptor mediated disorder is schizoaffective disorder, psychosis, psychosis associated with Alzheimer's disease, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch Type (HCHWA-D), Creutzfeldt-Jakob disease, prion disorders, psychosis associated with Parkinson's disease, Parkinson's disease-levodopa induced dyskinesia, psychotic depression, bipolar disorder, bipolar disorder with psychosis, Huntington's disease, cerebral amyloid angiopathy, Lewy body cognition. syndrome, Gilles de la Tourette syndrome, Friedreich's ataxia, amyotrophic lateral sclerosis, progressive supranuclear palsy, Huntington's chorea, dyskinesia, restless legs syndrome, major depressive disorder, dysthymia, recurrent brief depressive disorder, minor depressive disorder, bipolar disorder, mania, anxiety, Alzheimer's disease, hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D), Creutzfeldt-Jakob disease, prion disorders, Parkinson's disease, Parkinson's disease selected from levodopa-induced dyskinesia, dementia (including but not limited to AIDS-related dementia, vascular dementia, age-related dementia, dementia associated with Lewy bodies, and idiopathic dementia), Pick's disease, tauopathy, synucleinopathy, confusion, mild cognitive impairment, cognitive deficits associated with fatigue, learning disabilities, traumatic brain injury, autism, age-associated cognitive decline, Cushing's disease, attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADD), Dubowitz syndrome, FG syndrome, Down syndrome, developmental delay due to insulin-like growth factor I (IGF1) deficiency, hepatic encephalopathy syndrome, and Strauss syndrome, as well as addiction to one of the following substances: alcohol, cocaine, amphetamines, opioids, benzodiazepines, inhalants, nicotine, barbiturates, cocaine, or cannabis, uldomania, internet gaming disorder, acute pain, chronic pain, neuropathic pain, inflammatory pain, and nociceptive pain.

[0205] In certain embodiments, the muscarinic acetylcholine receptor mediated disorder is schizophrenia, psychosis, mild cognitive impairment, Alzheimer's disease, Parkinson's disease, Parkinson's disease-levodopa-induced dyskinesia, Huntington's disease, dyskinesia, cerebral amyloid angiopathy, dementia, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch Type (HCHWA-D), Creutzfeldt-Jakob Disease, a prion disorder, amyotrophic lateral sclerosis, progressive supranuclear palsy, autism, addiction, or a sleep disorder.

[0206] In certain embodiments, the muscarinic acetylcholine receptor mediated disorder is schizoaffective disorder, psychosis, delusional disorder, psychosis associated with Alzheimer's disease, psychosis associated with Parkinson's disease, psychotic depression, bipolar disorder, bipolar disorder with psychosis, Huntington's disease, dementia with Lewy bodies, Gilles de la Tourette syndrome, Friedreich's ataxia, Huntington's chorea, restless legs syndrome, major depressive disorder, dysthymia, recurrent brief depressive disorder, minor depressive disorder, mania, The symptoms include anxiety, Alzheimer's disease, Parkinson's disease, dementia, Pick's disease, tauopathy, synucleinopathy, confusion, cognitive deficits associated with fatigue, learning disabilities, traumatic brain injury, autism, age-related cognitive decline, Cushing's disease, attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADD), Dubowitz syndrome, FG syndrome, Down syndrome, developmental delay due to insulin-like growth factor I (IGF1) deficiency, hepatic encephalopathy syndrome, Strauss syndrome, or agitation associated with neurodegeneration.

[0207] Methods for activating muscarinic acetylcholine receptors Another aspect of the present invention provides a method for activating a muscarinic acetylcholine receptor, comprising contacting the muscarinic acetylcholine receptor with an effective amount of a compound described herein, such as a compound of Formula I, to activate the muscarinic acetylcholine receptor, as further described in the detailed description.

[0208] In certain embodiments, the muscarinic acetylcholine receptor is muscarinic acetylcholine receptor M4.

[0209] subject In certain embodiments, the subject is a human. In certain embodiments, the subject is an adult. In certain embodiments, the subject is a child.

[0210] Medical Use Another aspect of the invention provides the use of a compound described herein (such as a compound of Formula I, or other compound of Section I) in the manufacture of a medicament. In certain embodiments, the medicament is for treating a disorder described herein, such as a muscarinic acetylcholine receptor-mediated disorder.

[0211] Another aspect of the present invention provides the use of a compound described herein (such as a compound of Formula I, or other compound in Section I) to treat a medical disorder, e.g., a medical disorder described herein, such as a muscarinic acetylcholine receptor-mediated disorder.

[0212] Assays for assessing the biological activity of compounds in rats Compounds can be tested for their ability to affect behavioral activity in rats according to the following procedure. Animals: Adult male Sprague Dawley rats (Envigo, Indianapolis, IN, USA) are housed in a colony maintained at 23°C with a 12-hour light-dark cycle (lights on at 0600 h). At the start of the study, animals weighed 290-330 g and were equally divided into five groups (n=8 per group) and subjected to one of the treatment conditions listed below. Behavioral Procedures: Testing was performed in a Medassociates open-field chamber (27.3 cm x 27.3 cm x 20.3 cm, Medassociates, St. Albans, VT), where movements were automatically tracked and recorded using a 16-beam array. Pretreatment with the test substance was determined by the optimal route of administration to coincide with the Tmax during the amphetamine challenge session. All groups were treated subcutaneously with 0.5 mg / kg amphetamine (AMP). Test substances are tested in three dose groups, with half-log increments between doses. Risperidone (0.55 mg / kg, 30 min, sc) can be used as a positive control and is administered to Group 5. To determine the role of the test substance on AMP-induced hyperlocomotion, rats are placed in an open area and allowed to acclimate for 30 min before receiving 0.5 mg / kg AMP sc. Locomotor data (distance traveled) are recorded in 5-min intervals throughout a 90-min session. The AMP dose is selected based on its selective increase in locomotor behavior relative to stereotypy. The risperidone dose is selected to provide a reliable effect and serve as a positive control. Statistical analysis: Locomotor activity (before AMP administration) is calculated as the total distance traveled during the first 30 min of the experimental session. The AMP-induced response is calculated as the total distance traveled during the first 60 min of the experimental session, beginning immediately after AMP administration. Locomotor data may be analyzed by one-way ANOVA. If the overall ANOVA is significant, post-hoc comparisons may be performed using Dunnett's test and statistical significance determined as p<0.05.

[0213] IV. Combination Therapy Another aspect of the present invention provides combination therapy. The compounds described herein (such as compounds of Formula I, or other compounds in Section I) or their pharmaceutically acceptable salts can be used in combination with an additional therapeutic agent to treat a medical disorder, such as a muscarinic acetylcholine receptor-mediated disorder.

[0214] In some embodiments, the present invention provides a method of treating a disclosed disease or condition, comprising administering to a patient in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof and simultaneously or sequentially co-administering an effective amount of one or more additional therapeutic agents, such as those described herein. In some embodiments, the method comprises co-administering one additional therapeutic agent. In some embodiments, the method comprises co-administering two additional therapeutic agents. In some embodiments, the combination of a disclosed compound and one or more additional therapeutic agents acts synergistically.

[0215] One or more other therapeutic agents may be administered separately from the compounds or compositions of the invention as part of a multiple dose regimen. Alternatively, one or more other therapeutic agents may be part of a single dosage form, mixed with the compounds of the invention in a single composition. When administered as a multiple dose regimen, the one or more other therapeutic agents and the compounds or compositions of the invention may be administered simultaneously, sequentially, or within a period of each other, for example, within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 18, 20, 21, 22, 23, or 24 hours of each other. In some embodiments, the one or more other therapeutic agents and the compounds or compositions of the invention are administered more than 24 hours apart as a multiple dose regimen.

[0216] Additional Therapeutic Agents for Treating Muscarinic Acetylcholine Receptor-Mediated Disorders Depending on the disease, disorder, or condition to be treated, various pharmaceutically active agents can be selected for use in combination with the compounds of the present invention. Pharmaceutically active agents that can be used in combination with the compositions of the present invention include, but are not limited to:

[0217] (i) acetylcholinesterase inhibitors, such as donepezil hydrochloride (ARICEPT, MEMAC), physostigmine salicylate (ANTILIRIUM), physostigmine sulfate (ESERINE), metrifonate, neostigmine, ganstigmine, pyridostigmine (MESTINON), ambenonium (MYTELASE), demalpotassium, Debio 9902 (also known as ZT-1; Debiopharm), rivastigmine (EXELON), ladostigil, NP-0361, galantamine hydrobromide (RAZADYNE, RIMINYL, NIVALIN), tacrine (COGNEX), tolserin, velnacrine maleate, Memoquin, huperzine A (HUP-A; NeuroHitech), phenserine, edrophonium (ENLON, TENSILON), and INM-176;

[0218] (ii) amyloid-B (or a fragment thereof), such as AB1.15, ACC-001 (Elan / Wyeth), ACI-01, ACI-24, AN-1792, Afhtope AD-01, CAD106, and V-950 conjugated to a pan-HLA DR-binding epitope (PADRE);

[0219] (iii) antibodies (or fragments thereof) against amyloid-B, such as ponezumab, solanezumab, bapineuzumab (also known as AAB-001), AAB-002 (Wyeth / Elan), ACI-01-Ab7, BAN-2401, intravenous Ig (GAMMAGARD), LY2062430 (humanized m266; Lilly), R1450 (Roche), ACU-5A5, huCO91, and International Patent Publication No. WO 04 / 03286 8, WO05 / 025616, WO06 / 036291, WO06 / 069081, WO06 / 118959, U.S. Patent Publication Nos. US2003 / 0073655, US2004 / 0192898, US2005 / 0048049, US2005 / 0019328, European Patent Publication Nos. EP0994728 and EP1257584, and those disclosed in U.S. Patent No. 5,750,349;

[0220] (iv) Amyloid lowering or inhibitors (including those that reduce amyloid production, accumulation, and fibrillation), such as dimebon, davunetide, eprodisate, leuprolide, SK-PC-B70M, celecoxib, lovastatin, Anapsos, oxiracetam, pramiracetam, varenicline, nicergoline, colostrinin, bisnorcymserine (also known as BNC), NICS-15 (Humanetics), E-2012 (Eisai), pioglitazone, clioquinol (also known as PBT1), PBT2 (Prana Biotechnology), flurbiprofen (ANSAID, FROBEN) and its R-enantiomer tarenflurvir 34 (FLURIZAN), nitroflurbiprofen, fenoprofen (FENOPRON, NALFON), ibuprofen (ADVIL, MOTRIN, NUROFEN), ibuprofen lysinate, meclofenamic acid, meclofenamate sodium (MECLOMEN), indomethacin (INDOCIN), diclofenac sodium (VOLTAREN), diclofenac potassium, sulindac (CLINORIL), sulindac sulfide, diflunisal (DOLOBID), naproxen (NAPROSYN), naproxen sodium (ANAPROX, ALEVE), ARC031 (Archer Pharmaceuticals), CAD-106 (Cytos), LY450139 (Lilly), insulin-degrading enzyme (also known as insulysin), ginkgo leaf extract EGb-761 (ROKAN, TEBONIN), tramiprosate (CEREBRIL, ALZHEMED), eprodisate (FIBRILLEX, KIACTA), compound W [3,5-bis(4-nitrophenoxy)benzoic acid], NGX-96992, neprilysin (also known as neutral endopeptide enzymes (NEP), scyllo-inositol (also known as cyclitol), atorvastatin (LIPITOR), simvastatin (ZOCOR), KLVFF-(EEX)3, SKF-74652, ibutamoren mesylate, BACE inhibitors such as ASP-1702, SCH-745966, JNJ-715754, AMG-0683, AZ-12304146, BMS-782450, GSK-188909, NB-533, E2609, and TTP-854;Gamma secretase modulators, such as ELND-007; and RAGE (receptor for advanced glycation end products) inhibitors, such as those disclosed in U.S. Pat. No. 7,285,293, including TTP488 (Transtech) and TTP4000 (Transtech), and PTI-777;

[0221] (v) alpha-adrenergic receptor agonists, such as guanfacine (INTUNIV, TENEX), clonidine (CATAPRES), metaraminol (ARAMINE), methyldopa (ALDOMET, DOPAMET, NOVOMEDOPA), tizanidine (ZANAFLEX), phenylephrine (also known as neosynephrine), methoxamine, cirazoline, guanfacine (INTUNIV), lofexidine, xylazine, modafinil (PROVIGIL), adrafinil, and armodafinil (NUVIGIL);

[0222] (vi) beta-adrenergic receptor blockers (beta-blockers), such as carteolol, esmolol (BREVIBLOC), labetalol (NORMODYNE, TRANDATE), oxprenolol (LARACOR, TRASACOR), pindolol (VISKEN), propanolol (INDERAL), sotalol (BETAPACE, SOTALEX, SOTACOR), timolol (BLOCADREN, TIMOPTIC), acebutolol (SECTRAL, PRENT), nadolol (CORGARD), metoprolol tartrate (LOPRESSOR), metoprolol succinate (TOPROL-XL), atenolol (TENORMIN), butoxamine, and SR 59230A (Sanofi);

[0223] (vii) Anticholinergics, e.g., amitriptyline (ELAVIL, ENDEP), butriptyline, benztropine mesylate (COGENTIN), trihexyphenidyl (ARTANE), diphenhydramine (BENADRYL), orphenadrine (NORFLEX), hyoscyamine, atropine (ATROPEN), scopolamine (TRANSDERMSCOP), scopolamine methylbromide (PARMINE), dicycloverine (BENTYL, BYCLOMINE, DIBENT, DILOM) INE), tolterodine (DETROL), oxybutynin (DITROPAN, LYRINELXL, OXYTROL), pentienate bromide, propantheline (PRO-BANTHINE), cyclizine, imipramine hydrochloride (TOFRANIL), imipramine maleate (SURMONTIL), lofepramine, desipramine (NORPRAMIN), doxepin (SINEQUAN, ZONALON), trimipramine (SURMONTIL), and glycopyrrolate (ROBINUL)

[0224] (viii) anticonvulsants, such as carbamazepine (TEGRETOL, CARBATROL), oxcarbazepine (TRILEPTAL), phenytoin sodium (PHENYTEK), fosphenytoin (CEREBYX, PRODILANTIN), divalproex sodium (DEPAKOTE), gabapentin (NEURONTIN), pregabalin (LYRICA), topirimate (TOPAMAX), valproic acid (DEPAKENE), sodium valproate (DEPACON), 1-benzyl-5-bromouracil, progabide, beclamide, zonisamide (TRERIEF, EXCEGRAN), CP-465022, retigabine, talampanel, and primidone (MYSOLINE);

[0225] (ix) antipsychotics, such as lurasidone (LATUDA, also known as SM-13496; Dainippon Sumitomo), aripiprazole (ABILIFY), chlorpromazine (THORAZINE), haloperidol (HALDOL), iloperidone (FANAPTA), flupentixol decanoate (DEPIXOL, FLUANXOL), reserpine (SERPLAN), pimozide (ORAP), fluphenazine decanoate, fluphenazine hydrochloride, prochlorperazine (COMPRO), asenapine (SAPHRIS), loxapine (LOXITANE), molindone (MO) BAN), perphenazine, thioridazine, thiothixine, trifluoperazine (STELAZINE), ramelteon, clozapine (CLOZARIL), norclozapine (ACP-104), risperidone (RISPERDAL), paliperidone (INVEGA), melperone, olanzapine (ZYPREXA), quetiapine (SEROQUEL), talnetant, amisulpride, ziprasidone (GEODON), blonanserin (LONASEN), and ACP-103 (Acadia Pharmaceuticals);

[0226] (x) calcium channel blockers, such as lomerizine, ziconotide, nilvadipine (ESCOR, NIVADIL), diperdipine, amlodipine (NORVASC, ISTIN, AMLODIN), felodipine (PLENDIL), nicardipine (CARDENE), nifedipine (ADALAT, PROCARDIA), MEM 1003 and its parent compound nimodipine (NIMOTOP), nisoldipine (SULAR), nitrendipine, lacidipine (LACIPIL, MOTENS), lercanidipine (ZANIDIP), rifariidine, diltiazem (CARDIZEM), verapamil (CALAN, VERELAN), AR-R18565 (AstraZeneca), and enecadine;

[0227] (xi) Catechol O-methyltransferase (COMT) inhibitors, such as nitecapone, tolcapone (TASMAR), entacapone (COMTAN), and tropolone;

[0228] (xii) central nervous system stimulants, such as atomoxetine, reboxetine, yohimbine, caffeine, phenmetrazine, phendimetrazine, pemoline, fencamfamin (GLUCOENERGAN, REACTIVAN), fenetylline (CAPTAGON), pipradol (MERETRAN), deanol (also known as dimethylaminoethanol), methylphenidate (DAYTRANA), methylphenidate hydrochloride (RITALIN), and dexmethylphenidate (FOCALIN), amphetamines (alone or in combination with other CNS stimulants, e.g., ADDERALL (amphetamine aspartate, amphetamine sulfate, dextroamphetamine saccharate, and dextroamphetamine sulfate)), dextroamphetamine sulfate (DEXEDRINE, DEXTROSTAT), methamphetamine (DESOXYN), lisdexamfetamine (VYVANSE), and benzphetamine (DIDREX);

[0229] (xiii) Corticosteroids, such as prednisone (STERAPRED, DELTASONE), prednisolone (PRELONE), prednisolone acetate (OMNIPRED, PREDMILD, PRED FORTE), prednisolone sodium phosphate (ORAPRED ODT), methylprednisolone (MEDROL); methylprednisolone acetate (DEPOMEDROL), and methylprednisolone sodium succinate (A-METHAPRED, SOLU-MEDROL);

[0230] (xiv) dopamine receptor agonists, such as apomorphine (APOKYN), bromocriptine (PARLODEL), cabergoline (DOSTINEX), dihydrexidine, dihydroergocriptine, fenoldopam (CORLOPAM), lisuride (DOPERGIN), terguride spergolide (PERMAX), piribedil (TRIVASTAL, TRASTAL), pramipexole (MIRAPEX), quinpirole, ropinirole (REQUIP), rotigotine (NEUPRO), SKF-82958 (Glaxo-SmithKline), cariprazine, pardoprunox and sarizotan; (xv) dopamine receptor antagonists, such as chlorpromazine, fluphenazine, haloperidol, loxapine, lisuride peridon, thioridazine, thiothixene, trifluoperazine, tetrabenazine (NITOMAN, XENAZINE), 7-hydroxyamoxapine, droperidol (INAPSINE, DRIDOL, DROPLETAN), domperidone (MOTILIUM), L-741742, L-745870, raclopride, SB-277011A, SCH-23390, ecopipam, SKF-83566, and metoclopramide (REGLAN);

[0231] (xvi) dopamine reuptake inhibitors, such as bupropion, safinamide, nomifensine maleate (MERITAL), vanoxerine (also known as GBR-12909) and its decanoate ester DBL-583, and amineptine;

[0232] (xvii) gamma-amino-butyric acid (GABA) receptor agonists, such as baclofen (LIORESAL, KEMSTRO), cyclophen, pentobarbital (NEMBUTAL), progabide (GABRENE), and clomethiazole;

[0233] (xviii) Histamine 3 (H3) antagonists, such as ciproxyfan, tiprolisant, S-38093, ildavisant, pitolisant, GSK-239512, GSK-207040, JNJ-5207852, JNJ-17216498, HPP-404, SAR-110894, trans-N-ethyl-3-fluoro-3-[3-fluoro-4-(pyrrolidin-l-ylmethyl)phenyl]cyclobutanecarboxamide (PF-3654746 and those disclosed in U.S. Patent Publication Nos. US2005-0043354, US2005-0267095, US2005-0256135, US2008-0096955, US2007-1079175, and US2008-0176925; International Patent Publication Nos. WO2006 / 15138431 and WO2007 / 088462; and U.S. Patent No. 7,115,600);

[0234] (xix) Immunomodulators, such as glatiramer acetate (also known as copolymer-1; COPAXONE), MBP-8298 (synthetic myelin basic protein peptide), dimethyl fumarate, fingolimod (also known as FTY720), roquinimex (LINOMIDE), laquinimod (also known as ABR-215062 and SAIK-MS), ABT-874 (human anti-IL-12 antibody; Abbott), rituximab (RITUXAN), alemtuzumab (CAMPATH), daclizumab (ZENAPAX), and natalizumab (TYSABRI);

[0235] (xx) immunosuppressants, such as methotrexate (TREXALL, RHEUMATREX), mitoxantrone (NOVANTRONE), mycophenolate mofetil (CELLCEPT), mycophenolate sodium (MYFORTIC), azathioprine (AZASAN, IMURAN), mercaptopurine (PURI-NETHOL), cyclophosphamide (NEOSAR, CYTOXAN), chlorambucil (LEUKERAN), cladribine (LEUSTATIN, MYLINAX), alpha-fetoprotein, etanercept (ENBREL), and 4-(benzyloxy)-5-[(5-undecyl-2H-pyrrol-2-ylidene)methyl]-1H,1'H-2,2'-bipyrrole (also known as PNU-156804);

[0236] (xxi) Interferons, such as interferon beta-1a (AVONEX, REBIF) and interferon beta-1b (BETASERON, BETAFERON);

[0237] (xxii) levodopa (or its methyl or ethyl esters) alone or in combination with a DOPA decarboxylase inhibitor (e.g., carbidopa (SINEMET, CARBILEV, PARCOPA), benserazide (MADOPAR), α-methyldopa, monofluoromethyldopa, difluoromethyldopa, brocresine, or m-hydroxybenzylhydrazine);

[0238] (xxiii) N-methyl-D-aspartate (NMDA) receptor antagonists, for example, memantine (NAMENDA, AXURA, EBIXA), amantadine (SYMMETREL), acamprosate (CAMPRAL), besonprodil, ketamine (KETALAR), delsemin, dexanabinol, dexephaloxane, dextromethorphan, dextrorphan, traxoprodil, CP-283097, himantane, indantadol, ipenoxazone, and L-701252 (Merck), lancisemine, levorphanol (DROMORAN), LY-233536 and LY-235959 (both Lilly), methadone, (DOLOPHINE), neramexane, perzinfotel, phencyclidine, tianeptine (STABLON), dizocilpine (also known as MK-801), EAB-318 (Wyeth), ibogaine, voacangine, tiletamine, riluzole (RILUTEK), aptiganel (CERESOTAT), gavestenel, and remacimide;

[0239] (xxiv) Monoamine oxidase (MAO) inhibitors, such as selegiline (EMSAM), selegiline hydrochloride (1-deprenyl, ELDEPRYL, ZELAPAR), dimethylselegiline, brofaromine, phenelzine (NARDIL), tranylcypromine (PARNATE), moclobemide (AURORIX, MANERIX), befloxatone, safinamide, isocarboxazid (MARPLAN), nialamide (NIAMID), rasagiline (AZILECT), iproniazid (MARSILID, IPROZID, IPRONID), CHF-3381 (Chiesi Farmaceutici), iproclozide, toloxatone (HUMORYL, PERENUM), bifemelane, desoxypeganine, harmine (also known as terepatin or banasterin), harmaline, linezolid (ZYVOX, ZYVOXID), and pargyline (EUDATIN, SUPIRDYL);

[0240] (xxv) muscarinic receptor (especially Ml subtype) agonists, such as cevimeline, levetiracetam, bethanechol chloride (DUVOID, URECHOLINE), itameline, pilocarpine (SALAGEN), NGX267, arecoline, L-687306 (Merck), L-689660 (Merck), flutresonium iodide (FURAMON, FURANOL), flutresonium benzenesulfonate, flutresonium p-toluenesulfonate, McN-A-343, oxotremorine, sabcomeline, AC-90222 (Acadia Pharmaceuticals), and carbachol (CARBASTAT, MIOSTAT, CARBOPTIC);

[0241] (xxvi) Neuroprotective drugs, such as bosutinib, condoliase, ilomoclomol, lamotrigine, perampanel, aniracetam, minaprim, riluzole, N-hydroxy-1,2,4,9-tetrahydro-3H-carbazol-3-imine, desmoteplase, anatibant, astaxanthin, neuropeptide NAP (e.g., AL-108 and AL-208; both of which are available from Allon) Therapeutics), neurostrol, perampenel, ispronicline, bis(4-BD glucopyranosyloxybenzyl)-2-BD-glucopyranosyl-2-isobutyltartaric acid (also known as dactylolhin B or DHB), formobactin, xaliproden (xAPRILA), lactacystin, dimebolin hydrochloride (DIMEBON), dysfenton (CEROVIVE), arundic acid (ONO-2506, PROGLIA, CEREACT), citicoline (also known as cytidine 5'-diphosphocholine), edaravone (RADICUT), AEOL-10113, and AEOL-10150 (all from Aeolus Pharmaceuticals), AGY-94806 (also known as SA-450 and Msc-1), granulocyte colony-stimulating factor (also known as AX-200), BAY-38-7271 (also known as KN-387271; Bayer AG), ancrod (VIPRINEX, ARWIN), DP-b99 (D-Pharm Ltd), HF-0220 (17-β-hydroxyepiandrosterone; Newron Pharmaceuticals), HF-0420 (also known as oligotropin), pyridoxal 5'-phosphate (also known as MC-1), microplasmin, S-18986, piclozotan, NP031112, tacrolimus, L-seryl-L-methionyl-L-alanyl-L-lysyl-L-glutamyl-glycyl-L-valine, AC-184897 (Acadia Pharmaceuticals), ADNF-14 (National Institutes of Health), stilbazulenyl nitrone, SUNN8075 (Daiichi Suntory Biomedical Research), and zonanepanel;

[0242] (xxvii) nicotine receptor agonists, such as epibatidine, bupropion, CP-601927, varenicline, ABT-089 (Abbott), ABT-594, AZD-0328 (AstraZeneca), EVP-6124, R3487 (also known as MEM3454; Roche / Memory Pharmaceuticals), R4996 (also known as MEM63908; Roche / Memory Pharmaceuticals), TC-4959 and TC-5619 (all Targacept), and RJR-2403;

[0243] (xxviii) norepinephrine (noradrenaline) reuptake inhibitors, such as atomoxetine (STRATTERA), doxepin (APONAL, ADAPIN, SINEQUAN), nortriptyline (AVENTYL, PAMELOR, NORTRILEN), amoxapine (ASENDIN, DEMOLOX, MOXIDIL), reboxetine (EDRONAX, VESTRA), viloxazine (VIVALAN), maprotiline (DEPRILEPT, LUDIOMIL, PSYMION), bupropion (WELLBUTRIN), and ladaxafine;

[0244] (xxix) Phosphodiesterase (PDE) inhibitors, including, but not limited to, (a) PDE1 inhibitors (e.g., vinpocetine (CAVINTON, CERACTIN, INTELECTOL) and those disclosed in U.S. Pat. No. 6,235,742, (b) PDE2 inhibitors (e.g., erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), BAY 60-7550, and those described in U.S. Pat. No. 6,174,884), (c) PDE3 inhibitors (e.g., anagrelide, cilostazol, milrinone, olprinone, parogrelil, and pimobendan), (d) PDE4 inhibitors (e.g., apremilast, ibudilastroflumilast, rolipram, Ro20-1724, ibudilast (KETAS), piclamilast (also known as RP7 3401), CDP840, cilomilast (ARIFLO), roflumilast, tofimilast, oglemilast (also known as GRC3886), tetomilast (also known as OPC-6535), lilimifast, theophylline (UNIPHYL, THEOLAIR), allofylline (also known as LAS-31025), doxofylline, RPR-122818, or mesembrine), and (e)PDES 38 inhibitors (e.g., sildenafil (VIAGRA, REVATIO), tadalafil (CIALIS), vardenafil (LEVITRA, VIVANZA), udenafil, avanafil, dipyridamole (PERSANTINE), E-4010, E-4021, E-8010, zaprinast, iodenafil, mirodenafil, DA-8159, and those disclosed in International Patent Applications WO2002 / 020521, WO2005 / 049616, WO2006 / 120552, WO2006 / 126081, WO2006 / 126082, WO2006 / 126083, and WO2007 / 122466), (f) PDE7 inhibitors; (g) PDE8 inhibitors;(h) PDE9 inhibitors (e.g., BAY 73-6691 (Bayer AG) and those disclosed in U.S. Patent Publication Nos. US2003 / 0195205, US2004 / 0220186, US2006 / 0111372, US2006 / 0106035, and U.S. Patent Application No. 12 / 118,062 (filed May 9, 2008)), (i) PDE10 inhibitors, such as 2-({4-[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]phenoxylmethyl)quinolin-3(4H)-one and SCH-1518291; and (j) PDE11 inhibitors;

[0245] (xxx) Quinolines, such as quinine (including its hydrochloride, dihydrochloride, sulfate, hydrogen sulfate, and gluconate), chloroquine, sontoquine, hydroxychloroquine (PLAQUENIL), mefloquine (LARIAM), and amodiaquine (CAMOQUIN, FLAVOQUINE);

[0246] (xxxi) B-secretase inhibitors, such as ASP-1702, SCH-745966, JNJ-715754, AMG-0683, AZ-12304146, BMS-782450, GSK-188909, NB-533, LY-2886721, E-2609, HPP-854, (+)-phenserine tartrate (POSIPHEN), LSN-2434074 (also known as LY-2434074), KMI-574, SCH-745966, AcrER (N2-acetyl-D-arginyl-L-arginine), loxistatin (also known as E64d), and CA074Me;

[0247] (xxxii) y-secretase inhibitors and modulators, such as BMS-708163 (Avagacest), WO20060430064 (Merck), DSP8658 (Dainippon), ITI-009, L-685458 (Merck), ELANG, ELAN-Z, 4-chloro-N-[(2S)-3-ethyl-1-hydroxypentan-2-yl]benzenesulfonamide;

[0248] (xxxiii) Serotonin (5-hydroxytryptamine) lA (5-HT,A) receptor antagonists, such as spiperone, levo-pindolol, BMY 7378, NAD-299, S-(-)-UH-301, NAN 190, lecozotan;

[0249] (xxxiv) serotonin (5-hydroxytryptamine) 2C (5-HT2c) receptor agonists, such as babicaserin and diclonapine;

[0250] (xxxv) serotonin (5-hydroxytryptamine) 4 (5-HT4) receptor agonists, for example, PRX-03140 (Epix);

[0251] (xxxvi) Serotonin (5-hydroxytryptamine) 6 (5-HT,) receptor antagonists, for example, A-964324, AVI-101, AVN-211, mianserin (TORVOL, BOLVIDON, NORVAL), methiothepin (also known as methythepin), ritanserin, ALX-1161, ALX-1175, MS-245, LY-483518 (also known as SGS518; Lilly), MS-245, Ro 04-6790, Ro 43-68544, Ro 63-0563, Ro 65-7199, Ro 65-7674, SB-399885, SB-214111, SB-258510, SB-271046, SB-357134, SB-699929, SB-271046, SB-742457 (GlaxoSmithKline), Lu AE58054 (Lundbeck A / S), and PRX-07034(Epix);50

[0252] (xxxvii) Serotonin (5-HT) reuptake inhibitors, such as alaprolclate, citalopram (CELEXA, CIPRAMIL), escitalopram (LEXAPRO, CIPRALEX), clomipramine (ANAFRANIL), duloxetine (CYMBALTA), femoxetine (MALEXIL), fenfluramine (PONDIMIN), norfenfluramine, fluoxetine (PROZAC), fluvoxamine (LU) VOX), indalpine, milnacipran (IXEL), paroxetine (PAXIL, SEROXAT), sertraline (ZOLOFT, LUSTRAL), trazodone (DESYREL, MOLIPAXIN), venlafaxine (EFFEXOR), zimelidine (NORMUD, ZELMID), bicifadine, desvenlafaxine (PRISTIQ), brasofensine, vilazodone, cariprazine, neuralstem, and tesofensine;

[0253] (xxxviii) trophic factors, such as nerve growth factor (NGF), basic fibroblast growth factor (bFGF; ERSOFERMIN), neurotrophin-3 (NT-3), cardiotrophin-1, brain-derived neurotrophic factor (BDNF), neublastin, meteorin, and glial cell line-derived neurotrophic factor (GDNF), and agents that stimulate the production of trophic factors, such as propentofylline, idebenone, PYM50028 (COGANE; Phytopharm), and AIT-082 (NEOTROFIN);

[0254] (xxxix) Glycine transporter-1 inhibitors, such as parifurtine, ORG-25935, JNJ-17305600, and ORG-26041;

[0255] (xl) AMPA-type glutamate receptor modulators, for example, perampanel, mivampatol, cerulampanel, GSK-729327, N-{(3S,4S)-4-[4-(5-cyanothiophen-2-yl)phenoxy]tetrahydro-furan-3-ylpropane-2-sulfonamide, etc.

[0256] (xli) Janus kinase inhibitors (JAK), such as, but not limited to, tofacitinib, ruxolitinib, baricitinib, CYT387, GLPG0634, lestaurtinib, pacritinib, and TG101348.

[0257] (xlii) Interleukin-1 receptor-associated kinase 4 inhibitors (IRAK4), for example, but not limited to, PF-06650833.

[0258] In certain embodiments, the additional therapeutic agent is an orthosteric agonist of a muscarinic acetylcholine receptor.

[0259] In certain embodiments, the methods described herein further comprise administering to a subject in need thereof a therapeutically effective amount of an orthosteric agonist of a muscarinic acetylcholine receptor. In certain embodiments, the orthosteric agonist of a muscarinic acetylcholine receptor is administered to the subject simultaneously with a substituted tetrahydropyrrolo-pyridinone compound described herein, e.g., a compound of Formula I.

[0260] In certain embodiments, the subject is administered a pharmaceutical composition comprising (i) an orthosteric agonist of a muscarinic acetylcholine receptor and (ii) a substituted tetrahydropyrrolo-pyridinone compound described herein, e.g., a compound of Formula I.

[0261] In certain embodiments, the orthosteric agonist of the muscarinic acetylcholine receptor is administered to the subject separately from the substituted tetrahydropyrrolo-pyridinone compound described herein, e.g., the compound of Formula I. In certain embodiments, the orthosteric agonist of the muscarinic acetylcholine receptor is administered to the subject via a first pharmaceutical composition, and the substituted tetrahydropyrrolo-pyridinone compound described herein, e.g., the compound of Formula I, is administered to the subject via a second pharmaceutical composition.

[0262] In certain embodiments, the amount of (i) an orthosteric agonist of a muscarinic acetylcholine receptor and / or (ii) a substituted tetrahydropyrrolo-pyridinone compound described herein, e.g., a compound of Formula I, administered to a patient is reduced compared to when either (i) an orthosteric agonist of a muscarinic acetylcholine receptor or (ii) a substituted tetrahydropyrrolo-pyridinone compound described herein, e.g., a compound of Formula I, is used in a monotherapy treatment.

[0263] Thus, another aspect of the present invention provides a method for treating a disorder ameliorated by muscarinic receptor activation in a subject in need thereof, wherein the method comprises administering to the subject a substituted tetrahydropyrrolo-pyridinone compound described herein, e.g., a compound of Formula I, in combination with an orthosteric agonist of a muscarinic acetylcholine receptor (e.g., xanomeline or a salt thereof), wherein the orthosteric agonist of a muscarinic acetylcholine receptor and the substituted tetrahydropyrrolo-pyridinone compound act on the same muscarinic acetylcholine receptor subtype. In certain embodiments, the orthosteric agonist of a muscarinic acetylcholine receptor and the substituted tetrahydropyrrolo-pyridinone compound act on the M1 or M4 subtype muscarinic acetylcholine receptor.

[0264] The terms "muscarinic orthosteric agonist," "orthosteric muscarinic agonist," and "muscarinic agonist" refer to agents that activate muscarinic acetylcholine receptors. "Orthosteric" refers to the site on the receptor where an endogenous ligand binds and exerts its effect. That is, muscarinic orthosteric agonists bind to the site on the muscarinic acetylcholine receptor where an endogenous muscarinic ligand binds and exerts its effect.

[0265] Muscarinic acetylcholine receptors are G protein-coupled receptors with five distinct receptor subtypes (M1-M5), each of which is present in the CNS with different tissue distributions. The term "muscarinic acetylcholine receptor" refers to a G protein-coupled receptor that binds to the neurotransmitter acetylcholine. "M1" refers to muscarinic acetylcholine receptor subtype 1. "M2" refers to muscarinic acetylcholine receptor subtype 2. "M3" refers to muscarinic acetylcholine receptor subtype 3. "M4" refers to muscarinic acetylcholine receptor subtype 4. "M5" refers to muscarinic acetylcholine receptor subtype 5.

[0266] Muscarinic acetylcholine receptor agonists can be selective, preferring binding to only one muscarinic receptor subtype; partially selective, preferring binding to two to four subtypes; or nonselective, preferentially binding to each of the five subtypes. Muscarinic acetylcholine receptor agonists can be parasympathomimetic. Their mechanism of action varies depending on which receptor is activated. For example, lithium and valproate, mood stabilizers used to treat bipolar depression, can act on the muscarinic system primarily via the M4 subtype receptor. Genetic evidence directly links the muscarinic system to alcohol dependence.

[0267] In certain embodiments, the agonist of the muscarinic acetylcholine receptor is an orthosteric agonist of the muscarinic acetylcholine receptor. In certain embodiments, the orthosteric agonist of the muscarinic acetylcholine receptor is a compound in the following table or a pharmaceutically acceptable salt thereof: [Table 3-1] [Table 3-2]

[0268] In certain embodiments, the agonist of the muscarinic acetylcholine receptor is selected from the group consisting of 77-LH-28-1, A 72055, AF 125, AF 150(S), aceclidine, albamelin, arecoline, bethanechol, carbachol, cevimeline, CI 1017, CMI 1145, CMI 936, FPL 14995, flumethide, HTL-0016878, iperoxo, itramelin, KST 5452, L 670,548, L 687,306, L 689,660, L 686,986, methacholine, N-desmethylclozapine, MCD 386, miramelin, NC 111585, nebracetam, NGX267, ORG 20091, oxotremorine, PD 142505, PD 151832, PDC 008004, pilocarpine, RU 35963, sabcomeline, SR 46559A, talsaclidine, tazomeline, thiopilocarpine, tremorine, bedaclidine, xanomeline, WAY-131256, WAY-132983, YM 796, YM 954, or a pharmaceutically acceptable salt thereof.

[0269] In certain embodiments, the muscarinic acetylcholine receptor agonist is an orthosteric muscarinic acetylcholine receptor agonist selected from xanomeline or a pharmaceutically acceptable salt thereof. Xanomeline has activity at both M1 and M4 muscarinic acetylcholine receptors.

[0270] In certain embodiments, the agonist of the muscarinic acetylcholine receptor is selected from the group consisting of 77-LH-28-1, A 72055, AF 125, AF 150(S), albamelin, bethanechol, carbachol, cevimeline, CI 1017, FPL 14995, iperoxo, itramelin, KST 5452, L 687,306, L 689,660, L 686,986, methacholine, N-desmethylclozapine, MCD 386, miramelin, NC 111585, nebracetam, NGX267, ORG 20091, oxotremorine, PD 142505, PD 151832, pilocarpine, sabcomeline, SR 46559A, talsaclidine, tazomeline, thiopilocarpine, tremorine, bedaclidine, xanomeline, WAY-131256, WAY-132983, YM 796, YM 954, or a pharmaceutically acceptable salt thereof.

[0271] In certain embodiments, the methods described herein further comprise administering to a subject in need thereof a therapeutically effective amount of an orthosteric antagonist of a muscarinic acetylcholine receptor, hi certain embodiments, the orthosteric antagonist of a muscarinic acetylcholine receptor is trospium chloride.

[0272] Further considerations The dosage and dosing regimen of the active ingredients used in the combination therapy can be determined by the attending physician. In certain embodiments, the compound described herein (such as a compound of Formula I, or other compounds in Section I) and the additional therapeutic agent(s) are administered at doses typically utilized when such agents are used as monotherapy to treat the disorder. In other embodiments, the compound described herein (such as a compound of Formula I, or other compounds in Section I) and the additional therapeutic agent(s) are administered at doses lower than those typically utilized when such agents are used as monotherapy to treat the disorder. In certain embodiments, the compound described herein (such as a compound of Formula I, or other compounds in Section I) and the additional therapeutic agent(s) are present in the same composition suitable for oral administration.

[0273] In certain embodiments, a compound described herein (such as a compound of Formula I, or other compounds in Section I) and the additional therapeutic agent(s) may act additively or synergistically. A synergistic combination may allow for the use of lower dosages of one or more agents of the combination therapy and / or less frequent administration of one or more agents. Lower dosages or less frequent administration of one or more agents may reduce the toxicity of the treatment without reducing the efficacy of the treatment.

[0274] Another aspect of the invention is a kit comprising a therapeutically effective amount of a compound described herein (such as a compound of Formula I, or other compound in Section I), a pharmaceutically acceptable carrier, vehicle, or diluent, and, optionally, at least one additional therapeutic agent as listed above.

[0275] III. Pharmaceutical Composition and Administration Considerations As indicated above, the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of one or more of the above-mentioned compounds, formulated with one or more pharmaceutically acceptable carriers (excipients) and / or diluents. The pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those suitable for: (1) oral administration, such as drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., buccal, sublingual, and those intended for systemic absorption, boluses, powders, granules, and pastes for application to the tongue; (2) parenteral administration, such as by subcutaneous, intramuscular, intravenous, or epidural injection, e.g., sterile solutions or suspensions, or sustained-release formulations; (3) topical application, such as creams, ointments, or controlled-release patches or sprays applied to the skin; (4) vaginal or rectal administration, such as pessaries, creams, or foams; (5) sublingual; (6) ophthalmic; (7) transdermal; or (8) nasal administration. In certain embodiments, the present invention provides pharmaceutical compositions comprising a compound described herein (such as a compound of Formula I, or other compounds in Section I) and a pharmaceutically acceptable carrier.

[0276] As used herein, the phrase "therapeutically effective amount" means an amount of a compound, substance, or composition, including a compound of the invention, that is effective to produce some desired therapeutic effect on at least a subpopulation of cells in an animal, at a reasonable benefit / risk ratio applicable to any medical treatment.

[0277] The expression "pharmaceutically acceptable" is employed herein to refer to compounds, substances, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, and commensurate with a reasonable benefit / risk ratio.

[0278] Wetting agents, emulsifying agents, and lubricating agents, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring, and perfuming agents, preservatives, and antioxidants can also be present in the composition.

[0279] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium hydrogen sulfate, sodium disulfite, sodium sulfite, etc.; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, etc.; and (3) metal chelators, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0280] Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, and / or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any method well known in the art of pharmacy. The amount of active ingredient which may be combined with a carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. The amount of active ingredient which may 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. Generally, this amount will range from about 0.1% to about 99% of the active ingredient, preferably from about 5% to about 70%, and most preferably from about 10% to about 30%, of one hundred percent.

[0281] In certain embodiments, a formulation of the invention comprises an excipient selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle-forming agents such as bile acids, and polymeric carriers such as polyesters and polyanhydrides, and a compound of the invention. In certain embodiments, the formulation renders the compound of the invention orally bioavailable.

[0282] Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present 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.

[0283] Formulations of the present invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored base, usually sucrose and gum arabic or tragacanth), powder, granules, or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil emulsion, or as an elixir or syrup, or as pastilles (using an inert base such as gelatin and glycerin, or sucrose and gum arabic), and / or mouthwash, each containing a predetermined amount of a compound of the present invention as an active ingredient. The compounds of the present invention may also be administered as a bolus, electuary, or paste.

[0284] In the solid dosage forms of the present invention for oral administration (capsules, tablets, pills, dragees, powders, granules, lozenges, etc.), 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, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or gum arabic; (3) humectants, such as glycerol; (4) disintegrants, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain (5) dissolution retarders, such as paraffin; (6) absorption enhancers, such as quaternary ammonium compounds and surfactants, such as poloxamers and sodium lauryl sulfate; (7) wetting agents, such as cetyl alcohol, glycerol monostearate, and nonionic surfactants; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid, and mixtures thereof; (10) coloring agents; and (11) controlled-release agents, such as crospovidone or ethylcellulose. In the case of capsules, tablets, and pills, pharmaceutical compositions may also contain buffering agents. Solid compositions of a similar type may also be employed as fillers for soft and hard-shell gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0285] Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surfactants, or dispersants. Molded tablets can be made by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine.

[0286] Tablets and other solid dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills, and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. Solid dosage forms can also be formulated to provide delayed or controlled release of the active ingredient therein, for example, using hydroxypropylmethylcellulose, other polymer matrices, liposomes, and / or microspheres in various proportions to provide the desired release profile. Rapid release formulations may also be prepared, for example, by lyophilization. Solid formulations can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved in sterile water or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be composed to release the active ingredient(s) only, or preferentially, in a delayed manner in a certain portion of the gastrointestinal tract. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.

[0287] The liquid dosage form for oral administration of the compound of the present invention includes pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.In addition to the active ingredient, the liquid dosage form may contain an inert diluent commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof.

[0288] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, coloring agents, perfumes, and preservatives.

[0289] Suspensions may contain, in addition to the active compound, suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0290] Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be provided as suppositories, which may be prepared by mixing one or more compounds of the invention with one or more suitable non-irritating excipients or carriers including, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, which are solid at room temperature but liquid at body temperature and therefore will melt in the rectal or vaginal cavity and release the active compound(s).

[0291] Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.

[0292] Dosage forms for topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.

[0293] The ointments, pastes, creams and gels may contain, in addition to the active compounds of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0294] Powders and sprays can contain, in addition to the compounds herein, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain conventional propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0295] Transdermal patches have the additional advantage of providing controlled delivery of the compound of the present invention into the body.Such dosage forms can be prepared by dissolving or dispersing the compound in a suitable medium.Absorption enhancers can also be used to increase the amount of compound that penetrates the skin.This amount of penetration can be controlled by either providing a rate-controlling membrane or dispersing the compound in a polymer matrix or gel.

[0296] Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention.

[0297] Pharmaceutical compositions of the invention suitable for parenteral administration may comprise one or more compounds of the invention in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions immediately before use, and may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes that render the preparation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0298] Examples of suitable aqueous and non-aqueous carriers that can be employed in the pharmaceutical compositions of the present invention include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0299] These compositions may also contain auxiliary agents such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms on the subject compounds can be ensured by the inclusion of various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars and sodium chloride, in the compositions. Furthermore, prolonged absorption of injectable drugs can be brought about by the inclusion of agents that delay absorption, such as aluminum monostearate and gelatin.

[0300] In some cases, it is desirable to slow down the absorption of drugs from subcutaneous or intramuscular injection in order to prolong the effect of drugs.This can be achieved by using a liquid suspension of crystalline or amorphous substances with poor water solubility.The absorption rate of a drug depends on its dissolution rate, which may depend on crystal size and crystalline form.Alternatively, delayed absorption of parenterally administered drugs can be achieved by dissolving or suspending the drug in an oil vehicle.

[0301] Injectable depot forms can be made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. The rate of drug release can be controlled depending on the ratio of drug to polymer and the nature of the particular polymer employed. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot formulations can also be prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0302] When the compound of the present invention is administered to humans and animals as a pharmaceutical, it can be administered as it is or as a pharmaceutical composition containing, for example, 0.1 to 99% (more preferably, 10 to 30%) of the active ingredient in combination with a pharmaceutically acceptable carrier.

[0303] The preparation of the present invention can be administered orally, parenterally, topically, or rectally.Of course, it can be administered in a form suitable for each administration route.For example, it can be administered in the form of tablets or capsules, by injection, inhalation, eye drops, ointments, suppositories, etc., including administration by injection, infusion, or inhalation; topical administration by lotion or ointment; and rectal administration by suppositories.Oral administration is preferred.

[0304] As used herein, the phrases "parenteral administration" and "parenterally administered" refer to modes of administration other than enteral and topical administration, usually by injection, including, but not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

[0305] As used herein, the terms "systemic administration," "systemically administered," "peripheral administration," and "peripherally administered" refer to administration of a compound, drug, or other substance other than directly into the central nervous system, whereby it enters the patient's system and is subjected to metabolism and other similar processes, e.g., subcutaneous administration.

[0306] These compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, e.g., by spray, rectally, intravaginally, parenterally, intracisternally and topically, by powders, ointments or drops, buccal and sublingual administration.

[0307] Regardless of the route of administration selected, the compounds of the present invention, which may be used in a suitable hydrated form, and / or the pharmaceutical compositions of the present invention are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art.

[0308] Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention may be varied to provide an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration without causing toxicity to the patient.

[0309] The selected dosage level will depend upon a variety of factors, including the activity of the particular compound of the invention, or ester, salt, or amide thereof, employed, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound employed, the rate and extent of absorption, the duration of treatment, other drugs, compounds, and / or substances used in combination with the particular compound employed, the age, sex, weight, condition, general health, and medical history of the patient being treated, and similar factors well known in the medical arts.

[0310] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian can start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than those required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0311] In general, a suitable daily dose of a compound of the present invention will be that amount of compound that is the lowest effective dose to produce a therapeutic effect. Such an effective dose will generally depend on the factors described above. Preferably, the compound is administered at about 0.01 mg / kg to about 200 mg / kg, more preferably about 0.1 mg / kg to about 100 mg / kg, and even more preferably about 0.5 mg / kg to about 50 mg / kg. When the compounds described herein are co-administered with another agent (e.g., a sensitizer), the effective amount may be less than when that agent is used alone.

[0312] If desired, the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally in unit dosage forms. Preferred administration is a once-daily dose.

[0313] The present invention further provides unit dosage forms (such as tablets or capsules) containing a therapeutically effective amount of a compound described herein for the treatment of a medical disorder described herein. [Example]

[0314] The invention having thus been generally described will be more readily understood by reference to the following examples, which are included merely to illustrate certain aspects and embodiments of the invention and are not intended to limit the invention.

[0315] General synthesis and analytical methods Analytical data are included in the procedures, general procedure diagrams, or tables in the examples. 1H NMR data were collected on a Bruker Avance 400 MHz instrument equipped with a 5 mm QNP probe, a Bruker Avance III 400 MHz instrument equipped with a 5 mm BBFO probe, or a Fourier 300 MHz instrument equipped with a 5 mm dual probe probe; chemical shifts are quoted in parts per million (ppm). LC / MS was performed on an Acquity UPLC H-Class (quaternary pump / PDA detector) coupled to a QDa mass spectrometer, an Acquity UPLC (binary pump / PDA detector) coupled to a ZQ mass spectrometer, or an Acquity UPLC equipped with a Waters DAD coupled to an SQD2 mass spectrometer. For LC / MS data, the method numbers provided in Table 2 were used to indicate the LC / MS conditions. [Table 4]

[0316] Purification method As for the general procedures, intermediates and final compounds may be purified by any technique or combination of techniques known to those skilled in the art. Some non-limiting examples include flash chromatography performed on a COMBIFLASH® Companion purification system or a Biotage SP1 purification system (products were purified using an Isolute® SPE Si II cartridge ("Isolute SPE Si cartridge" refers to a pre-packed polypropylene column containing unbonded activated silica with irregular particles of 50 μm average particle size and 60 Å nominal pore size) and a solvent or combination of solvents that elutes the desired compound (heptane, EtOAc, DCM, MeOH, MeCN, water, etc.); a Waters Mass Directed FractionLynx system (2767 autosampler, System Fluidics Organizer, 2998 photodiode array, 2545 pump, 3×515 pumps, QDa mass spectrometer), a Gilson system (GX281 autosampler, 322 pump, 155 UV / vis detector), and RP-HPLC purification performed on an Interchim PuriFlash 4125 connected to a UV DAD (see Table 3 for some non-limiting conditions); a Waters SFC purification (see Table 3 for some non-limiting conditions) performed on a Thar Prep100 system (P200 CO2 pump, 2545 modifier pump, 2998 UV / VIS detector, 2767 liquid handler, Stacked Injection Module) or a Waters Thar Investigator semi-preparative system (Waters Fluid Delivery Module, 2998 UV / VIS detector, Waters Fraction Collection Module); recrystallization from a suitable solvent (MeOH, EtOH, IPA, EtOAc, toluene, etc.) or solvent combination (EtOAc / heptane, EtOAc / MeOH, etc.); precipitation from solvent combinations (DMF / water, DMSO / DCM, EtOAc / heptane, etc.);These include trituration with a suitable solvent (such as EtOAc, DCM, MeCN, MeOH, EtOH, IPA, n-PrOH, etc.); extraction by dissolving the compound in a liquid and washing with a suitable immiscible liquid (such as DCM / water, EtOAc / water, DCM / saturated NaHCO3, EtOAc / saturated NaHCO3, DCM / 10% aqueous HCl, EtOAc / 10% aqueous HCl, etc.); and / or distillation (simple distillation, fractional distillation, Kugelrohr, etc.). Descriptions of these techniques can be found in the following references: Gordon, AJ and Ford, RA "The Chemist's Companion", 1972; Palleros, DR "Experimental Organic Chemistry", 2000; Still, WC, Kahn and M. Mitra, AJ Org. Chem. 1978, 43(14), 2923-2925; Yan, B. "Analysis and Purification Methods in Combinatorial Chemistry" 2003; Harwood, LM, Moody, CJ and Percy, JM "Experimental Organic Chemistry: Standard and Microscale, 2; nd Edition”, 1999. [Table 5-1] [Table 5-2] Abbreviation ℃ Celsius DAD Diode Array Detector DCM dichloromethane DEA Diethylamine DMA N,N-dimethylacetamide DMF N,N-methylformamide DMSO dimethyl sulfoxide EtOAc ethyl acetate EtOH ethanol H hours(s) H2O Water HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HCl hydrochloride HCOOH formic acid IMS Industrial Denatured Alcohol IPA Isopropyl Alcohol LC / MS Liquid Chromatography / Mass Spectrometry LiCl Lithium chloride m / z mass-to-charge ratio MeCN acetonitrile MeOH Methanol MgSO4 Magnesium Sulfate MHz Megahertz Min Minute(s) MS mass spectrometer Na2SO4 Sodium Sulfate NaHCO3 Sodium bicarbonate NaOH Sodium hydroxide NH4HCO3 Ammonium bicarbonate NH4OH Ammonium hydroxide NMR nuclear magnetic resonance Pd(dppf)Cl2 [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(PPh3)4 tetrakis(triphenylphosphine)palladium(0) PdCl2(PPh3)2 Bis(triphenylphosphine)palladium(II) dichloride RP-HPLC Reversed-phase high-performance liquid chromatography R t retention time RT room temperature SFC Supercritical Fluid Chromatography TBME tert-butyl methyl ether THF tetrahydrofuran UPLC Ultra High Performance Liquid Chromatography

[0317] Example 1 - Synthesis of Compound Intermediate 5: 3-chloro-1,4-dimethyl-6-(1-(trifluoromethyl)-1H-pyrazole-4-carbonyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one The title compound was prepared according to the following procedure.

[0318] Intermediate 1: Preparation of but-2-ynoyl chloride [ka] To a solution of 2-butynoic acid (13 g, 155 mmol) in DCM (550 mL) was added DMF (0.6 mL) and oxalyl chloride (14 mL, 162 mmol) dropwise. The reaction was stirred at room temperature for 5 hours. The reaction mixture was carried on directly to the next step as a yellow solution. 1 H NMR (400 MHz, CDCl3) δ 5.30 (s, 3H).

[0319] Intermediate 2: Preparation of (Z)-tert-butyl 3-(methylimino)pyrrolidine-1-carboxylate [ka] A reaction vessel was charged with N-boc-3-pyrrolidinone (29 g, 155 mmol) and dissolved in 2 M methylamine in THF (130 mL, 260 mmol). The reaction was stirred at room temperature for 15 minutes and then heated to 60° C. The reaction was stirred at 60° C. for 5 hours, and then the reaction mixture was concentrated in vacuo to give the title compound as a yellow oil (31 g, quantitative). The material was carried on to the next step without characterization.

[0320] Intermediate 3: Preparation of tert-butyl 1,4-dimethyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate [ka] To a solution of tert-butyl (Z)-3-(methylimino)pyrrolidine-1-carboxylate (31 g, 155 mmol) and triethylamine (65 mL, 464 mmol) in DCM (400 mL) at 0° C. was added a solution of but-2-ynoyl chloride (16 g, 155 mmol) dropwise over 2 h. The reaction was stirred at 0° C. for 1.5 h. The reaction was allowed to warm to room temperature and stirred at room temperature for 48 h. The reaction mixture was then partitioned between DCM and distilled water. The organic layer was separated. The combined organic layers were washed with saturated brine, dried (MgSO4), and concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc to MeOH, gradient elution) to give the title compound (13 g, 32%) as a brown solid. LC / MS (Table 2, Method A): R t = 1.24 min; m / z = 265 [M+H] + .

[0321] Intermediate 4: Preparation of tert-butyl 3-chloro-1,4-dimethyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate [ka] To a solution of tert-butyl 1,4-dimethyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (5 g, 19 mmol) in DMF (50 mL) and MeCN (100 mL) under a nitrogen atmosphere was added N-chlorosuccinimide (2.9 g, 22 mmol), and the reaction was heated to 55° C. The reaction was stirred at 55° C. under a nitrogen atmosphere for 1.5 hours. The reaction mixture was allowed to cool to room temperature and quenched by pouring into distilled water (1 L). The mixture was stirred for 30 minutes. The reaction mixture was filtered, washed with distilled water, and concentrated under vacuum to give the title compound as a light brown solid (2.8 g, 50%). LC / MS (Table 2, Method A): R t = 1.20 min; m / z = 299 [M+H] + .

[0322] Intermediate 5: Preparation of 3-chloro-1,4-dimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride [ka] To a solution of tert-butyl 3-chloro-1,4-dimethyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (2.8 g, 9.4 mmol) in DCM (40 mL) was added 4 M HCl in 1,4-dioxane (48 mL, 192 mmol). The reaction was stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo to give the title compound as a light brown solid (2.2 g, 97%). LC / MS (Table 2, Method A): t = 0.66 min; m / z = 199 [M+H] + .

[0323] Example 2 - Synthesis of Compound I-1: 3-chloro-1,4-dimethyl-6-(1-(trifluoromethyl)-1H-pyrazole-4-carbonyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one [ka] To a solution of 3-chloro-1,4-dimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride (40 mg, 0.16 mmol) and 1-(trifluoromethyl)pyrazole-4-carboxylic acid (35 mg, 0.19 mmol) in DMF (1.5 mL) was added N,N-diisopropylethylamine (97 mL, 0.56 mmol) and HATU (109 mg, 0.29 mmol). The reaction was stirred at room temperature for 0.5 h. The reaction mixture was then partitioned between EtOAc and aqueous sodium bicarbonate. The organic layer was separated. The combined organic layers were washed with saturated brine, dried (NaSO), and concentrated in vacuo. The residue was purified by reverse-phase HPLC (Table 3, Method 1) to afford the title compound as an off-white solid (9.1 mg, 16%). 1H NMR (400 MHz, DMSO-d6) δ 9.10 (d, J=2.3 Hz, 1H), 8.42 (s, 1H), 5.22 - 5.20 (m, 1H), 5.00 (t, J=2.3 Hz, 1H), 4.91 (s, 1H), 4.71 (s, 1H), 3.48 (d, J=2.3 Hz, 3H), 2.28 (d, J=3.0 Hz, 3H). LC / MS (Table 2, Method B): R t = 3.46 min; m / z = 361 [M+H] + .

[0324] Example 3 - Preparation of further compounds The compounds in Table 4 were prepared from compound Intermediate 5 and the starting materials indicated using procedures similar to those described for the preparation of compound I-1. [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5] [Table 6-6] [Table 6-7]

[0325] Example 4 - Compound Intermediate 7: Synthesis of lithium 2-cyclobutylbenzo[d]thiazole-6-carboxylate The title compound was prepared according to the following procedure.

[0326] Intermediate 6: Preparation of ethyl 2-cyclobutylbenzo[d]thiazole-6-carboxylate [ka] To a suspension of ethyl 2-chloro-1,3-benzothiazole-6-carboxylate (200 mg, 0.83 mmol) and Pd(PPh3)4 (48 mg, 0.041 mmol) in THF (4 mL) under a nitrogen atmosphere was added 0.5 M bromo(cyclobutyl)zinc in THF (2.0 mL, 0.99 mmol). The reaction was heated to 60 °C and stirred at 60 °C for 5 h. The reaction mixture was allowed to cool to room temperature and quenched by the addition of distilled water, then partitioned with EtOAc. The organic layer was separated. The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash column chromatography (cyclohexane to EtOAc, gradient elution) to give the title compound (96 mg, 44%) as a white solid. LC / MS (Table 2, Method A): R t = 1.69 min; m / z = 262 [M+H] + .

[0327] Intermediate 7: Preparation of lithium 2-cyclobutylbenzo[d]thiazole-6-carboxylate [ka] To a solution of ethyl 2-cyclobutylbenzo[d]thiazole-6-carboxylate (96 mg, 0.37 mmol) in THF (1.8 mL) was added a solution of lithium hydroxide monohydrate (77 mg, 1.8 mmol) in distilled water (0.7 mL). The reaction was stirred at room temperature for 72 hours. The reaction mixture was then concentrated in vacuo to give the title compound as a white solid (87 mg, 99%). The material was carried on to the next step without characterization.

[0328] Example 5 - Compound I-51: Synthesis of 3-chloro-6-(2-cyclobutylbenzo[d]thiazole-6-carbonyl)-1,4-dimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one [ka] To a suspension of 3-chloro-1,4-dimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride (35 mg, 0.14 mmol) and lithium 2-cyclobutylbenzo[d]thiazole-6-carboxylate (40 mg, 0.17 mmol) in DMF (1.2 mL) was added HATU (96 mg, 0.25 mmol) and N,N-diisopropylethylamine (0.085 mL, 0.49 mmol). The reaction was stirred at room temperature for 1 hour. The reaction mixture was then partitioned between DCM and saturated aqueous sodium bicarbonate. The organic layer was separated. The combined organic layers were washed with saturated brine, dried (NaSO), and concentrated in vacuo. The residue was triturated with hot MeCN to afford the title compound (15 mg, 26%) as an off-white solid. 1 H NMR (400 MHz: DMSO-d6) δ 8.36 - 8.36 (m, 1H), 8.03 (d, J=8.4 Hz, 1H), 7.71 (dd, J=1.6, 8.4 Hz, 1H), 4.95 (s, 1H), 4.92 (s, 1H), 4.77 (s, 1H), 4.70 (s, 1H), 4.06 - 4.02 (m, 1H), 3.48 (s, 1.5H), 3.29 (s, 1.5H), 2.48 - 2.36 (m, 4H), 2.27 (s, 1.5H), 2.16 - 2.06 (m, 2.5H), 2.01 - 1.97 (m, 1H).LC / MS (Table 2, Method C): R t = 4.01 min; m / z = 413 [M+H] + .

[0329] Example 6 - Synthesis of further compounds The following intermediates in Table 5 were prepared from ethyl 2-chloro-1,3-benzothiazole-6-carboxylate and the starting materials indicated using reaction protocols similar to those described for Intermediate 7. [Table 7]

[0330] Example 7 - Compound I-52: Synthesis of 3-chloro-6-(2-cyclopropylbenzo[d]thiazole-6-carbonyl)-1,4-dimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one [ka] The title compound was prepared from the appropriate starting materials, 3-chloro-1,4-dimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride and lithium 2-cyclopropylbenzo[d]thiazole-6-carboxylate, using a reaction protocol similar to that described for Example 50: 3-chloro-6-(2-cyclobutylbenzo[d]thiazole-6-carbonyl)-1,4-dimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one. The title compound was triturated with 10% aqueous DMSO to give an off-white solid (36 mg, 41%). 1 H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.92 (d, J=8.4 Hz, 1H), 7.67 (dd, J=1.6, 8.4 Hz, 1H), 4.95 (s, 1H), 4.91 (s, 1H), 4.76 (s, 1H), 4.71 (s, 1H), 3.47 (s, 1.5H), 3.29 (s, 1.5H), 2.60 - 2.54 (m, 1H), 2.26 (s, 1.5H), 2.10 (s, 1.5H), 1.30 - 1.24 (m, 2H), 1.19 - 1.14 (m, 2H). LC / MS (Table 2, Method C): R t = 3.60 min; m / z = 399 [M+H] + .

[0331] Example 8 - Synthesis of Compound Intermediate 9: 3-chloro-1,4-dimethyl-6-(1-((3-methyloxetan-3-yl)methyl)-1H-pyrazole-4-carbonyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one [ka] To a suspension of 3-chloro-1,4-dimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride (150 mg, 0.64 mmol) and 4-pyrazolecarboxylic acid (79 mg, 0.71 mmol) in DCM (3 mL) was added HATU (315 mg, 0.83 mmol) and triethylamine (0.27 mL, 1.9 mmol). The reaction was stirred for 2 hours. The reaction mixture was filtered to give the title compound as a tan solid (138 mg, 74%). LC / MS (Table 2, Method F): t = 1.25 min; m / z = 292 [M+H] + .

[0332] Example 9 - Compound I-53: Synthesis of 3-chloro-1,4-dimethyl-6-(1-((3-methyloxetan-3-yl)methyl)-1H-pyrazole-4-carbonyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one [ka] To a suspension of 3-chloro-1,4-dimethyl-6-(1H-pyrazole-4-carbonyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one (61 mg, 0.21 mmol) in DMF (1 mL) at 0 °C, sodium hydride (60%, 13 mg, 0.31 mmol) was added and the reaction was stirred for 15 minutes. This was followed by the addition of 3-(bromomethyl)-3-methyl-oxetane (45 mg, 0.27 mmol). The reaction was allowed to warm to room temperature and stirred at room temperature for 1.25 hours. The reaction mixture was quenched by the addition of distilled water (1 mL) and concentrated in vacuo. The residue was purified by reverse-phase HPLC (Table 3, Method 1) to give the title compound as a white solid (9.0 mg, 11%). 1H NMR (400 MHz: DMSO-d6) δ 8.45 (s, 1H), 8.02 (d, J=3.0 Hz, 1H), 5.15 - 5.12 (m, 1H), 4.94 (s, 1H), 4.87 (s, 1H), 4.68 (s, 1H), 4.64 LC / MS (Table 2, Method B): R t = 2.82 min; m / z = 377 [M+H] + .

[0333] Example 10 - Synthesis of further compounds The following examples in Table 6 were prepared from intermediate 9 and the starting materials indicated using reaction protocols similar to those described for I-53. [Table 8]

[0334] Example 11 - Synthesis of Compound Intermediate 12: 3-chloro-1,4-dimethyl-6-(5-(2,2,2-trifluoroethyl)isoxazole-3-carbonyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one The title compound was prepared according to the following procedure.

[0335] Intermediate 10: Preparation of ethyl 5-(bromomethyl)isoxazole-3-carboxylate [ka] To a solution of ethyl 2-chloro-2-(hydroxyimino)acetate (5 g, 33 mmol) in diethyl ether (25 mL) at 0 °C was added dropwise 10.2 M propargyl bromide solution (4.9 mL, 50 mmol). This was followed by the dropwise addition of triethylamine (5.1 mL, 36 mmol) in diethyl ether (5 mL). The reaction was allowed to warm to room temperature and stirred at room temperature for 16 hours. The reaction mixture was then partitioned between EtOAc and distilled water. The organic layer was separated. The combined organic layers were washed with saturated brine, dried (MgSO4), and concentrated in vacuo. The residue was purified by flash column chromatography (cyclohexane to EtOAc, gradient elution) to give the title compound (1.1 g, 14%). 1 H NMR (400 MHz: CDCl3) δ 6.74 (d, J=3.6 Hz, 1H), 4.50 (s, 2H), 4.49 - 4.42 (m, 2H), 1.42 (t, J=7.2 Hz, 3H).

[0336] Intermediate 11: Preparation of ethyl 5-(2,2,2-trifluoroethyl)isoxazole-3-carboxylate [ka] To a solution of ethyl 5-(bromomethyl)isoxazole-3-carboxylate (295 mg, 1.3 mmol) in DMF (10 mL) was added copper(I) iodide (456 mg, 2.4 mmol) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (0.72 mL, 5.7 mmol). The reaction was heated to 100° C. and stirred at 100° C. for 16 hours. The reaction mixture was then partitioned between EtOAc and distilled water. The organic layer was separated. The combined organic layers were washed with saturated brine, dried (MgSO4), and concentrated in vacuo. The residue was purified by flash column chromatography (cyclohexane in EtOAc, gradient elution) to give the title compound (138 mg, 49%) as a yellow oil. LC / MS (Table 2, Method A): R t = 1.31 min; UV only.

[0337] Intermediate 12: Preparation of 5-(2,2,2-trifluoroethyl)isoxazole-3-carboxylic acid [ka] A reaction vessel was charged with ethyl 5-(2,2,2-trifluoroethyl)isoxazole-3-carboxylate (65 mg, 0.29 mmol) and 6 M HCl (5.0 mL, 30 mmol). The reaction was heated to 100° C. and stirred at 100° C. for 3 h. The reaction mixture was then concentrated in vacuo and the residue was azeotroped with MeCN to afford the title compound as a yellow gum (154 mg, 62%). 1 H NMR (400 MHz: DMSO-d6) δ 6.87 (s, 1H), 4.22 (q, J=10.9 Hz, 2H).

[0338] Example 12 - Compound I-58: Synthesis of 3-chloro-1,4-dimethyl-6-(5-(2,2,2-trifluoroethyl)isoxazole-3-carbonyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one [ka] To a solution of 5-(2,2,2-trifluoroethyl)isoxazole-3-carboxylic acid (65 mg, 0.33 mmol) and 3-chloro-1,4-dimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride (50 mg, 0.21 mmol) in DCM (2 mL) was added triethylamine (0.089 mL, 0.64 mmol) and HATU (97 mg, 0.26 mmol). The reaction was stirred at room temperature for 30 minutes. The reaction mixture was then partitioned between EtOAc and distilled water. The organic layer was separated. The combined organic layers were washed with saturated brine, dried (MgSO), and concentrated in vacuo. The residue was purified by reverse-phase HPLC (Table 3, Method 4, nonlinear gradient from 20% to 80% MeCN) to give the title compound as an off-white solid (48.2 mg, 60%). 1H NMR (400 MHz: DMSO-d6) δ 6.95 (s, 1H), 5.22 (s, 1H), 5.01 - 4.95 (m, 2H), 4.77 - 4.76 (m, 1H), 4.28 (q, J=10.9 Hz, 2H), 3.49 (s, 1.5H), 3.42 (s, 1.5H), 2.28 (s, 1.5H), 2.22 (s, 1.5H).LC / MS (Table 2, Method E): R t = 3.92 min; m / z = 376 [M+H] + .

[0339] Example 13 - Compound Intermediate 14: Synthesis of lithium 1-(pyridin-3-ylmethyl)-1H-pyrazole-4-carboxylate The title compound was prepared according to the following procedure.

[0340] Intermediate 13: Preparation of ethyl 1-(pyridin-3-ylmethyl)-1H-pyrazole-4-carboxylate [ka] To a suspension of ethyl 4-pyrazolecarboxylate (150 mg, 1.1 mmol) in DMF (2 mL) at 0° C. was added sodium hydride (60%, 64 mg, 1.6 mmol) and the reaction was stirred for 10 minutes. This was followed by the addition of 3-(bromomethyl)pyridine hydrobromide (298 mg, 1.2 mmol) and triethylamine (0.45 mL, 3.2 mmol). The reaction was allowed to warm to room temperature and stirred at room temperature for 4 hours. The reaction mixture was quenched by the addition of distilled water and then partitioned with EtOAc. The organic layer was separated. The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash column chromatography (DCM to MeOH, gradient elution) to give the title compound as a yellow gum (154 mg, 62%). LC / MS (Table 2, Method F): R t = 0.23 min; m / z = 232 [M+H] + .

[0341] Intermediate 14: Preparation of lithium 1-(pyridin-3-ylmethyl)-1H-pyrazole-4-carboxylate [ka] To a solution of ethyl 1-(pyridin-3-ylmethyl)-1H-pyrazole-4-carboxylate (154 mg, 0.67 mmol) in THF (5 mL) and water (1 mL) was added lithium hydroxide monohydrate (28 mg, 0.67 mmol), and the reaction was stirred at room temperature for 16 hours. An additional amount of lithium hydroxide monohydrate (56 mg, 1.3 mmol) and MeOH (1 mL) was added, and the reaction was stirred for 2.5 hours. The reaction mixture was concentrated in vacuo to give the title compound as an off-white solid (181 mg, quantitative). LC / MS (Table 2, Method F): t = 0.23 min; m / z = 204 [M+H] +

[0342] Example 14 - Compound I-59: Synthesis of 3-chloro-1,4-dimethyl-6-(1-(pyridin-3-ylmethyl)-1H-pyrazole-4-carbonyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one [ka] To a suspension of lithium 1-(pyridin-3-ylmethyl)-1H-pyrazole-4-carboxylate (43 mg, 0.20 mmol) in DMF (3 mL) was added HATU (84 mg, 0.22 mmol) and triethylamine (0.071 mL, 0.51 mmol). Following this, 3-chloro-1,4-dimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride (40 mg, 0.17 mmol) was added, and the reaction was stirred at room temperature for 18 hours. The reaction mixture was then partitioned between EtOAc and distilled water. The organic layer was separated. The combined organic layers were dried (NaSO) and concentrated in vacuo. The residue was purified by reverse-phase HPLC (Table 3, Method 1) to afford the title compound as an off-white solid (5.7 mg, 9%). 1H NMR (400 MHz: DMSO-d6) δ 8.60 - 8.57 (m, 2H), 8.54 (dd, J=1.6, 4.8 Hz, 1H), 8.04 (d, J=3.1 Hz, 1H), 7.73 - 7.70 (m, 1H), 7.41 (dd, J=5.0, 7.7 Hz, 1H), 5.47 (s, 2H), 5.17 - 5.15 (m, 1H), 4.96 (s, 1H), 4.87 (s, 1H), 4.68 - 4.67 (m, 1H), 3.48 (d, J=6.7 Hz, 3H), 2.27 (d, J=7.7 Hz, 3H).LC / MS (Table 2, Method E): R t = 2.77 min; m / z = 384 [M+H] + .

[0343] Example 15 - Synthesis of additional compounds The following intermediates in Table 7 were prepared from ethyl 4-pyrazolecarboxylate and the starting materials indicated using reaction protocols similar to those described for Intermediate 14. [Table 9]

[0344] Example 16 - Synthesis of further compounds The following compounds in Table 8 were prepared from Intermediate 5 and the indicated starting materials using reaction protocols similar to those described for I-12. [Table 10]

[0345] Example 17 - Synthesis of Compound Intermediate 23: Lithium 2-((2,2-difluorocyclopropyl)methyl)thiazole-5-carboxylate The title compound was prepared according to the following procedure.

[0346] Preparation of Intermediate 19: 2-(2,2-difluorocyclopropyl)-N-(2,4-dimethoxybenzyl)acetamide [ka] To a solution of 2-(2,2-difluorocyclopropyl)acetic acid (150 mg, 1.1 mmol), 2,4-dimethoxybenzylamine (0.20 mL, 1.3 mmol), and HATU (545 mg, 1.4 mmol) in DCM (2 mL) was added N,N-diisopropylethylamine (0.58 mL, 3.3 mmol). The reaction was stirred at room temperature for 2 hours. The reaction mixture was then partitioned between DCM and distilled water. The organic layer was separated. The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash column chromatography (cyclohexane in EtOAc, gradient elution) to give the title compound as a colorless oil that crystallized on standing (278 mg, 88%). LC / MS (Table 2, Method F): R t = 1.43 min; m / z = 286 [M+H] + .

[0347] Preparation of Intermediate 20: 2-(2,2-difluorocyclopropyl)-N-(2,4-dimethoxybenzyl)ethanethioamide [ka] To a solution of 2-(2,2-difluorocyclopropyl)-N-(2,4-dimethoxybenzyl)acetamide (218 mg, 0.76 mmol) in toluene (5 mL) was added Lawesson's reagent (185 mg, 0.46 mmol), and the reaction was then heated to 95° C. The reaction was stirred at 95° C. for 1 h. The reaction mixture was concentrated in vacuo and directly purified by flash column chromatography (cyclohexane in EtOAc, gradient elution) to afford the title compound as a colorless oil (169 mg, 73%). LC / MS (Table 2, Method F): t = 1.69 min; m / z = 302 [M+H] + .

[0348] Intermediate 21: Preparation of 2-(2,2-difluorocyclopropyl)ethanethioamide [ka] To a solution of 2-(2,2-difluorocyclopropyl)-N-(2,4-dimethoxybenzyl)ethanethioamide (75 mg, 0.25 mmol) and anisole (0.14 mL, 1.2 mmol) in DCM (4 mL) was added trifluoroacetic acid (1.0 mL, 13 mmol). The reaction was stirred at room temperature for 18 h. The reaction mixture was then concentrated in vacuo and purified directly by flash column chromatography (cyclohexane in EtOAc, gradient elution) to afford the title compound as a yellow oil (27 mg, 72%). The material was carried on to the next step without characterization.

[0349] Preparation of Intermediate 22: Ethyl 2-((2,2-difluorocyclopropyl)methyl)thiazole-5-carboxylate [ka] A reaction vessel was charged with 2-(2,2-difluorocyclopropyl)ethanethioamide (47 mg, 0.37 mmol), ethyl 2-chloro-3-oxo-propanoate (51 mg, 0.40 mmol), and dissolved in toluene (2 mL). The reaction was then heated to 90° C. and stirred at 90° C. for 2 hours. The reaction mixture was concentrated in vacuo and directly purified by flash column chromatography (cyclohexane in EtOAc, gradient elution) to afford the title compound as a yellow oil (30 mg, 39%). LC / MS (Table 2, Method F): t = 1.62 min; m / z = 248 [M+H] + .

[0350] Intermediate 23: Preparation of lithium 2-((2,2-difluorocyclopropyl)methyl)thiazole-5-carboxylate [ka] To a solution of ethyl 2-[(2,2-difluorocyclopropyl)methyl]thiazole-5-carboxylate (30 mg, 0.12 mmol) in THF (1 mL) and water (0.5 mL) was added lithium hydroxide monohydrate (5.6 mg, 0.13 mmol). The reaction was stirred at room temperature for 2 hours. The reaction mixture was then concentrated in vacuo to give the title compound as a pale yellow solid (27 mg, 99%). LC / MS (Table 2, Method F): t = 1.26 min; m / z = 220 [M+H] + .

[0351] Example 18 - Compound I-64: Synthesis of 3-chloro-6-(2-(cyclopropyl-difluoromethyl)thiazole-5-carbonyl)-1,4-dimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one [ka] To a suspension of lithium 2-((2,2-difluorocyclopropyl)methyl)thiazole-5-carboxylate (22 mg, 0.099 mmol) and 3-chloro-1,4-dimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride (19 mg, 0.082 mmol) in DMF (2 mL) was added N,N-diisopropylethylamine (0.050 mL, 0.29 mmol) and HATU (47 mg, 0.12 mmol). The reaction was stirred at room temperature for 2 hours. The reaction mixture was then concentrated in vacuo and directly purified by reverse-phase HPLC (Table 3, Method 3) to afford the title compound as an off-white solid (14 mg, 44%). 1H NMR (400 MHz: DMSO-d6) δ 8.43 (d, J=2.6 Hz, 1H), 5.28 (s, 1H), 5.07 (t, J=2.3 Hz, 1H), 4.93 (s, 1H), 4.73 (s, 1H), 3.48 (d, J=4.8 Hz, 3H), 3.24 - 3.19 (m, 2H), 2.28 (d, J=3.4 Hz, 3H), 2.25 - 2.09 (m, 1H), 1.79 - 1.69 (m, 1H), 1.49 - 1.40 (m, 1H).LC / MS (Table 2, Method B): R t = 3.98 min; m / z = 400 [M+H] + .

[0352] Example 19 - Synthesis of additional compounds The following compounds in Table 9 were prepared from Intermediate 5 and the starting materials indicated using reaction protocols similar to those described for I-16. [Table 11]

[0353] Example 20 - Compound Intermediate 28: Synthesis of lithium 2-(cyclopropyldifluoromethyl)thiazole-5-carboxylate The title compound was prepared according to the following procedure.

[0354] Intermediate 24: Preparation of N-methoxy-N-methylcyclopropanecarboxamide [ka] To a suspension of N,O-dimethylhydroxylamine hydrochloride (2.2 g, 22 mmol) in DCM (55 mL) at 0° C. was added triethylamine (6.1 mL, 44 mmol) dropwise. This was followed by the dropwise addition of cyclopropanecarbonyl chloride (2.0 mL, 22 mmol). The reaction was allowed to warm to room temperature and stirred at room temperature for 1 h. The reaction mixture was then partitioned between DCM and saturated aqueous sodium bicarbonate solution. The organic layer was separated. The combined organic layers were washed with 1 M HCl, saturated brine, and passed through a phase separator. The filtrate was concentrated in vacuo to give the title compound (2.6 g, 92%) as a colorless liquid. 1 H NMR (400 MHz: CDCl3) δ 3.76 (s, 3H), 3.21 (s, 3H), 2.19 - 2.09 (m, 1H), 1.01 - 0.97 (m, 2H), 0.84 - 0.79 (m, 2H).

[0355] Intermediate 25: Preparation of ethyl 2-(cyclopropanecarbonyl)thiazole-5-carboxylate [ka] To a solution of ethyl thiazole-5-carboxylate (1.2 mL, 12 mmol) and N-methoxy-N-methyl-cyclopropanecarboxamide (1.2 mL, 12 mmol) in THF (44 mL) was added dropwise a solution of 1 M lithium bis(trimethylsilyl)amide in THF (17 mL, 18 mmol) at −78° C. under a nitrogen atmosphere. The reaction was stirred at −78° C. for 2 hours. The reaction mixture was quenched by the addition of saturated aqueous ammonium chloride, allowed to warm to room temperature, and then partitioned between EtOAc and distilled water. The organic layer was separated. The combined organic layers were washed with saturated brine, dried (NaSO), and concentrated in vacuo. The residue was purified by flash column chromatography (cyclohexane to EtOAc, gradient elution) to give the title compound (692 mg, 27%) as a pale yellow oil. LC / MS (Table 2, Method A): R t = 1.46 min; m / z = 226 [M+H] +.

[0356] Intermediate 26: Preparation of ethyl 2-(2-cyclopropyl-1,3-dithiolan-2-yl)thiazole-5-carboxylate [ka] To a solution of ethyl 2-(cyclopropanecarbonyl)thiazole-5-carboxylate (486 mg, 2.2 mmol) in toluene (6 mL) was added boron trifluoride diethyl etherate (0.32 mL, 2.6 mmol) and 1,2-ethanedithiol (0.54 mL, 6.5 mmol). The reaction was heated to 100° C. and stirred at 100° C. for 5 hours. The reaction mixture was allowed to cool to room temperature and then concentrated in vacuo. The residue was directly purified by flash column chromatography (cyclohexane to EtOAc) to give the title compound as a colorless oil (103 mg, 16%). LC / MS (Table 2, Method A): R t = 1.62 min; m / z = 302 [M+H] + .

[0357] Preparation of Intermediate 27: Ethyl 2-(cyclopropyldifluoromethyl)thiazole-5-carboxylate [ka] To a suspension of N-iodosuccinimide (192 mg, 0.85 mmol) in DCM (1 mL) was added dropwise hydrogen fluoride pyridine (70% HF, 0.88 mL, 9.8 mmol) at −78° C. This was followed by the dropwise addition of a solution of ethyl 2-(2-cyclopropyl-1,3-dithiolan-2-yl)thiazole-5-carboxylate (103 mg, 0.34 mmol) in DCM (1 mL). The reaction mixture was warmed to −30° C. and stirred at −30° C. for 2.5 hours. The reaction mixture was quenched by the addition of saturated aqueous sodium bicarbonate solution and then partitioned with DCM. The organic layer was separated. The combined organic layers were washed with saturated brine, passed through a phase separator, and the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography (cyclohexane in DCM) to give the title compound (18 mg, 21%) as an orange oil. LC / MS (Table 2, Method A): R t = 1.56 min; m / z = 248 [M+H] + .

[0358] Intermediate 28: Preparation of lithium 2-(cyclopropyldifluoromethyl)thiazole-5-carboxylate [ka] To a solution of ethyl 2-(cyclopropyldifluoromethyl)thiazole-5-carboxylate (18 mg, 0.073 mmol) in MeOH (0.75 mL) was added a solution of lithium hydroxide monohydrate (3.4 mg, 0.080 mmol) in water (0.25 mL), and the reaction was stirred at room temperature for 3 hours. The reaction mixture was then concentrated in vacuo to give the title compound as a yellow solid (16 mg, 98%). The material was carried on to the next step without characterization.

[0359] Example 21 - Synthesis of Compound I-67: 3-chloro-6-(2-(cyclopropyldifluoromethyl)thiazole-5-carbonyl)-1,4-dimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one [ka] To a solution of lithium 2-(cyclopropyldifluoromethyl)thiazole-5-carboxylate (16 mg, 0.071 mmol) in DMF (0.5 mL) was added HATU (32 mg, 0.085 mmol), followed by the dropwise addition of a solution of 3-chloro-1,4-dimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride (18 mg, 0.078 mmol) and N,N-diisopropylethylamine (31 mL, 0.18 mmol) in DMF (0.5 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated in vacuo and directly purified by reverse-phase HPLC (Table 3, Method 3) to give the title compound as an off-white solid (14 mg, 48%). 1 H NMR (400 MHz: DMSO-d6) δ 8.68 - 8.65 (m, 1H), 5.32 - 4.77 (m, 4H), 3.49 - 3.48 (m, 3H), 2.29 - 2.27 (m, 3H), 2.04 - 1.91 (m, 1H), 0.85 - 0.78 (m, 4H). LC / MS (Table 2, Method B): R t = 4.18 min; m / z = 400 [M+H] + .

[0360] Example 22 - Synthesis of Compound Intermediate 31: Lithium 1-methyl-5-(trifluoromethyl)-1H-pyrrole-3-carboxylate The title compound was prepared according to the following procedure.

[0361] Preparation of Intermediate 29: Methyl 5-(trifluoromethyl)-1H-pyrrole-3-carboxylate [ka] To a solution of methyl lH-pyrrole-3-carboxylate (310 mg, 2.5 mmol) in DMF (2 mL) was added 0.5 M trifluoroiodomethane in THF (5.0 mL, 2.5 mmol) and sodium hydride (60%, 145 mg, 3.7 mmol).

[0362] The reaction was stirred under a nitrogen atmosphere for 30 minutes. The reaction mixture was partitioned between distilled water and DCM. The organic layer was separated and concentrated in vacuo. The residue was purified by flash column chromatography (cyclohexane to diethyl ether, gradient elution) to afford the title compound as a mixture of regioisomers (3:7, 77 mg, 5%). 1 H NMR (400 MHz, CDCl3) d 8.94 - 8.93 (m, 1H), 7.53 - 7.53 (m, 1H), 7.05 (s, 1H), 3.86 (s, 3H).

[0363] Preparation of Intermediate 30: Methyl 1-methyl-5-(trifluoromethyl)-1H-pyrrole-3-carboxylate [ka] To a solution of methyl 5-(trifluoromethyl)-1H-pyrrole-3-carboxylate (75 mg, 0.39 mmol) in DMF (1 mL) was added sodium hydride (12 mg, 0.51 mmol) and the reaction was stirred at room temperature for 1 h. Iodomethane (0.24 mL, 3.9 mmol) was then added and the reaction was stirred at room temperature for 1 h. The reaction mixture was quenched by the addition of sodium bicarbonate solution and then partitioned with EtOAc. The combined organic layers were washed with 5% LiCl solution, dried (MgSO4), and concentrated in vacuo. This material was purified by flash column chromatography (cyclohexane to diethyl ether, gradient elution) to provide the title compound (12 mg, 15%). 1 H NMR (400 MHz, CDCl3) δ 7.35 (d, J=1.8 Hz, 1H), 7.01 (s, 1H), 3.83 (s, 3H), 3.77 (s, 3H).

[0364] Intermediate 31: Preparation of lithium 1-methyl-5-(trifluoromethyl)-1H-pyrrole-3-carboxylate [ka] To a solution of methyl 1-methyl-5-(trifluoromethyl)pyrrole-3-carboxylate (12 mg, 0.06 mmol) in THF (0.50 mL) was added lithium hydroxide monohydrate (7.3 mg, 0.17 mmol) and distilled water (0.25 mL). The reaction was stirred at room temperature for 5 hours. The reaction mixture was concentrated in vacuo to give the title compound as a white solid (21 mg, quantitative). The material was carried forward without characterization.

[0365] Example 23 - Compound I-68: Synthesis of 3-chloro-1,4-dimethyl-6-(1-methyl-5-(trifluoromethyl)-1H-pyrrole-3-carbonyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one [ka] To a solution of lithium 1-methyl-5-(trifluoromethyl)pyrrole-3-carboxylate (11 mg, 0.057 mmol) in DMF (0.5 mL) was added HATU (33 mg, 0.086 mmol), followed by a solution of 3-chloro-1,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-one hydrochloride (19 mg, 0.080 mmol) and N,N-diisopropylethylamine (0.050 mL, 0.29 mmol) in DMF (0.5 mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then concentrated in vacuo and directly purified by reverse-phase HPLC (Table 3, Method 5) to give the title compound as an off-white solid (3.5 mg, 16%). 1 H NMR (400 MHz, DMSO)δ 7.80 (d, J=2.0 Hz, 1H), 7.10 (s, 1H), 5.12 (s, 1H), 4.93 (s, 1H), 4.86 (s, 1H), 4.67 (s, 1H), 3.80 (s, 3H), 3.46 (d, J=6.6 Hz, 3H), 2.25 (d, J=7.3 Hz, 3H). (Table 2, Method B): R t = 3.89 min; m / z = 374.2 [M+H] +

[0366] Example 24 - Synthesis of Compound Intermediate 40: 3-chloro-1-(cyclopropylmethyl)-4-methyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride The title compound was prepared according to the following procedure.

[0367] Preparation of Intermediate 32: 2-Chloro-6-methoxy-4-methylnicotinonitrile [ka] To a suspension of 2,6-dichloro-4-methylnicotinonitrile (84 g, 450 mmol) in MeOH (840 mL) under a nitrogen atmosphere at 1.5 °C, 4.4 M sodium methoxide (108 mL, 472 mmol) was added dropwise over 5 h. The reaction was allowed to warm to room temperature and stirred at room temperature for 16 h. The reaction mixture was cooled to 3 °C and slowly quenched by the addition of distilled water (100 mL) and stirred for 30 min. The reaction mixture was allowed to warm to room temperature, concentrated in vacuo, and then partitioned between EtOAc and distilled water. The organic layer was separated. The combined organic layers were washed with saturated brine, dried (NaSO), and concentrated in vacuo. The residue was further recrystallized from MeOH to afford the title compound as a white solid and a mixture of regioisomers (5:1, 36 g, 37%). 1 H NMR (300 MHz: CDCl3) δ 6.91 (s, 0.2H), 6.61 (s, 1H), 4.05 (s, 0.6H), 3.98 (s, 3H), 2.49 (s, 3.6H).

[0368] Preparation of Intermediate 33: Methyl 3-cyano-6-methoxy-4-methylpicolinate [ka] To a suspension of 2-chloro-6-methoxy-4-methylnicotinonitrile (5 g, 27 mmol) and Pd(dppf)Cl complex (2.3 g, 2.7 mmol) in MeOH (50 mL) with DCM was added triethylamine (11 mL, 82 mmol). The reaction was purged with carbon monoxide and then heated to 70 °C. The reaction was stirred at 70 °C under a carbon monoxide atmosphere for 20 h. The reaction mixture was allowed to cool to room temperature and filtered through Celite, rinsing with DCM. The filtrate was concentrated in vacuo and directly purified by flash column chromatography (cyclohexane to EtOAc, gradient elution) to afford the title compound as a white solid and a mixture of regioisomers (5:1, 3.9 g, 65%). 1 H NMR (300 MHz: CDCl3) δ 7.64 (s, 0.2H), 6.84 (s, 1H), 4.13 (s, 0.6H), 4.04 (s, 3H), 4.03 (s, 3H), 3.98 (s, 0.6H), 2.59 (s, 0.6H), 2.56 (s, 3H).

[0369] Intermediate 34: Preparation of 2-methoxy-4-methyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one [ka] To a suspension of methyl 3-cyano-6-methoxy-4-methylpicolinate (3.9 g, 19 mmol) in EtOH (80 mL) was added Raney nickel (5 mL) suspended in water. The reaction was then evacuated and placed under a hydrogen atmosphere. The reaction was heated to 40° C. and stirred under a hydrogen atmosphere at 40° C. for 36 hours. The reaction mixture was allowed to cool to room temperature and filtered through Celite, washing with DCM. The filtrate was concentrated in vacuo, filtered, and washed with distilled water. The filtrate was concentrated in vacuo to give the title compound as a white solid (1.5 g, 44%). 1 H NMR (300 MHz: CDCl3) δ 7.47 (s, 1H), 6.74 (s, 1H), 4.33 (s, 2H), 4.05 (s, 3H), 2.34 (s, 3H).

[0370] Preparation of Intermediate 35: tert-Butyl 2-Methoxy-4-methyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate [ka] To a suspension of 2-methoxy-4-methyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (1.5 g, 8.3 mmol) in THF (22 mL) at 0° C. was added 10 M borane dimethyl sulfide complex (4.1 mL, 41 mmol) dropwise. The reaction was heated to 75° C. and stirred at 75° C. for 16 hours. The reaction mixture was cooled to 0° C. and then quenched by the dropwise addition of MeOH (10 mL, 247 mmol), followed by the dropwise addition of 6 M HCl (2.5 mL, 15 mmol). The reaction was then heated to 70° C. and stirred at 70° C. for 2 hours. The reaction was allowed to cool to room temperature and then basified by the addition of 2 M aqueous NaOH. Di-tert-butyl dicarbonate (3.6 g, 17 mmol) was added and the reaction was stirred at room temperature for 48 hours. The reaction mixture was then partitioned between EtOAc and distilled water. The organic layer was separated. The combined organic layers were washed with saturated brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by flash column chromatography (DCM to EtOAc, gradient elution) to give the title compound as a white solid (760 mg, 34%). LC / MS (Table 2, Method A): R t = 1.53 min; m / z = 265 [M+H] + .

[0371] Intermediate 36: Preparation of 4-methyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride [ka] A reaction vessel was charged with tert-butyl 2-methoxy-4-methyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (300 mg, 1.1 mmol) and 6 M HCl in 1,4-dioxane (9.5 mL, 57 mmol). The reaction was stirred at room temperature for 15 minutes and then heated to 100° C. The reaction was stirred at 100° C. for 16 hours. The reaction mixture was allowed to cool to room temperature and then concentrated in vacuo to give the title compound as an off-white solid (213 mg, quantitative). The material was carried on to the next step without characterization.

[0372] Preparation of Intermediate 37: tert-Butyl 4-methyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate [ka] To a suspension of 4-methyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride (289 mg, 1.6 mmol) in DMF (5 mL) and THF (10 mL) was added triethylamine (1.1 mL, 7.8 mmol) and di-tert-butyl dicarbonate (0.71 mL, 3.1 mmol). The reaction was stirred at room temperature for 2 hours. The reaction mixture was then concentrated in vacuo and directly purified by flash column chromatography (DCM to MeOH, gradient elution) to give the title compound as a white solid (300 mg, 77%). LC / MS (Table 2, Method A): R t = 0.98 min; m / z = 251 [M+H] + .

[0373] Preparation of Intermediate 38: tert-Butyl 1-(cyclopropylmethyl)-4-methyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate [ka] To a suspension of tert-butyl 4-methyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (171 mg, 0.68 mmol) and potassium carbonate (283 mg, 2.1 mmol) in MeCN (0.48 mL) was added (iodomethyl)cyclopropane (0.23 mL, 2.7 mmol). The reaction was heated to 115 °C and stirred at 115 °C for 8 h. The reaction mixture was allowed to cool to room temperature and then partitioned between DCM and distilled water. The organic layer was separated. The combined organic layers were washed with saturated brine, dried (MgSO), and concentrated in vacuo. The residue was purified by flash column chromatography (DCM to EtOAc, gradient elution) to afford the title compound (92 mg, 44%) as a white solid. 1 H NMR (300 MHz: CDCl3) δ 6.32 (s, 1H), 4.67 - 4.58 (m, 2H), 4.49 - 4.40 (m, 2H), 3.79 - 3.74 (m, 2H), 2.10 (s, 3H), 1.52 (s, 9H), 1.31 - 1.17 (m, 1H), 0.61 - 0.49 (m, 2H), 0.47 - 0.37 (m, 2H).

[0374] Preparation of Intermediate 39: tert-Butyl 3-chloro-1-(cyclopropylmethyl)-4-methyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate [ka] To a solution of tert-butyl 1-(cyclopropylmethyl)-4-methyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (92 mg, 0.76 mmol) in MeCN (1.2 mL) and DMF (0.6 mL) was added N-chlorosuccinimide (57 mg, 1.4 mmol). The reaction was heated to 55° C. and stirred at 55° C. for 1.5 hours. The reaction mixture was allowed to cool to room temperature and then partitioned between DCM and distilled water. The organic layer was separated. The combined organic layers were washed with saturated brine, dried (NaSO), and concentrated in vacuo. The residue was purified by flash column chromatography (DCM to EtOAc, gradient elution) to give the title compound (59 mg, 58%). LC / MS (Table 2, Method F): t = 1.66 min; m / z = 339 [M+H] + .

[0375] Preparation of Intermediate 40: 3-chloro-1-(cyclopropylmethyl)-4-methyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride [ka] A reaction vessel was charged with tert-butyl 3-chloro-1-(cyclopropylmethyl)-4-methyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (60 mg, 0.18 mmol) and 4 M HCl in 1,4-dioxane (1.3 mL, 5.3 mmol), and the reaction was stirred at room temperature for 2 hours. The reaction mixture was then concentrated in vacuo and azeotroped with toluene to give the title compound as an off-white solid (50 mg, quantitative). The material was carried on to the next step without characterization.

[0376] Example 25 - Synthesis of Compound I-69: 3-chloro-1-(cyclopropylmethyl)-6-(2-(cyclopropylmethyl)thiazole-5-carbonyl)-4-methyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one [ka] To a solution of 3-chloro-1-(cyclopropylmethyl)-4-methyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride (26 mg, 0.095 mmol) and 2-(cyclopropylmethyl)thiazole-5-carboxylic acid (21 mg, 0.11 mmol) in DMF (1.5 mL) was added N,N-diisopropylethylamine (0.058 mL, 0.33 mmol) and HATU (65 mg, 0.17 mmol). The reaction was stirred at room temperature for 0.5 h. The reaction mixture was then partitioned between DCM and aqueous sodium bicarbonate. The organic layer was separated. The combined organic layers were washed with saturated brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by reverse-phase HPLC (Table 3, Method 4, nonlinear gradient from 20% to 80% MeCN) to afford the title compound as an off-white solid (24 mg, 61%). 1 H NMR (400 MHz: DMSO-d6) δ 8.42 (s, 0.5H), 8.38 (s, 0.5H), 5.29 - 5.27 (m, 1H), 5.07 - 5.03 (m, 1H), 4.95 (s, 1H), 4.72 (s, 1H), 3.88 (dd, J=7.0, 15.3 Hz, 2H), 2.93 (d, J=7.0 Hz, 2H), 2.45 (d, J=7.0 Hz, 1H), 2.28 (d, J=3.4 Hz, 3H), 1.33 - 1.22 (m, 1H), 1.19 - 1.11 (m, 1H), 0.64 - 0.58 (m, 2H), 0.52 - 0.41 (m, 3H), 0.36 - 0.33 (m, 2H).nLC / MS (Table 2, Method B): R t = 4.51 min; m / z = 404 [M+H] + .

[0377] Example 26 - Synthesis of additional compounds The following intermediates in Table 10 were prepared from intermediate 37 and the starting materials indicated using reaction protocols similar to those described for I-40. [Table 12]

[0378] Example 27 - Synthesis of additional compounds The following compounds in Table 11 were prepared from the indicated intermediates or starting materials using reaction protocols similar to those described for I-69. [Table 13]

[0379] Example 28 - Synthesis of Compound Intermediate 43: 3-chloro-4-methoxy-1,5-dimethyl-6-(1-(trifluoromethyl)-1H-pyrazole-4-carbonyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one The title compound was prepared according to the following procedure.

[0380] Preparation of Intermediate 42: tert-Butyl 3-chloro-4-methoxy-1,5-dimethyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate [ka] To a solution of tert-butyl 4-methoxy-1,5-dimethyl-2-oxo-5,7-dihydropyrrolo[3,4-b]pyridine-6-carboxylate (164 mg, 0.56 mmol) in MeCN (2.6 mL) and DMF (1.3 mL) was added N-chlorosuccinimide (98 mg, 0.74 mmol). The reaction was warmed to 50° C. and stirred at 50° C. for 20 minutes. The reaction mixture was allowed to cool to room temperature and then partitioned between distilled water and EtOAc. The organic layer was separated. The combined organic layers were washed with 5% aqueous LiCl, saturated brine, dried (NaSO), and concentrated in vacuo. The residue was purified by column chromatography (DCM to EtOAc, gradient elution) to give the title compound (165 mg, 90%) as a white foam. LC / MS (Table 2, Method A): t= 1.37 min; m / z = 329.1 [M+H] +

[0381] Preparation of Intermediate 43: 3-Chloro-4-methoxy-1,5-dimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one Hydrochloride [ka] To a solution of tert-butyl 3-chloro-4-methoxy-1,5-dimethyl-2-oxo-5,7-dihydropyrrolo[3,4-b]pyridine-6-carboxylate (85 mg, 0.259 mmol) in DCM (0.3 mL) was added dropwise 4M HCl in 1,4-dioxane (1.6 mL, 6.5 mmol), and the reaction was stirred at room temperature for 1.5 hours. The reaction mixture was then concentrated in vacuo and azeotroped with MeCN to give the title compound as a white solid (72 mg, quantitative). LC / MS (Table 2, Method A): t = 0.78 min; m / z = 229.0 [M+H] + .

[0382] Example 29 - Synthesis of Compound I-73: 3-chloro-4-methoxy-1,5-dimethyl-6-(1-(trifluoromethyl)-1H-pyrazole-4-carbonyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one [ka] To a solution of 3-chloro-4-methoxy-1,5-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-one hydrochloride (69 mg, 0.26 mmol) and 1-(trifluoromethyl)pyrazole-4-carboxylic acid (51 mg, 0.28 mmol) in DMF (1.4 mL) was added N,N-diisopropylethylamine (0.16 mL, 0.91 mmol) and HATU (108 mg, 0.28 mmol). The reaction was stirred at room temperature for 0.5 h. The reaction mixture was directly purified by reverse-phase HPLC (Table 2, Method 7) to give the title compound as a white solid (3.6 mg, 4%). 1H NMR (400 MHz, DMSO-d6) δ 8.31 - 8.27 (m, 1H), 8.10 - 8.05 (m, 1H), 5.58 - 5.36 (m, 1H), 5.01 - 4.96 (m, 1H), 4.85 - 4.74 (m, 1H), 4.18 - 4.09 (m, 3H), 3.54 - 3.49 (m, 3H), 1.60 - 1.40 (m, 3H). LC / MS (Table 2, Method C): R t = 3.77 min; m / z = 391.2 [M+H] + .

[0383] Example 30 - Synthesis of additional compounds The following compounds in Table 12 were prepared from intermediate 43 and the starting materials indicated using reaction protocols similar to those described for I-73. [Table 14]

[0384] Example 31 - Synthesis of Compound Intermediate 46: (R)-3-chloro-1,4,5-trimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride The title compound was prepared according to the following procedure.

[0385] Intermediate 44: Preparation of (R)-tert-butyl 1,4,5-trimethyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate [ka] A reaction vessel was charged with tert-butyl (2R)-2-methyl-4-oxo-pyrrolidine-1-carboxylate (3.5 g, 18 mmol) and 2 M methylamine in THF (44 mL, 88 mmol), and the reaction was heated to 80° C. The reaction was stirred at 80° C. for 4.5 hours. The reaction mixture was allowed to cool to room temperature and then concentrated in vacuo to provide the crude imine. In a separate reaction vessel, 1-chloro-N,N,2-trimethyl-1-propenylamine (3.3 mL, 25 mmol) was added dropwise to a solution of 2-butynoic acid (2.1 g, 25 mmol) in DCM (84 mL) at 0° C. under a nitrogen atmosphere. The reaction was stirred at 0° C. for 3 hours. The reaction mixture was then added dropwise to a solution of the crude imine and triethylamine (4.7 mL, 34 mmol) in DCM (84 mL). The reaction was stirred at 0° C. under a nitrogen atmosphere for 30 minutes. The reaction was allowed to warm to room temperature and stirred at room temperature for 6 days. The reaction mixture was quenched by the addition of saturated aqueous sodium bicarbonate solution and then partitioned with DCM. The organic layer was separated and passed through a phase separator, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (DCM to EtOAc, gradient elution) to give the title compound as an orange foam (12 g, 22%). LC / MS (Table 2, Method A): R t = 1.21 min; m / z = 279 [M+H] + .

[0386] Intermediate 45: Preparation of (R)-3-chloro-1,4,5-trimethyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate tert-butyl ester [ka] To a solution of tert-butyl (R)-1,4,5-trimethyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (200 mg, 0.72 mmol) in DMF (1.7 mL) and MeCN (3.4 mL) was added N-chlorosuccinimide (124 mg, 0.93 mmol). The reaction was heated to 50° C. and stirred at 50° C. for 1 h. The reaction mixture was allowed to cool to room temperature and then quenched by pouring into distilled water (50 mL). The reaction was stirred for 30 min, filtered, and then partitioned with EtOAc. The organic layer was separated. The combined organic layers were washed with saturated brine, dried (NaSO), and concentrated in vacuo. The residue was purified by flash column chromatography (cyclohexane to EtOAc, gradient elution) to afford the title compound (45 mg, 14%) as a yellow solid. LC / MS (Table 2, Method A): R t = 1.41 min; m / z = 312 [M+H] + .

[0387] Intermediate 46: Preparation of (R)-3-chloro-1,4,5-trimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride [ka] A reaction vessel was charged with (R)-tert-butyl 3-chloro-1,4,5-trimethyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (45 mg, 0.1 mmol) and 4M HCl in 1,4-dioxane (0.5 mL, 2 mmol), and the reaction was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo to give the title compound as a red solid (33 mg, quantitative). LC / MS (Table 2, Method A): t = 0.87 min; m / z = 213 [M+H] + .

[0388] Example 32 - Compound I-76: Synthesis of (R)-3-chloro-1,4,5-trimethyl-6-(1-(trifluoromethyl)-1H-pyrazole-4-carbonyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one [ka] To a solution of 1-(trifluoromethyl)pyrazole-4-carboxylic acid (20 mg, 0.11 mmol) and HATU (42 mg, 0.11 mmol) in DMF (0.75 mL) was added a solution of (R)-3-chloro-1,4,5-trimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride (32 mg, 0.96 mmol) and N,N-diisopropylethylamine (0.059 mL, 0.38 mmol) in DMF (0.75 mL). The reaction was stirred at room temperature for 5 hours. The reaction mixture was then concentrated in vacuo and directly purified by reverse-phase HPLC (Table 3, Method 4) to give the title compound as an off-white solid (23 mg, 65%). 1 H NMR (400 MHz: DMSO-d6) δ 9.10 (s, 0.2H), 9.05 (s, 0.8H), 8.42 (s, 0.2H), 8.37 (s, 0.8H), 5.64 - 5.60 (m, 0.2H), 5.44 - 5.39 (m, 0.8H), 5.23 (dd, J=2.8, 15.4 Hz, 0.8H), 5.04 (d, J=15.2 Hz, 0.8H), 4.93 (d, J=17.2 Hz, 0.2H), 4.81 (dd, J=2.4, 17.3 Hz, 0.2H), 3.47 - 3.45 (m, 3H), 2.31 - 2.28 (m, 3H), 1.43 (d, J=6.1 Hz, 2.4H), 1.27 (d, J=6.1 Hz, 0.6H). LC / MS (Table 2, Method B): R t = 3.68 min; m / z = 375 [M+H] + .

[0389] Example 33 - Synthesis of additional compounds The following compounds in Table 13 were prepared from the indicated intermediate 46 and starting materials using reaction protocols similar to those described for I-76. [Table 15]

[0390] Example 34 - Intermediate 48: Synthesis of (R)-1,3,4,5-tetramethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride The title compound was prepared according to the following procedure.

[0391] Intermediate 47: Preparation of (R)-1,3,4,5-tetramethyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate tert-butyl ester [ka] A reaction vessel was charged with (R)-tert-butyl 3-chloro-1,4,5-trimethyl-2-oxo-5,7-dihydropyrrolo[3,4-b]pyridine-6-carboxylate (715 mg, 2.3 mmol), potassium carbonate (950 mg, 6.9 mmol), Pd(dppf)Cl2 (170 mg, 0.23 mmol), trimethylboroxine (0.48 mL, 3.4 mmol), and solvated with 1,4-dioxane (18 mL). The reaction was evacuated, purged with argon (×3), heated to 100 °C, and stirred at 100 °C for 16 h. The reaction mixture was allowed to cool to room temperature, and trimethylboroxine (0.3 mL) was added, followed by Pd(dppf)Cl2 (85 mg). The reaction was warmed to 100 °C and stirred at 100 °C for 16 h. The reaction mixture was allowed to cool to room temperature, filtered through Celite, and washed with EtOAc. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography (TBME to EtOAc / IMS (3:1), gradient elution) to give the title compound as a brown gum (470 mg, 70%). LC / MS (Table 2, Method F): t = 1.51 min; m / z = 293.2 [M+H] +.

[0392] Intermediate 48: Preparation of (R)-1,3,4,5-tetramethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride [ka] To a solution of (R)-1,3,4,5-tetramethyl-2-oxo-5,7-dihydropyrrolo[3,4-b]pyridine-6-carboxylate tert-butyl (470 mg, 1.5 mmol) in DCM (2 mL) was added dropwise 4M HCl in 1,4-dioxane (9.0 mL, 36 mmol), and the reaction was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated in vacuo and azeotroped with MeCN to give the title compound as a brown solid (395 mg, quantitative). LC / MS (Table 2, Method A): R t = 0.91 min; m / z = 193.1 [M+H] + .

[0393] Example 35 - Synthesis of Compound I-78: (R)-1,3,4,5-tetramethyl-6-(1-(trifluoromethyl)-1H-pyrazole-4-carbonyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one [ka] To a solution of (5R)-1,3,4,5-tetramethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-one hydrochloride (330 mg, 1.4 mmol) in DMF (6 mL) was added N,N-diisopropylethylamine (0.88 mL, 5.1 mmol), followed by a solution of 1-(trifluoromethyl)pyrazole-4-carboxylic acid (286 mg, 1.6 mmol) and HATU (603 mg, 1.6 mmol) in DMF (6 mL). The reaction was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and directly purified by reverse-phase HPLC (Table 3, Method 8) to give the title compound as an off-white solid (247 mg, 48%). 1H NMR (400 MHz: DMSO-d6) δ 9.10 (s, 0.2H), 9.04 (s, 0.8H), 8.42 (s, 0.2H), 8.37 (s, 0.8H), 5.58 - 5.56 (m, 0.2H), 5.39 - 5.32 (m, 0.8H), 5.21 (d, J=15.0 Hz, 0.8H), 4.99 (d, J=14.9 Hz, 0.8H), 4.88 (d, J=16.9 Hz, 0.2H), 4.78 (d, J=16.9 Hz, 0.2H), 3.39 (d, J=4.2 Hz, 3H), 2.14 (d, J=5.9 Hz, 3H), 1.99 (s, 3H), 1.41 (d, J=6.1 Hz, 2.3H), 1.24 (d, J=6.0 Hz, 0.7H). LC / MS (Table 2, Method C): R t = 3.44 min; m / z = 355 [M+H] + .

[0394] Example 36 - Synthesis of Compound Intermediate 54: 4-Methoxy-1,5-dimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one Hydrochloride The title compound was prepared according to the following procedure.

[0395] Preparation of Intermediate 49: 1-(tert-butyl) 3-ethyl 2-methyl-4-oxopyrrolidine-1,3-dicarboxylate [ka] To a solution of ethyl 2-(tert-butoxycarbonylamino)acetate (13 g, 65 mmol) and ethyl trans-2-butenoate (10 mL, 84 mmol) in THF (210 mL) at 0° C., 1 M potassium tert-butoxide in THF (77 mL, 77 mmol) was added dropwise over 20 minutes. The reaction was allowed to warm to room temperature and stirred at room temperature for 16 hours. The reaction mixture was quenched by the addition of 10% aqueous citric acid (75 mL) and then partitioned with EtOAc. The organic layer was separated. The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash column chromatography (cyclohexane to diethyl ether, gradient elution) to give the title compound (11 g, 65%) as a pale yellow oil. LC / MS (Table 2, Method A): R t = 1.42 min; UV only.

[0396] Preparation of Intermediate 50: 1-(tert-butyl) 3-ethyl 2-methyl-4-(methylamino)-2,5-dihydro-1H-pyrrole-1,3-dicarboxylate [ka] To a solution of 1-(tert-butyl) 3-ethyl 2-methyl-4-oxopyrrolidine-1,3-dicarboxylate (5 g, 18 mmol) in acetic acid (23 mL) at 0° C. was added 2 M methylamine in THF (14 mL, 29 mmol). The reaction was allowed to warm to room temperature and stirred at room temperature for 16 hours. The reaction mixture was then partitioned between DCM and saturated aqueous sodium bicarbonate solution. The organic layer was separated. The combined organic layers were washed with saturated brine, passed through a phase separator, and the filtrate was concentrated in vacuo to give the title compound as an orange oil (5.2 g, 99%). LC / MS (Table 2, Method A): R t = 1.74 min; m / z = 285 [M+H] + .

[0397] Preparation of Intermediate 51: 1-(tert-butyl) 3-ethyl 2-methyl-4-(N-methylacetamido)-2,5-dihydro-1H-pyrrole-1,3-dicarboxylate [ka] To a solution of 1-(tert-butyl) 3-ethyl 2-methyl-4-(methylamino)-2,5-dihydro-1H-pyrrole-1,3-dicarboxylate (6.7 g, 24 mmol) in 1,4-dioxane (80 mL) was added sodium hydride (60%, 1.9 g, 47 mmol), and the reaction was stirred at room temperature for 15 minutes. Acetyl chloride (2.5 mL, 35 mmol) was then added, and the reaction mixture was stirred at 40° C. for 3 hours. The reaction mixture was then partitioned between distilled water and EtOAc. The organic layer was separated. The combined organic layers were dried (MgSO4), concentrated in vacuo, and the residue was purified by flash column chromatography (cyclohexane to EtOAc, gradient elution) to give the title compound (4.3 g, 55%) as an oil. 1 H NMR (400 MHz, CDCl3) δ 4.97 - 4.77 (m, 1H), 4.45 - 4.09 (m, 4H), 3.09 - 3.04 (m, 3H), 2.07 - 2.03 (m, 3H), 1.50 - 1.43 (m, 9H), 1.32 - 1.24 (m, 6H).

[0398] Preparation of Intermediate 52: tert-Butyl 4-hydroxy-1,5-dimethyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate [ka] To a solution of 1-(tert-butyl) 3-ethyl 2-methyl-4-(N-methylacetamido)-2,5-dihydro-1H-pyrrole-1,3-dicarboxylate (2.4 g, 7.4 mmol) in THF (72 mL) under a nitrogen atmosphere was added 1 M potassium tert-butoxide in THF (15 mL, 15 mmol), and the reaction was stirred at room temperature for 0.25 h. The reaction mixture was partitioned between distilled water and EtOAc. The aqueous phase was acidified and further partitioned with EtOAc. The organic layer was separated. The combined organic layers were dried (MgSO), concentrated in vacuo, and triturated with diethyl ether to give the title compound as a white solid (1.5 g, 74%). 1 H NMR (400 MHz, CDCl3) δ 6.12 (s, 1H), 5.08 - 4.97 (m, 1H), 4.70 (d, J=15.8 Hz, 1H), 4.58 - 4.49 (m, 1H), 3.43 (s, 3H), 1.54 - 1.46 (m, 12H).

[0399] Preparation of Intermediate 53: tert-Butyl 4-methoxy-1,5-dimethyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate [ka] To a solution of tert-butyl 4-hydroxy-1,5-dimethyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (400 mg, 1.4 mmol) in DMF (13 mL) was added potassium carbonate (296 mg, 2.1 mmol) and iodomethane (0.27 mL, 4.3 mmol). The reaction was stirred at room temperature for 1.75 hours. The reaction mixture was partitioned between distilled water and EtOAc. The organic layer was separated. The combined organic layers were washed with 5% aqueous LiCl, saturated brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by flash column chromatography (DCM to MeOH, gradient elution) to give the title compound (186 mg, 44%) as a white foam. LC / MS (Table 1, Method A): R t= 1.27 min; m / z = 295.0 [M+H] + .

[0400] Preparation of Intermediate 54: 4-Methoxy-1,5-dimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one Hydrochloride [ka] To a solution of tert-butyl 4-methoxy-1,5-dimethyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (20 mg, 0.068 mmol) in DCM (0.10 mL) was added dropwise 4M HCl in 1,4-dioxane (0.42 mL, 1.7 mmol), and the reaction was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and azeotroped with MeCN to give the title compound as a white solid (16 mg, quantitative). LC / MS (Table 1, Method A): R t = 0.64 min; m / z = 195.1 [M+H] + .

[0401] Example 37 - Compound I-79: Synthesis of 4-methoxy-1,5-dimethyl-6-(1-(trifluoromethyl)-1H-pyrazole-4-carbonyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one [ka] To a solution of 4-methoxy-1,5-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-one hydrochloride (16 mg, 0.068 mmol) in DMF (0.25 mL) was added N,N-diisopropylethylamine (0.041 mL, 0.24 mmol), followed by a solution of 1-(trifluoromethyl)pyrazole-4-carboxylic acid (13 mg, 0.075 mmol) and HATU (28 mg, 0.075 mmol) in DMF (0.25 mL). The reaction was stirred at room temperature for 1 hour. The reaction mixture was directly purified by reverse-phase HPLC (Table 3, Method 8) to give the title compound as a white solid (3.4 mg, 14%). 1H NMR (400 MHz: CDCl3) δ 8.28 (d, J=9.3 Hz, 1H), 8.09 (d, J=13.7 Hz, 1H), 5.89 (s, 1H), 5.48 (s, 0.4H), 5.34 (s, 0.6H), 4.97 - 4.92 (m, 1H), 4.83 - 4.75 (m, 1H), 3.82 (s, 3.82 (s, 3H), 3.43 (d, J=12.7 Hz, 3H), 1.53 (d, J=6.4 Hz, 1.5H, obscured by solvent peak), 1.42 (d, J=6.0 Hz, 1.5H). LC / MS (Table 2, Method C): R t = 3.45 min; m / z = 357.3 [M+H] + .

[0402] Example 38 - Synthesis of further compounds The following compounds in Table 14 were prepared from intermediate 54 and the starting materials indicated using reaction protocols similar to those described for I-79. [Table 16]

[0403] Example 39 - Synthesis of Compound Intermediate 58: 4-Methoxy-1,3,5-trimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one Hydrochloride The title compound was prepared according to the following procedure.

[0404] Preparation of Intermediate 55: 1-(tert-butyl) 3-ethyl 2-methyl-4-(N-methylpropionamido)-2,5-dihydro-1H-pyrrole-1,3-dicarboxylate [ka] A reaction vessel was charged with 1-(tert-butyl) 3-ethyl 2-methyl-4-(methylamino)-2,5-dihydro-1H-pyrrole-1,3-dicarboxylate (4.9 g, 17 mmol) and solvated with propionic anhydride (17 mL, 129 mmol). The reaction was heated to 150° C. and stirred at 150° C. for 5 hours. The reaction mixture was allowed to cool to room temperature and then concentrated in vacuo to give the title compound as a dark red oil (6.4 g, quantitative). LC / MS (Table 2, Method A): R t = 1.68 min; m / z = 341 [M+H] + .

[0405] Preparation of Intermediate 56: tert-Butyl 4-hydroxy-1,3,5-trimethyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate [ka] To a solution of 1-(tert-butyl) 3-ethyl 2-methyl-4-(N-methylpropionamido)-2,5-dihydro-1H-pyrrole-1,3-dicarboxylate (6.4 g, 19 mmol) in THF (95 mL) was added potassium tert-butoxide (11 g, 94 mmol), and the reaction was stirred at room temperature for 10 minutes. The reaction mixture was cooled to 0° C. and then quenched by adding TBME (50 mL), 5 M acetic acid in TBME (20 mL), and distilled water (30 mL). The reaction mixture was warmed to room temperature, concentrated in vacuo, and then partitioned with DCM. The organic layer was separated. The combined organic layers were washed with saturated brine, dried (NaSO), and concentrated in vacuo. The residue was purified by flash column chromatography (cyclohexane in IPA, gradient elution) to give the title compound (1.34 g, 24%) as an orange foam. LC / MS (Table 2, Method A): t = 0.69 min; m / z = 298 [M+H] + .

[0406] Preparation of Intermediate 57: tert-Butyl 4-Methoxy-1,3,5-trimethyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate [ka] To a suspension of tert-butyl 4-hydroxy-1,3,5-trimethyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (500 mg, 1.7 mmol) in THF (8 mL) was added trimethyloxonium tetrafluoroborate (502 mg, 3.4 mmol). The reaction was cooled to 0 °C, and sodium hydride (60%, 82 mg, 2.0 mmol) was added portionwise. The reaction was stirred at 0 °C for 1.5 hours. The reaction mixture was then partitioned between EtOAc and distilled water. The organic layer was separated. The combined organic layers were washed with saturated brine, dried (Na SO ), and concentrated in vacuo. The residue was purified by flash column chromatography (cyclohexane in acetone, gradient elution) to give the title compound (200 mg, 38%) as a brown oil. LC / MS (Table 2, Method A): R t = 1.19 min; m / z = 309 [M+H] + .

[0407] Preparation of Intermediate 58: 4-Methoxy-1,3,5-trimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one Hydrochloride [ka] To a solution of tert-butyl 4-methoxy-1,3,5-trimethyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (200 mg, 0.65 mmol) in DCM (1.6 mL) was added 4M HCl in 1,4-dioxane (1.6 mL, 6.5 mmol), and the reaction was stirred at room temperature for 16 hours. The reaction mixture was then concentrated in vacuo to give the title compound as a dark red solid (181 mg, quantitative). LC / MS (Table 2, Method A): t= 0.72 min; m / z = 209 [M+H] + .

[0408] Example 40 - Compound I-82: Synthesis of 4-methoxy-1,3,5-trimethyl-6-(1-(trifluoromethyl)-1H-pyrazole-4-carbonyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one as a racemic mixture of stereoisomers [ka] To a solution of 1-(trifluoromethyl)pyrazole-4-carboxylic acid (81 mg, 0.45 mmol) in DMF (1.25 mL) was added HATU (171 mg, 0.45 mmol), followed by a solution of 4-methoxy-1,3,5-trimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride (100 mg, 0.41 mmol) and N,N-diisopropylethylamine (0.21 mL, 1.23 mmol) in DMF (1.25 mL). The reaction was stirred at room temperature for 1 hour. The reaction mixture was then directly purified by reverse-phase HPLC (Table 3, Method 2) to afford the title compound as an off-white solid (88 mg, 58%). 1 H NMR (400 MHz: DMSO-d6) δ 9.05 (s, 1H), 8.37 (s, 1H), 5.48 - 5.42 (m, 1H), 5.22 - 5.18 (m, 1H), 5.05 - 5.00 (m, 1H), 3.82 (s, 3H), 3.38 (s, 3H), 1.94 (s, 3H), 1.44 (d, J=5.7 Hz, 3H). LC / MS (Table 2, Method C): R t = 3.40 min; m / z = 371 [M+H] + .

[0409] Example 41 - Synthesis of additional compounds The following compounds in Table 15 were prepared from intermediate 58 and the starting materials indicated using reaction protocols similar to those described for I-82. [Table 17]

[0410] Example 42 - Intermediate 59: Synthesis of 4-methoxy-1,3-dimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride [ka] To a solution of tert-butyl 4-methoxy-1,3-dimethyl-2-oxo-5,7-dihydropyrrolo[3,4-b]pyridine-6-carboxylate (100 mg, 0.34 mmol) in DCM (0.2 mL) was added 4M HCl in 1,4-dioxane (2.1 mL, 8.5 mmol). The reaction was stirred at room temperature for 2 hours. The reaction mixture was then concentrated in vacuo to give the title compound as a pink solid (90 mg, quantitative). LC / MS (Table 2, Method A): t = 0.72 min; m / z = 195 [M+H] + .

[0411] Example 43 - Compound I-85: Synthesis of 4-methoxy-1,3-dimethyl-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carbonyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one [ka] To a solution of lithium 1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxylate (39 mg, 0.20 mmol) and N,N-diisopropylethylamine (0.10 mL, 0.59 mmol) in DMF (2 mL) was added HATU (96 mg, 0.25 mmol) and 4-methoxy-1,3-dimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride (45 mg, 0.20 mmol). The reaction was stirred at room temperature for 2 hours. The reaction mixture was then partitioned between EtOAc and saturated aqueous sodium bicarbonate. The organic layer was separated. The combined organic layers were washed with saturated brine, dried (NaSO), and concentrated in vacuo. The residue was purified by reverse-phase HPLC (Table 3, Method 1, nonlinear gradient from 40% to 100% MeOH) to afford the title compound as an off-white solid (40 mg, 55%). 1 H NMR (400 MHz: DMSO-d6) δ 8.53 - 8.49 (m, 1H), 8.15 - 8.10 (m, 1H), 5.29 - 5.09 (m, 4H), 4.89 (s, 1H), 4.83 (s, 1H), 3.94 - 3.92 (m, 3H), 3.43 - 3.41 (m, 3H), 1.91 (s, 3H). LC / MS (Table 2, Method E): R t = 3.07 min; m / z = 371 [M+H] + .

[0412] Example 44 - Synthesis of additional compounds The following compounds in Table 16 were prepared from Intermediate 85 and the starting materials indicated using reaction protocols similar to those described for I-59. [Table 18]

[0413] Example 45 - Synthesis of Compound Intermediate 61: 4-ethoxy-1,3-dimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride The title compound was prepared according to the following procedure.

[0414] Preparation of Intermediate 60: tert-Butyl 4-ethoxy-1,3-dimethyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate [ka] To a suspension of sodium hydride (60%, 80 mg, 2.0 mmol) in THF (10 mL) at 0 °C was added tert-butyl 4-hydroxy-1,3-dimethyl-2-oxo-5,7-dihydropyrrolo[3,4-b]pyridine-6-carboxylate (280 mg, 1.0 mmol), and the reaction was stirred at 0 °C for 15 minutes. The reaction was warmed to room temperature, and triethyloxonium tetrafluoroborate (380 mg, 2.0 mmol) was added. The reaction was stirred at room temperature for 1 hour. The reaction mixture was then partitioned between EtOAc and distilled water. The organic layer was separated. The combined organic layers were washed with saturated brine, dried (NaSO), and concentrated in vacuo. The residue was purified by flash column chromatography (DCM in MeOH, gradient elution) followed by flash column chromatography (EtOAc in IMS, gradient elution) to afford the title compound (74 mg, 18%) as a colorless oil. 1 H NMR (400 MHz: CDCl3) δ 4.66 - 4.53 (m, 4H), 4.09 - 3.96 (m, 2H), 3.49 - 3.42 (m, 3H), 2.06 (d, J=5.9 Hz, 3H), 1.52 (s, 9H), 1.41 - 1.32 (m, 3H).

[0415] Intermediate 61: Preparation of 4-ethoxy-1,3-dimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride [ka] To a solution of tert-butyl 4-ethoxy-1,3-dimethyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (70 mg, 0.23 mmol) in DCM (0.5 mL) was added 4M HCl in 1,4-dioxane (1.4 mL, 5.7 mmol), and the reaction was stirred at room temperature for 1.5 hours. The reaction mixture was then concentrated in vacuo and azeotroped with MeCN to give the title compound as a brown solid (54 mg, 57%). LC / MS (Table 2, Method A): t = 1.33 min; m / z = 209 [M+H] + .

[0416] Example 46 - Compound I-88: Synthesis of 4-ethoxy-1,3-dimethyl-6-(1-(trifluoromethyl)-1H-pyrazole-4-carbonyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one [ka] To a solution of 1-(trifluoromethyl)pyrazole-4-carboxylic acid (30 mg, 0.17 mmol) and N,N-diisopropylethylamine (0.068 mL, 0.39 mmol) in DMF (2 mL) was added HATU (74 mg, 0.20 mmol) and 4-ethoxy-1,3-dimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride (54 mg, 0.13 mmol). The reaction was stirred at room temperature for 1.25 h. The reaction mixture was then partitioned between EtOAc and saturated aqueous sodium bicarbonate. The organic layer was separated. The combined organic layers were washed with saturated brine, dried (NaSO), and concentrated in vacuo. The residue was purified by reverse-phase HPLC (Table 3, Method 4) to afford the title compound (21 mg, 42%) as an off-white solid. 1H NMR (400 MHz: DMSO-d6) δ 9.10 - 9.08 (m, 1H), 8.41 (s, 1H), 5.16 - 5.11 (m, 2H), 4.88 - 4.82 (m, 2H), 4.18 - 4.10 (m, 2H), 3.41 - 3.40 (m, 3H), 1.93 (s, 3H), 1.35 - 1.29 (m, 3H).LC / MS (Table 2, Method E): R t = 3.49 min; m / z = 371 [M+H] + .

[0417] Example 47 - Synthesis of Compound Intermediate 63: 4-(difluoromethoxy)-1,3-dimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride The title compound was prepared according to the following procedure.

[0418] Preparation of Intermediate 62: tert-Butyl 4-(difluoromethoxy)-1,3-dimethyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate [ka] To a suspension of tert-butyl 4-hydroxy-1,3-dimethyl-2-oxo-5,7-dihydropyrrolo[3,4-b]pyridine-6-carboxylate (100 mg, 0.18 mmol) in DMF (0.9 mL) was added cesium carbonate (116 mg, 0.36 mmol), and the reaction was then heated to 100° C. Methyl chlorodifluoroacetate (0.038 mL, 0.36 mmol) was added, and the reaction was stirred at 100° C. for 2.5 hours. The reaction mixture was then partitioned between EtOAc and distilled water. The organic layer was separated. The combined organic layers were washed with saturated brine, dried (NaSO), and concentrated in vacuo. The residue was purified by reverse-phase HPLC (Table 3, Method 8) to give the title compound as a white solid (130 mg, quantitative). LC / MS (Table 2, Method A): R t = 1.79 min; m / z = 331 [M+H] +.

[0419] Preparation of Intermediate 63: 4-(Difluoromethoxy)-1,3-dimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one Hydrochloride [ka] To a solution of tert-butyl 4-(difluoromethoxy)-1,3-dimethyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (70 mg, 0.21 mmol) in DCM (0.5 mL) was added 4M HCl in 1,4-dioxane (1.3 mL, 5.3 mmol). The reaction was stirred at room temperature for 1 hour. The reaction mixture was then concentrated in vacuo and azeotroped with MeCN to give the title compound as a brown solid (59 mg, 99%). LC / MS (Table 2, Method A): t = 1.38 min; m / z = 231 [M+H] + .

[0420] Example 48 - Compound I-89: Synthesis of 4-(difluoromethoxy)-1,3-dimethyl-6-(1-(trifluoromethyl)-1H-pyrazole-4-carbonyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one [ka] To a solution of 4-(difluoromethoxy)-1,3-dimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride (56 mg, 0.21 mmol) and N,N-diisopropylethylamine (0.013 mL, 0.74 mmol) in DMF (0.75 mL) was added a solution of 1-(trifluoromethyl)pyrazole-4-carboxylic acid (44 mg, 0.24 mmol) and HATU (92 mg, 0.24 mmol) in DMF (0.75 mL). The reaction was stirred at room temperature for 30 minutes. The reaction mixture was concentrated in vacuo and directly purified by reverse-phase HPLC (Table 3, Method 4) to give the title compound as an off-white solid (69 mg, 83%).1 H NMR (400 MHz: DMSO-d6) δ 9.11 - 9.07 (m, 1H), 8.43 - 8.37 (m, 1H), 7.38 - 6.96 (m, 1H), 5.24 - 5.22 (m, 1H), 5.01 (t, J=2.4 Hz, 1H), 4.94 (s, 1H), 4.72 (s, 1H), 3.46 (s, 3H), 1.99 (s, 3H).LC / MS (Table 2, Method B): R t = 3.67 min; m / z = 393 [M+H] + .

[0421] Example 49 - Synthesis of Compound Intermediate 64: 1,3-dimethyl-4-(methylthio)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride [ka] A reaction vessel was charged with tert-butyl 1,3-dimethyl-4-methylsulfanyl-2-oxo-5,7-dihydropyrrolo[3,4-b]pyridine-6-carboxylate (330 mg, 1.1 mmol) and 4 M HCl in 1,4-dioxane (5.3 mL, 21 mmol). The reaction was stirred at room temperature for 2 hours. The reaction mixture was then concentrated in vacuo and azeotroped with toluene to give the title compound as a pink solid (264 mg, quantitative). LC / MS (Table 2, Method A): t = 0.79 min; m / z = 211 [M+H] + .

[0422] Example 50 - Compound I-90: Synthesis of 1,3-dimethyl-4-(methylthio)-6-(1-(trifluoromethyl)-1H-pyrazole-4-carbonyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one [ka] To a solution of 1-(trifluoromethyl)pyrazole-4-carboxylic acid (44 mg, 0.24 mmol) in DMF (1 mL) was added HATU (100 mg, 0.26 mmol), triethylamine (0.085 mL, 0.61 mmol), and 1,3-dimethyl-4-(methylthio)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride (50 mg, 0.20 mmol). The reaction was stirred at room temperature for 2 hours. The reaction mixture was then partitioned between DCM and saturated aqueous sodium bicarbonate. The organic layer was separated, dried, and concentrated in vacuo. The residue was directly purified by reverse-phase HPLC (Table 3, Method 4, nonlinear gradient from 20% to 80% MeCN) to afford the title compound as an off-white solid (46 mg, 61%). 1 H NMR (400 MHz: DMSO-d6) δ 9.09 (d, J=4.0 Hz, 1H), 8.40 (td, J=0.7, 11.3 Hz, 1H), 5.19 - 5.18 (m, 1H), 5.06 (t, J=2.4 Hz, 1H), 4.90 (s, 1H), 4.77 (s, 1H), 3.43 (d, J=1.4 Hz, 3H), 2.45 (s, 3H), 2.21 (d, J=5.4 Hz, 3H).LC / MS (Table 2, Method B): R t = 3.91 min; m / z = 373 [M+H] + .

[0423] Example 51 - Synthesis of additional compounds The following compounds in Table 17 were prepared from Intermediate 64 and the starting materials indicated using reaction protocols similar to those described for I-90. [Table 19]

[0424] Example 52 - Synthesis of Compound Intermediate 68: 1,4,5-trimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride The title compound was prepared according to the following procedure.

[0425] Intermediate 65: Preparation of (E)-tert-butyl 2-methyl-4-(methylimino)pyrrolidine-1-carboxylate [ka] A reaction vessel was charged with tert-butyl 2-methyl-4-oxo-pyrrolidine-1-carboxylate (5 g, 25 mmol) and dissolved in 2 M methylamine in THF (63 mL, 125 mmol). The reaction was heated to 80° C. and stirred at 80° C. for 18 hours. The reaction mixture was concentrated in vacuo to give the title compound as a yellow oil (5.3 g, quantitative). The material was carried on to the next step without characterization.

[0426] Preparation of Intermediate 66: tert-Butyl 2-methyl-4-(N-methylbut-2-ynamido)-2,5-dihydro-1H-pyrrole-1-carboxylate [ka] To a solution of but-2-ynoyl chloride (2.6 g, 25 mmol) in DCM (60 mL) at 0° C. under a nitrogen atmosphere, tert-butyl (E)-2-methyl-4-(methylimino)pyrrolidine-1-carboxylate (5.3 g, 25 mmol) and triethylamine (6.9 mL, 50 mmol) were added dropwise. The reaction was stirred at 0° C. for 30 minutes. The reaction was allowed to warm to room temperature and stirred at room temperature for 5.5 days. The reaction mixture was then partitioned into saturated aqueous sodium bicarbonate, passed through a phase separator, and the filtrate concentrated in vacuo. The residue was purified by flash column chromatography (DCM to MeOH, gradient elution) followed by reverse-phase HPLC (Table 3, Method 2, nonlinear gradient from 10% to 90% MeCN) to afford the title compound as a white solid (976 mg, 14%). LC / MS (Table 2, Method A): R t = 1.20 min; m / z = 279 [M+H] + .

[0427] Intermediate 67: Preparation of tert-butyl 1,4,5-trimethyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate [ka] To a solution of tert-butyl 2-methyl-4-(N-methylbut-2-ynamido)-2,5-dihydro-1H-pyrrole-1-carboxylate (976 mg, 3.5 mmol) in DCM (35 mL) was added silver tetrafluoroborate (34 mg, 0.18 mmol) and chloro(triphenylphosphine)gold (87 mg, 0.18 mmol). The reaction was stirred at room temperature for 16 hours. The reaction was heated to reflux and stirred at reflux for 27.5 hours. The reaction mixture was then concentrated in vacuo and directly purified by flash column chromatography (DCM to MeOH, gradient elution) to afford the title compound as a brown gum (750 mg, 77%). LC / MS (Table 2, Method A): R t = 1.20 min; m / z = 279 [M+H] + .

[0428] Intermediate 68: Preparation of 1,4,5-trimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride [ka] A reaction vessel was charged with tert-butyl 1,4,5-trimethyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (0.049 mL, 0.37 mmol) and 4 M HCl in 1,4-dioxane (5.0 mL, 20 mmol). The reaction was stirred at room temperature for 1 hour. The reaction mixture was then concentrated in vacuo to give the title compound as a beige solid (80 mg, quantitative). LC / MS (Table 2, Method A): t = 0.56 min; m / z = 179 [M+H] + .

[0429] Example 53 - Compound I-92: Synthesis of 1,4,5-trimethyl-6-(1-(trifluoromethyl)-1H-pyrazole-4-carbonyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one [ka] To a solution of 1,4,5-trimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride (80 mg, 0.37 mmol) and 1-(trifluoromethyl)pyrazole-4-carboxylic acid (81 mg, 0.45 mmol) in DMF (2 mL) was added N,N-diisopropylethylamine (0.23 mL, 1.3 mmol) and HATU (213 mg, 0.56 mmol). The reaction was stirred at room temperature for 2 h. The reaction mixture was then partitioned between DCM and saturated aqueous sodium bicarbonate. The organic layer was separated. The combined organic layers were washed with saturated brine, dried (NaSO), and concentrated in vacuo. The residue was purified by SFC purification (Table 3, Method 9) to give the title compound of unknown absolute configuration—stereoisomer 1 (10 mg, 8%) as an off-white solid. 1 H NMR (300 MHz: DMSO-d6) δ 9.10 (s, 0.2H), 9.06 (s, 0.8H), 8.43 (s, 0.2H), 8.38 (s, 0.8H), 6.21 (s, 1H), 5.60 - 5.57 (m, 0.2H), 5.38 - 5.32 (m, 0.8H), 5.23 (dd, J=2.6, 15.3 Hz, 0.8H), 5.02 (d, J=15.3 Hz, 0.8H), 4.90 (d, J=17.3 Hz, 0.2H), 4.83 - 4.78 (m, 0.2H), 3.37 (d, J=5.1 Hz, 3H), 2.18 (s, 3H), 1.44 (d, J=6.0 Hz, 2.4H), 1.26 (d, J=6.1 Hz, 0.6H).LC / MS (Table 2, Method B): R t = 3.23 min; m / z = 341 [M+H] + .

[0430] Example 54 - Synthesis of additional compounds The following compounds in Table 18 were prepared from intermediate 68 and the starting materials indicated using reaction protocols similar to those described for I-92. [Table 20]

[0431] Example 55 - Synthesis of Compound Intermediate 69: 1,4-dimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride [ka] A reaction vessel was charged with tert-butyl 1,4-dimethyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (606 mg, 2.3 mmol) and 4 M HCl in 1,4-dioxane (14 mL, 57 mmol) was added at 0° C. The reaction was allowed to warm to room temperature and stirred at room temperature for 1.5 hours. The reaction mixture was concentrated in vacuo and azeotroped with toluene to afford the title compound as an off-white solid (540 mg, quantitative). 1 H NMR (400 MHz: DMSO-d6) δ 0.35 - 10.35 (m, 2H), 6.23 (s, 1H), 4.58 (s, 2H), 4.34 (t, J=5.3 Hz, 2H), 3.34 (s, 3H), 2.11 (s, 3H). LC / MS (Table 2, Method A): R t = 0.39 min; m / z = 165 [M+H] + .

[0432] Example 56 - Compound I-104: Synthesis of 1,4-dimethyl-6-(1-methyl-1H-pyrazole-4-carbonyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one [ka] To a solution of 1,4-dimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride (40 mg, 0.17 mmol), 1-methyl-1H-pyrazole-4-carboxylic acid (26 mg, 0.20 mmol), and HATU (116 mg, 0.31 mmol) in DCM (1.5 mL) was added N,N-diisopropylethylamine (0.10 mL, 0.59 mmol). The reaction was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated in vacuo and directly purified by reverse-phase HPLC (Table 3, Method 5, nonlinear gradient from 20% to 80% MeOH) to afford the title compound as an off-white solid (35 mg, 75%). 1 H NMR (400 MHz: DMSO-d6) δ 8.36 (d, J=8.3 Hz, 1H), 7.95 (d, J=6.3 Hz, 1H), 6.20 (s, 1H), 5.11 - 5.08 (m, 1H), 4.88 - 4.82 (m, 2H), 4.60 (s, 1H), 3.92 (s, 3H), 3.39 (d, J=6.9 Hz, 3H), 2.15 (d, J=5.0 Hz, 3H). LC / MS (Table 2, Method E): R t = 2.2 min; m / z = 273 [M+H] + .

[0433] Example 57 - Synthesis of Compound Intermediate 74: 1,4,7-trimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride The title compound was prepared according to the following procedure.

[0434] Preparation of Intermediate 70: 2-acetyl-6-methoxy-4-methylnicotinonitrile [ka] A reaction vessel was charged with 2-chloro-6-methoxy-4-methylnicotinonitrile (1.3 g, 7.2 mmol), PdCl(PPh) (354 mg, 0.51 mmol), tributyl(1-ethoxyvinyl)tin (2.9 mL, 8.7 mmol), and toluene (11 mL). The reaction was evacuated and purged with argon (×3) and then heated to 115 °C. The reaction was stirred at 115 °C under a nitrogen atmosphere for 2 hours. The reaction mixture was cooled to 0 °C and quenched by the dropwise addition of 6 M HCl (2.5 mL). The reaction was allowed to cool to room temperature and stirred at room temperature for 20 minutes. The reaction mixture was cooled to 0 °C and then basified by the addition of 6 M aqueous NaOH. The reaction was allowed to cool to room temperature, stirred at room temperature for 30 minutes, filtered through Celite, and washed with EtOAc. The filtrate was partitioned between EtOAc and distilled water. The organic layer was separated. The combined organic layers were washed with saturated brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by flash column chromatography (cyclohexane to EtOAc, gradient elution) to give the title compound as a white solid (918 mg, 67%). LC / MS (Table 2, Method A): R t = 1.26 min; m / z = 191 [M+H] + .

[0435] Intermediate 71: Preparation of 2-methoxy-4,7-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine [ka] To a suspension of 2-acetyl-6-methoxy-4-methylnicotinonitrile (800 mg, 4.2 mmol) in EtOH (24 mL) was added Raney nickel (0.25 g, 4.2 mmol) suspended in water. The reaction was then evacuated and placed under a hydrogen atmosphere. The reaction was heated to 40° C. and stirred under a hydrogen atmosphere at 40° C. for 16 hours. The reaction mixture was allowed to cool to room temperature and filtered through Celite, washing with distilled water. The filtrate was concentrated in vacuo to give the title compound as a pink oil (420 mg, 44%). LC / MS (Table 2, Method A): R t = 0.98 min; m / z = 179 [M+H]+ .

[0436] Preparation of Intermediate 72: tert-Butyl 2-Methoxy-1,4,7-trimethyl-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate [ka] To a solution of 2-methoxy-4,7-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine (420 mg, 2.4 mmol) in 1,4-dioxane (6 mL) and distilled water (6 mL) was added sodium bicarbonate (396 mg, 4.7 mmol) and di-tert-butyl dicarbonate (617 mg, 2.8 mmol). The reaction was stirred at room temperature for 16 hours. The reaction mixture was then partitioned between EtOAc and distilled water. The organic layer was separated. The combined organic layers were washed with saturated brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by flash column chromatography (cyclohexane to EtOAc, gradient elution) to give the title compound (350 mg, 77%) as a yellow oil. LC / MS (Table 2, Method A): R t = 1.67 min; m / z = 279 [M+H] + .

[0437] Preparation of Intermediate 73: tert-Butyl 1,4,7-trimethyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate [ka] A reaction vessel was charged with tert-butyl 2-methoxy-1,4,7-trimethyl-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (335 mg, 1.2 mmol) and potassium acetate (354 mg, 3.6 mmol) and solvated with MeCN (7 mL) under a nitrogen atmosphere. Following this, iodomethane (0.75 mL, 12 mmol) was added, and the reaction was then heated to 80°C. The reaction was stirred at 80°C for 16 hours. The reaction mixture was allowed to cool to room temperature and filtered through Celite, washing with EtOAc. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (DCM to MeOH, gradient elution) followed by reverse-phase HPLC (Table 3, Method 8, nonlinear gradient from 0% to 95% MeCN) to afford the title compound as a white solid (198 mg, 59%). LC / MS (Table 2, Method A): R t = 1.20 min; m / z = 279 [M+H] + .

[0438] Intermediate 74: Preparation of 1,4,7-trimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride [ka] To a solution of tert-butyl 1,4,7-trimethyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (195 mg, 0.70 mmol) in 1,4-dioxane (2 mL) was added 4 M HCl in 1,4-dioxane (3.5 mL, 14 mmol), and the reaction was stirred at room temperature for 2 hours. The reaction mixture was then concentrated in vacuo to give the title compound as a white solid (210 mg, quantitative). The material was carried on to the next step without characterization.

[0439] Example 58 - Compound I-107: Synthesis of 1,4,7-trimethyl-6-(1-methyl-1H-pyrazole-4-carbonyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one [ka] To a solution of 1-methyl-1H-pyrazole-4-carboxylic acid (68 mg, 0.54 mmol) in DMF (1 mL) was added HATU (279 mg, 0.73 mmol), followed by a solution of 1,4,7-trimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride (105 mg, 0.49 mmol) and N,N-diisopropylethylamine (0.30 mL, 1.7 mmol) in DMF (2.5 mL). The reaction was stirred at room temperature for 16 hours. The reaction mixture was directly purified by reverse-phase HPLC (Table 3, Method 8, nonlinear gradient from 5% to 50% MeCN) to afford the title compound as an off-white solid (74 mg, 53%). 1 H NMR (400 MHz: DMSO-d6) δ 8.34 (s, 0.2H), 8.29 (s, 0.8H), 7.97 (s, 0.2H), 7.89 (s, 0.8H), 6.19 (s, 1H), 5.66 - 5.64 (m, 0.2H), 5.54 - 5.48 (m, 0.8H), 4.90 (dd, J=3.0, 12.7 Hz, 0.8H), 4.72 (d, J=12.6 Hz, 0.8H), 4.64 (d, J=12.7 Hz, 0.2H), 4.47 (d, J=16.3 Hz, 0.2H), 3.90 (s, 3H), 3.40 (d, LC / MS (Table 2, Method C): R t = 2.22 min; m / z = 287 [M+H] + .

[0440] Example 59 - Synthesis of additional compounds The following compounds in Table 19 were prepared from intermediate 74 and the starting materials indicated using reaction protocols similar to those described for I-105. [Table 21]

[0441] Example 60 - Synthesis of Compound Intermediate 76: 3-chloro-1,4,7-trimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride The title compound was prepared according to the following procedure.

[0442] Preparation of Intermediate 75: tert-Butyl 3-chloro-1,4,7-trimethyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate [ka] To a solution of tert-butyl 1,4,7-trimethyl-2-oxo-5,7-dihydropyrrolo[3,4-b]pyridine-6-carboxylate (0.40 g, 1.4 mmol) in MeCN (6.7 mL) and DMF (3.3 mL) was added N-chlorosuccinimide (0.25 g, 1.9 mmol). The reaction was warmed to 50° C. and stirred at 50° C. for 20 minutes. The reaction mixture was allowed to cool to room temperature and then partitioned between distilled water and EtOAc. The organic layer was separated. The combined organic layers were washed with 5% LiCl solution, saturated brine, dried (NaSO), and concentrated in vacuo. The residue was purified by flash column chromatography (cyclohexane to IPA, gradient elution) to give the title compound (355 mg, 79%) as a yellow oil. LC / MS (Table 2, Method A): R t = 1.50 min; m / z = 313 [M+H] + .

[0443] Preparation of Intermediate 76: 3-Chloro-1,4,7-trimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one Hydrochloride [ka] To a solution of tert-butyl 3-chloro-1,4,7-trimethyl-2-oxo-5,7-dihydropyrrolo[3,4-b]pyridine-6-carboxylate (355 mg, 1.1 mmol) in DCM (5 mL) was added 4M HCl in 1,4-dioxane (5.7 mL, 23 mmol), and the reaction was stirred at room temperature for 4 days. The reaction mixture was filtered, washed with DCM, and concentrated in vacuo to give the title compound as a purple solid (246 mg, 87%). LC / MS (Table 2, Method A): t = 0.77 min; m / z = 213 [M+H] + .

[0444] Example 61 - Compound I-108: Synthesis of 3-chloro-1,4,7-trimethyl-6-(1-(trifluoromethyl)-1H-pyrazole-4-carbonyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one [ka] To a solution of 1-(trifluoromethyl)pyrazole-4-carboxylic acid (95 mg, 0.53 mmol) in DMF (1.5 mL) was added HATU (201 mg, 0.53 mmol), followed by a solution of 3-chloro-1,4,7-trimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-one hydrochloride (120 mg, 0.48 mmol) and N,N-diisopropylethylamine (0.29 mL, 1.7 mmol) in DMF (1.5 mL). The reaction was stirred at room temperature for 16 h. The reaction mixture was purified directly by reverse-phase HPLC (Table 3, Method 8, nonlinear gradient from 5% to 98% MeCN) followed by SFC purification (Table 3, Method 7) to afford the title compound of unknown absolute configuration - stereoisomer 1 as an off-white solid (49 mg, 27%). 1H NMR (400 MHz: DMSO-d6) δ 9.04 (s, 1H), 8.37 (s, 1H), 5.61 - 5.53 (m, 1H), 5.03 (dd, J=4.2, 12.6 Hz, 1H), 4.84 (d, J=12.1 Hz, 1H), 3.48 (s, 3H), 2.25 (s, 3H), 1.50 (d, J=5.3 Hz, 3H). LC / MS (Table 2, Method B): R t = 3.75 min; m / z = 375.2 [M+H] + .

[0445] Example 62 - Synthesis of additional compounds The following compounds in Table 20 were prepared from Intermediate 76 and the starting materials indicated using reaction protocols similar to those described for I-108. [Table 22]

[0446] Example 63 - Intermediate 79: Synthesis of 1,4-dimethyl-3-(trifluoromethyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride The title compound was prepared according to the following procedure.

[0447] Preparation of Intermediate 77: tert-Butyl 3-iodo-1,4-dimethyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate [ka] To a solution of tert-butyl 1,4-dimethyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (200 mg, 0.76 mL) in DMF (2 mL) and MeCN (4 mL) was added N-iodosuccinimide (238 mg, 1.1 mmol), and the reaction was heated to 50° C. The reaction was stirred at 50° C. for 1 hour. The reaction mixture was then partitioned between EtOAc and distilled water. The organic layer was separated. The combined organic layers were washed with saturated brine, dried (NaSO), and concentrated in vacuo. The residue was purified by flash column chromatography (cyclohexane to EtOAc, gradient elution) to give the title compound (268 mg, 72%) as a yellow oil. LC / MS (Table 2, Method F): t = 1.36 min; m / z = 391 [M+H] + .

[0448] Preparation of Intermediate 78: tert-Butyl 1,4-dimethyl-2-oxo-3-(trifluoromethyl)-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate [ka] To a solution of tert-butyl 3-iodo-1,4-dimethyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (268 mg, 0.69 mmol) and copper(I) iodide (157 mg, 0.82 mmol) in DMF (6.7 mL) was added methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (0.10 mL, 0.82 mmol), and the reaction was heated to 75 °C. The reaction was stirred at 75 °C for 26 h. The reaction mixture was allowed to cool to room temperature and then partitioned between EtOAc and distilled water. The organic layer was separated. The combined organic layers were washed with saturated brine, dried (NaSO), and concentrated in vacuo. The residue was purified by flash column chromatography (cyclohexane to EtOAc, gradient elution) to afford the title compound (112 mg, 49%) as a pale yellow solid. LC / MS (Table 2, Method F): R t= 1.37 min; m / z = 333 [M+H] + .

[0449] Preparation of Intermediate 79: 1,4-Dimethyl-3-(trifluoromethyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one Hydrochloride [ka] A reaction vessel was charged with tert-butyl 1,4-dimethyl-2-oxo-3-(trifluoromethyl)-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (112 mg, 0.34 mmol) at 0° C., and 4 M HCl in 1,4-dioxane (2.1 mL, 8.4 mmol) was added. The reaction was allowed to warm to room temperature and stirred at room temperature for 18 hours. The reaction mixture was then concentrated in vacuo and azeotroped with toluene to give the title compound as a beige solid (85 mg, 93%). LC / MS (Table 2, Method A): t = 0.82 min; m / z = 233 [M+H] + .

[0450] Example 64 - Compound I-110: Synthesis of 1,4-dimethyl-6-(1-methyl-1H-pyrazole-4-carbonyl)-3-(trifluoromethyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one [ka] To a solution of 1,4-dimethyl-3-(trifluoromethyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride (40 mg, 0.15 mmol), 1-methyl-1H-pyrazole-4-carboxylic acid (23 mg, 0.18 mmol), and HATU (102 mg, 0.27 mmol) in DCM (1 mL) was added N,N-diisopropylethylamine (0.091 mL, 0.52 mmol). The reaction was stirred at room temperature for 1 hour. The reaction mixture was then partitioned between EtOAc and distilled water. The organic layer was separated. The combined organic layers were washed with saturated brine, dried (NaSO), and concentrated in vacuo. The residue was purified by reverse-phase HPLC (Table 3, Method 1) to give the title compound as an off-white solid (25 mg, 48%). 1 H NMR (300 MHz: DMSO-d6) δ 8.42 (s, 1H), 8.00 (s, 1H), 5.22 (s, 1H), 4.99 - 4.95 (m, 2H), 4.72 (s, 1H), 3.96 (s, 3H), 3.48 (d, J=9.1 Hz, 3H), 2.39 - 2.33 (m, 3H). LC / MS (Table 2, Method B): R t = 3.07 min; m / z = 341 [M+H] + .

[0451] Example 65 - Synthesis of Compound Intermediate 81: 1,3,4-trimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride The title compound was prepared according to the following procedure.

[0452] Intermediate 80: Preparation of tert-butyl 1,3,4-trimethyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate [ka] A reaction vessel was charged with tert-butyl 3-chloro-1,4-dimethyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (4.6 g, 15 mmol), potassium carbonate (6.4 g, 46 mmol), trimethylboroxine (3.2 mL, 23 mmol), and Pd(dppf)Cl (1.2 g, 1.6 mmol) and solvated with 1,4-dioxane (120 mL). The reaction was evacuated and purged with argon (×3) and then heated to 100 °C. The reaction was stirred at 100 °C under a nitrogen atmosphere for 18 hours. The reaction mixture was allowed to cool to room temperature and filtered through Celite, rinsing with EtOAc. The filtrate was concentrated in vacuo and purified by flash column chromatography (TBME to EtOAc:IMS 3:1, gradient elution) to give the title compound as a pale yellow solid (3.5 g, 80%). LC / MS (Table 2, Method F): t = 1.45 min; m / z = 279 [M+H] + .

[0453] Intermediate 81: Preparation of 1,3,4-trimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride [ka] To a solution of tert-butyl 1,3,4-trimethyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (3.5 g, 13 mmol) in DCM (50 mL) was added 4 M HCl in 1,4-dioxane (60 mL, 240 mmol) and the reaction was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and then triturated with diethyl ether to give the title compound as a pink solid (2.5 g, 91%). LC / MS (Table 2, Method A): R t = 0.72 min; m / z = 179 [M+H] + .

[0454] Example 66 - Compound I-111: Synthesis of 6-(2-cyclopropylbenzo[d]thiazole-6-carbonyl)-1,3,4-trimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one [ka] To a solution of lithium 2-cyclopropylbenzo[d]thiazole-6-carboxylate (33 mg, 0.15 mmol), N,N-diisopropylethylamine (0.073 mL, 0.42 mmol), and HATU (69 mg, 0.18 mmol) in DMF (1.5 mL) was added 1,3,4-trimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride (30 mg, 0.14 mmol). The reaction was stirred at room temperature for 2.5 hours. The reaction mixture was then partitioned between DCM and saturated aqueous sodium bicarbonate. The organic layer was separated. The combined organic layers were washed with saturated brine, dried (NaSO), and concentrated in vacuo. The residue was purified by reverse-phase HPLC (Table 3, Method 4) to afford the title compound (21 mg, 39%) as an off-white solid. 1 H NMR (400 MHz: DMSO-d6) δ 8.32 (dd, J=1.4, 3.5 Hz, 1H), 7.94 - 7.92 (m, 1H), 7.69 (dd, J=1.8, 8.4 Hz, 1H), 4.95 - 4.89 (m, 2H), 4.75 - 4.66 (m, 2H), 3.43 (s, 1.5H), 3.24 (s, 1.5H), 2.62 - 2.55 (m, 1H), 2.14 - 2.13 (m, 1.5H), 2.01 - 1.96 (m, 4.5H), 1.32 - 1.26 (m, 2H), 1.25 - 1.16 (m, 2H). LC / MS (Table 1, Method B): R t = 3.67 min; m / z = 380 [M+H] + .

[0455] Example 67 - Synthesis of additional compounds The following compounds in Table 21 were prepared from Intermediate 81 and the starting materials indicated using reaction protocols similar to those described for I-111. [Table 23]

[0456] Example 68 - Synthesis of Compound Intermediate 83: 3-Fluoro-1,4-dimethyl-6-(1-(trifluoromethyl)-1H-pyrazole-4-carbonyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one The title compound was prepared according to the following procedure.

[0457] Preparation of Intermediate 82: tert-Butyl 3-fluoro-1,4-dimethyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate [ka] To a solution of tert-butyl (Z)-3-(methylimino)pyrrolidine-1-carboxylate (5.4 g, 27 mmol) in toluene (22 mL) was added ethyl 2-fluoroacetoacetate (3.9 mL, 31 mmol) and triethylamine (7.6 mL, 55 mmol). The reaction was evacuated, purged with argon (x3), and heated to 110°C. The reaction was stirred at 110°C for 17 hours. The reaction mixture was allowed to cool to room temperature and then concentrated in vacuo. The residue was directly purified by flash column chromatography (DCM to MeCN, gradient elution) to afford the title compound as a pale yellow solid (713 mg, 9%). LC / MS (Table 2, Method A): R t = 1.33 min; m / z = 283 [M+H] + .

[0458] Preparation of Intermediate 83: 3-Fluoro-1,4-dimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one Hydrochloride [ka] To a solution of tert-butyl 3-fluoro-1,4-dimethyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (710 mg, 2.5 mmol) in DCM (0.5 mL) was added 4M HCl in 1,4-dioxane (16 mL, 63 mmol), and the reaction was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and azeotroped with MeCN to give the title compound as a white solid (578 mg, quantitative). LC / MS (Table 2, Method B): R t = 0.53 min; m / z = 183 [M+H] + .

[0459] Example 69 - Compound I-113: Synthesis of 3-fluoro-1,4-dimethyl-6-(1-(trifluoromethyl)-1H-pyrazole-4-carbonyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one [ka] To a solution of 1-(trifluoromethyl)pyrazole-4-carboxylic acid (36 mg, 0.20 mmol) in DMF (0.75 mL) was added HATU (77 mg, 0.20 mmol), followed by a solution of 3-fluoro-1,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-one; hydrochloride (40 mg, 0.18 mmol) and N,N-diisopropylethylamine (0.11 mL, 0.64 mmol) in DMF (0.75 mL). The reaction was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and directly purified by reverse-phase HPLC (Table 3, Method 5) to give the title compound as an off-white solid (30 mg, 46%). 1 H NMR (400 MHz: DMSO-d6) δ 9.09 - 9.05 (m, 1H), 8.39 (s, 1H), 5.16 - 4.95 (m, 2H), 4.86 - 4.66 (m, 2H), 3.46 - 3.43 (m, 3H), 2.15 - 2.13 (m, 3H). LC / MS (Table 1, Method E): R t= 3.09 min; m / z = 345.2 [M+H] + .

[0460] Example 70 - Synthesis of Compound Intermediate 86: (R)-3-fluoro-1,4,5-trimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride The title compound was prepared according to the following procedure.

[0461] Intermediate 84: Preparation of (R,Z)-tert-butyl 2-methyl-4-(methylimino)pyrrolidine-1-carboxylate [ka] A reaction vessel was charged with tert-butyl (2R)-2-methyl-4-oxo-pyrrolidine-1-carboxylate (220 mg, 1.1 mmol) and solvated with 2 M methylamine in THF (1.1 mL, 2.2 mmol). The reaction was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo to give the title compound as a yellow oil (240 mg, quantitative). The material was carried on to the next step without characterization.

[0462] Intermediate 85: Preparation of (R)-tert-butyl 3-fluoro-1,4,5-trimethyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate [ka] To a solution of tert-butyl (4E)-2-methyl-4-methylimino-pyrrolidine-1-carboxylate (0.23 g, 1.1 mmol) in toluene (1.4 mL) was added triethylamine (301 uL, 2.2 mmol) and ethyl 2-fluoroacetoacetate (0.16 mL, 1.24 mmol). The reaction was warmed to 120 °C and stirred at 120 °C for 16 hours. The reaction mixture was allowed to cool to room temperature and then partitioned between EtOAc and saturated sodium bicarbonate. The organic layer was separated. The combined organic layers were washed with saturated brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by flash column chromatography (DCM to EtOAc, gradient elution) to give the title compound (37 mg, 12%) as a yellow solid. LC / MS (Table 1, Method F): R t = 1.42 min; m / z = 297.2 [M+H] + .

[0463] Intermediate 86: Preparation of (R)-3-fluoro-1,4,5-trimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride [ka] To a solution of tert-butyl (5R)-3-fluoro-1,4,5-trimethyl-2-oxo-5,7-dihydropyrrolo[3,4-b]pyridine-6-carboxylate (17 mg, 0.057 mmol) in DCM (0.2 mL) was added 4M HCl in 1,4-dioxane (0.36 mL, 1.4 mmol), and the reaction was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and azeotroped with MeCN to give the title compound as a brown solid (14 mg, quantitative). LC / MS (Table 2, Method A): t = 0.68 min; m / z = 197.1 [M+H] +

[0464] Example 71 - Synthesis of Compound I-114: (R)-3-fluoro-1,4,5-trimethyl-6-(1-(trifluoromethyl)-1H-pyrazole-4-carbonyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one [ka] To a solution of (5R)-3-fluoro-1,4,5-trimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-one hydrochloride (16 mg, 0.067 mmol) in DMF (0.5 mL) was added N,N-diisopropylethylamine (0.041 mL, 0.24 mmol), followed by a solution of 1-(trifluoromethyl)pyrazole-4-carboxylic acid (13 mg, 0.074 mmol) and HATU (28 mg, 0.074 mmol) in DMF (0.5 mL). The reaction was stirred at room temperature for 1 hour. The reaction mixture was directly purified by reverse-phase HPLC (Table 3, Method 8) to give the title compound as an off-white solid (13 mg, 54%). 1 H NMR (400 MHz: CDCl3) δ 8.33 - 8.28 (m, 1H), 8.09 - 8.07 (m, 1H), 5.54 - 5.51 (m, 0.7H), 5.31 - 5.29 (m, 0.3H), 4.99 - 4.96 (m, 1H), 4.83 - 4.78 (m, 1H), 3.56 - 3.50 (m, 3H), 2.20 (s, 3H),1.56 - 1.54 (m, 2H),1.45 (d, J=5.9 Hz, 1H). LC / MS (Table 2, Method D): R t = 3.26 min; m / z = 359.6 [M+H] + .

[0465] Example 72 - Compound characterization Physical characterization data for exemplary compounds is provided in Table 22 below. [Table 24-1] [Table 24-2] [Table 24-3] [Table 24-4] [Table 24-5] [Table 24-6] [Table 24-7] [Table 24-8] [Table 24-9]

[0466] Example 73 - Activation of Muscarinic Acetylcholine Receptors Exemplary compounds were tested for their ability to activate muscarinic acetylcholine receptors. The experimental procedures and results are described below.

[0467] Part I - Experimental Procedure for Human and Rat M4 PAM pERK Assays Chinese hamster ovary (CHO) cells expressing either the hM4 or rM4 receptor were bulked up in culture and then frozen in assay-ready vials (5 × 10 6 The day before the assay, vial(s) were thawed and cells were seeded into 384-well white proxy plates at 1000 / well for hM4 cells and 2000 / well for rM4 cells in 10 μL of growth medium (Ham's / F12 with Glutamax and 10% FCS) and incubated overnight at 37°C / 5% CO2.

[0468] The following morning, the growth medium was removed by "shaking" over a waste container, the inverted plate was tapped against a tissue, and then replaced with 10 μL of wash medium (Ham's / F12 with Glutamax and 8 mM HEPES, NB: serum-free). The wash medium was then similarly removed and replaced with 8 μL / well of serum-free medium. The plate was then re-incubated at 37°C / 5% CO2 for an additional 4 hours.

[0469] Test compounds were solubilized in DMSO to 10 mM, and the acoustic dispensing and compound management group prepared compound addition plates consisting of duplicate 10-point concentration-response curves (CRCs) (top concentration 10 μM, 1 / 2 log dilution series).

[0470] After 4 hours of incubation in serum-free medium, EC 20 A 4 μL aliquot of a 3x compound solution containing acetylcholine (final concentration 10 nM) was added to the cell plate using a 384-well plate, followed by plate transfer. The plate lid was then replaced, and the cells were incubated for 5 minutes at 37°C / 5% CO2. After this final incubation, all cellular processes were stopped by adding 4 μL / well of lysis and blocking buffer, and the plate was incubated for 30 minutes at room temperature on an orbital shaker (gentle setting). A final addition of 4 μL / well of antibody detection mix containing both Europium-Cryptate (donor) and d2 (acceptor) tagged detection components was then followed by a further 2 hours of incubation at room temperature. The plate was then read using a TR-FRET (time-resolved fluorescence resonance energy transfer)-based protocol.

[0471] Part II - Experimental procedure for M4 GTPγS PAM assay The M4 GTPγS PAM method was used. For the GTPγS binding assay, membranes were prepared from CHO-K1 cells stably expressing the human M4 receptor. Briefly, cells were grown in five-layer cell culture flasks. Cells were washed with 50 mL of PBS and then dissociated with 0.05% trypsin. Dissociated cells were then collected by centrifugation at 650 × g for 8 minutes at 4 °C. The pellet was washed again with PBS by centrifugation and resuspended in 30 mL of 20 mM HEPES, 10 mM EDTA, pH 7.4. After standing on ice for 30 minutes, membranes were collected by centrifugation at 50,000 × g for 15 minutes at 4 °C, resuspended in 30 mL of 20 mM HEPES, 0.1 mM EDTA, pH 7.4, and collected again by centrifugation. The pellet was then washed twice by centrifugation in 30 mL of 20 mM HEPES, pH 7.4, and stored at -80°C until the day of assay. On the day of assay, the pellet was thawed on ice and resuspended in 1 mL of 20 mM HEPES, pH 7.4, 10 mM MgCl2, 100 mM NaCl using a Dounce homogenizer. Membrane protein concentration was determined by BCA protein assay (Promega, Madison, WI) according to Promega guidelines.

[0472] On the day of the assay, a serial dilution series of test PAM compounds was prepared in assay buffer (20 mM HEPES, 10 mM MgCl2, 100 mM NaCl) to 4x the final assay concentration. 25 ml / well of membrane homogenate (containing 5 mg of membrane protein) was prepared in assay buffer supplemented with GDP at 4x the final assay concentration (final assay concentrations of GDP are 5 µM in M2 and 0.1 µM in M4) and dispensed into a 96-well polypropylene U-bottom Greiner plate. 25 ml of vehicle or test PAM compound diluted to 4x the final assay concentration in assay buffer was added to the membranes, and the plate was incubated for 10-15 min at room temperature with gentle shaking. Then, 25 ml of EC20 acetylcholine in assay buffer at 4x the final assay concentration was added to the assay plate (EC20 final assay concentration is 40 nM in human M4).

[0473] The plate was then incubated for an additional 10-15 minutes with shaking. 35 25 mL of S-GTP (Perkin Elmer, Waltham, MA) was added to the assay mixture. The binding reaction was allowed to proceed for 1 hour at room temperature on a shaker. The membranes in the assay reaction were then transferred to a GF / C filter plate (Unifilter, Perkin Elmer) and washed three times with cold GDP-free assay buffer using a FilterMate Harvester (Perkin Elmer). The filter plate was then dried overnight at 40°C, followed by the addition of 20 mL / well of Beta Plate Scintillation fluid. The top and bottom of the plate were sealed and then read on a TopCount scintillation counter (Perkin Elmer, Waltham, MA).

[0474] Part III - Results The results are shown in Table 23 below. Compounds with activity designated "A" had an EC 50 Compounds with an EC<100 nM and activity designated "B" have an EC<100 nM in the range of 100 nM to 500 nM. 50 Compounds with an activity designated "C" have an EC 50 Compounds with activity designated "D" have an EC 50 >2000 nM. N / A indicates no data available. [Table 25-1] [Table 25-2] [Table 25-3] [Table 25-4]

[0475] Example 74 - Ability of compounds to affect behavioral activity in rats Exemplary compounds were tested for their ability to affect the behavior of rats pretreated with amphetamine. The experimental procedures and results are described below.

[0476] Part I - Experimental Procedure Animals: Adult male Sprague Dawley rats (Envigo, Indianapolis, IN, USA) were housed in a colony maintained at 23°C with a 12-h light / dark cycle (lights on at 0600 h). Animals weighed 290-330 g at the start of the study and were equally divided into five groups (n = 8 per group) and subjected to one of the treatment conditions listed below. The animal protocol was approved by the Institutional Animal Care and Use Committee.

[0477] Behavioral Procedures: Testing was performed in a Medassociates open-field chamber (27.3 cm x 27.3 cm x 20.3 cm, Medassociates, St. Albans, VT), where movement was automatically tracked and recorded using a 16-beam array. Pretreatment with test substance was determined to optimize the route of administration and coincide with the Tmax during the amphetamine challenge session. All groups were treated with 0.5 mg / kg amphetamine (AMP) subcutaneously. Test substances (i.e., test compounds) were tested in three dose groups, with a half-log increase between doses. Risperidone (0.55 mg / kg, 30 min, subcutaneous) was used as a positive control and administered to Group 5. To determine the role of the test substance on AMP-induced hyperlocomotion, rats were placed in an open area and allowed to acclimate for 30 min before receiving 0.5 mg / kg AMP subcutaneously. Locomotion data (distance traveled) were recorded in 5-min intervals throughout the 90-min session. The AMP dose was chosen based on its selective increase in motor behavior relative to stereotypy, and the risperidone dose was chosen to provide a robust effect and serve as a positive control.

[0478] Statistical analysis: Locomotor activity (before AMP administration) was calculated as the total distance traveled during the first 30 min of the experimental session. AMP-evoked responses were calculated as the total distance traveled during the first 60 min of the experimental session, starting immediately after AMP administration. Locomotor data were analyzed by one-way ANOVA. If the overall ANOVA was significant, post-hoc comparisons were performed with Dunnett's test, and statistical significance was determined as p<0.05.

[0479] Part II - Results Rats administered any of the following test compounds at the indicated doses exhibited a reduction in amphetamine-induced excessive locomotor activity, indicating a beneficial effect of the test compounds on the rats. [Table 26]

[0480] Incorporation by Reference The entire disclosure of each patent document and scientific article referenced herein is incorporated by reference for all purposes.

[0481] equivalent The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. Therefore, the foregoing embodiments should be considered in all respects as illustrative and not limiting of the invention described herein. The scope of the present invention is, therefore, indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced within the scope of the present invention.

Claims

1. Formula I: 【Chemistry 1】 or a pharmaceutically acceptable salt thereof (wherein R １ is C １－６ Alkyl, C １－６ Haloalkyl, C ３－６ cycloalkyl, -(C １－６ alkylene)-(C ３－６ cycloalkyl), or hydrogen; R ２ Ha, Halo, C １－４ Alkyl, C １－４ haloalkyl, or hydrogen; R ３ is C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxyl, -S-(C １－４ alkyl), or halo; R ４ are each independently C １－４ Alkyl, C １－４ represents haloalkyl or halo, R ５ are each independently C １－６ Alkyl, halo, C １－６ Haloalkyl, C ３－６ Cycloalkyl, hydroxyl, C １－６ Alkoxyl, -(C １－６ alkylene)-(C １－６ alkoxyl), -(C １－６ alkylene)-(C ３－６ cycloalkyl), -(C １－６ haloalkylene)-(C ３－６ cycloalkyl), or -(C １－６ alkylene)-(C ３－６ halocycloalkyl), or two R ５ together with the atoms therebetween to form a 4- to 7-membered ring containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur; R ６ is (i)-(C ０－４ alkylene)-(3- to 7-membered saturated or unsaturated heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), (ii)-(C ０－４ (iii)-(C alkylene)-(5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or (iv)-(C ０－４ alkylene)-phenyl, wherein the heterocyclyl, the heteroaryl, and the phenyl are selected from 0, 1, 2, or 3 R ７ is replaced by R ７ are each independently C １－６ Alkyl, halo, C １－６ Haloalkyl, C ３－６ cycloalkyl, hydroxyl, or C １－６ represents alkoxyl, A １ is a 5- to 6-membered monocyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8- to 10-membered bicyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or phenyl, wherein the heteroaryl and the phenyl are joined together by n R ５ and t R ６ is replaced by m is 0, 1, 2, or 3; n is 0, 1, or 2; t is 0 or 1).

2. 2. The compound of claim 1, wherein the compound is a compound of formula I:

3. 3. The compound of claim 1, wherein m is 0.

4. 3. The compound of claim 1, wherein m is 1.

5. The compound has the formula Ia: 【Chemistry 2】 or a pharmaceutically acceptable salt thereof.

6. A １ is a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and said heteroaryl is a 5-6 membered monocyclic heteroaryl containing n R ６ and t R ６ The compound of any one of claims 1 to 5, substituted with

7. A １ is a 5-membered monocyclic heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, and said heteroaryl is ５ and t R ６ The compound of any one of claims 1 to 5, substituted with

8. A １ is pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyrrolyl, thiophenyl, or pyridinyl, each of which is selected from n R ５ and t R ６ The compound of any one of claims 1 to 5, substituted with

9. A １ is pyrazolyl, imidazolyl, oxazolyl, or isoxazolyl, each of which is selected from n R ５ and t R ６ The compound of any one of claims 1 to 5, substituted with

10. A １ is n R ５ and t R ６ The compound of any one of claims 1 to 5, which is pyrazolyl substituted with

11. R ６ But -(C １－４ alkylene)—a 3- to 7-membered saturated or unsaturated heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heterocyclyl is selected from 1, 2, or 3 R ７ The compound of any one of claims 1 to 10, substituted with

12. R ６ But -(C １－４ alkylene)-(5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur) or -(C １－４ alkylene)-phenyl, wherein said heteroaryl and said phenyl are selected from 0, 1, 2, or 3 R ７ The compound of any one of claims 1 to 10, substituted with

13. The compound according to any one of claims 1 to 12, wherein t is 1.

14. The compound according to any one of claims 1 to 10, wherein t is 0.

15. The compound according to any one of claims 1 to 14, wherein n is 1.

16. The compound has formula Ib, formula Ic, formula Id, or formula Ie: 【Transformation 3】 or a pharmaceutically acceptable salt thereof.

17. The compound has formula If or formula Ig: 【Chemistry 4】 or a pharmaceutically acceptable salt thereof.

18. The compound is of formula Ih, Ii, Ij, Ik, Il, or Im: 【Transformation 5】 or a pharmaceutically acceptable salt thereof.

19. R １ But C １－６ The compound of any one of claims 1 to 18, which is alkyl.

20. R １ The compound according to any one of claims 1 to 18, wherein is methyl.

21. R ２ But halo or C １－４ The compound of any one of claims 1 to 20, which is alkyl.

22. R ２ The compound of any one of claims 1 to 20, wherein is chloro or fluoro.

23. R ２ The compound according to any one of claims 1 to 20, wherein is methyl.

24. R ３ But C １－４ The compound of any one of claims 1 to 23, which is alkyl.

25. R ３ The compound according to any one of claims 1 to 23, wherein is methyl.

26. R ３ But C １－４ The compound of any one of claims 1 to 23, which is alkoxyl.

27. R ４ But C １－４ The compound of any one of claims 1 to 26, which is alkyl.

28. R ４ The compound according to any one of claims 1 to 26, wherein is methyl.

29. R ５ However, each independently, C １－６ Alkyl, halo, C １－６ Haloalkyl, C ３－６ Cycloalkyl, hydroxyl, C １－６ Alkoxyl, -(C １－６ alkylene)-(C １－６ alkoxyl), -(C １－６ alkylene)-(C ３－６ cycloalkyl), or -(C １－６ alkylene)-(C ３－６ 29. The compound according to any one of claims 1 to 28, wherein the aryl group is a cycloalkyl group.

30. R ５ However, each independently, C １－６ Alkyl, halo, C １－６ Haloalkyl, C ３－６ cycloalkyl, or -(C １－６ alkylene)-(C ３－６ 29. The compound according to any one of claims 1 to 28, wherein R represents a cycloalkyl group.

31. R ５ But C １－６ The compound of any one of claims 1 to 28, which is haloalkyl.

32. R ５ But, -CF ３ The compound according to any one of claims 1 to 28,

33. R ５ But C １－６ The compound of any one of claims 1 to 28, which is alkyl.

34. A compound of Table 1 herein, or a pharmaceutically acceptable salt thereof.

35. A pharmaceutical composition comprising a compound according to any one of claims 1 to 34 and a pharmaceutically acceptable carrier.

36. 36. A method for treating a muscarinic acetylcholine receptor-mediated disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 34 to treat the muscarinic acetylcholine receptor-mediated disorder.

37. 37. The method of claim 36, wherein the muscarinic acetylcholine receptor-mediated disorder is a neurological disorder.

38. 37. The method of claim 36, wherein the muscarinic acetylcholine receptor-mediated disorder is a movement disorder, a mood disorder, or a cognitive disorder.

39. 37. The method of claim 36, wherein the muscarinic acetylcholine receptor-mediated disorder is an attention disorder or an addictive disorder.

40. 37. The method of claim 36, wherein the muscarinic acetylcholine receptor mediated disorder is schizophrenia, psychosis, mild cognitive impairment, Alzheimer's disease, Parkinson's disease, Parkinson's disease-levodopa-induced dyskinesia, Huntington's disease, dyskinesia, cerebral amyloid angiopathy, dementia, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch Type (HCHWA-D), Creutzfeldt-Jakob Disease, a prion disorder, amyotrophic lateral sclerosis, progressive supranuclear palsy, autism, addiction, or a sleep disorder.

41. The muscarinic acetylcholine receptor-mediated disorder is selected from the group consisting of schizoaffective disorder, psychosis, delusional disorder, psychosis associated with Alzheimer's disease, psychosis associated with Parkinson's disease, psychotic depression, bipolar disorder, bipolar disorder with psychosis, Huntington's disease, dementia with Lewy bodies, Gilles de la Tourette's syndrome, Friedreich's ataxia, Huntington's chorea, dyskinesia, restless legs syndrome, major depressive disorder, dysthymia, recurrent brief depressive disorder, minor depressive disorder, mania, anxiety, Alzheimer ... dementia with Lewy bodies, dementia with Lewy bodies, dementia with Lewy bodies, dementia with Lewy bodies, dementia with Lewy bodies, dementia with Lewy bodies, dementia with Lewy bodies, dementia with Lewy bodies, dementia with Lewy bodies, dementia with Lewy bodies, dementia with Lewy bodies, dementia with Lewy bodies, dementia with Lewy bodies, dementia with Lewy bodies, dementia with Lewy bodies, dementia with Lewy bodies, dementia with Lewy bodies, dementia with Lewy bodies, dementia with Lewy bodies, dementia with Lewy bodies, dementia with Lewy bodies, 37. The method of claim 36, wherein the agitation is associated with Immer's disease, Parkinson's disease, dementia, Pick's disease, tauopathy, synucleinopathy, confusion, cognitive deficits associated with fatigue, learning disabilities, traumatic brain injury, autism, age-related cognitive decline, Cushing's disease, attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADD), Dubowitz syndrome, FG syndrome, Down syndrome, developmental delay due to insulin-like growth factor I (IGF1) deficiency, hepatic encephalopathy syndrome, Strauss syndrome, or neurodegenerative related agitation.

42. 37. The method of claim 36, wherein the muscarinic acetylcholine receptor-mediated disorder is dementia-related psychosis, schizophrenia, Alzheimer's disease, Parkinson's disease, depression, movement disorder, pain, drug addiction, tauopathy, or synucleinopathy.

43. 37. The method of claim 36, wherein the muscarinic acetylcholine receptor-mediated disorder is schizophrenia.

44. 37. The method of claim 36, wherein the muscarinic acetylcholine receptor-mediated disorder is pain.

45. 37. The method of claim 36, wherein the muscarinic acetylcholine receptor-mediated disorder is neuropathic pain.

46. 37. The method of claim 36, wherein the muscarinic acetylcholine receptor-mediated disorder is inflammatory pain or nociceptive pain.

47. 37. The method of claim 36, wherein the muscarinic acetylcholine receptor-mediated disorder is chronic pain.

48. 48. The method of any one of claims 36 to 47, further comprising administering to the subject in need thereof a therapeutically effective amount of an orthosteric agonist of a muscarinic acetylcholine receptor.

49. 49. The method of claim 48, wherein the orthosteric agonist of the muscarinic acetylcholine receptor is administered to the subject simultaneously with the compound of any one of claims 1 to 34.

50. 49. The method of claim 48, wherein the subject is administered a pharmaceutical composition comprising (i) an orthosteric agonist of the muscarinic acetylcholine receptor and (ii) a compound of any one of claims 1 to 34.

51. 49. The method of claim 48, wherein the orthosteric agonist of the muscarinic acetylcholine receptor is administered to the subject separately from the compound of any one of claims 1 to 34.

52. 49. The method of claim 48, wherein the orthosteric agonist of a muscarinic acetylcholine receptor is administered to the subject via a first pharmaceutical composition, and the compound of any one of claims 1 to 34 is administered to the subject via a second pharmaceutical composition.

53. 53. The method of any one of claims 48 to 52, wherein the amount of (i) the orthosteric agonist of the muscarinic acetylcholine receptor and / or (ii) the compound of any one of claims 1 to 34 administered to the patient is reduced compared to when either (i) the orthosteric agonist of the muscarinic acetylcholine receptor or (ii) the compound of any one of claims 1 to 34 is used in monotherapy treatment.

54. 48. The method of any one of claims 36 to 47, further comprising administering to the subject in need thereof a therapeutically effective amount of an orthosteric antagonist of a muscarinic acetylcholine receptor.

55. The method of any one of claims 36 to 54, wherein the subject is a human.

56. 35. A method of activating a muscarinic acetylcholine receptor, comprising contacting the muscarinic acetylcholine receptor with an effective amount of a compound of any one of claims 1 to 34 to activate the muscarinic acetylcholine receptor.

57. The method of any one of claims 36 to 56, wherein the muscarinic acetylcholine receptor is muscarinic acetylcholine receptor M4.

58. Formula II: 【Transformation 6】 or a salt thereof (wherein R １Ａ is C １－６ Alkyl, C １－６ Haloalkyl, C ３－６ cycloalkyl, -(C １－６ alkylene)-(C ３－６ cycloalkyl), or hydrogen; R ２Ａ Ha, Halo, C １－４ Alkyl, C １－４ haloalkyl, or hydrogen; R ３Ａ is C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxyl, C １－４ Haloalkoxyl, -S-(C １－４ alkyl), or halo; R ４Ａ and R ５Ａ are independently hydrogen, C １－４ Alkyl, C １－４ haloalkyl, or halo; Z １ is hydrogen or —C(O) ２ (C １－６ alkyl).

59. R １Ａ is hydrogen, methyl, or 【Transformation 7】 59. The compound of claim 58, wherein:

60. R ２Ａ is hydrogen, fluoro, chloro, methyl, or —CF ３ 60. The compound of claim 58 or 59, wherein:

61. R ３Ａ Methyl, -OCH ３ , -OCH ２ CH ３ , -OCHF ２ , or -SCH ３ The compound according to any one of claims 58 to 60,

62. R ４Ａ The compound of any one of claims 58 to 61, wherein is hydrogen or methyl.

63. R ５Ａ The compound of any one of claims 58 to 62, wherein is hydrogen or methyl.

64. Z １ The compound of any one of claims 58 to 63, wherein is hydrogen or tert-butoxycarbonyl.

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