Substituted tetrahydropyrrolo-pyridone compounds and their use in treatment of medical conditions

Abstract

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

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of and priority to U.S. Provisional Patent Application Serial No. 63 / 433,191, filed December 16, 2022, the contents of which are hereby incorporated by reference in their entirety. Technical Field

[0003] The present invention provides substituted tetrahydropyrrolo-pyridone compounds, pharmaceutical compositions, and their use in treating muscarinic acetylcholine receptor-mediated disorders. Background Art

[0004] Muscarinic acetylcholine receptor-mediated conditions, such as major depressive disorder (MDD), bipolar disorder (BPD), and schizophrenia, are psychiatric illnesses that remain a significant public health problem. Currently available antidepressants, mood stabilizers, and antipsychotics can alleviate some of the symptoms of mood disorders in some patients, but are only partially effective in a significant number of patients, and many are refractory to currently available medications. Patients with major depressive disorder often experience at least two weeks of pervasive low mood, low self-esteem, and a loss of interest or pleasure in normally pleasurable activities. Patients with bipolar disorder often experience periods of depression and periods of abnormally elevated mood, each lasting from a few days to a few weeks. Patients with schizophrenia often experience active social avoidance, passive social withdrawal, emotional withdrawal, and anxiety. In some cases, supportive therapies can be used to help alleviate the symptoms of muscarinic acetylcholine receptor-mediated conditions; however, supportive therapies do not directly treat the condition and are not a good long-term solution to meet the patient's medical needs.

[0005] Compounds that modulate muscarinic acetylcholine receptors can be used to treat conditions associated with muscarinic acetylcholine receptor activity, such as major depressive disorder, bipolar disorder, and schizophrenia. Muscarinic acetylcholine receptors are a type of acetylcholine receptor that form G protein-coupled receptor complexes on the cell membranes of certain neurons and other cells. U.S. Patent No. 10,604,519 describes certain compounds as having activity at the M4 muscarinic acetylcholine receptor. However, new compounds with improved drug-like properties are needed to treat conditions mediated by muscarinic acetylcholine receptors.

[0006] The present invention satisfies the foregoing needs and provides other related advantages. Summary of the Invention

[0007] The present invention provides substituted tetrahydropyrrolo-pyridone compounds, pharmaceutical compositions, and their use in treating muscarinic acetylcholine receptor-mediated disorders. Specifically, one aspect of the present invention provides a collection of substituted tetrahydropyrrolo-pyridone compounds, such as compounds represented by Formula I:

[0008]

[0009] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in the detailed description. Other classes of substituted tetrahydropyrrolo-pyridone compounds are further described in the detailed description. The compound can be included as part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier.

[0010] Another aspect of the present invention provides a method for treating a muscarinic acetylcholine receptor-mediated disorder. 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 a muscarinic acetylcholine receptor-mediated disorder, as further described in the detailed description.

[0011] 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

[0012] The present invention provides substituted tetrahydropyrrolo-pyridone compounds, pharmaceutical compositions and their uses in treating muscarinic acetylcholine receptor-mediated disorders. Unless otherwise noted, the practice of the present invention employs conventional techniques of organic chemistry, pharmacology, molecular biology (including recombinant technology), cell biology, biochemistry and immunology. Such techniques are explained in the literature, such as "Comprehensive Organic Synthesis" (BM Trost & I. Fleming, ed., 1991-1992); "Handbook of experimental immunology" (DM Weir & C.C. Blackwell, ed.); "Current protocols in molecular biology" (FM Ausubel et al., ed., 1987, and regularly updated); and "Current protocols in immunology" (JE Coligan et al., ed., 1991), each of which is incorporated herein by reference in its entirety.

[0013] Various aspects of the present invention are described in the following sections; however, the various aspects of the present invention described in a particular section are not limited to any particular section. In addition, when a variable is not defined, the previous definition of the variable shall prevail.

[0014] definition

[0015] The compounds of the present invention include those generally described herein and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, unless otherwise indicated, the following definitions shall apply. Unless otherwise indicated, these definitions apply regardless of whether the term is used alone or in combination with other terms. Thus, the definition of "alkyl" applies to the "alkyl" portion of "alkyl" as well as "-O-alkyl," etc. For the purposes of the present invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th edition. In addition, the general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th edition, edited by Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0016] As used herein, the term "aliphatic" or "aliphatic group" means a straight (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain (which is fully saturated or contains one or more unsaturated units) or a monocyclic or bicyclic hydrocarbon (which is fully saturated or contains one or more unsaturated units), but which is not aromatic (also referred to herein as "cycloaliphatic") and has a single point of attachment to the rest of the molecule. 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 yet other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in yet 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 unsaturated units, but is not aromatic, and has a single 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, and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0017] As used herein, the term "bicycle" or "bicyclic ring system" refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or with one or more unsaturated units, with one or more common atoms between the two rings of the ring system. Therefore, the term includes any allowed ring fusion, such as ortho-fused or spiro-fused. As used herein, the term "heterobicycle" is a subset of "bicyclic", which requires one or more heteroatoms to be present in one or both rings of the bicyclic. Such heteroatoms may be present at the ring junction and may be 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, etc. In some embodiments, the bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. As used herein, the term "bridged bicyclic" refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, having at least one bridge bond. As defined by IUPAC, a "bridge bond" is a non-branched chain of multiple atoms or an atom or a valence bond connecting two bridgeheads, wherein a "bridgehead" is any backbone atom of a ring system bonded to three or more backbone atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Such bridged bicyclic groups are well known in the art and include those groups described below, wherein each group is connected to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise indicated, a bridged bicyclic group is optionally substituted by one or more substituents as described for an aliphatic group. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bicyclics include:

[0018]

[0019] Exemplary bridged bicyclic rings include:

[0020]

[0021] The term "lower alkyl" refers to a C 1-4 Straight or branched chain alkyl groups. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl.

[0022] The term "lower haloalkyl" refers to a C 1-4 Straight-chain or branched-chain alkyl.

[0023] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocyclic ring, such as N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR +(as in N-substituted pyrrolidinyl)).

[0024] As used herein, the term "unsaturated" means that the moiety has one or more units of unsaturation.

[0025] As used herein, the term "divalent C 1-8 (or C 1-6 ) saturated or unsaturated straight or branched hydrocarbon chain" refers to divalent alkylene, alkenylene and alkynylene chains as defined herein that are straight or branched.

[0026] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2) n -, wherein 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 chain in which one or more methylene hydrogen atoms are replaced by a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0027] The term "-(C0 alkylene)-" refers to a bond. Thus, the term "-(C0 alkylene)-" 0-3 Alkylene)-" encompasses bonds (i.e., C0) and -(C 1-3 alkylene)-group.

[0028] The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond and in which one or more hydrogen atoms are replaced by a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0029] The term "halogen" refers to F, Cl, Br or I.

[0030] The term "aryl" as in "aralkyl," "aralkyloxy," or "aryloxyalkyl," used alone or as part of a larger moiety, refers to a monocyclic or bicyclic ring system having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system has 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, anthracenyl, and the like, which may carry one or more substituents. As used herein, groups in which an aromatic ring is fused to one or more non-aromatic rings, such as dihydroindanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, are also included within the scope of the term "aryl." The term "phenylene" refers to a polyvalent phenyl group having an appropriate number of open valences to occupy the group to which it is attached.

[0031] The terms "heteroaryl" and "heteroar-" (e.g., "heteroaralkyl" or "heteroaralkoxy"), used alone or as part of a larger moiety, refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 pi electrons shared in the cyclic array; and having one to five heteroatoms in addition to 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 includes, but is not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. As used herein, the terms "heteroaryl" and "heteroar-" also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, wherein, 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, tetrahydroquinolyl, and tetrahydroisoquinolyl. Heteroaryl groups can be monocyclic or bicyclic. The term "heteroaryl" can be used interchangeably with the terms "heteroaryl ring," "heteroaryl," or "heteroaromatic," any of which includes rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.

[0032] The term "heteroarylene" refers to a polyvalent heteroaryl group having an appropriate number of open valences to occupy the groups to which it is attached. For example, a "heteroarylene" group having two groups attached is a divalent heteroaryl group; a "heteroarylene" group having three groups attached is a trivalent heteroaryl group.

[0033] As used herein, the terms "heterocycle," "heterocyclyl," "heterocyclic group," and "heterocyclic ring" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is saturated or partially unsaturated and has one or more, preferably one to four, heteroatoms as defined above in addition to carbon atoms. The term "nitrogen," when used with respect to a ring atom of a heterocycle, includes substituted nitrogen. For example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur, or nitrogen, nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or + NR (as in N-substituted pyrrolidinyl).

[0034] The heterocycle can be attached to its side group at any heteroatom or carbon atom to produce a stable structure, and any ring atom can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolane, diazepanyl, oxazepanyl, thiazepanyl, 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 also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. A heterocyclyl group can be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclyl group, wherein the alkyl and heterocyclyl portions are independently and optionally substituted. The term "oxo-heterocyclyl" refers to a heterocyclyl group substituted with one or more oxo groups. The term "heterocyclylene" refers to a polyvalent heterocyclylene group having the appropriate number of open valences to occupy the groups to which it is attached. For example, a "heterocyclylene" is a divalent heterocyclyl group if two groups are attached, and a "heterocyclylene" is a trivalent heterocyclyl group if three groups are attached. The term "oxo-heterocyclylene" refers to a multivalent oxo-heterocyclylene group having the appropriate number of open valencies to occupy the group to which it is attached.

[0035] As used herein, the term "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond. As defined herein, the term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties.

[0036] As described herein, the compounds of the present invention may contain "optionally substituted" moieties. In general, the term "substituted", whether or not preceded by the term "optionally", means that one or more hydrogens of the designated moiety are replaced by a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted by more than one substituent selected from a designated group, the substituent at each position may be the same or different. The combination of substituents envisioned by the present invention is preferably a combination that forms a stable or chemically feasible compound. As used herein, the term "stable" refers to a compound that does not substantially change when subjected to conditions that allow its production, detection, and in certain embodiments, its recovery, purification, and use for one or more of the purposes disclosed herein.

[0037] Each optional substituent on a substitutable carbon is independently selected from the following monovalent substituents: halogen; -(CH2); 0–4 R o ; –(CH2) 0–4 OR o ;-O(CH2) 0-4 R o 、–O–(CH2) 0–4 C(O)OR o ; –(CH2) 0–4 CH(OR o )2;–(CH2) 0– 4SR o ; –(CH2) 0–4 Ph, which can be R o Substitution; –(CH2) 0–4 O(CH2) 0–1 Ph, which can be R o Substitution; –CH=CHPh, which can be replaced by R o Substitution; –(CH2) 0–4 O(CH2) 0–1 -pyridyl, which may be R o Substitution; –NO2; –CN; –N3; -(CH2) 0–4 N(R o )2;–(CH2) 0–4 N(R o )C(O)R o ;–N(R o )C(S)R o ; –(CH2) 0–4 N(R o )C(O)NR o 2;-N(R o )C(S)NR o 2;–(CH2) 0–4 N(R o )C(O)OR o ;–N(R o )N(R o )C(O)R o ;-N(R o )N(R o )C(O)NR o 2;-N(R o )N(R o )C(O)OR o ; –(CH2) 0–4 C(O)R o ;–C(S)R o ; –(CH2) 0–4 C(O)ORo ;–(CH2) 0–4 C(O)SR o ;-(CH2) 0–4 C(O)OSiR o 3;–(CH2) 0–4 OC(O)R o ;–OC(O)(CH2) 0–4 SR–、SC(S)SR o ;–(CH2) 0–4 SC(O)R o ;–(CH2) 0–4 C(O)NR o 2;–C(S)NR o 2;–C(S)SR o ;–SC(S)SR o ,-(CH2) 0–4 OC(O)NR o 2;-C(O)N(OR o )R o ;–C(O)C(O)R o ;–C(O)CH2C(O)R o ;–C(NOR o )R o ;-(CH2) 0–4 SSR o ;-(CH2) 0–4 S(O)2R o ;–(CH2) 0–4 S(O)2OR o ;–(CH2) 0–4 OS(O)2R o ;–S(O)2NR o 2;-S(O)(NR o )R o ;–S(O)2N=C(NR o 2)2;-(CH2) 0–4 S(O)R o ;-N(R o )S(O)2NR o 2;–N(R o )S(O)2R o ;–N(OR o )R o ;–C(NH)NR o 2;–P(O)2R o ;-P(O)R o 2;-OP(O)R o 2;–OP(O)(OR o )2;SiRo 3;–(C 1–4 linear or branched alkylene)O–N(R o )2; or –(C 1–4 linear or branched alkylene) C(O)O–N(R o )2.

[0038] Each R o are independently hydrogen, C 1–6 Aliphatic, –CH2Ph, –O(CH2) 0–1 Ph, -CH2-(5-6 membered heteroaryl ring), or a 5-6 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 occurrences of R o Together with their intervening atoms, they form a 3-12 membered saturated, partially unsaturated or aromatic monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be selected from ═O and ═S. o A divalent substituent on a saturated carbon atom of o Optionally substituted with monovalent substituents independently selected from halogen, -(CH2) 0–2 R · 、–(halogen R · ),–(CH2) 0–2 OH, –(CH2) 0–2 OR · 、–(CH2) 0–2 CH(OR · )2;-O(halogen R · ), –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– 2SH, –(CH2) 0–2 NH2, –(CH2) 0–2 NHR · 、–(CH2) 0–2 NR · 2. –NO2, –SiR · 3. –OSiR · 3. -C(O)SR · ,–(C 1–4 linear or branched alkylene)C(O)OR · , or –SSR · .

[0039] Each R · Independently selected from C 1–4 Aliphatic, –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, and wherein each R · is unsubstituted or, when preceded by a halo, substituted only with one or more halogens; or wherein the optional substituents on the saturated carbon are divalent substituents independently selected from the group consisting of: =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 S-, or the divalent substituent attached to the adjacent substitutable carbon of the "optionally substituted" group is -O(CR * 2) 2–3 O–, where each independent occurrence of R * Selected from hydrogen, C 1–6 an aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0040] When R * C 1-6 When aliphatic, R * Optionally halogen, -R · 、-(halogen R · ), -OH, -OR · 、-O(halogen R · )、-CN、-C(O)OH、-C(O)OR · , –NH2, –NHR · ,–NR · 2 or –NO2, where each R · Independently selected from C 1–4 Aliphatic, –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, and wherein each R · is unsubstituted or, when preceded by a halo, is substituted only by one or more halogens.

[0041] Optional substituents on the substitutable nitrogen are independently -R ,–NR 2. –C(O)R 、–C(O)OR 、–C(O)C(O)R 、–C(O)CH2C(O)R 、-S(O)2R 、-S(O)2NR 2. –C(S)NR 2. –C(NH)NR 2, or –N(R )S(O)2R ; where each R are independently hydrogen, C 1–6 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 occurrences of R Together with their intervening atoms, they form an unsubstituted 3-12 membered saturated, partially unsaturated or aromatic monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; wherein when R C 1-6 When aliphatic, R Optionally halogen, –R · 、-(halogen R · ),-OH, –OR · 、–O(halogen R · ), –CN, –C(O)OH, –C(O)OR · , –NH2, –NHR · ,–NR · 2 or –NO2, where each R · Independently selected from C 1-4 Aliphatic, –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, and wherein each R · is unsubstituted or, when preceded by a halo, is substituted only by one or more halogens.

[0042] As used herein, the term "pharmaceutically acceptable salt" refers to salts that are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reactions, etc., and that are commensurate with a reasonable benefit / risk ratio, within the scope of reasonable medical judgment. Pharmaceutically acceptable salts are well known in the art. For example, SM 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 formed of an amino group with an inorganic acid (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or an organic acid (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or salts formed by using other methods used in the art (such as ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like.

[0043] In addition, acids generally considered suitable for forming pharmaceutically useful salts from basic drug compounds are discussed, for example, in P. Stahl et al., Camille G. (ed.) 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) 33201-217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; and The Orange Book (on the website of Food & Drug Administration, Washington, DC). The disclosures of these are incorporated herein by reference.

[0044] Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N + (C 1-4 Representative alkali metal or alkaline earth metal salts include sodium salts, lithium salts, potassium salts, calcium salts, magnesium salts, and the like. Other pharmaceutically acceptable salts include (where appropriate) non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0045] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds of the invention are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. The invention includes compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds comprising the replacement of a hydrogen by deuterium or tritium or a carbon by 13 C- or 14 Compounds having the structures of the present invention that are C-enriched and substituted with carbon are within the scope of the present invention. Such compounds are useful, for example, as analytical tools, probes in biological assays, or therapeutic agents according to the present invention.

[0046] By methods well known to those skilled in the art, such as by chromatography and / or fractional crystallization, diastereomeric mixtures can be separated into their single diastereomers based on the differences in physical chemistry. Enantiomeric mixtures can be converted into diastereomeric mixtures by reacting with suitable optically active compounds (for example, chiral auxiliary agents, such as chiral alcohols or Mosher's acid chlorides), separating diastereomers and converting (for example, hydrolyzing) single diastereomers into corresponding pure enantiomers, and separating enantiomers. Alternatively, the specific enantiomers of the compound of the present invention can be prepared by asymmetric synthesis. Further, when containing basic functional groups (such as amino) or acidic functional groups (such as carboxylic acid) in the molecule, diastereomeric salts are formed with suitable optically active acids or bases, and the diastereomers thus formed are subsequently split by fractional crystallization or chromatographic methods known in the art, and the pure enantiomers are subsequently reclaimed.

[0047] Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other or other selected stereoisomers. The chiral centers in the compounds of the invention may have the S or R configuration as defined by the IUPAC 1974 recommendations. In addition, if the compounds described herein may exist as atropisomers (e.g., substituted biaryls), all forms of such atropisomers are considered part of the present invention.

[0048] Chemical names, common names, and chemical structures are used interchangeably to describe the same structure. If both a chemical structure and a chemical name are used to refer to a chemical compound, and there is an ambiguity between the structure and the name, the structure controls. It should also be noted that any carbon and heteroatom with unsaturated valences in the text, schemes, examples, and tables herein are assumed to have sufficient hydrogen atoms to satisfy the valences.

[0049] As used herein, the terms "a" and "an" mean "one or more" and include the plural unless the context is inappropriate.

[0050] The term "alkyl" refers to a saturated straight or branched chain hydrocarbon, such as a straight or branched chain group of 1-12, 1-10, or 1-6 carbon atoms, referred to herein as C1-C 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, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, and the like.

[0051] The term "cycloalkyl" refers to a monovalent saturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group having 3-12, 3-8, 4-8, or 4-6 carbon atoms derived from a cycloalkane, referred to herein as, for example, a "C3-C6 cycloalkyl." Exemplary cycloalkyl groups include cyclohexyl, cyclopentyl, cyclobutyl, and cyclopropyl. The term "cycloalkylene" refers to a divalent cycloalkyl group.

[0052] The term "haloalkyl" refers to an alkyl group substituted with at least one halogen. Exemplary haloalkyl groups include -CH2F, -CHF2, -CF3, -CH2CF3, -CF2CF3, etc. The term "haloalkylene" refers to a divalent haloalkyl group.

[0053] The term "hydroxyalkyl" refers to an alkyl group substituted with at least one hydroxy group. Exemplary hydroxyalkyl groups include -CH2CH2OH, -C(H)(OH)CH3, -CH2C(H)(OH)CH2CH2OH, and the like.

[0054] The terms "alkenyl" and "alkynyl" are art-recognized and refer to unsaturated aliphatic groups of similar length and which may replace the alkyl groups described above, but that contain at least one double or triple bond, respectively.

[0055] The term "alkoxyl" or "alkoxy" is art-recognized and refers to an alkyl group as defined above having an oxygen group attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy, etc. The term "haloalkoxy" refers to an alkoxy group substituted with at least one halogen. Exemplary haloalkoxy groups include -OCH2F, -OCHF2, -OCF3, -OCH2CF3, -OCF2CF3, etc.

[0056] The term "oxo" is art-recognized and refers to a "=O" substituent. For example, cyclopentane substituted with an oxo group is cyclopentanone.

[0057] symbol" ” indicates a connection point.

[0058] When any substituent or variable occurs more than one time in any constituent or compound of the invention, its definition on each occurrence is independent of its definition at every other occurrence unless otherwise indicated.

[0059] One or more compounds of the present invention may exist in unsolvated form as well as in solvated form with pharmaceutically acceptable solvents such as water, ethanol, etc., and the present invention is intended to include both solvated and unsolvated forms. The term "solvate or solvated" means the physical association of a compound of the present invention with one or more solvent molecules. This physical association involves varying degrees of ionic bonding and covalent bonding, including hydrogen bonding. In some cases, the solvate will be able to separate, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" encompasses solution phase and separable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, etc. "Hydrate" refers to a solvate in which the solvent molecule is H2O.

[0060] As used herein, the terms "subject" and "patient" are used interchangeably and refer to an organism to be 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 include humans.

[0061] The term "EC 50 ” is art-recognized and refers to the concentration of a compound required to achieve 50% of the maximal response.

[0062] 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 preventive result). An effective amount can be administered in one or more administrations, uses, 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, such as alleviating, reducing, regulating, improving, or eliminating, that results in improvement of a condition, disease, disorder, or the like, or improves a symptom thereof.

[0063] As used herein, the term "pharmaceutical composition" refers to the combination of an active agent with an inert or active carrier, making the composition particularly suitable for diagnostic or therapeutic use, either in vivo or ex vivo.

[0064] As used herein, the term "pharmaceutically acceptable carrier" refers to any standard pharmaceutical carrier, such as phosphate-buffered saline solution, water, emulsions (e.g., such as oil / water emulsions 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, e.g., Martin, Remington's Pharmaceutical Sciences, 15th Edition, Mack Publ. Co., Easton, PA

[1975] .

[0065] For therapeutic use, salts of the compounds of the invention are considered pharmaceutically acceptable.However, salts of acids and bases that are not pharmaceutically acceptable may also be useful, for example, in the preparation or purification of pharmaceutically acceptable compounds.

[0066] In addition, when the compounds of the present invention contain 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 ("inner salts") may be formed. Such acidic and basic salts used within the scope of the present invention are pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts. Such salts of the compounds of the present invention can be formed, for example, by reacting the compounds of the present invention with an amount of acid or base (such as an equivalent amount) in a medium (such as a medium in which the salt is precipitated) or in an aqueous medium, followed by lyophilization.

[0067] Throughout this specification, when compositions are described as having, including, or comprising specific components, or when processes and methods are described as having, including, or comprising specific steps, it is also contemplated that there are compositions of the invention consisting essentially of, or consisting of, the recited components, and that there are processes and methods according to the invention consisting essentially of, or consisting of, the recited process steps.

[0068] Generally, percentages of compositions specified are by weight unless otherwise indicated.

[0069] I. Substituted Tetrahydropyrrolo-pyridone Compounds

[0070] One aspect of the present invention provides substituted tetrahydropyrrolo-pyridinone compounds. The compounds can be used in the pharmaceutical compositions and treatment methods described herein. The following sections describe exemplary compounds and exemplary procedures for making these compounds.

[0071] One aspect of the present invention provides a compound represented by Formula I:

[0072]

[0073] or a pharmaceutically acceptable salt thereof, wherein:

[0074] R 1 C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -(C 1-6 alkylene)-(C 3-6 cycloalkyl) or hydrogen;

[0075] R 2 For halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 cycloalkyl, cyano or hydrogen;

[0076] R 3 C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, -S-(C 1-4 alkyl), hydrogen or halo;

[0077] R 4 Each occurrence represents C independently 1-4 Alkyl, C 1-4 haloalkyl or halo;

[0078] R 5 Each occurrence represents C independently 1-6 Alkyl, halogen, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -SO2-(C 1-6 Halogenated alkyl), -SO2-(C 1-6 alkyl), cyano, hydroxyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, -(C 1-6 alkylene)-(C 1-6 Alkoxy), -(C 1-6 alkylene)-(C 3-6 Cycloalkyl), -(C 1-6 alkylene)-(C 3-6 Halogenated cycloalkyl) or -O-(C 1-6 alkylene)-(C 3-6 cycloalkyl); or two occurrences of R 5 Together with its intervening atoms, it forms a 4-7 membered ring containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen and sulfur;

[0079] A 1 is phenyl or a 5-6 membered monocyclic heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the phenyl and heteroaryl are replaced by n occurrences of R 5 replace;

[0080] X 1 For-(C 1-4 Alkylene)-(a 3-5 membered saturated ring containing 1 nitrogen atom, wherein the ring is replaced by 0, 1, 2, 3 or 4 occurrences of C 1-4 Alkyl substituted)-***, wherein *** is 1 connection point; and

[0081] m and n are independently 0, 1, 2 or 3.

[0082] The definitions of the variables in the above formula I encompass a plurality of chemical groups. The present application contemplates embodiments in which, for example, i) the definition of a variable is a single chemical group selected from the above chemical groups, ii) the definition of a variable is a set of two or more chemical groups selected from the above chemical groups, and iii) a compound is defined by a combination of variables, wherein the variable is defined by either (i) or (ii).

[0083] In certain embodiments, the compound is a compound of Formula I.

[0084] As generally defined above, R 1 C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -(C 1-6 alkylene)-(C 3-6 In certain embodiments, R 1 C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, or -(C 1-6 alkylene)-(C 3-6 In certain embodiments, R 1 C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -(C 1-6 alkylene)-(C 3-6 In certain embodiments, R 1 C 1-6 Alkyl, C 3-6 Cycloalkyl, -(C 1-6 alkylene)-(C 3-6 In certain embodiments, R 1 C 1-6 Alkyl, C 1-6 Haloalkyl, -(C 1-6 alkylene)-(C 3-6 In certain embodiments, R 1 C 1-6Alkyl, C 1-6 Halogenated alkyl, C 3-6 cycloalkyl, or hydrogen.

[0085] In certain embodiments, R 1 C 3-6 Cycloalkyl, -(C 1-6 alkylene)-(C 3-6 In certain embodiments, R 1 C 1-6 Haloalkyl, -(C 1-6 alkylene)-(C 3-6 In certain embodiments, R 1 C 1-6 Halogenated alkyl, C 3-6 In certain embodiments, R 1 C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, or -(C 1-6 alkylene)-(C 3-6 In certain embodiments, R 1 C 1-6 Alkyl, -(C 1-6 alkylene)-(C 3-6 In certain embodiments, R 1 C 1-6 Alkyl, C 3-6 In certain embodiments, R 1 C 1-6 Alkyl, C 3-6 Cycloalkyl, or -(C 1-6 alkylene)-(C 3-6 In certain embodiments, R 1 C 1-6 Alkyl, C 1-6 In certain embodiments, R 1 C 1-6 Alkyl, C 1-6 Haloalkyl, or -(C 1-6 alkylene)-(C 3-6 In certain embodiments, R 1 C 1-6 Alkyl, C 1-6 Haloalkyl, or C 3-6 Cycloalkyl.

[0086] In certain embodiments, R 1 C 1-6 In certain embodiments, R 1 C1-4 In certain embodiments, R 1 C 1-3 In certain embodiments, R 1 C 2-6 In certain embodiments, R 1 C 3-6 In certain embodiments, R 1 In certain embodiments, R 1 For ethyl.

[0087] In certain embodiments, R 1 C 1-6 In certain embodiments, R 1 C 1-4 In certain embodiments, R 1 C 1-3 In certain embodiments, R 1 C 2-6 In certain embodiments, R 1 C 3-6 In certain embodiments, R 1 C 1-6 In certain embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 It is -CH2CHF2.

[0088] In certain embodiments, R 1 C 3-6 In certain embodiments, R 1 C 4-6 In certain embodiments, R 1 C 5-6 In certain embodiments, R 1 It is cyclopropyl.

[0089] In certain embodiments, R 1 For-(C 1-6 alkylene)-(C 3-6 In certain embodiments, R 1 For-(C 1-4 alkylene)-(C 3-6 In certain embodiments, R 1 For-(C 2-6 alkylene)-(C 3-6In certain embodiments, R 1 For-(C 1-4 alkylene)-(C 5-6 In certain embodiments, R 1 For-(C 1-3 alkylene)-(C 4-6 In certain embodiments, R 1 For-(C 1-2 alkylene)-(C 3-5 In certain embodiments, R 1 It is -CH2-cyclopropyl.

[0090] In certain embodiments, R 1 For hydrogen.

[0091] In certain embodiments, R 1 Select from those depicted in Table 1.

[0092] As generally defined above, R 2 For halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 In certain embodiments, R 2 C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 In certain embodiments, R 2 For halogen, C 1-4 Halogenated alkyl, C 3-6 In certain embodiments, R 2 For halogen, C 1-4 Alkyl, C 3-6 In certain embodiments, R 2 For halogen, C 1-4 Alkyl, C 1-4 In certain embodiments, R 2 For halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 In certain embodiments, R 2 For halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, or cyano.

[0093] In certain embodiments, R 2 is a halogen group, C 1-4 Alkyl, or C 1-4In certain embodiments, R 2 C 1-4 Alkyl, C 1-4 In certain embodiments, R 2 is a halogen group, C 1-4 In certain embodiments, R 2 is a halogen group, C 1-4 Alkyl, or hydrogen.

[0094] In certain embodiments, R 2 C 1-4 In certain embodiments, R 2 C 1-4 In certain embodiments, R 2 C 1-4 Alkyl or C 1-4 In certain embodiments, R 2 In certain embodiments, R 2 is halogen or C 1-4 In certain embodiments, R 2 is halogen or C 1-4 alkyl.

[0095] In certain embodiments, R 2 In certain embodiments, R 2 In certain embodiments, R 2 is F. In certain embodiments, R 2 For Cl.

[0096] In certain embodiments, R 2 C 1-4 In certain embodiments, R 2 C 1-3 In certain embodiments, R 2 C 2-4 In certain embodiments, R 2 C 3-4 In certain embodiments, R 2 In certain embodiments, R 2 For ethyl.

[0097] In certain embodiments, R 2 C 1-4 In certain embodiments, R 2 C 1-3 In certain embodiments, R 2 C 2-4In certain embodiments, R 2 C 3-4 In certain embodiments, R 2 C 1-4 In certain embodiments, R 2 In some embodiments, R 2 In some embodiments, R 4 In some embodiments, R 4 It is -CH2CHF2.

[0098] In certain embodiments, R 2 C 3-6 In certain embodiments, R 2 C 4-6 In certain embodiments, R 2 C 5-6 In certain embodiments, R 2 In certain embodiments, R 2 is a C4 cycloalkyl group. In certain embodiments, R 2 In certain embodiments, R 2 In certain embodiments, R 2 In certain embodiments, R 2 It is cyclopropyl.

[0099] In certain embodiments, R 2 For hydrogen.

[0100] In certain embodiments, R 2 It is a cyano group.

[0101] In certain embodiments, R 2 Select from those depicted in Table 1.

[0102] As generally defined above, R 3 C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, -S-(C 1-4 In certain embodiments, R 3 C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, -S-(C 1-4 In certain embodiments, R 3 C 1-4 Halogenated alkyl, C1-4 Alkoxy, -S-(C 1-4 In certain embodiments, R 3 C 1-4 Alkyl, C 1-4 Alkoxy, -S-(C 1-4 In certain embodiments, R 3 C 1-4 Alkyl, C 1-4 Halogenated alkyl, -S-(C 1-4 In certain embodiments, R 3 C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 In certain embodiments, R 3 C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, or -S-(C 1-4 alkyl).

[0103] In certain embodiments, R 3 C 1-4 Alkoxy, -S-(C 1-4 In certain embodiments, R 3 C 1-4 Halogenated alkyl, -S-(C 1-4 In certain embodiments, R 3 C 1-4 Halogenated alkyl, C 1-4 In certain embodiments, R 3 C 1-4 Halogenated alkyl, C 1-4 Alkoxy, or -S-(C 1-4 In certain embodiments, R 3 C 1-4 Alkyl, -S-(C 1-4 In certain embodiments, R 3 C 1-4 Alkyl, C 1-4 In certain embodiments, R 3 C 1-4 Alkyl, C 1-4 Alkoxy, or -S-(C 1-4 In certain embodiments, R 3 C 1-4 Alkyl, C 1-4 In certain embodiments, R3 C 1-4 Alkyl, C 1-4 Haloalkyl, or -S-(C 1-4 In certain embodiments, R 3 C 1-4 Alkyl, C 1-4 Haloalkyl, or C 1-4 Alkoxy.

[0104] In certain embodiments, R 3 C 1-4 In certain embodiments, R 3 C 1-3 In certain embodiments, R 3 C 2-4 In certain embodiments, R 3 C 3-4 In certain embodiments, R 3 In certain embodiments, R 3 For ethyl.

[0105] In certain embodiments, R 3 C 1-4 In certain embodiments, R 3 C 1-3 In certain embodiments, R 3 C 2-4 In certain embodiments, R 3 C 3-4 In certain embodiments, R 3 C 1-4 In certain embodiments, R 3 In some embodiments, R 3 In some embodiments, R 3 In some embodiments, R 3 It is -CH2CHF2.

[0106] In certain embodiments, R 3 C 1-4 In certain embodiments, R 3 C 1-3 In certain embodiments, R 3 C 2-4 In certain embodiments, R 3 C 3-4 In certain embodiments, R 3is -OCH3, -OCH2CH3, -OCH(CH3)2, or -OC(CH3)3. In certain embodiments, R 3 In certain embodiments, R 3 In certain embodiments, R 3 is -OCH(CH3)2. In certain embodiments, R 3 is -OC(CH3)3. In certain embodiments, R 3 It is -OCHF2.

[0107] In certain embodiments, R 3 For-S-(C 1-4 In certain embodiments, R 3 For-S-(C 1-3 In certain embodiments, R 3 For-S-(C 2-4 In certain embodiments, R 3 For-S-(C 3-4 In certain embodiments, R 3 It is -SCH3, -SCH2CH3, -SCH(CH3)2, or -SC(CH3)3.

[0108] In certain embodiments, R 3 In certain embodiments, R 3 In certain embodiments, R 3 is F. In certain embodiments, R 3 In certain embodiments, R 3 For hydrogen.

[0109] In certain embodiments, R 3 Select from those depicted in Table 1.

[0110] As generally defined above, R 4 Each occurrence represents C independently 1-4 Alkyl, C 1-4 In certain embodiments, R 4 Each occurrence represents C independently 1-4 In certain embodiments, R 4 Each occurrence represents C independently 1-4 In certain embodiments, R 4 Each occurrence represents C independently 1-4 Alkyl or C 1-4 In certain embodiments, R 4Each occurrence represents C independently 1-4 In certain embodiments, R 4 Each occurrence represents C independently 1-3 In certain embodiments, R 4 Each occurrence represents C independently 2-4 In certain embodiments, R 4 Each occurrence represents C independently 3-4 In certain embodiments, R 4 Each occurrence independently represents methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, isobutyl or tert-butyl. In certain embodiments, R 4 Each occurrence independently represents a methyl group or an ethyl group.

[0111] In certain embodiments, R 4 Each occurrence represents C independently 1-4 In certain embodiments, R 4 Each occurrence represents C independently 1-3 In certain embodiments, R 4 Each occurrence represents C independently 2-4 In certain embodiments, R 4 Each occurrence represents C independently 3-4 In certain embodiments, R 4 C 1-4 Haloalkyl, wherein halogen is F.

[0112] In certain embodiments, R 4 Each occurrence independently represents a halo. In certain embodiments, R 4 Each occurrence independently represents F or Cl.

[0113] In certain embodiments, R 4 C 1-4 Alkyl, C 1-4 In certain embodiments, R 4 C 1-4 In certain embodiments, R 4 C 1-4 In certain embodiments, R 4 C 1-4 Alkyl or C 1-4 Halogenated alkyl.

[0114] In certain embodiments, R 4 C 1-4 In certain embodiments, R 4 C1-3 In certain embodiments, R 4 C 2-4 In certain embodiments, R 4 C 3-4 In certain embodiments, R 4 In certain embodiments, R 4 For ethyl.

[0115] In certain embodiments, R 4 C 1-4 In certain embodiments, R 4 C 1-3 In certain embodiments, R 4 C 2-4 In certain embodiments, R 4 C 3-4 In certain embodiments, R 4 C 1-4 In certain embodiments, R 4 C 1-4 In certain embodiments, R 4 C 1-3 In certain embodiments, R 4 C 2-4 In certain embodiments, R 4 C 3-4 In certain embodiments, R 4 In some embodiments, R 4 In some embodiments, R 4 In some embodiments, R 4 It is -CH2CHF2.

[0116] In certain embodiments, R 4 In certain embodiments, R 4 In certain embodiments, R 4 is F. In certain embodiments, R 4 For Cl.

[0117] In certain embodiments, R 4 Select from those depicted in Table 1.

[0118] As generally defined above, R 5 Each occurrence represents C independently 1-6 Alkyl, halogen, C1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -SO2-(C 1-6 Halogenated alkyl), -SO2-(C 1-6 alkyl), cyano, hydroxyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, -(C 1-6 alkylene)-(C 1-6 Alkoxy), -(C 1-6 alkylene)-(C 3-6 Cycloalkyl), -(C 1-6 alkylene)-(C 3-6 Halogenated cycloalkyl) or -O-(C 1-6 alkylene)-(C 3-6 cycloalkyl); or two occurrences of R 5 Together with its intervening atoms, it forms a 4-7 membered ring containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur. 5 Each occurrence independently represents a halogen, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -SO2-(C 1-6 Halogenated alkyl), -SO2-(C 1-6 alkyl), cyano, hydroxyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, -(C 1-6 alkylene)-(C 1- 6 alkoxy), -(C 1-6 alkylene)-(C 3-6 Cycloalkyl), -(C 1-6 alkylene)-(C 3-6 Halogenated cycloalkyl) or -O-(C 1-6 alkylene)-(C 3-6 cycloalkyl); or two occurrences of R 5 Together with its intervening atoms, it forms a 4-7 membered ring containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0119] In certain embodiments, R 5 Each occurrence represents C independently 1-6 Alkyl, halogen, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -SO2-(C 1-6 Halogenated alkyl), -SO2-(C 1-6 alkyl), cyano, hydroxyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C1-6 Halogenated alkoxy, -(C 1-6 alkylene)-(C 1-6 Alkoxy), -(C 1-6 alkylene)-(C 3-6 Cycloalkyl), -(C 1-6 alkylene)-(C 3-6 Halogenated cycloalkyl) or -O-(C 1-6 alkylene)-(C 3-6 In certain embodiments, R 5 Each occurrence represents C independently 1-6 Alkyl, halogen, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, cyano, hydroxyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy.

[0120] In certain embodiments, R 5 Each occurrence represents C independently 1-6 Alkyl, halogen, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, hydroxyl, C 1-6 Alkoxy, -(C 1-6 alkylene)-(C 1-6 Alkoxy), -(C 1-6 alkylene)-(C 3-6 cycloalkyl), or -(C 1-6 alkylene)-(C 3-6 In certain embodiments, R 5 Each occurrence represents C independently 1-6 Alkyl, halogen, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, or -(C 1-6 alkylene)-(C 3-6 In certain embodiments, R 5 Each occurrence independently represents a halo or C 1-6 Halogenated alkyl.

[0121] In certain embodiments, R 5 Each occurrence represents C independently 1-6 In certain embodiments, R 5 Each occurrence independently represents a methyl group or an ethyl group.

[0122] In certain embodiments, R 5 Each occurrence independently represents a halo. In certain embodiments, R 5Each occurrence independently represents F or Cl.

[0123] In certain embodiments, R 5 Each occurrence represents C independently 1-6 In certain embodiments, R 5 Each occurrence represents C independently 1-4 In certain embodiments, R 5 Each occurrence represents C independently 2-6 In certain embodiments, R 5 Each occurrence represents C independently 1-6 In certain embodiments, R 5 Each occurrence independently represents -CF3, -CHF2, -CH2CF3, or -CH2CHF2.

[0124] In certain embodiments, R 5 Each occurrence represents C independently 3-6 In certain embodiments, R 5 Each occurrence represents C independently 4-6 In certain embodiments, R 5 Each occurrence represents C independently 5-6 In certain embodiments, R 5 Each occurrence independently represents cyclopropyl or cyclopentyl.

[0125] In certain embodiments, R 5 Each occurrence independently represents -SO2-(C 1-6 In certain embodiments, R 5 Each occurrence independently represents -SO2-(C 1-3 In certain embodiments, R 5 Each occurrence independently represents -SO2-(C 1-3 haloalkyl), wherein halogen is F. In certain embodiments, R 5 Each occurrence independently represents -SO2-(C 1-6 In certain embodiments, R 5 Each occurrence independently represents -SO2-(C 1-3 alkyl).

[0126] In certain embodiments, R 5 Each occurrence represents C independently 1-6 In certain embodiments, R 5 Each occurrence represents C independently 1-3 Hydroxyalkyl.

[0127] In certain embodiments, R 5 Each occurrence represents C independently 1-6 In certain embodiments, R 5 Each occurrence represents C independently 1-3 Alkoxy.

[0128] In certain embodiments, R 5 Each occurrence represents C independently 1-6 In certain embodiments, R 5 Each occurrence represents C independently 1-3 In certain embodiments, R 5 Each occurrence represents C independently 1-3 Haloalkoxy, wherein halogen is F.

[0129] In certain embodiments, R 5 Each occurrence represents independently -(C 1-6 alkylene)-(C 1-6 In certain embodiments, R 5 Each occurrence represents independently -(C 1-3 alkylene)-(C 1-3 In certain embodiments, R 5 Each occurrence independently represents -CH2-(C 1-6 alkoxy).

[0130] In certain embodiments, R 5 Each occurrence represents independently -(C 1-6 alkylene)-(C 3-6 In certain embodiments, R 5 Each occurrence represents independently -(C 1-3 alkylene)-(C 3-6 In certain embodiments, R 5 Each occurrence independently represents -CH2-(C 3-6 In certain embodiments, R 5 Each occurrence represents independently -(C 1-6 alkylene)-(C 3-6 In certain embodiments, R 5 Each occurrence represents independently -(C 1-3 alkylene)-(C 3-6 In certain embodiments, R 5 Each occurrence independently represents -CH2-(C 3-6In certain embodiments, R 5 Each occurrence independently represents -O-(C 1-6 alkylene)-(C 3-6 In certain embodiments, R 5 Each occurrence independently represents -O-(C 1-3 alkylene)-(C 3-6 In certain embodiments, R 5 Each occurrence independently represents -O-CH2-(C 3-6 cycloalkyl).

[0131] In certain embodiments, two occurrences of R 5 Together with their intervening atoms, they form a 4-7 membered ring containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur. 5 Together with their intervening atoms, they form a 4-6 membered ring containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur. 5 Together with their intervening atoms they form a 4-6 membered ring containing 1 heteroatom independently selected from oxygen, nitrogen and sulfur.

[0132] In certain embodiments, R 5 C 1-6 In certain embodiments, R 5 In certain embodiments, R 5 In certain embodiments, R 5 For ethyl.

[0133] In certain embodiments, R 5 In certain embodiments, R 5 is F or Cl. In certain embodiments, R 5 is F. In certain embodiments, R 5 For Cl.

[0134] In certain embodiments, R 5 C 1-6 In certain embodiments, R 5 C 1-4 In certain embodiments, R 5 C 2-6 In certain embodiments, R 5 C 1-6 In certain embodiments, R 5 is -CF3, -CHF2, -CH2CF3, or -CH2CHF2. In certain embodiments, R5 It is -CF3.

[0135] In certain embodiments, R 5 C 3-6 In certain embodiments, R 5 C 4-6 In certain embodiments, R 5 C 5-6 In certain embodiments, R 5 In certain embodiments, R 5 It is cyclopropyl.

[0136] In certain embodiments, R 5 -SO2-(C 1-6 In certain embodiments, R 5 -SO2-(C 1-3 In certain embodiments, R 5 -SO2-(C 1-3 haloalkyl), wherein halogen is F. In certain embodiments, R 5 -SO2-(C 1-6 In certain embodiments, R 5 -SO2-(C 1-3 alkyl).

[0137] In certain embodiments, R 5 C 1-6 In certain embodiments, R 5 C 1-3 In certain embodiments, R 5 is -CH2OH.

[0138] In certain embodiments, R 5 C 1-6 In certain embodiments, R 5 C 1-3 Alkoxy.

[0139] In certain embodiments, R 5 C 1-6 In certain embodiments, R 5 C 1-3 In certain embodiments, R 5 C 1-3 Haloalkoxy, wherein halogen is F.

[0140] In certain embodiments, R 5 For-(C 1-6 alkylene)-(C1-6 In certain embodiments, R 5 For-(C 1-3 alkylene)-(C 1-3 In certain embodiments, R 5 -CH2-(C 1-6 alkoxy).

[0141] In certain embodiments, R 5 For-(C 1-6 alkylene)-(C 3-6 In certain embodiments, R 5 For-(C 1-3 alkylene)-(C 3-6 In certain embodiments, R 5 -CH2-(C 3-6 In certain embodiments, R 5 For-(C 1-6 alkylene)-(C 3-6 In certain embodiments, R 5 For-(C 1-3 alkylene)-(C 3-6 In certain embodiments, R 5 -CH2-(C 3-6 halocycloalkyl).

[0142] In certain embodiments, R 5 -O-(C 1-6 alkylene)-(C 3-6 In certain embodiments, R 5 -O-(C 1-3 alkylene)-(C 3-6 In certain embodiments, R 5 -O-CH2-(C 3-6 cycloalkyl).

[0143] In certain embodiments, R 5 Each occurrence independently represents those depicted in Table 1 .

[0144] As generally defined above, A 1 is phenyl or a 5-6 membered monocyclic heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the phenyl and heteroaryl are replaced by n occurrences of R 5 Substitution; 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, wherein the heteroaryl is replaced by n occurrences of R 5Substitution; In certain embodiments, A 1 is R that appears n times 5 Substituted phenyl.

[0145] 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 replaced by n occurrences of R 5 Substitution; In certain embodiments, A 1 is a 6-membered monocyclic heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heteroaryl is replaced by n occurrences of R 5 Substitution; In certain embodiments, A 1 is pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyrrolyl or thienyl, each of which is replaced by n occurrences of R 5 In certain embodiments, A 1 is pyridyl or pyrimidinyl, each of which is replaced by n occurrences of R 5 In certain embodiments, A 1 is pyridazinyl or pyrazinyl, each of which is replaced by n occurrences of R 5 In certain embodiments, A 1 is pyrazinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, pyrrolyl or thienyl, each of which is replaced by n occurrences of R 5 replace.

[0146] In certain embodiments, A 1 Select from those depicted in Table 1.

[0147] As generally defined above, X 1 For-(C 1-4 Alkylene)-(a 3-5 membered saturated ring containing 1 nitrogen atom, wherein the ring is replaced by 0, 1, 2, 3 or 4 occurrences of C 1-4 Alkyl substituted)-***, wherein *** is 1 In certain embodiments, X 1 -CH2- (a 3-5 membered saturated ring containing 1 nitrogen atom, wherein the ring is replaced by 0, 1, 2, 3 or 4 occurrences of C 1-4 Alkyl substituted)-***, wherein *** is 1 In certain embodiments, X 1 -CH2CH2- (a 3-5 membered saturated ring containing 1 nitrogen atom, wherein the ring is replaced by 0, 1, 2, 3 or 4 occurrences of C 1-4 Alkyl substituted)-***, wherein *** is 1 In certain embodiments, X1 is -CH2- (a 3-membered saturated ring containing 1 nitrogen atom, wherein the ring is replaced by 0, 1, 2, 3 or 4 occurrences of C 1-4 Alkyl substituted)-***, wherein *** is 1 In certain embodiments, X 1 -CH2- (a 4-membered saturated ring containing 1 nitrogen atom, wherein the ring is replaced by 0, 1, 2, 3 or 4 occurrences of C 1-4 Alkyl substituted)-***, wherein *** is 1 In certain embodiments, X 1 is -CH2-(a 5-membered saturated ring containing 1 nitrogen atom, wherein the ring is substituted with 0, 1, 2, 3 or 4 occurrences of C1-4 alkyl)-***, wherein *** is the same as A 1 In certain embodiments, X 1 is -CH2-(a 4-membered saturated ring containing one nitrogen atom, wherein the ring is substituted with one occurrence of C1 alkyl)-***, wherein *** is the same as A 1 In certain embodiments, X 1 is -CH2-(a 5-membered saturated ring containing one nitrogen atom, wherein the ring is substituted with two occurrences of C1 alkyl)-***, wherein *** is the same as A 1 connection point.

[0148] In certain embodiments, X 1 for Where *** is the same as A 1 connection point.

[0149] In certain embodiments, X 1 for Where *** is the same as A 1 connection point.

[0150] 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.

[0151] As generally defined above, n is 0, 1, 2, or 3. In certain embodiments, n is 1, 2, or 3. In certain embodiments, n is 0, 2, or 3. In certain embodiments, n is 0, 1, or 3. In certain embodiments, n is 0, 1, or 2. In certain embodiments, n is 2 or 3. In certain embodiments, n is 0 or 1. In certain embodiments, n is 0 or 3. In certain embodiments, n is 0 or 2. In certain embodiments, n is 1 or 2. In certain embodiments, n is 1 or 3. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3.

[0152] In certain embodiments, the compound of Formula I is further defined as Formula Ia, or a pharmaceutically acceptable salt thereof, wherein all indicated variables are as defined above in the description of Formula I:

[0153]

[0154] In certain embodiments, the compound of Formula I is further defined as Formula Ib or Ic, or a pharmaceutically acceptable salt thereof, wherein all indicated variables are as defined above in the description of Formula I:

[0155]

[0156] In certain embodiments, the compound of Formula I is further defined as Formula Id or Ie, or a pharmaceutically acceptable salt thereof, wherein all indicated variables are as defined above in the description of Formula I:

[0157]

[0158] In certain embodiments, the compound of Formula I is further defined as Formula If or Ig, or a pharmaceutically acceptable salt thereof, wherein all indicated variables are as defined above in the description of Formula I:

[0159]

[0160] In certain embodiments, the compound of Formula I is further defined as Formula Ih, Ii, Ij, Ik, Il, Im, In, Io, Ip, or Iq, or a pharmaceutically acceptable salt thereof, wherein all indicated variables are as defined above in the description of Formula I:

[0161]

[0162]

[0163] The above description describes various embodiments in relation to the compounds of formula I. This patent application specifically contemplates combinations of all embodiments.

[0164] Exemplary specific compounds

[0165] In certain embodiments, the compound is a compound listed in Table 1, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound listed in Table 1.

[0166] Table 1. Exemplary compounds

[0167]

[0168]

[0169]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177]

[0178]

[0179]

[0180] Synthesis method

[0181] The following synthetic schemes illustrate methods for preparing the compounds described herein. The schemes are provided for illustration purposes only and are not intended to limit the scope or spirit of the invention. The starting materials shown in the schemes can be obtained from commercial sources or can be prepared according to procedures described in the literature.

[0182] Scheme 1 shows a general method for the preparation of tetrahydropyrrolo-pyridone C. Tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one A is coupled with carboxylic acid B using amide bond forming conditions (e.g., HATU-mediated acid-amine coupling) to afford tetrahydropyrrolo-pyridone C.

[0183] Solution 1.

[0184]

[0185] In this scheme, it will be appreciated by those skilled in the art that the functional group present on each part of the molecule should be compatible with the proposed reagent and reaction. Substituents incompatible with reaction conditions are apparent to those skilled in the art, and therefore alternative methods (such as, using protecting groups or substitution reactions) have been pointed out. Protecting group chemistry and strategy are well known in the art, such as described in " Protecting Groups in Organic Synthesis ", TW Greene and PGM Wuts, 3rd edition, John Wiley&Sons, 1999, in detail, the full content of the document is incorporated herein by reference. Those skilled in the art can also easily modify the modular synthesis route shown in scheme 1, to provide other compounds by carrying out functional group conversion to intermediate and final compound. Such functional group conversion is well known in the art, such as described in " Comprehensive Organic Synthesis " (BM Trost&I.Fleming, editor, 1991-1992).

[0186] Compounds that can be used in synthetic procedures

[0187] Another aspect of the present invention provides compounds that can be used for synthetic procedures. For example, one aspect of the present invention provides compounds of formula II:

[0188]

[0189] or a salt thereof; wherein:

[0190] R 1A C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -(C 1-6 alkylene)-(C 3-6 cycloalkyl) or hydrogen;

[0191] R 2A For halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 cycloalkyl, or hydrogen;

[0192] R 3A C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, -S-(C 1-4 alkyl), hydrogen or halo;

[0193] R 4A C 1-4 Alkyl, C1-4 haloalkyl, or hydrogen;

[0194] R 5A is hydrogen or C 1-4 alkyl; and

[0195] Z 1 is hydrogen or -C(O)2(C 1-6 alkyl).

[0196] The definitions of the variables in the above formula II encompass a plurality of chemical groups. The present application contemplates embodiments in which, for example, i) the definition of a variable is a single chemical group selected from the above chemical groups, ii) the definition of a variable is a set of two or more chemical groups selected from the above chemical groups, and iii) a compound is defined by a combination of variables, wherein the variable is defined by (i) or (ii).

[0197] In certain embodiments, the compound is of Formula II.

[0198] As generally defined above, R 1A C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -(C 1-6 alkylene)-(C 3-6 In certain embodiments, R 1A For hydrogen, methyl, In certain embodiments, R 1A In certain embodiments, R 1A In certain embodiments, R 1A for In certain embodiments, R 1A In certain embodiments, R 1A In certain embodiments, R 1A C 1-6 In certain embodiments, R 1A C 1-6 In certain embodiments, R 1A C 3-6 In certain embodiments, R 1A For-(C 1-6 alkylene)-(C 3-6 In certain embodiments, R 1A is selected from the groups depicted in the compounds of Table 1-A below.

[0199] As generally defined above, R 2A For halogen, C 1-4 Alkyl, C1-4 Halogenated alkyl, C 3-6 In certain embodiments, R 2A is hydrogen, methyl, ethyl, fluorine, chlorine, bromine, -CF3, or cyclopropyl. 2A In certain embodiments, R 2A In certain embodiments, R 2A In certain embodiments, R 2A In certain embodiments, R 2A In certain embodiments, R 2A In certain embodiments, R 2A In certain embodiments, R 2A In certain embodiments, R 2A In certain embodiments, R 2A C 1-4 In certain embodiments, R 2A C 1-4 In certain embodiments, R 2A C 3-6 In certain embodiments, R 2A is selected from the groups depicted in the compounds of Table 1-A below.

[0200] As generally defined above, R 3A C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, -S-(C 1-4 In certain embodiments, R 3A is hydrogen, methyl, methoxy, or -SCH3. In certain embodiments, R 3A In certain embodiments, R 3A In certain embodiments, R 3A In certain embodiments, R 3A In certain embodiments, R 3A C 1-4 In certain embodiments, R 3A C 1-4 In certain embodiments, R 3A C 1-4 In certain embodiments, R 3A For-S-(C 1-4 In certain embodiments, R 3A In certain embodiments, R 3Ais selected from the groups depicted in the compounds of Table 1-A below.

[0201] As generally defined above, R 4A C 1-4 Alkyl, C 1-4 In certain embodiments, R 4A In certain embodiments, R 4A In certain embodiments, R 4A In certain embodiments, R 4A C 1-4 In certain embodiments, R 4A C 1-4 In certain embodiments, R 4A is selected from the groups depicted in the compounds of Table 1-A below.

[0202] As generally defined above, R 5A is hydrogen or C 1-4 In certain embodiments, R 5A In certain embodiments, R 5A C 1-4 In certain embodiments, R 5A is selected from the groups depicted in the compounds of Table 1-A below.

[0203] As generally defined above, Z 1 is hydrogen or -C(O)2(C 1-6 In certain embodiments, Z 1 In certain embodiments, Z 1 In certain embodiments, Z 1 In certain embodiments, Z 1 -C(O)2(C 1-6 In certain embodiments, Z 1 is selected from the groups depicted in the compounds of Table 1-A below.

[0204] The above description describes a number of embodiments associated with the compound of formula II. This patent application specifically contemplates the combination of all embodiments.

[0205] Another aspect of the present invention provides the compounds shown in Table 1-A below.

[0206] Table 1-A

[0207]

[0208]

[0209] In certain embodiments, R 1A For hydrogen, methyl, In certain embodiments, R 2A is hydrogen, methyl, ethyl, fluorine, chlorine, bromine, -CF3, or cyclopropyl. 3A is hydrogen, methyl, methoxy, or -SCH3. In certain embodiments, R 4A In certain embodiments, R 5A In certain embodiments, Z 1 is hydrogen or tert-butoxycarbonyl.

[0210] II. Therapeutic Applications

[0211] 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 specific compound of Formula I is a compound as defined by one of the embodiments described in Section I above.

[0212] The methods described herein can be further defined according to other characteristics, such as identification of the muscarinic acetylcholine receptor-mediated disorder and / or subject.

[0213] Muscarinic acetylcholine receptor-mediated conditions 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 cholinesterase can provide a therapeutic effect. Exemplary muscarinic acetylcholine receptor-mediated conditions include schizophrenia, movement disorders, mood disorders, cognitive disorders, attention disorders, addictive disorders, and pain. In certain embodiments, the muscarinic acetylcholine receptor-mediated condition is selected from schizophrenia, movement disorders, mood disorders, cognitive disorders, attention disorders, addictive disorders, and neurological conditions. In certain embodiments, the muscarinic acetylcholine receptor-mediated condition is a movement disorder, mood disorder, or cognitive disorder. In certain embodiments, the muscarinic acetylcholine receptor-mediated condition is selected from attention disorders and addictive disorders.

[0214] In certain embodiments, the muscarinic acetylcholine receptor-mediated disorder is schizophrenia or a related disorder. Disorders related to schizophrenia include schizoaffective disorder, psychotic disorder, Alzheimer's disease-related psychosis, hereditary cerebral hemorrhage with amyloidosis, Dutch type (HCHWA-D), Creutzfeldt-Jakob disease, prion disease, Parkinson's disease-related psychosis, 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.

[0215] In certain embodiments, the muscarinic acetylcholine receptor-mediated disorder is selected from schizoaffective disorder, psychosis, delusional disorder, Alzheimer's disease-related psychosis, hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D), Creutzfeldt-Jakob disease, prion disease, Parkinson's disease-related psychosis, 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, Alzheimer's disease-related psychosis, hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D), Creutzfeldt-Jakob disease, prion disease, Parkinson's disease-related psychosis, psychotic depression, bipolar disorder, bipolar disorder with psychosis, Huntington's disease, cerebral amyloid angiopathy, and dementia with Lewy bodies.

[0216] In certain embodiments, the muscarinic acetylcholine receptor-mediated condition is a movement disorder. Exemplary movement disorders include Tourette syndrome, Friederich's ataxia, amyotrophic lateral sclerosis, progressive supranuclear palsy, Huntington's disease, dyskinesia, restless legs syndrome, and other diseases or conditions in which symptoms include excessive movement, twitching, and spasms. In certain embodiments, the muscarinic acetylcholine receptor-mediated condition is selected from the group consisting of Tourette syndrome, Friederich's ataxia, amyotrophic lateral sclerosis, progressive supranuclear palsy, Huntington's disease, dyskinesia, and restless legs syndrome.

[0217] In certain embodiments, the muscarinic acetylcholine receptor-mediated condition 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 condition is selected from major depressive disorder, dysthymia, recurrent brief depressive disorder, minor depressive disorder, bipolar disorder, mania, and anxiety.

[0218] In certain embodiments, the muscarinic acetylcholine receptor-mediated disorder is a cognitive disorder. Exemplary cognitive disorders are diseases or disorders characterized by cognitive deficits (e.g., abnormal working memory, problem-solving ability, etc.), such as Alzheimer's disease, hereditary cerebral hemorrhage with amyloidosis, Dutch type (HCHWA-D), Creutzfeldt-Jakob disease, prion diseases, Parkinson's disease, Parkinson's disease-levodopa-induced movement disorders, cerebral amyloid angiopathy, dementia (e.g., AIDS-related dementia, vascular dementia, age-related dementia, Lewy body-related dementia, and idiopathic dementia), Pick's disease, tauopathies, synucleinopathies, confusion, mild cognitive impairment, fatigue-related cognitive deficits, learning disabilities, traumatic brain injury, autism, age-related cognitive decline, and Cushing's disease (a type of cognitive impairment associated with autoimmune diseases).

[0219] In certain embodiments, the muscarinic acetylcholine receptor-mediated disorder is selected from Alzheimer's disease, hereditary cerebral hemorrhage with amyloidosis, Dutch type (HCHWA-D), Creutzfeldt-Jakob disease, a prion disease, Parkinson's disease, Parkinson's disease-levodopa-induced dyskinesia, cerebral amyloid angiopathy, dementia (e.g., AIDS-related dementia, vascular dementia, age-related dementia, Lewy body-associated dementia, and idiopathic dementia), Pick's disease, tauopathies, synucleinopathies, confusion, mild cognitive impairment, fatigue-related cognitive deficits, learning disabilities, traumatic brain injury, autism, age-related cognitive decline, and Cushing's disease.

[0220] In certain embodiments, the muscarinic acetylcholine receptor-mediated disorder is an attention disorder. Exemplary attention disorders are diseases or conditions characterized by abnormal or reduced attention span, such as attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADD), Dubois syndrome, FG syndrome, Down syndrome, growth retardation due to insulin-like growth factor 1 (IGF1) deficiency, hepatic encephalopathy syndrome, and Strauss syndrome.

[0221] In certain embodiments, the muscarinic acetylcholine receptor-mediated disorder is selected from the group consisting of attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADD), Dubois syndrome, FG syndrome, Down syndrome, growth retardation due to insulin-like growth factor 1 (IGF1) deficiency, hepatic encephalopathy syndrome, and Strauss syndrome.

[0222] In certain embodiments, the muscarinic acetylcholine receptor mediated condition is an addictive disorder. Exemplary addictive disorders are diseases or conditions characterized by addiction or substance dependence as defined in the Diagnostic & Statistical Manual V (DSM-5). Such conditions are generally characterized by physical dependence, withdrawal, and tolerance to substances. These substances include, but are not limited to, alcohol, cocaine, amphetamines, opioids, benzodiazepines, Drugs, inhalants, nicotine, barbiturates, cocaine and marijuana. Addictive disorders also encompass behaviors that patients perform compulsively or persistently, regardless of obvious negative consequences. For example, those skilled in the art recognize that ludomania (gambling addiction or compulsive gambling) is an addictive behavior that often has devastating consequences. In certain embodiments, the addictive behavior may be internet gaming disorder (gaming addiction), as defined in DSM-5.

[0223] In certain embodiments, the muscarinic acetylcholine receptor-mediated disorder is addiction to one of the following substances: alcohol, cocaine, amphetamines, opioids, benzodiazepines drugs, inhalants, nicotine, barbiturates, cocaine, or marijuana; gambling addiction; and Internet gaming disorder.

[0224] In certain embodiments, the muscarinic acetylcholine receptor-mediated disorder is a neurological disorder. Exemplary neurological disorders are pain, physical pain, or discomfort caused by disease or injury. Pain is a subjective experience, and the perception of pain is carried out by the central nervous system (CNS). Typically, noxious (peripheral) stimuli are delivered to the CNS in advance, but pain is not always associated with nociception. Clinical pain is diverse, originating from different underlying pathophysiological mechanisms and requiring different treatments. Several major types of clinical pain have been characterized: acute pain, chronic pain, neuropathic pain, inflammatory pain, and nociceptive pain.

[0225] In certain embodiments, the muscarinic acetylcholine receptor-mediated condition is selected from acute pain, chronic pain, neuropathic pain, inflammatory pain, and nociceptive pain. In certain embodiments, the muscarinic acetylcholine receptor-mediated condition is acute pain. In certain embodiments, the muscarinic acetylcholine receptor-mediated condition is chronic pain. In certain embodiments, the muscarinic acetylcholine receptor-mediated condition is neuropathic pain. In certain embodiments, the muscarinic acetylcholine receptor-mediated condition is inflammatory pain. In certain embodiments, the muscarinic acetylcholine receptor-mediated condition is nociceptive pain. In certain embodiments, the muscarinic acetylcholine receptor-mediated condition is inflammatory pain or nociceptive pain.

[0226] In certain embodiments, the muscarinic acetylcholine receptor-mediated disorder is selected from schizoaffective disorder, psychosis, Alzheimer's disease-related psychosis, hereditary cerebral hemorrhage with amyloidosis Dutch type (HCHWA-D), Creutzfeldt-Jakob disease, prion disease, Parkinson's disease-related psychosis, Parkinson's disease-levodopa-induced dyskinesia, psychotic depression, bipolar disorder, bipolar disorder with psychosis, Huntington's disease, cerebral amyloid angiopathy, Lewy body dementia, Tourette syndrome, Friedreich's ataxia, amyotrophic lateral sclerosis, progressive supranuclear palsy, Huntington's disease, movement disorders, 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 Dutch type (HCHWA-D), (HCHWA-D), Creutzfeldt-Jakob disease, prion diseases, Parkinson's disease, Parkinson's disease-levodopa-induced dyskinesia, dementia (including but not limited to AIDS-related dementia, vascular dementia, age-related dementia, Lewy body-related dementia, and idiopathic dementia), Pick's disease, tauopathies, synucleinopathies, confusion, mild cognitive impairment, fatigue-related cognitive deficits, learning disabilities, traumatic brain injury, autism, age-related cognitive decline, Cushing's disease, attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADD), Dubowitz syndrome, Ferris-Gilch syndrome, Down syndrome, growth retardation due to insulin-like growth factor I (IGF1) deficiency, hepatic encephalopathy syndrome, and Strauss syndrome, and addiction to any of the following substances: alcohol, cocaine, amphetamines, opioids, benzodiazepines drugs, inhalants, nicotine, barbiturates, cocaine or marijuana, gambling addiction, internet gaming disorder, acute pain, chronic pain, neuropathic pain, inflammatory pain, and nociceptive pain.

[0227] 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, movement disorders, cerebral amyloid angiopathy, dementia, hereditary cerebral hemorrhage with amyloidosis Dutch type (HCHWA-D), Creutzfeldt-Jakob disease, prion disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, autism, addiction, or a sleep disorder.

[0228] In certain embodiments, the muscarinic acetylcholine receptor-mediated disorder is schizoaffective disorder, psychosis, delusional disorder, Alzheimer's disease-related psychosis, Parkinson's disease-related psychosis, psychotic depression, bipolar disorder, bipolar disorder with psychosis, Huntington's disease, dementia with Lewy bodies, Tourette syndrome, Friedreich's ataxia, Huntington's disease, restless legs syndrome, major depressive disorder, dysthymia, recurrent brief depressive disorder, minor depressive disorder, mania, anxiety, Alzheimer's disease , Parkinson's disease, dementia, Pick's disease, tauopathies, synucleinopathies, confusion, cognitive deficits related to fatigue, learning disabilities, traumatic brain injury, autism, age-related cognitive decline, Cushing's disease, attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADD), Dubois syndrome, Ferris-Gilchoff syndrome, Down syndrome, growth retardation due to insulin-like growth factor I (IGF1) deficiency, hepatic encephalopathy syndrome, Strauss syndrome, or agitation related to neurodegeneration.

[0229] Methods for activating muscarinic acetylcholine receptors

[0230] 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.

[0231] In certain embodiments, the muscarinic acetylcholine receptor is muscarinic acetylcholine receptor M4.

[0232] Subjects

[0233] In certain embodiments, the subject is a human. In certain embodiments, the subject is an adult. In certain embodiments, the subject is a child.

[0234] Medical uses

[0235] Another aspect of the invention provides the use of a compound described herein (such as a compound of Formula I or other compounds in Section I) in the manufacture of a medicament. In certain embodiments, the medicament is used to treat a disorder described herein, such as a muscarinic acetylcholine receptor-mediated disorder.

[0236] Another aspect of the invention provides the use of a compound described herein (such as a compound of Formula I or other compounds in Section I) for treating a medical condition (such as a medical condition described herein, such as a muscarinic acetylcholine receptor mediated condition).

[0237] Assays for evaluating compound bioactivity in rats

[0238] The ability of compounds to affect behavioral activity in rats can be tested according to the following procedure. Animals: Adult male Sprague Dawley rats (Envigo, Indianapolis, IN, USA) were housed in colonies maintained at 23°C with a 12-hour light / dark cycle (lights on at 0600 hours). At the start of the study, all animals weighed 290-330g and were evenly divided into 5 groups (n=8 / group) and received one of the following treatment conditions. Behavioral Procedure: Studies were conducted in MedAssociates open field chambers (27.3cm x 27.3cm x 20.3cm, MedAssociates, St. Albans, VT), where movement was automatically tracked and recorded by 16 array beams. The Tmax of the test article during the amphetamine-induced phase was determined to be consistent with the administration pretreatment of the optimal route of administration. All groups were treated subcutaneously with 0.5mg / kg amphetamine (AMP). The test article was tested in three dose groups with a half-log increase between doses. Risperidone (0.55 mg / kg, 30 minutes, sc) can be used as a positive control and is administered to Group 5. To determine the effect of the test article on AMP-induced hyperlocomotion, rats are placed in an open field and allowed to acclimate for 30 minutes before receiving 0.5 mg / kg AMP sc. During the entire 90-minute period, locomotor data (distance traveled) are recorded in 5-minute units. The dose of AMP is selected based on the selective increase in locomotor behavior relative to stereotyped behavior. A dose of risperidone that produces a reliable effect and serves as a positive control is selected. Statistical analysis: Spontaneous migration (before AMP administration) is calculated as the total distance traveled during the first 30 minutes of the experimental phase. AMP-induced responses are calculated as the total distance traveled during the last 60 minutes of the experimental phase starting immediately after AMP administration. Locomotor data can be analyzed by one-way ANOVA. When there is a significant overall ANOVA, post hoc comparisons can be performed by Dunnett's test, and statistical significance is determined as p<0.05.

[0239] IV. Combination Therapy

[0240] Another aspect of the present invention provides combination therapies. The compounds described herein (such as compounds of Formula I or other compounds in Section I) or pharmaceutically acceptable salts thereof can be used in combination with other therapeutic agents to treat medical conditions, such as autoimmune conditions or muscarinic acetylcholine receptor-mediated conditions.

[0241] 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 concurrently or sequentially 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 the disclosed compounds and the additional one or more therapeutic agents has a synergistic effect.

[0242] One or more other therapeutic agents can be administered separately from the compounds or compositions of the present invention as part of a multiple dosing regimen. Alternatively, one or more other therapeutic agents can be part of a single dosage form, mixed in a single composition with the compounds of the present invention. If administered in a multiple dose regimen, one or more other therapeutic agents and the compounds or compositions of the present invention can be administered simultaneously, sequentially, or within a period of time, 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. In some embodiments, one or more other therapeutic agents and the compounds or compositions of the present invention are administered in a multiple dosing regimen that is spaced more than 24 hours apart.

[0243] Other therapeutic agents for the treatment of muscarinic acetylcholine receptor-mediated disorders

[0244] Depending on the disease, condition or disorder to be treated, various pharmaceutical agents may be selected for use in combination with the compounds of the present invention. Pharmaceutical agents that may be used in combination with the compositions of the present invention include, but are not limited to:

[0245] (i) acetylcholinesterase inhibitors such as donepezil hydrochloride (ARICEPT, MEMA C), physostigmine salicylate (ANTILIRIUM), physostigmine sulfate (ESERINE), metrifonate, neostigmine, ganstigmine, pyridostigmine (MESTINON), ambenonium (MYTE LASE), demarcarium, Debio 9902 (also known as ZT-1; Debiopharm), rivastigmine (EXELON), ladostigid, NP-0361, galantamine hydrobromide (RAZADYNE, RIMINYL, NIVALIN), tacrine (COGNEX), tolserine, vespermumillin maleate, memoquin, huperzine A (HUP-A; NeuroHitech), phenylserine, edrophonium (ENLON, TENSILON), and INM-176;

[0246] (ii) amyloid-B (or fragments 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);

[0247] (iii) antibodies to amyloid-B (or fragments thereof), 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 publications. those disclosed in Publication Nos. WO04 / 032868, WO05 / 025616, WO06 / 036291, WO06 / 069081, WO06 / 118959 and U.S. Patent Publication Nos. US2003 / 0073655, US2004 / 0192898, US2005 / 0048049, US2005 / 0019328, European Patent Publication Nos. EP0994728 and 1257584, and U.S. Patent No. 5,750,349;

[0248] (iv) amyloid lowering agents or inhibitors (including drugs that reduce amyloid production, accumulation and fibrillation), such as dimebon, dafnetide, erosartan, 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 Biotechnolo gy), flurbiprofen (ANSAID, FROBEN) and its R-enantiomer taflubil 34 (FLU) RIZAN), nitroflurbiprofen, fenoprofen (FENOPRON, NALFON), ibuprofen (ADVIL, MOTRIN, NUROFEN), ibuprofen lysine, meclofenamic acid, meclofenamatesodium (MECLOMEN), indomethacin (INDOC IN), 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 insulinolysin) sulysin), Ginkgo biloba extract EGb-761 (ROKAN, TEBONIN), tramisart (CEREBRIL, ALZHEMED), irosart (FIBRILLEX, KIACTA), compound W [3,5-bis(4-nitrophenoxy)benzoic acid], NGX-96992, neprilysin (also known as neutral endopeptidase (NEP)), scyllo-inositol (also known as scyllito l), atorvastatin (LIPITOR), simvastatin (ZOCOR), KLVFF-(EEX)3, SKF-74652, ibumolen mesylate, BACE inhibitors such as ASP-1702, SCH-745966, JNJ-715754, AMG-0683, AZ-12304146, BMS-782450, GS K-188909, NB-533, E2609, and TTP-854; γ-secretase modulators, such as ELN D-007;and RAGE (receptor for advanced glycation endproducts) inhibitors, such as TTP488 (Transtech) and TTP4000 (Transtech), and those disclosed in U.S. Pat. No. 7,285,293, including PTI-777;

[0249] (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, cilazoline, guanfacine (INTU NIV), lofexidine, xylazine, modafinil (PROVIGIL), adrafinil, and armofinil (NUVIGIL);

[0250] (vi) beta-adrenergic receptor blockers (beta blockers), such as carteolol, esmolol (BREVIBLOC), labetalol (NORMODYNE, TRANDATE), oxprenolol (LARACOR, TRASACOR), pindolol (VISKEN), propranolol (IN DERAL), 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);

[0251] (vii) Anticholinergics such as amitriptyline (ELAVIL, ENDEP), butritriptyline, benztropine mesylate (COGENTIN), trihexyphenidyl (ARTANE), diphenhydramine (BENADRYL), orphenadrine (NORFLEX), hyoscyamine, atropine (ATROPEN), scopolamine (TRANSDERMSCOP), methylscopolamine bromide (PARMINE), dicyclomine (BENTYL, BYCLOMINE, DIBENT, DILOMINE), tolterodine (DETROL), oxybutynin (DITROPAN, LYRINEL XL, OXYTROL), penthienate (PENTINOID), and fentanyl (PENTINOID). bromide), propantheline (PRO-BANTHINE), cyclizine, imipramine hydrochloride (TOFRANIL), imipramine maleate (SURMONTIL), lofepramine, desipramine (NORPRAMIN), doxepin (SINEQUAN, ZONALON), trimipramine (SUR MONTIL), and glycopyrrolate (ROBINUL)

[0252] (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), valproate sodium (DEPACON), 1-benzyl-5-bromouracil, plogabamide, beclamide, zonisamide (TRERIEF, EXCEGRAN), CP-465022, retigabine, talampanel, and primidone (MYSOLINE);

[0253] (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 (MOBAN), 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);

[0254] (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), lifarizine, diltiazem (CARDIZEM), verapamil (CALAN, VERELAN), AR-R 18565 (AstraZeneca), and enecardin;

[0255] (xi) catechol O-methyltransferase (COMT) inhibitors such as niticapine, tolcapone (TASMAR), entacapone (COMTAN) and tropolone;

[0256] (xii) central nervous system stimulants such as atomoxetine, reboxetine, yohimbine, caffeine, phendimetrazine, phendimetrazine, pemoline, fencamfamine (Glucoenergan, Reactivan), fenethylamine (Captagon), meretran, dapoxetine (also known as dimethylaminoethanol), methylphenidate (Daytran), methylphenidate hydrochloride (Ritalin), dexmethylphenidate (Focalin), amphetamines (alone or in combination with other CNS stimulants, e.g., Adderall (amphetamine aspartate, amphetamine sulfate, dextroamphetamine succinate, and dextroamphetamine sulfate)), dextroamphetamine sulfate (Dexedrine, Destrostat), methamphetamine (Desoxyn), rivoamphetamine (Vyvanse), and benzphetamine (Didrex);

[0257] (xiii) Corticosteroids, such as prednisone (STERAPRED, DELTASONE), prednisolone (PRELONE), prednisolone acetate (OMNIPRED, PRED MILD, PRED FORTE), prednisolone sodium phosphate (ORAPRED ODT), methylprednisolone (MEDROL); methylprednisolone acetate (DEPOMEDROL) and methylprednisolone sodium succinate (A-METHAPRED, SOLU-MEDROL);

[0258] (xiv) Dopamine receptor agonists, such as apomorphine (APOKYN), bromocriptine (PARLODEL), cabergoline (DOSTINEX), dihydrexidine, dihydroergocryptine, fenoldopam (CORLOPAM), lisuride (DOPERGIN), terguride, spergolide (PERMAX), piribedil (TRIVASTAL, TRASTAL), pramipexole (MIRAPEX), quinpirole, ropinirole (REQUIP), rotigotine (NEUPRO), SKF-8295 8 (Glaxo-SmithKline), cariprazine, paldorunol, and sarizoltan; (xv) dopamine receptor antagonists such as chlorpromazine, fluphenazine, haloperidol, loxapine, risperidone, thioridazine, thiothixene, trifluoperazine, tetrabenazine (NITOMAN, XENAZINE), 7-hydroxyamoxapine, droperidol (INAPSINE, DRIDOL, DROPLETAN), domperidone (MOTILIUM), L-741742, L-745870, raclopride, SB-277011A, SCH-23390, ecopipan, SKF-83566, and metoclopramide (REGLAN);

[0259] (xvi) dopamine reuptake inhibitors such as bupropion, safinamide, nomifensine maleate (MERITAL), vanoxerine (also known as GBR-12909) and its decanoate DBL-583, and ami neptine;

[0260] (xvii) gamma-amino-butyric acid (GABA) receptor agonists, such as baclofen (LIORESAL, KEMSTRO), siclofen, pentobarbital (NEMBUTAL), progabamide (GABRENE), and clomethiazole;

[0261] (xviii) histamine 3 (H3) antagonists such as ciproxifan, tiprolisant, S-38093, idapyrrolidone, tilorisant, GSK-239512, GSK-207040, JNJ-5207852, JNJ-17216498, HPP-404, SAR-110894, trans-N-ethyl-3-fluoro-3 -[3-Fluoro-4-(pyrrolidin-1-ylmethyl)phenylcyclobutanecarboxamide (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);

[0262] (xix) immunomodulators such as glatiramer acetate (also known as copolymer-1; COPAX ONE), MBP-8298 (synthetic myelin basic protein peptide), dimethyl fumarate, fingolimod (also known as FTY720), roquinemod (LINOMIDE), laquinimod (also known as ABR-215062 and SAIK-MS), ABT-874 (human anti-IL-12 antibody; Abbott), rituximab (RITUXAN), alentuzumab (CAMPATH), daclizumab (ZENAPAX), and natalizumab (TYSABRI);

[0263] (xx) immunosuppressants such as methotrexate (TREXALL, RHEUMATREX), mitoxantrone (NOVANTRONE), mycophenolate mofetil (CELLCEPT), mycophenolate sodium (MYFORTIC), azathioprine (AZASAN, IMURAN), mercaptopurine (PURI-NETHO L), cyclophosphamide (NEOSAR, CYTOXAN), chlorambucil (LEUKERAN), cladribine (LEUSTATIN, MYLINAX), alpha-fetoprotein, etanercept (ENBREL), and 4-(benzyloxy)-5-[(5-undecyl-2H-pyrrol-2-methylene)methyl]-1H,1'H-2,2'-bipyrrole (also known as PNU-156804);

[0264] (xxi) interferons, including interferon beta-la (AVONEX, REBIF) and interferon beta-lb (BETASERON, BETAFERON);

[0265] (xxii) levodopa (or its methyl or ethyl ester), alone or in combination with a dopa-decarboxylase inhibitor (e.g., carbidopa (SINEMET, CARBILEV, PARCOPA), benserazide (MADOPAR), α-methyldopa, monofluoromethyldopa, difluoromethyldopa, bromocrisine, or m-hydroxybenzylhydrazine);

[0266] (xxiii) N-methyl-D-aspartate (NMDA) receptor antagonists, such as memantine (NA MENDA, AXURA, EBIXA), amantadine (SYMMETREL), acamprosate (CA MPRAL), besonprodil, ketamine (KETALAR), dexanabinol, dexefaxen, dextromethorphan, dextrorphan, troxolidine, CP-283097, himantane, idantadol, ipexazone, L-701252 (Merck), lancicemine, levorphanol (DROMORAN), LY-233536 and LY-235959 (both from Lilly), methadone (DOLOPHINE), neramexane, perginfortep, phencyclidine, tianeptine (STABLON), dizocilpine (also known as MK-801), EAB-318 (Wyeth), ibogaine, voacangine (Vocan) gine), tiletamine, riluzole (RILUTEK), atiganel (CERESOTAT), galvistinide, and remacimide;

[0267] (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), niramide (NIAMID), rasagiline (AZILECT), iproniazide (MARSILID, IPROZID, IPRONID), CHF-3381 (Chiesi Farmaceutici), iproclozide, toloxatone (HUMORYL, PERENUM), difemelane, desoxypeganine, harmine (also known as telepathine or banasterine), harm aline, linezolid (ZYVOX, ZYVOXID), and pargyline (EUDATIN, SUPIR DYL);

[0268] (xxv) muscarinic receptor (particularly M1 subtype) agonists such as cevimeline, levetiracetam, bethanechol (DUVOID, URECHOLINE), itameline, pilocarpine (SALAGEN), NGX267, arecoline, L-687306 (Merck), L-689660 (Merck), furathonium iodide (FURAMON, FURANOL), furathonium besylate, furathonium toluenesulfonate, McN-A-343, oxotremorine, sabcomeline, AC-90222 (Acadia Pharmaceuticals), and carbachol (CARBASTAT, MIOSTAT, CARBOPTIC);

[0269] (xxvi) Neuroprotective drugs such as bosutinib, condoliase, airmoclomol, lamotrigine, perampanel, aniracetam, minaprim, riluzole, N-hydroxy-1,2,4,9-tetrahydro-3H-carbazole-3-imide, desmoteplase, atibant, astaxanthin, neuropeptide NAP (e.g., AL-108 and AL-208; both Allon Therapeutics), neurostrol, perampenel, isopycine, bis(4-β-D-glucopyranosyloxybenzyl)-2-β-D-glucopyranosyl-2-isobutyltartrate (also known as Dactylorhiza B) B) or DHB), formobactin, xaliproden (xAPRILA), lactacystin, dimeboline hydrochloride (DIMEBON), desufenton (CEROVIVE), alendronate (ONO-2506, PROGLIA, CEREACT), citicoline (also known as cytidine 5'-diphosphocholine), edaravone (RADICUT), AEOL-10113 and AEOL-10150 (both 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), ancrodase (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, pyclozotan, 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 zonampanel;

[0270] (xxvii) nicotinic 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 (both from Targacept), and RJR-2403;

[0271] (xxviii) norepinephrine (norepinephrine) 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 radaxafine;

[0272] (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, pagrelib and pimobendan), (d) PDE4 inhibitors (e.g., apremilast, ibudilastroflumilast, rolipram, Rolipram) and roxithromycin). 20-1724, ibudilast (KETAS), piramilast (also known as RP73401), CDP840, cilomilast (ARIFLO), roflumilast, tofimilast, oliminast (also known as GRC 3886), tetomilast (also known as OPC-6535), lirimifast, theophylline (UNIPHYL, THEOLAIR), arofylline (also known as LAS-31025), doxofylline, RPR-122818, or mesembrine), and (e) PDES 38 inhibitors (e.g., sildenafil (VI AGRA, REVATIO), tadalafil (CIALIS), vardenafil (LEVITRA, VIV ANZA), udenafil, avanafil, dipyridamole (PERSANTINE), E-4010, E-4021, E-8010, zaprinast, iodenafil, milonafil, 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. Serial 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]phenoxymethyl)quinolin-3(4H)-one and SCH-1518291; and (j) PDE11 inhibitors;

[0273] (xxx) Quinolines, such as quinine (including its hydrochloride, dihydrochloride, sulfate, hydrogen sulfate, and gluconate), chloroquine, sontoquine, hydroxychloroquine (PLAQUENIL), mefloquine (LARIAM), and amodiaquine (CAMOQUIN, FLAVOQUINE);

[0274] (xxxi) beta-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, (+)-phenylserine 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;

[0275] (xxxii) γ-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;

[0276] (xxxiii) serotonin (5-hydroxytryptamine) 1A (5-HT, A) receptor antagonists, such as spiperone, levo-pindolol, BMY 7378, NAD-299, S-(-)-UH-301, NAN 190, lecozotan;

[0277] (xxxiv) serotonin (5-hydroxytryptamine) 2C (5-HT2c) receptor agonists, such as valcaserin and zicronapine;

[0278] (xxxv) serotonin (5-hydroxytryptamine) 4 (5-HT4) receptor agonists, such as PRX-03140 (Epix);

[0279] (xxxvi) serotonin (5-hydroxytryptamine) 6 (5-HT) receptor antagonists, such as A-964324, AVI-101, AVN-211, mianserin (TORVOL, BOLVIDON, NORVAL), methiothepin (also known as metitepine), 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

[0280] (xxxvii) serotonin (5-HT) reuptake inhibitors such as alapropylate, citalopram (CELEXA, CIPRAMIL), escitalopram (LEXAPRO, CIPRALEX), clomipramine (ANAFRANIL), duloxetine (CYMBALTA), femoxetine (MALE XIL), fenfluramine (PONDIMIN), desfenfluramine, fluoxetine (PROZAC), fluvoxamine (LUVOX), indalpine, milnacipran (IXEL), paroxetine (PAXIL, SER OXAT), sertraline (ZOLOFT, LUSTRAL), trazodone (DESYREL, MOLIP AXIN), venlafaxine (EFFEXOR), zimelidine (NORMUD, ZELMID), bicifadine, desvenlafaxine (PRISTIQ), busofensine, vilazodone, cariprazine, neuralstem, and tesofensine;

[0281] (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-derived neurotrophic factor (GDNF), and agents that stimulate the production of trophic factors, such as propentofylline, idebenone, PYM50028 (COGANE; Phytopharm), and AIT-082 (NEOTROFIN);

[0282] (xxxix) Glycine transporter-1 inhibitors such as paliflutine, ORG-25935, JNJ-17305600, and ORG-26041;

[0283] (xl) AMPA-type glutamate receptor modulators, such as perampanel, mibampatol, selupanel, GSK-729327, N-{(3S,4S)-4-[4-(5-cyanothiophen-2-yl)phenoxy]tetrahydro-furan-3-ylpropane-2-sulfonamide, and the like.

[0284] (xli) Janus kinase inhibitors (JAK), such as, but not limited to, tofacitinib, ruxolitinib, baricitinib, CYT387, GLPG0634, letutinib, paritinib, and TG101348.

[0285] (xlii) Interleukin-1 receptor-associated kinase 4 inhibitors (IRAK4), such as but not limited to PF-06650833.

[0286] In certain embodiments, the additional therapeutic agent is an orthosteric agonist of a muscarinic acetylcholine receptor.

[0287] 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 concurrently with a substituted tetrahydropyrrolo-pyridone compound described herein (such as a compound of Formula I).

[0288] In certain embodiments, a pharmaceutical composition comprising (i) an orthosteric agonist of a muscarinic acetylcholine receptor and (ii) a substituted tetrahydropyrrolo-pyridone compound described herein, such as a compound of Formula I, is administered to a subject.

[0289] In certain embodiments, an orthosteric agonist of a muscarinic acetylcholine receptor is administered to a subject separately from a substituted tetrahydropyrrolo-pyridone compound described herein, such as a compound of Formula I. In certain embodiments, an orthosteric agonist of a muscarinic acetylcholine receptor is administered to a subject via a first pharmaceutical composition, and a substituted tetrahydropyrrolo-pyridone compound described herein, such as a compound of Formula I, is administered to a subject via a second pharmaceutical composition.

[0290] In certain embodiments, the amount of (i) an orthosteric agonist of a muscarinic acetylcholine receptor and / or (ii) a substituted tetrahydropyrrolo-pyridone compound described herein, such as a compound of Formula I, administered to a patient is reduced compared to the use of (i) an orthosteric agonist of a muscarinic acetylcholine receptor or (ii) a substituted tetrahydropyrrolo-pyridone compound described herein, such as a compound of Formula I, in monotherapy treatment.

[0291] Thus, another aspect of the present invention provides a method for treating a condition that is ameliorated by muscarinic receptor activation in a subject in need thereof, wherein the method comprises administering to the subject a substituted tetrahydropyrrolo-pyridone compound as described herein (such as 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-pyridone compound act on the same muscarinic acetylcholine receptor subtype. In certain embodiments, the orthosteric agonist of a muscarinic acetylcholine receptor and the substituted tetrahydropyrrolo-pyridone compound act on the M1 subtype or the M4 subtype of a muscarinic acetylcholine receptor.

[0292] The terms "muscarinic orthosteric agonist," "orthosteric muscarinic agonist," and "muscarinic agonist" refer to agents that activate muscarinic acetylcholine receptors. "Orthosteric" refers to the receptor site where endogenous ligands bind to produce their effects. That is, muscarinic orthosteric agonists bind to the site of the muscarinic acetylcholine receptor where endogenous muscarinic ligands bind to produce their effects.

[0293] Muscarinic acetylcholine receptors are G protein-coupled receptors with five distinct receptor subtypes (M1–M5), each present in the CNS with distinct tissue distributions. The term "muscarinic acetylcholine receptor" refers to G protein-linked receptors that bind to the neurotransmitter acetylcholine. "M1" refers to subtype I muscarinic acetylcholine receptors. "M2" refers to subtype II muscarinic acetylcholine receptors. "M3" refers to subtype III muscarinic acetylcholine receptors. "M4" refers to subtype IV muscarinic acetylcholine receptors. "M5" refers to subtype V muscarinic acetylcholine receptors.

[0294] Muscarinic acetylcholine receptor agonists can be selective, binding preferentially to only one muscarinic receptor subtype; partially selective, binding preferentially to two to four subtypes; or nonselective, binding preferentially to each of the five subtypes. Muscarinic acetylcholine receptor agonists can also be parasympathomimetics. Their mechanisms of action differ depending on the receptor activated. For example, the mood stabilizers lithium and valproate, used to treat bipolar depression, may primarily affect the muscarinic system through the M4 subtype of receptor. Genetic evidence directly links the muscarinic system to alcohol addiction.

[0295] 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:

[0296]

[0297]

[0298] In certain embodiments, the agonist of the muscarinic acetylcholine receptor is an orthosteric agonist of the muscarinic acetylcholine receptor selected from the group consisting of 77-LH-28-1, A72055, AF 125, AF 150(S), aceclidine, avameline, arecoline, bethanechol, carbachol, cevimeline, CI 1017, CMI 1145, CMI 936, FPL 14995, furmethide, HTL-0016878, iperoxo, itrameline, KST 5452, L 670,548, L 687,306, L689,660, L 686,986, methacholine, N-desmethylclozapine, MCD 386, mirameline, NC 111585, neliraracetam, NGX267, ORG 20091, oxotremorine, PD 142505, PD 151832, PDC 008004, pilocarpine, RU 35963, sabcomeline, SR46559A, talidine, tazomeline, thiopilocarpine, tremorine, vedaclidine, xanomeline, WAY-131256, WAY-132983, YM 796, YM 954, or a pharmaceutically acceptable salt thereof.

[0299] In certain embodiments, the agonist of the muscarinic acetylcholine receptor is an orthosteric agonist of the muscarinic acetylcholine receptor selected from xanomeline or a pharmaceutically acceptable salt thereof. Xanomeline is active at both M1 and M4 muscarinic acetylcholine receptors.

[0300] In certain embodiments, the agonist of the muscarinic acetylcholine receptor is an M1 orthosteric agonist of the muscarinic acetylcholine receptor selected from the group consisting of 77-LH-28-1, A72055, AF 125, AF 150(S), avameline, bethanechol, carbachol, cevimeline, CI 1017, FPL 14995, iperoxo, itrameline, KST 5452, L 687,306, L 689,660, L 686,986, methacholine, N-desmethylclozapine, MCD 386, mirameline, NC 111585, neliraracetam, NGX267, ORG 20091, oxotremorine, PD 142505, PD 151832, pilocarpine, sabcomeline, SR46559A, taxalide, tazomeline, thiopilocarpine, tremorine, vedaclidine, xanomeline, WAY-131256, WAY-132983, YM 796, YM 954, or a pharmaceutically acceptable salt thereof.

[0301] 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. In certain embodiments, the orthosteric antagonist of a muscarinic acetylcholine receptor is trospium chloride.

[0302] Additional considerations

[0303] The dosage and administration regimen of the active ingredients used in the combination therapy can be determined by the attending clinician. In certain embodiments, the compound as described herein (such as the compound of formula I or other compounds in Part I) and the additional therapeutic agent are administered at a dosage commonly used when such agents are used as a monotherapy for treating the disease. In other embodiments, the compound as described herein (such as the compound of formula I or other compounds in Part I) and the additional therapeutic agent are administered at a dosage lower than the dosage commonly used when such agents are used as a monotherapy for treating the disease. In certain embodiments, the compound as described herein (such as the compound of formula I or other compounds in Part I) and the additional therapeutic agent are present in the same composition suitable for oral administration.

[0304] In certain embodiments, the compounds described herein (such as compounds of Formula I or other compounds in Section I) and the additional therapeutic agent may act additively or synergistically. Synergistic combinations can allow the use of lower doses of one or more agents and / or less frequent administration of one or more agents of the combination therapy. Lower doses or less frequent administration of one or more agents can reduce the toxicity of the therapy without reducing the efficacy of the therapy.

[0305] 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 compounds in Part I), a pharmaceutically acceptable carrier, vehicle or diluent, and optionally at least one additional therapeutic agent listed above.

[0306] III. Pharmaceutical Composition and Dosage Considerations

[0307] As described above, the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of one or more of the compounds described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and / or diluents. The pharmaceutical compositions can be specifically formulated for administration in solid or liquid form, including those suitable for: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets (e.g., tablets for buccal, sublingual, and systemic absorption), boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous, or epidural injection, for example, as a sterile solution or suspension or sustained-release formulation; (3) topical application, for example, as a cream, ointment, or controlled-release patch or spray applied to the skin; (4) intravaginally or rectally, for example, as a pessary, cream, or foam; (5) sublingually; (6) ophthalmically; (7) transdermally; or (8) nasally. 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.

[0308] As used herein, the phrase "therapeutically effective amount" refers to an amount of a compound of the invention, material, or composition comprising a compound of the invention effective to produce some desired therapeutic effect in at least a subpopulation of animal cells at a reasonable benefit / risk ratio applicable to any medical treatment.

[0309] As used herein, the phrase "pharmaceutically acceptable" refers to compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0310] Wetting agents, emulsifiers and lubricants, 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 compositions.

[0311] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, 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.

[0312] The preparations of the present invention include preparations suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and / or parenteral administration. The preparations can be conveniently present in unit dosage form and can be prepared by any method known in the pharmaceutical field. The amount of active ingredient that can be combined with a carrier material to prepare a single dosage form will vary with the subject being treated, particularly the mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be the amount of the compound that produces a therapeutic effect. Generally speaking, in one hundred parts, this amount is about 0.1% to about 99% active ingredient, preferably about 5% to about 70%, and most preferably about 10% to about 30%.

[0313] In certain embodiments, the formulations of the present invention comprise excipients selected from cyclodextrins, celluloses, liposomes, micelle formers (e.g., bile acids), and polymeric carriers (e.g., polyesters and polyanhydrides); and a compound of the present invention. In certain embodiments, the formulations described above allow the compounds of the present invention to be orally bioavailable.

[0314] The method for preparing these preparations or compositions comprises the step of combining the compound of the present invention with a carrier and optionally one or more auxiliary ingredients. In general, the preparation is prepared by uniformly and intimately associating the compound of the present invention with a liquid carrier, or a finely divided solid carrier, or both, and then, if necessary, shaping the product.

[0315] 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 acacia or tragacanth), powders, granules, or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as a lozenge (using an inert base such as gelatin and glycerin, or sucrose and acacia) and / or as a mouthwash, etc., each containing a predetermined amount of a compound of the present invention as the active ingredient. The compounds of the present invention may also be administered in the form of a pill, electuary, or paste.

[0316] In solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules, troches, 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, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and / or acacia; (3) wetting agents such as glycerol; (4) disintegrants such as agar-agar, calcium carbonate, , potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution inhibitors such as paraffin wax; (6) absorption accelerators such as quaternary ammonium compounds and surfactants such as poloxamers and sodium lauryl sulfate; (7) wetting agents such as, for example, cetyl alcohol, glyceryl monostearate, and nonionic surfactants; (8) absorbents such as kaolin and bentonite; (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) release controlling agents such as cross-linked polyvinylpyrrolidone or ethylcellulose. For capsules, tablets, and pills, the pharmaceutical composition may also contain a buffering agent. Solid compositions of a similar type may also be used as fillers in soft-filled and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0317] Tablets can be prepared by compression or molding, optionally with one or more auxiliary ingredients. Compressed tablets can be prepared using a binder (e.g., gelatin or hydroxypropyl methylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (e.g., sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), a surfactant, or a dispersant. Molded tablets can be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine.

[0318] 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 field of pharmaceutical formulations. They may also be formulated to provide a slow or controlled release of the active ingredient, using, for example, hydroxypropyl methylcellulose in varying proportions to provide a desired release profile, other polymer matrices, liposomes, and / or microspheres. They may be formulated for rapid release, such as freeze drying. They may be sterilized, for example, by filtering through a filter membrane that retains bacteria or by immediately incorporating a sterilizing agent in the form of a sterile solid composition that is soluble in sterile water or some other sterile injection medium before use. These compositions may also optionally contain an opacifier and may also be compositions that release the active ingredient only in, or preferably in, a certain portion of the gastrointestinal tract, optionally in a delayed manner. Examples of usable embedding compositions include polymeric substances and waxes. The active ingredient may also be in microencapsulated form and may suitably contain one or more of the above-mentioned excipients.

[0319] Liquid dosage forms for oral administration of the compounds of the present invention include 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, for example, water or other solvents, solubilizers, and emulsifiers, such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (specifically, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuranol, polyethylene glycol, and fatty acid esters of sorbitan and mixtures thereof.

[0320] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0321] Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0322] Formulations of the pharmaceutical compositions of the present invention for rectal or vaginal administration may be presented as suppositories which may be prepared by mixing one or more compounds of the present invention with one or more suitable non-irritating excipients or carriers (including, for example, cocoa butter, polyethylene glycol, suppository wax or salicylates) and which are solid at room temperature but liquid at body temperature and therefore will melt in the rectum or vaginal cavity and release the active compound.

[0323] Formulations of the present invention suitable for vaginal administration also include pessaries, hemostats, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.

[0324] Dosage forms for topical or transdermal administration of the compounds of the present invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound can be mixed under sterile conditions with a pharmaceutically acceptable carrier and with any preservatives, buffers, or propellants that may be necessary.

[0325] 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, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0326] In addition to the compound of this invention, powders and sprays can contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these substances. Sprays can additionally contain conventional propellants, such as chlorofluorocarbons and volatile unsubstituted hydrocarbons (such as butane or propane).

[0327] Transdermal patches have the added advantage of providing the controlled delivery of the compound of the present invention to the body. Such dosage forms can be prepared by dissolving the compound in or being dispersed in a suitable medium. Absorption enhancers can also be used to increase the transdermal amount of the compound. The speed of this flux can be controlled by providing a rate-controlled membrane or by being dispersed in a polymer matrix or a gel.

[0328] Ophthalmic formulations, eye ointments, powders, solutions, etc. are also contemplated as being within the scope of this invention.

[0329] Pharmaceutical compositions of the present invention suitable for parenteral administration include one or more compounds of the present invention in combination with one or more of the following: pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders to be reconstituted into sterile injectable solutions or dispersions prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0330] Examples of suitable aqueous and non-aqueous carriers that can be employed in the pharmaceutical compositions of the present invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters (such as ethyl oleate). Suitable fluidity can be maintained, for example, by using a coating material (such as lecithin), in the case of dispersions, by maintaining the desired particle size and by using a surfactant.

[0331] These compositions also can contain adjuvants, such as preservatives, wetting agents, emulsifiers and dispersants.Prevention of the microbial effects of the subject compound can be ensured by including various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, etc. It is also desirable to include isotonic agents, such as sugar, sodium chloride, etc. in the composition. In addition, the prolonged absorption of the injectable pharmaceutical form can be completed by including delayed absorption agents such as aluminum monostearate and gelatin.

[0332] In some cases, in order to prolong the effect of the drug, it is necessary to slow down the absorption of the drug for subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a crystalline or amorphous material with low water solubility. The absorption rate of the drug then depends on its dissolution rate, which in turn can depend on crystal size and crystalline form. Alternatively, the delayed absorption of a drug form administered parenterally can be accomplished by dissolving or suspending the drug in an oil vehicle.

[0333] Injectable reservoir form is prepared by forming a microencapsulated matrix of the subject compound in biodegradable polymers such as polylactide-polyglycolide.Depending on the ratio of the drug to the polymer and the property of the specific polymer adopted, the rate of drug release can be controlled.The example of other biodegradable polymers includes poly (orthoesters) and poly (anhydrides).Reservoir injectable formulations are also prepared by embedding the drug in a liposome or microemulsion compatible with body tissues.

[0334] When the compounds of the present invention are administered to humans and animals as medicines, they can be given as medicines themselves or as pharmaceutical compositions containing, for example, 0.1 to 99% (more preferably 10 to 30%) of active ingredients in combination with pharmaceutically acceptable carriers.

[0335] The preparations of the present invention can be administered orally, parenterally, topically, or rectally. Of course, they are given in a form suitable for each route of administration. For example, they are administered in tablet or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc., by injection, infusion, or inhalation; topically by lotion or ointment; and rectally by suppository. Oral administration is preferred.

[0336] As used herein, the phrases "parenteral administration" and "parenteral administration" mean modes of administration other than enteral and topical administration, usually by injection, and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.

[0337] As used herein, the phrases "systemic administration," "systemic administration," "peripheral administration," and "peripheral administration" refer to the administration of a compound, drug, or other substance other than directly into the central nervous system so that it enters the patient's system to undergo metabolism and other similar processes, e.g., subcutaneous administration.

[0338] The compounds can be administered to humans and other animals for therapeutic purposes by any suitable route of administration, including orally, nasally (e.g., by spray), rectally, vaginally, parenterally, intracisternal, and topically (e.g., by powders, ointments, or drops), including buccal and sublingual.

[0339] Regardless of the route of administration selected, the compound of the present invention, which may be used in a suitable hydrated form, and / or the pharmaceutical composition of the present invention may be formulated into a pharmaceutically acceptable dosage form by conventional methods known to those skilled in the art.

[0340] Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which achieves the desired therapeutic response for a particular patient, composition, and mode of administration without being toxic to the patient.

[0341] The selected dosage level will depend upon a variety of factors, including the activity of the specific compound of the present invention employed, or its ester, salt or amide, the route of administration, the time of administration, the rate of excretion or metabolism of the specific compound employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and / or materials used in combination with the specific compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

[0342] A physician or veterinarian having ordinary skill in the art can readily determine the effective amount of the desired pharmaceutical composition and prescribe it. For example, a physician or veterinarian can start the dosage of the compound of the invention used in the pharmaceutical composition at a level lower than that required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved.

[0343] In general, a suitable daily dose of a compound of the present invention is the amount of the compound at the lowest dose that is effective to produce a therapeutic effect. This 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 at about 0.1 mg / kg to about 100 mg / kg, and even more preferably at about 0.5 mg / kg to about 50 mg / kg. When a compound as described herein is co-administered with another agent (e.g., as a sensitizer), the effective amount may be lower than when the agent is used alone.

[0344] If desired, the effective daily dose of the active compound may optionally be administered in unit dosage form as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day. Preferably the dose is administered once daily.

[0345] The present invention also provides unit dosage forms, such as tablets or capsules, comprising a therapeutically effective amount of a compound described herein for treating the medical conditions described herein.

[0346] Example

[0347] Having now generally described the invention, the invention 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.

[0348] General synthetic and analytical methods

[0349] Analytical data are contained in the following procedures, in the description of the general procedures, or in the tables of the examples. Unless otherwise stated, all 1 H NMR data were collected on a Bruker Avance 400 MHz (equipped with a 5 mm QNP probe), a Bruker Avance III 400 MHz, 5 mm BBFO probe, or a Fourier 300 MHz, 5 mm dual probe. Chemical shifts are reported in parts per million (ppm). LC / MS was performed on an Acquity UPLC H-Class coupled to a QDa mass spectrometer (quaternary pump / PDA detector), an Acquity UPLC coupled to a ZQ mass spectrometer (binary pump / PDA detector), or an Acquity UPLC coupled to a SQD2 mass spectrometer with a Waters DAD. LC / MS data refer to the LC / MS conditions using the method numbers provided in Table 2.

[0350] Table 2. LC / MS analysis method

[0351]

[0352]

[0353] Purification method

[0354] For the general procedures, intermediates and final compounds can be purified by any technique or combination of techniques known to those skilled in the art. Some non-limiting examples include in COMBI Flash chromatography was performed on a Companion purification system or a Biotage SP1 purification system using SPE Si II columns ("Isolute SPE Si columns" refer to pre-packed polypropylene columns containing unbonded activated silica gel, with irregular particles having an average particle size of 50 μm and a nominal porosity), and the solvent or solvent combination (heptane, EtOAc, DCM, MeOH, MeCN, water, etc.) used to elute the desired compound to purify the product; RP-HP LC purification was performed on a Waters Mass Directed FractionLynx system (2767 autosampler, System Fluidics Organizer, 2998 photodiode array, 2545 pump, 3x515 pump, QDa mass spectrometer), a Gilson system (GX281 autosampler, 322 pump, 155 UV / vis detector), an Interchim PuriFlash 4125 coupled to a UV DAD (see Table 3 for some non-limiting conditions); SFC purification was performed on a Waters Thar Prep100 system (P200 CO2 pump, 2545 modified pump, 2998 UV / VIS detector, 2767 liquid handler with stacked injection module) or a Waters Thar Investigator semi-preparative system (Watson). ers fluid delivery module, 2998 UV / VIS detector, Waters fraction collection module) (see Table 3 for some non-limiting conditions); recrystallization from an appropriate solvent (MeOH, EtOH, IPA, EtOAc, toluene, etc.) or solvent combination (EtOAc / heptane, EtOAc / MeOH, etc.); precipitation from a solvent combination (DMF / water, DMSO / DCM, EtOAc / heptane, etc.); trituration with an appropriate solvent (EtOAc, DCM, MeCN, MeOH, EtOH, IPA, n-PrOH, etc.); extraction by dissolving the compound in a liquid and washing with an appropriate immiscible liquid (DCM / water, EtOAc / water, DCM / saturated NaHCO3, EtOAc / saturated NaHCO3, DCM / 10% aqueous HCl, EtOAc / 10% aqueous HCl, etc.); and / or distillation (simple, fractional, Kugelrohr, etc.).Descriptions of these techniques can be found in the following references: Gordon, AJ and Ford, RA "The Chemist's Companion", 1972; Pal leros, 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, 2nd Edition", 1999.

[0355] Table 3. RP-HPLC and SFC purification methods

[0356]

[0357]

[0358]

[0359] abbreviation

[0360] ℃ degrees Celsius

[0361] DAD diode array detector

[0362] DCM dichloromethane

[0363] DEA Diethylamine

[0364] DMA N,N-dimethylacetamide

[0365] DMF N,N-dimethylformamide

[0366] DMSO dimethyl sulfoxide

[0367] EtOAc

[0368] EtOH

[0369] H hour

[0370] H2O water

[0371] HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0372] HCl hydrochloride

[0373] HCOOH Formic acid

[0374] IMS Industrial Methylated Spirits

[0375] IPA Isopropyl alcohol

[0376] [Ir(1,5-cod)Cl]2 Bis(1,5-cyclooctadiene)diiridium(I) dichloride

[0377] LC / MS liquid chromatography / mass spectrometry

[0378] LiCl lithium chloride

[0379] m / z mass-to-charge ratio

[0380] MeCN Acetonitrile

[0381] MeOH methanol

[0382] MgSO4 magnesium sulfate

[0383] MHz Megahertz

[0384] Min minutes

[0385] MS mass spectrometer

[0386] Na2SO4 sodium sulfate

[0387] NaHCO3 sodium bicarbonate

[0388] NaOH sodium hydroxide

[0389] NH4HCO3 ammonium bicarbonate

[0390] NH4OH ammonium hydroxide

[0391] NMR Nuclear Magnetic Resonance

[0392] Pd(dppf)Cl2 [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride

[0393] Pd(PPh3)4Tetrakis(triphenylphosphine)palladium(0)

[0394] Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0)

[0395] PdCl2(PPh3)2 Bis(triphenylphosphine)palladium(II) dichloride

[0396] rac-BINAP (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl

[0397] RP-HPLC Reversed-phase high-performance liquid chromatography

[0398] R t Retention time

[0399] RT Room temperature

[0400] SFC Supercritical Fluid Chromatography

[0401] TBME tert-butyl methyl ether

[0402] THF Tetrahydrofuran

[0403] UPLC Ultra-Performance Liquid Chromatography

[0404] Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

[0405] Xantphos Pd G3 [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate

[0406] XPhos 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

[0407] XPhos Pd G2 Chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)

[0408] Example 1 -Synthesis of Compound Int-11: 2-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)lithium acetate

[0409] The title compound was prepared according to the following procedure.

[0410] Preparation of Int-1 :2-chloro-6-methoxy-4-methylnicotinonitrile

[0411]

[0412] To a suspension of 2,6-dichloro-4-methylnicotinonitrile (84 g, 450 mmol) in MeOH (840 mL) was added 4.4 M sodium methoxide (108 mL, 472 mmol) dropwise at 1.5 ° C. under a nitrogen atmosphere over 5 h. The reaction was allowed to warm to RT and stirred at RT for 16 h. The reaction mixture was cooled to 3 ° C. and quenched by slowly adding distilled water (100 mL) and stirring for 30 minutes. The reaction mixture was allowed to warm to RT, 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 (Na2SO4) and concentrated in vacuo. The residue was further recrystallized from MeOH to give the title compound as a white solid and a mixture of regioisomers (5:1, 36 g, 37%). 1 H NMR (300MHz: CDCl3) δ6.61 (s, 1H), 3.98 (s, 3H), 2.49 (s, 3H).

[0413] Preparation of Int-2 :3-cyano-6-methoxy-4-methylpicolinic acid methyl ester

[0414]

[0415] To a suspension of 2-chloro-6-methoxy-4-methylnicotinonitrile (5 g, 27 mmol) and a complex of Pd(dppf)Cl2 and DCM (2.3 g, 2.7 mmol) in MeOH (50 mL) 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 cooled to RT, filtered through celite and washed with DCM. The filtrate was concentrated in vacuo and purified directly by flash column chromatography (cyclohexane to EtOAc, gradient elution) to give the title compound as a mixture of white solid and regioisomers (5:1, 3.9 g, 65%). 1 H NMR (300MHz: CDCl3) δ6.84(s,1H),4.04(s,3H),4.03(s,3H),2.56(s,3H).

[0416] Preparation of Int-3 :2-methoxy-4-methyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[0417]

[0418] To a suspension of methyl 3-cyano-6-methoxy-4-methylpicolinate (3.9 g, 19 mmol) in EtOH (80 mL) was added Raney nickel suspended in water (5 mL). The reaction was then evacuated and placed under a hydrogen atmosphere. The reaction was heated to 40 ° C and stirred at 40 ° C under a hydrogen atmosphere for 36 h. The reaction mixture was cooled to RT, filtered through celite and washed 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(300MHz:CDCl3)δ7.47(s,1H),6.74(s,1H),4.33(s,2H),4.05(s,3H),2.34(s,3H)

[0419] Preparation of Int-4 :2-methoxy-4-methyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylic acid tert-butyl ester

[0420]

[0421] 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) was added 10 M borane dimethyl sulfide complex (4.1 mL, 41 mmol) at 0 ° C. The reaction was heated to 75 ° C and stirred at 75 ° C for 16 h. The reaction mixture was cooled to 0 ° C and then quenched by the dropwise addition of MeOH (10 mL, 247 mmol) followed by 6 M HCl (2.5 mL, 15 mmol). The reaction was then heated to 70 ° C and stirred at 70 ° C for 2 h. The reaction was cooled to RT and then basified by the addition of 2 M NaOH aqueous solution. Di-tert-butyl dicarbonate (3.6 g, 17 mmol) was added and the reaction was stirred at RT for 48 h. 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 afford the title compound as a white solid (760 mg, 34%). LC / MS (Table 2, Method A): R t =1.53min; m / z=265[M+H] + .

[0422] Preparation of Int-5 :1,4-dimethyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylic acid tert-butyl ester

[0423]

[0424] Under a nitrogen atmosphere, iodomethane (0.094 mL, 1.5 mmol) was added to a suspension of tert-butyl 2-methoxy-4-methyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (200 mg, 0.76 mmol) and potassium acetate (223 mg, 2.3 mmol) in MeCN (4 mL). The reaction was heated to 80 ° C and stirred at 80 ° C for 35 h. The reaction mixture was cooled to RT and then distributed between EtOAc and distilled water. The organic layer was separated. The combined organic layer was washed with 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 as an orange solid (136 mg, 63%). LC / MS (Table 2, Method A): R t =1.12min; m / z=265[M+H] + .

[0425] Preparation of Int-6 :1,4-Dimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride

[0426]

[0427] To a solution of 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) in 1,4-dioxane (1 mL) was added 4M HCl in 1,4-dioxane (0.95 mL, 3.8 mmol) and the reaction was stirred at RT for 36 h. The reaction mixture was concentrated in vacuo to afford the title compound as a pink solid (45 mg, quantitative). The material was carried forward to the next step without characterization.

[0428] Preparation of Int-7 : tert-Butyl 3-(2-ethoxy-2-oxoethylidene)azetidine-1-carboxylate

[0429]

[0430] At 0 ° C, (ethoxycarbonylmethylene) triphenylphosphine (22g, 63mmol) was added portionwise to a solution of tert-butyl 3-oxoazetidine-1-formate (10g, 58mmol) in DCM (76mL). The reaction was then heated to 40 ° C and stirred at 40 ° C for 4h. The reaction mixture was cooled to RT and concentrated in vacuo. The residue was suspended in a cyclohexane / TBME (2: 1, 100mL) mixture, and the reaction was stirred at RT for 1h. The reaction mixture was filtered, washed with a cyclohexane / TBME (2: 1) mixture and concentrated in vacuo. The residue was purified by flash column chromatography (cyclohexane to EtOAc, gradient elution) to give the title compound as a colorless oil (13g, 95%). 1 H NMR (400MHz: CDCl3) δ5.79-5.75(m,1H),4.84-4.80(m,2H),4.61-4.58(m,2H),4.21-4.15(m,2H),1.46(s,9H),1.31-1.27(m,3H).

[0431] Preparation of Int-8: tert-Butyl 3-(2-ethoxy-2-oxyethyl)azetidine-1-carboxylate

[0432]

[0433] To a solution of tert-butyl 3-(2-ethoxy-2-oxoethylidene)azetidine-1-carboxylate (13 mL, 56 mmol) in IMS (60 mL) was added 10% palladium on carbon (250 mg, 0.24 mmol). The reaction was then evacuated and placed under a hydrogen atmosphere. The reaction was stirred at RT under a hydrogen atmosphere for 18 h. The reaction mixture was filtered through celite, and the filtrate was concentrated in vacuo to give the title compound as a colorless oil (13 g, 97%). 1 H NMR (400MHz: CDCl3) δ 4.16-4.06 (m, 4H), 3.63-3.58 (m, 2H), 2.92-2.83 (m, 1H), 2.61 (d, J = 7.8Hz, 2H), 1.43 (s, 9H), 1.25 (t, J = 7.1Hz, 3H).

[0434] Preparation of Int-9 : 2-(azetidin-3-yl)ethyl acetate 2,2,2-trifluoroacetate

[0435]

[0436] To a solution of tert-butyl 3-(2-ethoxy-2-oxoethyl)azetidine-1-carboxylate (13 g, 54 mmol) in DCM (176 mL) was added trifluoroacetic acid (50 mL, 653 mmol) and the reaction was stirred at RT for 1 h. The reaction mixture was concentrated in vacuo and azeotroped with toluene to give the title compound as a yellow oil (19 g, quantitative). 1 H NMR (400MHz: CDCl3) δ11.28(s,1H),8.99(s,1H),8.66(s,1H),4.31-4.22(m,2H),4.16(q,J=7 .2Hz,2H),4.02-3.91(m,2H),3.35-3.25(m,1H),2.72(d,J=7.4Hz,2H),1.27(t,J=7.0Hz,3H).

[0437] Preparation of Int-10 : ethyl 2-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)acetate

[0438]

[0439] To a solution of 4-chloro-2-(trifluoromethyl)pyridine (1.6 g, 8.8 mmol), ethyl 2-(azetidin-3-yl)acetate 2,2,2-trifluoroacetic acid (4.7 g, 13 mmol) and cesium fluoride (1.3 g, 8.8 mmol) in DMSO (29 mL) was added triethylamine (4.8 mL, 34 mmol). The reaction was heated to 100 ° C and stirred at 100 ° C for 5 h. The reaction mixture was cooled to RT and then partitioned between DCM 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) and subsequently by flash column chromatography (DCM to EtOAc, gradient elution) to give the title compound as a light yellow oil (1.3 g, 51%). 1 H NMR(400MHz:CDCl3)δ8.28(d,J=5.7Hz,1H),6.57(d,J=2.3Hz,1H),6.31(dd,J=2.2,5.6Hz,1H),4.22-4. 13(m,4H),3.71(dd,J=5.4,8.1Hz,2H),3.22-3.14(m,1H),2.72(d,J=7.8Hz,2H),1.27(t,J=7.1Hz,3H).

[0440] Preparation of Int-11 : 2-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)lithium acetate

[0441]

[0442] To a solution of ethyl 2-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)acetate (1.3 g, 4.5 mmol) in MeOH (6.5 mL) and distilled water (1.5 mL) was added lithium hydroxide monohydrate (189 mg, 4.5 mmol) and the reaction was stirred at RT for 1.5 h. The reaction mixture was concentrated in vacuo to give the title compound as an off-white solid (1.26 g, quantitative). LC / MS (Table 2, Method B): R t =0.75min; m / z=261[M+H] + .

[0443] Example 2 -Synthesis of Compound I-1: 1,4-dimethyl-6-(2-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)acetyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one

[0444]

[0445] To a solution of 2-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)lithium acetate (66 mg, 0.25 mmol) in DMF (1 mL) was added HATU (128 mg, 0.34 mmol), followed by a solution of 1,4-dimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride (45 mg, 0.22 mmol) and N,N-diisopropylethylamine (0.098 mL, 561 mmol) in DMF (1 mL). The reaction was stirred at RT for 1 h. The reaction mixture was then partitioned between EtOAc and aqueous sodium bicarbonate solution. The organic layer was separated. The combined organic layers were washed with 5% aqueous LiCl solution, saturated brine, dried (Na2SO4) 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 (41 mg, 43%). 1H NMR (300 MHz: DMSO-d6) δ 8.22 (d, J = 5.8 Hz, 1H), 6.73 (t, J = 2.2, 1H), 6.54 (dd, J = 2.1, 5.5 Hz, 1H), 6.19 (s, 1H), 4.90 (s, 1H), 4.67 (s, 2H), 4.45 (s, 1H), 4.19 (t, J = 8.2 Hz, 2H), 3.71 (dd, J = 5.6, 8.4 Hz, 2H), 3.32 (s, 3H, partially obscured by solvent peak), 3.17-3.10 (m, 1H), 2.83 (dd, J = 3.6, 7.7 Hz, 2H), 2.10 (d, J = 6.8 Hz, 3H). LC / MS (Table 2, Method C): R t =2.55min; m / z=407[M+H] + .

[0446] Example 3 Synthesis of 1,4-dimethyl-6-(2-(1-(4-(methylsulfonyl)phenyl)azetidin-3-yl)acetyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one

[0447] The title compound was prepared according to the following procedure.

[0448] Preparation of Int-12 : ethyl 2-(1-(4-(methylsulfonyl)phenyl)azetidin-3-yl)acetate

[0449]

[0450] The reaction vessel is charged with 2-(azetidine-3-yl)ethyl acetate 2,2,2-trifluoroacetic acid (250mg, 0.78mmol), 4-bromophenyl methyl sulfone (201mg, 0.86mmol), racemic-BINAP (18mg, 0.029mmol), tris(dibenzylideneacetone)dipalladium (0) (18mg, 0.019mmol), cesium carbonate (760mg, 2.3mmol), and solvated in 1,4-dioxane (4mL). The reaction is evacuated, purged with argon (x3), and then heated to 101°C. The reaction is stirred at 101°C for 18h. The reaction mixture is cooled to RT and then distributed between distilled water and EtOAc. The organic layer is separated. The organic layer is separated and concentrated in vacuo by a phase separator. The residue was purified by flash column chromatography (DCM to MeOH, gradient elution) to give the title compound as an orange oil (170 mg, 66%). 1H NMR(400MHz:CDCl3)δ7.77(d,J=9.1Hz,2H),6.56(d,J=8.7Hz,2H),4.28-4.18(m,J=8.0Hz,4H),3.77 (dd,J=5.7,8.2Hz,2H),3.25-3.14(m,1H),3.01(s,3H),2.75(d,J=7.4Hz,2H),1.29(t,J=7.1Hz,3H).

[0451] Preparation of Int-13 : 2-(1-(4-(methylsulfonyl)phenyl)azetidin-3-yl)lithium acetate

[0452]

[0453] To a solution of ethyl 2-[1-(4-methylsulfonylphenyl)azetidin-3-yl]acetate (168 g, 0.51 mmol) in THF (5 mL) and distilled water (2 mL) was added lithium hydroxide monohydrate (23 mg, 0.56 mmol) and the reaction was stirred at RT for 18 h. The reaction mixture was concentrated in vacuo to give the title compound as a solid (150 mg, quantitative). LC / MS (Table 1, Method B): R t =1.11min; m / z=270[M+H] + .

[0454] Preparation of compound I-2 :1,4-dimethyl-6-(2-(1-(4-(methylsulfonyl)phenyl)azetidin-3-yl)acetyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one

[0455]

[0456] To a solution of 2-(1-(4-(methylsulfonyl)phenyl)azetidin-3-yl)lithium acetate (66 mg, 0.24 mmol) and HATU (114 mg, 0.30 mmol) in DMF (0.5 mL) was added 1,4-dimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride (40 mg, 0.20 mmol) and N,N-diisopropylethylamine (0.12 mL, 0.7 mmol) in DMF (0.5 mL). The reaction was stirred for 1 h at RT. The reaction mixture was then partitioned between DCM and aqueous sodium bicarbonate solution. The organic layer was separated. The combined organic layers were passed through a phase separator and concentrated in vacuo. The residue was purified by reverse phase HPLC (Table 2, Method 2) to give the title compound as an off-white solid (24 mg, 27%). 1H NMR (400 MHz: DMSO-d6) δ 7.65 (d, J = 9.2 Hz, 2H), 6.55-6.49 (m, 2H), 6.19 (s, 1H), 4.92-4.44 (m, 4H), 4.13 (dd, J = 7.9, 7.9 Hz, 2H), 3.68-3.62 (m, 2H), 3.32 (s, 3H), 3.17-3.10 (m, 1H), 3.07 (s, 3H), 2.83 (dd, J = 3.1, 7.7 Hz, 2H), 2.10 (dd, J = 0.7, 7.5 Hz, 3H). LC / MS (Table 1, Method E): R t =2.96min; m / z=416[M+H] +

[0457] Example 4 -Synthesis of other compounds

[0458] The compounds in Table 4 were prepared using procedures similar to those described herein for the preparation of compound Int-11 or Int-132 from compound Int-9. The starting materials used are listed in Table 4. The abbreviation "quantitative" refers to quantitative yield.

[0459] Table 4: Other compounds

[0460]

[0461]

[0462]

[0463]

[0464]

[0465] Example 4B - Preparation of other compounds

[0466] The compounds in Table 5 were prepared using procedures similar to those described above for the preparation of compound 1-1. The starting materials used are listed in Table 5.

[0467] Table 5: Other compounds

[0468]

[0469]

[0470]

[0471]

[0472] Example 5-Synthesis of Compound Int-64: Lithium 2-(1-(6-cyclopropylpyridazin-4-yl)azetidin-3-yl)acetate

[0473] The title compound was prepared according to the following procedure.

[0474] Preparation of Int-62 :5-chloro-3-cyclopropylpyridazine

[0475]

[0476] Under a nitrogen atmosphere, 5M cyclopropylzinc bromide solution (7.8 mL, 3.9 mmol) was added portionwise to a solution of 3,5-dichloropyridazine (500 mg, 3.4 mmol) and Pd(PPh3)4 (115 mg, 0.10 mmol) in THF (2.5 mL) and the reaction was stirred at RT for 3 h. The reaction mixture was then partitioned between EtOAc and saturated sodium bicarbonate. The organic layer was separated, filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (cyclohexane to EtOAc, gradient elution) to give the title compound as an oil (155 mg, 30%). The material was carried to the next step without characterization.

[0477] Preparation of Int-63 : ethyl 2-(1-(6-cyclopropylpyridazin-4-yl)azetidin-3-yl)acetate

[0478]

[0479] To a solution of ethyl 2-(azetidin-3-yl)acetate 2,2,2-trifluoroacetate (484 mg, 1.5 mmol) and N,N-diisopropylethylamine (0.87 mL, 5.0 mmol) in DMA (1.5 mL) was added a solution of 5-chloro-3-cyclopropylpyridazine (155 mg, 1.0 mmol) in DMA (1.0 mL), and the reaction was heated to 105 ° C. The reaction was stirred at 105 ° C for 19 h. The reaction mixture was cooled to RT and then distributed between EtOAc and saturated sodium bicarbonate. The organic layer was separated. The combined organic layer was washed with saturated brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc to IMS, gradient elution) and then by flash column chromatography (DCM to EtOAc, gradient elution) to give the title compound as a brown solid (110 mg, 42%). LC / MS (Table 2, Method A): R t =1.21min; m / z=262[M+H] + .

[0480] Preparation of Int-64:2-(1-(6-cyclopropylpyridazin-4-yl)azetidin-3-yl)lithium acetate

[0481]

[0482] To a solution of ethyl 2-(1-(6-cyclopropylpyridazin-4-yl)azetidin-3-yl)acetate (110 g, 0.42 mmol) in THF (5.0 mL) and distilled water (1.0 mL) was added lithium hydroxide monohydrate (26 mg, 0.63 mmol) and the reaction was stirred at RT for 66 h. The reaction mixture was concentrated in vacuo and azeotroped with MeCN to give the title compound as a brown solid (115 mg, quantitative). 1 H NMR(400MHz:DMSO-d6)δ8.19(d,J=2.7Hz,1H),6.21(d,J=2.6Hz,1H),4.03(t,J=8.2Hz,2H),3.58(dd ,J=6.0,8.0Hz,2H),3.00-2.89(m,1H),2.22(d,J=7.8Hz,2H),2.02-1.94(m,1H),0.96-0.90(m,4H).

[0483] Example 6 : Synthesis of compound I-38: 6-(2-(1-(6-cyclopropylpyridazin-4-yl)azetidin-3-yl)acetyl)-1,4-dimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one

[0484]

[0485] To a suspension of 2-(1-(6-cyclopropylpyridazin-4-yl)azetidin-3-yl)lithium acetate (46 mg, 0.19 mmol) in DMF (1.5 mL) was added HATU (86 mg, 0.23 mmol), N,N-diisopropylethylamine (0.091 mL, 0.52 mmol) and 1,4-dimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride (35 mg, 0.17 mmol), and the reaction was stirred at RT for 1 h. The reaction mixture was then partitioned between DCM and saturated aqueous sodium bicarbonate solution. The organic layer was separated, passed through a phase separator and concentrated in vacuo. The residue was purified by reverse phase HPLC (Table 3, Method 2) to give the title compound as an off-white solid (20 mg, 28%). 1H NMR (400 MHz: DMSO-d6) δ 8.28-8.26 (m, 1H), 6.31-6.29 (m, 1H), 6.19 (s, 1H), 4.90 (s, 1H), 4.67 (s, 2H), 4.45 (s, 1H), 4.16 (t, J = 8.3 Hz, 2H), 3.71-3.66 (m, 2H), 3.35-3.30 (m, 3H, three protons were obscured by the solvent peak), 3.17-3.09 (m, 1H), 2.85-2.80 (m, 2H), 2.12-2.09 (m, 3H), 2.05-1.98 (m, 1H), 0.98-0.94 (m, 4H). LC / MS (Table 2, Method E): R t =2.79min; m / z=380[M+H] + .

[0486] Example 7 -Synthesis of Compound Int-66: Sodium 2-(1-(2-methoxy-6-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)acetate

[0487] The title compound was prepared according to the following procedure.

[0488] Preparation of Int-65 : ethyl 2-(1-(2-chloro-6-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)acetate

[0489]

[0490] Under a nitrogen atmosphere, a reaction vessel was charged with 2-chloro-4-iodo-6-(trifluoromethyl)pyridine (237 mg, 0.77 mmol), ethyl 2-(azetidin-3-yl)acetate 2,2,2-trifluoroacetate (300 mg, 0.70 mmol), cesium carbonate (684 mg, 2.1 mmol), Pd2(dba)3 (32 mg, 0.035 mmol), racemic-BINAP (22 mg, 0.035 mmol), and solvated in 1,4-dioxane (15 mL). The reaction was heated to 100°C and stirred at 100°C for 16 h. 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 as a brown gum (131 mg, 58%). LC / MS (Table 2, Method B): R t =1.88min; m / z=323[M+H] + .

[0491] Preparation of Int-66 : Sodium 2-(1-(2-methoxy-6-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)acetate

[0492]

[0493] To a solution of 2-(1-(2-chloro-6-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)ethyl acetate (131 mg, 0.41 mmol) in MeOH (3 mL) was added a solution of sodium methoxide in MeOH (0.14 mL, 0.61 mmol), and the reaction was heated to reflux. The reaction was stirred at reflux for 21 h. The reaction mixture was concentrated in vacuo to give the title compound as a yellow gum (198 mg, quantitative). LC / MS (Table 2, Method B): R t =1.59min; m / z=291[M+H] + .

[0494] Example 8 -Synthesis of Compound I-39: 6-(2-(1-(2-methoxy-6-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)acetyl)-1,4-dimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one

[0495]

[0496] To a suspension of sodium 2-(1-(2-methoxy-6-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)acetate (78 mg, 0.25 mmol) in DMF (3 mL) was added HATU (123 mg, 0.32 mmol), triethylamine (0.10 mL, 0.75 mmol) and 1,4-dimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride (50 mg, 0.25 mmol), and the reaction was stirred at RT for 16 h. The reaction mixture was then partitioned between EtOAc and saturated aqueous sodium bicarbonate solution. 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) to give the title compound as an off-white solid (7.5 mg, 7%). 1H NMR (400MHz: DMSO-d6) δ6.51(dd,J=1.9,1.9Hz,1H),6.19(s,1H),5.84(dd,J=2.0,2.0Hz,1H),4.90(s,1H),4.67(s,2H),4.44(s,1H),4.15(dd,J=8. 2,8.2Hz,2H),3.81(s,3H),3.67(dd,J=5.7,8.2Hz,2H),3.32(s,3H),3.10 (dd, J=7.3, 7.3Hz, 1H), 2.81 (dd, J=3.5, 7.6Hz, 2H), 2.10 (d, J=6.1Hz, 3H). LC / MS (Table 2, Method C): R t =4.15min; m / z=437[M+H] + .

[0497] Example 9 -Synthesis of Compound Int-70: Lithium 2-(1-(4-cyano-3-cyclopropyl-5-(trifluoromethyl)phenyl)azetidin-3-yl)acetate

[0498] The title compound was prepared according to the following procedure.

[0499] Preparation of Int-67 :2-Bromo-1-cyclopropyl-5-fluoro-3-(trifluoromethyl)benzene

[0500]

[0501] 1,2-dibromo-5-fluoro-3-(trifluoromethyl)benzene (1.5 g, 4.7 mmol), cyclopropylboronic acid (801 mg, 9.3 mmol), Pd(dppf)Cl2 (170 mg, 0.23 mmol), tripotassium phosphate (3.0 g, 14 mmol) were charged into the reaction vessel and solvated in 1,4-dioxane (24 mL) and water (1.2 mL). The reaction was evacuated, purged with argon (x3), and then heated to 90 ° C. The reaction was stirred at 90 ° C for 2 h. The reaction mixture was cooled to RT, filtered through diatomaceous earth and washed with EtOAc. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (cyclohexane, isocratic) to give the title compound as a yellow liquid (936 mg, 71%). LC / MS (Table 2, Method A): R t =1.89min; UV only.

[0502] Preparation of Int-68 :2-cyclopropyl-4-fluoro-6-(trifluoromethyl)benzonitrile

[0503]

[0504] The reaction vessel was charged with Pd(PPh3)4(327mg, 0.28mmol), zinc cyanide (398mg, 3.4mmol) and zinc (185mg, 2.8mmol), followed by a solution of 2-bromo-1-cyclopropyl-5-fluoro-3-(trifluoromethyl)benzene (800mg, 2.8mmol) in 1-methyl-2-pyrrolidone (14mL). The reaction was evacuated, purged with argon (x3), and then heated to 110°C. The reaction was stirred at 110°C for 16h. The reaction mixture was cooled to RT, filtered through diatomaceous earth and washed with toluene. The filtrate was then distributed with distilled water, and 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 12) to give the title compound as a white solid (241mg, 37%). LC / MS (Table 2, Method A): R t =2.08min; UV only.

[0505] Preparation of Int-69 : ethyl 2-(1-(4-cyano-3-cyclopropyl-5-(trifluoromethyl)phenyl)azetidin-3-yl)acetate

[0506]

[0507] To a suspension of 2-cyclopropyl-4-fluoro-6-(trifluoromethyl)benzonitrile (208 mg, 0.91 mmol) and potassium carbonate (414 mg, 3.0 mmol) in DMSO (2.8 mL) was added 2-(azetidin-3-yl)ethyl acetate 2,2,2-trifluoroacetate (0.27 mL, 1.2 mmol) and the reaction was heated to 60 ° C. The reaction was stirred at 60 ° C for 2 h. The reaction mixture was cooled to RT and then distributed 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 to give the title compound as a brown oil (348 mg, 92%). LC / MS (Table 2, Method A): R t =2.17min; m / z=353[M+H] + .

[0508] Preparation of Int-70 : 2-(1-(4-cyano-3-cyclopropyl-5-(trifluoromethyl)phenyl)azetidin-3-yl)lithium acetate

[0509]

[0510] To a solution of ethyl 2-(1-(4-cyano-3-cyclopropyl-5-(trifluoromethyl)phenyl)azetidin-3-yl)acetate (150 mg, 0.43 mmol) in THF (5.0 mL) and distilled water (1.0 mL) was added lithium hydroxide monohydrate (20 mg, 0.48 mmol) and the reaction was stirred at RT for 4 h. The reaction mixture was concentrated in vacuo and azeotroped with MeCN to give the title compound as a white solid (148 mg, quantitative). LC / MS (Table 2, Method A): R t =1.36min; m / z=325[M+H] + .

[0511] Example 10 -Synthesis of Compound I-40: 2-cyclopropyl-4-(3-(2-(1,4-dimethyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2-oxoethyl)azetidin-1-yl)-6-(trifluoromethyl)benzonitrile

[0512]

[0513] Under nitrogen atmosphere, to a solution of 2-(1-(4-cyano-3-cyclopropyl-5-(trifluoromethyl)phenyl)azetidin-3-yl)lithium acetate (80 mg, 0.24 mmol), HATU (110 mg, 0.29 mmol) and N,N-diisopropylethylamine (0.12 mL, 0.69 mmol) in DMF (1 mL) was added a solution of 1,4-dimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride (45 mg, 0.22 mmol) in DMF (1.0 mL), and the reaction was stirred at RT for 16 h. The reaction mixture was then partitioned between EtOAc and aqueous sodium bicarbonate solution. The organic layer was separated. The combined organic layers were washed with 5% aqueous LiCl solution, dried (Na2SO4) and concentrated in vacuo. The residue was purified by reverse phase HPLC (Table 3, Method 4) to give the title compound as an off-white solid (2.2 mg, 2%). 1H NMR (400 MHz: DMSO-d6) δ 6.60-6.56 (m, 1H), 6.19 (s, 1H), 6.11 (s, 1H), 4.89 (s, 1H), 4.66 (s, 2H), 4.44 (s, 1H), 4.22-4.17 (m, 2H), 3.72 (dd, J = 5.8, 8.8 Hz, 2H), 3.34-3.33 (m, 3H, three protons were obscured by the solvent peak), 3.16-3.04 (m, 1H), 2.81 (dd, J = 3.4, 7.8 Hz, 2H), 2.19-2.13 (m, 1H), 2.12-2.09 (m, 3H), 1.13-1.08 (m, 2H), 0.90-0.85 (m, 2H). LC / MS (Table 2, Method E): R t =4.28min; m / z=471[M+H] +

[0514] Example 11 -Synthesis of Compound I-74: Lithium 2-methyl-2-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)propionate

[0515] The title compound was prepared according to the following procedure.

[0516] Preparation of Int-71 : tert-Butyl 3-(1-methoxy-2-methyl-1-oxopropan-2-yl)azetidine-1-carboxylate

[0517]

[0518] To a solution of 2-(1-tert-butoxycarbonylazetidin-3-yl)-2-methyl-propionic acid (250 mg, 1.0 mmol) in anhydrous MeOH (7.5 mL) and toluene (7.5 mL) was added a 2M solution of (trimethylsilyl)diazomethane in diethyl ether (0.62 mL, 1.2 mmol) under a nitrogen atmosphere at 0°C. The reaction was allowed to warm to RT and stirred at RT for 2 h. The reaction mixture was concentrated in vacuo, and the residue was purified directly by flash column chromatography (cyclohexane to EtOAc, gradient elution) to give the title compound as a colorless oil (190 mg, 72%). 1 H NMR (300MHz: CDCl3) δ3.92 (t, J = 9.0 Hz, 2H), 3.74 (dd, J = 6.1, 9.3 Hz, 2H), 3.67 (s, 3H), 2.86-2.75 (m, 1H), 1.44 (s, 9H), 1.18 (s, 6H).

[0519] Preparation of Int-72:2-(azetidin-3-yl)-2-methylpropionic acid methyl ester 2,2,2-trifluoroacetate

[0520]

[0521] To a solution of tert-butyl 3-(1-methoxy-2-methyl-1-oxopropane-2-yl)azetidine-1-carboxylate (190 g, 0.74 mmol) in DCM (150 mL) was added trifluoroacetic acid (0.68 mL, 8.9 mmol) and the reaction was stirred at RT for 1 h. The reaction mixture was concentrated in vacuo and azeotroped with toluene to give the title compound as a brown oil (275 mg, quantitative). The material was carried forward to the next step without characterization.

[0522] Preparation of Int-73 : methyl 2-methyl-2-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)propanoate

[0523]

[0524] To a DMSO (1.7 mL) solution of 4-chloro-2-(trifluoromethyl)pyridine (146 g, 0.80 mmol), methyl 2-(azetidin-3-yl)-2-methylpropanoate 2,2,2-trifluoroacetate (200 mg, 0.73 mmol) and cesium fluoride (122 mg, 0.80 mmol) was added triethylamine (0.40 mL, 2.9 mmol) and the reaction was heated to 100 ° C. The reaction was stirred at 100 ° C for 16 h. The reaction mixture was cooled to RT and then distributed between DCM and distilled water. The organic layer was separated. The combined organic layer was 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 yellow oil (171 mg, 77%). 1 H NMR(300MHz:CDCl3)δ8.28(d,J=5.7Hz,1H),6.57(d,J=2.2Hz,1H),6.32(dd,J=2.2,5.7Hz,1H), 4.03(t,J=8.6Hz,2H),3.83(dd,J=6.0,8.6Hz,2H),3.68(s,3H),3.14-3.03(m,1H),1.23(s,6H).

[0525] Preparation of Int-74 : Lithium 2-methyl-2-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)propionate

[0526]

[0527] To a solution of methyl 2-methyl-2-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)propanoate (171 g, 0.57 mmol) in THF (0.80 mL) and distilled water (0.25 mL) was added lithium hydroxide monohydrate (24 mg, 0.57 mmol) and the reaction was stirred at RT for 16 h. Lithium hydroxide monohydrate (2.4 mg, 0.057 mmol) was added and the reaction was heated to 50 ° C. The reaction was stirred at 50 ° C for 5 h. The reaction mixture was cooled to RT and concentrated in vacuo to give the title compound as a white solid (167 mg, quantitative). The material was carried on to the next step without characterization.

[0528] Example 12 -Synthesis of Compound I-41: 1,4-dimethyl-6-(2-methyl-2-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)propanoyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one

[0529]

[0530] To a solution of 1,4-dimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride (38 mg, 0.19 mmol), 2-methyl-2-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)propanoate (72 mg, 0.25 mmol) and HATU (108 mg, 0.28 mmol) in DMF (1.5 mL) was added N,N-diisopropylethylamine (0.099 mL, 0.57 mmol) and the reaction was stirred at RT for 3 h. The reaction mixture was then partitioned between EtOAc and aqueous sodium bicarbonate solution. The organic layer was separated. The combined organic layer was washed with saturated brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by reverse phase HPLC (Table 3, Method 4, non-linear gradient from 20% to 80% MeCN) to give the title compound as an off-white solid (51 mg, 62%). 1H NMR (300 MHz: DMSO-d6) δ 8.22 (d, J = 5.8 Hz, 1H), 6.72 (d, J = 2.3 Hz, 1H), 6.54 (dd, J = 2.2, 5.7 Hz, 1H), 6.18 (s, 1H), 5.09 (s, 1H), 4.88 (s, 1H), 4.71 (s, 1H), 4.49 (s, 1H), 4.03 (t, J = 8.8 Hz, 2H), 3.82 (dd, J = 6.1, 9.0 Hz, 2H), 3.36 (s, 3H), 3.31-3.24 (m, 1H), 2.13 (s, 3H), 1.30 (s, 6H). LC / MS (Table 2, Method C): R t =3.01min; m / z=435[M+H] + .

[0531] Example 13 -Synthesis of Compound Int-77: 1,3,4-Trimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride

[0532] The title compound was prepared according to the following procedure.

[0533] Preparation of Int-75 :3-chloro-1,4-dimethyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylic acid tert-butyl ester

[0534]

[0535] To a solution of tert-butyl 1,4-dimethyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (201g, 0.76mmol) in DMF (6mL) was added N-chlorosuccinimide (127mg, 0.95mmol) and the reaction was stirred at RT for 4.5h. The reaction mixture was then distributed between EtOAc and distilled water. The organic layer was separated. The combined organic layer was washed with 5% LiCl aqueous solution, saturated brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash column chromatography (DCM to MeCN, gradient elution) to give the title compound as a white solid (160mg, 70%). LC / MS (Table 2, Method A): R t =1.26min; m / z=299[M+H] + .

[0536] Preparation of Int-76 :1,3,4-trimethyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylic acid tert-butyl ester

[0537]

[0538] The 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 (100 mg, 0.34 mmol), a complex of Pd(dppf)Cl2 and DCM (28 mg, 0.034 mmol), potassium carbonate (139 mg, 1.0 mmol) and solvated in 1,4-dioxane (2.5 mL). The reaction was evacuated, purged with argon (x3), and trimethylboroxine (0.070 mL, 0.50 mmol) was added. The reaction was heated to 100 ° C and stirred at 100 ° C for 18 h. The reaction mixture was cooled to RT, filtered through celite and washed with EtOAc. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography (DCM to MeCN, gradient elution) to give the title compound as a light yellow solid (92 mg, 83%). LC / MS (Table 2, Method A): R t =1.23min; m / z=279[M+H] + .

[0539] Preparation of Int-77 :1,3,4-Trimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride

[0540]

[0541] 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 (440 mg, 1.6 mmol) in DCM (1 mL) was added a 4M solution of HCl in 1,4-dioxane (7.9 mL, 32 mmol) and the reaction was stirred at RT for 1 h. The reaction mixture was concentrated in vacuo to afford the title compound as a brown solid (352 mg, quantitative). The material was carried forward to the next step without characterization.

[0542] Example 14 -Synthesis of Compound I-42: 1,3,4-Trimethyl-6-(2-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)acetyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one

[0543]

[0544] To a solution of 2-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)lithium acetate (114 mg, 0.43 mmol) in DMF (1.5 mL) was added HATU (222 mg, 0.59 mmol), followed by a solution of 1,3,4-trimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride (84 mg, 0.39 mmol) and N,N-diisopropylethylamine (0.20 mL, 1.2 mmol) in DMF (1.5 mL). The reaction was stirred at RT for 30 min. The reaction mixture was then partitioned between EtOAc and aqueous sodium bicarbonate solution. 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 MeOH, gradient elution) to give the title compound as a white solid (369 mg, quantitative). 1 H NMR (400 MHz:CDCl3) δ8.29 (d, J = 5.7 Hz, 1H), 6.58 (d, J = 2.2 Hz, 1H), 6.33 (dd, J = 2.3, 5.7 Hz, 1H), 4.76-4.61 (m, 2H), 4.28 (t, J = 8.1 Hz, 2H), 3.73 (dd, J = 5.3, 8.2 Hz, 2H), 3.48-3.46 (m, 3H), 3.36-3.27 (m, 1H), 2.81-2.77 (m, 2H), 2.14-2.10 (m, 6H). 1.58 (s, 2H). LC / MS (Table 2, Method D): R t =3.54min; m / z=421[M+H] + .

[0545] Example 15 -Synthesis of other compounds

[0546] The compounds in Table 6 were prepared using procedures similar to those described above for the preparation of compound 1-42. The starting materials used are listed in Table 6.

[0547] Table 6: Other compounds

[0548]

[0549]

[0550] Synthesis of compound I-60: 6-(2-(1-(4-cyclopropyl-3-fluorophenyl)-2-methylazetidin-3-yl)ethyl Acyl)-1,3,4-trimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one

[0551] The title compound was prepared according to the following procedure.

[0552] Preparation of Int-78:3-(2-methoxy-2-oxoethyl)-2-methylazetidine-1-carboxylic acid tert-butyl ester

[0553]

[0554] The reaction vessel was charged with 2-(1-tert-butoxycarbonyl-2-methyl-azetidin-3-yl)acetic acid (200 mg, 0.87 mmol), toluene (6 mL) and MeOH (4 mL), followed by a 2M (trimethylsilyl)diazomethane solution (0.50 mL, 1.00 mmol). The reaction was stirred at RT for 15 minutes, and another portion of 2M (trimethylsilyl)diazomethane solution (0.050 mL, 0.10 mmol) was added repeatedly until most of the starting material was consumed. The reaction was stirred for 30 minutes. The reaction mixture was then concentrated in vacuo and purified by flash column chromatography (DCM to EtOAc, gradient elution) to give the title compound as a colorless oil (135 mg, 64%). 1 H NMR (400MHz, CDCl3) δ4.45-4.38(m,0.6H),4.05-3.90(m,1.4H),3.68(s,3H),3.52-3.47(m,1H),3 .01-2.90(m,0.6H),2.65-2.51(m,3H),2.47-2.38(m,0.4H),1.48-1.38(m,9H),1.28-1.23(m,2H).

[0555] Preparation of Int-79 :2-(2-methylazetidin-3-yl)acetate 2,2,2-trifluoroacetate

[0556]

[0557] To a solution of tert-butyl 3-(2-methoxy-2-oxo-ethyl)-2-methyl-azetidine-1-carboxylate (135 mg, 0.56 mmol) in DCM (3 mL) was added trifluoroacetic acid (0.42 mL, 5.6 mmol) and the reaction was stirred at RT for 1 h. The reaction mixture was concentrated in vacuo to give the title compound as a light yellow oil (200 mg, 98%). 1H NMR (400MHz, CDCl3) δ8.73-8.51(m,1H),8.16-8.10(m,1H),4.83-4.72(m,0.6H),4.42-4.10(m,1.4H),3.87-3.79(m,1H),3. 72-3.71(m,3H),3.38-3.30(m,0.6H),3.01-2.94(m,0.4H),2.74-2.68(m,2H),1.62(d,J=6.8Hz,1.2H),1.51-1.42(m,1.8H).

[0558] Preparation of Int-80 :Methyl 2-(1-(4-cyclopropyl-3-fluorophenyl)-2-methylazetidin-3-yl)acetate

[0559]

[0560] The reaction vessel was charged with 2-(2-methylazetidine-3-yl)methyl acetate; 2,2,2-trifluoroacetic acid (200 mg, 0.54 mmol), 4-bromo-1-cyclopropyl-2-fluoro-benzene (174 mg, 0.81 mmol), cesium carbonate (878 mg, 2.7 mmol) and 1,4-dioxane (5 mL). The reaction was evacuated, purged with argon (x3), and Xantphos (31 mg, 0.054 mmol) was added, followed by Xantphos Pd G3 (51 mg, 0.054 mmol). The reaction mixture was warmed to 100 ° C and stirred at 100 ° C under argon for 17 h. The reaction mixture was cooled to RT and distributed between EtOAc and distilled water. The organic layer was separated. The combined organic layer was washed with saturated brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash column chromatography (cyclohexane to EtOAc, gradient elution) to afford the title compound as a yellow oil (85 mg, 57%). The material was carried forward to the next step without further characterization.

[0561] Preparation of Int-81 :2-(1-(4-cyclopropyl-3-fluorophenyl)-2-methylazetidin-3-yl)lithium acetate

[0562]

[0563] To a solution of methyl 2-[1-(4-cyclopropyl-3-fluoro-phenyl)-2-methyl-azetidin-3-yl]acetate (85 mg, 0.31 mmol) in THF (2.5 mL) and distilled water (0.50 mL) was added lithium hydroxide monohydrate (16 mg, 0.38 mmol) and the reaction was stirred at RT for 3 h. The reaction mixture was concentrated in vacuo and azeotroped with MeCN to give the title compound as a yellow glass (85 mg, quantitative). LC / MS (Table 1, Method A): Rt = 1.31 min; m / z = 264.1 [M+H] +

[0564] Preparation of compound I-60 :6-(2-(1-(4-cyclopropyl-3-fluorophenyl)-2-methylazetidin-3-yl)acetyl)-1,3,4-trimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one

[0565]

[0566] To a solution of 2-(1-(4-cyclopropyl-3-fluorophenyl)-2-methylazetidin-3-yl)lithium acetate (85 mg, 0.32 mmol) in DMF (2 mL) was added N,N-diisopropylethylamine (0.15 mL, 0.85 mmol), HATU (140 mg, 0.37 mmol) and 1,3,4-trimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-one hydrochloride (61 mg, 0.28 mmol). The reaction was stirred at RT for 1 h. The reaction mixture was then partitioned between saturated sodium bicarbonate solution and EtOAc. 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 2, Method 4, non-linear gradient from 20% to 80% MeCN) to give the title compound as an off-white solid (59 mg, 48%). 1HNMR (400 MHz: DMSO-d6) δ 6.80 (t, J = 8.3 Hz, 1H), 6.24-6.19 (m, 2H), 4.99-4.94 (m) and 4.86 (s, 1H), 4.77-4.74 (m), 4.69-4.64 (m) and 4.48-4.44 (m, 3H), 4.24-4.17 (m) and 4.06-4.00 (m, 1H), 3.75-3.67 (m, 1H), 3.56- 3.52 (m, 0.6H), 3.39-3.37 (m, 3H), 3.21 (t, J = 6.5 Hz, 0.4H), 3.06-2.64 (m, 3H), 2.11-2.05 (m, 3H), 2.01-1.97 (m, 3H), 1.91-1.83 (m, 1H), 1.46-1.42 (m) and 1.32-1.28 (m, 3H in total), 0.88-0.82 (m, 2H), 0.59-0.54 (m, 2H).

[0567] Preparation of other compounds

[0568] The compounds in Table 7 were prepared using procedures similar to those described for the preparation of compound 1-60.

[0569] Table 7.

[0570]

[0571] Example 16 -Synthesis of Compound I-84: Lithium 2-(1-(3-cyclopropyloxy-4-fluorophenyl)azetidin-3-yl)acetate

[0572] The title compound was prepared according to the following procedure.

[0573] Preparation of Int-82 :4-Bromo-2-cyclopropyloxy-1-fluorobenzene

[0574]

[0575] To a suspension of 5-bromo-2-fluoro-phenol (500 mg, 2.6 mmol) and cesium carbonate (2.3 g, 7.1 mmol) in DMA (5.0 mL) was added bromocyclopropane (0.84 mL, 11 mmol) and the reaction was heated to 150 ° C. The reaction was stirred at 150 ° C for 18 h. The reaction mixture was cooled to RT and then distributed between DCM and distilled water. The organic layer was separated, passed through a phase separator and concentrated in vacuo. The residue was purified by flash column chromatography (cyclohexane to EtOAc, gradient elution) to give the title compound as a clear oil (477 mg, 79%). LC / MS (Table 2, Method A): R t=1.70min; UV only.

[0576] Preparation of Int-83 : ethyl 2-(1-(3-cyclopropyloxy-4-fluorophenyl)azetidin-3-yl)acetate

[0577]

[0578] The reaction vessel is charged with ethyl 2-(azetidine-3-yl)acetate 2,2,2-trifluoroacetate (400mg, 0.93mmol), 4-bromo-2-cyclopropyloxy-1-fluorobenzene (259mg, 1.1mmol), Xantphos (27mg, 0.047mmol), XantPhos Pd G3 (44mg, 0.047mmol), cesium carbonate (0.91g, 2.8mmol) and solvated in 1,4-dioxane (8mL). The reaction is evacuated, purged with argon (x3), and heated to 100 ° C. The reaction is stirred at 100 ° C for 6h. The reaction mixture is cooled to RT, filtered through diatomaceous earth and washed with EtOAc. The filtrate is concentrated in vacuo. The residue is purified by flash column chromatography (cyclohexane to DCM, gradient elution) to give the title compound as a clear oil (133mg, 49%). LC / MS (Table 2, Method A): R t =1.62min; m / z=294[M+H] + .

[0579] Preparation of Int-84 : 2-(1-(3-cyclopropyloxy-4-fluorophenyl)azetidin-3-yl)lithium acetate

[0580]

[0581] To a solution of ethyl 2-(1-(3-cyclopropyloxy-4-fluorophenyl)azetidin-3-yl)acetate (133 g, 0.45 mmol) in THF (3.0 mL) and distilled water (1.0 mL) was added lithium hydroxide monohydrate (38 mg, 0.91 mmol) and the reaction was stirred at RT for 16 h. The reaction mixture was concentrated in vacuo to afford the title compound as a light yellow solid (126 mg, quantitative). The material was carried forward to the next step without characterization.

[0582] Example 17 -Synthesis of Compound I-63: 6-(2-(1-(3-cyclopropyloxy-4-fluorophenyl)azetidin-3-yl)acetyl)-1,3,4-trimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one

[0583]

[0584] To a solution of 1,3,4-trimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride (40 mg, 0.19 mmol) and N,N-diisopropylethylamine (0.097 mL, 0.56 mmol) in DMF (0.5 mL) was added a suspension of 2-(1-(3-cyclopropyloxy-4-fluorophenyl)azetidin-3-yl)lithium acetate (60 mg, 0.20 mmol) and HATU (92 mg, 0.24 mmol) in DMF (0.5 mL). The reaction was stirred for 1 h at RT. The reaction mixture was then partitioned between DCM and aqueous sodium bicarbonate solution. 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 (EtOAc to IMS, gradient elution) to give the title compound as a white solid (52 mg, 63%). 1 H NMR (400 MHz:CDCl3) δ 6.91 (dd, J = 8.7, 11.2 Hz, 1H), 6.36 (dd, J = 2.7, 7.0 Hz, 1H), 5.96-5.91 (m, 1H), 4.75-4.70 (m, 2H), 4.65-4.59 (m, 2H), 4.10 (t, J = 7.4 Hz, 2H), 3.80-3.74 (m, 1H), 3.56 (dd, J = 5.4, 7.0 Hz, 2H), 3.47 (s, 3H), 3.22-3.14 (m, 1H), 2.82-2.77 (m, 2H), 2.13-2.09 (m, 6H), 0.85-0.74 (m, 4H). LC / MS (Table 2, Method D): R t =4.16min; m / z=426[M+H] + .

[0585] Example 18 -Synthesis of Compound I-87: Lithium 2-(1-(5-cyclopropyl-4-(trifluoromethyl)thiazol-2-yl)azetidin-3-yl)acetate

[0586] The title compound was prepared according to the following procedure.

[0587] Preparation of Int-85 : ethyl 2-(1-(5-bromo-4-(trifluoromethyl)thiazol-2-yl)azetidin-3-yl)acetate

[0588]

[0589] To a solution of 5-bromo-2-chloro-4-(trifluoromethyl)thiazole (220 mg, 0.83 mmol) and N,N-diisopropylethylamine (0.58 mL, 3.3 mmol) in 1,4-dioxane (2.0 mL) was added 2-(azetidin-3-yl)ethyl acetate 2,2,2-trifluoroacetate (398 mg, 1.2 mmol) in 1,4-dioxane (2.0 mL), and the reaction was stirred at RT for 1 h. The reaction was then heated to 40 ° C and stirred at 40 ° C for 22.5 h. The reaction mixture was cooled to RT and then distributed between EtOAc and saturated sodium bicarbonate aqueous solution. 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) to give the title compound as a light yellow oil (235 mg, 76%). LC / MS (Table 2, Method A): R t =1.75min; m / z=373[M+H] + .

[0590] Preparation of Int-86 : ethyl 2-(1-(5-cyclopropyl-4-(trifluoromethyl)thiazol-2-yl)azetidin-3-yl)acetate

[0591]

[0592] The reaction vessel was charged with ethyl 2-(1-(5-bromo-4-(trifluoromethyl)thiazol-2-yl)azetidin-3-yl)acetate (150 mg, 0.40 mmol), Pd(PPh3)4(46 mg, 0.040 mmol), potassium carbonate (167 mg, 1.2 mmol), cyclopropylboronic acid (104 mg, 1.2 mmol) and solvated in 1,4-dioxane (10 mL). The reaction was evacuated, purged with argon (x3), and heated to 100°C. The reaction was stirred at 100°C for 17 h. The reaction mixture was cooled to RT and 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) to give the title compound as a yellow oil (120 mg, 80%). LC / MS (Table 2, Method A): R t =1.72min; m / z=335[M+H] + .

[0593] Preparation of Int-87 : 2-(1-(5-cyclopropyl-4-(trifluoromethyl)thiazol-2-yl)azetidin-3-yl)lithium acetate

[0594]

[0595] To a solution of ethyl 2-(1-(5-cyclopropyl-4-(trifluoromethyl)thiazol-2-yl)azetidin-3-yl)acetate (115 mg, 0.31 mmol) in THF (2.5 mL) and distilled water (0.5 mL) was added lithium hydroxide monohydrate (16 mg, 0.37 mmol) and the reaction was stirred at RT for 3 h. The reaction mixture was concentrated in vacuo and azeotroped with MeCN to give the title compound as a brown solid (104 mg, 98%). LC / MS (Table 2, Method B): R t =1.50min; m / z=307[M+H] + .

[0596] Example 19 -Synthesis of Compound I-64: 6-(2-(1-(5-cyclopropyl-4-(trifluoromethyl)thiazol-2-yl)azetidin-3-yl)acetyl)-1,3,4-trimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one

[0597]

[0598] To a suspension of 2-(1-(5-cyclopropyl-4-(trifluoromethyl)thiazol-2-yl)azetidin-3-yl)lithium acetate (64 mg, 0.19 mmol) and 1,3,4-trimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride (40 mg, 0.19 mmol) in DMF (1.0 mL) was added HATU (92 mg, 0.24 mmol) and N,N-diisopropylethylamine (0.097 mL, 0.56 mmol). The reaction was stirred at RT for 45 min. The reaction mixture was then partitioned between EtOAc and aqueous sodium bicarbonate solution. The organic layer was separated. The combined organic layers were washed with saturated brine, passed through a phase separator and concentrated in vacuo. The residue was purified by reverse phase HPLC (Table 3, Method 11) to give the title compound as an off-white solid (37 mg, 42%). 1H NMR (400 MHz: DMSO-d6) δ 4.86 (s, 1H), 4.67-4.62 (m, 2H), 4.44 (s, 1H), 4.13 (t, J = 8.1 Hz, 2H), 3.69 (t, J = 6.8 Hz, 2H), 3.35-3.33 (m, 3H), 3.17-3.07 (m, 1H), 2.84-2.78 (m, 2H), 2.07-2.05 (m, 4H), 1.98 (s, 3H), 1.08-1.02 (m, 2H), 0.63-0.58 (m, 2H). LC / MS (Table 2, Method F): R t =4.36min; m / z=467[M+H] + .

[0599] Example 20 -Synthesis of Compound I-65: 6-(2-(1-(4-cyclopropyl-5-(trifluoromethyl)thiazol-2-yl)azetidin-3-yl)acetyl)-1,3,4-trimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one

[0600]

[0601] The title compound: 6-(2-(1-(5-cyclopropyl-4-(trifluoromethyl)thiazol-2-yl)azetidin-3-yl)acetyl)-1,3,4-trimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one was prepared from the appropriate starting material, 4-bromo-2-chloro-5-(trifluoromethyl)thiazole, using a procedure similar to that described in Example 64. The compound was purified by reverse phase HPLC (Table 3, Method 4, non-linear gradient from 20% to 80% MeCN), followed by reverse phase HPLC (Table 3, Method 2, non-linear gradient from 40% to 100% MeOH), followed by flash column chromatography (EtOAc to IMS, gradient elution) to give the title compound as a white solid (16 mg, 70%). 1 H NMR (400 MHz: DMSO-d6) δ 4.88-4.86 (m, 1H), 4.65 (s, 2H), 4.45-4.42 (m, 1H), 4.16 (t, J = 7.5 Hz, 2H), 3.72 (t, J = 6.9 Hz, 2H), 3.34 (d, J = 5.1 Hz, 3H, partially obscured by the solvent peak), 3.17-3.10 (m, 1H), 2.82 (t, J = 7.8 Hz, 2H), 2.06 (d, J = 1.8 Hz, 3H), 1.98 (s, 4H), 1.36-1.19 (m, 1H), 0.96-0.89 (m, 4H). LC / MS (Table 2, Method F): Rt =4.76min; m / z=467[M+H] + .

[0602] Example 21 -Synthesis of Compound Int-88: 3-Chloro-1,4-dimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride

[0603]

[0604] 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 (32 mg, 0.11 mmol) in 1,4-dioxane (0.5 mL) was added 4M HCl in 1,4-dioxane (0.54 mL, 2.1 mmol) and the reaction was stirred at RT for 19 h. The reaction mixture was concentrated in vacuo to afford the title compound as an off-white solid (28 mg, quantitative). The material was carried forward to the next step without characterization.

[0605] Example 22 -Synthesis of Compound I-66: 3-Chloro-1,4-dimethyl-6-(2-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)acetyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one

[0606]

[0607] To a solution of 2-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)lithium acetate (35 mg, 0.13 mmol) in DMF (0.5 mL) was added HATU (68 mg, 0.18 mmol), followed by a solution of 3-chloro-1,4-dimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride (28 mg, 0.12 mmol) and N,N-diisopropylethylamine (0.052 mL, 0.30 mmol) in DMF (0.75 mL). The reaction was stirred at RT for 30 min. The reaction mixture was then partitioned between EtOAc and aqueous sodium bicarbonate solution. The organic layer was separated. The combined organic layers were washed with 5% aqueous LiCl solution, saturated brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by reverse phase HPLC (Table 3, Method 2) followed by reverse phase HPLC (Table 3, Method 3) to give the title compound as an off-white solid (12 mg, 22%). 1HNMR(300MHz:DMSO-d6)δ8.22(d,J=5.6Hz,1H),6.73(t,J=1.9Hz,1H),6.55 (d,J=5.6Hz,1H),4.94-4.93(m,1H),4.72(dd,J=2.2,8.6Hz,2H),4.51-4.49 (m,1H),4.19(t,J=8.3Hz,2H),3.71(dd,J=5.7,8.3Hz,2H),3.43(d,J=8.7Hz ,3H),3.17-3.11(m,1H),2.84(dd,J=6.1,7.5Hz,2H),2.23(d,J=6.8Hz,3H). LC / MS (Table 2, Method E): R t =3.69min; m / z=441[M+H] + .

[0608] Example 23 -Synthesis of other compounds

[0609] The compounds in Table 8 were prepared using procedures similar to those described above for the preparation of compound 1-3. The starting materials used are listed in Table 8.

[0610] Table 8: Other compounds

[0611]

[0612] Example 24 -Synthesis of Compound I-91: 2-(1-(pyridazin-4-yl)azetidin-3-yl)lithium acetate

[0613] The title compound was prepared according to the following procedure.

[0614] Preparation of Int-89 : ethyl 2-(1-(3,6-dichloropyridazin-4-yl)azetidin-3-yl)acetate

[0615]

[0616] The reaction vessel was charged with 3,4,6-trichloropyridazine (382 mg, 2.1 mmol), ethyl 2-(azetidin-3-yl)acetate 2,2,2-trifluoroacetate (536 mg, 2.1 mmol), N,N-diisopropylethylamine (1.1 mL, 6.3 mmol) and solvated in 2-propanol (4 mL). The reaction was stirred at RT for 1.5 h. The reaction mixture was concentrated in vacuo and the residue was purified directly by flash column chromatography (cyclohexane to EtOAc, gradient elution) to give the title compound as a white solid (178 mg, 29%). LC / MS (Table 2, Method B): R t=1.44min; m / z=290[M+H] + .

[0617] Preparation of Int-90 : ethyl 2-(1-(pyridazin-4-yl)azetidin-3-yl)acetate

[0618]

[0619] To a solution of ethyl 2-(1-(3,6-dichloropyridazine-4-yl)azetidine-3-yl)acetate (175 mg, 0.60 mmol) and sodium acetate (198 mg, 2.4 mmol) in IMS (2 mL) and distilled water (2 mL) was added 10% palladium on carbon (17 mg, 0.16 mmol). The reaction was then evacuated and placed under a hydrogen atmosphere. The reaction was stirred at RT under a hydrogen atmosphere for 18.25 h. The reaction mixture was filtered through diatomaceous earth, washed with DCM, and the filtrate was concentrated in vacuo to give the title compound as a colorless jelly (141 mg, quantitative). LC / MS (Table 2, Method G): R t =1.31min; m / z=222[M+H] + .

[0620] Preparation of Int-91 : 2-(1-(pyridazin-4-yl)azetidin-3-yl)lithium acetate

[0621]

[0622] To a solution of ethyl 2-(1-(pyridazine-4-yl)azetidin-3-yl)acetate (135 g, 0.61 mmol) in MeOH (1 mL), distilled water (1 mL) and THF (2 mL) was added lithium hydroxide monohydrate (96 mg, 1.8 mmol) and the reaction was stirred at RT for 3 h. The reaction mixture was concentrated in vacuo to give the title compound as a yellow gum (201 mg, quantitative). LC / MS (Table 2, Method B): R t =0.18min; m / z=194[M+H] + .

[0623] Example 25 -Synthesis of Compound I-81: 3-Chloro-1,4-dimethyl-6-(2-(1-(pyridazin-4-yl)azetidin-3-yl)acetyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one

[0624]

[0625] To a solution of 2-(1-(pyridazine-4-yl)azetidine-3-yl)lithium acetate (64 mg, 0.26 mmol) in DMF (1 mL) was added HATU (105 mg, 0.28 mmol), triethylamine (0.089 mL, 0.64 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). The reaction was stirred at RT for 2 h. The reaction mixture was then partitioned between DCM and distilled water. The organic layer was separated using a phase separator and concentrated in vacuo. The residue was purified by reverse phase HPLC (Table 3, Method 2) to give the title compound as an off-white solid (11 mg, 14%). 1 H NMR (400 MHz: DMSO-d6) δ 8.58 (d, J = 6.0 Hz, 1H), 8.48-8.46 (m, 1H), 6.51-6.48 (m, 1H), 4.93 (s, 1H), 4.71 (dd, J = 2.2, 8.1 Hz, 2H), 4.51 (dd, J = 2.5, 2.5 Hz, 1H), 4.19 (t, J = 8.3 Hz, 2H), 3.71 (dd, J = 5.7, 8.3 Hz, 2H), 3.43 (d, J = 8.2 Hz, 3H), 3.19-3.11 (m, 1H), 2.84 (dd, J = 6.0, 7.7 Hz, 2H), 2.22 (d, J = 6.3 Hz, 3H). LC / MS (Table 2, Method E): R t =2.54min; m / z=374[M+H] + .

[0626] Example 26 -Synthesis of Compound I-92: (±)-2-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)propanoic acid

[0627]

[0628] Under a nitrogen atmosphere, 4-chloro-2-(trifluoromethyl)pyridine (0.096 mL, 0.74 mmol) was added to a solution of 2-(azetidin-3-yl)propanoic acid; 2,2,2-trifluoroacetic acid (150 mg, 0.62 mmol) and potassium carbonate (341 mg, 2.5 mmol) in MeCN (1.5 mL) and the reaction was heated to 80 ° C. The reaction was stirred at 80 ° C for 17.5 h. The reaction mixture was cooled to RT, filtered through celite and washed with EtOAc. The filtrate was concentrated in vacuo. The residue was suspended in 1M sodium hydroxide solution, neutralized with 1M HCl, and then partitioned with EtOAc. The organic layer was separated. The combined organic layers were washed with saturated brine, dried (Na2SO4) and concentrated in vacuo to give the title compound as an off-white solid (25 mg, 15%). 1 H NMR(400MHz:DMSO-d6)δ8.20(d,J=5.8Hz,1H),6.71(d,J=2.1Hz,1H),6.52(dd,J=2.2,5.8Hz,1H), 4.12-4.04(m,2H),3.76-3.71(m,2H),2.92-2.82(m,1H),2.70-2.62(m,1H),1.07(d,J=7.2Hz,3H).

[0629] Example 27 -Synthesis of Compound I-82: 3-Chloro-1,4-dimethyl-6-(2-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)propanoyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one

[0630]

[0631] To a solution of (±)-2-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)propanoic acid (50 mg, 0.18 mmol) in DMF (0.5 mL) was added HATU (83 mg, 0.22 mmol), followed by a solution of 3-chloro-1,4-dimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride (43 mg, 0.18 mmol) and N,N-diisopropylethylamine (0.13 mL, 0.73 mmol) in DMF (0.75 mL). The reaction was stirred at RT for 16 h. The reaction mixture was then partitioned between EtOAc and aqueous sodium bicarbonate solution. The organic layer was separated. The combined organic layers were washed with 5% aqueous LiCl solution, saturated brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by SFC (Table 3, Method 8) to give the title compound of unknown absolute configuration - stereoisomer 1 as an off-white solid (8.5 mg, 10%). 1 H NMR (400 MHz: DMSO-d6) δ 8.23 ​​(d, J = 5.0 Hz, 1H), 6.73-6.71 (m, 1H), 6.56-6.52 (m, 1H), 5.16-4.47 (m, 4H), 4.17-4.01 (m, 2H), 3.81-3.65 (m, 2H), 3.45-3.42 (m, 3H), 3.10-2.98 (m, 2H), 2.24-2.22 (m, 3H), 1.12 (d, J = 6.7 Hz, 3H). LC / MS (Table 2, Method C): R t =3.05min; m / z=455[M+H] + .

[0632] Example 28 -Synthesis of Compound I-83: ​​3-Chloro-1,4-dimethyl-6-(2-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)propanoyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one

[0633]

[0634] The title compound was prepared using a procedure similar to that described for compound 1-82. The compound was purified by SFC (Table 3, Method 8) to give the title compound of unknown absolute configuration - stereoisomer 2 as an off-white solid (8.6 mg, 10%). 1H NMR (400 MHz: DMSO-d6) δ 8.23 ​​(d, J = 5.0 Hz, 1H), 6.73-6.71 (m, 1H), 6.56-6.52 (m, 1H), 5.16-4.47 (m, 4H), 4.17-4.01 (m, 2H), 3.81-3.65 (m, 2H), 3.45-3.42 (m, 3H), 3.10-2.98 (m, 2H), 2.24-2.22 (m, 3H), 1.12 (d, J = 6.7 Hz, 3H). LC / MS (Table 2, Method E): R t =3.74min; m / z=455[M+H] + .

[0635] Example 29 -Synthesis of Compound Int-96: 3-Fluoro-1,4-dimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride

[0636] The title compound was prepared according to the following procedure.

[0637] Preparation of Int-93 :3-Bromo-1,4-dimethyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylic acid tert-butyl ester

[0638]

[0639] To a solution of tert-butyl 1,4-dimethyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (120 g, 0.45 mmol) in MeCN (2 mL) and DMF (1 mL) was added N-bromosuccinimide (113 mg, 0.64 mmol) and the reaction was heated to 50°C. The reaction was stirred at 50°C for 1 h. The reaction mixture was cooled to RT and distilled water was added. The reaction mixture was filtered, washed with distilled water, and concentrated in vacuo to afford the title compound as a white solid (114 mg, 73%). 1 H NMR (300MHz: CDCl3) δ4.63-4.47 (m, 4H), 3.51 (d, J = 2.0Hz, 3H), 2.26 (s, 3H), 1.52 (s, 9H).

[0640] Preparation of Int-94 :(6-(tert-Butoxycarbonyl)-1,4-dimethyl-2-oxo-2,5,6,7-tetrahydro-1H-pyrrolo[3,4-b]pyridin-3-yl)boronic acid

[0641]

[0642] The reaction vessel was charged with tert-butyl 3-bromo-1,4-dimethyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (592 mg, 1.7 mmol), tetrahydroxydiboron (464 mg, 5.2 mmol), potassium acetate (508 mg, 5.2 mmol), XPhos Pd G2 (34 mg, 0.043 mmol), XPhos (41 mg, 0.086 mmol) and solvated in IMS (18 mL). The reaction was evacuated, purged with argon (x3), and then heated to 80 ° C. The reaction was stirred at 80 ° C for 3.5 h. The reaction mixture was cooled to RT, filtered through celite and washed with EtOAc. The filtrate was concentrated in vacuo, and the residue was then distributed between EtOAc and distilled water. The organic layer was separated. The combined organic layer was washed with saturated brine, dried (Na2SO4) and concentrated in vacuo. The residue was triturated with DCM, filtered, and the filtrate concentrated in vacuo to give the title compound as a white solid (140 mg, 26%). LC / MS (Table 2, Method B): R t =1.22min; m / z=309[M+H] + .

[0643] Preparation of Int-95 :3-Fluoro-1,4-dimethyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylic acid tert-butyl ester

[0644]

[0645] To a solution of sodium hydroxide (69 mg, 1.7 mmol) in MeOH (3.2 mL) was added (6-(tert-butoxycarbonyl)-1,4-dimethyl-2-oxo-2,5,6,7-tetrahydro-1H-pyrrolo[3,4-b]pyridin-3-yl)boronic acid (445 mg, 1.4 mmol) and the reaction was stirred at RT for 15 min. The reaction was cooled to 0 ° C and silver trifluoromethanesulfonate (1.1 g, 4.3 mmol) was added. The reaction was stirred at 0 ° C for 30 min. The reaction mixture was concentrated in vacuo, azeotroped with acetone, and the residue was dissolved in acetone (8 mL). 4A molecular sieves (800 mg) and Selectfluor (R) fluorination reagent (537 mg, 1.5 mmol) were added at 0 ° C, and the reaction was stirred at 0 ° C for 30 min. The reaction mixture was warmed to RT, filtered through celite, and washed with DCM. The filtrate was concentrated in vacuo, and the residue 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 (DCM to MeOH, gradient elution) to give the title compound as a white solid (76 mg, 18%). LC / MS (Table 2, Method B): R t =1.25min; m / z=283[M+H] + .

[0646] Preparation of Int-96 :3-Fluoro-1,4-dimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride

[0647]

[0648] The reaction vessel was charged with tert-butyl 3-fluoro-1,4-dimethyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (76 mg, 0.27 mmol) and a 4M HCl solution in 1,4-dioxane (1.7 mL, 6.7 mmol) and the reaction was stirred at RT for 3 h. The reaction mixture was concentrated in vacuo and azeotroped with toluene to afford the title compound as an off-white solid (58 mg, 80%). LC / MS (Table 2, Method A): R t =0.42min; m / z=183[M+H] + .

[0649] Example 30 -Synthesis of Compound I-84: 3-Fluoro-1,4-dimethyl-6-(2-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)acetyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one

[0650]

[0651] To a solution of 3-fluoro-1,4-dimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride (58 mg, 0.27 mmol), 2-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)lithium acetate (85 mg, 0.32 mmol) and HATU (182 mg, 0.48 mmol) in DMF (1.7 mL) was added N,N-diisopropylethylamine (0.16 mL, 0.93 mmol). The reaction was stirred at RT for 18 h. The reaction mixture was then partitioned between EtOAc and aqueous sodium bicarbonate solution. 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 2) to give the title compound as an off-white solid (47 mg, 41%). 1 H NMR (400 MHz: DMSO-d6) δ 8.22 (d, J = 5.6 Hz, 1H), 6.74-6.72 (m, 1H), 6.56-6.54 (m, 1H), 4.91-4.88 (m, 1H), 4.72-4.66 (m, 2H), 4.48 (s, 1H), 4.19 (t, J = 8.2 Hz, 2H), 3.70 (dd, J = 5.6, 8.3 Hz, 2H), 3.41 (d, J = 10.2 Hz, 3H), 3.18-3.09 (m, 1H), 2.83 (dd, J = 5.8, 7.6 Hz, 2H), 2.13-2.09 (m, 3H). LC / MS (Table 2, Method E): R t =3.44min; m / z=425[M+H] + .

[0652] Example 31 -Synthesis of other compounds

[0653] The compounds in Table 9 were prepared using procedures similar to those described above for the preparation of compound 1-84. The starting materials used are listed in Table 9.

[0654] Table 9: Other compounds

[0655]

[0656]

[0657] Example 32-Synthesis of Compound Int-99: 1-Methyl-4-(trifluoromethyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride

[0658] The title compound was prepared according to the following procedure.

[0659] Preparation of Int-97 :(Z)-3-(methylimino)pyrrolidine-1-carboxylic acid tert-butyl ester

[0660]

[0661] A reaction vessel was charged with N-Boc-3-pyrrolidone (2 g, 11 mmol) and dissolved in a 2 M solution of methylamine in THF (9.2 mL, 18 mmol). The reaction was stirred at RT for 15 min and then heated to 60°C. The reaction was stirred at 60°C for 5 h. The reaction mixture was allowed to cool to RT and then concentrated in vacuo to afford the title compound as a yellow oil (2.2 g, quantitative). The material did not need to be fully characterized before proceeding to the next step.

[0662] Preparation of Int-98 :1-methyl-2-oxo-4-(trifluoromethyl)-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylic acid tert-butyl ester

[0663]

[0664] To a solution of tert-butyl (Z)-3-(methylimino)pyrrolidine-1-carboxylate (500 mg, 2.5 mmol) and ethyl 2-fluoroacetoacetate (0.36 mL, 2.9 mmol) in toluene (2 mL) was added triethylamine (0.70 mL, 5.0 mmol) and the reaction was heated to 110°C, then stirred at 110°C for 12 h. The reaction was then heated to 140°C and stirred at 140°C for 2 h. The reaction mixture was cooled to RT, concentrated in vacuo, and directly purified by flash column chromatography (DCM to MeCN, gradient elution) to give the title compound as a brown gum (83 mg, 9%). 1 HNMR (400MHz: CDCl3) δ6.80-6.78 (m, 1H), 4.68-4.54 (m, 4H), 3.49 (d, J = 2.1Hz, 3H), 1.52 (s, 9H).

[0665] Preparation of Int-99 :1-Methyl-4-(trifluoromethyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride

[0666]

[0667] To a solution of tert-butyl 1-methyl-2-oxo-4-(trifluoromethyl)-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (41 mg, 0.13 mmol) in DCM (0.5 mL) was added a 4M solution of HCl in 1,4-dioxane (0.64 mL, 2.6 mmol) and the reaction was stirred at RT for 17 h. The reaction mixture was concentrated in vacuo to give the title compound as a brown solid (35 mg, 85%). LC / MS (Table 2, Method A): R t =0.77min; m / z=219[M+H] + .

[0668] Example 33 -Synthesis of Compound I-91: 1-Methyl-6-(2-(1-(pyridin-3-yl)azetidin-3-yl)acetyl)-4-(trifluoromethyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one

[0669]

[0670] To a solution of 2-(1-(pyridin-3-yl)azetidine-3-yl)lithium acetate (26 mg, 0.13 mmol) and HATU (63 mg, 0.17 mmol) in DMF (0.5 mL) was added a solution of 1-methyl-4-(trifluoromethyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridine-2-one hydrochloride (35 mg, 0.11 mmol) and N,N-diisopropylethylamine (0.067 mL, 0.39 mmol). The reaction was stirred at RT for 1.5 h. The reaction mixture was then partitioned between DCM and a saturated aqueous sodium bicarbonate solution. The organic layer was separated, passed through a phase separator and concentrated in vacuo. The residue was purified by SFC (Table 3, Method 9) and subsequently purified by reverse phase HPLC (Table 3, Method 4) to give the title compound as an off-white solid (1.6 mg, 4%). 1H NMR (400 MHz: DMSO-d6) δ 7.91 (ddd, J = 1.5, 2.9, 4.4 Hz, 1H), 7.82 (ddd, J = 0.6, 2.9, 4.7 Hz, 1H), 7.18-7.14 (m, 1H), 6.84-6.79 (m, 1H), 6.78 (dd, J = 1.1, 1.1 Hz, 1H), 4.99-4.53 (m, 4H), 4.06 (dt, J = 2.3, 7.7 Hz, 2H), 3.57 (dd, J = 5.9, 7.3 Hz, 2H), 3.44 (d, J = 8.7 Hz, 3H), 3.15-3.04 (m, 1H), 2.85 (dd, J = 7.7, 13.7 Hz, 2H). LC / MS (Table 2, Method C): R t =2.43min; m / z=393[M+H] + .

[0671] Example 34 -Synthesis of Compound I-92

[0672] The compounds in Table 10 were prepared using procedures similar to those described above for the preparation of compound 1-91. The starting materials used are listed in Table 10.

[0673] Table 10: Other compounds

[0674]

[0675] Example 35 -Synthesis of Compound Int-104: 3-Chloro-4-methyl-1-(2,2,2-trifluoroethyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride

[0676] The title compound was prepared according to the following procedure.

[0677] Preparation of Int-100 :4-methyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one

[0678]

[0679] A reaction vessel was charged with tert-butyl 2-methoxy-4-methyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (500 mg, 1.9 mmol) and 6M HCl (13 mL, 76 mmol). The reaction was stirred at RT for 15 min and then heated to 100°C. The reaction was stirred at 100°C for 32 h. The reaction mixture was cooled to RT, concentrated in vacuo, and purified by SCX-2 column chromatography (MeOH to MeOH [2M NH3], gradient elution) to afford the title compound as a yellow solid (274 mg, 96%). 1 H NMR (400MHz, MeOD) δ6.24 (s, 1H), 4.09-4.04 (m, 4H), 2.20 (s, 3H).

[0680] Preparation of Int-101 :4-methyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylic acid tert-butyl ester

[0681]

[0682] To a suspension of 4-methyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one (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 RT for 2 h. The reaction mixture was then concentrated in vacuo and purified directly by flash column chromatography (DCM to MeOH, gradient elution) to give the title compound as a white solid (130 mg, 46%). LC / MS (Table 2, Method B): R t =1.19min; m / z=251[M+H] + .

[0683] Preparation of Int-102 : tert-Butyl 4-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate

[0684]

[0685] To a suspension of tert-butyl 4-methyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (47 mg, 0.19 mmol) and potassium carbonate (78 mg, 0.56 mmol) in MeCN (2.8 mL) was added 1,1,1-trifluoro-2-iodoethane (0.074 mL, 0.75 mmol), and the reaction was heated to 115 ° C. The reaction was stirred at 115 ° C for 8 h. The reaction mixture was cooled to RT and then distributed 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 (DCM to EtOAc, gradient elution) to give the title compound as a white solid (34 mg, 22%). LC / MS (Table 2, Method B): R t =1.51min; m / z=333[M+H] + .

[0686] Preparation of Int-103 : tert-Butyl 3-chloro-4-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate

[0687]

[0688] To a solution of tert-butyl 4-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (36 mg, 0.11 mmol) in MeCN (0.5 mL) and DMF (0.25 mL) was added N-chlorosuccinimide (21 mg, 0.15 mmol), and the reaction was heated to 55 ° C. The reaction was stirred at 55 ° C for 1.5 h. The reaction mixture was cooled to RT and then distributed between DCM 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 MeOH, gradient elution) to give the title compound as a white solid (27 mg, 68%). LC / MS (Table 2, Method B): R t =1.68min; m / z=367[M+H] + .

[0689] Preparation of Int-104 :3-Chloro-4-methyl-1-(2,2,2-trifluoroethyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride

[0690]

[0691] A reaction vessel was charged with tert-butyl 3-chloro-4-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (27 mg, 0.074 mmol) and a 4M solution of HCl in 1,4-dioxane (0.46 mL, 1.8 mmol). The reaction was stirred at room temperature for 3 h. The reaction mixture was concentrated in vacuo to afford the title compound as an off-white solid (23 mg, quantitative). The material was carried forward to the next step without characterization.

[0692] Example 36 -Synthesis of Compound I-93: 3-Chloro-4-methyl-6-(2-(1-(pyridin-3-yl)azetidin-3-yl)acetyl)-1-(2,2,2-trifluoroethyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one

[0693]

[0694] To a suspension of 2-(1-(pyridin-3-yl)azetidine-3-yl)lithium acetate (17 mg, 0.086 mmol) in DMF (0.5 mL) was added HATU (42 mg, 0.11 mmol), followed by a solution of 3-chloro-4-methyl-1-(2,2,2-trifluoroethyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride (22 mg, 0.073 mmol) and N,N-diisopropylethylamine (0.051 mL, 0.29 mmol) in DMF (0.5 mL). The reaction was stirred at RT for 45 min. The reaction mixture was then partitioned between DCM and aqueous sodium bicarbonate solution. 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 2, non-linear gradient from 40% to 100% MeOH) to give the title compound as an off-white solid (16 mg, 50%). 1H NMR (300 MHz: DMSO-d6) δ 7.91-7.90 (m, 1H), 7.82 (d, J = 2.8 Hz, 1H), 7.16 (dd, J = 4.6, 8.2 Hz, 1H), 6.83-6.80 (m, 1H), 4.97-4.85 (m, 3H), 4.73 (dd, J = 2.5, 10.3 Hz, 2H), 4.52 (t, J = 2.7 Hz, 1H), 4.06 (t, J = 7.6 Hz, 2H), 3.60-3.55 (m, 2H), 3.13-3.06 (m, 1H), 2.82 (t, J = 7.3 Hz, 2H), 2.26 (d, J = 6.8 Hz, 3H). LC / MS (Table 2, Method E): R t =3.70min; m / z=441[M+H] + .

[0695] Example 37 -Synthesis of other compounds

[0696] The compounds in Table 11 were prepared using procedures similar to those described above for the preparation of compound 1-93. The starting materials used are listed in Table 11.

[0697] Table 11: Other compounds

[0698]

[0699] Example 38 -Synthesis of Compound Int-105: 4-Methoxy-1,3-dimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride

[0700] The title compound was prepared according to the following procedure.

[0701] Preparation of Int-105 :4-Methoxy-1,3-dimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride

[0702]

[0703] To a solution of tert-butyl 4-methoxy-1,3-dimethyl-2-oxo-5,7-dihydropyrrolo[3,4-b]pyridine-6-carboxylate (330 mg, 1.1 mmol) in DCM (5 mL) was added a solution of 4M HCl in 1,4-dioxane (5.6 mL, 22 mmol) and the reaction was stirred at RT for 4 h. The reaction mixture was then concentrated in vacuo to give the title compound as a pink solid (266 mg, quantitative). LC / MS (Table 2, Method A): R t=0.59min; m / z=195[M+H] + .

[0704] Example 39 -Synthesis of Compound I-97: 4-Methoxy-1,3-dimethyl-6-(2-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)acetyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one

[0705]

[0706] To a solution of 2-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)lithium acetate (63 mg, 0.24 mmol) and HATU (91 mg, 0.24 mmol) in DMF (0.75 mL) was added a solution of 4-methoxy-1,3-dimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride (50 mg, 0.22 mmol) and N,N-diisopropylethylamine (0.13 mL, 0.76 mmol) in DMF (0.75 mL). The reaction was stirred at RT for 1 h. The reaction mixture was then partitioned between EtOAc and saturated aqueous sodium bicarbonate solution. The organic layer was separated. The combined organic layers were washed with 5% aqueous LiCl solution, saturated brine, dried (Na2SO4) and concentrated in vacuo. The residue was triturated with 10% aqueous DMSO and washed with distilled water to give the title compound as a brown solid (40 mg, 55%). 1 H NMR (400 MHz: DMSO-d6) δ 8.21 (d, J = 5.7 Hz, 1H), 6.71 (d, J = 2.1 Hz, 1H), 6.53 (dd, J = 2.0, 5.7 Hz, 1H), 4.91 (t, J = 2.2 Hz, 1H), 4.87 (s, 1H), 4.71-4.68 (m, 1H), 4.63 (s, 1H), 4.17 (t, J = 8.3 Hz, 2H), 3.86 (d, J = 2.4 Hz, 3H), 3.69 (dd, J = 5.7, 8.3 Hz, 2H), 3.34 (d, J = 7.1 Hz, 3H, partially obscured by the solvent peak), 3.18-3.08 (m, 1H), 2.89-2.80 (m, 2H), 1.88 (s, 3H). LC / MS (Table 2, Method F): R t =2.66min; m / z=437[M+H] + .

[0707] Example 40 -Synthesis of other compounds

[0708] The compounds in Table 12 were prepared using procedures similar to those described above for the preparation of compound 1-97. The starting materials used are described in Table 12.

[0709] Table 12: Other compounds

[0710]

[0711] Example 41 -Synthesis of Compound I-106: 4-Methyl-6-(2-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)acetyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one

[0712]

[0713] To a solution of 4-methyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one (270 mg, 1.8 mmol) and 2-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)lithium acetate (502 mg, 1.9 mmol) in DMF (10 mL) was added HATU (889 mg, 2.3 mmol) and N,N-diisopropylethylamine (0.47 mL, 2.7 mmol). The reaction was stirred at RT for 1 h. The reaction mixture was concentrated in vacuo and purified directly by reverse phase HPLC (Table 3, Method 5) to give the title compound as a white solid (243 mg, 34%). LC / MS (Table 2, Method F): R t =2.57min; m / z=393[M+H] + .

[0714] Example 42 -Synthesis of Compound I-101: 1-(cyclopropylmethyl)-4-methyl-6-(2-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)acetyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one

[0715]

[0716] To a suspension of 4-methyl-6-(2-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)acetyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one (50 mg, 0.13 mmol) and potassium carbonate (53 mg, 0.38 mmol) in MeCN (2 mL) was added (bromomethyl)cyclopropane (0.025 mL, 0.26 mmol), and the reaction was heated to 80 ° C. The reaction was stirred at 80 ° C for 16 h. The reaction mixture was cooled to RT, concentrated in vacuo, and purified directly by reverse phase HPLC (Table 3, Method 4, non-linear gradient from 20% to 80% MeCN) to give the title compound as an off-white solid (16 mg, 28%). 1 H NMR(400MHz:DMSO-d6)δ8.22(d,J=5.6Hz,1H),6.73(t,J=2.5Hz,1H),6.57- 6.53(m,1H),6.20(d,J=4.9Hz,1H),4.95-4.92(m,1H),4.68(d,J=16.9Hz,2H ),4.44(s,1H),4.22-4.16(m,2H),3.76-3.68(m,4H),3.17-3.10(m,1H),2.8 5(t,J=8.2Hz,2H),2.11-2.09(m,3H),1.27-1.16(m,1H),0.49-0.34(m,4H). LC / MS (Table 2, Method C): R t =3.07min; m / z=447[M+H] + .

[0717] Example 43 -Synthesis of Compound Int-110: 1-(Cyclopropylmethyl)-4-methyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride

[0718] The title compound was prepared according to the following procedure.

[0719] Preparation of Int-107 :But-2-ynoyl chloride

[0720]

[0721] To a solution of 2-butynoic acid (454 mg, 5.4 mmol) in DCM (12 mL) was added 1-chloro-N,N,2-trimethyl-1-propenamine (0.79 mL, 5.9 mmol) dropwise at 0°C under nitrogen. The reaction was stirred at 0°C for 2 h. The reaction mixture was carried forward to the next step without characterization.

[0722] Preparation of Int-108:tert-Butyl (Z)-3-((cyclopropylmethyl)imino)pyrrolidine-1-carboxylate

[0723]

[0724] To a solution of N-Boc-3-pyrrolidone (1g, 5.4mmol) in DCM (30mL) was added magnesium sulfate (1.3g, 11mmol) and cyclopropanemethylamine (2.3mL, 27.0mmol). The reaction was then heated to 40°C and stirred at 40°C for 22h. The reaction mixture was cooled to RT, filtered through diatomaceous earth and washed with DCM. The filtrate was concentrated in vacuo to obtain the title compound as a yellow oil (1.2g, quantitative). The material can be entered into the next step without characterization.

[0725] Preparation of Int-109 :1-(cyclopropylmethyl)-4-methyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylic acid tert-butyl ester

[0726]

[0727] To a solution of but-2-ynoyl chloride (533 mg, 5.2 mmol) in DCM (6 mL) was added dropwise (Z)-tert-butyl 3-((cyclopropylmethyl)imino)pyrrolidine-1-carboxylate (1.2 g, 5.2 mmol) and triethylamine (1.4 mL, 10 mmol) at 0 ° C. under a nitrogen atmosphere. The reaction was stirred at 0 ° C. for 30 min. The reaction was allowed to warm to RT and stirred at RT for 64 h. Saturated aqueous sodium bicarbonate solution was then added and the reaction was stirred for 10 min. The reaction mixture was passed through a phase separator and concentrated in vacuo and purified by flash column chromatography (DCM to EtOAc, gradient elution) to give the title compound as a yellow oil (365 mg, 23%). LC / MS (Table 1, Method B): R t =1.48min; m / z=305[M+H] + .

[0728] Preparation of Int-110 :1-(Cyclopropylmethyl)-4-methyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride

[0729]

[0730] To a solution of tert-butyl 1-(cyclopropylmethyl)-4-methyl-2-oxo-5,7-dihydropyrrolo[3,4-b]pyridine-6-carboxylate (37 mg, 0.12 mmol) in DCM (0.20 mL) was added a 4M solution of HCl in 1,4-dioxane (0.85 mL, 3.4 mmol) and the reaction was stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and azeotroped with toluene to give the title compound as a white solid (30 mg, quantitative). The material was not characterized and was carried to the next step.

[0731] Example 44 -Synthesis of Compound I-102: 1-cyclopropyl-4-methyl-6-(2-(1-(4-(trifluoromethyl)phenyl)azetidin-3-yl)acetyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one

[0732]

[0733] To a suspension of 2-[1-[4-(trifluoromethyl)phenyl]azetidin-3-yl]lithium acetate (39 mg, 0.15 mmol) and 1-(cyclopropylmethyl)-4-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-2-one hydrochloride (29 mg, 0.12 mmol) in DMF (0.6 mL) was added N,N-diisopropylethylamine (0.064 mL, 0.37 mmol) and HATU (69 mg, 0.18 mmol). The reaction was stirred at RT for 30 min. 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, dried (Na2SO4) and concentrated in vacuo. The residue was purified by reverse phase HPLC (Table 3, Method 3, non-linear gradient from 20% to 80% MeCN) to give the title compound as an off-white solid (11 mg, 20%). 1 H NMR(400MHz:DMSO-d6)δ7.47(d,J=8.4Hz,2H),6.52(d,J=7.3Hz,2H),6.20(d,J= 4.5Hz,1H),4.95-4.92(m,1H),4.69(dd,J=2.3,14.5Hz,2H),4.44(s,1H),4.12- 4.06(m,2H),3.76-3.68(m,2H),3.61(t,J=6.6Hz,2H),3.16-3.06(m,1H),2.84( dd,J=7.7,9.7Hz,2H),2.11-2.09(m,3H),1.26-1.16(m,1H),0.49-0.34(m,4H). LC / MS (Table 1, Method E): Rt =4.76min; m / z=446.2[M+H] + .

[0734] Example 45 -Synthesis of Int-113: 1-cyclopropyl-4-methyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride

[0735] The title compound was prepared according to the following procedure.

[0736] Preparation of Int-111 :(Z)-3-(cyclopropylimino)pyrrolidine-1-carboxylic acid tert-butyl ester

[0737]

[0738] To a solution of N-Boc-3-pyrrolidone (1g, 5.4mmol) in DCM (30mL) was added magnesium sulfate (1.3g, 11mmol) and cyclopropylamine (1.9mL, 27mmol). The reaction was then heated to 40°C and stirred at 40°C for 16h. The reaction mixture was cooled to RT, filtered through diatomaceous earth and washed with DCM. The filtrate was concentrated in vacuo to give the title compound as a yellow oil (1.2g, quantitative). The material was not characterized and entered into the next step.

[0739] Preparation of Int-112 :1-cyclopropyl-4-methyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylic acid tert-butyl ester

[0740]

[0741] To a solution of (Z)-3-(cyclopropylimino)pyrrolidine-1-carboxylic acid tert-butyl ester (1.2 g, 5.4 mmol) in DCM (12 mL) was added dropwise triethylamine (1.4 mL, 10 mmol) and a solution of butane-2-ynoyl chloride (554 mL, 5.4 mmol) in DCM (12 mL) at 0 ° C. Under a nitrogen atmosphere, the reaction mixture was stirred at 0 ° C for 1 h. The reaction was allowed to warm to RT and stirred at RT for 2 h. The reaction mixture was then distributed between DCM and distilled water. The organic layer was separated. The combined organic layers were washed with saturated brine, passed through a phase separator and concentrated in vacuo. The residue was purified by flash column chromatography (DCM to EtOAc, gradient elution) to give the title compound as a brown solid (235 mg, 11%). LC / MS (Table 2, Method A): R t =1.20min; m / z=291[M+H] + .

[0742] Preparation of Int-113 :1-cyclopropyl-4-methyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride

[0743]

[0744] To a solution of tert-butyl 1-cyclopropyl-4-methyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (230 mg, 0.79 mmol) in 1,4-dioxane (2 mL) was added a 4M solution of HCl in 1,4-dioxane (4 mL, 16 mmol) and the reaction was stirred at RT for 1 h. The reaction mixture was concentrated in vacuo to give the title compound as a brown solid (160 mg, 64%). LC / MS (Table 2, Method A): R t =0.57min; m / z=191[M+H] + .

[0745] Example 46 -Synthesis of Compound I-103: 1-cyclopropyl-4-methyl-6-(2-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)acetyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one

[0746]

[0747] To a solution of 2-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)lithium acetate (103 mg, 0.39 mmol) in DMF (1 mL) was added HATU (201 mg, 0.53 mmol), followed by a solution of 1-cyclopropyl-4-methyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride (80 mg, 0.35 mmol) and N,N-diisopropylethylamine (0.15 mL, 0.88 mmol) in DMF (2 mL). The reaction was stirred at RT for 1.5 h. The reaction mixture was then partitioned between EtOAc and aqueous sodium bicarbonate solution. The organic layer was separated. The combined organic layers were washed with 5% aqueous LiCl solution, saturated brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by reverse phase HPLC (Table 3, Method 2, non-linear gradient from 40% to 100% MeCN) to give the title compound as an off-white solid (23 mg, 15%). 1H NMR (400 MHz: DMSO-d6) δ 8.22 (d, J = 5.6 Hz, 1H), 6.73 (t, J = 2.0 Hz, 1H), 6.58-6.54 (m, 1H), 6.14 (s, 1H), 4.96 (s, 1H), 4.74 (s, 1H), 4.62 (t, J = 2.7 Hz, 1H), 4.40 (s, 1H), 4.21-4.16 (m, 2H), 3.74-3.68 (m, 2H), 3.17-3.10 (m, 1H), 2.95-2.81 (m, 3H), 2.07 (dd, J = 0.9, 6.8 Hz, 3H), 1.06-0.99 (m, 2H), 0.89-0.82 (m, 2H). LC / MS (Table 2, Method C): R t =2.77min; m / z=433[M+H] + .

[0748] Example 47 -Synthesis of Compound Int-114: 1,3-Dimethyl-4-(methylthio)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride

[0749]

[0750] The 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 a solution of 4M HCl in 1,4-dioxane (5.3 mL, 21 mmol) and the reaction was stirred at RT for 2 h. 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): R t =0.79min; m / z=211[M+H] + .

[0751] Example 48 -Synthesis of Compound Int-104: 1,3-Dimethyl-4-(methylthio)-6-(2-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)acetyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one

[0752]

[0753] To a solution of 2-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)lithium acetate (54 mg, 0.20 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) in DMF (5 mL) was added HATU (100 mg, 0.26 mmol) and N,N-diisopropylethylamine (0.11 mL, 0.61 mmol). The reaction was stirred at RT for 2 h. The reaction mixture was then partitioned between DCM and saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried (MgSO 4 ) and concentrated in vacuo. The residue was purified by reverse phase HPLC (Table 3, Method 4, non-linear gradient from 20% to 80% MeCN) to give the title compound as an off-white solid (11 mg, 12%). 1 H NMR (400 MHz: DMSO-d6) δ 8.22 (d, J = 5.6 Hz, 1H), 6.73 (t, J = 2.4 Hz, 1H), 6.57-6.53 (m, 1H), 4.93 (s, 1H), 4.79 (t, J = 2.5 Hz, 1H), 4.69 (s, 1H), 4.57 (s, 1H), 4.19 (t, J = 8.3 Hz, 2H), 3.74-3.68 (m, 2H), 3.38 (d, J = 8.2 Hz, 3H), 3.17-3.09 (m, 1H), 2.86. LC / MS (Table 2, Method E): R t =4.04min; m / z=453[M+H] + .

[0754] Example 49 -Synthesis of Compound Int-115: 4-Methyl-1-(2,2,2-trifluoroethyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride

[0755]

[0756] A reaction vessel was charged with tert-butyl 4-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (24 mg, 0.072 mmol) and a 4M HCl solution in 1,4-dioxane (0.51 mL, 2.0 mmol). The reaction was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo and azeotroped with toluene to afford the title compound as a white solid (20 mg, quantitative). The material was carried forward to the next step without characterization.

[0757] Example 50-Synthesis of Compound Int-105: 4-Methyl-1-(2,2,2-trifluoroethyl)-6-(2-(1-(4-(trifluoromethyl)phenyl)azetidin-3-yl)acetyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one

[0758]

[0759] To a suspension of 2-(1-(4-(trifluoromethyl)phenyl)azetidin-3-yl)lithium acetate (23 mg, 0.086 mmol) and 4-methyl-1-(2,2,2-trifluoroethyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride (19 mg, 0.072 mmol) in DMF (0.6 mL) was added N,N-diisopropylethylamine (0.038 mL, 0.22 mmol) and HATU (41 mg, 0.11 mmol). The reaction was stirred at RT for 30 min. The reaction mixture was then partitioned between DCM and aqueous sodium bicarbonate solution. 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 an off-white solid (6.8 mg, 19%). 1 H NMR (300 MHz: DMSO-d6) δ 7.45 (d, J = 8.6 Hz, 2H), 6.50 (d, J = 8.5 Hz, 2H), 6.29 (d, J = 4.8 Hz, 1H), 4.90-4.72 (m, 3H), 4.68 (s, 2H), 4.45 (s, 1H), 4.08 (t, J = 7.8 Hz, 2H), 3.60 (t, J = 6.6 Hz, 2H), 3.12-3.05 (m, 1H), 2.83-2.78 (m, 2H), 2.13 (d, J = 7.1 Hz, 3H). LC / MS (Table 2, Method F): R t =4.72min; m / z=474[M+H] + .

[0760] Example 51 -Synthesis of Compound Int-117: 3-Chloro-1-(cyclopropylmethyl)-4-methyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride

[0761] The title compound was prepared according to the following procedure.

[0762] Preparation of Int-116: tert-Butyl 3-chloro-1-(cyclopropylmethyl)-4-methyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate

[0763]

[0764] 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 (118g, 0.39mmol) in MeCN (1.8mL) and DCM (0.9mL) was added N-chlorosuccinimide (74mg, 0.55mmol) and the reaction was stirred at RT for 2h. The reaction mixture was then distributed between DCM and distilled water. The organic layer was separated. The combined organic layer was 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 (18mg, 14%). LC / MS (Table 2, Method B): R t =1.67min; m / z=339[M+H] + .

[0765] Preparation of Int-117 :3-Chloro-1-(cyclopropylmethyl)-4-methyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride

[0766]

[0767] 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 (84 mg, 0.25 mmol) and a 4M HCl solution in 1,4-dioxane (1.7 mL, 6.9 mmol) and the reaction was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo and azeotroped with toluene to afford the title compound as a white solid (69 mg, quantitative). The material was carried forward to the next step without characterization.

[0768] Example 52 -Synthesis of Compound I-106: 3-Chloro-1-(cyclopropylmethyl)-4-methyl-6-(2-(1-(pyrimidin-5-yl)azetidin-3-yl)acetyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one

[0769]

[0770] To a solution of 3-chloro-1-(cyclopropylmethyl)-4-methyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride (23 mg, 0.084 mmol) in DMF (1.2 mL) was added N,N-diisopropylethylamine (0.051 mL, 0.29 mmol) followed by a solution of 2-(1-(pyrimidin-5-yl)azetidin-3-yl)lithium acetate (20 mg, 0.10 mmol) and HATU (57 mg, 0.15 mmol) in DMF (0.7 mL). The reaction was stirred for 1 h at RT. The reaction mixture was then partitioned between DCM and aqueous sodium bicarbonate solution. 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 2) to give the title compound as an off-white solid (17 mg, 49%). 1 H NMR(400MHz:DMSO-d6)δ8.53(s,1H),8.04(d,J=2.0Hz,2H),4.96(s,1H),4.73(s,2H),4.50(s,1H),4.16-4.11(m,2H),3.80(dd,J=7.0, 15.9Hz,2H),3.68-3.63(m,2H),3.17-3.10(m,1H),2.85(t,J=7.3Hz,2H),2.23(d,J=4.9Hz,3H),1.30-1.20(m,1H),0.51-0.37(m,4H). LC / MS (Table 2, Method C): R t =3.20min; m / z=414[M+H] + .

[0771] Example 53 -Synthesis of Compound Int-119: 3-Ethyl-1,4-dimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride

[0772] The title compound was prepared according to the following procedure.

[0773] Preparation of Int-118 :3-ethyl-1,4-dimethyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylic acid tert-butyl ester

[0774]

[0775] The reaction vessel was charged with tert-butyl 3-bromo-1,4-dimethyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (78 mg, 0.23 mmol), Pd(PPh3)4 (26 mg, 0.023 mmol), tripotassium phosphate (145 mg, 0.68 mmol), ethylboronic acid (25 mg, 0.34 mmol) and solvated in 1,4-dioxane (3 mL). The reaction was evacuated, purged with argon (x3), and heated to 100 ° C. The reaction was stirred at 100 ° C for 16 h. The reaction mixture was cooled to RT, filtered through celite and washed with EtOAc. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography (DCM to MeOH, gradient elution) to give the title compound as a white solid (74 mg, 56%). LC / MS (Table 2, Method B): R t =1.34min; m / z=293[M+H] + .

[0776] Preparation of Int-119 :3-Ethyl-1,4-dimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride

[0777]

[0778] To a solution of tert-butyl 3-ethyl-1,4-dimethyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (74 mg, 0.13 mmol) in 1,4-dioxane (0.5 mL) was added a 4M solution of HCl in 1,4-dioxane (0.79 mL, 3.2 mmol) and the reaction was stirred at RT for 1 h. The reaction mixture was concentrated in vacuo and azeotroped with toluene to give the title compound as a white solid (29 mg, quantitative). The material was carried forward to the next step without characterization.

[0779] Example 54 -Synthesis of Compound I-107: 3-Ethyl-1,4-dimethyl-6-(2-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)acetyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one

[0780]

[0781] To a suspension of 2-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)lithium acetate (44 mg, 0.16 mmol) and 3-ethyl-1,4-dimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride (58 mg, 0.13 mmol) in DMF (1.5 mL) was added HATU (72 mg, 0.19 mmol) and N,N-diisopropylethylamine (0.066 mL, 0.38 mmol). The reaction was stirred at RT for 30 min. The reaction mixture was then partitioned between EtOAc and aqueous sodium bicarbonate solution. The organic layer was separated. The combined organic layer was washed with saturated brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by reverse phase HPLC (Table 3, Method 4, non-linear gradient from 20% to 80% MeCN) to give the title compound as an off-white solid (22 mg, 40%). 1 H NMR (400 MHz:CDCl3)δ8.22(d,J=5.6 Hz,1H),6.73(d,J=1.8 Hz,1H),6.55(d,J=5.6 Hz,1H),4.89-4.89(m,1H),4.69-4.66(m,2H),4.47(s,1H),4.19(t,J=8.3 Hz,2H),3.73-3.68(m,2H),3.36(d,J=7.7 Hz,3H, partly obscured by solvent peak),3.17-3.09(m,1H),2.83(t,J=7.7 Hz,2H),2.54-2.48(m,2H, partly obscured by solvent peak),2.10(d,J=5.1 Hz,3H),0.98(t,J=7.3 Hz,3H). LC / MS (Table 2, Method E): R t =3.91min; m / z=435[M+H] + .

[0782] Example 55 -Synthesis of Compound Int-122: 1,4-Dimethyl-3-(trifluoromethyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride

[0783] The title compound was prepared according to the following procedure.

[0784] Preparation of Int-120 :3-iodo-1,4-dimethyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylic acid tert-butyl ester

[0785]

[0786] To a solution of tert-butyl 1,4-dimethyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (200g, 0.76mmol) in DMF (2mL) and MeCN (4mL) was added N-iodosuccinimide (238mg, 1.1mmol) and the reaction was heated to 50°C. The reaction was stirred at 50°C for 1h. 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 as a yellow oil (268mg, 72%). LC / MS (Table 2, Method B): R t =1.36min; m / z=391[M+H] + .

[0787] Preparation of Int-121 :1,4-dimethyl-2-oxo-3-(trifluoromethyl)-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylic acid tert-butyl ester

[0788]

[0789] 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 cooled to RT and then distributed 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 light yellow solid (112 mg, 49%). LC / MS (Table 2, Method B): R t =1.37min; m / z=333[M+H] + .

[0790] Preparation of compound Int-122 :1,4-dimethyl-3-(trifluoromethyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride

[0791]

[0792] Under cooling to 0 ° C, the 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). A solution of 4M HCl in 1,4-dioxane (2.1 mL, 8.4 mmol) was added and the reaction was allowed to warm to RT and stirred at RT for 18 h. 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): R t =0.82min; m / z=233[M+H] + .

[0793] Example 56 -Synthesis of Compound I-108: 1,4-dimethyl-6-(2-(1-(pyridin-3-yl)azetidin-3-yl)acetyl)-3-(trifluoromethyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one

[0794]

[0795] 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), 2-(1-(pyridin-3-yl)azetidin-3-yl)acetate (35 mg, 0.18 mmol) and HATU (102 mg, 0.27 mmol) in DMF (1 mL) was added N,N-diisopropylethylamine (0.091 mL, 0.52 mmol). The reaction was stirred at RT for 1 h. The reaction mixture was then partitioned between EtOAc and aqueous sodium bicarbonate solution. 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) to give the title compound as an off-white solid (11 mg, 19%). 1 H NMR (400 MHz: DMSO-d6) δ 7.95 (dd, J = 1.1, 4.7 Hz, 1H), 7.86 (d, J = 2.8 Hz, 1H), 7.20 (dd, J = 4.7, 8.2 Hz, 1H), 6.88-6.84 (m, 1H), 5.04 (s, 1H), 4.80 (s, 2H), 4.56 (t, J = 2.4 Hz, 1H), 4.10 (t, J = 7.7 Hz, 2H), 3.61 (t, J = 6.6 Hz, 2H), 3.43 (d, J = 7.8 Hz, 3H), 3. LC / MS (Table 2, Method C): R t=2.61min; m / z=407[M+H] + .

[0796] Example 57 -Synthesis of Compound Int-124: 3-Cyclopropyl-1,4-dimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride

[0797] The title compound was prepared according to the following procedure.

[0798] Preparation of Int-123 :3-cyclopropyl-1,4-dimethyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylic acid tert-butyl ester

[0799]

[0800] To a solution of tert-butyl 3-bromo-1,4-dimethyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (40 mg, 0.12 mmol), cyclopropylboronic acid (17 mg, 0.20 mmol) and potassium carbonate (48 mg, 0.35 mmol) in 1,4-dioxane (1 mL) was added a complex of Pd(dppf)Cl2 and DCM (10 mg, 0.012 mmol). The reaction was evacuated, purged with argon (x3), and heated to 100 ° C. The reaction was stirred at 100 ° C for 12 h. The reaction mixture was cooled to RT, filtered through diatomaceous earth and washed with DCM. The filtrate was 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 yellow foam (32 mg, 60%). LC / MS (Table 2, Method B): R t =1.14min; m / z=305[M+H] + .

[0801] Preparation of compound Int-124 :3-cyclopropyl-1,4-dimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride

[0802]

[0803] To a solution of tert-butyl 3-cyclopropyl-1,4-dimethyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (32 mg, 0.11 mmol) in DCM (5.0 mL) was added a 4M solution of HCl in 1,4-dioxane (0.53 mL, 2.1 mmol) and the reaction was stirred at RT for 3 h. The reaction mixture was concentrated in vacuo to give the title compound as a purple solid (26 mg, quantitative). 1 H NMR (400MHz: DMSO-d6) δ9.78(s,1H),4.54(s,2H),4.34(s,2H),3.30(s,3H),2.19(s,3H),1.57-1.50(m,1H),0.82-0.76(m,4H).

[0804] Example 58 -Synthesis of Compound I-109: 3-Cyclopropyl-1,4-dimethyl-6-(2-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)acetyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one

[0805]

[0806] To a solution of 3-cyclopropyl-1,4-dimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride (26 mg, 0.11 mmol) and 2-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)lithium acetate (34 mg, 0.13 mmol) in DMF (1 mL) was added HATU (62 mg, 0.16 mmol) and N,N-diisopropylethylamine (0.066 mL, 0.38 mmol). The reaction was stirred at RT 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 layer was washed with saturated brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by reverse phase HPLC (Table 3, Method 4, non-linear gradient from 20% to 80% MeCN) to give the title compound as an off-white solid (16 mg, 32%). 1H NMR(400MHz:DMSO-d6)δ8.22(d,J=5.6Hz,1H),6.74-6.72(m,1H),6.56-6.54 (m,1H),4.89-4.86(m,1H),4.68-4.65(m,2H),4.46-4.43(m,1H),4.18(t,J=8 .3Hz,2H),3.73-3.68(m,2H),3.31(d,J=7.5Hz,3H),3.16-3.06(m,1H),2.83( t,J=8.5Hz,2H),2.19(d,J=5.0Hz,3H),1.58-1.46(m,1H),0.82-0.77(m,4H). LC / MS (Table 2, Method E): R t =4.19 min; m / z=447 [M+H] +

[0807] Example 59 -Synthesis of Compound I-125: 3-Bromo-1,4-dimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride

[0808]

[0809] To a solution of tert-butyl 3-bromo-1,4-dimethyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (32 mg, 0.11 mmol) in DCM (2.0 mL) was added a 4M HCl solution in 1,4-dioxane (2.2 mL, 8.7 mmol) and the reaction was stirred at RT for 2 h. The reaction mixture was concentrated in vacuo to give the title compound as a brown solid (122 mg, quantitative). The material was not characterized and was carried to the next step.

[0810] Example 60 -Synthesis of Compound I-110: 3-Bromo-1,4-dimethyl-6-(2-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)acetyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one

[0811]

[0812] To a solution of 2-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)lithium acetate (128 mg, 0.48 mmol) in DMF (1.5 mL) was added HATU (199 mg, 0.52 mmol), followed by a solution of 3-bromo-1,4-dimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride (122 mg, 0.48 mmol) and N,N-diisopropylethylamine (0.23 mL, 1.3 mmol). The reaction was stirred at RT for 1.5 h. The reaction mixture was then partitioned between EtOAc and saturated aqueous sodium bicarbonate solution. 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 2) to give the title compound as an off-white solid (27 mg, 23%). 1 H NMR (400 MHz: DMSO-d6) δ 8.22 (d, J = 5.6 Hz, 1H), 6.73 (t, J = 1.9 Hz, 1H), 6.55 (d, J = 5.8 Hz, 1H), 4.91-4.90 (m, 1H), 4.74-4.66 (m, 2H), 4.53-4.50 (m, 1H), 4.19 (t, J = 8.2 Hz, 2H), 3.71 (dd, J = 5.6, 8.4 Hz, 2H), 3.44 (d, J = 8.5 Hz, 3H), 3.17-3.10 (m, 1H), 2.86-2.81 (m, 2H), 2.25 (d, J = 6.9 Hz, 3H). LC / MS (Table 2, Method E): R t =3.73min; m / z=485[M+H] +

[0813] Example 61 -Synthesis of Compound I-111: 1,4-dimethyl-2-oxo-6-(2-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)acetyl)-2,5,6,7-tetrahydro-1H-pyrrolo[3,4-b]pyridine-3-carbonitrile

[0814]

[0815] Under a nitrogen atmosphere, the reaction vessel was charged with copper (I) cyanide (44 mg, 0.50 mmol), followed by a solution of 3-bromo-1,4-dimethyl-6-(2-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)acetyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one (120 mg, 0.25 mmol) in DMF (2.5 mL), and the reaction was heated to 120 ° C. The reaction was stirred at 120 ° C for 9 h. The reaction mixture was allowed to cool to RT and then partitioned between DCM and distilled water. The organic layer was separated. The combined organic layers were washed with saturated brine, passed through a phase separator and concentrated in vacuo. The residue was purified by reverse phase HPLC (Table 3, Method 2) to give the title compound as an off-white solid (7.3 mg, 6%). 1 H NMR (400 MHz: DMSO-d6) δ 8.23 ​​(d, J = 5.8 Hz, 1H), 6.73 (t, J = 1.9 Hz, 1H), 6.57-6.54 (m, 1H), 5.01 (s, 1H), 4.75 (d, J = 18.2 Hz, 2H), 4.50 (s, 1H), 4.19 (t, J = 8.3 Hz, 2H), 3.70 (t, J = 6.7 Hz, 2H), 3.42 (d, J = 9.5 Hz, 3H), 3.17-3.10 (m, 1H), 2.84 (t, J = 7.0). LC / MS (Table 2, Method E): R t =3.54min; m / z=432[M+H] + .

[0816] Example 62 -Synthesis of Compound Int-127: 1,3-Dimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride

[0817] The title compound was prepared according to the following procedure.

[0818] Preparation of Int-126 :1,3-dimethyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylic acid tert-butyl ester

[0819]

[0820] Under a nitrogen atmosphere, triisopropylsilane (0.14 mL, 0.67 mmol) and triethylamine (0.25 mL, 1.8 mmol) were added to a suspension of tert-butyl 1,3-dimethyl-2-oxo-4-(trifluoromethylsulfonyloxy)-5,7-dihydropyrrolo[3,4-b]pyridine-6-carboxylate (250 mg, 0.61 mmol) and PdCl2(PPh3)2 (43 mg, 0.061 mmol) in DMF (1.5 mL) under nitrogen atmosphere. The reaction was heated to 85°C and stirred at 85°C for 22 h. The reaction mixture was cooled to RT and then partitioned between EtOAc and distilled water. The organic layer was separated. The combined organic layers were washed with 5% aqueous LiCl solution, saturated brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by reverse phase HPLC (Table 3, Method 5) to give the title compound as a white solid (50 mg, 31%). LC / MS (Table 2, Method A): R t =1.17min; m / z=265[M+H] + .

[0821] Preparation of Int-127 :1,3-Dimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride

[0822]

[0823] To a solution of tert-butyl 1,3-dimethyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (48 mg, 0.18 mmol) in DCM (1 mL) was added a solution of 4M HCl in 1,4-dioxane (0.91 mL, 3.6 mmol) and the reaction was stirred at RT for 2 h. The reaction mixture was then concentrated in vacuo to give the title compound as a brown oily solid. The material used in the next step was assumed to be in quantitative yield. LC / MS (Table 2, Method A): R t =0.43min; m / z=165[M+H] + .

[0824] Example 63 -Synthesis of Compound I-112: 1,3-Dimethyl-6-(2-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)acetyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one

[0825]

[0826] To a suspension of lithium 2-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)acetate (53 mg, 0.20 mmol) in DMF (0.75 mL) was added HATU (76 mg, 0.20 mmol), followed by a solution of 1,3-dimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride (assumed 0.182 mg) and N,N-diisopropylethylamine (0.079 mL, 0.45 mmol) in DMF (0.75 mL). The reaction was stirred at RT for 20 min. The reaction mixture was then partitioned between DCM and aqueous sodium bicarbonate solution. The organic layer was separated. The combined organic layers were washed with 5% aqueous LiCl solution, saturated brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by reverse phase HPLC (Table 3, Method 4) to give the title compound as an off-white solid (33 mg, 44%). 1 H NMR (400 MHz: DMSO-d6) δ 8.22 (d, J = 5.6 Hz, 1H), 7.35 (d, J = 9.3 Hz, 1H), 6.73 (t, J = 2.1 Hz, 1H), 6.56-6.52 (m, 1H), 4.87 (s, 1H), 4.66-4.62 (m, 2H), 4.43 (s, 1H), 4.19 (t, J = 8.2 Hz, 2H), 3.70 (dd, J = 5.7, 8.5 Hz, 2H), 3.39 (d, J = 8.1 Hz, 3H), 3.16-3.08 (m, 1H), 2.82 (d, J = 7.7 Hz, 2H), 2.03 (s, 3H). LC / MS (Table 2, Method E): R t =3.83min; m / z=407[M+H] + .

[0827] Example 64 -Synthesis of Compound Int-130: 1,4,5-Trimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride

[0828] The title compound was prepared according to the following procedure.

[0829] Preparation of Int-128 :(E)-2-Methyl-4-(methylimino)pyrrolidine-1-carboxylic acid tert-butyl ester

[0830]

[0831] A reaction vessel was charged with tert-butyl 2-methyl-4-oxo-pyrrolidine-1-carboxylate (5 g, 25 mmol) and dissolved in a 2 M solution of methylamine in THF (63 mL, 125 mmol). The reaction was heated to 80°C and stirred at 80°C for 18 h. The reaction mixture was concentrated in vacuo to afford the title compound as a yellow oil (5.3 g, quantitative). The material was carried forward to the next step without characterization.

[0832] Preparation of Int-129 :1,4,5-trimethyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylic acid tert-butyl ester

[0833]

[0834] To a solution of butane-2-ynoyl chloride (261 mg, 2.5 mmol) in DCM (6 mL) at 0 ° C. under a nitrogen atmosphere, (E)-2-methyl-4-(methylimino)pyrrolidine-1-carboxylic acid tert-butyl ester (540 g, 2.5 mmol) and triethylamine (0.67 mL, 4.8 mmol) were added. The reaction was stirred at 0 ° C. for 30 min. The reaction was allowed to warm to RT and stirred at RT for 40 h. Saturated aqueous sodium bicarbonate solution was added and the reaction was stirred for 10 min. The reaction mixture was passed through a phase separator and concentrated in vacuo and purified by flash column chromatography (DCM to MeOH, gradient elution) to give the title compound as a white solid (217 mg, 31%). LC / MS (Table 2, Method A): R t =1.20min; m / z=279[M+H] + .

[0835] Preparation of Int-130 :1,4,5-Trimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride

[0836]

[0837] The 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 (217 mg, 0.78 mmol) and a solution of 4M HCl in 1,4-dioxane (3.9 mL, 16 mmol) and the reaction was stirred at RT for 1 h. The reaction mixture was then concentrated in vacuo to give the title compound as a light brown gum (167 mg, quantitative). LC / MS (Table 2, Method A): R t =0.55min; m / z=179[M+H] + .

[0838] Example 65 -Synthesis of Compound I-113: (±)-1,4,5-trimethyl-6-(2-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)acetyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one

[0839]

[0840] To a solution of 1,4,5-trimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride (167 mg, 0.78 mmol) and 2-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)lithium acetate (207 mg, 0.78 mmol) in DMF (5 mL) was added HATU (384 mg, 1.0 mmol) and N,N-diisopropylethylamine (0.41 mL, 2.3 mmol). The reaction was stirred at RT for 16 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 saturated brine, dried (MgSO 4 ) and concentrated in vacuo. The residue was purified by reverse phase HPLC (Table 3, Method 4, non-linear gradient from 20% to 80% MeCN) followed by SFC purification (Table 3, Method 6) to give the title compound of unknown absolute configuration - stereoisomer 1 as an off-white solid (69 mg, 21%). 1 H NMR(400MHz:DMSO-d6)δ8.27(d,J=5.6Hz,1H),6.78(dd,J=2.1,5.5Hz,1H),6.62-6.57(m,1H),6.23( s,1H),5.30-5.27(m,0.4H),5.14-5.13(m,0.6H),4.96(d,J=17.3Hz,0.6H),4.90-4.82(m,1H),4.57( dd, J = 3.1, 16.6 Hz, 0.4H), 4.27-4.17 (m, 2H), 3.82-3.72 (m, 2H), 3.38 (d, J = 7.7 Hz, 3H, partially obscured by the solvent peak), 3.21-3.14 (m, 1H), 3.04-3.00 (m, 0.3H), 2.94-2.77 (m, 1.7H), 2.19 (s, 3H), 1.43 (dd, J = 6.1, 16.9 Hz, 3H). LC / MS (Table 2, Method C): R t =2.92min; m / z=421[M+H] + .

[0841] Example 66 -Synthesis of other compounds

[0842] The compounds in Table 14 were prepared using procedures similar to those described above for the preparation of compound 1-113. The starting materials used are listed in Table 14.

[0843] Table 14: Other compounds

[0844]

[0845] Example 67 -Synthesis of Compound Int-134: (S)-1,4,5-Trimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride

[0846] The title compound was prepared according to the following procedure.

[0847] Preparation of Int-131 :(S)-(5-(dimethyl(oxo)-λ 6 -sulfaneylidene)-4-oxopentan-2-yl)carbamic acid tert-butyl ester

[0848]

[0849] To a suspension of 2S boc-beta-homo-ala-OH (5.0 g, 25 mmol) and triethylamine (14 mL, 102 mmol) in THF (100 mL) was added HATU (10 g, 27 mmol), and the reaction was stirred at RT for 3 h. In a separate reaction vessel, a 1 M solution of potassium tert-butoxide in THF (88 mL, 88 mmol) was added to a suspension of trimethylsulfoxide chloride (11 g, 88 mmol) in THF (20 mL), and the reaction was heated to 60 ° C. The reaction was stirred at 60 ° C for 3 h. The reaction mixture was cooled to 0 ° C, and the first reaction mixture was added dropwise over 20 min. The reaction was allowed to warm to RT and stirred at RT for 16 h. 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 MeOH, gradient elution) to give the title compound as a colorless oil (5.9 g, 87%).

[0850] Preparation of Int-132 :(S)-2-Methyl-4-oxopyrrolidine-1-carboxylic acid tert-butyl ester

[0851]

[0852] Under nitrogen atmosphere, (S)-(5-(dimethyl(oxo)-λ 6To a solution of tert-butyl (-sulfanyl)-4-oxopentan-2-yl)carbamate (5.9 g, 21 mmol) in chloroform (155 mL) was added [Ir(1,5-cod)Cl]2 (429 mg, 0.64 mmol), and the reaction mixture was stirred at reflux for 16 h. The reaction mixture was allowed to warm to RT and then partitioned between chloroform 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 yellow oil (2.7 g, 64%). 1 H NMR(300MHz:CDCl3)δ4.47-4.40(m,1H),3.91(d,J=19.7Hz,1H),3.64(d,J=19.6Hz,1H), 2.81(dd,J=9.2,18.3Hz,1H), 2.20(d,J=18.3Hz,1H), 1.49(s,9H), 1.25(d,J=6.5Hz,3H).

[0853] Preparation of Int-133 :(S)-1,4,5-trimethyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylic acid tert-butyl ester

[0854]

[0855] A reaction vessel was charged with a solution of (S)-tert-butyl 2-methyl-4-oxopyrrolidine-1-carboxylate (2.7 g, 14 mmol) and 2M methylamine in THF (34 mL, 68 mmol). The reaction was heated to 80°C and stirred at 80°C for 3 h. The reaction mixture was allowed to cool to RT and then concentrated in vacuo to yield the crude imine. In a separate reaction vessel, 1-chloro-N,N,2-trimethyl-1-propenamine (2.5 mL, 19 mmol) was added dropwise to a solution of 2-butynoic acid (1.6 g, 19 mmol) in DCM (65 mL) at 0°C under a nitrogen atmosphere. The reaction was stirred at 0°C for 1 h. The reaction mixture solution was then added dropwise to a solution of the crude imine and triethylamine (3.6 mL, 26 mmol) in DCM (65 mL). The reaction was stirred at 0°C under a nitrogen atmosphere for 30 min. The reaction was allowed to warm to RT and stirred at RT for 16 h. The reaction mixture was quenched by adding saturated aqueous sodium bicarbonate solution and then distributed with DCM. The organic layer was separated, washed with saturated brine, 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 a yellow oil (1.2 g, 32%). LC / MS (Table 2, Method A): R t=1.70 min; m / z=179 [M+H-Boc group] + .

[0856] Preparation of Int-134 :(S)-1,4,5-Trimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride

[0857]

[0858] The reaction vessel was charged with (S)-1,4,5-trimethyl-2-oxo-1,2,5,7-tetrahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylic acid tert-butyl ester (207 mg, 0.74 mmol) and a solution of 4M HCl in 1,4-dioxane (4.1 mL, 16 mmol) and the reaction was stirred at RT for 2 h. The reaction mixture was then concentrated in vacuo to give the title compound as a light brown solid (162 mg, quantitative). LC / MS (Table 2, Method B): R t =0.18min; m / z=179[M+H] + .

[0859] Example 68 -Synthesis of Compound I-116: (S)-1,4,5-trimethyl-6-(2-(1-(4-(trifluoromethyl)phenyl)azetidin-3-yl)acetyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one

[0860]

[0861] To a solution of ((S)-1,4,5-trimethyl-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one hydrochloride (52 mg, 0.24 mmol) and lithium 2-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)acetate (69 mg, 0.26 mmol) in DMF (1 mL) was added HATU (120 mg, 0.32 mmol) and N,N-diisopropylethylamine (0.13 mL, 0.73 mmol). The reaction was stirred at RT 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 saturated brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by reverse phase HPLC (Table 3, Method 4) to give the title compound as an off-white solid (44 mg, 43%). 1H NMR(400MHz:DMSO-d6)δ7.46(d,J=8.4Hz,2H),6.54-6.49(m,2H),6.18(s,1H),5.28-5.2 2(m,0.3H),5.13-5.06(m,0.7H),4.92(d,J=15.6Hz,0.7H),4.85-4.78(m,1H),4.52(dd,J =3.0,17.1 Hz,0.3H),4.13-4.04 (m,2H),3.68-3.57 (m,2H),3.32 (s,3H, partially obscured by solvent peak),3.14-3.05 (m,1H),3.01-2.94 (m,0.3H),2.89-2.68 (m,1.7H),2.15 (s,3H),1.41-1.35 (m,3H). LC / MS (Table 2, Method E): R t =4.44min; m / z=420[M+H] + .

[0862] Example 69 -Synthesis of Compound I-117: (R)-1,4,5-trimethyl-6-(2-(1-(4-(trifluoromethyl)phenyl)azetidin-3-yl)acetyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one

[0863]

[0864] The title compound was prepared from the appropriate starting material, (3R)-3-(tert-butoxycarbonylamino)butanoic acid, using a procedure similar to that described for compound (S)-1,4,5-trimethyl-6-(2-(1-(4-(trifluoromethyl)phenyl)azetidin-3-yl)acetyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one. The compound was purified by reverse phase HPLC (Table 3, Method 4) to afford the title compound as an off-white solid (30 mg, 29%). 1H NMR(400MHz:DMSO-d6)δ7.46(d,J=8.5Hz,2H),6.54-6.49(m,2H),6.18(s,1H),5.26-5.23(m, 0.3H),5.12-5.08(m,0.7H),4.93(d,J=15.8Hz,0.7H),4.85-4.78(m,1H),4.53(dd,J=1.7,16. 6 Hz, 0.3H), 4.13-4.04 (m, 2H), 3.68-3.57 (m, 2H), 3.33 (d, J = 7.5 Hz, 3H, partially obscured by the solvent peak), 3.13-3.06 (m, 1H), 2.98 (dd, J = 8.3, 16.6 Hz, 0.3H), 2.89-2.68 (m, 1.7H), 2.14 (s, 3H), 1.41-1.35 (m, 3H). LC / MS (Table 2, Method E): R t =4.44min; m / z=420[M+H] + .

[0865] Example 70 -Synthesis of Compound I-118: 3-Chloro-1,4,5-trimethyl-6-(2-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)acetyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one

[0866]

[0867] To a solution of 1,4,5-trimethyl-6-(2-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)acetyl)-1,5,6,7-tetrahydro-2H-pyrrolo[3,4-b]pyridin-2-one (20 mg, 0.048 mmol) in MeCN (0.2 mL) and DMF (0.4 mL) was added N-chlorosuccinimide (7.3 mg, 0.55 mmol), and the reaction was heated to 35 ° C. The reaction was stirred at 35 ° C for 5 h. The reaction mixture was allowed to cool to RT and then partitioned between DCM 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 reverse phase HPLC (Table 3, Method 2, 100% MeOH in 40% non-linear gradient) to give the title compound as a white solid (5.3 mg, 24%). 1HNMR(400MHz:DMSO-d6)δ8.22(d,J=5.6Hz,1H),6.73(dd,J=2.2,4.7Hz,1H),6.57-6.53(m,1H), 5.36-5.30(m,0.3H),5.20-5.14(m,0.7H),4.96(d,J=14.7Hz,0.7H),4.88-4.81(m,1H),4.55(d d, J = 3.3, 15.4 Hz, 0.3H), 4.22-4.13 (m, 2H), 3.78-3.62 (m, 2H), 3.43 (d, J = 7.7 Hz, 3H), 3.16-3.09 (m, 1H), 3.03-2.96 (m, 0.3H), 2.90-2.75 (m, 1.7H), 2.26 (s, 3H), 1.38 (dd, J = 6.0, 16.2 Hz, 3H). LC / MS (Table 2, Method C): R t =3.07min; m / z=455[M+H] + .

[0868] Example 71 -Compound characterization

[0869] Table 15 below provides physical characterization data for exemplary synthetic intermediate compounds.

[0870] Table 15. Compounds 1 H NMR data and LC / MS methods

[0871]

[0872]

[0873]

[0874]

[0875]

[0876] Table 16 below provides physical characterization data for exemplary compounds.

[0877] Table 16. Compounds 1 H NMR data and LC / MS data

[0878]

[0879]

[0880]

[0881]

[0882]

[0883]

[0884]

[0885]

[0886]

[0887]

[0888]

[0889]

[0890] Example 72 -Muscarinic acetylcholine receptor activation

[0891] Exemplary compounds were tested for their ability to activate muscarinic acetylcholine receptors. The experimental procedures and results are provided below.

[0892] Part I - Experimental Procedure for Human and Rat M4 PAM pERK Assays

[0893] Chinese hamster ovary (CHO) cells expressing hM4 or rM4 receptors were expanded in culture and frozen in assay-ready vials (5x10 6 The day before the assay, the vials were thawed and the cells were seeded in 384-well white proxiplates (hM4 cells at 1000 cells / well and rM4 cells at 2000 cells / well) in 10 μL of growth medium (Hams / F12 containing glutamax and 10% FCS) and incubated overnight at 37°C / 5% CO2.

[0894] The next morning, the growth medium was ejected through a chamber, the inverted plate was tapped onto the tissue, and then replaced with 10 μL of wash medium (Hams / F12 containing glutamax and 8 mM HEPES, NB: serum-free). The wash medium was then removed in the same manner and replaced with 8 μL / well of serum-free medium. The plate was then re-incubated at 37°C / 5% CO2 for another 4 hours.

[0895] Compounds for testing were dissolved in DMSO to 10 mM, and compound addition plates consisting of replicate ten-point concentration response curves (CRCs) (10 μM top concentration, 1 / 2 log dilution series) were prepared by the acoustic dispensing and compound administration team.

[0896] After 4 hours of incubation in serum-free medium, the plate was transferred to a 384-well plate containing acetylcholine EC. 20 A 4 μL aliquot of the 3x compound solution (10 nM final concentration) was added to the cell plate. The plate lid was then replaced and the cells were incubated at 37°C / 5% CO2 for 5 min. Following this final incubation, all cell processes were terminated by adding 4 μL / well lysis and blocking buffer, and the plate was incubated on an orbital shaker (soft setting) at RT for 30 minutes. Finally, 4 μL / well antibody detection mix containing europium-cryptate (donor) and d2 (acceptor) labeled detection components was added, followed by an additional incubation of 2 hours at RT before reading the plate using a TR-FRET (time-resolved fluorescence resonance energy transfer)-based protocol.

[0897] Part II - Experimental Procedure for the M4 GTPgS PAM Assay

[0898] The M4 GTPgS PAM method was used. Membranes for the GTPgS binding assay were prepared from CHO-K1 cells stably expressing the human M4 receptor. Briefly, cells were grown in 5-layer cell culture flasks. Cells were washed with 50 mL of PBS and then dissociated with 0.05% trypsin. The dissociated cells were then collected by centrifugation at 650 x g for 8 minutes at 4°C. The pellet was washed again in PBS by centrifugation and resuspended in 30 mL of 20 mM HEPES, 10 mM EDTA, pH 7.4. After 30 minutes on ice, the membranes were collected by centrifugation at 50,000 x 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 in 30 mL of 20 mM HEPES, pH 7.4 by centrifugation and stored at -80°C until the day of the assay. On the day of the 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 dounce homogenization. Membrane protein concentration was determined by BCA protein assay (Promega, Madison, WI) according to Promega guidelines.

[0899] On the same day of measurement, test PAM compound is serially diluted to 4X final assay concentration in assay buffer (20mM HEPES, 10mM MgCl , 100mM NaCl).Prepare 25ml / pore membrane homogenate (containing 5mg membrane protein) in the assay buffer (the final assay concentration of GDP is M2 5uM and M4 0.1uM) that is supplemented with 4X final assay concentration GDP, and be assigned to 96-well polypropylene, U-shaped bottom Greiner flat plates.To add 25ml carrier or the test PAM compound of the 4x final assay concentration diluted in assay buffer to the film, and flat plate is gently shaken incubation 10-15 minute at room temperature.Then, 25mL EC20 acetylcholine is added to the assay flat plate at the solution of 4x final assay concentration in assay buffer (for people M4, EC20 final assay concentration is 40nM).

[0900] The plate was then incubated with shaking for another 10-15 minutes. 25 mL of 0.4 nM 35 A solution of S-GTP (Perkin Elmer, Waltham, MA) in assay buffer was added to the assay mixture. The binding reaction was carried out on a shaker at room temperature for 1 hour. The membrane in the assay reaction was 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 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).

[0901] Part III - Results

[0902] The results are shown in Table 17 below. The EC values ​​of the compounds with activity designated as "A" were 50 <50 nM; EC of compounds with activity designated "B" 50 The EC values ​​for compounds with activity designated as "C" ranged from 50 nM to 200 nM. 50 The EC values ​​for compounds with activity designated as "D" range from greater than 200 nM to 1000 nM. 50 >1000nM. N / A indicates no data available.

[0903] Table 17.

[0904]

[0905]

[0906]

[0907]

[0908] Example 73 -Compounds' ability to affect behavioral activity in rats

[0909] The ability of the exemplary compounds to influence the behavior of rats pre-treated with amphetamine was tested. The experimental procedures and results are provided below.

[0910] Part I - Experimental Procedure

[0911] Animals: Adult male Sprague Dawley rats (Envigo, Indianapolis, IN, USA) were housed in colonies maintained at 23°C with a 12-hour light / dark cycle (lights on at 0600 hours). At the start of the study, all animals weighed 290-330 g and were divided equally into five groups (n = 8 / group) and received one of the following treatment conditions. The animal protocol was approved by the Animal Care and Use Committee.

[0912] Behavioral procedures: The study was conducted 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 by 16 array beams. The Tmax of the amphetamine-induced phase was consistent with the administration pretreatment of the test article and the optimal administration route. All groups were treated subcutaneously with 0.5 mg / kg amphetamine (AMP). The test article (i.e., test compound) was tested in three dose groups, with a half-logarithmic increase between doses. Risperidone (0.55 mg / kg, 30 minutes, subcutaneous administration) was used as a positive control and was applied to the 5th group. In order to determine the effect of the test article on the excessive movement induced by AMP, rats were placed in an open area and allowed to adapt for 30 minutes, and then 0.5 mg / kg AMP was administered subcutaneously. During the entire 90-minute phase, movement data (distance traveled) were recorded in 5-minute units. The dose of AMP was chosen based on a selective increase in locomotor behavior relative to stereotypic behavior. A dose of risperidone was chosen that produced a reliable effect and served as a positive control.

[0913] Statistical Analysis: Spontaneous locomotion (before AMP administration) was calculated as the total distance traveled during the first 30 minutes of the experimental phase. AMP-induced responses were calculated as the total distance traveled during the last 60 minutes of the experimental phase, which began immediately after AMP administration. Locomotor data were analyzed by one-way ANOVA. Post hoc comparisons were performed by Dunnett's test when there was a significant overall ANOVA, and statistical significance was determined at p < 0.05.

[0914] Part II - Results

[0915] Rats receiving the indicated doses of one of the following test compounds exhibited a reduction in amphetamine-induced locomotor hyperactivity, indicating a beneficial effect of the test compound on the rats:

[0916] Compound number Dosage of compound I-4 10 mg / kg I-14 32 mg / kg I-42 32 mg / kg I-88 10 mg / kg

[0917] Incorporated by Reference

[0918] The entire disclosure of each patent document and scientific article mentioned herein is incorporated by reference for all purposes.

[0919] Equivalent solutions

[0920] The present invention may be embodied in other specific forms without departing from the spirit or essential characteristics of the present invention. The foregoing embodiments are therefore to be considered in all respects as illustrative rather than restrictive 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 equivalence of the claims are intended to be embraced herein.

Claims

1. A compound represented by formula I: or a pharmaceutically acceptable salt thereof, wherein: R 1 C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -(C 1-6 alkylene)-(C 3-6 cycloalkyl) or hydrogen; R 2 For halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 cycloalkyl, cyano or hydrogen; R 3 C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, -S-(C 1-4 alkyl), hydrogen or halo; R 4 Each occurrence represents C independently 1-4 Alkyl, C 1-4 haloalkyl or halo; R 5 Each occurrence represents C independently 1-6 Alkyl, halogen, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -SO2-(C 1-6 Halogenated alkyl), -SO2-(C 1-6 alkyl), cyano, hydroxyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, -(C 1-6 alkylene)-(C 1-6 Alkoxy), -(C 1-6 alkylene)-(C 3-6 Cycloalkyl), -(C 1-6 alkylene)-(C 3-6 Halogenated cycloalkyl) or -O-(C 1-6 alkylene)-(C 3-6 cycloalkyl); or two occurrences of R 5 Together with its intervening atoms, it forms a 4-7 membered ring containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen and sulfur; A 1 is phenyl or a 5-6 membered monocyclic heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the phenyl and heteroaryl are replaced by n occurrences of R 5 replace; X 1 For-(C 1-4 Alkylene)-(a 3-5 membered saturated ring containing 1 nitrogen atom, wherein the ring is replaced by 0, 1, 2, 3 or 4 occurrences of C 1-4 Alkyl substituted)-***, wherein *** is 1 connection point; and m and n are independently 0, 1, 2 or 3.

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

3. The compound according to claim 1 or 2, wherein X 1 For-(C 1-4 Alkylene)-(a 4-membered saturated ring containing 1 nitrogen atom, wherein the ring is surrounded by 0, 1, 2, 3 or 4 occurrences of C 1-4 alkyl substituted)-***.

4. The compound of claim 1 or 2, wherein X 1 is -(CH2)-(a 4-membered saturated ring containing 1 nitrogen atom, wherein the ring is replaced by 0, 1 or 2 occurrences of C 1-4 alkyl substituted)-***.

5. The compound of claim 1, wherein the compound is a compound of formula Ia or a pharmaceutically acceptable salt thereof:

6. The compound of any one of claims 1 to 5, wherein A 1 is R that appears n times 5 Substituted phenyl.

7. The compound of any one of claims 1 to 5, wherein A 1 is a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heteroaryl is replaced by n occurrences of R 5 replace.

8. The compound of any one of claims 1 to 5, wherein A 1 is pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyrrolyl or thienyl, each of which is replaced by n occurrences of R 5 replace.

9. The compound of any one of claims 1 to 5, wherein A 1 is pyridyl or pyrimidinyl, each of which is replaced by n occurrences of R 5 replace.

10. The compound of any one of claims 1 to 5, wherein A 1 is pyridazinyl or pyrazinyl, each of which is replaced by n occurrences of R 5 replace.

11. The compound of any one of claims 1 to 5, wherein A 1 is pyrazinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, pyrrolyl or thienyl, each of which is replaced by n occurrences of R 5 replace.

12. The compound of any one of claims 1 to 11, wherein n is 1.

13. The compound of any one of claims 1 to 11, wherein n is 2.

14. The compound of any one of claims 1 to 13, wherein R 4 C 1-4 alkyl.

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

16. The compound of any one of claims 1-13, wherein m is 0.

17. The compound of claim 1, wherein the compound is a compound of Formula Ib or Ic, or a pharmaceutically acceptable salt thereof:

18. The compound of claim 1, wherein the compound is a compound of Formula Id or Ie, or a pharmaceutically acceptable salt thereof:

19. The compound of claim 1, wherein the compound is a compound of Formula If or Ig, or a pharmaceutically acceptable salt thereof:

20. The compound of claim 1, wherein the compound is a compound of Formula Ih, Ii, Ij, Ik, Il, Im, In, Io, Ip, or Iq, or a pharmaceutically acceptable salt thereof:

21. The compound of any one of claims 1 to 20, wherein R 1 C 1-6 alkyl.

22. The compound of any one of claims 1 to 20, wherein R 1 It is a methyl group.

23. The compound of any one of claims 1 to 22, wherein R 2 is hydrogen, halogen, or C 1-4 alkyl.

24. The compound of any one of claims 1 to 22, wherein R 2 For hydrogen.

25. The compound of any one of claims 1 to 22, wherein R 2 It is a halogen group.

26. A compound as described in any one of claims 1 to 22, wherein R 2 It is chlorine or fluorine.

27. A compound as described in any one of claims 1 to 22, wherein R 2 It is a methyl group.

28. A compound as described in any one of claims 1 to 27, wherein R 3 C 1-4 alkyl.

29. The compound of any one of claims 1 to 27, wherein R 3 It is a methyl group.

30. The compound of any one of claims 1 to 27, wherein R 3 C 1-4 Alkoxy.

31. The compound of any one of claims 1 to 30, wherein R 5 Each occurrence represents C independently 1-6 Alkyl, halogen, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, hydroxyl, C 1-6 Alkoxy, -(C 1-6 alkylene)-(C 1-6 Alkoxy), -(C 1-6 alkylene)-(C 3-6 cycloalkyl), or -(C 1-6 alkylene)-(C 3-6 halocycloalkyl).

32. A compound as described in any one of claims 1 to 30, wherein R 5 Each occurrence represents C independently 1-6 Alkyl, halogen, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, or -(C 1-6 alkylene)-(C 3-6 cycloalkyl).

33. A compound as described in any one of claims 1 to 30, wherein R 5 Each occurrence independently represents a halo or C 1-6 Halogenated alkyl.

34. A compound as described in any one of claims 1 to 30, wherein R 5 C 1-6 Halogenated alkyl.

35. A compound as described in any one of claims 1 to 30, wherein R 5 It is -CF3.

36. A compound as described in any one of claims 1 to 30, wherein R 5 It is a halogen group.

37. A compound as described in any one of claims 1 to 30, wherein R 5 For F.

38. A compound as described in any one of claims 1 to 30, wherein R 5 C 1-6 alkyl.

39. A compound as described in Table 1 herein, or a pharmaceutically acceptable salt thereof.

40. A pharmaceutical composition comprising a compound according to any one of claims 1 to 39 and a pharmaceutically acceptable carrier.

41. A method of treating a muscarinic acetylcholine receptor-mediated disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-39 to treat the muscarinic acetylcholine receptor-mediated disorder.

42. The method of claim 41, wherein the muscarinic acetylcholine receptor-mediated disorder is a neurological disorder.

43. The method of claim 41, wherein the muscarinic acetylcholine receptor-mediated disorder is a movement disorder, a mood disorder, or a cognitive disorder.

44. The method of claim 41, wherein the muscarinic acetylcholine receptor-mediated disorder is an attention disorder or an addictive disorder.

45. The method of claim 41, 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, movement disorders, cerebral amyloid angiopathy, dementia, hereditary cerebral hemorrhage with amyloidosis Dutch type (HCHWA-D), Creutzfeldt-Jakob disease, prion disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, autism, addiction, or a sleep disorder.

46. ​​The method of claim 41, wherein the muscarinic acetylcholine receptor-mediated disorder is schizoaffective disorder, psychosis, delusional disorder, Alzheimer's disease-related psychosis, Parkinson's disease-related psychosis, psychotic depression, bipolar disorder, bipolar disorder with psychosis, Huntington's disease, dementia with Lewy bodies, Tourette syndrome, Friedreich's ataxia, Huntington's chorea, restless legs syndrome, major depressive disorder, dysthymia, recurrent brief depressive disorder, minor depressive disorder, mania, anxiety, Alzheimer's disease, Parkinson's disease, dementia, Pick's disease, tauopathies, synucleinopathies, confusion, cognitive deficits related to fatigue, learning disabilities, traumatic brain injury, autism, age-related cognitive decline, Cushing's disease, attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADD), Dubois syndrome, Ferris-Gilchon syndrome, Down syndrome, growth retardation due to insulin-like growth factor 1 (IGF1) deficiency, hepatic encephalopathy syndrome, Strauss syndrome, or agitation related to neurodegeneration.

47. The method of claim 41, wherein the muscarinic acetylcholine receptor-mediated disorder is a dementia-related psychiatric disorder, schizophrenia, Alzheimer's disease, Parkinson's disease, depression, movement disorders, pain, drug addiction, tauopathy, or synucleinopathy 48. The method of claim 41, wherein the muscarinic acetylcholine receptor-mediated disorder is schizophrenia.

49. The method of claim 41, wherein the muscarinic acetylcholine receptor-mediated disorder is pain.

50. The method of claim 41, wherein the muscarinic acetylcholine receptor-mediated disorder is neuropathic pain.

51. The method of claim 41, wherein the muscarinic acetylcholine receptor-mediated condition is inflammatory pain or nociceptive pain.

52. The method of claim 41, wherein the muscarinic acetylcholine receptor-mediated disorder is chronic pain.

53. The method of any one of claims 41-52, further comprising administering to the subject in need thereof a therapeutically effective amount of an orthosteric agonist of the muscarinic acetylcholine receptor.

54. The method of claim 53, wherein the orthosteric agonist of the muscarinic acetylcholine receptor is administered to the subject concurrently with the compound of any one of claims 1-39.

55. The method of claim 53, wherein the subject is administered a pharmaceutical composition comprising (i) the orthosteric agonist of the muscarinic acetylcholine receptor and (ii) the compound of any one of claims 1-39.

56. The method of claim 53, wherein the orthosteric agonist of the muscarinic acetylcholine receptor is administered to the subject separately from the compound of any one of claims 1-39.

57. The method of claim 53, 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 1-39 is administered to the subject via a second pharmaceutical composition.

58. The method of any one of claims 53-57, wherein the amount of (i) the orthosteric agonist of the muscarinic acetylcholine receptor and / or (ii) the compound of any one of claims 1-39 administered to the patient is reduced compared to use of (i) the orthosteric agonist of the muscarinic acetylcholine receptor or (ii) the compound of any one of claims 1-39 in monotherapy treatment.

59. The method of any one of claims 41-52, further comprising administering to the subject in need thereof a therapeutically effective amount of an orthosteric antagonist of the muscarinic acetylcholine receptor.

60. The method of any one of claims 41-59, wherein the subject is a human.

61. A method of activating a muscarinic acetylcholine receptor, the method comprising contacting the muscarinic acetylcholine receptor with an effective amount of a compound of any one of claims 1-39 to activate the muscarinic acetylcholine receptor.

62. The method of any one of claims 41-61, wherein the muscarinic acetylcholine receptor is muscarinic acetylcholine receptor M4.

63. A compound represented by formula II: or a salt thereof; wherein: R 1A C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -(C 1-6 alkylene)-(C 3-6 cycloalkyl) or hydrogen; R 2A For halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 cycloalkyl, or hydrogen; R 3A C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, -S-(C 1-4 alkyl), hydrogen or halo; R 4A C 1-4 Alkyl, C 1-4 haloalkyl, or hydrogen; R 5A is hydrogen or C 1-4 alkyl; and Z 1 is hydrogen or -C(O)2(C 1-6 alkyl).

64. The compound of claim 63, wherein R 1A For hydrogen, methyl, Cyclopropyl or -CH2CF3.

65. The compound of claim 63 or 64, wherein R 2A It is hydrogen, methyl, ethyl, fluorine, chlorine, bromine, -CF3, or cyclopropyl.

66. A compound as described in any one of claims 63-65, wherein R 3A is hydrogen, methyl, methoxy, or -SCH3.

67. A compound as described in any one of claims 63-66, wherein R 4A is hydrogen or methyl.

68. A compound as described in any one of claims 63-67, wherein R 5A For hydrogen.

69. A compound as described in any one of claims 63-68, wherein Z 1 is hydrogen or tert-butoxycarbonyl.

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