Positive allosteric modulators of the muscarinic acetylcholine receptor M1

Abstract

N-biarylmethylene-substituted pyrrolopyridinone, pyrrolopyrazinone, pyrrolopyrimidinone, and isoindolin-1-one compounds having a tertiary alcohol-containing group substituted on the biarylmethylene are positive allosteric modulators of the muscarinic acetylcholine receptor M1 (mAChR M1). The compounds and pharmaceutical compositions can be used in the treatment of neurological disorders, psychiatric disorders, or a combination thereof.

Description

[Technical Field]

[0001] Related Applications This application claims priority to U.S. Provisional Patent Application No. 63 / 416,842, filed October 17, 2022, the entire contents of which are incorporated herein by reference.

[0002] The present disclosure relates to compounds, compositions, and methods for treating diseases and / or disorders associated with the muscarinic acetylcholine receptor M1, such as neurological and psychiatric disorders. [Background technology]

[0003] Positive allosteric modulators are compounds that bind to a site on a target protein that is different from the orthosteric agonist binding site. These modulators enhance the affinity or efficacy of orthosteric agonists. For example, selective muscarinic M1 positive allosteric modulators increase the affinity at the orthosteric binding site for acetylcholine (ACh), the endogenous agonist for the muscarinic M1 receptor, or increase the efficacy induced by ACh. In some systems, compounds may also have intrinsic activity that activates the receptor in the absence of an orthosteric ligand. Thus, positive allosteric modulation (potentiation) may be an attractive mechanism for enhancing appropriate physiological receptor activation.

[0004] Cholinergic neurotransmission involves activation of nicotinic acetylcholine receptors (nAChRs) or muscarinic acetylcholine receptors (mAChRs) by binding of the endogenous orthosteric agonist ACh. Acetylcholinesterase (AChE) inhibitors, which block the hydrolysis of ACh, have been approved in the United States for use in the palliative, but not disease-modifying, treatment of cognitive deficits in patients with Alzheimer's disease (AD).

[0005] mAChRs are members of family A GPCRs and include five subtypes designated M1, M2, M3, M4, and M5. M1, M3, and M5 primarily couple to Gq and activate phospholipase C, while M2 and M4 primarily couple to Gq and activate phospholipase C. i / o and associated effector systems. These five distinct mAChR subtypes have been identified in the mammalian central nervous system, where they are widespread and differentially expressed. M1-M5 mAChRs have diverse roles in cognitive, sensory, motor, and autonomic functions. Activation of various muscarinic receptors, particularly the M1 subtype, has been proposed as a mechanism for enhancing cognition in disorders such as AD and schizophrenia (as well as negative symptoms). Thus, selective positive allosteric modulators of mAChR subtypes that control processes involved in cognitive function could prove superior to AChE inhibitors for the treatment of AD and related disorders, as these compounds may exhibit improved selectivity for specific mAChRs.

[0006] Attempts to generate selective M1 agonists have been largely unsuccessful, in part due to the high degree of conservation of the orthosteric ACh binding site. As a result, mAChR agonists in clinical studies induce the same adverse effects of AChE inhibitors by activating peripheral mAChRs. To fully understand the physiological roles of individual mAChR subtypes and further explore the therapeutic utility of mACh receptors in AD, schizophrenia, and other disorders, there is a need to develop compounds that are highly selective modulators of M1 and other individual mAChR subtypes. Therefore, because the allosteric sites of mAChRs are less highly conserved, allosteric modulation may be an advantageous pathway.

[0007] Despite advances in research on muscarinic receptors (mAChRs), there remains a lack of compounds that are potent, effective, and selective positive allosteric modulators of M1 mAChRs and that are also effective in the treatment of neurological and psychiatric disorders associated with cholinergic activity or other nervous system diseases in which muscarinic M1 receptors may be involved. Summary of the Invention

[0008] In one aspect, disclosed is a compound of formula (I), or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, A 1 teeth, [ka] is selected from the group consisting of Z 1 is N or CR z1 and; Z 2 is N or CR z2 and; Z 3 is N or CR z3 and; Z 4 is N or CR z4 and; where Z 1 , Z 2 , Z 3 , and Z 4 0, 1, or 2 of is N; R z1 , R z2 , R z3 , and R z4 H, D, halogen, C 1~4 Alkyl, C 1~4 Deuterioalkyl, C 1~2 Fluoroalkyl, C 2~4 Alkenyl, cyano, -OC 1~2 Alkyl, -OC 1~2 Deuterioalkyl, -OC1~2 Fluoroalkyl, and C 3~4 independently selected from the group consisting of cycloalkyl; R 1 , R 2 , R 3 and R 4 H, D, C 1~4 Alkyl, C 1~4 Deuterioalkyl, C 1~4 Fluoroalkyl, halogen, cyano, G 1 , -OR a , -OC 2~3 Alkylene-OR b , and -N(R c )(R d ) independently selected from the group consisting of: R a , R b , R c , and R d is H, C 1~4 Alkyl, C 1~4 Deuterioalkyl, C 1~4 Fluoroalkyl, G 1 , and -C 1~3 Alkylene-G 1 wherein, instead, R c and R d is R c and R d together with the nitrogen to which it is attached to form a 4-8 membered heterocyclyl optionally containing one additional heteroatom selected from the group consisting of O, N, and S, wherein the 4-8 membered heterocyclyl is selected from halogen, oxo, C 1~4 Alkyl, C 1~4 Deuterioalkyl, C 1~4 Fluoroalkyl, OH, -OC 1~4 Alkyl, -OC 1~4 Deuterioalkyl and -OC 1~4 optionally substituted with 1 to 4 substituents independently selected from the group consisting of fluoroalkyl; G 1 is C 3~6cycloalkyl or a 4- to 8-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from the group consisting of O, N, and S, wherein the cycloalkyl and heterocyclyl are not substituted with halogen, oxo, C 1~4 Alkyl, C 1~4 Deuterioalkyl, C 1~4 Fluoroalkyl, OH, -OC 1~4 Alkyl, -OC 1~4 Deuterioalkyl and -OC 1~4 optionally substituted with 1 to 4 substituents independently selected from the group consisting of fluoroalkyl; R 5 is a 5-12 membered heteroaryl containing 1-3 heteroatoms independently selected from the group consisting of N, O, and S, or R 5 is a 6- to 12-membered aryl, and heteroaryl and aryl are R 6 and 1 to 4 substituents R 7 optionally further substituted with; R 6 is -C(R 6a )(R 6b )OH; R 6a is C 1~4 Alkyl, C 1~4 Deuterioalkyl, C 1~4 Haloalkyl, C 3~6 Cycloalkyl, -C 1~3 Alkylene-C 3~6 Cycloalkyl, and -C 1~5 Alkylene-X 1 wherein each cycloalkyl is selected from the group consisting of halogen and C 1~4 optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl; R 6b is C 1~4 Alkyl, C 1~4 Deuterioalkyl, C 1~4 Haloalkyl, C 3~6 Cycloalkyl, and -C 1~3 Alkylene-C 3~6cycloalkyl, wherein each cycloalkyl is selected from the group consisting of halogen and C 1~4 optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl; Or R 6a and R 6b are taken together with the carbon to which they are attached to form a 3- to 7-membered carbocyclic ring or a 3- to 7-membered heterocyclic ring containing one heteroatom selected from the group consisting of O, N, and S, and the carbocyclic and heterocyclic rings are free to be substituted with halogen, cyano, C 1~4 Alkyl, C 1~4 Deuterioalkyl, C 1~4 Haloalkyl, OH, -OC 1~4 Alkyl, -OC 1~4 Deuterioalkyl, -OC 1~4 Haloalkyl, -C(O)C 1~4 Alkyl and -C(O)OC 1~4 optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl; X 1 -SR 6c , -SOR 6c , -SO2R 6c , and -S(O)(NR 6d )R 6c selected from the group consisting of: R 6c is C 1~4 Alkyl, C 1~4 Deuterioalkyl, C 1~4 Haloalkyl, C 3~6 Cycloalkyl, and -C 1~3 Alkylene-C 3~6 cycloalkyl, wherein each cycloalkyl is selected from the group consisting of halogen and C 1~4 optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl; R 6d is H, C 1~4 Alkyl, C 1~4 Deuterioalkyl, C 1~4 Haloalkyl, C 3~6 Cycloalkyl, and -C 1~3 Alkylene-C 3~6cycloalkyl, wherein each cycloalkyl is selected from the group consisting of halogen and C 1~4 optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl; R 7 Each occurrence of represents a halogen, cyano, or C 1~4 Alkyl, C 1~4 Deuterioalkyl, C 1~4 Haloalkyl, OH, -OC 1~4 Alkyl, -OC 1~4 Deuterioalkyl, -OC 1~4 Haloalkyl, C 3~6 Cycloalkyl, and -C 1~3 Alkylene-C 3~6 cycloalkyl, wherein each cycloalkyl is independently selected from the group consisting of halogen and C 1~4 optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl; R 8a and R 8b are independently selected from the group consisting of H, D, CH3, and CD3; R 9a and R 9b is independently H or D.

[0009] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0010] In another aspect, the present invention provides a method for the treatment of a disorder associated with muscarinic acetylcholine receptor activity in a mammal, comprising administering to the mammal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof.

[0011] In another aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof, for use in the treatment of a disorder associated with muscarinic acetylcholine receptor activity.

[0012] In another aspect, the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof, in the manufacture of a medicament for the treatment of a disorder associated with muscarinic acetylcholine receptor activity.

[0013] In another aspect, the present invention provides a kit comprising a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof, and instructions for use.

[0014] In another aspect, the present invention provides compounds of Formula (I), or pharmaceutically acceptable salts or compositions thereof, that have minimal to substantially no M1 agonist activity relative to acetylcholine. The relative lack of M1 agonist activity is expected to avoid or reduce the propensity for adverse cholinergic effects at therapeutic concentrations and / or doses. DETAILED DESCRIPTION OF THE INVENTION

[0015] Detailed Description Disclosed herein are positive allosteric modulators of the M1 muscarinic acetylcholine receptor M1 (mAChR M1). The modulators may have the structure of Formula (I). Compounds of Formula (I) exhibit high affinity for mAChR M1 and may also exhibit selectivity over other muscarinic acetylcholine receptors. Compounds of Formula (I) can be used to treat or prevent diseases and disorders associated with mAChR M1 by modulating mAChR M1 activity. mAChR M1 has been implicated in several different diseases and disorders, including, but not limited to, neurological and psychiatric disorders.

[0016] Because the orthosteric binding sites of mAChR isoforms are highly conserved, selective modulators of mAChRs that bind at the orthosteric site remain elusive. One strategy for selectively binding and modulating mAChRs involves identifying allosteric sites that are susceptible to modulation by small molecules. In particular, positive allosteric modulation of mAChR M1 can result in potentiation of mAChR M1 receptors and provide therapeutic benefits for disorders associated with mAChR M1 dysfunction.

[0017] 1.Definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In case of conflict, the present specification, including definitions, will control. Preferred methods and materials are described below, although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. The materials, methods, and examples disclosed herein are illustrative only and are not intended to be limiting.

[0018] As used herein, the terms "comprise," "include," "having," "having," "can," "containing," and variations thereof are intended to be open-ended transitional phrases, terms, or words that do not exclude the possibility of additional acts or structures. The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. The present disclosure also contemplates other embodiments that "comprise," "consist," and "consist essentially of" the embodiments or elements provided herein, whether or not explicitly stated.

[0019] The modifier "about" used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (e.g., it includes the smallest degree of error associated with measurement of the particular quantity). The modifier "about" should also be considered to reveal a range defined by the absolute values ​​of the two endpoints. For example, the expression "about 2 to about 4" also discloses the range "2 to 4." The term "about" can refer to plus or minus 10% of the indicated number. For example, "about 10%" can indicate a range of 9% to 11%, and "about 1" can mean 0.9 to 1.1. Other meanings of "about," such as rounding, may be apparent from the context; thus, for example, "about 1" can also mean 0.5 to 1.4.

[0020] Definitions of specific functional groups and chemical terms are described in more detail below. For purposes of this disclosure, chemical elements are defined as defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th (back cover), and specific functional groups are generally defined as described therein. Further, general principles of organic chemistry and specific functional groups and reactivity are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March's Advanced Organic Chemistry, 5 th Edition, John Wiley&Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; Carruthers, Some Modern Methods of Organic Synthesis, 3 rd Edition, Cambridge University Press, Cambridge, 1987, the contents of each of which are incorporated herein by reference in their entirety.

[0021] The term "alkyl," as used herein, means a straight or branched saturated hydrocarbon chain. The terms "lower alkyl" or "C 1-6 "Alkyl" means a straight or branched chain hydrocarbon containing 1 to 6 carbon atoms. 1-4 "Alkyl" means a straight or branched chain saturated hydrocarbon containing from 1 to 4 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

[0022] The term "alkenyl," as used herein, means a straight or branched hydrocarbon chain containing at least one carbon-carbon double bond.

[0023] The term "alkylene," as used herein, refers to a divalent group derived from a straight or branched saturated chain hydrocarbon, for example, of 1 to 6 carbon atoms. Representative examples of alkylene include, but are not limited to, -CH-, -CH(CH)-, -C(CH)-, -CHCH-, -CH(CH)CH-, -C(CH)CH-, -CHCHCH-, -CH(CH)CHCH-, -C(CH)CHCH-, -CHC(CH)CH-, -CHCHCHCHCH-, and -CHCHCHCHCHCH-.

[0024] The term "alkenylene," as used herein, refers to a divalent group derived from a straight or branched chain hydrocarbon having at least one carbon-carbon double bond.

[0025] The term "aryl," as used herein, refers to phenyl or a phenyl attached to a parent molecular moiety and fused to a cycloalkane group (e.g., the aryl can be indan-4-yl), a 6-membered arene group (i.e., the aryl can be naphthyl), or a non-aromatic heterocycle (e.g., the aryl can be benzo[d][1,3]dioxol-5-yl). The term "phenyl" is used to refer to a substituent, and the term "6-membered arene" is used to refer to a fused ring. A 6-membered arene is monocyclic (e.g., benzene or benzo). An aryl can be monocyclic (phenyl) or bicyclic (e.g., a 9- to 12-membered fused bicyclic ring system).

[0026] The term "cycloalkane," as used herein, refers to a saturated ring system containing all carbon atoms as ring members and zero double bonds. The term "cycloalkyl" is used herein to refer to a cycloalkane when it is present as a substituent. A cycloalkyl can be a monocyclic cycloalkyl (e.g., cyclopropyl), a fused bicyclic cycloalkyl (e.g., decahydronaphthalenyl), a bridged cycloalkyl (two non-adjacent atoms of a ring are connected by an alkylene bridge of 1, 2, 3, or 4 carbon atoms) (e.g., bicyclo[2.2.1]heptanyl), or a spirocyclic. Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantyl, and bicyclo[1.1.1]pentanyl.

[0027] The term "cycloalkene," as used herein, refers to a non-aromatic monocyclic or polycyclic all-carbon ring system containing at least one carbon-carbon double bond and preferably having 5 to 10 carbon atoms per ring. The term "cycloalkenyl" is used herein to refer to a cycloalkene when it is present as a substituent. A cycloalkenyl can be a monocyclic cycloalkenyl (e.g., cyclopentenyl), a fused bicyclic cycloalkenyl (e.g., octahydronaphthalenyl), or a bridged cycloalkenyl (two non-adjacent atoms of a ring are joined by an alkylene bridge of 1, 2, 3, or 4 carbon atoms) (e.g., bicyclo[2.2.1]heptenyl). Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, or cycloheptenyl.

[0028] The term "deuterioalkyl," as used herein, refers to an alkyl in which one or more hydrogen atoms are deuterium isotopes, i.e., 2 "Deuterioalkyl" means an alkyl group, as defined herein, in which the alkyl group is H. Representative examples of deuterioalkyl include CD3, CH2CD3, and CD2CD3.

[0029] The term "fluoroalkyl," as used herein, refers to an alkyl group, as defined herein, in which one, two, three, four, five, six, seven, or eight hydrogen atoms have been replaced by a fluoro group. Representative examples of fluoroalkyl include CHF, CHF, CF, and CHCF.

[0030] The term "fluorodeuterioalkyl," as used herein, refers to a fluoroalkyl group in which one or more hydrogen atoms are isotopes of deuterium, i.e., 2

[0033] By "fluorodeuterioalkyl" is meant a fluoroalkyl group, as defined herein, wherein the fluoroalkyl group is H. Representative examples of fluorodeuterioalkyl include CD2F, CDF2, and CD2CF3.

[0031] The term "halogen" or "halo" as used herein means Cl, Br, I, or F.

[0032] The term "haloalkyl," as used herein, means an alkyl group, as defined herein, in which one, two, three, four, five, six, seven, or eight hydrogen atoms are replaced by halogen.

[0033] The term "halodeuterioalkyl," as used herein, refers to an alkyl group in which one or more hydrogen atoms in the alkyl group are deuterium isotopes, i.e., 2 H. Representative examples of halodeuterioalkyl include CD2F, CDF2, CD2CF 3、 Examples include CD2Cl, CDCl2, and CD2CCl3.

[0034] The term "heteroaryl" as used herein refers to an aromatic monocyclic heteroatom-containing ring (monocyclic heteroaryl) or a bicyclic ring system containing at least one monocyclic heteroaryl (bicyclic heteroaryl). The term "heteroaryl" is used herein to refer to a heteroarene when present as a substituent, and the term "heteroarene" is used in the case of ring fusion. A monocyclic heteroaryl is a 5- or 6-membered ring containing at least one heteroatom independently selected from the group consisting of N, O, and S (e.g., 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N). A 5-membered aromatic monocyclic ring has two double bonds, and a 6-membered aromatic monocyclic ring has three double bonds. Bicyclic heteroaryls are 8- to 12-membered ring systems and include fused bicyclic heteroaromatic ring systems (i.e., "fully aromatic" 10π-electron systems), such as monocyclic heteroaryl rings fused to 6-membered arenes (e.g., quinolin-4-yl, indol-1-yl), monocyclic heteroaryl rings fused to 5- to 6-membered monocyclic heteroarenes (e.g., naphthyridinyl), and phenyl fused to 5- to 6-membered monocyclic heteroarenes (e.g., quinolin-5-yl, indol-4-yl). Bicyclic heteroaryl / heteroarene groups include 9-membered fused bicyclic heteroaromatic ring systems having four double bonds and at least one heteroatom contributing a lone pair of electrons to the fully aromatic 10π-electron system, such as ring systems with a nitrogen atom at the ring junction (e.g., imidazopyridine) and benzoxadiazolyl. Bicyclic heteroaryl also includes fused bicyclic systems consisting of one heteroaromatic ring and one non-aromatic ring, such as a monocyclic heteroaryl ring fused to a monocyclic carbocyclic ring (e.g., 6,7-dihydro-5H-cyclopenta[b]pyridinyl) or a monocyclic heteroaryl ring fused to a monocyclic heterocyclic ring (e.g., 2,3-dihydrofuro[3,2-b]pyridinyl). A bicyclic heteroaryl is attached to the parent molecular moiety at an aromatic ring atom.Representative examples of heteroaryl include, but are not limited to, indolyl (e.g., indol-1-yl, indol-2-yl, indol-4-yl), pyridinyl (including pyridin-2-yl, pyridin-3-yl, pyridin-4-yl), pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl (e.g., pyrazol-4-yl), pyrrolyl, benzopyrazolyl, 1,2,3-triazolyl (e.g., triazol-4-yl), 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, imidazolyl, thiazolyl (e.g., thiazol-4-yl), isothiazolyl, thienyl, benzimidazolyl (e.g., benzimidazol-5-yl), benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzothienyl, benzofuranyl, isobenzofuranyl, furanyl, oxazolyl, isoxazolyl, purinyl, isoindolyl, quinoxalinyl, indazolyl (e.g., indazol-4-yl, indazol-5-yl), quinazolinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, isoquinolinyl, quinolinyl, imidazo[1,2-a]pyridinyl (e.g., imidazo[1,2-a]pyridin-6-yl), naphthyridinyl, pyridoimidazolyl, thiazolo[5,4-b]pyridin-2-yl, and thiazolo[5,4-d]pyrimidin-2-yl.

[0035] The term "heterocycle" or "heterocyclic" as used herein means a monocyclic heterocycle, a bicyclic heterocycle, or a tricyclic heterocycle. The term "heterocyclyl" is used herein to refer to a heterocycle when it is present as a substituent. A monocyclic heterocycle is a 3-, 4-, 5-, 6-, 7-, or 8-membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S. A 3- or 4-membered ring contains zero or one double bond and one heteroatom selected from the group consisting of O, N, and S. A 5-membered ring contains zero or one double bond and one, two, or three heteroatoms selected from the group consisting of O, N, and S. A 6-membered ring contains zero, one, or two double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. The 7- and 8-membered rings contain 0, 1, 2, or 3 double bonds and 1, 2, or 3 heteroatoms selected from the group consisting of O, N, and S. Representative examples of monocyclic heterocycles include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, 2-oxo-3-piperidinyl, 2-oxoazepan-3-yl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxazolidinyl, oxazolin ... Examples include cetyl, oxepanyl, oxocanyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, 1,2-thiazinanyl, 1,3-thiazinanyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidethiomorpholinyl (thiomorpholinesulfone), thiopyranyl, and trithianyl.A bicyclic heterocycle is a monocyclic heterocycle fused to a 6-membered arene, or a monocyclic heterocycle fused to a monocyclic cycloalkane, or a monocyclic heterocycle fused to a monocyclic cycloalkene, or a monocyclic heterocycle fused to a monocyclic heterocycle, or a monocyclic heteroarene, or a spiroheterocyclic group, or a bridged monocyclic heterocycle system (wherein two non-adjacent atoms of the ring are joined by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, or an alkenylene bridge of 2, 3, or 4 carbon atoms). A bicyclic heterocyclyl is attached to the parent molecular moiety at a non-aromatic ring atom (e.g., indolin-1-yl). Representative examples of bicyclic heterocyclyl include, but are not limited to, chroman-4-yl, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzotin-2-yl, 1,2,3,4-tetrahydroisoquinolin-2-yl, 2-azaspiro[3.3]heptan-2-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, azabicyclo[2.2.1]heptyl (including 2-azabicyclo[2.2.1]hept-2-yl), azabicyclo[3.1.0]heptyl, and 2-azabicyclo[2.2.1]heptyl. hexanyl (including 3-azabicyclo[3.1.0]hexan-3-yl), 2,3-dihydro-1H-indol-1-yl, isoindolin-2-yl, octahydrocyclopenta[c]pyrrolyl, octahydropyrrolopyridinyl, tetrahydroisoquinolinyl, 7-oxabicyclo[2.2.1]heptanyl, hexahydro-2H-cyclopenta[b]furanyl, 2-oxaspiro[3.3]heptanyl, and 3-oxaspiro[5.5]undecanyl. Tricyclic heterocycles are exemplified by a bicyclic heterocycle fused with a 6-membered arene, or a bicyclic heterocycle fused with a monocyclic cycloalkane, or a bicyclic heterocycle fused with a monocyclic cycloalkene, or a bicyclic heterocycle fused with a monocyclic heterocycle, or a bicyclic heterocycle in which two non-adjacent atoms of the bicyclic ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, or an alkenylene bridge of 2, 3, or 4 carbon atoms.Examples of tricyclic heterocycles include, but are not limited to, octahydro-2,5-epoxypentalene, hexahydro-2H-2,5-methanocyclopenta[b]furan, hexahydro-1H-1,4-methanocyclopenta[c]furan, aza-adamantane (1-azatricyclo[3.3.1.13,7]decane), and oxa-adamantane (2-oxatricyclo[3.3.1.13,7]decane). These monocyclic, bicyclic, and tricyclic heterocyclyls are linked to the parent molecular moiety at a non-aromatic ring atom.

[0036] The terms "hydroxyl" or "hydroxy," as used herein, refer to an --OH group.

[0037] The terms "alkyl," "cycloalkyl," "alkylene," and the like, are used with a symbol indicating the number of atoms present in the group in a particular instance (e.g., "C 1~4 Alkyl," "C 3~6 cycloalkyl," "C 1~4 These symbols are used as commonly understood by those skilled in the art. For example, the designation "C" followed by a numeric subscript indicates the number of carbon atoms present in the group that follows. As used herein, "C" refers to the number of carbon atoms present in the group that follows. m ~C n "," "C m ~C n " or "C m~n (where "m" and "n" are integers) refers to the number of carbon atoms in the relevant group. That is, a group can contain from "m" to "n" (inclusive) carbon atoms. Thus, for example, a "C1-C6 alkyl" group refers to all alkyl groups having from 1 to 6 carbons, i.e., CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, CH3CH(CH)3CH2-, CH3CH(CH)3CH2-, and (CH3)3C-. Thus, a "C3 alkyl" is an alkyl group having 3 carbon atoms (i.e., n-propyl, isopropyl). "C 1~4When a range is given, such as in "C", the members of the group that follow can have any number of carbon atoms that fall within the recited range. 1~4 "Alkyl," for example, is an alkyl group having 1 to 4 carbon atoms of any configuration (i.e., straight or branched). When "m" and "n" are not specified for a group, the broadest range described in those definitions is assumed.

[0038] Dashed line [ka] represents optional unsaturation between the atoms forming the bond. The bond may be unsaturated (e.g., C=C, C=N, C=O) or saturated (e.g., CC, CN, CO). When the dashed bond is present in a ring system, it may form part of an aromatic ring system.

[0039] The term "substituted" refers to a group that can be further substituted with one or more substituents that are not hydrogen. The substituents can include, for example, halogen, =0 (oxo), =S (thioxo), cyano, nitro, fluoroalkyl, alkoxyfluoroalkyl, fluoroalkoxy, alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, heteroalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycle, cycloalkylalkyl, heteroarylalkyl, arylalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkylene, aryloxy, phenoxy, benzyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, -COOH, ketone, amide, carbamate, and acyl.

[0040] As used herein, an "optional substituent" is a substituent that may or may not be present on a group, such as a ring (e.g., phenyl) or a chain (e.g., alkyl), of another molecule. A group that is "optionally substituted" with a substituent means that the group is unsubstituted or substituted with a substituent.

[0041] For the compounds described herein, and in accordance with the permitted valences of atoms and substituents, groups and substituents can be selected such that selection and substitution results in stable compounds (e.g., which do not spontaneously undergo transformations such as by rearrangement, cyclization, elimination, etc.).

[0042] Pharmaceutically acceptable solvates and hydrates are complexes of a compound with one or more solvent or water molecules, or 1 to about 100, or 1 to about 10, or 1 to about 2, 3, or 4 solvent or water molecules.

[0043] As used herein, a "prodrug" refers to a compound that may not be pharmaceutically active but is converted into an active drug upon administration in vivo. Prodrugs may be designed to alter the metabolic stability or transport characteristics of a drug, mask side effects or toxicity, improve the flavor of a drug, or change other characteristics or properties of a drug. Prodrugs are often useful because they may be easier to administer than the parent drug. They may, for example, be bioavailable by oral administration, whereas the parent drug is not. Prodrugs may also have better solubility in pharmaceutical compositions than the active parent drug. Based on knowledge of in vivo pharmacodynamic processes and drug metabolism, one skilled in the art can design prodrugs of a compound once a pharmaceutically active compound is known (see, e.g., Nogrady (1985) Medicinal Chemistry: A Biochemical Approach, Oxford University Press, New York, pages 388-392).

[0044] The terms "polymorph" and "polymorphic form" refer to crystalline forms of the same molecule; as a result of the arrangement or conformation of the molecule in the crystal lattice, different polymorphs may have different physical properties, such as melting temperature, heat of fusion, solubility, dissolution rate, and / or vibrational spectrum. Polymorphs of a molecule can be obtained by several methods known in the art. Such methods include, but are not limited to, melt recrystallization, melt cooling, solvent recrystallization, desolvation, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, and sublimation. Techniques for characterizing polymorphs include, but are not limited to, differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), single crystal X-ray diffraction, vibrational spectroscopy, such as IR and Raman spectroscopy, solid-state NMR, high-temperature optical microscopy, scanning electron microscopy (SEM), electron crystallography and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility studies, and dissolution studies.

[0045] For the recitation of numerical ranges herein, each intervening number is specifically contemplated to the same degree of precision. For example, for the range 6 to 9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0 to 7.0, the numbers 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are specifically contemplated.

[0046] 2.Compound Throughout the embodiments and description of the compounds of the present invention, all instances of haloalkyl can be fluoroalkyl (e.g., any C 1~4 Haloalkyl is C 1~4 (which may be fluoroalkyl).

[0047] An unsubstituted or substituted ring, such as an aryl or heteroaryl, is composed of a ring system and any optional substituents of the ring system. Thus, a ring system can be defined independently of its substituents, so that any previous optional substituents remain present by redefining only the ring system. For example, a 5-12-membered heteroaryl having optional substituents can be further defined by specifying that the ring system of the 5-12-membered heteroaryl is a 5-6-membered heteroaryl (i.e., a 5-6-membered heteroaryl ring system), in which case, unless otherwise specified, any optional substituents of the 5-12-membered heteroaryl are still present on the 5-6-membered heteroaryl.

[0048] When heterocyclic and heteroaromatic ring systems are defined as "containing" or "comprising" specific heteroatoms (e.g., 1 to 3 heteroatoms independently selected from the group consisting of O, N, and S), any ring atom of the heterocyclic and heteroaromatic ring systems that is not one of the specified heteroatoms is a carbon atom.

[0049] Below, numbered embodiments of the invention are disclosed (e.g., E1, E1.1, E2, E2.1, etc.). In numbered embodiments, references to a series of previous embodiments in multiple subordination (e.g., "a compound described in any of E1-E2.6") are references to each embodiment listed sequentially in the range otherwise recited herein. For example, the range "any of E1-E2.6" means "any of E1, E1.1, E2, E2.1, E2.2, E2.3, E2.4, E2.5, or E2.6."

[0050] E1. A compound of formula (I) or a pharmaceutically acceptable salt thereof [ka] During the ceremony, A 1 teeth, [ka] is selected from the group consisting of Z 1 is N or CR z1 and; Z 2 is N or CR z2 and; Z 3 is N or CR z3 and; Z 4 is N or CR z4 and; where Z 1 , Z 2 , Z 3 , and Z 4 0, 1, or 2 of is N; R z1 , R z2 , R z3 , and R z4 H, D, halogen, C 1~4 Alkyl, C 1~4 Deuterioalkyl, C 1~2 Fluoroalkyl, C 2~4 Alkenyl, cyano, -OC 1~2 Alkyl, -OC 1~2 Deuterioalkyl, -OC 1~2 Fluoroalkyl, and C 3~4 independently selected from the group consisting of cycloalkyl; R 1 , R 2 , R 3 and R 4 H, D, C 1~4 Alkyl, C 1~4 Deuterioalkyl, C 1~4 Fluoroalkyl, halogen, cyano, G 1 , -OR a , -OC 2~3 Alkylene-OR b , and -N(R c )(R d ) independently selected from the group consisting of: R a , R b , R c , and R d is H, C 1~4 Alkyl, C 1~4Deuterioalkyl, C 1~4 Fluoroalkyl, G 1 , and -C 1~3 Alkylene-G 1 wherein, instead, R c and R d is R c and R d together with the nitrogen to which it is attached to form a 4-8 membered heterocyclyl optionally containing one additional heteroatom selected from the group consisting of O, N, and S, wherein the 4-8 membered heterocyclyl is selected from halogen, oxo, C 1~4 Alkyl, C 1~4 Deuterioalkyl, C 1~4 Fluoroalkyl, OH, -OC 1~4 Alkyl, -OC 1~4 Deuterioalkyl and -OC 1~4 optionally substituted with 1 to 4 substituents independently selected from the group consisting of fluoroalkyl; G 1 is C 3~6 cycloalkyl or a 4- to 8-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from the group consisting of O, N, and S, wherein the cycloalkyl and heterocyclyl are not substituted with halogen, oxo, C 1~4 Alkyl, C 1~4 Deuterioalkyl, C 1~4 Fluoroalkyl, OH, -OC 1~4 Alkyl, -OC 1~4 Deuterioalkyl and -OC 1~4 optionally substituted with 1 to 4 substituents independently selected from the group consisting of fluoroalkyl; R 5 is a 5-12 membered heteroaryl containing 1-3 heteroatoms independently selected from the group consisting of N, O, and S, or R 5 is a 6- to 12-membered aryl, and heteroaryl and aryl are R 6 and 1 to 4 substituents R 7 optionally further substituted with; R 6 is -C(R6a )(R 6b )OH; R 6a is C 1~4 Alkyl, C 1~4 Deuterioalkyl, C 1~4 Haloalkyl, C 3~6 Cycloalkyl, -C 1~3 Alkylene-C 3~6 Cycloalkyl, and -C 1~5 Alkylene-X 1 wherein each cycloalkyl is selected from the group consisting of halogen and C 1~4 optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl; R 6b is C 1~4 Alkyl, C 1~4 Deuterioalkyl, C 1~4 Haloalkyl, C 3~6 Cycloalkyl, and -C 1~3 Alkylene-C 3~6 cycloalkyl, wherein each cycloalkyl is selected from the group consisting of halogen and C 1~4 optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl; Or R 6a and R 6b are taken together with the carbon to which they are attached to form a 3- to 7-membered carbocyclic ring or a 3- to 7-membered heterocyclic ring containing one heteroatom selected from the group consisting of O, N, and S, and the carbocyclic and heterocyclic rings are free to be substituted with halogen, cyano, C 1~4 Alkyl, C 1~4 Deuterioalkyl, C 1~4 Haloalkyl, OH, -OC 1~4 Alkyl, -OC 1~4 Deuterioalkyl, -OC 1~4 Haloalkyl, -C(O)C 1~4 Alkyl and -C(O)OC 1~4 optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl; X 1 -SR 6c , -SOR 6c, -SO2R 6c , and -S(O)(NR 6d )R 6c selected from the group consisting of: R 6c is C 1~4 Alkyl, C 1~4 Deuterioalkyl, C 1~4 Haloalkyl, C 3~6 Cycloalkyl, and -C 1~3 Alkylene-C 3~6 cycloalkyl, wherein each cycloalkyl is selected from the group consisting of halogen and C 1~4 optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl; R 6d is H, C 1~4 Alkyl, C 1~4 Deuterioalkyl, C 1~4 Haloalkyl, C 3~6 Cycloalkyl, and -C 1~3 Alkylene-C 3~6 cycloalkyl, wherein each cycloalkyl is selected from the group consisting of halogen and C 1~4 optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl; R 7 Each occurrence of represents a halogen, cyano, or C 1~4 Alkyl, C 1~4 Deuterioalkyl, C 1~4 Haloalkyl, OH, -OC 1~4 Alkyl, -OC 1~4 Deuterioalkyl, -OC 1~4 Haloalkyl, C 3~6 Cycloalkyl, and -C 1~3 Alkylene-C 3~6 cycloalkyl, wherein each cycloalkyl is independently selected from the group consisting of halogen and C 1~4 optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl; R 8a and R 8b are independently selected from the group consisting of H, D, CH3, and CD3; R9a and R 9b are independently H or D.

[0051] E1.1.R z1 , R z2 , R z3 , and R z4 But H, D, halogen, C 1~2 Alkyl, C 1~2 Deuterioalkyl, C 1~2 Fluoroalkyl, cyano, -OC 1~2 Alkyl, -OC 1~2 Deuterioalkyl, -OC 1~2 Fluoroalkyl, and C 3~4 A compound according to E1, or a pharmaceutically acceptable salt thereof, independently selected from the group consisting of: cycloalkyl;

[0052] E2.R 1 and R 2 But H, D, C 1~4 Alkyl, C 1~4 Deuterioalkyl, C 1~4 Fluoroalkyl, halogen, cyano, C 3~6 Cycloalkyl, -OR a , -OC 2~3 Alkylene-OR b , and -N(R c )(R d ), wherein C 3~6 Cycloalkyl is halogen, oxo, C 1~4 Alkyl, C 1~4 Deuterioalkyl, C 1~4 Fluoroalkyl, OH, -OC 1~4 Alkyl, -OC 1~4 Deuterioalkyl and -OC 1~4 A compound according to E1 or E1.1, or a pharmaceutically acceptable salt thereof, optionally substituted with 1 to 4 substituents independently selected from the group consisting of fluoroalkyl.

[0053] E2.1.R 1 and R 2 But H, D, C 1~4 Alkyl, C1~4 Fluoroalkyl, halogen, C 3~6 Cycloalkyl, -OR a , -OC 2~3 Alkylene-OR b , and -N(R c )(R d or a pharmaceutically acceptable salt thereof.

[0054] E2.2.R 1 and R 2 are independently selected from the group consisting of H, CH3, CH(CH3)2, CD3, CF3, fluoro, chloro, cyano, cyclopropyl, cyclopentyl, -OCH3, -OCH2CH(CH3)2, -O-(CH2)2-OCH3, -N(CH3)2, and azetidin-1-yl, or a pharmaceutically acceptable salt thereof.

[0055] E2.3.R 1 and R 2 are independently selected from the group consisting of H, CH3, CH(CH3)2, CF3, fluoro, chloro, cyclopropyl, cyclopentyl, -OCH3, -OCH2CH(CH3)2, -O-(CH2)2-OCH3, -N(CH3)2, and azetidin-1-yl, or a pharmaceutically acceptable salt thereof.

[0056] E2.4.R 2 But C 1~4 Alkyl, halogen, and C 3~6 The compound according to any one of E1 to E2.1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of cycloalkyl.

[0057] E2.5.R 2 is selected from the group consisting of CH3, fluoro, chloro, and cyclopropyl, or a pharmaceutically acceptable salt thereof.

[0058] E2.6.R 2is H, or a pharmaceutically acceptable salt thereof.

[0059] E2.7.R 1 is H, or a pharmaceutically acceptable salt thereof.

[0060] E2.8.R 1 But C 1~4 The compound according to any one of E1 to E2.6, or a pharmaceutically acceptable salt thereof, wherein R is alkyl or halogen.

[0061] E2.9.R 1 is selected from the group consisting of CH3, fluoro, and chloro, or a pharmaceutically acceptable salt thereof.

[0062] E3.R 3 and R 4 But H, D, C 1~4 Alkyl, C 1~4 Deuterioalkyl, C 1~2 Fluoroalkyl, halogen, cyano, -OC 1~4 Alkyl, -OC 1~4 Deuterioalkyl and -OC 1~2 The compound according to any one of E1 to E2.9, or a pharmaceutically acceptable salt thereof, independently selected from the group consisting of: fluoroalkyl.

[0063] E3.1.R 3 But C 1~4 The compound according to any one of E1 to E3, or a pharmaceutically acceptable salt thereof, wherein R is alkyl or halogen.

[0064] E3.2.R 3 is halogen, or a pharmaceutically acceptable salt thereof.

[0065] E3.3.R 3 is fluoro; or a pharmaceutically acceptable salt thereof.

[0066] E3.4.R 3 is H, or a pharmaceutically acceptable salt thereof.

[0067] E3.5.R 4 But C 1~4 The compound according to any one of E1 to E3.4, or a pharmaceutically acceptable salt thereof, wherein R is alkyl or halogen.

[0068] E3.6.R 4 is halogen; or a pharmaceutically acceptable salt thereof.

[0069] E3.7.R 4 is fluoro; or a pharmaceutically acceptable salt thereof.

[0070] E3.8.R 4 is H, or a pharmaceutically acceptable salt thereof.

[0071] E4.A 1 but, [ka] The compound according to any one of E1 to E3.8, or a pharmaceutically acceptable salt thereof, wherein:

[0072] E5.A 1 but, [ka] or a pharmaceutically acceptable salt thereof.

[0073] E6.A 1 but, [ka] or a pharmaceutically acceptable salt thereof.

[0074] E7.A 1 but, [ka] and / or A 1 but, [ka] and / or A 1 but, [ka] and / or A 1 but, [ka] or a pharmaceutically acceptable salt thereof.

[0075] E8.A 1 but, [ka] The compound according to any one of E1 to E3.8, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

[0076] E8.1.A 1 but, [ka] or a pharmaceutically acceptable salt thereof.

[0077] E8.2.A 1 but, [ka] or a pharmaceutically acceptable salt thereof.

[0078] E8.3.A 1 but, [ka] or a pharmaceutically acceptable salt thereof.

[0079] E8.4.A 1 but, [ka] or a pharmaceutically acceptable salt thereof.

[0080] E8.5.A 1 but, [ka] or a pharmaceutically acceptable salt thereof.

[0081] E9.R 5 The compound according to any one of E1 to E8.5, or a pharmaceutically acceptable salt thereof, wherein is substituted 5-12 membered heteroaryl.

[0082] E10.R 5 The compound according to any one of E1 to E9, wherein the ring system of the substituted 5- to 12-membered heteroaryl in the formula (I) is a 5- to 6-membered heteroaryl containing 1 to 3 nitrogen atoms, or a pharmaceutically acceptable salt thereof.

[0083] E10.1. The compound according to E10, or a pharmaceutically acceptable salt thereof, wherein the ring system of the 5-6 membered heteroaryl containing 1-3 nitrogen atoms is selected from the group consisting of pyridin-3-yl, 1H-pyrazol-4-yl, and 1H-pyrazol-5-yl.

[0084] E10.2.R 5 but, [ka] selected from the group consisting of: R 7a But C 1~4 Alkyl, C 1~4 Deuterioalkyl, C 1~4 Haloalkyl, C 3~6 Cycloalkyl, and -C 1~3 Alkylene-C 3~6 cycloalkyl, wherein each cycloalkyl is selected from the group consisting of halogen and C 1~4 The compound according to E10.1, or a pharmaceutically acceptable salt thereof, optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl.

[0085] E10.3.R 7a But C 1~4 The compound according to E10.2, or a pharmaceutically acceptable salt thereof, wherein R is alkyl.

[0086] E10.4.R 7a is CH3, or a pharmaceutically acceptable salt thereof.

[0087] E11.R 5 The compound according to any one of E1 to E9, wherein the ring system of the substituted 5-12 membered heteroaryl in the formula (I) is a 9-10 membered heteroaryl containing 1-3 nitrogen atoms, or a pharmaceutically acceptable salt thereof.

[0088] E12. The compound according to E11, wherein the 9-10 membered heteroaryl ring system is selected from the group consisting of 2H-indazol-4-yl, 2H-indazol-3-yl, 2H-indazol-5-yl, 2H-indazol-6-yl, 2H-indazol-7-yl, 1H-indazol-3-yl, 1H-indazol-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-8-yl, 1H-indol-3-yl, 1H-benzo[d][1,2,3]triazol-7-yl, pyrazolo[1,5-a]pyridin-4-yl, pyrazolo[1,5-a]pyridin-5-yl, and [1,2,4]triazolo[1,5-a]pyridin-8-yl, or a pharmaceutically acceptable salt thereof.

[0089] E12.1.R 5 But two R 7 A compound according to E11 or E12, or a pharmaceutically acceptable salt thereof, which is substituted by a substituent.

[0090] E12.2.R 5 But one R 7 A compound according to E11 or E12, or a pharmaceutically acceptable salt thereof, which is substituted by a substituent.

[0091] E12.3.R 5 But there are 0 R 7 A compound according to E11 or E12, or a pharmaceutically acceptable salt thereof, which is substituted by a substituent.

[0092] E13.R 5 but, [ka] [ka] selected from the group consisting of: R 7a But C 1~4 Alkyl, C 1~4 Deuterioalkyl, C 1~4 Haloalkyl, C3~6 Cycloalkyl, and -C 1~3 Alkylene-C 3~6 cycloalkyl, wherein each cycloalkyl is selected from the group consisting of halogen and C 1~4 A compound according to any one of E12, E12.2, or E12.3, or a pharmaceutically acceptable salt thereof, optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl.

[0093] E14.R 5 but, [ka] and R 7a But C 1~4 Alkyl, C 1~4 Deuterioalkyl, C 1~4 Haloalkyl, C 3~6 Cycloalkyl, and -C 1~3 Alkylene-C 3~6 cycloalkyl, wherein each cycloalkyl is selected from the group consisting of halogen and C 1~4 optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl; R 7b , R 7c , and R 7d But hydrogen, halogen, cyano, C 1~4 Alkyl, C 1~4 Deuterioalkyl, C 1~4 Haloalkyl, OH, -OC 1~4 Alkyl, -OC 1~4 Deuterioalkyl, -OC 1~4 Haloalkyl, C 3~6 Cycloalkyl, and -C 1~3 Alkylene-C 3~6 cycloalkyl, wherein each cycloalkyl is independently selected from the group consisting of halogen and C 1~4 The compound according to any one of E12 to E13, or a pharmaceutically acceptable salt thereof, optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl.

[0094] E14.1.R 7b , R 7c , and R 7d are independently selected from the group consisting of hydrogen, fluoro, chloro, cyano, CH3, CD3, CF3, OH, OCH3, OCD3, OCHF2, OCF3, and cyclopropyl, or a pharmaceutically acceptable salt thereof.

[0095] E15.R 5 but, [ka] The compound according to any one of E13 to E14.1, or a pharmaceutically acceptable salt thereof, wherein:

[0096] E16.R 7a But C 1~2 Alkyl or C 1~2 A compound according to any one of E13 to E15, or a pharmaceutically acceptable salt thereof, which is deuterioalkyl.

[0097] E16.1.R 7a is CH3 or CD3, or a pharmaceutically acceptable salt thereof.

[0098] E17.R 5 is substituted 6-12 membered aryl, or a pharmaceutically acceptable salt thereof.

[0099] E17.1.R 5 The compound according to any one of E1 to E8.5 or E17, wherein the 6- to 12-membered aryl ring system is phenyl, or a pharmaceutically acceptable salt thereof.

[0100] E17.2.R 5 The compound according to any one of E1 to E8.5 or E17, wherein the 6- to 12-membered aryl ring system is naphthalenyl, or a pharmaceutically acceptable salt thereof.

[0101] E17.3.R 5 The compound according to any one of E1 to E8.5 or E17, wherein the 6- to 12-membered aryl ring system is benzo[d][1,3]dioxol-4-yl or benzo[d][1,3]dioxol-5-yl, or a pharmaceutically acceptable salt thereof.

[0102] E18.R 5 but, [ka] is selected from the group consisting of R 7a , R 7b , R 7c , and R 7d But halogen, cyano, C 1~4 Alkyl, C 1~4 Deuterioalkyl, C 1~4 Haloalkyl, OH, -OC 1~4 Alkyl, -OC 1~4 Deuterioalkyl, -OC 1~4 Haloalkyl, C 3~6 Cycloalkyl, and -C 1~3 Alkylene-C 3~6 cycloalkyl, wherein each cycloalkyl is independently selected from the group consisting of halogen and C 1~4 A compound according to any one of E17 to E17.3, or a pharmaceutically acceptable salt thereof, optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl.

[0103] E18.1.R 7a , R 7b , R 7c , and R 7d are independently halogen or C 1~4 The compound according to E18, or a pharmaceutically acceptable salt thereof, wherein R is alkyl.

[0104] E18.2.R 7a , R 7b , R 7c , and R 7dis independently selected from the group consisting of fluoro, chloro, and CH3, or a pharmaceutically acceptable salt thereof.

[0105] E18.3.R 5 but, [ka] A compound according to any one of E18 to E18.1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

[0106] E18.4.R 5 but, [ka] A compound according to E18.2 or E18.3 selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

[0107] E19.R 6 but, [ka] The compound according to any one of E1 to E18.4, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

[0108] E19.1.R 6 but, [ka] or a pharmaceutically acceptable salt thereof.

[0109] E20.R 6 but, [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0110] E21.R 6 but, [ka] or a pharmaceutically acceptable salt thereof.

[0111] E22.R 6 but, [ka] or a pharmaceutically acceptable salt thereof.

[0112] E23. The compound of formula (I) has the formula: [ka] The compound according to any one of E1 to E22, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the compounds:

[0113] E23.1.R z1 is hydrogen, or a pharmaceutically acceptable salt thereof.

[0114] E23.2.R z1 is halogen, or a pharmaceutically acceptable salt thereof.

[0115] E23.3.R z1 is fluoro; or a pharmaceutically acceptable salt thereof.

[0116] E23.4.R z2is hydrogen, or a pharmaceutically acceptable salt thereof.

[0117] E23.5.R z3 is hydrogen, or a pharmaceutically acceptable salt thereof.

[0118] E23.6.R z3 is halogen, or a pharmaceutically acceptable salt thereof.

[0119] E23.7.R z3 is bromo, or a pharmaceutically acceptable salt thereof.

[0120] E23.8.R z3 But C 1~4 The compound according to any one of E1 to E23.4, or a pharmaceutically acceptable salt thereof, wherein R is alkyl.

[0121] E23.9.R z3 The compound according to E23.8, or a pharmaceutically acceptable salt thereof, wherein is methyl, ethyl, or isopropyl.

[0122] E23.10.R z3 But C 2~4 The compound according to any one of E1 to E23.4, or a pharmaceutically acceptable salt thereof, which is alkenyl.

[0123] E23.11.R z3 is vinyl, or a pharmaceutically acceptable salt thereof.

[0124] E23.12.R z3 But C 3~4 The compound according to any one of E1 to E23.4, or a pharmaceutically acceptable salt thereof, which is cycloalkyl.

[0125] E23.13.R z3is cyclopropyl; or a pharmaceutically acceptable salt thereof.

[0126] E23.14.R z4 is hydrogen, or a pharmaceutically acceptable salt thereof.

[0127] E23.15.R z4 is halogen; or a pharmaceutically acceptable salt thereof.

[0128] E23.16.R z4 is fluoro; or a pharmaceutically acceptable salt thereof.

[0129] E24. The compound according to any one of E23 or E23.4 to E23.16, wherein the compound of formula (I) is a compound of formula (Ia), or a pharmaceutically acceptable salt thereof.

[0130] E24.1. A compound according to any one of E23 to E23.4 or E23.14 to E23.16, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (Ib):

[0131] E24.2. A compound according to any one of E23 to E23.13, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (Ic):

[0132] E24.3. The compound according to any one of E23 or E23.4 to E23.13, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (Id):

[0133] E24.4. A compound according to any one of E23, E23.4, or E23.14 to E23.16, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (Ie):

[0134] E24.5. A compound according to any one of E23 to E23.16, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (If):

[0135] E25.Formula [ka] or a pharmaceutically acceptable salt thereof.

[0136] E25.1.Formula [ka] or a pharmaceutically acceptable salt thereof.

[0137] E25.2.Formula [ka] or a pharmaceutically acceptable salt thereof.

[0138] E25.3.Formula [ka] or a pharmaceutically acceptable salt thereof.

[0139] E25.4.Formula [ka] or a pharmaceutically acceptable salt thereof.

[0140] E25.5.Formula [ka] or a pharmaceutically acceptable salt thereof.

[0141] E25.6.Formula [ka] or a pharmaceutically acceptable salt thereof.

[0142] E25.7.Formula [ka] or a pharmaceutically acceptable salt thereof.

[0143] E25.8.Formula [ka] or a pharmaceutically acceptable salt thereof.

[0144] E25.9.Formula [ka] or a pharmaceutically acceptable salt thereof.

[0145] E25.10.Formula [ka] or a pharmaceutically acceptable salt thereof.

[0146] E25.11.Formula [ka] or a pharmaceutically acceptable salt thereof.

[0147] E25.12.Formula [ka] or a pharmaceutically acceptable salt thereof.

[0148] E26.A 1 but, [ka] A compound according to any one of E1 to E6, E9, E11 to 16.1, or E19 to E25.12, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

[0149] E26.1.A 1 but, [ka] or a pharmaceutically acceptable salt thereof.

[0150] E26.2.A 1 but, [ka] or a pharmaceutically acceptable salt thereof.

[0151] E26.3.A 1 but, [ka] or a pharmaceutically acceptable salt thereof.

[0152] E26.4.A 1 but, [ka] or a pharmaceutically acceptable salt thereof.

[0153] E26.5.A 1 but, [ka] or a pharmaceutically acceptable salt thereof.

[0154] E26.6.A 1 but, [ka] or a pharmaceutically acceptable salt thereof.

[0155] E26.7.A 1 but, [ka] or a pharmaceutically acceptable salt thereof.

[0156] E26.8.A 1 but, [ka] or a pharmaceutically acceptable salt thereof.

[0157] E26.9.A 1 but, [ka] or a pharmaceutically acceptable salt thereof.

[0158] E27.R 8a and R 8b is H, or a pharmaceutically acceptable salt thereof.

[0159] E28.1.R 8a is H and R 8b is CH3, or a pharmaceutically acceptable salt thereof.

[0160] E28.2.R 8a is CH3;R 8b is H, or a pharmaceutically acceptable salt thereof.

[0161] E29.R 9a and R 9b is H, or a pharmaceutically acceptable salt thereof.

[0162] E30.R 9a and R 9b is D, or a pharmaceutically acceptable salt thereof.

[0163] E31. A compound of E1 selected from the compounds of Table 15, or a pharmaceutically acceptable salt thereof.

[0164] E31.1. The compound according to E31, which is 6-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.

[0165] E31.2. The compound according to E31, which is 6-(2-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)-6-methylbenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0166] E31.3. The compound according to E31, which is 6-(2-cyclopropyl-6-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0167] E31.4. The compound according to E31, which is 6-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-(methyl-d3)-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0168] E31.5. The compound according to E31, which is 6-((3,5-difluoro-4'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0169] E31.6. The compound according to E31, which is 6-(2,6-difluoro-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.

[0170] E31.7. The compound according to E31, which is 6-((3,3',5-trifluoro-4'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0171] E31.8. The compound according to E31, which is 6-((3'-chloro-3,5-difluoro-4'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0172] E31.9. The compound according to E31, which is 6-((3-fluoro-4'-(2-hydroxypropan-2-yl)-5-methyl-[1,1'-biphenyl]-4-yl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0173] E31.10. The compound according to E31, which is 6-((3-cyclopropyl-5-fluoro-4'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0174] E31.11. The compound according to E31, which is 6-((4'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0175] E31.12. The compound according to E31, which is 6-((4'-(2-hydroxypropan-2-yl)-3-methyl-[1,1'-biphenyl]-4-yl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0176] E31.13. The compound according to E31, which is 6-((3-fluoro-4'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.

[0177] E31.14. The compound according to E31, which is 6-((3-fluoro-4'-(2-hydroxypropan-2-yl)-5-isobutoxy-[1,1'-biphenyl]-4-yl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.

[0178] E31.15. The compound according to E31, which is 6-(2-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-(methyl-d3)-2H-indazol-4-yl)-6-methylbenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.

[0179] E31.16. The compound according to E31, which is 6-(2-cyclopropyl-6-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-(methyl-d3)-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.

[0180] E31.17. The compound according to E31, which is 6-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)benzo[d][1,3]dioxol-5-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.

[0181] E31.18. The compound according to E31, which is 6-(2-fluoro-4-(7-(2-hydroxypropan-2-yl)benzo[d][1,3]dioxol-5-yl)-6-methylbenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0182] E31.19. The compound according to E31, which is 6-(2,6-difluoro-4-(4-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-6-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.

[0183] E31.20. The compound according to E31, which is 6-(2-fluoro-4-(4-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-6-yl)-6-methylbenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.

[0184] E31.21. The compound according to E31, which is 6-(2-fluoro-4-(4-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-6-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.

[0185] E31.22. The compound according to E31, which is 6-(4-(4-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-6-yl)-2-methylbenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.

[0186] E31.23. The compound according to E31, which is 6-(4-(4-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-6-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.

[0187] E31.24. The compound according to E31, which is 6-(2,6-difluoro-4-(6-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.

[0188] E31.25. The compound according to E31, which is 6-(2-fluoro-4-(6-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)-6-methylbenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.

[0189] E31.26. The compound according to E31, which is 6-(2-fluoro-4-(6-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.

[0190] E31.27. The compound according to E31, which is 6-(4-(6-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)-2-methylbenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.

[0191] E31.28. The compound according to E31, which is 6-(2,6-difluoro-4-(3-(2-hydroxypropan-2-yl)-1-methyl-1H-pyrazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.

[0192] E31.29. The compound according to E31, which is 6-(2-fluoro-4-(3-(2-hydroxypropan-2-yl)-1-methyl-1H-pyrazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.

[0193] E31.30. The compound according to E31, which is 6-(2-fluoro-4-(3-(2-hydroxypropan-2-yl)-1-methyl-1H-pyrazol-4-yl)-6-methylbenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.

[0194] E31.31. The compound according to E31, which is 6-(4-(3-(2-hydroxypropan-2-yl)-1-methyl-1H-pyrazol-4-yl)-2-methylbenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0195] E31.32. The compound according to E31, which is 6-(4-(3-(2-hydroxypropan-2-yl)-1-methyl-1H-pyrazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0196] E31.33. The compound according to E31, which is 6-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-5-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.

[0197] E31.34. The compound according to E31, which is 6-(2-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-5-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.

[0198] E31.35. The compound according to E31, which is 6-(4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-5-yl)-2-methylbenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0199] E31.36. The compound according to E31, which is 6-(4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-5-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0200] E31.37. The compound according to E31, which is 6-(2,6-difluoro-4-(5-(2-hydroxypropan-2-yl)quinolin-8-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.

[0201] E31.38. The compound according to E31, which is 6-(2,6-difluoro-4-(8-(2-hydroxypropan-2-yl)quinolin-5-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0202] E31.39. The compound according to E31, which is 6-(2,6-difluoro-4-(8-(2-hydroxypropan-2-yl)quinolin-6-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.

[0203] E31.40. The compound according to E31, which is 6-(2,6-difluoro-4-(6-(2-hydroxypropan-2-yl)-1-methyl-1H-indol-3-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.

[0204] E31.41. The compound according to E31, which is 6-(2-chloro-6-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-5-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.

[0205] E31.42. The compound according to E31, which is 6-(2,6-difluoro-4-(5-(2-hydroxypropan-2-yl)pyridin-3-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.

[0206] E31.43. The compound according to E31, which is 6-((3,5-difluoro-3'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0207] E31.44. The compound according to E31, which is 6-((3-fluoro-4'-(2-hydroxypropan-2-yl)-5-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0208] E31.45. The compound according to E31, which is 6-((3-chloro-5-fluoro-4'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.

[0209] E31.46. The compound according to E31, which is 6-((3,5-dichloro-4'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0210] E31.47. The compound according to E31, which is 6-((3,3',5,5'-tetrafluoro-4'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0211] E31.48. The compound according to E31, which is 6-((2',3,5,5'-tetrafluoro-4'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0212] E31.49. The compound according to E31, which is 6-((2,5-difluoro-4'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0213] E31.50. The compound according to E31, which is 6-(2-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-5-yl)-6-methylbenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0214] E31.51. The compound according to E31, which is 6-(2,6-difluoro-4-(6-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-3-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.

[0215] E31.52. The compound according to E31, which is 6-(2,6-difluoro-4-(6-(2-hydroxypropan-2-yl)-1-methyl-1H-indazol-3-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0216] E31.53. The compound according to E31, which is 6-(2-fluoro-4-(8-(2-hydroxypropan-2-yl)quinolin-5-yl)-6-methylbenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.

[0217] E31.54. The compound according to E31, which is 6-(2,6-difluoro-4-(7-(3-hydroxypentan-3-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.

[0218] E31.55. The compound according to E31, which is 6-(2-fluoro-4-(7-(3-hydroxypentan-3-yl)-2-methyl-2H-indazol-4-yl)-6-methylbenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.

[0219] E31.56. The compound according to E31, which is 6-((2',3,5-trifluoro-4'-(2-hydroxypropan-2-yl)-3'-methyl-[1,1'-biphenyl]-4-yl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0220] E31.57. The compound according to E31, which is 6-(2-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.

[0221] E31.58. The compound according to E31, which is 6-(4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)-2-methylbenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0222] E31.59. The compound according to E31, which is 6-(4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0223] E31.60. The compound according to E31, which is 6-(2-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)-6-methoxybenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.

[0224] E31.61. The compound according to E31, which is 6-(2-chloro-6-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.

[0225] E31.62. The compound according to E31, which is 6-(2,5-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.

[0226] E31.63. The compound according to E31, which is 6-(2,3-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.

[0227] E31.64. The compound according to E31, which is 6-(2,6-dichloro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.

[0228] E31.65. The compound according to E31, which is 6-(2-chloro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)-6-methylbenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.

[0229] E31.66. The compound according to E31, which is 6-(2-cyclopentyl-6-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.

[0230] E31.67. The compound according to E31, which is 6-(2-chloro-6-cyclopropyl-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0231] E31.68. The compound according to E31, which is 6-(2-cyclopropyl-6-fluoro-4-(3-(2-hydroxypropan-2-yl)-1-methyl-1H-pyrazol-5-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0232] E31.69. The compound according to E31, which is 6-(4-(3-(2-hydroxypropan-2-yl)-1-methyl-1H-pyrazol-5-yl)-2-methylbenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0233] E31.70. The compound according to E31, which is 6-(2-fluoro-4-(7-(3-hydroxypentan-3-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0234] E31.71. The compound according to E31, which is 6-(2,6-difluoro-4-(4-(2-hydroxypropan-2-yl)naphthalen-1-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0235] E31.72. The compound according to E31, which is 6-(2-fluoro-4-(4-(2-hydroxypropan-2-yl)naphthalen-1-yl)-6-methylbenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0236] E31.73. The compound according to E31, which is 6-(2-fluoro-4-(4-(2-hydroxypropan-2-yl)naphthalen-1-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0237] E31.74. The compound according to E31, which is 6-(2-fluoro-4-(5-(2-hydroxypropan-2-yl)-1H-benzo[d][1,2,3]triazol-7-yl)-6-methylbenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0238] E31.75. The compound according to E31, which is 6-(2-fluoro-4-(5-(2-hydroxypropan-2-yl)-1H-benzo[d][1,2,3]triazol-7-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0239] E31.76. The compound according to E31, which is 6-(2-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)-6-(trifluoromethyl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.

[0240] E31.77. The compound according to E31, which is 6-(2-(dimethylamino)-6-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.

[0241] E31.78. The compound according to E31, which is 6-(2-(azetidin-1-yl)-6-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0242] E31.79. The compound according to E31, which is 6-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-1-methyl-1H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.

[0243] E31.80. The compound according to E31, which is 6-(4-(7-(1-cyclopropyl-1-hydroxyethyl)-2-methyl-2H-indazol-4-yl)-2,6-difluorobenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0244] E31.81. The compound according to E31, which is 6-(2,6-difluoro-4-(2-methyl-7-(1,1,1-trifluoro-2-hydroxybutan-2-yl)-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0245] E31.82. The compound according to E31, which is 6-(2,6-difluoro-4-(7-(2-hydroxybutan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.

[0246] E31.83. The compound according to E31, which is 6-(2,6-difluoro-4-(5-(2-hydroxypropan-2-yl)-1H-benzo[d][1,2,3]triazol-7-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0247] E31.84. The compound according to E31, which is 6-(4-(7-(dicyclopropyl(hydroxy)methyl)-2-methyl-2H-indazol-4-yl)-2,6-difluorobenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0248] E31.85. The compound according to E31, which is 6-(4-(7-(dicyclopropyl(hydroxy)methyl)-2-methyl-2H-indazol-4-yl)-2-fluoro-6-methylbenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0249] E31.86. The compound according to E31, which is 6-(2,6-difluoro-4-(5-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-7-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.

[0250] E31.87. The compound according to E31, which is 6-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)benzo[d][1,3]dioxol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0251] E31.88. The compound according to E31, which is 6-(2-cyclopropyl-6-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-5-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0252] E31.89. The compound according to E31, which is 6-(2,6-difluoro-4-(7-(3-hydroxyoxetan-3-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0253] E31.90. The compound according to E31, which is 6-(2,6-difluoro-4-(7-(3-hydroxytetrahydrofuran-3-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0254] E31.91. The compound according to E31, which is 6-(2,6-difluoro-4-(7-(1-hydroxycyclopentyl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0255] E31.92. The compound according to E31, which is 6-(2,6-difluoro-4-(7-(4-hydroxytetrahydro-2H-pyran-4-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0256] E31.93. The compound according to E31, which is 6-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl-1,1,1,3,3,3-d6)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0257] E31.94. The compound according to E31, which is (R)-6-(1-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)phenyl)ethyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0258] E31.95. The compound according to E31, which is 6-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl-1,1,1-d3)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0259] E31.96. The compound according to E31, which is 6-(2,6-difluoro-4-(7-(1-hydroxycyclobutyl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0260] E31.97. The compound according to E31, which is 6-(2,6-difluoro-4-(7-(2-hydroxy-1-(methylsulfonyl)propan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0261] E31.98. The compound according to E31, which is (S)-6-(1-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)phenyl)ethyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0262] E31.99. The compound according to E31, which is 6-(4-(2-ethyl-7-(2-hydroxypropan-2-yl)-2H-indazol-4-yl)-2,6-difluorobenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0263] E31.100. The compound according to E31, which is 6-(4-(7-(1,1-difluoro-2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)-2,6-difluorobenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0264] E31.101. The compound according to E31, which is 4-(4-(3,5-difluoro-4-((5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)methyl)phenyl)-2-methyl-2H-indazol-7-yl)-4-hydroxycyclohexane-1-carbonitrile, or a pharmaceutically acceptable salt thereof.

[0265] E31.102. The compound according to E31, which is (R)-6-(2,6-difluoro-4-(7-(2-hydroxybutan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0266] E31.103. The compound according to E31, which is (S)-6-(2,6-difluoro-4-(7-(2-hydroxybutan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0267] E31.104. The compound according to E31, which is 6-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-isopropyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0268] E31.105. The compound according to E31, which is 6-(4-(7-(3,3-difluoro-1-hydroxycyclobutyl)-2-methyl-2H-indazol-4-yl)-2,6-difluorobenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0269] E31.106. The compound according to E31, which is 2-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-4-fluoroisoindolin-1-one, or a pharmaceutically acceptable salt thereof.

[0270] E31.107. The compound according to E31, which is 6-(2,6-difluoro-4-(2-(2-hydroxypropan-2-yl)pyrazolo[1,5-a]pyridin-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0271] E31.108. The compound according to E31, which is 6-(2,6-difluoro-4-(2-(2-hydroxypropan-2-yl)pyrazolo[1,5-a]pyridin-5-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0272] E31.109. The compound according to E31, which is 6-((5-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)pyrazin-2-yl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0273] E31.110. The compound according to E31, which is 6-((5-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)pyrimidin-2-yl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0274] E31.111. The compound according to E31, which is 6-((2-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)pyrimidin-5-yl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0275] E31.112. The compound according to E31, which is 6-((6-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)pyridazin-3-yl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0276] E31.113. The compound according to E31, which is tert-butyl 3-(4-(3,5-difluoro-4-((5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)methyl)phenyl)-2-methyl-2H-indazol-7-yl)-3-hydroxyazetidine-1-carboxylate, or a pharmaceutically acceptable salt thereof.

[0277] E31.114. The compound according to E31, which is 6-(2,6-difluoro-4-(7-(3-hydroxyazetidin-3-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0278] E31.115. The compound according to E31, which is 6-(2,6-difluoro-4-(5-(2-hydroxypropan-2-yl)-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-8-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0279] E31.116. The compound according to E31, which is 6-(2-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)-6-methoxybenzyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, or a pharmaceutically acceptable salt thereof.

[0280] E31.117. The compound according to E31, which is 6-((3,5-difluoro-4'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)methyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, or a pharmaceutically acceptable salt thereof.

[0281] E31.118. The compound according to E31, which is 6-((3-fluoro-4'-(2-hydroxypropan-2-yl)-5-methyl-[1,1'-biphenyl]-4-yl)methyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, or a pharmaceutically acceptable salt thereof.

[0282] E31.119. The compound according to E31, which is 6-((3-fluoro-4'-(2-hydroxypropan-2-yl)-5-methoxy-[1,1'-biphenyl]-4-yl)methyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, or a pharmaceutically acceptable salt thereof.

[0283] E31.120. The compound according to E31, which is 6-((3-chloro-5-fluoro-4'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)methyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, or a pharmaceutically acceptable salt thereof.

[0284] E31.121. The compound according to E31, which is 6-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, or a pharmaceutically acceptable salt thereof.

[0285] E31.122. The compound according to E31, which is 6-(2-chloro-6-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, or a pharmaceutically acceptable salt thereof.

[0286] E31.123. The compound according to E31, which is 6-(2-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)-6-methylbenzyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, or a pharmaceutically acceptable salt thereof.

[0287] E31.124. The compound according to E31, which is 6-((3-fluoro-5-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)pyridin-2-yl)methyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, or a pharmaceutically acceptable salt thereof.

[0288] E31.125. The compound according to E31, which is 6-(2-(dimethylamino)-6-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, or a pharmaceutically acceptable salt thereof.

[0289] E31.126. The compound according to E31, which is 6-(2-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)-6-(2-methoxyethoxy)benzyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, or a pharmaceutically acceptable salt thereof.

[0290] E31.127. The compound according to E31, which is 6-((3-fluoro-4'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)methyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, or a pharmaceutically acceptable salt thereof.

[0291] E31.128. The compound according to E31, which is 6-((4'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)methyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, or a pharmaceutically acceptable salt thereof.

[0292] E31.129. The compound according to E31, which is 6-((4'-(2-hydroxypropan-2-yl)-3-methyl-[1,1'-biphenyl]-4-yl)methyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, or a pharmaceutically acceptable salt thereof.

[0293] E31.130. The compound according to E31, which is 6-(2-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, or a pharmaceutically acceptable salt thereof.

[0294] E31.131. The compound according to E31, which is 6-(4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, or a pharmaceutically acceptable salt thereof.

[0295] E31.132. The compound according to E31, which is 6-(4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)-2-methylbenzyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, or a pharmaceutically acceptable salt thereof.

[0296] E31.133. The compound according to E31, which is 6-(2-cyclopropyl-6-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, or a pharmaceutically acceptable salt thereof.

[0297] E31.134. The compound according to E31, which is 6-(2-chloro-6-cyclopropyl-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, or a pharmaceutically acceptable salt thereof.

[0298] E31.135. The compound according to E31, which is 6-(2-(azetidin-1-yl)-6-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, or a pharmaceutically acceptable salt thereof.

[0299] E31.136. The compound according to E31, which is 6-(2-cyclopentyl-6-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, or a pharmaceutically acceptable salt thereof.

[0300] E31.137. The compound according to E31, which is 6-((3,5-difluoro-4'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one, or a pharmaceutically acceptable salt thereof.

[0301] E31.138. The compound according to E31, which is 6-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one, or a pharmaceutically acceptable salt thereof.

[0302] E31.139. The compound according to E31, which is 6-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one, or a pharmaceutically acceptable salt thereof.

[0303] E31.140. The compound according to E31, which is 2-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one, or a pharmaceutically acceptable salt thereof.

[0304] E31.141. The compound according to E31, which is 2-((3,5-difluoro-4'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)methyl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one, or a pharmaceutically acceptable salt thereof.

[0305] E31.142. The compound according to E31, which is 6-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one-7,7-d2, or a pharmaceutically acceptable salt thereof.

[0306] E31.143. The compound according to E31, which is 6-(2-cyclopropyl-6-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one-7,7-d2, or a pharmaceutically acceptable salt thereof.

[0307] E31.144. The compound according to E31, which is 6-(2-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)-6-methylbenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one-7,7-d2, or a pharmaceutically acceptable salt thereof.

[0308] E31.145. The compound according to E31, which is 6-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-(methyl-d3)-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one-7,7-d2, or a pharmaceutically acceptable salt thereof.

[0309] E31.146. The compound according to E31, which is 6-(2-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-(methyl-d3)-2H-indazol-4-yl)-6-methylbenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5one-7,7-d2, or a pharmaceutically acceptable salt thereof.

[0310] E31.147. The compound according to E31, which is 6-(2-cyclopropyl-6-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-(methyl-d3)-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one-7,7-d2, or a pharmaceutically acceptable salt thereof.

[0311] E31.148. The compound according to E31, which is 6-(2,5-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one-7,7-d2, or a pharmaceutically acceptable salt thereof.

[0312] E31.149. The compound according to E31, which is 6-(2,3-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one-7,7-d2, or a pharmaceutically acceptable salt thereof.

[0313] E31.150. The compound according to E31, which is 6-(2-chloro-6-cyclopropyl-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one-7,7-d2, or a pharmaceutically acceptable salt thereof.

[0314] E31.151. The compound according to E31, which is 6-(2-(azetidin-1-yl)-6-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one-7,7-d2, or a pharmaceutically acceptable salt thereof.

[0315] E31.152. The compound according to E31, which is 6-(2-cyclopentyl-6-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one-7,7-d2, or a pharmaceutically acceptable salt thereof.

[0316] E31.153. The compound according to E31, which is 6-(4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)-2-isopropylbenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one-7,7-d2, or a pharmaceutically acceptable salt thereof.

[0317] E31.154. The compound according to E31, which is 2-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-7-fluoroisoindolin-1-one; or a pharmaceutically acceptable salt thereof.

[0318] E31.155. The compound according to E31, which is 2-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-5-yl)benzyl)-7-fluoroisoindolin-1-one; or a pharmaceutically acceptable salt thereof.

[0319] E31.156. The compound according to E31, which is 2-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl-1,1,1,3,3,3-d6)-2-methyl-2H-indazol-4-yl)benzyl)-7-fluoroisoindolin-1-one, or a pharmaceutically acceptable salt thereof.

[0320] E31.157. The compound according to E31, which is 2-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-1-methyl-1H-indazol-4-yl)benzyl)-7-fluoroisoindolin-1-one; or a pharmaceutically acceptable salt thereof.

[0321] E31.158. The compound according to E31, which is 2-(4-(7-(1,1-difluoro-2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)-2,6-difluorobenzyl)-7-fluoroisoindolin-1-one, or a pharmaceutically acceptable salt thereof.

[0322] E31.159. The compound according to E31, which is 2-(2,6-difluoro-4-(7-(3-hydroxyoxetan-3-yl)-2-methyl-2H-indazol-4-yl)benzyl)-7-fluoroisoindolin-1-one, or a pharmaceutically acceptable salt thereof.

[0323] E31.160. The compound according to E31, which is 7-fluoro-2-(2-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)isoindolin-1-one, or a pharmaceutically acceptable salt thereof.

[0324] E31.161. The compound according to E31, which is 7-fluoro-2-(4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)-2-methylbenzyl)isoindolin-1-one; or a pharmaceutically acceptable salt thereof.

[0325] E31.162. The compound according to E31, which is 7-fluoro-2-(2-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)-6-methylbenzyl)isoindolin-1-one, or a pharmaceutically acceptable salt thereof.

[0326] E31.163. The compound according to E31, which is 2-(2,5-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-7-fluoroisoindolin-1-one, or a pharmaceutically acceptable salt thereof.

[0327] E31.164. The compound according to E31, which is 2-(2,3-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-7-fluoroisoindolin-1-one; or a pharmaceutically acceptable salt thereof.

[0328] E31.165. The compound according to E31, which is 2-(2-chloro-6-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-7-fluoroisoindolin-1-one; or a pharmaceutically acceptable salt thereof.

[0329] E31.166. The compound according to E31, which is 7-fluoro-2-(2-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-5-yl)benzyl)isoindolin-1-one; or a pharmaceutically acceptable salt thereof.

[0330] E31.167. The compound according to E31, which is 7-fluoro-2-(4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-5-yl)-2-methylbenzyl)isoindolin-1-one, or a pharmaceutically acceptable salt thereof.

[0331] E31.168. The compound according to E31, which is 7-fluoro-2-(2-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-5-yl)-6-methylbenzyl)isoindolin-1-one, or a pharmaceutically acceptable salt thereof.

[0332] E31.169. The compound according to E31, which is 2-(2,5-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-5-yl)benzyl)-7-fluoroisoindolin-1-one, or a pharmaceutically acceptable salt thereof.

[0333] E31.170. The compound according to E31, which is 2-(2,3-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-5-yl)benzyl)-7-fluoroisoindolin-1-one, or a pharmaceutically acceptable salt thereof.

[0334] E31.171. The compound according to E31, which is 2-(2-chloro-6-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-5-yl)benzyl)-7-fluoroisoindolin-1-one; or a pharmaceutically acceptable salt thereof.

[0335] E31.172. The compound according to E31, which is 2-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)isoindolin-1-one, or a pharmaceutically acceptable salt thereof.

[0336] E31.173. The compound according to E31, which is 3-bromo-6-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0337] E31.174. The compound according to E31, which is 6-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.

[0338] E31.175. The compound according to E31, which is 3-cyclopropyl-6-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0339] E31.176. The compound according to E31, which is 6-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-3-ethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.

[0340] E31.177. The compound according to E31, which is 6-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-3-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.

[0341] E32. 6-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)-6-methylbenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2-cyclopropyl-6-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-(methyl-d3)-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-(methyl-d3)-2H-indazol-4-yl)-6-methylbenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2-chloro-6-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2,6-difluoro-4-(7-(4-hydroxytetrahydro-2H-pyran-4-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl-1,1,1-d3)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; and 6-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one-7,7-d2 or a pharmaceutically acceptable salt thereof.

[0342] E33. The compound according to any one of E1 to E32, or a pharmaceutically acceptable salt thereof, having at least 50% deuterium incorporation at each deuterium label.

[0343] E33.1. A compound according to E33, or a pharmaceutically acceptable salt thereof, having at least 75% deuterium incorporation at each deuterium label.

[0344] E33.2. A compound according to E33 or E33.1, or a pharmaceutically acceptable salt thereof, having at least 90% deuterium incorporation at each deuterium label.

[0345] E33.3. A compound according to any one of E33 to E33.2, or a pharmaceutically acceptable salt thereof, having at least 99% deuterium incorporation at each deuterium label.

[0346] E33.4. A compound according to any one of E33 to E33.3, or a pharmaceutically acceptable salt thereof, having a deuterium incorporation of at least 99.5% at each deuterium label.

[0347] E34. A hydrate, solvate, polymorph, or prodrug of a compound according to any one of E1 to E33.4, or a pharmaceutically acceptable salt thereof.

[0348] E35. A pharmaceutical composition comprising a compound, hydrate, solvate, polymorph, or prodrug according to any one of E1 to E34, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0349] E36. A method for treating a disorder associated with muscarinic acetylcholine receptor activity in a mammal, comprising administering to the mammal an effective amount of a compound, hydrate, solvate, polymorph, or prodrug described in any of E1-E34, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in E35.

[0350] E37. The method of E36, wherein the mammal is a human.

[0351] E38. The method of E36 or E37, wherein the muscarinic acetylcholine receptor is mAChR M1.

[0352] E39. The method of any of E36-E38, wherein the mammal has been diagnosed with a disorder in need of treatment prior to the administering step.

[0353] E40. The method of any of E36-E39, further comprising the step of identifying a mammal in need of treatment for the disorder.

[0354] E41. The method according to any one of E36 to E40, wherein the disorder is a neurological disorder or a psychiatric disorder, or a combination thereof.

[0355] E42. The method of any of E36-E41, wherein the disorder is psychosis, schizophrenia, conduct disorder, disruptive behavior disorder, bipolar disorder, psychotic episode of anxiety, anxiety associated with psychosis, psychotic mood disorder, severe major depressive disorder, mood disorder associated with psychotic disorder, acute mania, depression associated with bipolar disorder, mood disorder associated with schizophrenia, behavioral signs of mental retardation, conduct disorder, autistic disorder, movement disorder, Tourette's syndrome, akinetic-rigid syndrome, movement disorder associated with Parkinson's disease, tardive dyskinesia, drug-induced and neurodegenerative-based dyskinesia, attention deficit hyperactivity disorder, cognitive impairment, dementia, or memory impairment, or a combination thereof.

[0356] E43. The method of any of E36-E41, wherein the disorder is Alzheimer's disease, schizophrenia, a sleep disorder, a pain disorder, or a cognitive disorder, or a combination thereof.

[0357] E44. The method of E43, wherein the pain disorder is neuropathic pain, central pain syndrome, post-operative pain syndrome, bone and joint pain, repetitive motion pain, dental pain, cancer pain, myofascial pain, perioperative pain, chronic pain, dysmenorrhea, inflammatory pain, headache, migraine, cluster headache, headache, primary hyperalgesia, secondary hyperalgesia, primary allodynia, secondary allodynia, or a combination thereof.

[0358] E45. A compound, hydrate, solvate, polymorph, or prodrug according to any of E1-E34, or a pharmaceutically acceptable salt thereof, or a composition according to E35, for use in treating a disorder associated with muscarinic acetylcholine receptor activity in a mammal.

[0359] E46. Use of a compound, hydrate, solvate, polymorph, or prodrug according to any of E1-E34, or a pharmaceutically acceptable salt thereof, or a composition according to E35, for the preparation of a medicament for the treatment of a disorder associated with muscarinic acetylcholine receptor activity in a mammal.

[0360] Compound names and / or structures can be assigned / determined by using the Struct=Name naming algorithm as part of CHEMDRAW®, version 19.1 or 20.0.

[0361] Compounds may exist as stereoisomers where asymmetric or chiral centers are present. Stereoisomers are "R" or "S" depending on the configuration of substituents around a chiral carbon atom. As used herein, the terms "R" and "S" refer to configurations as defined in the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, in Pure Appl. Chem., 1976, 45:13-30. The present disclosure contemplates various stereoisomers and mixtures thereof, which are expressly included within the scope of the present invention. Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or diastereomers. In compounds of Formula (I), when a specific configuration is not indicated at a chiral center (e.g., carbon), the compound includes all possible stereoisomers.

[0362] Individual stereoisomers of this compound can be prepared from commercially available starting materials containing asymmetric or chiral centers by synthesis or by preparation of a racemic mixture followed by resolution methods well known to those skilled in the art. These resolution methods are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography, and optional liberation of the optically pure product from the auxiliary (as described in Furniss, Hannaford, Smith, and Tatchell, "Vogel's Textbook of Practical Organic Chemistry," 5th edition (1989), Longman Scientific & Technical, Essex CM20 2JE, England), or (2) direct separation of a mixture of optical enantiomers on a chiral chromatography column, or (3) fractional recrystallization methods.

[0363] It is to be understood that the compounds may have tautomeric forms as well as geometric isomers which also constitute embodiments of the present disclosure.

[0364] In the compounds of formula (I), and any subformula, any "hydrogen" or "H", whether explicitly stated or implicit in the structure, is a hydrogen isotope. 1 H (protium) and 2 Includes H (deuterium).

[0365] The present disclosure also includes isotopically labeled compounds (e.g., deuterium labeled), where an atom in an isotopically labeled compound is identified as a particular isotope of the atom. Examples of isotopes suitable for inclusion in compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, including, but not limited to, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, respectively. 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F and 36 Examples include Cl.

[0366] Isotopically enriched forms of compounds of formula (I), or any subformula, may generally be prepared by conventional techniques known to those skilled in the art, or by processes similar to those described in the accompanying Examples, substituting an appropriate isotopically enriched reagent for a non-isotopically enriched reagent. The degree of isotopic enrichment may be characterized as the percent incorporation of a particular isotope at an isotopically labeled atom (e.g., % deuterium incorporation in a deuterium-labeled atom).

[0367] The disclosed compounds can exist as pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to a water- or oil-soluble or dispersible salt or zwitterion of the compound suitable for treating disorders without undue toxicity, irritation, or allergic reactions, at a reasonable benefit / risk ratio and effective for its intended use. These salts can be prepared during the final isolation and purification of the compound or separately by reacting the amino group of the compound with a suitable acid. For example, the compound can be dissolved in a suitable solvent, such as, but not limited to, methanol and water, and treated with at least one acid equivalent, such as hydrochloric acid. The resulting salt can be precipitated, isolated by filtration, and dried under reduced pressure. Alternatively, the solvent and excess acid can be removed under reduced pressure to provide the salt. Representative salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, isethionate, fumarate, lactate, maleate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, oxalate, maleate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, glutamate, para-toluenesulfonate, undecanoate, hydrochloride, hydrobromide, sulfate, phosphate, and the like. The amino groups of the compounds can also be quaternized with alkyl chlorides, bromides and iodides such as methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, stearyl, and the like.

[0368] Base addition salts can be prepared during the final isolation and purification of the disclosed compounds by reaction of the carboxyl group with a suitable base, such as the hydroxide, carbonate, or bicarbonate of a metal cation, such as lithium, sodium, potassium, calcium, magnesium, or aluminum, or a primary, secondary, or tertiary organic amine. Quaternary amine salts can also be prepared, such as those derived from methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, and N,N'-dibenzylethylenediamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like.

[0369] 3. Pharmaceutical Compositions The disclosed compounds can be incorporated into pharmaceutical compositions suitable for administration to a subject (such as a patient, which can be human or non-human). The disclosed compounds can also be provided as a formulation, such as a spray-dried dispersion formulation.

[0370] These pharmaceutical compositions and formulations may contain a "therapeutically effective amount" or a "prophylactically effective amount" of the agent. A "therapeutically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. The therapeutically effective amount of the composition can be determined by one of ordinary skill in the art and may vary depending on factors such as the individual's disease state, age, sex, and weight, and the ability of the composition to elicit a desired response in the individual. A therapeutically effective amount is also an amount in which the therapeutically beneficial effects of any of the compounds of the present invention (e.g., Formula (I)) outweigh any toxic or harmful effects. A "prophylactically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Generally, since a prophylactic dose is used in subjects prior to or at an early stage of disease, the prophylactically effective amount will be lower than the therapeutically effective amount.

[0371] For example, a therapeutically effective amount of a compound of formula (I) may be from about 1 mg / kg to about 1000 mg / kg, from about 5 mg / kg to about 950 mg / kg, from about 10 mg / kg to about 900 mg / kg, from about 15 mg / kg to about 850 mg / kg, from about 20 mg / kg to about 800 mg / kg, from about 25 mg / kg to about 750 mg / kg, from about 30 mg / kg to about 700 mg / kg, from about 35 mg / kg to about 650 mg / kg, from about 40 mg / kg to about 600 mg / kg, from about 45 mg / kg to about 650 mg / kg, from about 50 mg / kg to about 550 mg / kg, from about 60 mg / kg to about 650 mg / kg, from about 70 mg / kg to about 750 mg / kg, from about 80 mg / kg to about 850 mg / kg, from about 90 mg / kg to about 950 mg / kg, from about 90 mg / kg to about 950 mg / kg, from about 100 mg / kg to about 1000 mg / kg, from about 150 mg / kg to about 15 ... The dose may be from about 500 mg / kg to about 550 mg / kg, from about 50 mg / kg to about 500 mg / kg, from about 55 mg / kg to about 450 mg / kg, from about 60 mg / kg to about 400 mg / kg, from about 65 mg / kg to about 350 mg / kg, from about 70 mg / kg to about 300 mg / kg, from about 75 mg / kg to about 250 mg / kg, from about 80 mg / kg to about 200 mg / kg, from about 85 mg / kg to about 150 mg / kg, and from about 90 mg / kg to about 100 mg / kg.

[0372] The pharmaceutical compositions and formulations may include a pharmaceutically acceptable carrier. As used herein, the term "pharmaceutically acceptable carrier" refers to any type of non-toxic, inert solid, semi-solid, or liquid filler, diluent, encapsulating material, or formulation auxiliary. Some examples of materials that can serve as pharmaceutically acceptable carriers include sugars, such as, but not limited to, lactose, glucose, and sucrose; starches, such as, but not limited to, corn starch and potato starch; cellulose and its derivatives, such as, but not limited to, sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as, but not limited to, cocoa butter and suppository wax; oils, such as, but not limited to, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols; for example, propylene glycol; esters, for example, but not limited to, ethyl oleate and ethyl laurate; agar; buffers, for example, but not limited to, magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol and phosphate buffer; and other non-toxic compatible lubricants, for example, but not limited to, sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

[0373] Thus, the compounds and their physiologically acceptable salts and solvents can be formulated, for example, in solid dosages, eye drops, oil-based topical preparations, by injection, inhalation (through the mouth or nose), administration by implant, or for oral, buccal, parenteral, or rectal administration. Techniques and formulations can generally be found in "Remington's Pharmaceutical Sciences" (Meade Publishing Co., Easton, Pa.). Therapeutic compositions generally must be sterile and stable under the conditions of manufacture and storage.

[0374] The route by which the disclosed compounds are administered and the form of the composition will determine the type of carrier used, which may be in a variety of forms suitable for, for example, systemic administration (e.g., oral, rectal, nasal, sublingual, buccal, implanted, or parenteral) or topical administration (e.g., skin, lung, nose, ear, eye, liposome delivery system, or iontophoresis).

[0375] Carriers for systemic administration generally include at least one diluent, lubricant, binder, disintegrant, colorant, flavor, sweetener, antioxidant, preservative, flow agent, solvent, suspending agent, wetting agent, surfactant, combinations thereof, etc. All carriers are optional within the composition.

[0376] Suitable diluents include sugars such as glucose, lactose, dextrose, and sucrose; diols such as propylene glycol; calcium carbonate; sodium carbonate; sugar alcohols such as glycerin; mannitol; and sorbitol. The amount of diluent in a systemic or topical composition is generally about 50 to about 90%.

[0377] Suitable lubricants include silica, talc, stearic acid and its magnesium and calcium salts, calcium sulfate; and liquid lubricants such as polyethylene glycol and vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and cocoa oil. The amount of lubricant in a systemic or topical composition is generally about 5 to about 10%.

[0378] Suitable binders include polyvinylpyrrolidone, magnesium aluminum silicate, starches such as corn starch and potato starch, gelatin, tragacanth, and cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, methylcellulose, microcrystalline cellulose, and sodium carboxymethylcellulose. The amount of binder in a systemic composition is generally about 5 to about 50%.

[0379] Suitable disintegrants include agar, alginic acid and its sodium salt, effervescent mixtures, croscarmellose, crospovidone, sodium carboxymethyl starch, sodium starch glycolate, clays, and ion exchange resins. The amount of disintegrant in a systemic or topical composition is generally about 0.1 to about 10%.

[0380] Suitable coloring agents include coloring agents such as the FD&C dyes. If used, the amount of coloring agent in a systemic or topical composition is generally about 0.005 to about 0.1%.

[0381] Suitable flavors include menthol, peppermint, and fruit flavors. If used, the amount of flavor in a systemic or topical composition is generally about 0.1 to about 1.0%.

[0382] Suitable sweeteners include aspartame and saccharin. The amount of sweetener in a systemic or topical composition is generally from about 0.001 to about 1%.

[0383] Suitable antioxidants include butylhydroxyanisole ("BHA"), butylhydroxytoluene ("BHT"), and vitamin E. The amount of antioxidant in a systemic or topical composition is generally from about 0.1 to about 5%.

[0384] Suitable preservatives include benzalkonium chloride, methylparaben, and sodium benzoate. The amount of preservative in a systemic or topical composition is generally from about 0.01 to about 5%.

[0385] Suitable glidants include silicon dioxide. The amount of glidant in a systemic or topical composition is generally about 1 to about 5%.

[0386] Suitable solvents include water, isotonic saline, ethyl oleate, glycerin, castor oil hydroxide, alcohols such as ethanol, and phosphate buffers. The amount of solvent in a systemic or topical composition is generally from about 0 to about 100%.

[0387] Suitable suspending agents include AVICEL RC-591 (from FMC Corporation of Philadelphia, PA) and sodium alginate. The amount of suspending agent in a systemic or topical composition is generally about 1 to about 8%.

[0388] Suitable surfactants include lecithin, polysorbate 80, and sodium lauryl sulfate, and TWEENS (from Atlas Powder Company of Wilmington, Delaware). Suitable surfactants include those disclosed in CTFA Cosmetic Ingredient Handbook, 1992, pp. 587-592; Remington's Pharmaceutical Sciences, 15th Ed. 1975, pp. 335-337; and McCutcheon's Volume 1, Emulsifiers & Detergents, 1994, North American Edition, pp. 236-239. The amount of surfactant in a systemic or topical composition is generally about 0.1% to about 5%.

[0389] The amounts of components in a systemic composition may vary depending on the type of systemic composition being prepared, but generally, a systemic composition will contain 0.01% to 50% of an active compound (e.g., a compound of Formula (I)) and 50% to 99.99% of one or more carriers. Compositions for parenteral administration generally contain 0.1% to 10% of an active substance and 90% to 99.9% of a carrier (including diluents and solvents).

[0390] Compositions for oral administration can be in various dosage forms. For example, solid dosage forms include tablets, capsules, granules, and bulk powders. These oral dosage forms contain a safe and effective amount of an active ingredient, typically at least about 5%, more specifically about 25% to about 50%. These oral dosage compositions contain about 50% to about 95%, more specifically about 50% to about 75%, of a carrier.

[0391] Tablets can be compressed, tablet triturated, enteric coated, sugar coated, film coated, or multiple compressed. Tablets generally contain an active ingredient and a carrier containing components selected from diluents, lubricants, binders, disintegrants, colorants, flavors, sweeteners, flow agents, and combinations thereof. Specific diluents include calcium carbonate, sodium carbonate, mannitol, lactose, and cellulose. Specific binders include starch, gelatin, and sucrose. Specific disintegrants include alginic acid and croscarmellose. Specific lubricants include magnesium stearate, stearic acid, and talc. Specific coloring agents are FD&C dyes, which can be added for appearance. Chewable tablets preferably contain sweeteners such as aspartame and saccharin, or flavors such as menthol, peppermint, and fruit flavors, or combinations thereof.

[0392] Capsules (including implants, sustained-release, and sustained release formulations) generally contain an active compound (e.g., a compound of Formula (I)) and a carrier comprising one or more diluents disclosed above in a gelatin-containing capsule. Granules generally contain a disclosed compound and preferably a glidant, such as silicon dioxide, to improve flow properties. Implants can be biodegradable or non-biodegradable.

[0393] The selection of ingredients in a carrier for an oral composition depends on secondary considerations such as taste, cost, and shelf stability, which are not critical for purposes of this invention.

[0394] The solid compositions can be coated by conventional methods, typically with pH or time-dependent coatings, to release the disclosed compounds in the gastrointestinal tract or near the desired site of application, or at various locations and times to maintain the desired effect. The coatings typically include one or more components selected from the group consisting of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate, ethylcellulose, EUDRAGIT® coating (available from Evonik Industries of Essen, Germany), wax, and shellac.

[0395] The composition for oral administration can be in liquid form. For example, suitable liquid forms include aqueous solutions, emulsions, suspensions, solutions reconstituted from non-effervescent granules, suspensions reconstituted from non-effervescent granules, effervescent preparations reconstituted from effervescent granules, elixirs, tinctures, syrups, etc. The liquid composition for oral administration generally comprises the disclosed compound and a carrier, i.e., a carrier selected from diluents, colorants, flavorants, sweeteners, preservatives, solvents, suspending agents, and surfactants. The oral liquid composition preferably comprises one or more components selected from colorants, flavorants, and sweeteners.

[0396] Other compositions useful for achieving systemic delivery of target compounds include sublingual, buccal and nasal dosage forms.These compositions generally comprise one or more soluble fillers, such as diluents including sucrose, sorbitol and mannitol; and binders such as gum arabic, microcrystalline cellulose, carboxymethylcellulose and hydroxypropylmethylcellulose.These compositions can also comprise lubricants, colorants, flavors, sweeteners, antioxidants and flow agents.

[0397] The disclosed compounds can be administered topically. Topical compositions that can be applied topically to the skin can be in any form, including solids, solutions, oils, creams, ointments, gels, lotions, shampoos, leave-in and rinse-off hair conditioners, emulsions, cleansers, moisturizers, sprays, skin patches, etc. The topical composition comprises the disclosed compound (e.g., a compound of Formula (I)) and a carrier. The carrier of the topical composition preferably facilitates penetration of the compound into the skin. The carrier may further comprise one or more optional components.

[0398] The amount of carrier used with the disclosed compound is sufficient to provide a useful amount of the composition for administration per unit dose of the compound. Techniques and compositions for making dosage forms useful in the methods of the present invention are described in the following references: Modern Pharmaceutics, Chapters 9 and 10, Banker & Rhodes, eds. (1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms, 2nd Ed., (1976).

[0399] The carrier may comprise a single component or a combination of two or more components. In topical compositions, the carrier comprises a topical carrier. Suitable topical carriers include one or more components selected from phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols, symmetrical alcohols, aloe vera gel, allantoin, glycerin, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 myristyl propionate, dimethyl isosorbide, castor oil, and combinations thereof. More specifically, carriers for skin application include propylene glycol, dimethyl isosorbide, and water, more specifically phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols, and symmetrical alcohols.

[0400] The carrier of the topical composition may further include one or more ingredients selected from emollients, propellants, solvents, humectants, thickeners, powders, fragrances, dyes, and preservatives, all of which are optional.

[0401] Suitable emollients include stearyl alcohol, glyceryl monoricinoleate, glyceryl monostearate, propane-1,2-diol, butane-1,3-diol, mink oil, cetyl alcohol, isopropyl isostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecane-2-ol, isocetyl alcohol, cetyl palmitate, sebacillus acidophilus, sorbitan ol ... Examples of emollients for topical use include di-n-butyl phosphate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, peanut oil, castor oil, acetylated lanolin alcohol, petroleum oil, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, myristyl myristate, and combinations thereof. Specific emollients for skin include stearyl alcohol and polydimethylsiloxane. The amount of emollient in topical compositions for skin applications is generally about 5% to about 95%.

[0402] Suitable propellants include propane, butane, isobutane, dimethyl ether, carbon dioxide, nitrous oxide, and combinations thereof. The amount of propellant in a topical composition is generally from about 0% to about 95%.

[0403] Suitable solvents include water, ethyl alcohol, methylene chloride, isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, and combinations thereof. Specific solvents include ethyl alcohol and homotopic alcohols. The amount of solvent in a topical composition is generally about 0% to about 95%.

[0404] Suitable humectants include glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate, gelatin, and combinations thereof. Specific humectants include glycerin. The amount of humectant in a topical composition is generally 0% to 95%.

[0405] The amount of thickener in a topical composition is generally from about 0% to about 95%.

[0406] Suitable powders include beta-cyclodextrin, hydroxypropyl cyclodextrin, chalk, talc, Fuller's earth, kaolin, starch, gum, colloidal silicon dioxide, sodium polyacrylate, tetraalkylammonium smectite, trialkylarylammonium smectite, chemically modified magnesium aluminum silicate, organically modified montmorillonite clay, hydrated aluminum silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethylcellulose, ethylene glycol monostearate, and combinations thereof. The amount of powder in a topical composition is generally 0% to 95%.

[0407] The amount of fragrance in the topical composition is generally from about 0% to about 0.5%, particularly from about 0.001% to about 0.1%.

[0408] Suitable pH-adjusting additives include HCl or NaOH in an amount sufficient to adjust the pH of the topical pharmaceutical composition.

[0409] a. Spray-dried dispersion formulation The disclosed compounds can be formulated as spray-dried dispersions (SDDs). SDDs are single-phase, amorphous molecular dispersions of a drug in a polymer matrix. They are solid solutions containing the compound molecularly "dissolved" in a solid matrix. SDDs are obtained by dissolving the drug and polymer in an organic solvent and then spray-drying the solution. The use of spray drying for pharmaceutical applications can result in amorphous dispersions with increased solubility of Biopharmaceutical Classification System (BCS) Class II (high permeability, low solubility) and Class IV (low permeability, low solubility) drugs. Formulation and operating conditions are selected so that the solvent evaporates rapidly from the droplets, providing insufficient time for phase separation or crystallization. SDDs exhibit long-term stability and manufacturability. For example, SDDs have demonstrated a shelf life of more than two years. Advantages of SDD include, but are not limited to, enhanced oral bioavailability of poorly water-soluble compounds, delivery using conventional solid dosage forms (e.g., tablets and capsules), a reproducible, controllable, and scalable manufacturing process, and broad applicability to structurally diverse insoluble compounds with a wide range of physical properties.

[0410] Thus, in one embodiment, the present disclosure may provide a spray-dried dispersion formulation comprising a compound of formula (I).

[0411] 4. Therapeutic Uses and Methods The disclosed compounds are positive allosteric modulators of mAChR M1. Thus, through positive allosteric modulation, the compounds indirectly activate the muscarinic receptor subtype M1. In one embodiment, the disclosed compounds enhance the agonist response (e.g., acetylcholine) of mAChR M1. In a further embodiment, the disclosed compounds increase the mAChR M1 response to a non-maximal concentration of an agonist in the presence of the compound compared to the response to the agonist in the absence of the compound. Enhancement of mAChR M1 activity can be demonstrated by methodologies known in the art. For example, activation of mAChR M1 activity can be demonstrated by Ca 2+ Positive allosteric modulator activity can be determined by measuring calcium flux in response to an agonist, e.g., acetylcholine, in cells loaded with a sensitive fluorescent dye (e.g., Fluo-4). In a further embodiment, calcium flux was measured as an increase in the fluorescence resting ratio. In yet a further embodiment, positive allosteric modulator activity is measured by measuring the EC 20 The concentration-dependent increase in the acetylcholine response (ie, the response of mAChR M1 at a concentration of acetylcholine that produces 20% of the maximal response) was analyzed.

[0412] In one embodiment, the disclosed compounds can activate a mAChR M1 response as an increase in calcium fluorescence in mAChR M1-transfected CHO-K1 cells in the presence of the compound compared to the response of comparable CHO-K1 cells in the absence of the compound. For example, the disclosed compounds can have an EC of less than or equal to 10 μM, less than or equal to 5 μM, less than or equal to 2.5 μM, less than or equal to 1 μM, less than or equal to 500 nM, less than or equal to 250 nM, less than or equal to 100 nM, or less than or equal to 50 nM. 50In one embodiment, the mAChR M1-transfected CHO-K1 cells are transfected with human mAChR M1. In another embodiment, the mAChR M1-transfected CHO-K1 cells are transfected with rat mAChR M1.

[0413] In one embodiment, the disclosed compounds exhibit weak or substantially no agonist activation of the mAChR M1 response (i.e., lack of activation in the absence of a known agonist, e.g., acetylcholine). The lack of agonist activity can be measured as a weak or no increase in calcium fluorescence in mAChR M1-transfected CHO-K1 cells in the presence of the compound compared to the response of comparable CHO-K1 cells in the absence of the compound. The lack of mAChR M1 agonist activity can be determined as a percent response to acetylcholine. For example, the disclosed compounds can have mAChR M1 agonist activity to acetylcholine that is equal to or less than 30%, equal to or less than 25%, equal to or less than 20%, equal to or less than 15%, equal to or less than 10%, equal to or less than 5%, or equal to or less than 1%. The disclosed compounds can have substantially no mAChR M1 agonist activity. In further embodiments, the disclosed compounds exhibit positive allosteric modulation of the mAChR M1 response to acetylcholine as described herein at concentrations that have weak or substantially no agonist activity as described herein. The absence of mAChR M1 agonist activity may contribute to a reduction in the likelihood of adverse cholinergic effects.

[0414] In one embodiment, the disclosed compounds exhibit an enhanced mAChR M1 response to acetylcholine, as an increase in response to a non-maximal concentration of acetylcholine in mammalian mAChR M1-transfected CHO-K1 cells in the presence of the compound compared to the response to acetylcholine in the absence of the compound. For example, CHO-K1 cells can be transfected with human mAChR M1. For example, CHO-K1 cells can be transfected with rat mAChR M1. For example, the compound has an EC of less than or equal to 10 μM, less than or equal to 5 μM, less than or equal to 2.5 μM, less than or equal to 1 μM, less than or equal to 500 nM, less than or equal to 250 nM, or less than or equal to 100 nM. 50 The disclosed compounds can exhibit positive allosteric modulation of mAChR M1 at concentrations greater than or equal to 10 μM, less than or equal to 5 μM, less than or equal to 2.5 μM, less than or equal to 1 μM, less than or equal to 500 nM, less than or equal to 250 nM, less than or equal to 100 nM, or less than or equal to 50 nM. Alternatively, the disclosed compounds exhibit an enhancement of the mAChR M1 response to acetylcholine as an increase in response to non-maximal concentrations of acetylcholine in CHO-K1 cells transfected with human mAChR M1 in the presence of the compound compared to the response to acetylcholine in the absence of the compound. For example, the compounds can exhibit an EC 50 Thus, positive allosteric regulation of mAChR M1 can be demonstrated.

[0415] In one embodiment, the disclosed compounds exhibit positive allosteric modulation of the mAChR M1 response to acetylcholine as an increase in response to a non-maximal concentration of acetylcholine in mAChR M1-transfected CHO-K1 cells in the presence of the compound compared to the response to acetylcholine in the absence of the compound. For example, the disclosed compounds have an EC50 of less than or equal to 10 μM, less than or equal to 5 μM, less than or equal to 2.5 μM, less than or equal to 1 μM, less than or equal to 500 nM, less than or equal to 250 nM, or less than or equal to 100 nM. 50 In one embodiment, the EC 200 for positive allosteric modulation can be used to measure the mAChR M1 response to acetylcholine. 50 is determined in CHO-K1 cells transfected with mAChR M1. In another embodiment, the CHO-K1 cells are transfected with human mAChR M1. In another embodiment, the CHO-K1 cells are transfected with rat mAChR M1.

[0416] EC50 of less than or equal to 0.5 μM, less than or equal to 0.25 μM, or less than or equal to 0.1 μM 50 All positive allosteric modulation of the mAChR M1 response to acetylcholine at 1000 kJ / s is considered to be a potent positive allosteric modulatory activity.

[0417] In one embodiment, the compound has an EC 0.1 or EC 1.2 or EC 1.3 or EC 1.4 or EC 1.5 or EC 1.6 or EC 1.7 or EC 1.8 or EC 1.9 or EC 1.9 or EC 1.1 or EC 1.2 or EC 1.4 or EC 1.5 or EC 1.5 or EC 1.5 or EC 1.6 or EC 1.7 or EC 1.8 or EC 1.9 or EC 1.5 ... 50 Less than EC 50can activate the mAChR M1 response in mAChR M1-transfected CHO-K1 cells. That is, the disclosed compounds can have selectivity for the mAChR M1 receptor over one or more of the mAChR M2, M3, M4, or M5 receptors. For example, the disclosed compounds can have an EC that is at least 5-fold lower than for mAChR M2, at least 10-fold lower than for mAChR M2, at least 20-fold lower than for mAChR M2, at least 30-fold lower than for mAChR M2, at least 50-fold lower than for mAChR M2, or at least 100-fold lower than for mAChR M2. 50 In another embodiment, the disclosed compounds have an EC that is at least 5-fold lower than that for mAChR M3, at least 10-fold lower than that for mAChR M3, at least 20-fold lower than that for M3, at least 30-fold lower than that for mAChR M3, at least 50-fold lower than that for mAChR M3, or at least 100-fold lower than that for mAChR M3. 50 In another embodiment, the disclosed compounds have an EC that is at least 5-fold lower than that for mAChR M4, at least 10-fold lower than that for mAChR M4, at least 20-fold lower than that for M4, at least 30-fold lower than that for mAChR M4, at least 50-fold lower than that for mAChR M4, or at least 100-fold lower than that for mAChR M4. 50 In another embodiment, the disclosed compounds have an EC50 that is at least 5-fold lower than that for mAChR M5, at least 10-fold lower than that for mAChR M5, at least 20-fold lower than that for mAChR M5, at least 30-fold lower than that for mAChR M5, at least 50-fold lower than that for mAChR M5, or at least 100-fold lower than that for mAChR M5. 50In another embodiment, the disclosed compounds have an EC that is at least 5-fold lower than for the mAChR M2, M3, M4, or M5 receptor, at least 10-fold lower than for the mAChR M2, M3, M4, or M5 receptor, at least 20-fold lower than for the mAChR M2, M3, M4, or M5 receptor, at least 30-fold lower than for the mAChR M2, M3, M4, or M5 receptor, at least 50-fold lower than for the mAChR M2, M3, M4, or M5 receptor, or at least 100-fold lower than for the mAChR M2, M3, M4, or M5 receptor. 50 In another embodiment, the compound activates the mAChR M1 response in mAChR M1-transfected CHO-K1 cells and is inactive with respect to one or more of the mAChR M1, mAChR M3, mAChR M4, or mAChR M5 responses in mAChR M2-, M3-, M4-, or M5-transfected CHO-K1 cells.

[0418] In one embodiment, the compound has an EC50 activity of less than or equal to 10 μM. 50 and exhibit selectivity for the M1 receptor over one or more of the mAChR M2, M3, M4, or M5 receptors. For example, the compound has an EC50 of less than or equal to 10 μM, less than or equal to 5 μM, less than or equal to 2.5 μM, less than or equal to 1 μM, less than or equal to 500 nM, less than or equal to 250 nM, less than or equal to 100 nM, or less than or equal to 50 nM. 50the compound may also have an EC50 that is at least 5-fold lower than for mAChR M2, at least 10-fold lower than for mAChR M2, at least 20-fold lower than for mAChR M2, at least 30-fold lower than for mAChR M2, or at least 50-fold lower than for mAChR M2. 50 In another embodiment, the compound has an EC50 of less than or equal to 10 μM, less than or equal to 5 μM, less than or equal to 2.5 μM, less than or equal to 1 μM, less than or equal to 500 nM, less than or equal to 250 nM, less than or equal to 100 nM, or less than or equal to 50 nM. 50 the compound may also have an EC50 that is at least 5-fold lower than that for mAChR M3, at least 10-fold lower than that for mAChR M3, at least 20-fold lower than that for mAChR M3, at least 30-fold lower than that for mAChR M3, or at least 50-fold lower than that for mAChR M3. 50 In another embodiment, the compound has an EC50 of less than or equal to 10 μM, less than or equal to 5 μM, less than or equal to 2.5 μM, less than or equal to 1 μM, less than or equal to 500 nM, less than or equal to 250 nM, less than or equal to 100 nM, or less than or equal to 50 nM. 50 the compound may also have an EC50 that is at least 5-fold lower than that for mAChR M4, at least 10-fold lower than that for mAChR M4, at least 20-fold lower than that for mAChR M4, at least 30-fold lower than that for mAChR M4, or at least 50-fold lower than that for mAChR M4. 50In another embodiment, the compound has an EC50 of less than or equal to 10 μM, less than or equal to 5 μM, less than or equal to 2.5 μM, less than or equal to 1 μM, less than or equal to 500 nM, less than or equal to 250 nM, less than or equal to 100 nM, or less than or equal to 50 nM. 50 the compound may also have an EC50 that is at least 5-fold lower than that for mAChR M5, at least 10-fold lower than that for mAChR M5, at least 20-fold lower than that for mAChR M5, at least 30-fold lower than that for mAChR M5, or at least 50-fold lower than that for mAChR M5. 50 In another embodiment, the compound has an EC50 of less than or equal to 10 μM, less than or equal to 5 μM, less than or equal to 2.5 μM, less than or equal to 1 μM, less than or equal to 500 nM, less than or equal to 250 nM, less than or equal to 100 nM, or less than or equal to 50 nM. 50 the compound may also have an EC50 that is at least 5-fold lower than for the mAChR M2, M3, M4, or M5 receptor, at least 10-fold lower than for the mAChR M2, M3, M4, or M5 receptor, at least 20-fold lower than for the mAChR M2, M3, M4, or M5 receptor, at least 30-fold lower than for the mAChR M2, M3, M4, or M5 receptor, or at least 50-fold lower than for the mAChR M2, M3, M4, or M5 receptor. 50 can activate the mAChR M1 response.

[0419] The disclosed compounds can be used in methods for treating medical disorders and / or diseases associated with mAChR M1. The methods of treatment can include administering to a subject in need of such treatment a therapeutically effective amount of a composition comprising a compound of formula (I).

[0420] The compounds can be administered to a subject in need thereof to modulate mAChR M1 for a variety of diverse biological processes. The present disclosure is directed to methods for administering compositions that enhance mAChR M1, a GPCR whose dysfunction is associated with, for example, neurological and psychiatric disorders.

[0421] The compounds may be useful for treating and preventing certain diseases and disorders associated with impaired mAChR M1 function in humans and animals. Treatment or prevention of such diseases and disorders can be achieved by modulating mAChR M1 in a subject in need thereof by administering to the subject a compound or composition of the present disclosure as part of a therapeutic regimen, either alone or in combination with another active agent.

[0422] In combination therapy, other drugs can be administered by commonly used route and in amount, therefore, simultaneously or sequentially with the disclosed compound.When the disclosed compound is used simultaneously with one or more other drugs, it is preferred to use a pharmaceutical composition in a unit dosage form containing such drugs and the disclosed compound.However, the combination therapy can also be administered on overlapping schedules.It is also expected that the combination of one or more active ingredients and the disclosed compound can be more effective than any single drug.

[0423] In one embodiment, the compound can be co-administered with anti-Alzheimer's agents, beta-secretase inhibitors, gamma-secretase inhibitors, orthosteric muscarinic agonists, muscarinic potentiators, cholinesterase inhibitors, HMG-CoA reductase inhibitors, NSAIDs, and anti-amyloid antibodies. In a further aspect, the compound can be administered in combination with sedatives, hypnotics, anxiolytics, antipsychotics (typical and atypical), selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), 5-HT2 antagonists, GlyT1 inhibitors, and the like (including, but not limited to, risperidone, clozapine, haloperidol, fluoxetine, prazepam, xanomeline, lithium, phenobarbitol, and salts and combinations thereof).

[0424] The compounds may be useful for treating a disease or disorder associated with dysfunction of mAChR M1, wherein the disease or disorder is selected from at least one of Alzheimer's disease, sleep disorders, pain disorders, cognitive disorders, psychosis, schizophrenia, conduct disorders, disruptive behavior disorders, bipolar disorder, psychotic episodes of anxiety, anxiety associated with psychosis, psychotic mood disorders, severe major depressive disorder, mood disorders associated with psychotic disorders, acute mania, depression associated with bipolar disorder, mood disorders associated with schizophrenia, behavioral manifestations of mental retardation, conduct disorders, autistic disorders, movement disorders, Tourette's syndrome, akinetic syndrome, movement disorders associated with Parkinson's disease, tardive dyskinesia, drug-induced and neurodegenerative-based dyskinesia, attention deficit hyperactivity disorder, cognitive disorders, dementia, and memory disorders.

[0425] The compounds may be useful for treating pain disorders, wherein the pain disorder is neuropathic pain, central pain syndromes, post-operative pain syndromes, bone and joint pain, repetitive motion pain, dental pain, cancer pain, myofascial pain, perioperative pain, chronic pain, dysmenorrhea, inflammatory pain, headache, migraine, cluster headache, headache, primary hyperalgesia, secondary hyperalgesia, primary allodynia, secondary allodynia, or a combination thereof.

[0426] The compounds disclosed herein are useful for treating, preventing, ameliorating, controlling, or reducing the risk of a variety of disorders in which a patient or subject would benefit from selective positive allosteric modulation of the M1 receptor. In one embodiment, treatment can involve selective M1 receptor modulation to an extent effective to affect cholinergic activity. Thus, the disorder can be associated with cholinergic activity, e.g., cholinergic hypofunction. In one embodiment, provided is a method for treating or preventing a disorder in a subject, comprising administering to the subject at least one disclosed compound; at least one disclosed pharmaceutical composition; and / or at least one disclosed product in a dosage and amount effective to treat the disorder in the subject.

[0427] Also provided are methods for treating one or more disorders in a subject in which muscarinic receptor activation is expected to be beneficial, comprising administering to the subject at least one disclosed compound; at least one disclosed pharmaceutical composition; and / or at least one disclosed product, in dosages and amounts effective to treat the disorder in the subject.

[0428] The present disclosure is directed to the use of the described chemical compositions to treat diseases or disorders in patients (preferably humans) where muscarinic receptor activation is expected to have a therapeutic effect, such as Alzheimer's disease (both palliative cognitive and disease modifying), cognitive decline, schizophrenia, pain disorders (including acute pain, neuropathic pain, and inflammatory pain), and sleep disorders, by administering one or more of the disclosed compounds or products.

[0429] Also provided is a method for the treatment of a disorder in a mammal comprising administering to the mammal at least one disclosed compound, composition, or medicament.

[0430] a. Neurological and psychiatric disorders The disclosed compounds have utility in treating a variety of neurological and psychiatric disorders, including one or more of the following conditions or diseases: schizophrenia (paranoid, disorganized, catatonic, or undifferentiated), schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to systemic illness, and substance-induced or drug-induced (phencyclidine, ketamine and other dissociative anesthetics, amphetamine and other stimulants, and cocaine) psychosis, psychotic disorder, psychosis associated with affective disorders, brief reactive psychosis, schizophrenic psychosis, "schizophrenia syndrome." spectrum disorders, such as schizophrenia or psychosis, including schizophrenic or schizotypal personality disorder, or illnesses associated with psychosis (e.g., major depression, manic-depressive (bipolar) disorder, Alzheimer's disease, and post-traumatic stress syndrome) (including both the positive and negative symptoms of schizophrenia) and other psychoses; cognitive disorders, including dementia (associated with Alzheimer's disease, ischemia, multi-infarct dementia, trauma, vascular problems or stroke, HIV disease, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, perinatal hypoxia, other systemic diseases, or substance abuse) disorders; delirium, amnestic disorders or age-related cognitive decline; anxiety disorders including acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, anxiety attacks, panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, specific phobia, substance-induced anxiety disorder and anxiety due to systemic illness; substance-related disorders and addictive behaviors (including substance-induced delirium, persistent dementia, persistent amnestic disorder, psychotic disorder or anxiety disorder; alcohol, amphetamines, cannabis, cocaine, hallucinogens, inhalants, nicotine, opioids, phencyclidine, sedatives, hypnotics or anxiolytics) obesity, bulimia nervosa and compulsive eating disorder; mood disorders including bipolar disorder, depressive disorder; depression including unipolar depression, seasonal depression and postnatal depression, premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PDD), mood disorders due to systemic illness and substance-induced mood disorders; learning disabilities, pervasive developmental disorders including autistic disorder, attention disorders including attention deficit hyperactivity disorder (ADHD) and conduct disorders; NMDA receptor-related disorders, such as autism, depression, benign amnesia, childhood learning disabilities and closed head injury;akinesia and akinetic rigidity syndromes (including Parkinson's disease, drug-induced parkinsonism, postencephalitic parkinsonism, progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, parkinsonism-ALS dementia complex and basal ganglia calcification), drug-induced parkinsonism (e.g., neuroleptic-induced parkinsonism, neuroleptic malignant syndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia, neuroleptic-induced tardive dyskinesia and medication-induced postural tremor), Gilles de la Tourette's syndrome, epilepsy, muscle spasms and disorders associated with muscle spasticity, or movement disorders including weakness, including tremor; tremor (e.g., resting tremor, postural tremor and intention tremor), chorea (e.g., Sydenham's chorea, Huntington's disease, benign hereditary chorea, Dyskinesias including neuroacanthocytosis, symptomatic chorea, drug-induced chorea, and hemiballismus, myoclonus (including generalized and focal myoclonus), tics (including simple, complex, and symptomatic tics), and dystonia (including generalized dystonias, e.g., idiopathic dystonia, drug-induced dystonia, symptomatic and paroxysmal dystonia, and focal dystonias, e.g., blepharospasm, buccal dystonia, spasmodic dysphonia, spasmodic torticollis, axial dystonia, dystonic writer's cramp, and hemiplegic dystonia); urinary incontinence; neuronal damage, including ocular damage, retinopathy or macular degeneration of the eye, tinnitus, hearing impairment and hearing loss, and cerebral edema; vomiting; and sleep disorders, including insomnia and narcolepsy.

[0431] 1. Cognitive impairment The present disclosure provides a method for treating cognitive disorders, comprising administering an effective amount of a compound of the present disclosure to a patient in need thereof. Specific cognitive disorders are dementia, delirium, amnestic disorders, and age-related cognitive decline. The fourth edition, text revision of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) (2000, American Psychiatric Association, Washington, DC) provides diagnostic tools that include cognitive disorders, including dementia, delirium, amnestic disorders, and age-related cognitive decline. As used herein, the term "cognitive disorder" includes treatment of those mental disorders as described in the DSM-IV-TR. Those skilled in the art will recognize that alternative nomenclatures, nosologies, and classification systems for mental disorders exist, and that these systems evolve with medical and scientific advances. Thus, the term "cognitive disorder" is intended to include similar disorders described in other diagnostic sources.

[0432] 2. Anxiety disorders The present disclosure provides a method for treating anxiety disorders, comprising administering an effective amount of a compound of the present disclosure to a patient in need thereof. Specific anxiety disorders are generalized anxiety disorder, obsessive-compulsive disorder, and panic attacks. The Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) (2000, American Psychiatric Association, Washington DC), 4th Edition, Text Revision, provides diagnostic tools for anxiety disorders including generalized anxiety disorder, panic disorder with or without agoraphobia, agoraphobia without a history of panic disorder, specific phobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, anxiety disorder due to systemic illness, substance-induced anxiety disorder, and anxiety disorder not otherwise specified. As used herein, the term "anxiety disorder" includes treatment of those mental disorders as described in DSM-IV-TR. Those skilled in the art will recognize that alternative nomenclatures, nosologies, and classification systems for mental disorders exist, and these systems evolve with medical and scientific advances. Thus, the term "anxiety disorders" is intended to include like disorders that are described in other diagnostic sources.

[0433] 3. Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disorder affecting elderly individuals, resulting in the progressive decline of memory and language skills and severe behavioral deficits. Hallmarks of the disease include degeneration of cholinergic neurons in the cerebral cortex, hippocampus, basal forebrain, and other brain regions important for memory and cognition. Other hallmarks of AD include neurofibrillary tangles composed of hyperphosphorylated tau and accumulation of amyloid-β peptide (Aβ). Aβ is a 39-43 amino acid peptide generated in the brain by proteolytic processing of β-amyloid precursor protein (APP) by β-amyloid cleaving enzyme (BACE) and gamma secretase, leading to the accumulation of Aβ in the brain. Aβ1-40 and 1-42 are the major aggregate-forming species of Aβ.

[0434] Activation of various muscarinic receptors, particularly the M1 subtype, has been proposed as a mechanism for enhancing cognition in disorders such as AD. Thus, without being bound by theory, it is believed that selective positive allosteric modulators of mAChR subtypes that control processes involved in cognitive function could prove superior to AChE inhibitors for the treatment of AD and related disorders because it is hypothesized that these compounds would exhibit improved selectivity for particular mAChRs.

[0435] Phase III clinical trials have demonstrated that orthosteric mAChR activators can be effective in improving cognitive performance in patients with AD. Furthermore, data suggest that administration of M1 activators reduces behavioral disturbances, including delusions, hallucinations, emotional outbursts, and other symptoms, in patients with neurodegenerative diseases, such as Alzheimer's disease. However, dose-limiting adverse effects, potentially due to lack of mAChR M1 selectivity, have led to the failure of previous M1 agonist initiation. In some cases, evidence suggests that mAChR activation may also have disease-modifying potential, in that these drugs can lower Aβ in AD patients. The M1-selective allosteric agonist TBPB has been found to have an effect on APP processing toward the non-amyloidogenic pathway and reduce Aβ 1-40 and 1-42 production in vitro. These data suggest that selective activation of M1 may provide a novel approach for both symptomatic and disease-modifying treatment of Alzheimer's disease.

[0436] 4. Schizophrenia Schizophrenia is a debilitating mental disorder characterized by a combination of negative (blunted affect, withdrawal, anhedonia) and positive (paranoia, hallucinations, delusions) symptoms and significant cognitive deficits. While schizophrenia remains an idiopathic disorder, it appears to arise from a complex interplay of biological, environmental, and genetic factors. Over 40 years ago, phencyclidine (PCP) was discovered to induce a psychotic state in humans very similar to that observed in schizophrenic patients. The finding that PCP's primary mechanism of action is that of a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) subtype of ionotropic glutamate receptors stimulated a series of studies that have led to the development of NMDA receptor hypofunction models of schizophrenia.

[0437] The present disclosure provides a method for treating schizophrenia or psychosis, comprising administering to a patient in need thereof an effective amount of a compound of the present disclosure. Specific schizophrenia or psychosis conditions are paranoid, disorganized, catatonic, or undifferentiated schizophrenia and substance-induced psychotic disorder. The Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) (2000, American Psychiatric Association, Washington DC), Fourth Edition, Text Revision, provides diagnostic tools including paranoid, disorganized, catatonic, or undifferentiated schizophrenia and substance-induced psychotic disorder.

[0438] NMDA receptor function can be regulated by activation of G protein-coupled receptors (GPCRs) known to physically and / or functionally interact with NMDA receptors. The NMDA receptor hypofunction hypothesis is a proposed explanation for the underlying cause of schizophrenia. According to this hypothesis, any drug that can enhance NMDA receptor currents (either directly by acting on regulatory sites on the NMDA receptor (e.g., the glycine coagonist binding site) or indirectly by activating GPCRs known to enhance NMDA receptor function (e.g., mAChR M1)) has the potential to ameliorate the symptoms of schizophrenia. In both preclinical and clinical studies, xanomeline, an M1 / M4-preferring orthosteric agonist, has proven effective in terms of positive, negative, and cognitive symptoms, indicating that M1 activation is a rational approach for the treatment of schizophrenia. More recently, the selective M1 allosteric agonist TBPB has shown efficacy in multiple preclinical models of schizophrenia.

[0439] As used herein, the term "schizophrenia or psychosis" includes treatment of those mental disorders as described in DSM-W-TR. Those skilled in the art will recognize that alternative nomenclatures, nosologies, and classification systems for mental disorders exist, and that these systems evolve with medical and scientific advances. Thus, the term "schizophrenia or psychosis" is intended to include similar disorders described in other diagnostic sources.

[0440] 5. Substance-related disorders and addictive behaviors The present disclosure provides a method for treating substance-related disorders and addictive behaviors, comprising administering to a patient in need thereof an effective amount of a compound of the present disclosure. Specific substance-related disorders and addictive behaviors are persistent dementia, persistent amnestic disorder, psychotic or anxiety disorder induced by a substance of abuse; and tolerance to, dependence on, or withdrawal from substance abuse. The fourth edition, text revision of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) (2000, American Psychiatric Association, Washington, DC) provides diagnostic tools including persistent dementia, persistent amnestic disorder, psychotic or anxiety disorder induced by a substance of abuse; and tolerance to, dependence on, or withdrawal from a substance of abuse. As used herein, the term "substance-related disorders and addictive behaviors" includes treatment of those mental disorders as described in DSM-IV-TR. Those skilled in the art will recognize that alternative nomenclatures, nosologies, and classification systems for mental disorders exist, and that these systems evolve with medical and scientific advances. Thus, the term "substance-related disorders and addictive behaviors" is intended to include like disorders described in other diagnostic sources.

[0441] 6.Pain In another aspect, the present disclosure provides a method for treating pain, comprising administering to a patient in need thereof an effective amount of a compound of the present disclosure. Particular pain embodiments are bone and joint pain (osteoarthritis), repetitive motion pain, dental pain, cancer pain, myofascial pain (muscle injury, fibromyalgia), perioperative pain (general surgery, gynecology), chronic pain, and neuropathic pain.

[0442] 7. Obesity and eating disorders The present disclosure provides a method for treating obesity or eating disorders associated with excessive food intake and associated complications, comprising administering an effective amount of a compound of the present disclosure to a patient in need thereof. Obesity is included as a systemic disease in the 10th edition of the International Classification of Diseases and Related Health Problems (ICD-10) (1992 World Health Organization). The text revision of the 4th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) (2000, American Psychiatric Association, Washington DC) provides diagnostic tools that include obesity in the presence of psychological factors that influence the medical condition. As used herein, the term "obesity or eating disorders associated with excessive food intake" includes treatment of those medical conditions and disorders described in ICD-10 and DSM-W-TR. Those skilled in the art will recognize that alternative nomenclatures, nosologies, and classification systems for systemic diseases exist, and that these systems evolve with medical and scientific advances. Thus, the term "obesity or eating disorders associated with excessive food intake" is intended to include like conditions and disorders described in other diagnostic sources.

[0443] The compounds are further useful in a method for the prevention, treatment, control, amelioration, or reduction of risk of the diseases, disorders and conditions noted herein. The compounds are further useful in a method for the prevention, treatment, control, amelioration, or reduction of risk of the aforementioned diseases, disorders and conditions in combination with other agents.

[0444] The present disclosure is further directed to the administration of selective M1 receptor modulators to improve treatment outcomes in conjunction with cognitive or behavioral therapy. That is, in one aspect, the present disclosure relates to a co-therapeutic method comprising administering to a mammal an effective amount and dosage of at least one compound of the present disclosure in conjunction with cognitive or behavioral therapy.

[0445] In another embodiment, the administration improves therapeutic results in conjunction with cognitive or behavioral therapy. Administration associated with cognitive or behavioral therapy can be continuous or intermittent. Administration does not have to be simultaneous with therapy, but can be before, during, and / or after therapy. For example, cognitive or behavioral therapy can be provided within 1, 2, 3, 4, 5, 6, or 7 days before or after administration of the compound. As a further example, cognitive or behavioral therapy can be provided within 1, 2, 3, or 4 weeks before or after administration of the compound. As another example, cognitive or behavioral therapy can be provided before or after administration within 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 half-lives of the administered compound.

[0446] b. Mode of administration Therapeutic methods can include any number of modes of administering the disclosed compositions. Modes of administration can include tablets, pills, dragees, hard and soft gel capsules, granules, pellets, aqueous, lipid, oily, or other solutions, emulsions such as oil-in-water emulsions, liposomes, aqueous or oily suspensions, syrups, elixirs, solid emulsions, solid dispersions, or dispersible powders. To prepare pharmaceutical compositions for oral administration, the agent can be mixed with commonly known and used adjuvants and excipients, such as gum arabic, talc, starch, sugars (e.g., mannitol, methylcellulose, lactose, etc.), gelatin, surfactants, magnesium stearate, aqueous or non-aqueous solvents, paraffin derivatives, crosslinking agents, dispersants, emulsifiers, lubricants, preservatives, flavorings (e.g., ethereal oils), solubility enhancers (e.g., benzyl benzoate or benzyl alcohol), or bioavailability enhancers (e.g., Gelucire™). In pharmaceutical compositions, the drug may also be dispersed in microparticles, such as nanoparticle compositions.

[0447] For parenteral administration, the drug may be dissolved or suspended in a physiologically acceptable diluent, such as water, a buffer, an oil with or without a solubilizer, a surfactant, a dispersant, or an emulsifier. Oils that can be used include, but are not limited to, olive oil, peanut oil, cottonseed oil, soybean oil, castor oil, and sesame oil. More generally, for parenteral administration, the drug may be in the form of an aqueous, lipid, oily, or other type of solution or suspension, or may even be administered in the form of a liposome or nanosuspension.

[0448] The term "parenteral," as used herein, refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.

[0449] c. Combination therapy In one aspect, the disclosed compounds can be used in combination with one or more other drugs in the treatment, prevention, control, amelioration, or reduction of risk of a disease or condition for which the disclosed compounds or other drugs have utility, where the drug combination is safer or more effective than either drug alone. Such other drugs can be administered simultaneously or sequentially with the disclosed compounds, by a route and in an amount commonly used therefor. When the disclosed compounds are used simultaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the disclosed compounds is preferred. However, combination therapy can also include treatments in which the disclosed compounds and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the disclosed compounds and other active ingredients can be used in lower doses than when each is used alone.

[0450] Accordingly, the pharmaceutical compositions include those that contain one or more other active ingredients, in addition to a compound of the present disclosure.

[0451] The above combinations include combinations of the disclosed compounds not only with one other active compound, but also with two or more other active compounds.Similarly, the disclosed compounds can be used in combination with other drugs used in the prevention, treatment, control, amelioration, or reduction of risk of diseases or conditions for which the disclosed compounds are useful.Such other drugs can be administered simultaneously or sequentially with the disclosed compounds, by a route and in an amount commonly used therefor.When the disclosed compounds are used simultaneously with one or more other drugs, pharmaceutical compositions containing such other drugs in addition to the disclosed compounds are preferred.Thus, pharmaceutical compositions include those containing one or more other active ingredients in addition to the disclosed compounds.

[0452] The weight ratio of the disclosed compound to the second active ingredient can vary and depends on the effective dose of each ingredient. Generally, an effective dose of each is used. Thus, for example, when the disclosed compound is combined with another drug, the weight ratio of the disclosed compound to the other drug is generally in the range of about 1000:1 to about 1:1000, preferably about 200:1 to about 1:200. The combination of the disclosed compound and the other active ingredient is generally also within the above range, but in each case, an effective dose of each active ingredient should be used.

[0453] In such combinations, the disclosed compounds and other active agents may be administered separately or together. Furthermore, the administration of one element may be prior to, concurrent to, or subsequent to the administration of the other agent.

[0454] Thus, the disclosed compounds can be used alone or in combination with other agents known to be beneficial in the target indications or other drugs that affect receptors or enzymes to increase the efficacy, safety, or usefulness of the disclosed compounds, or to reduce undesirable side effects or toxicity. The subject compounds and other agents can be co-administered in combination therapy or in fixed dose combinations.

[0455] In one embodiment, the disclosed compounds can be used in combination with anti-Alzheimer's agents, beta-secretase inhibitors, gamma-secretase inhibitors, HMG-CoA reductase inhibitors, NSAIDs including ibuprofen, vitamin E, and anti-amyloid antibodies. In another embodiment, the subject compounds are selected from the group consisting of sedatives, hypnotics, anxiolytics, antipsychotics, anxiolytics, cyclopyrrolones, imidazopyridines, pyrazolopyrimidines, minor tranquilizers, melatonin agonists and antagonists, melatonergic agents, benzodiazepines, barbiturates, 5HT-2 antagonists, and the like, such as: adinazolam, allobarbital, alonimide, alprazolam, amisulpride, amitriptyline, amobarbital, amoxapine, aripiprazole, amitriptyline ... Benzol, bentazepam, benzoctamine, brotizolam, bupropion, buspirone, butabarbital, butalbital, capride, carbochloral, chloral betaine, chloral hydrate, clomipramine, clonazepam, cloperidone, clorazepate, chlordiazepoxide, chloretate, chlorpromazine, clozapine, ciprazepam, desipramine, dexclamol, diazepam, dichloralphenazone, divalproex, diazepam Phenhydramine, doxepin, estazolam, ethchlorvynol, etomidate, fenobam, flunitrazepam, flupenthixol, fluphenazine, flurazepam, fluvoxamine, fluoxetine, fosazepam, glutethimide, halazepam, haloperidol, hydroxyzine, imipramine, lithium, lorazepam, lormetazepam, maprotiline, mecloqualone, melatonin, mephobarbital, meprobamate, methaqualone, midaflur, midazolam, nephrotic Fazodone, nisobamate, nitrazepam, nortriptyline, olanzapine, oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine, perphenazine, phenelzine, phenobarbital, prazepam, promethazine, propofol, protriptyline, quazepam, quetiapine, reclazepam, risperidone, loretamide, secobarbital, sertraline, suproclon, temazepam, thioridazine, thiothixene, tracazolate,The subject compounds may be used in combination with tranylcypromine, trazodone, triazolam, trepipam, tricetamide, triclofos, trifluoperazine, trimetozine, trimipramine, urdazepam, venlafaxine, zaleplon, ziprasidone, zolazepam, zolpidem, and salts thereof, and combinations thereof, or may be administered in conjunction with the use of physical methods, such as phototherapy or electrical stimulation.

[0456] In one embodiment, the disclosed compounds can be used in combination with levodopa (with or without a selective extracerebral decarboxylase inhibitor, e.g., carbidopa or benserazide), anticholinergics such as biperiden (optionally as its hydrochloride or lactate salt) and trihexyphenidyl (benzhexol) hydrochloride, COMT inhibitors such as entacapone, MOA-B inhibitors, antioxidants, A2a adenosine receptor antagonists, cholinergic agonists, NMDA receptor antagonists, serotonin receptor antagonists, and dopamine receptor agonists such as alentemol, bromocriptine, phenordopam, lisuride, naxagolide, pergolide, and pramipexole. It should be appreciated that the dopamine agonist may be in the form of a pharmaceutically acceptable salt, such as alentemol hydrobromide, bromocriptine mesylate, phenoldopam mesylate, naxagolide hydrochloride, and pergolide mesylate. Lisuride and pramipexole are commonly used in their non-salt form.

[0457] In one embodiment, the disclosed compounds can be used in combination with compounds from the phenothiazine, thioxanthene, heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine, and indolone classes of neuroleptics. Suitable examples of phenothiazines include chlorpromazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, perphenazine, and trifluoperazine perazine. Suitable examples of thioxanthenes include chlorprothixene and thiothixene. An example of a dibenzazepine is clozapine. An example of a butyrophenone is haloperidol. An example of a diphenylbutylpiperidine is pimozide. An example of an indolone is molindolone. Other neuroleptics include loxapine, sulpiride, and risperidone. The neuroleptics, when used in combination with the compound of interest, may be in the form of a pharmaceutically acceptable salt, such as chlorpromazine hydrochloride, mesoridazine besylate, thioridazine hydrochloride, acetophenazine maleate, fluphenazine hydrochloride, fluphenazine enanthate (flu r It should be recognized that the active ingredient may be phenazine enathate, fluphenazine decanoate, trifluoperazine hydrochloride, thiothixene hydrochloride, haloperidol decanoate, loxapine succinate, and molindone hydrochloride. Perphenazine, chlorprothixene, clozapine, haloperidol, pimozide, and risperidone are commonly used in non-salt form. Thus, the subject compounds can be used in combination with acetophenazine, alentemol, aripiprazole, amisulpride, benzhexol, bromocriptine, biperiden, chlorpromazine, chlorprothixene, clozapine, diazepam, phenodopam, fluphenazine, haloperidol, levodopa, levodopa with benserazide, levodopa with carbidopa, lisuride, loxapine, mesoridazine, molindrone, naxagolide, olanzapine, pergolide, perphenazine, pimozide, pramipexole, quetiapine, risperidone, sulpiride, tetrabenazine, trihexyphenidyl, thioridazine, thiothixene, trifluoperazine perazine, or ziprasidone.

[0458] In one embodiment, the disclosed compounds can be used in combination with antidepressants or anxiolytics, including norepinephrine reuptake inhibitors (including tertiary amine tricyclics and secondary amine tricyclics), selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors (SNRIs), corticotropin-releasing factor (CRF) antagonists, alpha-adrenergic receptor antagonists, neurokinin-1 receptor antagonists, atypical antidepressants, benzodiazepines, 5-HT1A agonists or antagonists, particularly 5-HT1A partial agonists, and corticotropin-releasing factor (CRF) antagonists. Specific drugs include amitriptyline, clomipramine, doxepin, imipramine, and trimipramine; amoxapine, desipramine, maprotiline, nortriptyline, and protriptyline; fluoxetine, fluvoxamine, paroxetine, and sertraline; isocarboxazid, phenelzine, tranylcypromine, and selegiline; moclobemide; venlafaxine; duloxetine; aprepitant; bupropion, lithium, nefazodone, trazodone, and viloxazine; alprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam, halazepam, lorazepam, oxazepam, and prazepam; buspirone, flesinoxan, gepirone, and ipsapirone, and pharmaceutically acceptable salts thereof.

[0459] 5. Kit In one aspect, the disclosure provides a compound comprising at least one of the disclosed compounds or a pharmaceutically acceptable salt thereof, and (a) at least one agent known to increase mAChR M1 activity; (b) at least one agent known to decrease mAChR M1 activity; (c) at least one agent known to treat a disorder associated with cholinergic activity; (d) instructions for treating disorders associated with cholinergic activity; (e) instructions for treating a disorder associated with M1 receptor activity; or (f) instructions for administering the compound in connection with cognitive or behavioral therapy; The present invention provides a kit comprising one or more of the following:

[0460] In some embodiments, at least one disclosed compound and at least one agent are co-formulated. In some embodiments, at least one disclosed compound and at least one agent are co-packaged. These kits can also include compounds and / or products that are co-packaged, co-formulated, and / or co-delivered with other components. For example, a drug manufacturer, drug distributor, physician, compounding store, or pharmacist can provide a kit that includes a disclosed compound and / or product and another component for delivery to a patient.

[0461] The disclosed kits can be used in conjunction with the disclosed methods of use.

[0462] These kits may include information, instructions, or both, that use of the kit will provide treatment for a physical disorder in a mammal (especially a human). The information and instructions may be in the form of words, images, or both. The kits may additionally or alternatively include a compound, composition, or both, which preferably has the benefit of treating or preventing a physical disorder in a mammal (e.g., a human); and information, instructions, or both, regarding the method of application of the compound or composition.

[0463] The compounds and processes of the present invention will be better understood by reference to the following examples, which are intended to illustrate, but not limit, the scope of the invention.

[0464] 6.Chemical synthesis The compounds of formula (I) may be prepared by synthetic processes or by metabolic processes. Preparation of compounds by metabolic processes includes those which occur in the human or animal body (in vivo) or which occur in vitro.

[0465] Compounds of formula (I) may be synthesized as shown in the schemes and examples below. [ka]

[0466] As shown in General Scheme I, S2 can be prepared by reductive amination and cyclization using benzylamine A with a suitable reducing agent (e.g., Na(OAc)3BH) to provide S2. 2 teeth, [ka] and X is R in formula (I). 5 or X is R 5 The groups include halogens, triflates, or boronic esters that can serve as precursors to [ka]

[0467] As shown in general scheme II, S2 can be prepared by nucleophilic displacement of a leaving group LG1 (e.g., halogen, triflate, mesylate, tosylate) with a benzylamine A, followed by cyclization in the presence of a base (e.g., DIEA) with heating in a suitable solvent (e.g., MeCN, DMF), where A 2 and X are as defined in General Scheme I. [ka]

[0468] As shown in general Scheme III, S2 can be prepared by nucleophilic displacement of a leaving group LG2 (e.g., halogen, triflate, mesylate, tosylate) using lactam S4 and a base (e.g., NaH) in a suitable solvent (e.g., DMF), where A 2and X are as defined in General Scheme I. [ka]

[0469] As shown in general Scheme IV, S2 (where X is a halogen or triflate) can be converted to the boronic ester S5 using conditions well known in the art. [ka]

[0470] As shown in General Scheme V, S5 can be converted to X2-R 5 The Suzuki reaction can be used to convert to S6, involving: where X2 is a halogen or triflate. [ka]

[0471] As shown in general Scheme VI, S2 (where X is a halogen or triflate) can be converted to S6 using the Suzuki reaction under conditions well known in the art. [ka]

[0472] As shown in General Scheme VII, compound S2 can be lactam ring enriched in deuterium by reaction with NaOD in a suitable solvent, such as THF / DO, where A 2 and X are as defined in General Scheme I. [ka]

[0473] As shown in General Scheme VIII, intermediates such as benzylamines of formula A-1 (e.g., X=halogen, R 5) can be prepared from a benzoic acid of formula A'. The benzoic acid of formula A' can be subjected to methylation reaction conditions, where A' is reacted with a methylating agent (e.g., MeI) in the presence of a base to form an intermediate methyl benzoate of formula A-2. The methyl benzoate of formula A-2 can then be subjected to reduction conditions, where A-2 is reacted with a suitable reducing agent (e.g., DIBAL-H) ​​to form an intermediate benzyl alcohol of formula A-3. The benzyl alcohol of formula A-3 can then be subjected to oxidation conditions, where A-3 is reacted with a suitable oxidizing agent (e.g., Dess-Martin periodinane) to form an intermediate benzaldehyde of formula A-4. The benzaldehyde of formula A-4 can then be reacted with an appropriate hydroxylamine (e.g., NHOH-HCl) to form an intermediate oxime of formula A-5. Finally, the oxime of formula A-5 can be subjected to reduction conditions, where A-5 reacts with a suitable reducing agent (eg, Zn dust / acetic acid) to form the benzylamine intermediate of formula A-1.

[0474] The compounds and intermediates can be isolated and purified by methods well known to those skilled in the art of organic synthesis. Examples of conventional methods for isolating and purifying compounds include, but are not limited to, chromatography on solid supports such as silica gel, alumina, or silica derivatized with alkylsilane groups by recrystallization at high or low temperatures, with optional pretreatment with activated carbon, as described in, for example, "Vogel's Textbook of Practical Organic Chemistry," 5th edition (1989), by Furniss, Hannaford, Smith, and Tatchell, pub. Longman Scientific & Technical, Essex CM20 2JE, England; thin-layer chromatography; distillation at various pressures; sublimation and trituration in vacuo.

[0475] The disclosed compounds may have at least one basic nitrogen, which allows the compound to be treated with an acid to form a desired salt. For example, the compound can be reacted with an acid at room temperature or above room temperature to provide the desired salt, which precipitates and is collected by filtration after cooling. Examples of acids suitable for this reaction include, but are not limited to, tartaric acid, lactic acid, succinic acid, mandelic acid, atrolactic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, benzenesulfonic acid, carbonic acid, fumaric acid, maleic acid, gluconic acid, acetic acid, propionic acid, salicylic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, citric acid, hydroxybutyric acid, camphorsulfonic acid, malic acid, phenylacetic acid, aspartic acid, or glutamic acid.

[0476] The reaction conditions and reaction times for each individual step may vary depending on the specific reactants employed and the substituents present in the reactants used. Specific procedures are provided in the Examples section. The reactions can be worked up in a conventional manner, for example, by removing the solvent from the residue, and further purified according to methodologies commonly known in the art, including, but not limited to, crystallization, distillation, extraction, trituration, and chromatography. Unless otherwise specified, starting materials and reagents are commercially available or can be prepared by one skilled in the art from commercially available materials using methods described in the chemical literature. When not commercially available, starting materials can be prepared by procedures selected from standard organic chemistry techniques, techniques analogous to the synthesis of known structurally similar compounds, and procedures similar to those described in the schemes or synthetic examples section above.

[0477] Routine experimentation, including appropriate manipulation of the reaction conditions, reagents and sequence of the synthetic route, protection of any chemical functionality that may not be compatible with the reaction conditions and deprotection at appropriate points in the reaction sequence of the method, is within the scope of the present invention. Suitable protecting groups and methods for protecting and deprotecting various substituents using such suitable protecting groups are well known to those skilled in the art, examples of which can be found in "Protective Groups in Organic Synthesis" (4), the entire contents of which are incorporated herein by reference. th ed.), PGM Wuts and TW Greene, John Wiley & Sons, NY (2006). Synthesis of the compounds of the present invention can be achieved by methods similar to those described in the synthetic schemes described above and in the specific examples.

[0478] When an optically active form of a disclosed compound is required, this can be obtained by carrying out one of the procedures described herein using optically active starting materials (prepared, for example, by asymmetric induction in an appropriate reaction step), or by resolution of a stereoisomeric mixture of the compound or intermediate using standard procedures (such as chromatographic separation, recrystallization, or enzymatic resolution).

[0479] Similarly, when a pure geometric isomer of a compound is required, it can be obtained by carrying out one of the above procedures using a pure geometric isomer as a starting material, or by resolution of a mixture of geometric isomers of the compound or intermediate using standard procedures, for example, chromatographic separation.

[0480] It will be understood that the synthetic schemes and specific examples described are illustrative and should not be construed as limiting the scope of the invention, which is defined in the appended claims. All alternatives, modifications, and equivalents of the synthetic methods and specific examples are included within the scope of the claims.

[0481] All NMR spectra were recorded on a 400 MHz AMX Bruker NMR spectrometer. 1 H chemical shifts are reported as δ values ​​in ppm (downfield) using deuterated solvent as internal standard. Data are reported as follows: chemical shift, multiplicity (s = singlet, bs = broad singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, m = multiplet, ABq = AB quartet), coupling constant, and integration. Reversed-phase LCMS analysis was performed using an Agilent 1200 system consisting of a binary pump equipped with a degasser, a high-performance autosampler, a thermostated column compartment, a C18 column, a diode array detector (DAD), and an Agilent 6150 MSD, with the following parameters: gradient conditions: 5% to 95% acetonitrile (aqueous phase: 0.1% TFA in water) over 1.4 min. Samples were separated on a Waters Acquity UPLC BEH C18 column (1.7 μm, 1.0 × 50 mm) at 0.5 mL / min, with column and solvent temperatures maintained at 55 °C. The DAD was set to scan from 190 to 300 nm, with signals at 220 nm and 254 nm (both with 4 nm bands). The MS detector was set with an electrospray ionization source, and low-resolution mass spectra were acquired by scanning from 140 to 700 AMU with a step size of 0.2 AMU and a peak width of 0.008 min at 0.13 cycles / sec. The drying gas flow was set to 13 liters / min at 300 °C, and the nebulizer pressure was set to 30 psi. The capillary needle voltage was set to 3000 V, and the fragmentor voltage was set to 100 V. Data acquisition was performed using Agilent Chemstation and Analytical Studio Reviewer software.

[0482] The following abbreviations may be used herein: AcOH acetic acid Ac2O acetic anhydride aq water-based atm atmospheric pressure CDCl3 chloroform-d CD3OD methanol-d4 CD3COOD Acetate-d4 Celite® Diatomaceous Earth Concentrated Cpd compounds CypMgBr Cyclopropylmagnesium Bromide DCE Dichloroethane DCl Hydrochloric acid-d DCM dichloromethane d double line dd double line double line Deoxo-Fluor bis(2-methoxyethyl)amino]sulfur trifluoride DIPEA / DIEA Diisopropylethylamine DIAD Diisopropyl azodicarboxylate DIBAL-H Diisobutylaluminum hydride DMF N,N-dimethylformamide DMF·DMA N,N-Dimethylformamide dimethyl acetal DMSO dimethyl sulfoxide DMSO-d6 Dimethyl sulfoxide-d6 (deuterated dimethyl sulfoxide) DO deuterium oxide (deuterated water or heavy water) dppf 1,1'-bis(diphenylphosphino)ferrocene dppp 1,3-bis(diphenylphosphino)propane ES-MS Electrospray Mass Spectrometry EtOAc ethyl acetate EtOH ethanol Et3N Triethylamine eq. / equiv equivalent h or hr Time HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HPLC High Performance Liquid Chromatography HRMS high-resolution mass spectrometry Hz Hertz iPA Isopropyl alcohol KOAc Potassium Acetate LCMS Liquid Chromatography Mass Spectrometry M molar concentration (concentration) mCPBA 3-chloroperbenzoic acid Me methyl MeCN acetonitrile MeI methyl iodide MeOH Methanol MHz Megahertz min mw microwave NaHMDS Sodium bis(trimethylsilyl)amide NaOAc Sodium Acetate NaOD Sodium deuteroxide NaSMe sodium methanethiolate Pd(OAc)2 Palladium(II) Acetate Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)Cl2 or PdCl2(dppf) (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride Ph Phenyl (PhSO2)2NF N-Fluorobenzenesulfonimide ppm parts per million RockPhos Palladacycle Gen-3 [(2-di-tert-butylphosphino-3-methoxy-6-methyl-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2-aminobiphenyl)]palladium(II) methanesulfonate RP reverse phase rt / rt / RT room temperature s single line sat. saturation soln. solution STAB Sodium triacetoxyborohydride TBTU 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate TFA trifluoroacetic acid TFAA Trifluoroacetic anhydride THF tetrahydrofuran [Example]

[0483] Preparation of intermediates Intermediate Example 1: (4-bromo-2-chloro-6-fluorophenyl)methanamine [ka] Step 1: (E / Z)-4-Bromo-2-chloro-6-fluorobenzaldehyde oxime. To a suspension of 4-bromo-2-chloro-6-fluorobenzaldehyde (3.56 g, 15 mmol) in ethanol (75 mL) was added sodium acetate (2.46 g, 30 mmol) and hydroxylamine hydrochloride (2.08 g, 30 mmol). After 1 h at rt, the reaction mixture was diluted with EtOAc and then washed with HO and brine. The organic layer was dried over NaSO, filtered, and concentrated to give the title compound, which was carried forward without further purification (3.75 g). 1 H NMR(400MHz,DMSO)δ 8.17(s,1H),7.75-7.69(m,2H),OH exchangeable proton; ES-MS[M+H] + =251.9 / 253.9. [ka]

[0484] Step 2: (4-Bromo-2-chloro-6-fluorophenyl)methanamine. To (E / Z)-4-bromo-2-chloro-6-fluorobenzaldehyde oxime (3.75 g, 15 mmol) in acetic acid (74 mL) was added zinc powder (4.85 g, 74.3 mmol). The nicotinate suspension was sonicated at rt for 3 h and then filtered through a pad of Celite®, which was thoroughly washed with 10% MeOH / DCM. The filtrate was concentrated under reduced pressure, azeotroped with toluene (3×), and then dried under vacuum to give the title compound. The product was carried forward without further purification. 1 H NMR(400MHz,DMSO-d6)δ 7.65-7.63(m,1H),7.62(dd,J=9.0,1.9Hz,1H),3.87(d,J=1.8Hz,2H),NH exchangeable proton;ES-MS[M+H] + =237.9 / 240.2.

[0485] The compounds shown in Table 1 may be prepared similarly to the compounds described above using the appropriate starting materials.

[0486] [Table 1]

[0487] Intermediate Example 2: (4-Bromo-2-cyclopropyl-6-fluorophenyl)methanamine [ka] Step 1: 4-Bromo-2-cyclopropyl-6-fluorobenzoic acid. To an oven-dried 250 mL flask was added 4-bromo-2,6-difluorobenzoic acid (5.0 g, 21.1 mmol) and THF (100 mL) under N2. The reaction was cooled to 0 °C, and cyclopropylmagnesium bromide (75.35 mL, 52.74 mmol) was slowly added. The ice bath was removed. After 16 h at rt, the reaction was cooled to 0 °C, recharged with cyclopropylmagnesium bromide (15.07 mL, 10.55 mmol, ca. 0.7 mol / L, 0.5 equiv.), and allowed to warm slowly to rt; after an additional 16 h, this step was repeated. The reaction was carefully quenched with water at 0 °C and concentrated under reduced pressure. The residue was acidified with 1 M HCl (aq). The aqueous phase was extracted with EtOAc (3x). The combined organic layers were washed with water, brine, dried (Na2SO4), filtered and concentrated to give the product (5.46 g), which was used directly in the next step without further purification. ES-MS [M+H] + =259.0 / 260.9. [ka]

[0488] Step 2: Methyl 4-bromo-2-cyclopropyl-6-fluorobenzoate: To a solution of 4-bromo-2-cyclopropyl-6-fluorobenzoic acid (5.46 g, 21.08 mmol) in DMF (42 mL) was added potassium carbonate (8.87 g, 63.23 mmol) at rt. MeI (2.62 mL, 42.15 mmol) was added dropwise. After 16 h, the reaction mixture was quenched with water and extracted with EtOAc (3x). The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated. The crude residue was purified using normal phase chromatography on silica gel (0-10% EtOAc / hexanes) to give the title compound (4.51 g, 65% yield). ES-MS [M+H] + =272.9 / 274.8. [ka]

[0489] Step 3: (4-Bromo-2-cyclopropyl-6-fluorophenyl)methanol. To a solution of methyl 4-bromo-2-cyclopropyl-6-fluorobenzoate (4.51 g, 16.51 mmol) in DCM (80 mL) was added dropwise diisobutylaluminum hydride solution (1.0 M in THF, 49.54 mL, 49.54 mmol) at 0 °C. The ice bath was removed. After 16 h at rt, the reaction was cooled to 0 °C and diisobutylaluminum hydride solution (16.51 mL, 16.51 mmol, 1.0 M in THF) was added. After 5 h at 0 °C, saturated aqueous NH4Cl was added dropwise to the reaction. The reaction mixture was filtered through Celite®, washed with EtOAc, and concentrated in vacuo. The crude residue was dissolved in DCM (20 mL), filtered through a hydrophobic phase separator, and then concentrated to give the title compound (3.96 g). 1 H NMR(400MHz,CDCl3)δ 7.09(dd,J=9.1,1.9Hz,1H),6.93(dt,J=1.8,0.8Hz,1H),4.88(d,J=1.9Hz,2H),2 .15(tt,J=8.4,5.3Hz,1H),1.10-0.97(m,2H),0.76-0.68(m,2H);ES-MS[M+H-H2O] + =227.0 / 228.9. [ka]

[0490] Step 4: 4-Bromo-2-cyclopropyl-6-fluorobenzaldehyde. To a solution of (4-bromo-2-cyclopropyl-6-fluorophenyl)methanol (1.74 g, 7.10 mmol) in DCM (40 mL) was added Dess-Martin periodinane (6.02 g, 14.20 mmol) at rt. After 2 h, the reaction was quenched by adding saturated aqueous NaHCO3. The reaction mixture was extracted with DCM (3x). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo to give the crude material. The crude material was purified using silica gel chromatography (0-20% EtOAc / hexanes) to give the title compound (1.66 g, 96% yield).1 H NMR(400MHz,CDCl3)δ 10.55(s,1H),7.17(dd,J=10.2,1.8Hz,1H),6.97(dd,J=1.8,1.0Hz,1H),2 .86(tt,J=8.5,5.4Hz,1H),1.17-1.05(m,2H),0.78-0.70(m,2H);MS[M+H] + =243.0 / 244.9. [ka]

[0491] Step 5: (E / Z)-4-Bromo-2-cyclopropyl-6-fluorobenzaldehyde oxime. The title compound was prepared in a similar manner to (E / Z)-4-bromo-2-chloro-6-fluorobenzaldehyde oxime. ES-MS [M+H] + =258.0 / 259.9. [ka]

[0492] Step 6: (4-Bromo-2-cyclopropyl-6-fluorophenyl)methanamine. The title compound was prepared in a similar manner to (4-bromo-2-chloro-6-fluorophenyl)methanamine. ES-MS [M+H] + =244.0 / 245.9.

[0493] The compounds shown in Table 2 may be prepared similarly to the compounds described above using the appropriate starting materials.

[0494] [Table 2]

[0495] Intermediate Example 3: (4-bromo-2-fluoro-6-isobutoxyphenyl)methanamine [ka] Step 1: 4-Bromo-2-fluoro-6-isobutoxybenzaldehyde. To a suspension of 6-fluoro-4-bromosalicylaldehyde (500 mg, 2.28 mmol) in MeCN (22.8 mL) was added K2CO3 (640 mg, 4.57 mmol), followed by 1-iodo-2-methylpropane (0.53 mL, 4.57 mmol). The mixture was stirred at 50 °C for 72 h and recharged with 1-iodo-2-methylpropane (0.53 mL, 4.57 mmol) every 24 h. After 72 h, water was added to the reaction mixture, and the resulting solution was extracted with EtOAc (3x). The combined organic layers were washed with water, brine, dried over Na2SO4, filtered, and concentrated. The crude material was purified using normal phase chromatography on silica gel (0–30% EtOAc / hexanes) to give the title compound (500 mg, 80% yield). ES-MS[M+H] + =275.0 / 276.9. [ka]

[0496] Step 2: (E / Z)-4-Bromo-2-fluoro-6-isobutoxybenzaldehyde oxime. The title compound was prepared in a similar manner to (E / Z)-4-Bromo-2-chloro-6-fluorobenzaldehyde oxime. ES-MS [M+H] + =289.9 / 291.9. [ka]

[0497] Step 3: (4-Bromo-2-fluoro-6-isobutoxyphenyl)methanamine The title compound was prepared in a similar manner to (4-bromo-2-chloro-6-fluorophenyl)methanamine. 1 H NMR(400MHz,DMSO-d6)δ 7.10(dd,J=8.9,1.8Hz,1H),7.06(t,J=1.5Hz,1H),3.83(d,J=6.4Hz,2H),3.73(s,2H),2.14-2.00(m,1H),0.99(d,J=6.7Hz,6H);ES-MS[M+H]+ =276.0 / 277.9.

[0498] Intermediate Example 4: 2-(aminomethyl)-5-bromo-3-fluoro-N,N-dimethylaniline [ka] Step 1: 4-Bromo-2-(dimethylamino)-6-fluorobenzaldehyde. To a suspension of 4-bromo-2,6-difluorobenzaldehyde (1.33 g, 6.0 mmol) in DMSO (8 mL) was added K2CO3 (2.02 g, 14.4 mmol), followed by dimethylamine hydrochloride (587 mg, 7.2 mmol). The mixture was stirred at 50 °C for 1 h. After cooling to rt, the reaction mixture was poured into ice-cold water and extracted with EtOAc (3x). The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude material was purified using normal-phase chromatography on silica gel (0–30% EtOAc / hexanes) to give the title compound (1.41 g, 95% yield). 1 H NMR(400MHz,CDCl3)δ 10.19(d,J=0.6Hz,1H),6.92(t,J=1.5Hz,1H),6.76(dd,J=10.4,1.7Hz,1H),2.93(s,6H);ES-MS[M+H] + =246.0 / 247.9. [ka]

[0499] Step 2: (E / Z)-4-Bromo-2-(dimethylamino)-6-fluorobenzaldehyde oxime. The title compound was prepared in a similar manner to (E / Z)-4-bromo-2-chloro-6-fluorobenzaldehyde oxime. 1 H NMR(400MHz,CDCl3)δ 8.20(s,1H),6.97(d,J=8.5Hz,2H),2.81(s,6H),OH exchangeable proton; ES-MS[M+H] + =261.0 / 262.9. [ka]

[0500] Step 3: 2-(aminomethyl)-5-bromo-3-fluoro-N,N-dimethylaniline. The title compound was prepared in a similar manner to (4-bromo-2-chloro-6-fluorophenyl)methanamine. 1 H NMR(400MHz,CDCl3)δ 7.06(t,J=1.6Hz,1H),7.00(dd,J=9.0,1.8Hz,1H),6.83(s,2H),4.14(d,J=1.1Hz,2H),2.70(s,6H);ES-MS[M+H] + =245.0 / 247.0.

[0501] Intermediate Example 5: 6-(4-Bromo-2-chloro-6-fluorobenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one [ka] A solution of methyl 2-formylnicotinate (297 mg, 1.80 mmol) and (4-bromo-2-chloro-6-fluorophenyl)methanamine (49 wt%, 921 mg, 1.89 mmol) in DCE (10 mL) was stirred for 10 min. Sodium triacetoxyborohydride (572 mg, 2.7 mmol) was added. After 16 h at rt, the reaction mixture was diluted with DCM and washed with a saturated solution of NaHCO and brine. The organic layer was dried over NaSO, filtered, and concentrated. The crude material was purified using normal phase chromatography on silica gel (0–100% EtOAc / DCM) to give the title compound (358 mg, 56% yield). 1 H NMR(400MHz,DMSO-d6)δ 8.74(dd,J=4.9,1.6Hz,1H),8.10(dd,J=7.7,1.6Hz,1H),7.72-7.63(m,2H),7.56-7.48(m,1H),4.88(d,J=1.9Hz,2H),4.37(s,2H);ES-MS[M+H] + =355.0 / 356.9.

[0502] The compounds shown in Table 3 may be prepared similarly to the compounds described above using the appropriate starting materials.

[0503] [Table 3-1]

[0504] [Table 3-2]

[0505] [Table 3-3]

[0506] Intermediate Example 6: 6-(4-Bromo-2,6-difluorobenzyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one [ka] A solution of methyl 3-formylpicolinate (661 mg, 4.0 mmol) and (4-bromo-2,6-difluorophenyl)methanamine (933 mg, 4.2 mmol) in DCE (20 mL) was stirred for 10 min. Sodium triacetoxyborohydride (1.272 g, 6.0 mmol) was added. After 16 h at rt, the reaction mixture was diluted with DCM and washed with a saturated solution of NaHCO and brine. The organic layer was dried over NaSO, filtered, and concentrated. The crude material was purified using normal phase chromatography on silica gel (0–10% MeOH / DCM) to give the title compound (1097 mg, 81% yield). 1 H NMR(400MHz,DMSO-d6)δ 8.70(dd,J=4.8,1.5Hz,1H),8.01(dd,J=7.8,1.5Hz,1H),7.59-7.49(m,3H),4.81(s,2H),4.40(s,2H);ES-MS[M+H] + =339.2 / 340.9.

[0507] The compounds shown in Table 4 may be prepared similarly to the compounds described above using the appropriate starting materials.

[0508] [Table 4-1]

[0509] [Table 4-2]

[0510] [Table 4-3]

[0511] Intermediate Example 7: 6-(4-Bromo-2,6-difluorobenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one [ka] Step 1: Methyl 3-(bromomethyl)pyrazine-2-carboxylate. To a solution of methyl 3-methylpyrazine-2-carboxylate (500 mg, 3.3 mmol) in carbon tetrachloride (33.0 mL) was added benzoyl peroxide (21.0 mg, 0.07 mmol) and N-bromosuccinimide (614 mg, 3.45 mmol) at room temperature. The resulting mixture was heated to 80 °C. After 16 h, the mixture was filtered over Celite®, washed with DCM, and concentrated to give the title compound (759 mg), which was carried forward without further purification. ES-MS [M+H] + =230.9 / 232.9. [ka]

[0512] Step 2: 6-(4-Bromo-2,6-difluorobenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one. A solution of methyl 3-(bromomethyl)pyrazine-2-carboxylate (750 mg, 1.68 mmol), 4-bromo-2,6-difluorobenzylamine (486 mg, 2.19 mmol), and N,N-diisopropylethylamine (1.47 mL, 8.42 mmol) in MeCN (5 mL) was stirred in a reaction vial at 45 °C for 18 h. The solvent was removed, and the crude residue was purified using normal phase chromatography on silica gel (0-100% EtOAc / DCM) to give the title compound (549 mg, 96% yield). ES-MS [M+H] + =340.0 / 341.9.

[0513] Intermediate Example 8: 6-(4-Bromo-2,6-difluorobenzyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one [ka] Step 1: Ethyl 4-(bromomethyl)pyrimidine-5-carboxylate. The title compound was prepared in a similar manner to methyl 3-(bromomethyl)pyrazine-2-carboxylate. 1 H NMR(400MHz,CDCl3)δ 9.27(s,1H),9.26(s,1H),4.93(s,2H),4.47(q,J=7.2,4.5Hz,2H),1.45(t,J=7.1Hz,3H);ES-MS[M+H] + =245.0 / 246.9. [ka]

[0514] Step 2: 6-(4-Bromo-2,6-difluorobenzyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one. The title compound was prepared in a similar manner to 6-(4-bromo-2,6-difluorobenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one. 1H NMR(400MHz,DMSO-d6)δ 9.35(s,1H),9.13(s,1H),7.57-7.50(m,2H),4.79(s,2H),4.53(s,2H);ES-MS[M+H] + =340.0 / 341.9.

[0515] Intermediate Example 9: 2-(4-Bromo-2,6-difluorobenzyl)-1,2-dihydro-3H-pyrrolo[3,4c]pyridin-3-one [ka] A solution of 6-aza-1-isoindolinone (200 mg, 1.49 mmol) in DMF (1.5 mL) was cooled to 0° C. NaH (60% dispersion in oil, 89.5 mg, 2.24 mmol) was added, and after 10 min, 4-bromo-2,6-difluorobenzyl bromide (0.25 mL, 1.64 mmol) was added dropwise. After 90 min at rt, the reaction mixture was filtered through Celite® and purified using RP HPLC to give the title compound (100 mg). 1 H NMR(400MHz,DMSO-d6)δ 8.89(d,J=1.1Hz,1H),8.73(d,J= ES-MS[M+H] + =339.0 / 341.0.

[0516] Intermediate Example 10: 6-[(5-bromopyrimidin-2-yl)methyl]-7H-pyrrolo[3,4-b]pyridin-5-one [ka] Step 1: Methyl 2-(chloromethyl)nicotinate. Methyl 2-methylnicotinate (1.0 g, 6.62 mmol) and trichlorocyanuric acid (2.31 g, 9.92 mmol) were dissolved in DCM (20 mL) and stirred at rt. After 20 h, the suspension was quenched with a saturated solution of NaHCO and extracted with DCM (3x). The combined extracts were washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound, which was used without further purification (1.23 g). 1 H NMR(400MHz,CDCl3)δ 8.73(dd,J=1.8,4.8Hz,1H),8.28(dd,J=1.8,7.9Hz,1H),7.36(dd,J=4.8,7.9Hz,1H),5.12(s,2H),3.97(s,3H);ES-MS[M+H] + =186.1. [ka]

[0517] Step 2: 6-[(5-Bromopyrimidin-2-yl)methyl]-7H-pyrrolo[3,4-b]pyridin-5-one. Methyl 2-(chloromethyl)pyridine-3-carboxylate (250 mg, 1.35 mmol), (5-bromopyrimidin-2-yl)methanamine hydrochloride (454 mg, 2.02 mmol), and DIEA (0.7 mL, 4.04 mmol) were dissolved in DMF (7.5 mL). After 16 h at 45 °C, the solution was quenched with saturated NaHCO solution and extracted with DCM (3x). The combined organic layers were washed with HO and brine, dried over NaSO, filtered, and concentrated under reduced pressure. The crude material was purified by normal phase chromatography on silica gel (0-100% EtOAc / hexanes) to give the title compound (273 mg, 80% yield). ES-MS [M+H] + =305.1 / 307.1.

[0518] The compounds shown in Table 5 may be prepared similarly to the compounds described above using the appropriate starting materials.

[0519] [Table 5]

[0520] Intermediate Example 11: 6-(4-bromo-2,6-difluorobenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one-7,7-d2 [ka] 6-(4-Bromo-2,6-difluorobenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (590 mg, 1.74 mmol) was dissolved in anhydrous THF (8.7 mL) and DO (4.35 mL). A solution of sodium deuteroxide (40 wt% in DO, 0.12 mL) was added. After 16 h at 45 °C, the mixture was diluted with DCM and the layers were separated. The organic layer was passed through a hydrophobic phase separator and concentrated under reduced pressure. Purification using normal phase chromatography on silica gel (0–100% EtOAc / DCM) afforded the title compound (500 mg, 84% yield). 1 H NMR(400MHz,CDCl3)δ 8.73(dd,J=5.0,1.6Hz,1H),8.14(dd,J=7.7,1.6Hz,1H),7.42(dd,J=7.7,4.9Hz,1H),7.22-7.12(m,2H),4.92(d,J=1.5Hz,2H);ES-MS[M+H] + =341.1 / 343.2.

[0521] The compounds shown in Table 6 may be prepared similarly to the compounds described above using the appropriate starting materials.

[0522] [Table 6]

[0523] Intermediate Example 12a: 2-(4-bromo-2,6-difluorobenzyl)-4-fluoroisoindolin-1-one [ka] To a solution of methyl 2-(bromomethyl)-3-fluorobenzoate (950 mg, 3.85 mmol) in MeCN (19.2 mL) was added (4-bromo-2,6-difluorophenyl)methanamine (853.8 mg, 3.85 mol) and N,N-diisopropylethylamine (1.34 mL, 7.70 mmol). The resulting mixture was stirred at 80 °C for 16 h, diluted with EtOAc, and washed with saturated NaHCO solution. The aqueous layer was extracted with EtOAc (3x). The combined extracts were washed with brine, dried over NaSO, filtered, and concentrated. Purification using normal phase chromatography on silica gel (0–100% EtOAc / hexanes) afforded the title compound (736 mg, 54% yield). 1 H NMR(400MHz,DMSO-d6)δ 7.58-7.49(m,4H),7.47-7.41(m,1H),4.77(s,2H),4.47(s,2H);ES-MS[M+H] + =356.0 / 358.0.

[0524] The compounds shown in Table 7a may be prepared similarly to the compounds described above using the appropriate starting materials.

[0525] [Table 7-a]

[0526] Intermediate Example 12b: 6-(2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one [ka] In a round-bottom flask, 6-(4-bromo-2,6-difluorobenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (678 mg, 2.0 mmol), PdCl(dppf) (147 mg, 0.2 mmol), bis(pinacolato)diboron (bis(pino (colato)diboron (761 mg, 3.0 mmol) and potassium acetate (589 mg, 6.0 mmol) were added. Degassed 1,4-dioxane (13.3 mL) was added. The reaction mixture was evacuated and purged with N (3x). After 3 h at 100 °C, the reaction mixture was filtered through a pad of Celite®, rinsed thoroughly with EtOAc / DCM, and concentrated under pressure. The crude residue was purified using normal phase chromatography on silica gel (0-70% EtOAc / DCM) to give the title compound (432 mg, 56% yield). 1 H NMR(400MHz,DMSO-d6)δ 8.74(dd,J=5.0,1.6Hz,1H),8.10(dd,J=7.7,1.6Hz,1H),7.51(dd,J=7.7,4.9H z,1H),7.29-7.23(m,2H),4.86(s,2H),4.41(s,2H),1.28(s,12H);ES-MS[M+H] + = 386.2 (boronic ester) and 307.4 (boronic acid).

[0527] The compounds shown in Table 7b may be prepared similarly to the compounds described above using the appropriate starting materials.

[0528] [Table 7-b1]

[0529] [Table 7-b2]

[0530] [Table 7-b3]

[0531] [Table 7-b4]

[0532] [Table 7-b5]

[0533] [Table 7-b6]

[0534] [Table 7-b7]

[0535] Intermediate Example 13: Methyl 4-bromo-2-methyl-2H-indazole-7-carboxylate [ka] To a solution of methyl 4-bromo-1H-indazole-7-carboxylate (prepared according to WO 2021 / 174165, 1.02 g, 4.0 mmol) in EtOAc (40 mL) was added trimethyloxonium tetrafluoroborate (1.18 g, 8.0 mmol). After 16 h at rt, the mixture was quenched with saturated NaHCO solution and extracted with EtOAc (3x). The combined extracts were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. Purification using normal phase chromatography on silica gel (0-50% EtOAc / hexanes) afforded the title compound (935 mg, 87% yield). 1 H NMR (400 MHz, DMSO-d) δ 8.61 (d, J = 0.6 Hz, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H), 4.24 (s, 3H), 3.88 (s, 3H); 2D NOESY (400 MHz, DMSO): crosspeak between N-methyl (CH, s at 4.24 ppm) and indazole CH (s at 8.61 ppm); ES-MS [M+H] + =269.0 / 270.9.

[0536] The compounds presented in Table 8 may be prepared in a manner similar to that described in the previous schemes and examples using the appropriate starting materials.

[0537] [Table 8]

[0538] Intermediate Example 14: Methyl 4-bromo-1-methyl-1H-indazole-7-carboxylate [ka] To a solution of methyl 4-bromo-1H-indazole-7-carboxylate (prepared according to WO 2021 / 174165, 225 mg, 1.0 mmol) in DMF (5.0 mL) was added sodium hydride (60% dispersion in oil, 80 mg, 2.0 mmol) at 0 °C. After 30 min, iodomethane was added to the resulting suspension, and the ice bath was removed. After 16 h, the mixture was diluted with water and extracted with DCM (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification using normal phase chromatography on silica gel (0–100% EtOAc / hexanes) afforded two separated isomers.

[0539] Isomer 1: methyl 4-bromo-2-methyl-2H-indazole-7-carboxylate (128 mg, 48% yield); 1 H NMR (400 MHz, DMSO) δ 8.61 (d, J = 0.6 Hz, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H), 4.24 (s, 3H), 3.88 (s, 3H); 2D NOESY (400 MHz, DMSO-d6): crosspeak between N-methyl (CH3, s at 4.24 ppm) and indazole CH (s at 8.61 ppm); ES-MS [M+H] + =269.0 / 270.9. Isomer 2: methyl 4-bromo-1-methyl-1H-indazole-7-carboxylate (73 mg, 27% yield); 1H NMR (400 MHz, DMSO) δ 8.19 (s, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.49 (d, J = 7.8 Hz, 1H), 4.16 (s, 3H), 3.94 (s, 3H); 2D NOESY (400 MHz, DMSO-d6): no correlation between N-methyl (CH3, s at 4.16 ppm) and indazole CH (s at 8.19 ppm); ES-MS [M+H] + =269.0 / 270.9.

[0540] The compounds presented in Table 9 may be prepared in a manner similar to that described in the previous schemes and examples using the appropriate starting materials.

[0541] [Table 9]

[0542] Intermediate Example 15: Methyl 4-bromo-2-(methyl-d3)-2H-indazole-7-carboxylate [ka] To a solution of 4-bromo-7-iodo-2-(methyl-d3)-2H-indazole (462 mg, 1.36 mmol) in DMSO (6 mL) and MeOH (3 mL) was added Pd(OAc)2 (61 mg, 0.27 mmol), 1,3-bis(diphenylphosphino)propane (140 mg, 0.34 mmol), and triethylamine (1.89 mL, 13.6 mmol). The resulting mixture was stirred at 45 °C under CO2 (1 atm). After 5 h, the mixture was diluted with EtOAc and filtered through a pad of Celite®. The filtrate was washed with water, brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified using normal phase chromatography on silica gel to give the title compound (286 mg, 77% yield). 1 H NMR(400MHz,CDCl3)δ 8.04(s,1H),7.93(d,J=7.7Hz,1H),7.30(d,J=7.7Hz,1H),4.00(s,3H);ES-MS[M+H]+ =271.9 / 273.9.

[0543] Intermediate Example 16: Methyl 8-bromo-2-methyl-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylate [ka] Step 1: Methyl (E / Z)-5-bromo-6-(N'-hydroxyacetimidamido)picolinate. To a solution of N,N-dimethylacetamide dimethyl acetal (247 μL, 1.7 mmol) and iPA (2.5 mL) was added methyl 6-amino-5-bromopicolinate (300 mg, 1.3 mmol). The resulting mixture was stirred at 85 °C for 3 h and then cooled to 50 °C. Hydroxyamine hydrochloride (117 mg, 1.7 mmol) was added in one portion. After 5 h at 50 °C, the reaction mixture was concentrated to dryness under reduced pressure. The crude residue was carried forward without further purification (374 mg). ES-MS [M+H] + =288.0 / 290.0.

[0544] Step 2: Methyl 8-bromo-2-methyl-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylate. To a solution of methyl (E / Z)-5-bromo-6-(N'-hydroxyacetimidamido)picolinate (374 mg, 1.30 mmol) in THF (3.0 mL) was added trifluoroacetic anhydride (0.54 mL, 3.9 mmol) at 0 °C. After 16 h at rt, the reaction mixture was quenched with a saturated solution of NaHCO and extracted with iPA / CHCl (1:3). The combined organic layers were concentrated under reduced pressure. The crude material was purified using normal phase chromatography on silica gel (0–10% MeOH / DCM and 1% NHOH) to give the title compound (342 mg, 97% yield). 1 H NMR(400MHz,CDCl3)δ 7.78(d,J=7.9Hz,1H),7.58(d,J=7.8Hz,1H),4.07(s,3H),2.72(s,3H);ES-MS[M+H]+ =270.0 / 271.9.

[0545] Intermediate Example 17: 2-(4-bromo-2-methyl-2H-indazol-7-yl)propan-2-ol [ka] A suspension of cerium(III) chloride (2.6 g, 10.42 mmol) and THF (13 mL) was stirred at 50 °C for 30 min and then cooled to 0 °C. A solution of methylmagnesium bromide (3.0 M in EtO, 3.47 mL, 10.42 mmol) was added. After 15 min at 0 °C, a solution of methyl 4-bromo-2-methyl-2H-indazole-7-carboxylate (935 mg, 3.47 mmol) in THF (4 mL) was added dropwise and stirred at 0 °C for 1 h. A saturated solution of NH Cl was added dropwise to the reaction mixture, which was then extracted with EtOAc (3x). The combined organic extracts were washed with brine, dried over Na SO , filtered, and concentrated under reduced pressure. Purification using normal phase chromatography on silica gel (0–100% EtOAc / hexanes) afforded the title compound. 1 H NMR(400MHz,DMSO-d6)δ 8.36(s,1H),7.27(d,J=7.5Hz,1H),7.21(d,J=7.5,1H),5.15(s,1H,4.19(s,3H),1.65(s,6H);ES-MS[M+H-H2O] + =252.9.

[0546] The compounds presented in Table 10 may be prepared in a manner similar to that described in the previous schemes and examples using the appropriate starting materials.

[0547] [Table 10]

[0548] Intermediate Example 18: 1-(4-Bromo-2-methyl-2H-indazol-7-yl)-1-cyclopropylethan-1-ol [ka] Under a N atmosphere, a solution of isopropylmagnesium chloride (2.0 M in THF, 0.150 mL, 0.3 mmol) was added dropwise to a solution of 4-bromo-7-iodo-2-methyl-2H-indazole (100 mg, 0.3 mmol) in THF (3 mL) at -40 °C. After stirring at -40 °C for 30 min, cyclopropyl methyl ketone (83 μL, 0.9 mmol) was added. After an additional 30 min, the reaction was quenched with saturated NH Cl, warmed to rt, and extracted with EtOAc (3x). The organic layers were combined, washed with brine, dried over Na SO , filtered, and concentrated under reduced pressure. The crude residue was purified using normal phase chromatography on silica gel (0–60% EtOAc / hexanes) to give the title compound. 1 H NMR(400MHz,CDCl3)δ 7.90(s,1H),7.19(d,J=7.5Hz,1H),7.10(d,J=7.5Hz,1H),4.20(s,3H),1. 65(s,3H),1.39(tt,J=8.4,5.4Hz,1H),0.56-0.35(m,4H);ES-MS[M+H-H2O] + =277.0 / 279.0

[0549] The compounds shown in Table 11 may be prepared similarly to the compounds described above using the appropriate starting materials.

[0550] [Table 11-1]

[0551] [Table 11-2]

[0552] [Table 11-3]

[0553] Intermediate Example 19: 2-(5-bromo-2-methyl-2H-indazol-7-yl)propan-2-ol [ka] To an oven-dried flask containing tetrabutylammonium chloride (106 mg, 0.38 mmol) was added THF (10 mL) and diethylene glycol dimethyl ether (0.81 mL, 5.69 mmol) at rt under N2. The reaction was cooled to 0 °C, and a solution of methylmagnesium bromide solution (3.0 M in Et2O, 1.90 mL, 5.69 mmol) was added. After 30 min, a solution of methyl 5-bromo-2-methyl-2H-indazole-7-carboxylate (510 mg, 1.90 mmol) in THF (10 mL) was added dropwise. After 3 h, the reaction was quenched with saturated NH4Cl and concentrated under reduced pressure. The crude material was diluted with water and extracted with EtOAc (3x). The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The crude material was purified by normal phase chromatography on silica gel (0-80% EtOAc / hexanes) to afford the title compound (354 mg, 69% yield). 1 H NMR(400MHz,CDCl3)δ 7.84(s,1H),7.69(d,J=1.7Hz,1H),7.22(d,J=1.7Hz,1H),4.21(s,3H),1.72(s,6H);ES-MS[M+H-H2O] + =251.0 / 252.9.

[0554] The compounds presented in Table 12 may be prepared in a manner similar to that described in the previous schemes and examples using the appropriate starting materials.

[0555] [Table 12-1]

[0556] [Table 12-2]

[0557] Intermediate Example 20: 2-(4-bromo-2-fluorophenyl)propan-2-ol [ka] To a suspension of methyl 4-bromo-2-fluorobenzoate (700 mg, 3 mmol) in THF (30 mL) was added a solution of methylmagnesium bromide (3 M in EtO, 10 mL, 30 mmol) at 0 °C. The mixture was stirred at rt for 1 h. The crude reaction mixture was then poured into an ice-cooled saturated aqueous solution of NH Cl and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na SO , filtered, and concentrated to give the title compound (670 mg, 96% yield). 1 H NMR(400MHz,DMSO-d6)δ 7.56(t,J=8.6Hz,1H),7.42(dd,J=11.3,2.0Hz,1H),7.38(dd,J=8.4,2.0Hz,1H),5.36(s,1H),1.45(d,J=1.4Hz,6H);ES-MS[M+H-H2O] + =214.9 / 216.9.

[0558] The compounds presented in Table 13 may be prepared in a manner similar to that described in the previous schemes and examples using the appropriate starting materials.

[0559] [Table 13]

[0560] Intermediate Example 21: 2-(4-bromo-2-methyl-2H-indazol-7-yl)-1-(methylsulfonyl)propan-2-ol [ka] To a solution of 2-(4-bromo-2-methyl-2H-indazol-7-yl)-1-(methylthio)propan-2-ol (38 mg, 0.12 mmol) in DCM (1 mL, 0.1 M) at 0 °C was added 3-chloroperbenzoic acid (46 mg, 0.27 mmol). After 45 min, the reaction was quenched with saturated NaHCO and extracted with DCM. The organic layers were combined, passed through a hydrophobic phase separator, and concentrated under reduced pressure. The crude residue was purified using normal phase chromatography on silica gel to give the title compound (19.2 mg, 46% yield). 1 H NMR(400MHz,CDCl3)δ 7.96(s,1H),7.36(d,J=7.5Hz,1H),7.28(d,J=7.6Hz,1H),4.99(s,1H),4.65(d,J=14.9Hz, 1H),4.23(s,3H),3.58(dd,J=14.9,1.1Hz,1H),2.23(s,3H),1.85(s,3H);ES-MS[M+H-H2O] += 329.0 / 331.0.

[0561] Intermediate Example 22: 2-(4-bromo-2-methyl-2H-indazol-7-yl)propan-1,1,1-d3-2-ol [ka] Step 1: 1-(4-Bromo-2-methyl-2H-indazol-7-yl)ethan-1-one. Under a N atmosphere, a solution of 4-bromo-7-iodo-2-methyl-2H-indazole (100 mg, 0.3 mmol) in THF (1.5 mL) was added dropwise at −40° C. to a solution of isopropylmagnesium chloride (2.0 M in THF, 0.30 mL, 0.3 mmol). After stirring at −40° C. for 30 min, N-methoxy-N-methylacetamide (158 μL, 1.5 mmol) was added. After an additional 1 h, the reaction was quenched with saturated NH4Cl, warmed to rt, and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified using normal phase chromatography on silica gel (0-100% EtOAc / hexanes) to afford the title compound (59 mg, 78% yield). 1H NMR(400MHz,DMSO-d6)δ 8.67(s,1H),7.74(d,J=7.7Hz,1H),7.43(d,J=7.7Hz,1H),4.26(s,3H),2.85(s,3H);ES-MS[M+H] + =253.1 / 254.9.

[0562] Step 2: 2-(4-Bromo-2-methyl-2H-indazol-7-yl)propan-1,1,1-d3-2-ol. To a solution of 1-(4-bromo-2-methyl-2H-indazol-7-yl)ethan-1-one (58 mg, 0.23 mmol) in THF (1.5 mL) was added methyl-d3-magnesium iodide solution (1.0 M in THF, 1.15 mL, 1.15 mmol) at 0 °C. After 1 h at 0 °C, the reaction was quenched with a saturated solution of NH4Cl and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified using normal phase chromatography on silica gel (0–100% EtOAc / hexanes) to give the title compound (43 mg, 69% yield). 1 H NMR(400MHz,DMSO-d6)δ 8.36(s,1H),7.27(d,J=7.6Hz,1H),7.21(d,J=7.6Hz,1H),5.14(s,1H),1.64(s,3H);ES-MS[M+H-H2O] + =254.0 / 256.0.

[0563] Intermediate Example 23: 2-(4-bromo-2-methyl-2H-indazol-7-yl)-1,1-difluoropropan-2-ol [ka] Step 1: 1-(4-Bromo-2-methyl-2H-indazol-7-yl)-2,2-difluoroethan-1-one. Under a N atmosphere, a solution of 4-bromo-7-iodo-2-methyl-2H-indazole (169 mg, 0.5 mmol) in THF (2.5 mL) was added dropwise at −40° C. to a solution of isopropylmagnesium chloride (2.0 M in THF, 0.5 mL, 1.0 mmol). After stirring at −40° C. for 30 min, 2,2-difluoro-N-methoxy-N-methylacetamide (0.29 mL, 2.5 mmol) was added. After 1 h, the reaction was quenched with a saturated solution of NH4Cl, warmed to rt, and extracted with EtOAc (3×). The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified using normal phase chromatography on silica gel (0-100% EtOAc / hexanes) to afford the title compound (77 mg, 53% yield). 1 H NMR(400MHz,DMSO-d6)δ 8.75(s,1H),7.96(d,J=7.7Hz,1H),7.54(d,J=7.8Hz,1H),7.44(t,J=53.2Hz,1H);ES-MS[M+H] + =289.0 / 291.0

[0564] Step 2: 2-(4-Bromo-2-methyl-2H-indazol-7-yl)-1,1-difluoropropan-2-ol. A suspension of cerium(III) chloride (266 mg, 1.07 mmol) in THF (1.7 mL) was stirred at 50 °C for 30 min, cooled to 0 °C, and a solution of methylmagnesium bromide (3.0 M in EtO, 3.47 mL, 10.42 mmol) was added. After 15 min, a solution of 1-(4-bromo-2-methyl-2H-indazol-7-yl)-2,2-difluoroethan-1-one (77 mg, 0.27 mmol) in THF (1 mL) was added dropwise and stirred at 0 °C for 1 h. To the resulting mixture was added saturated NH Cl solution dropwise, and the mixture was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na SO , filtered, and concentrated under reduced pressure. Purification using normal phase chromatography on silica gel (0-100% EtOAc / hexanes) afforded the title compound (68 mg, 84% yield). 1 H NMR(400MHz,DMSO-d6)δ 8.45(s,1H),7.37(d,J=7.6Hz,1H),7.30(d,J=7.6Hz,1H),6.72(t,J=55.8Hz,1H),6.01(s,1H),4.20(s,3H),1.68(s,3H);ES-MS[M+H] + =305.0 / 307.0.

[0565] Intermediate Example 24: 2-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazol-7-yl]propan-2-ol [ka] 2-(4-Bromo-2-methyl-indazol-7-yl)propan-2-ol (50 mg, 0.19 mmol), bis(pinacolato)diborane (71 mg, 0.28 mmol), Pd(dppf)Cl.CHCl (23 mg, 0.03 mmol), and KOAc (55 mg, 0.56 mmol) were dissolved in 1,4-dioxane (1.8 mL). The mixture was evacuated, purged with nitrogen, and stirred at 90 °C. After 16 h, the mixture was then diluted with EtOAc, filtered through a pad of Celite®, and concentrated under reduced pressure to give the title compound, which was used without further purification. ES-MS [M+H-H0] = 299.3.

[0566] Intermediate Example 25: 2-(4-(4-(aminomethyl)-3,5-difluorophenyl)-2-methyl-2H-indazol-7-yl)propan-2-ol [ka] A solution of 2-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazol-7-yl)propan-2-ol (950 mg, 3.0 mmol) in degassed 1,4-dioxane (22 mL) was added to the solution of (4-bromo-2,6-difluorophenyl)methanamine (777 mg, 3.5 mmol), cesium carbonate (2.95 g, 9.0 mmol), Pd(dppf)Cl 2( To the reaction mixture was added 220 mg (0.3 mmol) and water (4.4 mL). The reaction mixture was evacuated, purged with N2 (3x) and stirred at 100 °C. After 3 h, the mixture was diluted with EtOAc and DCM, filtered through a pad of Celite® and concentrated under reduced pressure. The crude material was purified using normal phase chromatography on silica gel (0-10% MeOH / DCM) to give the title compound (911 mg); 1 H NMR(400MHz,DMSO-d6)δ 8.56(s,1H),7.44(d,J=7.3Hz,1H),7.42-7.35(m,2H),7.20(d,J=7.3Hz,1H),4.20(s,3H),3.79(s,2H),1.70(s,6H);ES-MS[M+H-H2O]+ =314.2.

[0567] [Table 14-1]

[0568] [Table 14-2]

[0569] [Table 14-3]

[0570] [Table 14-4]

[0571] Preparation of representative compounds Example 1: 6-(2-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)-6-methylbenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (Compound 2) [ka] To a solution of 6-(2-fluoro-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (20 mg, 0.052 mmol) in degassed 1,4-dioxane (0.8 mL) was added Pd(dppf)Cl·DCM (8.5 mg, 0.01 mmol), cesium carbonate (51.3 mg, 0.16 mmol), 2-(4-bromo-2-methyl-2H-indazol-7-yl)propan-2-ol (18.7 mg, 0.07 mmol), and water (0.2 mL). The reaction mixture was evacuated and purged with N (3×) and stirred at 100 °C. After 2 h, the mixture was diluted with EtOAc and DCM, filtered through a pad of Celite®, and concentrated under reduced pressure. The crude material was purified using reverse phase HPLC to give the title compound (9.9 mg). 1 H NMR(400MHz,CDCl3)δ 8.70(dd,J=5.0,1.6Hz,1H),8.14(dd,J=7.7,1.6Hz,1H),8.03(s,1H), 7.41(dd,J=7.7,4.9Hz,1H),7.28(bs,1H),7.27-7.23(m,1H),7.21(d,J=7.2Hz,1H),7.10(d,J=7.2 Hz,1H),4.99(d,J=1.8Hz,2H),4.39(s,2H),4.25(s,3H),2.52(s,3H),1.77(s,6H);ES-MS[M+H-H2O] + =427.0.

[0572] Example 2: 6-((3-fluoro-4'-(2-hydroxypropan-2-yl)-5-isobutoxy-[1,1'-biphenyl]-4-yl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (Compound 14) [ka] 6-[(4-Bromo-2-fluoro-6-isobutoxy-phenyl)methyl]-7H-pyrrolo[3,4-b]pyridin-5-one (19 mg, 0.05 mmol), 4-(2-hydroxypropan-2-yl)phenylboronic acid (13 mg, 0.07 mmol), Pd(dppf)Cl (7 mg, 0.01 mmol), and CsCO (47.5 mg, 0.14 mmol) were combined in a reaction vial. Anhydrous 1,4-dioxane (1.0 mL) and water (0.20 mL) were added to the reaction vial. The mixture was evacuated and purged with nitrogen. After 2 h at 90 °C, the mixture was diluted with EtOAc and DCM and filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure. The crude material was purified using reverse-phase HPLC to give the title compound (4.5 mg). 1 H NMR(400MHz,DMSO-d6)δ 8.72(dd,J=4.9,1.6Hz,1H),8.10(dd,J=7.7,1.6Hz,1H),7.69-7.61(m,2 H),7.58-7.53(m,2H),7.51(dd,J=7.7,4.9Hz,1H),7.12(d,J=10.4Hz,2H) ,5.06(s,1H),4.84(d,J=1.5Hz,2H),4.34(s,2H),3.93(d,J=6.3Hz,2H),2.04(hept,J=6.6Hz,1H),1.45(s,6H),0.99(d,J=6.7Hz,6H);ES-MS[M+H] + =449.0.

[0573] Example 3: 6-(2,6-difluoro-4-(6-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (Compound 24) [ka] 2-(3-Bromo-2-methyl-2H-indazol-6-yl)propan-2-ol (13.5 mg, 0.05 mmol), 6-(2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (25.1 mg, 0.065 mmol), Pd(dppf)Cl (7.3 mg, 0.01 mmol), and CsCO (49.2 mg, 0.15 mmol) were combined in a reaction vial. Anhydrous 1,4-dioxane (1.0 mL) and water (0.20 mL) were added. The mixture was evacuated and purged with nitrogen. After 2 h at 100° C., the mixture was diluted with EtOAc and DCM and filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure. The crude material was purified using reverse-phase HPLC to give the title compound (9.4 mg). 1 H NMR(400MHz,DMSO-d6)δ 8.76(dd,J=4.9,1.6Hz,1H),8.54(d,J=1.0Hz,1H),8.12(dd,J=7.7,1.6Hz,1H),7.67(t,J= 1.2Hz,1H),7.53(dd,J=7.7,4.9Hz,1H),7.52-7.46(m,2H),7.38(d,J=1.3Hz,1H ),5.11(s,1H),4.92(s,2H),4.50(s,2H),4.16(s,3H),1.51(s,6H);ES-MS[M+H] + =449.1.

[0574] Example 4: 6-(2,6-difluoro-4-(6-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (Compound 51) [ka] 2-(3-Bromo-2-methyl-2H-indazol-6-yl)propan-2-ol (15.0 mg, 0.056 mmol), 6-(2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (25.8 mg, 0.067 mmol), Pd(dppf)Cl (4.1 mg, 0.006 mmol), and CsCO (54.8 mg, 0.16 mmol) were combined in a reaction vial. Anhydrous 1,4-dioxane (1.0 mL) and water (0.20 mL) were added. The mixture was evacuated and purged with nitrogen. After 2 h at 100° C., the mixture was diluted with EtOAc and DCM and filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure. The crude material was purified using reverse-phase HPLC to give the title compound (4.0 mg). 1 H NMR(400MHz,CDCl3)δ 8.73(d,J=4.6Hz,1H),8.15(dd,J=7.7,1.5Hz,1H),7.80(s,1H),7.54(d,J=8.9Hz,1H),7.41(dd,J=7.7,4.9Hz,1H),7. 32(dd,J=8.9,1.5Hz,1H),7.19-7.09(m,2H),5.04(d,J=1.3Hz,2H),4.50(s,2H),4.20(s,3H),1.65(s,6H);ES-MS[M+H] + =449.1.

[0575] Example 5: 6-(2,6-difluoro-4-(7-(3-hydroxyoxetan-3-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (Compound 89) [ka] 3-(4-Bromo-2-methyl-2H-indazol-7-yl)oxetan-3-ol (15.6 mg, 0.055 mmol), 6-(2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (27.6 mg, 0.072 mmol), Pd(dppf)Cl (8.1 mg, 0.01 mmol), and CsCO (54.1 mg, 0.17 mmol) were combined in a reaction vial. Anhydrous 1,4-dioxane (1.0 mL) and water (0.20 mL) were added. The mixture was evacuated and purged with nitrogen. After 2 h at 100° C., the mixture was diluted with EtOAc and DCM and filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure. The crude material was purified using reverse-phase HPLC to give the title compound (10.8 mg). 1 H NMR(400MHz,DMSO-d6)δ 8.76(dd,J=4.9,1.6Hz,1H),8.67(s,1H),8.12(dd,J=7.7,1.6Hz,1H),7.56-7.45(m,3H),7.36(d,J=7.3Hz,1H),7.27(d,J ES-MS[M+H] + =463.1.

[0576] Example 6: (R)-6-(1-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)phenyl)ethyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (Compound 94) [ka] 2-(4-Bromo-2-methyl-2H-indazol-7-yl)propan-2-ol (17 mg, 0.063 mmol), (R)-6-(1-(2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (30.3 mg, 0.076 mmol), Pd(dppf)Cl (9.3 mg, 0.013 mmol), and CsCO (62.1 mg, 0.19 mmol) were combined in a reaction vial. Anhydrous 1,4-dioxane (1.0 mL) and water (0.20 mL) were added. The mixture was evacuated and purged with nitrogen. After 2 h at 100° C., the mixture was diluted with EtOAc and DCM and filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure. The crude material was purified using reverse-phase HPLC to give the title compound (9.2 mg). 1 H NMR(400MHz,DMSO-d6)δ 8.78(dd,J=5.0,1.6Hz,1H),8.59(s,1H),8.08(dd,J=7.7,1.6Hz,1H),7.53(dd,J=7.7,4.9Hz,1H),7.45-7.39(m,3H),7.20(d,J=7.3Hz,1H),5.8 6(q,J=7.3Hz,1H),5.15(s,1H),4.85(d,J=17.8Hz,1H),4.55(d,J=17.8H z,1H),4.18(s,3H),1.77(d,J=7.3Hz,3H),1.69(s,6H);ES-MS[M+H-H2O] + =445.2.

[0577] Example 7: (R)-6-(2,6-difluoro-4-(7-(2-hydroxybutan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one and (S)-6-(2,6-difluoro-4-(7-(2-hydroxybutan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one [ka] To a solution of 2-(4-bromo-2-methyl-2H-indazol-7-yl)butan-2-ol (131.4 mg, 0.46 mmol) in anhydrous 1,4-dioxane (3.5 mL) was added 6-(2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (268.8 mg, 0.70 mmol), Pd(dppf)Cl (68.1 mg, 0.1 mmol), CsCO (456 mg, 0.17 mmol), and water (1.0 mL). The resulting mixture was evacuated and purged with nitrogen. After 4 h at 100 °C, the mixture was diluted with EtOAc, filtered through a pad of Celite®, and concentrated under reduced pressure. The crude material was purified using reverse-phase HPLC to give a racemic mixture, which was further resolved using SFC chiral separation (Chiralpak AS-H, 21 x 250 mm column, 0-50% EtOH / 0.1% DEA). After further purification using reverse-phase HPLC, two separate stereoisomers were obtained.

[0578] Isomer 1 (first eluting) (6-(2,6-difluoro-4-(7-(2-hydroxybutan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one): 1 H NMR(400MHz,CDCl3)δ 8.71(dd,J=4.9,1.6Hz,1H),8.14(dd,J=7.7,1.6Hz,1H),8.03(s,1H),7.40(dd,J=7.7 ,4.9Hz,1H),7.25-7.20(m,2H),7.17(d,J=7.3Hz,1H),7.11(d,J=7.2Hz,1H),5.15(s, 1H),5.01(s,2H),4.46(s,2H),4.24(s,3H),2.18-2.00(m,2H),1.69(s,3H),0.87(t,J=7.4Hz,3H);ES-MS[M+H-H2O] + =445.2.

[0579] Isomer 2 (second elution) (6-(2,6-difluoro-4-(7-(2-hydroxybutan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one): 1 H NMR(400MHz,CDCl3)δ 8.71(dd,J=5.0,1.6Hz,1H),8.14(dd,J=7.7,1.6Hz,1H),8.03(s,1H),7.40(dd,J=7.7 ,4.9Hz,1H),7.25-7.20(m,2H),7.17(d,J=7.3Hz,1H),7.11(d,J=7.3Hz,1H),5.15(s, 1H),5.01(s,2H),4.46(s,2H),4.24(s,3H),2.19-2.00(m,2H),1.69(s,3H),0.87(t,J=7.4Hz,3H);ES-MS[M+H-H2O] + =445.2.

[0580] Example 8: 6-[[5-[7-(1-hydroxy-1-methyl-ethyl)-2-methyl-indazol-4-yl]pyrimidin-2-yl]methyl]-7H-pyrrolo[3,4-b]pyridin-5-one (Compound 110) [ka] 6-((5-Bromopyrimidin-2-yl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (12 mg, 0.04 mmol), 2-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazol-7-yl]propan-2-ol (12 mg, 0.04 mmol), Pd(dppf)Cl CHCl (4 mg, 6 nmol), and CsCO (50 mg, 0.15 mmol) were dissolved in 1,4-dioxane (0.5 mL) and HO (0.1 mL). The mixture was evacuated and purged with nitrogen. After 16 h at 100 °C, the mixture was diluted with EtOAc, filtered through a pad of Celite®, and concentrated under reduced pressure. The crude material was purified using reverse phase HPLC to give the title compound (10.5 mg). 1H NMR(400MHz,CDCl3)δ 8.94(s,2H),8.76(dd,J=1.6,5.0Hz,1H),8.20(dd,J=1.6,7.7Hz,1H),7.99(s,1H),7.44(dd,J=5.0,7.7Hz,1H),7 .26(d,J=7.2Hz,1H),7.11(d,J=7.2Hz,1H),5.19(s,2H),4.73(s,2H),4.24(s,3H),1.77(s,6H);ES-MS[M+H-H2O] + = 397.2 and [M+H] + =415.2.

[0581] Example 9: 6-(2,6-difluoro-4-(7-(3-hydroxyazetidin-3-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (Compound 114) [ka] To a solution of tert-butyl 3-(4-(3,5-difluoro-4-((5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)methyl)phenyl)-2-methyl-2H-indazol-7-yl)-3-hydroxyazetidine-1-carboxylate (33.2 mg, 0.06 mmol) in DCM (1.0 mL) was added trifluoroacetic acid (0.14 mL, 1.77 mmol). The resulting mixture was stirred at rt for 4 h, then the mixture was slowly added to a solution of saturated NaHCO3 and extracted with iPA / CHCl3 (1:3, 3x). The combined extracts were concentrated under reduced pressure and purified using reverse-phase HPLC to give the title compound (4.3 mg). ES-MS [M+H] + =462.

[0582] Example 10: 6-(2-chloro-6-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (Compound 122) [ka] To a solution of 6-(2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (20.9 mg, 0.052 mmol) in anhydrous 1,4-dioxane (1.0 mL) was added 2-(4-bromo-2-methyl-2H-indazol-7-yl)propan-2-ol (27.9 mg, 0.11 mmol), Pd(dppf)Cl (7.6 mg, 0.01 mmol), CsCO (50.1 mg, 0.16 mmol), and water (0.2 mL). The mixture was evacuated and purged with nitrogen. After 2 h at 100 °C, the mixture was diluted with EtOAc, filtered through a pad of Celite®, and concentrated under reduced pressure. The crude material was purified using reverse phase HPLC to give the title compound (15.5 mg). 1 H NMR(400MHz,DMSO-d6)δ 8.72(dd,J=4.8,1.4Hz,1H),8.57(s,1H),8.02(dd,J=7.8,1.4Hz,1H),7.69(s,1H),7.61(dd,J=10.6,1.7Hz,1H),7.56(dd,J=7.7,4.8Hz,1H ),7.45(d,J=7.3Hz,1H),7.23(d,J=7.3Hz,1H),5.17(s,1H),5.00(d,J=1.7Hz,2H),4.40(s,2H),4.20(s,3H),1.70(s,6H);ES-MS[M+H-H2O] + =447.0.

[0583] Example 11: 6-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one (Compound 138) [ka] To a solution of 6-(2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one (20.1 mg, 0.052 mmol) in anhydrous 1,4-dioxane (1.0 mL) was added 2-(4-bromo-2-methyl-2H-indazol-7-yl)propan-2-ol (27.9 mg, 0.10 mmol), Pd(dppf)Cl (7.6 mg, 0.01 mmol), CsCO (51.0 mg, 0.16 mmol), and water (0.2 mL). The mixture was evacuated and purged with nitrogen. After 2 h at 100 °C, the mixture was diluted with EtOAc, filtered through a pad of Celite®, and concentrated under reduced pressure. The crude material was purified using reverse phase HPLC to give the title compound (14.0 mg). 1 H NMR(400MHz,DMSO-d6)δ 8.83(d,J=2.7Hz,1H),8.80(d,J=2.6Hz,1H),8.58(s,1H),7.46(dd,J=14.3,7.9Hz,3H),7.23(d, J=7.3Hz,1H),5.16(s,1H),4.95(s,2H),4.58(s,2H),4.19(s,3H),1.69(s,6H);ES-MS[M+H-H2O] + =432.0.

[0584] Example 12: 6-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one-7,7-d2 (Compound 142) [ka] To a suspension of 6-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (50 mg, 0.11 mmol) in THF (1.0 mL) was added DO (1.0 mL), followed by a solution of sodium deuterium oxide (40 wt% in DO, 14.6 μL, 0.22 mmol). The reaction was stirred at 45 °C. After 24 h, the reaction mixture was diluted with DCM, filtered through a hydrophobic phase separator, and concentrated under reduced pressure. Purification using reverse-phase HPLC afforded the title compound (35 mg, >98% deuterium uptake by HRMS). 1 H NMR(400MHz,DMSO-d6)δ 8.75(dd,J=4.9,1.6Hz,1H),8.59(s,1H),8.12(dd,J=7.7,1.6Hz,1H),7.53(dd,J=7.7,4.9Hz,1H),7.50- 7.41(m,3H),7.22(d,J=7.3Hz,1H),5.16(s,1H),4.91(s,2H),4.19(s,3H),1.69(s,6H);ES-MS[M+H-H2O] + =433.2.

[0585] Example 13: 6-(2,3-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one-7,7-d2 (Compound 149) [ka] To a solution of 2-(2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)isoindolin-1-one-3,3-d (28.1 mg, 0.073 mmol) in anhydrous 1,4-dioxane (0.8 mL) was added 2-(4-bromo-2-methyl-2H-indazol-7-yl)propan-2-ol (15 mg, 0.056 mmol), Pd(dppf)Cl (8.2 mg, 0.01 mmol), CsCO (54.8 mg, 0.17 mmol), and DO (0.2 mL). The mixture was evacuated and purged with nitrogen. After 2 h at 100 °C, the mixture was diluted with EtOAc, filtered through a pad of Celite®, and concentrated under reduced pressure. The crude material was purified using reverse phase HPLC to give the title compound (7.1 mg); 1 H NMR(400MHz,DMSO-d6)δ 8.78(dd,J=5.0,1.6Hz,1H),8.28(d,J=2.0Hz,1H),8.16(dd,J=7.7,1.6Hz,1H),7.56(dd,J=7.7,4.9Hz,1H),7.44(d,J=7.2Hz,1H),7.39(ddd ,J=8.3,6.6,1.6Hz,1H),7.31-7.23(m,1H),7.09(dd,J=7.3,1.1Hz,1H),5.16(s,1H),4.93(s,2H),4.16(s,3H),1.70(s,6H);ES-MS[M+H-H2O] + =433.3.

[0586] Example 14: 6-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (Compound 1) [ka] To a solution of 6-(2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (20 mg, 0.052 mmol) in degassed 1,4-dioxane (0.8 mL) was added Pd(dppf)Cl·DCM (8.5 mg, 0.01 mmol), cesium carbonate (51.3 mg, 0.16 mmol), 2-(4-bromo-2-methyl-2H-indazol-7-yl)propan-2-ol (18.7 mg, 0.07 mmol), and water (0.2 mL). The reaction mixture was evacuated and purged with N (3×) and stirred at 100 °C. After 2 h, the mixture was diluted with EtOAc and DCM, filtered through a pad of Celite®, and concentrated under reduced pressure. The crude material was purified using reverse phase HPLC to give the title compound (9.9 mg). 1 H NMR(400MHz,DMSO-d6)δ 8.75(dd,J=4.9,1.6Hz,1H),8.59(s,1H),8.12(dd,J=7.7,1.6Hz,1H),7.53(dd,J=7.7,4.9Hz,1H),7.50-7.41( m,3H),7.22(d,J=7.3Hz,1H),5.16(s,1H),4.91(s,2H),4.50(s,2H),4.19(s,3H),1.69(s,6H);ES-MS[M+H-H2O] + =431.2.

[0587] Example 15: 3-Bromo-6-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (Compound 173) [ka] To a solution of 2-(4-(4-(aminomethyl)-3,5-difluorophenyl)-2-methyl-2H-indazol-7-yl)propan-2-ol (911 mg, 2.75 mmol) in MeCN (14.0 mL) was added ethyl 5-bromo-2-(chloromethyl)nicotinate (prepared according to WO 2022221556, 696 mg, 2.5 mmol) and N,N-diisopropylethylamine (1.31 mL, 7.5 mmol). The resulting mixture was stirred at 80° C. for 16 h and concentrated under reduced pressure. Purification using reverse-phase HPLC afforded the title compound (950 mg, 72% yield). 1 H NMR(400MHz,DMSO-d6)δ 8.89(d,J=2.2Hz,1H),8.58(s,1H),8.36(d,J=2.2Hz,1H),7.51-7.41(m,3H),7.22(d,J=7. 3Hz,1H),5.16(s,1H),4.90(s,2H),4.49(s,2H),4.19(s,3H),1.69(s,6H);ES-MS[M+H-H2O] + =509.1.

[0588] Example 16: 6-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (Compound 174) [ka] 3-Bromo-6-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (39.5 mg, 0.075 mmol), trimethylboroxine in 1,4-dioxane (0.75 mml) mA mixture of e) (50 wt% in THF, 188 mg, 0.75 mmol), cesium carbonate (73.3 mg, 0.225 mmol), and Pd(dppf)Cl (11.0 mg, 0.015 mmol) was stirred at 80 °C. After 3 h, the mixture was filtered through a pad of Celite®, which was rinsed thoroughly with EtOAc and concentrated under reduced pressure. Purification using HPLC afforded the title compound (11.8 mg). 1 H NMR(400MHz,DMSO)δ 8.60-8.56(m,2H),7.94(dd,J=2.1,0.9Hz,1H),7.48-7.43(m,3H),7.22(d,J=7.3Hz,1H),5. 16(s,1H),4.90(s,2H),4.44(s,2H),4.19(s,3H),2.40(s,3H),1.69(s,6H);ES-MS[M+H-H2O] + =455.2.

[0589] Example 17: 3-Cyclopropyl-6-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (Compound 175) [ka] To a mixture of 3-bromo-6-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (39.5 mg, 0.075 mmol), cyclopropylboronic acid (64.4 mg, 0.75 mmol), potassium phosphate tribasic (48.4 mg, 0.225 mmol), tricyclohexylphosphine (8.4 mg, 0.03 mmol), and palladium(II) acetate (3.4 mg, 0.015 mmol) was added toluene (1.0 mL), followed by water (0.1 mL). The reaction mixture was evacuated and purged with N (3×) and stirred at 110 °C. After 16 h, the mixture was diluted with EtOAc and DCM, filtered through a pad of Celite®, and concentrated under reduced pressure. The crude material was purified using reverse phase HPLC to give the title compound (19.7 mg). 1 H NMR(400MHz,DMSO)δ 8.60(d,J=2.2Hz,1H),8.58(s,1H),7.70(d,J=2.2Hz,1H),7.48-7.43(m,3H),7.22(d,J=7.3Hz,1H),5.16(s,1H),4.89(s,2H) ),4.43(s,2H),4.19(s,3H),2.09(tt,J=8.4,5.1Hz,1H),1.69(s,6H),1.08-0.99(m,2H),0.87-0.79(m,2H);ES-MS[M+H-H2O] + =471.3.

[0590] Example 18: 6-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-3-ethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (Compound 176) [ka] Step 1: To a mixture of 3-bromo-6-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (79.1 mg, 0.15 mmol), potassium vinyltrifluoroborate (100.5 mg, 0.75 mmol), and Pd(dppf)Cl (22.0 mg, 0.03 mmol) was added N,N-diisopropylethylamine (58.2 mg, 0.45 mmol), followed by isopropyl alcohol (1.5 mL). The resulting mixture was stirred at 80 °C for 3 h and filtered through a pad of Celite®, which was thoroughly rinsed with EtOAc and concentrated under reduced pressure. Purification using normal phase chromatography on silica gel (0-100% EtOAc / hexanes) afforded the intermediate 6-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-3-vinyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (48 mg). 1 H NMR(400MHz,DMSO-d6)δ 8.84(d,J=2.0Hz,1H),8.59(s,1H),8.26(d,J=2.0Hz,1H),7.51-7.41(m,3H),7.22(d,J=7.3Hz,1H),6.88(dd,J=17.7,11.1Hz,1H) ,6.15(d,J=17.7Hz,1H),5.47(d,J=11.4Hz,1H),5.16(s,1H),4.91(s,2H),4.49(s,2H),4.19(s,3H),1.69(s,6H);ES-MS[M+H-H2O] + =457.3. [ka]

[0591] Step 2: To a solution of 6-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-3-vinyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (48 mg, 0.10 mmol) in n-butyl acetate (2.5 mL) and MeOH (1.0 mL) was added 10% palladium on carbon (25.3 mg, 0.24 mmol). The resulting mixture was stirred under a hydrogen atmosphere at rt for 16 h and then filtered through a pad of Celite®, which was rinsed thoroughly with MeOH / DCM (1:1; 20 mL) and concentrated. The crude material was purified using reverse-phase HPLC to give the title compound (15.3 mg). 1 H NMR(400MHz,DMSO-d6)δ 8.65-8.56(m,2H),7.97(d,J=2.0Hz,1H),7.45(t,J=7.8Hz,3H),7.22(d,J=7.3Hz,1H),5.16(s,1H),4.90(s ,2H),4.44(s,2H),4.19(s,3H),2.74(q,J=7.6Hz,2H),1.69(s,6H),1.22(t,J=7.6Hz,3H);ES-MS[M+H-H2O] + =459.2.

[0592] The compounds presented in Table 15 may be prepared in a manner similar to that described in the previous schemes and examples using the appropriate starting materials.

[0593] [Table 15-1]

[0594] [Table 15-2]

[0595] [Table 15-3]

[0596] Table 15-4

[0597] Table 15-5

[0598] Table 15-6

[0599] Table 15-7

[0600] Table 15-8

[0601] Table 15-9

[0602] Table 15-10

[0603] Table 15-11

[0604] Table 15-12

[0605] Table 15-13

[0606] Table 15-14

[0607] Table 15-15

[0608] Table 15-16

[0609] Table 15-17

[0610] Table 15-18

[0611] Table 15-19

[0612] Table 15-20

[0613] Table 15-21

[0614] Table 15-22

[0615] Table 15-23

[0616] Table 15-24

[0617] [Table 15-25]

[0618] [Table 15-26]

[0619] [Table 15-27]

[0620] [Table 15-28]

[0621] [Table 15-29]

[0622] [Table 15-30]

[0623] biological activity A cell line expressing muscarinic acetylcholine receptors Chinese hamster ovary (CHO-K1) cells stably expressing rat (r)M1 were purchased from the American Type Culture Collection and cultured according to their protocol. CHO cells stably expressing human (h)M2, hM3, and hM5 were previously described (Levey et al., 1991); hM1 and hM4 cDNAs were purchased from the Missouri S&T cDNA Resource; rM4 cDNA was provided by T.I. Bonner (National Institutes of Health, Bethesda, MD). rM2 and rM3 were cloned from a rat brain cDNA library and sequence-verified. hM1, rM2, rM3, hM4, and rM4 cDNAs were used to stably transfect CHO-K1 cells purchased from the American Type Culture Collection using Lipofectamine 2000. These cells were also transfected with chimeric G-proteins (G) using Lipofectamine 2000 to generate stable rM2, hM2, rM3, hM4, and rM4 cell lines for use in calcium mobilization assays. qi5 ) (provided by B.R. Conklin, University of California, San Francisco). rM1, hM1, rM3, hM3, rM5, and hM5 cells were grown in Ham's F-12 medium containing 10% heat-inactivated fetal bovine serum (FBS), 20 mM HEPES, and 50 μg / mL G418 sulfate. rM2-G qi5 , hM2-G qi5 , and hM4-G qi5 Cells were grown in the same medium also containing 500 μg / mL hygromycin B. Stable rM4-G qi5 Cells were grown in DMEM containing 10% heat-inactivated FBS, 20 mM HEPES, 400 μg / mL G418 sulfate, and 500 μg / mL hygromycin B.

[0624] b. Cell-based functional assay of muscarinic acetylcholine receptor activity For high-throughput measurements of agonist-induced increases in intracellular calcium, CHO-K1 cells stably expressing muscarinic receptors were plated at 15,000 cells / 20 μL / well in growth medium lacking G418 and hygromycin in Greiner 384-well black-wall tissue culture (TC)-treated clear-bottom plates (VWR). Cells were incubated overnight at 37°C and 5% CO. The next day, cells were washed using an ELX405 (BioTek) with four washes (80 μL) of assay buffer, then aspirated down to 20 μL. Next, 20 μL of 16 μM Fluo-4 / acetoxymethyl ester (Invitrogen, Carlsbad, CA) (prepared as a 2.3 mM stock in DMSO, mixed 1:1 with 10% (w / v) Pluronic F-127, and diluted in assay buffer) was added to the wells, and the cell plate was incubated for 50 min at 37°C and 5% CO. The dye was removed by washing with ELX405 (four washes (80 μL) of assay buffer), then aspirated down to 20 μL. Compound master plates were formatted in an 11-point CRC format (1:3 dilution) in 100% DMSO with a starting concentration of 10 mM using a BRAVO liquid handler (Agilent). Test compound CRCs were then transferred to daughter plates (240 nL) using an Echo acoustic plate reformatter (Labcyte, Sunnyvale, CA) and then diluted to a 2× stock in assay buffer (40 μL) using a Thermo Fisher Combi (Thermo Fisher Scientific, Waltham, MA).

[0625] Calcium flux was measured as an increase in the fluorescence static ratio using a Functional Drug Screening System (FDSS) 6000 (Hamamatsu Photonics, Tokyo, Japan). Compounds were added to cells (20 μL, 2×) using the FDSS 6000's automated system at 4 seconds of the 300-second protocol, and data were collected at 1 Hz. At 144 seconds of the 300-second protocol, 10 μL of EC 2012 μL of acetylcholine, a muscarinic receptor agonist, was added (5×), followed by EC 80 A concentration of acetylcholine was added (5x) at 230 seconds. Agonist activity was analyzed as a concentration-dependent increase in calcium mobilization upon compound addition. E for agonist activity max Values ​​are expressed relative to the maximum for acetylcholine. Positive allosteric modulator activity was determined using the EC 20 Antagonist activity was analyzed as a concentration-dependent increase in the acetylcholine response. 80 Concentration-response curves were generated using a four-parameter logistic equation in XLfit curve-fitting software (IDBS, Bridgewater, NJ) for Excel (Microsoft, Redmond, WA) or Prism (GraphPad Software, Inc., San Diego, CA).

[0626] The assay was also run in a second mode, where, after establishing a fluorescence baseline of approximately 3 seconds, an appropriate fixed concentration of the compound was added to the cells and the response in the cells was measured. After 140 seconds, an appropriate concentration of agonist was added and readings were taken for an additional 106 seconds. Data were converted as above to obtain the EC for the agonist in the presence of the test compound. 50 Values ​​were determined by non-linear curve fitting. EC 50 A decrease in the EC value (a shift to the left of the agonist concentration-response curve) is indicative of the degree of muscarinic positive allosteric modulation at a given concentration of the compound of the invention. 50 An increase in value (a shift to the right of the agonist concentration-response curve) is indicative of the degree of muscarinic antagonism at a given concentration of a compound of the invention. The second mode also indicates whether a compound of the invention affects the maximum response of a muscarinic receptor to an agonist.

[0627] c. Results and discussion of biological activity data Activity (EC 50 and E max ) was determined in the mAChR M1 cell-based functional assay as described above, and the data are shown in Table 16. The compound numbers correspond to the compound numbers used in Table 15. The data in Table 16 demonstrate that the disclosed compounds are positive allosteric modulators of human mAChR M1 and exhibit high PAM activity for the human mAChR M1 receptor.

[0628] [Table 16-1]

[0629] [Table 16-2]

[0630] [Table 16-3]

[0631] [Table 16-4]

[0632] [Table 16-5]

[0633] [Table 16-6]

[0634] It is understood that the above detailed description and accompanying examples are merely illustrative and are not to be taken as limitations on the scope of the invention, which is defined solely by the appended claims and their equivalents.

[0635] Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including but not limited to, with respect to chemical structure, substituents, derivatives, intermediates, synthesis, compositions, formulations, or methods of use of the invention, may be made without departing from the spirit and scope thereof.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof 【Chemistry 1】 [In the formula, A １ teeth, 【Chemistry 2】 is selected from the group consisting of Z １ is N or CR ｚ１ and Z ２ is N or CR ｚ２ and Z ３ is N or CR ｚ３ and Z ４ is N or CR ｚ４ and Here, Z １ , Z ２ , Z ３ , and Z ４ 0, 1, or 2 is N; R ｚ１ , R ｚ２ , R ｚ３ , and R ｚ４ H, D, halogen, C １～４ Alkyl, C １～４ Deuterioalkyl, C １～２ Fluoroalkyl, C ２～４ Alkenyl, cyano, -OC １～２ Alkyl, —OC １～２ Deuterioalkyl, —OC １～２ Fluoroalkyl, and C ３～４ independently selected from the group consisting of cycloalkyl; R １ , R ２ , R ３ and R ４ H, D, C １～４ Alkyl, C １～４ Deuterioalkyl, C １～４ Fluoroalkyl, halogen, cyano, G １ , -OR ａ , —O—C ２～３ Alkylene-OR ｂ , and −N(R ｃ ) (R ｄ ) independently selected from the group consisting of: R ａ , R ｂ , R ｃ , and R ｄ is H, C １～４ Alkyl, C １～４ Deuterioalkyl, C １～４ Fluoroalkyl, G １ , and -C １～３ Alkylene-G １ and wherein, alternatively, R ｃ and R ｄ is the R ｃ and R ｄ together with the nitrogen to which it is attached to form a 4-8 membered heterocyclyl optionally containing one additional heteroatom selected from the group consisting of O, N, and S, wherein said 4-8 membered heterocyclyl is selected from halogen, oxo, C １～４ Alkyl, C １～４ Deuterioalkyl, C １～４ Fluoroalkyl, OH, —OC １～４ Alkyl, —OC １～４ Deuterioalkyl, and —OC １～４ optionally substituted with 1 to 4 substituents independently selected from the group consisting of fluoroalkyl; G １ is C ３～６ cycloalkyl or a 4- to 8-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from the group consisting of O, N, and S, wherein said cycloalkyl and heterocyclyl are not halogen, oxo, C １～４ Alkyl, C １～４ Deuterioalkyl, C １～４ Fluoroalkyl, OH, —OC １～４ Alkyl, —OC １～４ Deuterioalkyl, and —OC １～４ optionally substituted with 1 to 4 substituents independently selected from the group consisting of fluoroalkyl; R ５ is a 5-12 membered heteroaryl containing 1-3 heteroatoms independently selected from the group consisting of N, O, and S, or R ５ is a 6- to 12-membered aryl, and the heteroaryl and aryl are R ６ and is substituted with 1 to 4 substituents R ７ optionally further substituted with; R ６ is -C(R ６ａ ) (R ６ｂ ) OH; R ６ａ is C １～４ Alkyl, C １～４ Deuterioalkyl, C １～４ Haloalkyl, C ３～６ Cycloalkyl, —C １～３ Alkylene-C ３～６ cycloalkyl, and —C １～５ Alkylene-X １ wherein each cycloalkyl is selected from the group consisting of halogen and C １～４ optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl; R ６ｂ is C １～４ Alkyl, C １～４ Deuterioalkyl, C １～４ Haloalkyl, C ３～６ cycloalkyl, and —C １～３ Alkylene-C ３～６ cycloalkyl, wherein each cycloalkyl is selected from the group consisting of halogen and C １～４ optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl; Or R ６ａ and R ６ｂ are taken together with the carbon to which they are attached to form a 3- to 7-membered carbocyclic ring or a 3- to 7-membered heterocyclic ring containing one heteroatom selected from the group consisting of O, N, and S, and said carbocyclic and heterocyclic rings are free from halogen, cyano, C １～４ Alkyl, C １～４ Deuterioalkyl, C １～４ Haloalkyl, OH, —OC １～４ Alkyl, —OC １～４ Deuterioalkyl, —OC １～４ Haloalkyl, —C(O)C １～４ Alkyl, and —C(O)OC １～４ optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl; X １ is -SR ６ｃ , -SOR ６ｃ , -SO ２ R ６ｃ , and —S(O)(NR ６ｄ ) R ６ｃ selected from the group consisting of: R ６ｃ is C １～４ Alkyl, C １～４ Deuterioalkyl, C １～４ Haloalkyl, C ３～６ cycloalkyl, and —C １～３ Alkylene-C ３～６ cycloalkyl, wherein each cycloalkyl is selected from the group consisting of halogen and C １～４ optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl; R ６ｄ is H, C １～４ Alkyl, C １～４ Deuterioalkyl, C １～４ Haloalkyl, C ３～６ cycloalkyl, and —C １～３ Alkylene-C ３～６ cycloalkyl, wherein each cycloalkyl is selected from the group consisting of halogen and C １～４ optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl; R ７ Each occurrence of represents a halogen, cyano, C １～４ Alkyl, C １～４ Deuterioalkyl, C １～４ Haloalkyl, OH, —OC １～４ Alkyl, —OC １～４ Deuterioalkyl, —OC １～４ Haloalkyl, C ３～６ cycloalkyl, and —C １～３ Alkylene-C ３～６ cycloalkyl, wherein each cycloalkyl is independently selected from the group consisting of halogen and C １～４ optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl; R ８ａ and R ８ｂ are H, D, and CH ３ , and CD ３ are independently selected from the group consisting of: R ９ａ and R ９ｂ are independently H or D.

2. R １ and R ２ But H, D, C １～４ Alkyl, C １～４ Deuterioalkyl, C １～４ Fluoroalkyl, halogen, cyano, C ３～６ cycloalkyl, —OR ａ , —O—C ２～３ Alkylene-OR ｂ , and −N(R ｃ ) (R ｄ wherein said C ３～６ Cycloalkyl is halogen, oxo, C １～４ Alkyl, C １～４ Deuterioalkyl, C １～４ Fluoroalkyl, OH, —OC １～４ Alkyl, —OC １～４ Deuterioalkyl, and —OC １～４ 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, optionally substituted with 1 to 4 substituents independently selected from the group consisting of fluoroalkyl.

3. R ３ and R ４ But H, D, C １～４ Alkyl, C １～４ Deuterioalkyl, C １～２ Fluoroalkyl, halogen, cyano, —OC １～４ Alkyl, —OC １～４ Deuterioalkyl, and —OC １～２ 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, independently selected from the group consisting of: fluoroalkyl;

4. A １ but, 【Transformation 3】 4. The compound according to claim 1, wherein:

5. A １ but, 【Chemistry 4】 5. The compound of claim 4, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

6. A １ but, 【Transformation 5】 6. The compound of claim 5, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

7. A １ but, 【Transformation 6】 and and / or A １ but, 【Transformation 7】 and and / or A １ but, 【Transformation 8】 and and / or A １ but, 【Chemistry 9】 7. The compound of claim 6, wherein:

8. A １ but, 【Chemistry 10】 4. The compound according to any one of claims 1 to 3, selected from the group consisting of:

9. R ５ The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein is substituted 5-12 membered heteroaryl.

10. R ５ The compound according to any one of claims 1 to 9, wherein the ring system of the substituted 5- to 12-membered heteroaryl in the formula (I) is a 5- to 6-membered heteroaryl containing 1 to 3 nitrogen atoms, or a pharmaceutically acceptable salt thereof.

11. R ５ The compound according to any one of claims 1 to 9, wherein the ring system of the substituted 5-12 membered heteroaryl in the formula (I) is a 9-10 membered heteroaryl containing 1 to 3 nitrogen atoms, or a pharmaceutically acceptable salt thereof.

12. 12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein the 9- to 10-membered heteroaryl ring system is selected from the group consisting of 2H-indazol-4-yl, 2H-indazol-3-yl, 2H-indazol-5-yl, 2H-indazol-6-yl, 2H-indazol-7-yl, 1H-indazol-3-yl, 1H-indazol-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-8-yl, 1H-indol-3-yl, 1H-benzo[d][1,2,3]triazol-7-yl, pyrazolo[1,5-a]pyridin-4-yl, pyrazolo[1,5-a]pyridin-5-yl, and [1,2,4]triazolo[1,5-a]pyridin-8-yl.

13. R ５ but, 【Chemistry 11】 【Chemistry 12】 is selected from the group consisting of R ７ａ But C １～４ Alkyl, C １～４ Deuterioalkyl, C １～４ Haloalkyl, C ３～６ cycloalkyl, and —C １～３ Alkylene-C ３～６ cycloalkyl, wherein each cycloalkyl is selected from the group consisting of halogen and C １～４ 13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl.

14. R ５ but, 【Chemistry 13】 and R ７ａ But C １～４ Alkyl, C １～４ Deuterioalkyl, C １～４ Haloalkyl, C ３～６ cycloalkyl, and —C １～３ Alkylene-C ３～６ cycloalkyl, wherein each cycloalkyl is selected from the group consisting of halogen and C １～４ optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl; R ７ｂ , R ７ｃ , and R ７ｄ But hydrogen, halogen, cyano, C １～４ Alkyl, C １～４ Deuterioalkyl, C １～４ Haloalkyl, OH, —OC １～４ Alkyl, —OC １～４ Deuterioalkyl, —OC １～４ Haloalkyl, C ３～６ cycloalkyl, and —C １～３ Alkylene-C ３～６ cycloalkyl, wherein each cycloalkyl is independently selected from the group consisting of halogen and C １～４ 13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl.

15. R ５ but, 【Chemistry 14】 15. The compound of claim 13 or 14, wherein:

16. R ７ａ But C １～２ Alkyl or C １～２ 16. The compound of any one of claims 13 to 15, or a pharmaceutically acceptable salt thereof, which is deuterioalkyl.

17. R ５ The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein is substituted 6- to 12-membered aryl.

18. R ５ but, 【Chemistry 15】 selected from the group consisting of: R ７ａ , R ７ｂ , R ７ｃ , and R ７ｄ But halogen, cyano, C １～４ Alkyl, C １～４ Deuterioalkyl, C １～４ Haloalkyl, OH, —OC １～４ Alkyl, —OC １～４ Deuterioalkyl, —OC １～４ Haloalkyl, C ３～６ cycloalkyl, and —C １～３ Alkylene-C ３～６ cycloalkyl, wherein each cycloalkyl is independently selected from the group consisting of halogen and C １～４ 18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl.

19. R ６ but, 【Chemistry 16】 19. The compound of any one of claims 1 to 18, selected from the group consisting of:

20. R ６ but, 【Chemistry 17】 [Chemistry 18] 20. The compound of claim 19, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

21. R ６ but, 【Chemistry 19】 21. The compound of claim 20, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

22. R ６ but, 【Chemistry 20】 22. The compound of claim 21, wherein:

23. The compound of formula (I) has the formula: 【Chemistry 21】 23. The compound according to any one of claims 1 to 22, selected from the group consisting of compounds of the formula:

24. 24. The compound according to claim 23, wherein the compound of formula (I) is a compound of formula (Ia), or a pharmaceutically acceptable salt thereof.

25. formula 【Chemistry 22】 25. The compound of claim 24, which is a compound of the formula: or a pharmaceutically acceptable salt thereof.

26. A １ but, 【Chemistry 23】 26. The compound of any one of claims 1 to 6, 9, 11 to 16, or 19 to 25, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

27. R ８ａ and R ８ｂ The compound of any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, wherein is H.

28. R ８ａ is H; R ８ｂ But CH ３ or R ８ａ But CH ３ and R ８ｂ The compound of any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, wherein is H.

29. R ９ａ and R ９ｂ The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein is H.

30. R ９ａ and R ９ｂ The compound according to any one of claims 1 to 29, wherein is D, or a pharmaceutically acceptable salt thereof.

31. 6-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)-6-methylbenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2-cyclopropyl-6-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-(methyl-d ３ )-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-((3,5-difluoro-4'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2,6-difluoro-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-((3,3',5-trifluoro-4'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-((3'-chloro-3,5-difluoro-4'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-((3-fluoro-4'-(2-hydroxypropan-2-yl)-5-methyl-[1,1'-biphenyl]-4-yl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-((3-cyclopropyl-5-fluoro-4'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-((4'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-((4'-(2-hydroxypropan-2-yl)-3-methyl-[1,1'-biphenyl]-4-yl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-((3-fluoro-4'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-((3-fluoro-4'-(2-hydroxypropan-2-yl)-5-isobutoxy-[1,1'-biphenyl]-4-yl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-(methyl-d ３ )-2H-indazol-4-yl)-6-methylbenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2-cyclopropyl-6-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-(methyl-d ３ )-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)benzo[d][1,3]dioxol-5-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2-fluoro-4-(7-(2-hydroxypropan-2-yl)benzo[d][1,3]dioxol-5-yl)-6-methylbenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2,6-difluoro-4-(4-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-6-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2-fluoro-4-(4-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-6-yl)-6-methylbenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2-fluoro-4-(4-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-6-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(4-(4-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-6-yl)-2-methylbenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(4-(4-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-6-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2,6-difluoro-4-(6-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2-fluoro-4-(6-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)-6-methylbenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2-fluoro-4-(6-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(4-(6-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)-2-methylbenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2,6-difluoro-4-(3-(2-hydroxypropan-2-yl)-1-methyl-1H-pyrazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2-fluoro-4-(3-(2-hydroxypropan-2-yl)-1-methyl-1H-pyrazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2-fluoro-4-(3-(2-hydroxypropan-2-yl)-1-methyl-1H-pyrazol-4-yl)-6-methylbenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(4-(3-(2-hydroxypropan-2-yl)-1-methyl-1H-pyrazol-4-yl)-2-methylbenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(4-(3-(2-hydroxypropan-2-yl)-1-methyl-1H-pyrazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-5-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-5-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-5-yl)-2-methylbenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-5-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2,6-difluoro-4-(5-(2-hydroxypropan-2-yl)quinolin-8-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2,6-difluoro-4-(8-(2-hydroxypropan-2-yl)quinolin-5-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2,6-difluoro-4-(8-(2-hydroxypropan-2-yl)quinolin-6-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2,6-difluoro-4-(6-(2-hydroxypropan-2-yl)-1-methyl-1H-indol-3-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2-chloro-6-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-5-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2,6-difluoro-4-(5-(2-hydroxypropan-2-yl)pyridin-3-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-((3,5-difluoro-3'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-((3-fluoro-4'-(2-hydroxypropan-2-yl)-5-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-((3-chloro-5-fluoro-4'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-((3,5-dichloro-4'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-((3,3',5,5'-tetrafluoro-4'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-((2',3,5,5'-tetrafluoro-4'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-((2,5-difluoro-4'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-5-yl)-6-methylbenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2,6-difluoro-4-(6-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-3-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2,6-difluoro-4-(6-(2-hydroxypropan-2-yl)-1-methyl-1H-indazol-3-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2-fluoro-4-(8-(2-hydroxypropan-2-yl)quinolin-5-yl)-6-methylbenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2,6-difluoro-4-(7-(3-hydroxypentan-3-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2-fluoro-4-(7-(3-hydroxypentan-3-yl)-2-methyl-2H-indazol-4-yl)-6-methylbenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-((2',3,5-trifluoro-4'-(2-hydroxypropan-2-yl)-3'-methyl-[1,1'-biphenyl]-4-yl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)-2-methylbenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)-6-methoxybenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2-chloro-6-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2,5-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2,3-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2,6-dichloro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2-chloro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)-6-methylbenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2-cyclopentyl-6-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2-chloro-6-cyclopropyl-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2-cyclopropyl-6-fluoro-4-(3-(2-hydroxypropan-2-yl)-1-methyl-1H-pyrazol-5-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(4-(3-(2-hydroxypropan-2-yl)-1-methyl-1H-pyrazol-5-yl)-2-methylbenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2-fluoro-4-(7-(3-hydroxypentan-3-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2,6-difluoro-4-(4-(2-hydroxypropan-2-yl)naphthalen-1-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2-fluoro-4-(4-(2-hydroxypropan-2-yl)naphthalen-1-yl)-6-methylbenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2-fluoro-4-(4-(2-hydroxypropan-2-yl)naphthalen-1-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2-fluoro-4-(5-(2-hydroxypropan-2-yl)-1H-benzo[d][1,2,3]triazol-7-yl)-6-methylbenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2-fluoro-4-(5-(2-hydroxypropan-2-yl)-1H-benzo[d][1,2,3]triazol-7-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)-6-(trifluoromethyl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2-(dimethylamino)-6-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2-(azetidin-1-yl)-6-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-1-methyl-1H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(4-(7-(1-cyclopropyl-1-hydroxyethyl)-2-methyl-2H-indazol-4-yl)-2,6-difluorobenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2,6-difluoro-4-(2-methyl-7-(1,1,1-trifluoro-2-hydroxybutan-2-yl)-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2,6-difluoro-4-(7-(2-hydroxybutan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2,6-difluoro-4-(5-(2-hydroxypropan-2-yl)-1H-benzo[d][1,2,3]triazol-7-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(4-(7-(dicyclopropyl(hydroxy)methyl)-2-methyl-2H-indazol-4-yl)-2,6-difluorobenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(4-(7-(dicyclopropyl(hydroxy)methyl)-2-methyl-2H-indazol-4-yl)-2-fluoro-6-methylbenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2,6-difluoro-4-(5-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-7-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)benzo[d][1,3]dioxol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2-cyclopropyl-6-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-5-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2,6-difluoro-4-(7-(3-hydroxyoxetan-3-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2,6-difluoro-4-(7-(3-hydroxytetrahydrofuran-3-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2,6-difluoro-4-(7-(1-hydroxycyclopentyl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2,6-difluoro-4-(7-(4-hydroxytetrahydro-2H-pyran-4-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl-1,1,1,3,3,3-d ６ )-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; (R)-6-(1-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)phenyl)ethyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl-1,1,1-d ３ )-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2,6-difluoro-4-(7-(1-hydroxycyclobutyl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2,6-difluoro-4-(7-(2-hydroxy-1-(methylsulfonyl)propan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; (S)-6-(1-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)phenyl)ethyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(4-(2-ethyl-7-(2-hydroxypropan-2-yl)-2H-indazol-4-yl)-2,6-difluorobenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(4-(7-(1,1-difluoro-2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)-2,6-difluorobenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 4-(4-(3,5-difluoro-4-((5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)methyl)phenyl)-2-methyl-2H-indazol-7-yl)-4-hydroxycyclohexane-1-carbonitrile; (R)-6-(2,6-difluoro-4-(7-(2-hydroxybutan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; (S)-6-(2,6-difluoro-4-(7-(2-hydroxybutan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-isopropyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(4-(7-(3,3-difluoro-1-hydroxycyclobutyl)-2-methyl-2H-indazol-4-yl)-2,6-difluorobenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 2-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-4-fluoroisoindolin-1-one; 6-(2,6-difluoro-4-(2-(2-hydroxypropan-2-yl)pyrazolo[1,5-a]pyridin-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2,6-difluoro-4-(2-(2-hydroxypropan-2-yl)pyrazolo[1,5-a]pyridin-5-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-((5-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)pyrazin-2-yl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-((5-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)pyrimidin-2-yl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-((2-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)pyrimidin-5-yl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-((6-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)pyridazin-3-yl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; tert-butyl 3-(4-(3,5-difluoro-4-((5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)methyl)phenyl)-2-methyl-2H-indazol-7-yl)-3-hydroxyazetidine-1-carboxylate; 6-(2,6-difluoro-4-(7-(3-hydroxyazetidin-3-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2,6-difluoro-4-(5-(2-hydroxypropan-2-yl)-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-8-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)-6-methoxybenzyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one; 6-((3,5-difluoro-4'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)methyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one; 6-((3-fluoro-4'-(2-hydroxypropan-2-yl)-5-methyl-[1,1'-biphenyl]-4-yl)methyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one; 6-((3-fluoro-4'-(2-hydroxypropan-2-yl)-5-methoxy-[1,1'-biphenyl]-4-yl)methyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one; 6-((3-chloro-5-fluoro-4'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)methyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one; 6-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one; 6-(2-chloro-6-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one; 6-(2-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)-6-methylbenzyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one; 6-((3-fluoro-5-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)pyridin-2-yl)methyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one; 6-(2-(dimethylamino)-6-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one; 6-(2-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)-6-(2-methoxyethoxy)benzyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one; 6-((3-fluoro-4'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)methyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one; 6-((4'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)methyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one; 6-((4'-(2-hydroxypropan-2-yl)-3-methyl-[1,1'-biphenyl]-4-yl)methyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one; 6-(2-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one; 6-(4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one; 6-(4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)-2-methylbenzyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one; 6-(2-cyclopropyl-6-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one; 6-(2-chloro-6-cyclopropyl-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one; 6-(2-(azetidin-1-yl)-6-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one; 6-(2-cyclopentyl-6-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one; 6-((3,5-difluoro-4'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one; 6-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one; 6-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one; 2-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one; 2-((3,5-difluoro-4'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)methyl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one; 6-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one-7,7-d ２ ; 6-(2-cyclopropyl-6-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one-7,7-d ２ ; 6-(2-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)-6-methylbenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one-7,7-d ２ ; 6-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-(methyl-d ３ )-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one-7,7-d ２ ; 6-(2-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-(methyl-d ３ )-2H-indazol-4-yl)-6-methylbenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one-7,7-d ２ ; 6-(2-cyclopropyl-6-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-(methyl-d ３ )-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one-7,7-d ２ ; 6-(2,5-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one-7,7-d ２ ; 6-(2,3-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one-7,7-d ２ ; 6-(2-chloro-6-cyclopropyl-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one-7,7-d ２ ; 6-(2-(azetidin-1-yl)-6-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one-7,7-d ２ ; 6-(2-cyclopentyl-6-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one-7,7-d ２ ; 6-(4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)-2-isopropylbenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one-7,7-d ２ ; 2-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-7-fluoroisoindolin-1-one; 2-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-5-yl)benzyl)-7-fluoroisoindolin-1-one; 2-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl-1,1,1,3,3,3-d ６ )-2-methyl-2H-indazol-4-yl)benzyl)-7-fluoroisoindolin-1-one; 2-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-1-methyl-1H-indazol-4-yl)benzyl)-7-fluoroisoindolin-1-one; 2-(4-(7-(1,1-difluoro-2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)-2,6-difluorobenzyl)-7-fluoroisoindolin-1-one; 2-(2,6-difluoro-4-(7-(3-hydroxyoxetan-3-yl)-2-methyl-2H-indazol-4-yl)benzyl)-7-fluoroisoindolin-1-one; 7-fluoro-2-(2-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)isoindolin-1-one; 7-fluoro-2-(4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)-2-methylbenzyl)isoindolin-1-one; 7-fluoro-2-(2-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)-6-methylbenzyl)isoindolin-1-one; 2-(2,5-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-7-fluoroisoindolin-1-one; 2-(2,3-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-7-fluoroisoindolin-1-one; 2-(2-chloro-6-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-7-fluoroisoindolin-1-one; 7-fluoro-2-(2-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-5-yl)benzyl)isoindolin-1-one; 7-fluoro-2-(4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-5-yl)-2-methylbenzyl)isoindolin-1-one; 7-fluoro-2-(2-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-5-yl)-6-methylbenzyl)isoindolin-1-one; 2-(2,5-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-5-yl)benzyl)-7-fluoroisoindolin-1-one; 2-(2,3-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-5-yl)benzyl)-7-fluoroisoindolin-1-one; 2-(2-chloro-6-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-5-yl)benzyl)-7-fluoroisoindolin-1-one; 2-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)isoindolin-1-one; 3-bromo-6-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 3-cyclopropyl-6-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-3-ethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; and 6-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-3-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one 10. The compound of claim 1 selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

32. 6-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)-6-methylbenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2-cyclopropyl-6-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-(methyl-d ３ )-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-(methyl-d ３ )-2H-indazol-4-yl)-6-methylbenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2-chloro-6-fluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2,6-difluoro-4-(7-(4-hydroxytetrahydro-2H-pyran-4-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl-1,1,1-d ３ )-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; and 6-(2,6-difluoro-4-(7-(2-hydroxypropan-2-yl)-2-methyl-2H-indazol-4-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one-7,7-d ２ 32. The compound of claim 1 or 31 selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

33. 33. The compound of any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, having at least 50% deuterium incorporation at each deuterium label.

34. A hydrate, solvate, polymorph, or prodrug of the compound of any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof.

35. 35. A pharmaceutical composition comprising a compound, hydrate, solvate, polymorph, or prodrug of any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

36. A method for treating a disorder associated with muscarinic acetylcholine receptor activity in a mammal, comprising administering to the mammal an effective amount of a compound, hydrate, solvate, polymorph, or prodrug of any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 35.

37. 37. The method of claim 36, wherein the mammal is a human.

38. 36. The method of claim 34 or 35, wherein the muscarinic acetylcholine receptor is mAChR M1.

39. 39. The method of any of claims 36-38, wherein said mammal has been diagnosed as in need of treatment for said disorder prior to said administering step.

40. 40. The method of any of claims 36-39, further comprising the step of identifying a mammal in need of treatment for said disorder.

41. 41. The method of any of claims 36 to 40, wherein the disorder is a neurological disorder or a psychiatric disorder, or a combination thereof.

42. 42. The method of any of claims 36 to 41, wherein the disorder is psychosis, schizophrenia, conduct disorder, disruptive behavior disorder, bipolar disorder, psychotic episode of anxiety, anxiety associated with psychosis, psychotic mood disorder, severe major depressive disorder, mood disorder associated with psychotic disorder, acute mania, depression associated with bipolar disorder, mood disorder associated with schizophrenia, behavioral signs of mental retardation, conduct disorder, autistic disorder, movement disorder, Tourette's syndrome, akinetic syndrome, movement disorder associated with Parkinson's disease, tardive dyskinesia, drug-induced and neurodegenerative-based dyskinesia, attention deficit hyperactivity disorder, cognitive impairment, dementia, or memory impairment, or a combination thereof.

43. 42. The method of any of claims 36 to 41, wherein the disorder is Alzheimer's disease, schizophrenia, a sleep disorder, a pain disorder, or a cognitive disorder, or a combination thereof.

44. 44. The method of claim 43, wherein the pain disorder is neuropathic pain, central pain syndrome, post-operative pain syndrome, bone and joint pain, repetitive motion pain, dental pain, cancer pain, myofascial pain, perioperative pain, chronic pain, dysmenorrhea, inflammatory pain, headache, migraine, cluster headache, headache, primary hyperalgesia, secondary hyperalgesia, primary allodynia, secondary allodynia, or a combination thereof.

45. A compound, hydrate, solvate, polymorph, or prodrug of any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 35, for use in treating a disorder associated with muscarinic acetylcholine receptor activity in a mammal.

46. Use of a compound, hydrate, solvate, polymorph, or prodrug, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 34, or a pharmaceutical composition according to claim 35, for the preparation of a medicament for the treatment of a disorder associated with muscarinic acetylcholine receptor activity in a mammal.

Images