Muscarinic acetylcholine receptor M4 antagonist

Abstract

Disclosed herein are compounds of formula (III) useful as antagonists of the muscarinic acetylcholine receptor M4 (mAChR M4). Also disclosed herein are methods of making the compounds, pharmaceutical compositions containing the compounds, and methods of using the compounds and compositions to treat neurodegenerative disorders. [Formula 1] TIFF2024500880000233.tif37170

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 129,196, filed October 22, 2020, U.S. Provisional Patent Application No. 63 / 170,899, filed April 5, 2021, and U.S. Provisional Patent Application No. 63 / 284,750, filed December 1, 2021, each of which is incorporated by reference in its entirety.

[0002] Government Interest Statement This invention was made with Government support under Grant W81XWH-19-1-0355 awarded by the Department of Defense. The Government has certain rights in this invention.

[0003] Technical Field The present disclosure relates to compounds, compositions and methods for treating disorders associated with muscarinic acetylcholine receptor dysfunction. [Background technology]

[0004] Parkinson's disease (PD) is the second most common neurodegenerative disease with increasing prevalence as a function of age. Furthermore, early-onset PD is also on the rise. The hallmark of PD is the progressive degeneration and loss of dopaminergic neurons in the substantia nigra (SN) and basal ganglia (BG), resulting in prominent motor symptoms including bradykinesia, tremor, rigidity, gait dysfunction, and postural instability. Currently, levodopa (L-DOPA) is the standard treatment for treating motor symptoms, but it is not curative and long-term use can cause L-DOPA-induced dyskinesia (LID).

[0005] Prior to L-DOPA, compounds with anticholinergic properties were the preferred PD treatment method. Cholinergic neurons provide important neuromodulatory control of the BG motor circuitry. The action of cholinergic pathways on the basal ganglia pathways is complex, but activation of muscarinic acetylcholine receptors (mAChRs) generally acts to oppose dopamine (DA) signaling. For example, mAChR agonists inhibit DA release and inhibit the multiple behavioral effects of drugs that increase DA levels and signaling. Interestingly, muscarinic acetylcholine receptor (mAChR) antagonists were the first available treatment for PD and are still widely used for the treatment of this disorder. Although many studies of the action of mAChR antagonists were conducted before the introduction of randomized controlled trials, recent well-controlled double-blind crossover design studies demonstrate significant improvements in multiple aspects of motor function in patients receiving mAChR antagonists. Unfortunately, mAChR antagonists have numerous peripheral adverse effects as well as numerous dose-limiting adverse effects that severely limit their clinical usefulness, including confusion and severe cognitive impairment.

[0006] Adverse effects associated with mAChR antagonists limit the dose that can be tolerated, so previous clinical studies may underestimate the efficacy that could be achieved if the dose of mAChR antagonists could be increased to achieve a more complete blockade of the specific mAChR subtypes responsible for the antiparkinsonian effects of these agents. 1 ~M 5 The mAChR antagonists, such as scopolamine, are nonselective across these subtypes, and many of their adverse effects are likely mediated by mAChR subtypes that are not involved in antiparkinsonian activity. Thus, compounds with a more selective profile for individual mAChRs may offer advantages in PD and related disorders such as dystonia. For example, several studies have demonstrated that M 4These results indicate that mAChR subtypes may play a dominant role in mAChR regulation of basal ganglia motor function. Summary of the Invention

[0007] One aspect of the present invention is a compound of formula (III): [ka] or a pharma- ceutically acceptable salt thereof, wherein: G 1 teeth, [ka] and G 1a teeth, [ka] and R is hydrogen, C 1~4 Alkyl, C 3~4 Cycloalkyl or -C 1~3 Alkylene-C 3~4 is cycloalkyl; R 1a is hydrogen, C 1~4 Alkyl, C 1~4 Fluoroalkyl, -OC 1~4 Alkyl, -OC 1~4 Fluoroalkyl, -OC 3~6 Cycloalkyl, -OCH 2 C 3~6 Cycloalkyl, -SO 2 C 1~4 Alkyl, -SO 2 C 3~6 Cycloalkyl, phenyl, or C 3~6 cycloalkyl, where phenyl and each C 3~6 Cycloalkyl is halogen, cyano, C 1~4 Alkyl, C 1~4 Haloalkyl, -OC 1~4 Alkyl and -OC 1~4optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkyl; R 1b is hydrogen, halogen, cyano, C 1~4 Alkyl, C 1~4 Fluoroalkyl or C 3~6 is cycloalkyl; Or alternatively, R 1a and R 1b together with the atoms to which they are attached form a 5- or 6-membered unsaturated or partially unsaturated carbocyclic or heterocyclic ring, which carbocyclic or heterocyclic ring is unsubstituted or is substituted with halogen, cyano, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 2~4 Alkenyl, C 3~6 Cycloalkyl, and -C 1~3 Alkylene-C 3~4 substituted with 1 to 4 substituents independently selected from the group consisting of cycloalkyl; R 2 CF 3 or CHF 2 and; R 2a Each occurrence independently represents a halogen, C 1~4 Alkyl, C 1~4 Fluoroalkyl, -OC 1~4 Alkyl or -OC 1~4 is a fluoroalkyl; n is 0, 1, or 2; R 3 is G 2 , -L 1 -G 2 , -L 2 -G 2 , -L 2 -L 1 -G 2 , -C 2~6 Alkylene-R 3a , C 3~7 Alkyl or C 3~7 is haloalkyl; R 4 is hydrogen or methyl; L 1 is C1~5 Alkylene or C 1~5 is a fluoroalkylene; L 2 is 1,1-cyclopropylene; G 2 is a C optionally fused to a 6- to 12-membered aryl, a 5- to 12-membered heteroaryl, a 4- to 12-membered heterocyclyl, or a 6-membered aromatic hydrocarbon; 3~12 carbocyclyl, where G 2 is halogen, cyano, oxo, C 1~4 Alkyl, C 1~4 Haloalkyl, -OR 13 , -N(R 13 ) 2 , -C 1~3 Alkylene-OR 13 , and -C 1~3 Alkylene-N(R 13 ) 2 optionally substituted with 1 to 5 substituents independently selected from the group consisting of: R 3a -OR 14 Or -N(R 14 ) 2 and; R 13 Each occurrence independently represents hydrogen, C 1~4 Alkyl, C 1~4 Haloalkyl, C 3~4 Cycloalkyl or -C 1~3 Alkylene-C 3~4 cycloalkyl, where, instead, two R 13 is two R 13 Along with the nitrogen to which it is attached, halogens and C 1~4 forming a 4-6 membered heterocyclic ring optionally substituted with 1-4 substituents independently selected from the group consisting of alkyl; R 14 Each occurrence independently represents hydrogen, C 1~4 Alkyl, C 1~4 Haloalkyl, G 3 , or -C 1~3 Alkylene-G 3 Instead, two R 14 is two R 14Along with the nitrogen to which it is attached, halogens and C 1~4 forming a 4-6 membered heterocyclic ring optionally substituted with 1-4 substituents independently selected from the group consisting of alkyl; G 3 is phenyl, monocyclic 5- to 6-membered heteroaryl, monocyclic 4- to 8-membered heterocyclyl, or monocyclic C 3~8 cycloalkyl, where G 3 is halogen, cyano, C 1~4 Alkyl, C 1~4 Haloalkyl, oxo, -OR 15 , and -N(R 15 ) 2 optionally substituted with 1 to 5 substituents independently selected from the group consisting of: R 15 Each occurrence independently represents hydrogen, C 1~4 Alkyl, C 1~4 Haloalkyl, C 3~4 Cycloalkyl or -C 1~3 Alkylene-C 3~4 cycloalkyl, where, instead, two R 15 is two R 15 Along with the nitrogen to which it is attached, halogens and C 1~4 Forms a 4-6 membered heterocyclic ring optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl.

[0008] Another aspect of the present invention is a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, wherein: G 1 teeth, [ka] and R is hydrogen, C 1~4 Alkyl, C 3~4 Cycloalkyl or -C 1~3 Alkylene-C 3~4is cycloalkyl; R 1a is hydrogen, C 1~4 Alkyl, C 1~4 Difluoroalkyl, -OC 1~4 Alkyl, -OC 1~4 Fluoroalkyl, -OC 3~6 Cycloalkyl, -OCH 2 C 3~6 Cycloalkyl, -SO 2 C 1~4 Alkyl, -SO 2 C 3~6 Cycloalkyl, phenyl, or C 3~6 cycloalkyl, where phenyl and each C 3~6 Cycloalkyl is halogen, cyano, C 1~4 Alkyl, C 1~4 Haloalkyl, -OC 1~4 Alkyl and -OC 1~4 optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkyl; R 1b is hydrogen, halogen, cyano, C 1~4 Alkyl, C 1~4 Fluoroalkyl or C 3~6 is cycloalkyl; Or alternatively, R 1a and R 1b together with the atoms to which they are attached form a 5- or 6-membered unsaturated or partially unsaturated carbocyclic or heterocyclic ring, which carbocyclic or heterocyclic ring is unsubstituted or is substituted with halogen, cyano, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 2~4 Alkenyl, C 3~6 Cycloalkyl, and -C 1~3 Alkylene-C 3~4 substituted with 1 to 4 substituents independently selected from the group consisting of cycloalkyl; R 2 CF 3 or CHF 2 and; R 3 is G 2 , -L1 -G 2 , -L 2 -G 2 , -L 2 -L 1 -G 2 , -C 2~6 Alkylene-R 3a , C 3~7 Alkyl or C 3~7 is haloalkyl; L 1 is C 1~5 is alkylene; L 2 is 1,1-cyclopropylene; G 2 is a C optionally fused to a 6- to 12-membered aryl, a 5- to 12-membered heteroaryl, a 4- to 12-membered heterocyclyl, or a 6-membered aromatic hydrocarbon; 3~12 carbocyclyl, where G 2 is halogen, cyano, oxo, C 1~4 Alkyl, C 1~4 Haloalkyl, -OR 13 , -N(R 13 ) 2 , -C 1~3 Alkylene-OR 13 , and -C 1~3 Alkylene-N(R 13 ) 2 optionally substituted with 1 to 5 substituents independently selected from the group consisting of: R 3a -OR 14 Or -N(R 14 ) 2 and; R 13 Each occurrence independently represents hydrogen, C 1~4 Alkyl, C 1~4 Haloalkyl, C 3~4 Cycloalkyl or -C 1~3 Alkylene-C 3~4 cycloalkyl, where, instead, two R 13 is two R 13 Along with the nitrogen to which it is attached, halogens and C 1~4forming a 4-6 membered heterocyclic ring optionally substituted with 1-4 substituents independently selected from the group consisting of alkyl; R 14 Each occurrence independently represents hydrogen, C 1~4 Alkyl, C 1~4 Haloalkyl, G 3 , or -C 1~3 Alkylene-G 3 Instead, two R 14 is two R 14 Along with the nitrogen to which it is attached, halogens and C 1~4 forming a 4-6 membered heterocyclic ring optionally substituted with 1-4 substituents independently selected from the group consisting of alkyl; G 3 is phenyl, monocyclic 5- to 6-membered heteroaryl, monocyclic 4- to 8-membered heterocyclyl, or monocyclic C 3~8 cycloalkyl, where G 3 is halogen, cyano, C 1~4 Alkyl, C 1~4 Haloalkyl, oxo, -OR 15 , and -N(R 15 ) 2 optionally substituted with 1 to 5 substituents independently selected from the group consisting of: R 15 Each occurrence independently represents hydrogen, C 1~4 Alkyl, C 1~4 Haloalkyl, C 3~4 Cycloalkyl or -C 1~3 Alkylene-C 3~4 cycloalkyl, where, instead, two R 15 is two R 15 Along with the nitrogen to which it is attached, halogens and C 1~4 Forms a 4-6 membered heterocyclic ring optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl.

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

[0010] In another aspect, the present invention provides a mAChR M 4 The present invention provides a method for treating a disorder in a subject that would benefit from antagonism of the agonist, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or (III), or a pharma- ceutically acceptable salt or composition thereof.

[0011] In another aspect, the present invention provides a method for the treatment of mAChR M 4 The present invention provides a method of antagonizing an anti-inflammatory agent comprising administering to a subject a therapeutically effective amount of a compound of formula (I) or (III), or a pharma- ceutically acceptable salt or composition thereof.

[0012] In another aspect, the present invention provides a method for treating a neurodegenerative disease, movement disorder, or brain disorder, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or (III), or a pharma- ceutically acceptable salt or composition thereof.

[0013] In another aspect, the present invention provides a compound of formula (I) or (III), or a pharma- ceutically acceptable salt or composition thereof, for use in a method for the treatment of a neurodegenerative disease, a movement disorder, or a brain disorder.

[0014] In another aspect, the present invention provides a method for the detection of mAChR M 4 The present invention provides a compound of formula (I) or (III), or a pharma- ceutically acceptable salt or composition thereof, for use in antagonizing

[0015] In another aspect, the present invention provides the use of a compound of formula (I) or (III), or a pharma- ceutically acceptable salt or composition thereof, in the manufacture of a medicament for the treatment of a neurodegenerative disease, a movement disorder, or a brain disorder.

[0016] In another aspect, the present invention provides a method for the treatment of mAChR M 4 The present invention provides the use of a compound of formula (I) or (III), or a pharma- ceutically acceptable salt or composition thereof, in the manufacture of a medicament for antagonizing

[0017] In another aspect, the invention provides a kit comprising a compound of formula (I) or (III), or a pharma- ceutically acceptable salt or composition thereof, and instructions for use. [Brief description of the drawings]

[0018] [Figure 1] 1 shows an Oak Ridge Thermal Ellipsoid Plot (ORTEP) from the X-ray crystal structure analysis of compound No. 61. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] Detailed Description 1.Definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled 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.

[0020] The terms "comprise," "including," "having," "having," "can," "containing," and variations thereof, as used herein, 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 expressly described.

[0021] The modifier "about" used in connection with a quantity is inclusive of the stated value and has a meaning dictated by the context (e.g., it includes the smallest degree of error associated with measurement of a particular quantity). The modifier "about" should also be considered to disclose 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 clear from the context, thus, for example, "about 1" can also mean 0.5 to 1.4.

[0022] 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 Ed. (inside 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 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.

[0023] The term "alkoxy" as used herein refers to the group -O-alkyl. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, and tert-butoxy.

[0024] 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 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.

[0025] The term "alkenyl," as used herein, means a straight or branched hydrocarbon chain containing at least one carbon-carbon double bond.

[0026] The term "alkoxyalkyl," as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.

[0027] The term "alkoxyfluoroalkyl," as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through a fluoroalkyl group, as defined herein.

[0028] The term "alkylene," as used herein, refers to a divalent group derived from a straight or branched chain saturated hydrocarbon. Representative examples of alkylene include, but are not limited to, -CH 2 -, -CD 2-, -CH 2 CH 2 -, -C(CH 3 )(H)-, -C(CH 3 )(D)-, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 - and -CH 2 CH 2 CH 2 CH 2 CH 2 -- are some examples.

[0029] The term "alkylamino," as used herein, means at least one alkyl group, as defined herein, appended to the parent molecular moiety through an amino group, as defined herein.

[0030] The term "amide" as used herein means -C(O)NR- or -NRC(O)-, where R can be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroalkyl.

[0031] The term "aminoalkyl," as used herein, means at least one amino group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein.

[0032] The term "amino" as used herein refers to -NR x R y (In the formula, R x and R y (which can be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroalkyl). In the case of an aminoalkyl group or any other moiety where amino is attached to two other moieties together, amino is represented by -NR x -(In the formula, R xcan be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroalkyl).

[0033] The term "aryl" as used herein refers to a phenyl or phenyl attached to a parent molecular moiety and fused to a cycloalkane group (e.g., the aryl can be indan-4-yl), a six-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 "six-membered arene" is used to refer to a fused ring. The six-membered arene is monocyclic (e.g., benzene or benzo). The aryl can be monocyclic (phenyl) or bicyclic (e.g., a 9-12 membered fused bicyclic ring system).

[0034] The term "cyanoalkyl," as used herein, means at least one --CN group, appended to the parent molecular moiety through an alkylene group, as defined herein.

[0035] The term "cyanofluoroalkyl," as used herein, means at least one --CN group, appended to the parent molecular moiety through a fluoroalkyl group, as defined herein.

[0036] The term "cycloalkoxy," as used herein, refers to a cycloalkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.

[0037] The term "cycloalkyl" or "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 cycloalkanes when present as a substituent. Cycloalkyl can be a monocyclic cycloalkyl (e.g., cyclopropyl), a fused bicyclic cycloalkyl (e.g., decahydronaphthalenyl), or 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). 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.

[0038] The term "cycloalkenyl" or "cycloalkene" as used herein means a non-aromatic monocyclic or polycyclic ring system containing all carbon atoms as ring members and at least one carbon-carbon double bond, preferably having 5-10 carbon atoms per ring. The term "cycloalkenyl" is used herein to refer to a cycloalkene when present as a substituent. A cycloalkenyl can be a monocyclic cycloalkenyl (e.g., cyclopentenyl), a fused bicyclic (e.g., octahydronaphthalenyl), or a bridged cycloalkenyl (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]heptenyl). Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, or cycloheptenyl. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, or cycloheptenyl.

[0039] The term "carbocyclyl" means "cycloalkyl" or "cycloalkenyl." The term "carbocycle" means "cycloalkane" or "cycloalkene." The term "carbocyclyl" refers to a "carbocycle" when present as a substituent.

[0040] The term "1,1-carbocyclylene" refers to a geminal divalent radical derived from a cycloalkyl. Representative examples include 1,1-C 3~6 Cycloalkylene (i.e. [ka] Another example is 1,1-cyclopropylene (i.e. [ka] ).

[0041] The term "fluoroalkyl" 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 fluorine. Representative examples of fluoroalkyl include, but are not limited to, 2-fluoroethyl, 2,2,2-trifluoroethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl, and trifluoropropyl (such as 3,3,3-trifluoropropyl).

[0042] The term "difluoroalkyl" as used herein means an alkyl group, as defined herein, in which two hydrogen atoms have been replaced by fluorine. Representative examples of difluoroalkyl include difluoromethyl and difluoroethyl.

[0043] The term "fluoroalkylene" as used herein means an alkylene group, as defined herein, in which one, two, three, four, five, six, seven, or eight hydrogen atoms are replaced by fluorine. Representative examples of fluoroalkylene include, but are not limited to, -CF2 -, -CH 2 CF 2 -, 1,2-difluoroethylene, 1,1,2,2-tetrafluoroethylene, 1,3,3,3-tetrafluoropropylene, 1,1,2,3,3-pentafluoropropylene, and perfluoropropylenes, such as 1,1,2,2,3,3-hexafluoropropylene.

[0044] The term "fluoroalkoxy" as used herein means at least one fluoroalkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of fluoroalkoxy include, but are not limited to, difluoromethoxy, trifluoromethoxy, and 2,2,2-trifluoroethoxy.

[0045] The term "halogen" or "halo" as used herein means Cl, Br, I or F.

[0046] The term "haloalkyl" as used herein means an alkyl group, as defined herein, in which 1, 2, 3, 4, 5, 6, 7, or 8 hydrogen atoms are replaced by halogen.

[0047] The term "haloalkoxy," as used herein, means at least one haloalkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.

[0048] The term "halocycloalkyl," as used herein, means a cycloalkyl group, as defined herein, in which one or more hydrogen atoms have been replaced by halogen.

[0049] The term "heteroalkyl," as used herein, means an alkyl group, as defined herein, in which one or more carbon atoms are replaced by a heteroatom selected from S, O, P, and N. Representative examples of heteroalkyls include, but are not limited to, alkyl ethers, secondary and tertiary alkyl amines, amides, and alkyl sulfides.

[0050] 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 heteroaromatic ring (bicyclic heteroaryl). The term "heteroaryl" is used herein to refer to a heteroarene when present as a substituent. 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 the group consisting of 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 heteroaryl groups are 8-12 membered ring systems, including fused bicyclic heteroaromatic ring systems (i.e., 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 monocyclic heteroarenes (e.g., naphthyridinyl), and phenyls fused to 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 to a 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.Other 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., For example, 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.

[0051] 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, oxazolidin ... Examples include cetanyl, 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, where two non-adjacent atoms of the 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. 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 heterocyclyls 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]hexanyl (including 3-azabicyclo[3.1.0]hexane), and the like. -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, 3-oxaspiro[5.5]undecanyl, 6-oxaspiro[2.5]octan-1-yl, and 3-oxabicyclo[3.1.0]hexan-6-yl. Tricyclic heterocycles are exemplified by a bicyclic heterocycle fused to a 6-membered arene, or a bicyclic heterocycle fused to a monocyclic cycloalkane, or a bicyclic heterocycle fused to a monocyclic cycloalkene, or a bicyclic heterocycle fused to a monocyclic heterocycle, or a bicyclic heterocycle in which two non-adjacent atoms of a 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.

[0052] The terms "hydroxyl" or "hydroxy" as used herein refer to an --OH group.

[0053] The term "hydroxyalkyl," as used herein, means at least one --OH group, appended to the parent molecular moiety through an alkylene group, as defined herein.

[0054] The term "hydroxyfluoroalkyl," as used herein, means at least one --OH group, appended to the parent molecular moiety through a fluoroalkyl group, as defined herein.

[0055] The terms "alkyl," "cycloalkyl," "alkylene," and the like are used with a symbol indicating the number of atoms present in the group in a specific instance (e.g., "C 1~4 Alkyl, C 3~6 Cycloalkyl, C 1~4 These symbols are used as commonly understood by those of ordinary skill in the art. For example, the designation "C" followed by a numeric suffix indicates the number of atoms present in the group that follows. Thus, "C 3 "Alkyl" is an alkyl group containing three carbon atoms (i.e., n-propyl, isopropyl). 1~4 When a range is given, such as "C", the members of the group that follow can have any number of carbon atoms within the stated range. 1~4"Alkyl" refers, for example, to an alkyl group having from 1 to 4 carbon atoms of any configuration (ie, straight chain or branched).

[0056] The term "substituted" refers to a group that may be further substituted with one or more non-hydrogen substituents. Substituents include, but are not limited to, halogen, =O (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.

[0057] For the compounds described herein, in accordance with the permitted valences of atoms and substituents, the groups and substituents can be selected such that selection and substitution result in stable compounds (e.g., which do not spontaneously undergo transformations such as those by rearrangement, cyclization, elimination, and the like).

[0058] As used herein, the term "mAChRM 4 A "receptor antagonist" is, for example, an agent that inhibits the mAChR M receptor in an animal, particularly a mammal (e.g., a human). 4 The term "agonist" refers to any exogenously administered compound or agent that directly or indirectly antagonizes

[0059] 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, in addition to 6 and 9, the numbers 7 and 8 are specifically contemplated, 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.

[0060] 2.Compound In one aspect, the present invention provides a compound of formula (I) or (III), wherein R, R 2 , R 3 , R 4 , G 1 and G 1a is as defined herein. As described below, formula (I) can have any of the subformulas: (IA), (I-A1), (I-A2), (IB), (I-B1), (I-B2), (II), (II-A), (II-A1), (II-A2), (II-B1), or (II-B2), all of which are subformulas of formula (III). Formula (III) may also have any of the sub-formulas, (IC), (I-C1), (I-C2), (ID), (I-D1), (I-D2), (III-A), (III-B), (III-A1), (III-B1), (III-A2), (III-B2), (IV), (IV-A), (IV-A1), (IV-A2), (IV-B), (IV-B1), (IV-B2), (V), (VA), (VB), (VI), (VI-A), and (VI-B).

[0061] An unsubstituted or substituted ring (i.e., optionally substituted), 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 any 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 indicated, any optional substituents of the 5-12 membered heteroaryl are still present on the 5-6 membered heteroaryl.

[0062] G 1 base [ka] In R 1a and R 1b is shown with an unspecified point of attachment and may be attached at any ring carbon atom available for substitution, i.e. [ka] It is.

[0063] In the following, numbered embodiments of the invention are disclosed, the first embodiment being designated E1a, subsequent embodiments being designated E1b, E1.1, E2, etc.

[0064] E1a. Compound of formula (III): [ka] or a pharma- ceutically acceptable salt thereof, G 1 teeth, [ka] and G 1a teeth, [ka] and R is hydrogen, C 1~4 Alkyl, C 3~4 Cycloalkyl or -C 1~3 Alkylene-C 3~4 is cycloalkyl; R 1a is hydrogen, C 1~4 Alkyl, C 1~4 Fluoroalkyl, -OC 1~4 Alkyl, -OC 1~4 Fluoroalkyl, -OC 3~6 Cycloalkyl, -OCH 2 C 3~6 Cycloalkyl, -SO 2 C 1~4 Alkyl, -SO 2 C 3~6 Cycloalkyl, phenyl, or C 3~6 cycloalkyl, where phenyl and each C 3~6 Cycloalkyl is halogen, cyano, C 1~4 Alkyl, C 1~4 Haloalkyl, -OC 1~4 Alkyl and -OC 1~4 optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkyl; R 1b is hydrogen, halogen, cyano, C 1~4 Alkyl, C 1~4 Fluoroalkyl or C 3~6 is cycloalkyl; Or alternatively, R 1a and R 1b together with the atoms to which they are attached form a 5- or 6-membered unsaturated or partially unsaturated carbocyclic or heterocyclic ring, which carbocyclic or heterocyclic ring is unsubstituted or is substituted with halogen, cyano, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 2~4 Alkenyl, C3~6 Cycloalkyl, and -C 1~3 Alkylene-C 3~4 substituted with 1 to 4 substituents independently selected from the group consisting of cycloalkyl; R 2 CF 3 or CHF 2 and; R 2a Each occurrence independently represents a halogen, C 1~4 Alkyl, C 1~4 Fluoroalkyl, -OC 1~4 Alkyl or -OC 1~4 is a fluoroalkyl; n is 0, 1, or 2; R 3 is G 2 , -L 1 -G 2 , -L 2 -G 2 , -L 2 -L 1 -G 2 , -C 2~6 Alkylene-R 3a , C 3~7 Alkyl or C 3~7 is haloalkyl; R 4 is hydrogen or methyl; L 1 is C 1~5 Alkylene or C 1~5 is a fluoroalkylene; L 2 is 1,1-cyclopropylene; G 2 is a C optionally fused to a 6- to 12-membered aryl, a 5- to 12-membered heteroaryl, a 4- to 12-membered heterocyclyl, or a 6-membered aromatic hydrocarbon; 3~12 carbocyclyl, where G 2 is halogen, cyano, oxo, C 1~4 Alkyl, C 1~4 Haloalkyl, -OR 13 , -N(R 13 ) 2 , -C 1~3 Alkylene-OR 13 , and -C1~3 Alkylene-N(R 13 ) 2 optionally substituted with 1 to 5 substituents independently selected from the group consisting of: R 3a -OR 14 Or -N(R 14 ) 2 and; R 13 Each occurrence independently represents hydrogen, C 1~4 Alkyl, C 1~4 Haloalkyl, C 3~4 Cycloalkyl or -C 1~3 Alkylene-C 3~4 cycloalkyl, where, instead, two R 13 is two R 13 Along with the nitrogen to which it is attached, halogens and C 1~4 forming a 4-6 membered heterocyclic ring optionally substituted with 1-4 substituents independently selected from the group consisting of alkyl; R 14 Each occurrence independently represents hydrogen, C 1~4 Alkyl, C 1~4 Haloalkyl, G 3 , or -C 1~3 Alkylene-G 3 Instead, two R 14 is two R 14 Along with the nitrogen to which it is attached, halogens and C 1~4 forming a 4-6 membered heterocyclic ring optionally substituted with 1-4 substituents independently selected from the group consisting of alkyl; G 3 is phenyl, monocyclic 5- to 6-membered heteroaryl, monocyclic 4- to 8-membered heterocyclyl, or monocyclic C 3~8 cycloalkyl, where G 3 is halogen, cyano, C 1~4 Alkyl, C 1~4 Haloalkyl, oxo, -OR 15 , and -N(R 15 ) 2 optionally substituted with 1 to 5 substituents independently selected from the group consisting of: R 15Each occurrence independently represents hydrogen, C 1~4 Alkyl, C 1~4 Haloalkyl, C 3~4 Cycloalkyl or -C 1~3 Alkylene-C 3~4 cycloalkyl, where, instead, two R 15 is two R 15 Along with the nitrogen to which it is attached, halogens and C 1~4 and forming a 4-6 membered heterocyclic ring optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl.

[0065] E1b. Compound of formula (III): [ka] or a pharma- ceutically acceptable salt thereof, G 1 teeth, [ka] and G 1a teeth, [ka] and R is hydrogen, C 1~4 Alkyl, C 3~4 Cycloalkyl or -C 1~3 Alkylene-C 3~4 is cycloalkyl; R 2 CF 3 or CHF 2 and; R 2a Each occurrence independently represents a halogen, C 1~4 Alkyl, C 1~4 Fluoroalkyl, -OC 1~4 Alkyl or -OC 1~4 is a fluoroalkyl; n is 0, 1, or 2; R3 is G 2 , -L 1 -G 2 , -L 2 -G 2 , -L 2 -L 1 -G 2 , -C 2~6 Alkylene-R 3a , C 3~7 Alkyl or C 3~7 is haloalkyl; R 4 is hydrogen or methyl; L 1 is C 1~5 Alkylene or C 1~5 is a fluoroalkylene; L 2 is 1,1-cyclopropylene; G 2 is a C optionally fused to a 6- to 12-membered aryl, a 5- to 12-membered heteroaryl, a 4- to 12-membered heterocyclyl, or a 6-membered aromatic hydrocarbon; 3~12 carbocyclyl, where G 2 is halogen, cyano, oxo, C 1~4 Alkyl, C 1~4 Haloalkyl, -OR 13 , -N(R 13 ) 2 , -C 1~3 Alkylene-OR 13 , and -C 1~3 Alkylene-N(R 13 ) 2 optionally substituted with 1 to 5 substituents independently selected from the group consisting of: R 3a -OR 14 Or -N(R 14 ) 2 and; R 13 Each occurrence independently represents hydrogen, C 1~4 Alkyl, C 1~4 Haloalkyl, C 3~4 Cycloalkyl or -C 1~3 Alkylene-C 3~4 cycloalkyl, where, instead, two R 13is two R 13 Along with the nitrogen to which it is attached, halogens and C 1~4 forming a 4-6 membered heterocyclic ring optionally substituted with 1-4 substituents independently selected from the group consisting of alkyl; R 14 Each occurrence independently represents hydrogen, C 1~4 Alkyl, C 1~4 Haloalkyl, G 3 , or -C 1~3 Alkylene-G 3 Instead, two R 14 is two R 14 Along with the nitrogen to which it is attached, halogens and C 1~4 forming a 4-6 membered heterocyclic ring optionally substituted with 1-4 substituents independently selected from the group consisting of alkyl; G 3 is phenyl, monocyclic 5- to 6-membered heteroaryl, monocyclic 4- to 8-membered heterocyclyl, or monocyclic C 3~8 cycloalkyl, where G 3 is halogen, cyano, C 1~4 Alkyl, C 1~4 Haloalkyl, oxo, -OR 15 , and -N(R 15 ) 2 optionally substituted with 1 to 5 substituents independently selected from the group consisting of: R 15 Each occurrence independently represents hydrogen, C 1~4 Alkyl, C 1~4 Haloalkyl, C 3~4 Cycloalkyl or -C 1~3 Alkylene-C 3~4 cycloalkyl, where, instead, two R 15 is two R 15 Along with the nitrogen to which it is attached, halogens and C 1~4 and forming a 4-6 membered heterocyclic ring optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl.

[0066] E1.1 The compound according to formula (III-A), E1a or E1b, or a pharma- ceutically acceptable salt thereof. [ka]

[0067] E1.2 The compound according to formula (III-B) E1a or E1b, or a pharma- ceutically acceptable salt thereof. [ka]

[0068] E1.3 The compound according to E1.1 of formula (III-A1), or a pharma- ceutically acceptable salt thereof. [ka]

[0069] E1.4 The compound according to E1.2 of formula (III-B1), or a pharma- ceutically acceptable salt thereof. [ka]

[0070] E1.5 The compound according to E1.1 of formula (III-A2), or a pharma- ceutically acceptable salt thereof. [ka]

[0071] E1.6 The compound according to E1.2 of formula (III-B2), or a pharma- ceutically acceptable salt thereof. [ka]

[0072] E2. Compounds of formula (I) E1a or E1b, or pharma- ceutically acceptable salts thereof [ka] (In the formula: R1a is hydrogen, C 1~4 Alkyl, C 1~4 Difluoroalkyl, -OC 1~4 Alkyl, -OC 1~4 Fluoroalkyl, -OC 3~6 Cycloalkyl, -OCH 2 C 3~6 Cycloalkyl, -SO 2 C 1~4 Alkyl, -SO 2 C 3~6 Cycloalkyl, phenyl, or C 3~6 cycloalkyl, where phenyl and each C 3~6 Cycloalkyl is halogen, cyano, C 1~4 Alkyl, C 1~4 Haloalkyl, -OC 1~4 Alkyl and -OC 1~4 optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkyl; R 1b is hydrogen, halogen, cyano, C 1~4 Alkyl, C 1~4 Fluoroalkyl or C 3~6 is cycloalkyl; Or alternatively, R 1a and R 1b together with the atoms to which they are attached form a 5- or 6-membered unsaturated or partially unsaturated carbocyclic or heterocyclic ring, which carbocyclic or heterocyclic ring is unsubstituted or is substituted with halogen, cyano, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 2~4 Alkenyl, C 3~6 Cycloalkyl, and -C 1~3 Alkylene-C 3~4 substituted with 1 to 4 substituents independently selected from the group consisting of cycloalkyl; R 2 CF 3 or CHF 2 and; L 1 is C 1~5 alkylene).

[0073] E2.1 A compound according to any of E1a, E1b, or E2 of formula (IA), or a pharma- ceutically acceptable salt thereof. [ka]

[0074] E2.2 The compound according to E2.1 of formula (I-A1), or a pharma- ceutically acceptable salt thereof. [ka]

[0075] E2.3 The compound according to E2.1 of formula (I-A2), or a pharma- ceutically acceptable salt thereof. [ka]

[0076] E2.4 A compound according to any of E1a, E1b, or E2 of formula (IB), or a pharma- ceutically acceptable salt thereof. [ka]

[0077] E2.5 The compound according to E2.4 of formula (I-B1), or a pharma- ceutically acceptable salt thereof. [ka]

[0078] E2.6 The compound according to E2.4 of formula (I-B2), or a pharma- ceutically acceptable salt thereof. [ka]

[0079] E2.7 A compound according to formula (IC) E1a or E1b, or a pharma- ceutically acceptable salt thereof. [ka]

[0080] E2.8 The compound according to E2.7 of formula (I-C1), or a pharma- ceutically acceptable salt thereof. [ka]

[0081] E2.9 The compound according to E2.7 of formula (I-C2), or a pharma- ceutically acceptable salt thereof. [ka]

[0082] E2.10 A compound according to formula (ID) E1a or E1b, or a pharma- ceutically acceptable salt thereof. [ka]

[0083] E2.11. The compound according to E2.10 of formula (I-D1), or a pharma- ceutically acceptable salt thereof. [ka]

[0084] E2.12. The compound according to E2.10 of formula (I-D2), or a pharma- ceutically acceptable salt thereof. [ka]

[0085] E3.R 3 But -L 1 -G 2 The compound according to any one of E1a to E2.12, or a pharma- ceutically acceptable salt thereof.

[0086] E4.R 3 But, G 2The compound according to any one of E1a to E2.12, or a pharma- ceutically acceptable salt thereof.

[0087] E5. G 2 is optionally substituted 4-12 membered heterocyclyl, or a pharma- ceutically acceptable salt thereof.

[0088] E6. G 2 or a pharma- ceutically acceptable salt thereof; or a 4-8 membered monocyclic heterocyclyl ring system, a 6-10 membered bridged bicyclic heterocyclyl ring system, a 7-12 membered fused bicyclic heterocyclyl ring system, or a 7-12 membered spiroheterocyclyl ring system, wherein the heterocyclyl ring system contains 1-2 heteroatoms independently selected from O, N, and S; or a pharma- ceutically acceptable salt thereof.

[0089] E6.1. G 2 or a pharma- ceutically acceptable salt thereof. The compound according to E6, wherein the optionally substituted 4-12 membered heterocyclyl ring system in is a 4-8 membered monocyclic heterocyclyl ring system; or a pharma- ceutically acceptable salt thereof.

[0090] E6.2. G 2 or a pharma- ceutically acceptable salt thereof. The compound according to E6, wherein the optionally substituted 4-12 membered heterocyclyl ring system in is a 7-12 membered fused bicyclic heterocyclyl ring system; or a pharma- ceutically acceptable salt thereof.

[0091] E6.3. G 2 or a pharma- ceutically acceptable salt thereof. The compound according to E6, wherein the optionally substituted 4-12 membered heterocyclyl ring system in is a 6-10 membered bridged bicyclic heterocyclyl ring system; or a pharma- ceutically acceptable salt thereof.

[0092] E6.4. G 2 or a pharma- ceutically acceptable salt thereof. The compound according to E6, wherein the optionally substituted 4-12 membered heterocyclyl ring system in

[0093] E6.5. G2 The compound according to any one of E5 to E6.4, wherein the heterocyclyl ring system in the formula: contains 1 to 2 ring oxygen atoms, or a pharma- ceutically acceptable salt thereof.

[0094] E7. G 2 or a pharmaceutically acceptable salt thereof.

[0095] E7.1. G 2 or a pharmaceutically acceptable salt thereof.

[0096] E7.2. G 2or a pharmaceutically acceptable salt thereof.

[0097] E7.3. G 2 or a pharmaceutically acceptable salt thereof.

[0098] E7.4. G 2 or a pharma- ceutically acceptable salt thereof. The compound according to E7.2, wherein the optionally substituted 4-12 membered heterocyclyl ring system in is octahydro-3aH-cyclohepta[b]furanyl; or a pharma- ceutically acceptable salt thereof.

[0099] E7.5. G 2 or a pharma- ceutically acceptable salt thereof. The compound according to E7.2, wherein the optionally substituted 4-12 membered heterocyclyl ring system is tetrahydropyranyl, oxepanyl, 1,4-dioxanyl, hexahydro-2H-cyclopenta[b]furanyl, or octahydro-3aH-cyclohepta[b]furanyl; or a pharma- ceutically acceptable salt thereof.

[0100] E7.6. G 2or a pharma- ceutically acceptable salt thereof. The compound according to E7.1, wherein the optionally substituted 4- to 12-membered heterocyclyl ring system in

[0101] E7.7. G 2 or a pharma- ceutically acceptable salt thereof. The compound according to E7, wherein the optionally substituted 4- to 12-membered heterocyclyl ring system is 5-oxaspiro[3.5]nonanyl; or a pharma- ceutically acceptable salt thereof.

[0102] E8. G 2 The optionally substituted 4- to 12-membered heterocyclyl ring system in the formula (I) is selected from the group consisting of oxetan-3-yl, tetrahydrofuran-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, oxepan-4-yl, 7-oxabicyclo[2.2.1]heptan-2-yl, 1,4-dioxan-2-yl, hexahydro-2H-cyclopenta[b]furan-3-yl, octahydro-3aH-cyclohepta[b]furan-3a-yl, 3-oxabicyclo[2.2.1]hept ...3aH-cyclohepta[b]furan-3a-yl, 3-oxabicyclo[2.2.1]heptan-2-yl, hexahydro-3aH-cyclohepta[b]furan-3a-yl, 3-oxabicyclo[2.2.1]heptan-2-yl, hexahydro-3aH-cyclohepta[b]furan-3a-yl, 3-oxabicyclo[2. The compound according to any one of E5 to E7, which is chloro[3.1.0]hexan-6-yl, 2-oxaspiro[3.3]heptan-6-yl, 3-oxaspiro[5.5]undecan-9-yl, 6-oxaspiro[2.5]octan-1-yl, tetrahydro-2H-thiopyran-4-yl, 5-oxaspiro[2.4]heptan-6-yl, or 2-oxabicyclo[2.1.1]hexan-4-yl, or 5-oxaspiro[3.5]nonan-8-yl, or a pharma- ceutically acceptable salt thereof.

[0103] E8.1. G 2The optionally substituted 4- to 12-membered heterocyclyl ring system in the formula (I) is selected from the group consisting of oxetan-3-yl, tetrahydrofuran-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, oxepan-4-yl, 7-oxabicyclo[2.2.1]heptan-2-yl, 1,4-dioxan-2-yl, hexahydro-2H-cyclopenta[b]furan-3-yl, octahydro-3aH-cyclohepta[b]furan-3a-yl, , 3-oxabicyclo[3.1.0]hexan-6-yl, 2-oxaspiro[3.3]heptan-6-yl, 3-oxaspiro[5.5]undecan-9-yl, 6-oxaspiro[2.5]octan-1-yl, tetrahydro-2H-thiopyran-4-yl, 5-oxaspiro[2.4]heptan-6-yl, or 2-oxabicyclo[2.1.1]hexan-4-yl, or a pharma- ceutically acceptable salt thereof.

[0104] E8.2. G 2 The optionally substituted 4- to 12-membered heterocyclyl ring system in the formula (I) is selected from the group consisting of oxetan-3-yl, tetrahydrofuran-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, oxepan-4-yl, 7-oxabicyclo[2.2.1]heptan-2-yl, 1,4-dioxan-2-yl, hexahydro-2H-cyclopenta[b]furan-3 ... E8.1, wherein the compound is octahydro-3aH-cyclohepta[b]furan-3a-yl, 3-oxabicyclo[3.1.0]hexan-6-yl, 2-oxaspiro[3.3]heptan-6-yl, 3-oxaspiro[5.5]undecan-9-yl, 6-oxaspiro[2.5]octan-1-yl, or tetrahydro-2H-thiopyran-4-yl, or a pharma- ceutically acceptable salt thereof.

[0105] E8.3. G 2or a pharmaceutically acceptable salt thereof.

[0106] E8.4. G 2 or a pharma- ceutically acceptable salt thereof. The compound according to E8.2, wherein the optionally substituted 4-12 membered heterocyclyl ring system in is octahydro-3aH-cyclohepta[b]furan-3a-yl;

[0107] E8.5. G 2 or a pharma- ceutically acceptable salt thereof.

[0108] E8.6. G 2 or a pharma- ceutically acceptable salt thereof. The compound according to E8.1, wherein the optionally substituted 4- to 12-membered heterocyclyl ring system in

[0109] E8.7. G 2or a pharma- ceutically acceptable salt thereof. The compound according to E8, wherein the optionally substituted 4- to 12-membered heterocyclyl ring system is 5-oxaspiro[3.5]nonan-8-yl;

[0110] E9. G 2 But halogen, hydroxy, oxo, C 1~4 Alkyl and -OC 1~4 The compound according to any one of E5 to E8.7, or a pharma- ceutically acceptable salt thereof, optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl.

[0111] E9.1. G 2 is optionally substituted with 1 to 4 substituents independently selected from the group consisting of fluoro and methyl, or a pharma- ceutically acceptable salt thereof.

[0112] E10. G 2 but, [ka] The compound according to any one of E1a to E9, or a pharma- ceutically acceptable salt thereof.

[0113] E10.1. G 2 but, [ka] The compound according to any one of E1a to E10, or a pharma- ceutically acceptable salt thereof.

[0114] E10.2. G 2 but, [ka] The compound according to any one of E1a to E10.1, or a pharma- ceutically acceptable salt thereof.

[0115] E10.3. G 2but, [ka] The compound according to any one of E1a to E10.2, or a pharma- ceutically acceptable salt thereof.

[0116] E10.4. G 2 but, [ka] The compound according to any one of E1a to E10.2, or a pharma- ceutically acceptable salt thereof.

[0117] E10.5. G 2 but, [ka] The compound according to any one of E1a to E10.1, or a pharma- ceutically acceptable salt thereof.

[0118] E10.6. G 2 but, [ka] The compound according to any one of E1a to E10, or a pharma- ceutically acceptable salt thereof.

[0119] E11. G 2 but, [ka] The compound according to any one of E1a to E10, or a pharma- ceutically acceptable salt thereof.

[0120] E11.1. G 2 but, [ka] The compound according to any one of E1a to E10.1 or E11, or a pharma- ceutically acceptable salt thereof.

[0121] E11.2. G 2 but, [ka] The compound according to any one of E1a to E11.1, or a pharma- ceutically acceptable salt thereof.

[0122] E11.3. G 2 but, [ka] The compound according to any one of E1a to E10.3 or E11 to E11.2, or a pharma- ceutically acceptable salt thereof.

[0123] E11.4. G 2 but, [ka] or a pharma- ceutically acceptable salt thereof.

[0124] E11.5. G 2 but, [ka] or a pharma- ceutically acceptable salt thereof.

[0125] E12. G 2 but, [ka] The compound according to any one of E1a to E11, or a pharma- ceutically acceptable salt thereof.

[0126] E12.1. G2 but, [ka] The compound according to any one of E1a to E11.1 or E12, or a pharma- ceutically acceptable salt thereof.

[0127] E12.2. G 2 but, [ka] The compound according to any one of E1a to E11.2 or E12.1, or a pharma- ceutically acceptable salt thereof.

[0128] E12.3. G 2 but, [ka] or a pharma- ceutically acceptable salt thereof.

[0129] E12.4. G 2 but, [ka] or a pharma- ceutically acceptable salt thereof.

[0130] E12.5. G 2 but, [ka] The compound according to any one of E12 to E12.4, or a pharma- ceutically acceptable salt thereof.

[0131] E12.6. G 2 but, [ka] The compound according to any one of E12 to E12.4, or a pharma- ceutically acceptable salt thereof.

[0132] E13. G 2 but, [ka] The compound according to any one of E1a to E12.3, or a pharma- ceutically acceptable salt thereof.

[0133] E14. G 2 In [ka] but, [ka] or a pharma- ceutically acceptable salt thereof.

[0134] E15. G 2 is optionally substituted 6-12 membered aryl, or a pharma- ceutically acceptable salt thereof.

[0135] E16. G 2 is optionally substituted 5-12 membered heteroaryl, or a pharma- ceutically acceptable salt thereof.

[0136] E17. G 2 is optionally fused to a six-membered aromatic hydrocarbon, 3~12 The compound according to any one of E1a to E4, or a pharma- ceutically acceptable salt thereof, wherein the compound is carbocyclyl.

[0137] E18. Optionally substituted C optionally fused to a 6-membered aromatic hydrocarbon 3~12 The carbocyclyl ring system is a monocyclic C 3~8The compound according to any one of E1a to E4, or E17, which is cycloalkyl, or a pharma- ceutically acceptable salt thereof.

[0138] E18.1. Optionally substituted C optionally fused to a six-membered aromatic hydrocarbon 3~12 The compound according to E18, wherein the carbocyclyl ring system is cyclohexyl; or a pharma- ceutically acceptable salt thereof.

[0139] E19. G 2 The compound according to any one of E1a to E4 or E17 to E18.1, or a pharma- ceutically acceptable salt thereof, wherein: is cyclohexyl.

[0140] E20. L 1 But, C 1~5 The compound according to any one of E1a to E3 or E5 to E19, or a pharma- ceutically acceptable salt thereof, wherein E1a is alkylene.

[0141] E21. L 1 But, CH 2 , C.H. 2 CH 2 , or C(CH 3 ) (H), or a pharma- ceutically acceptable salt thereof.

[0142] E22. L 1 But, CH 2 or a pharma- ceutically acceptable salt thereof.

[0143] E23. L 1 CH in 2 But, CD 2 or a pharma- ceutically acceptable salt thereof.

[0144] E23.1. L 1 CH in 2 is CHD, or a pharma- ceutically acceptable salt thereof.

[0145] E24.L1 But, CH 2 CH 2 or a pharma- ceutically acceptable salt thereof.

[0146] E25. L 1 CH in 2 CH 2 But, CD 2 CH 2 (i.e., -L 1 -G 2 But -CD 2 CH 2 -G 2 E24, or a pharma- ceutically acceptable salt thereof.

[0147] E26. L 1 But, C 1~5 The compound according to any one of E1a to E1.6, E2.1 to E3, or E5 to E19, which is fluoroalkylene, or a pharma- ceutically acceptable salt thereof.

[0148] E27.L 1 But, CH 2 CF 2 (i.e., -L 1 -G 2 But -CH 2 CF 2 -G 2 E26, or a pharma- ceutically acceptable salt thereof.

[0149] E28. L 1 CH in 2 CF 2 But, CD 2 CF 2 (i.e., -L 1 -G 2 But, -CD 2 CF 2 -G 2 E27, or a pharma- ceutically acceptable salt thereof.

[0150] E29. R 1a But hydrogen, C 1~4 Alkyl, C 1~4Difluoroalkyl, -OC 1~4 Alkyl, -OC 1~4 Fluoroalkyl, -OC 3~6 Cycloalkyl, -OCH 2 C 3~6 Cycloalkyl, -SO 2 C 1~4 Alkyl, -SO 2 C 3~6 Cycloalkyl, phenyl, or C 3~6 cycloalkyl, where phenyl and each C 3~6 Cycloalkyl is halogen, cyano, C 1~4 Alkyl, C 1~4 Haloalkyl, -OC 1~4 Alkyl and -OC 1~4 optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkyl; R 1b But hydrogen, halogen, cyano, C 1~4 Alkyl, C 1~4 Fluoroalkyl or C 3~6 The compound according to any one of E1a to E28, or a pharma- ceutically acceptable salt thereof, which is cycloalkyl.

[0151] E30.R 1a is hydrogen, -CH 3 , -C(CH 3 ) 3 , -CHF 2 , -C(CH 3 )F 2 , -OCH 3 , -SO 2 CH 3 , 5-fluoro-2-methylphenyl, cyclopropyl, 2,2-difluorocyclopropyl, 1-trifluoromethylcyclopropyl, or cyclobutyl; R 1b is hydrogen, cyano, CH 3 , or CF 3 The compound according to any one of E1a to E29, or a pharma- ceutically acceptable salt thereof.

[0152] E30.1. R 1a is hydrogen, -CH 3 , -CHF2 , -OCH 3 or cyclopropyl; R 1b is hydrogen, cyano, CH 3 , or CF 3 or a pharma- ceutically acceptable salt thereof.

[0153] E30.2. R 1b is hydrogen, or a pharma- ceutically acceptable salt thereof.

[0154] E31. G 1 but, [ka] The compound according to any one of E1a to E29, or a pharma- ceutically acceptable salt thereof.

[0155] E32. G 1 but, [ka] The compound according to any one of E1a to E29, or a pharma- ceutically acceptable salt thereof.

[0156] E33. G 1 but, [ka] (i.e., G 1a -G 1 -but, [ka] E1a to E32, or a pharma- ceutically acceptable salt thereof.

[0157] E33.1. G 1 but, [ka] or a pharma- ceutically acceptable salt thereof.

[0158] E34.R 1a and R 1b is hydrogen (i.e., G 1 but, [ka] E1a to E33, or a pharma- ceutically acceptable salt thereof.

[0159] E34.1. Formula (II) [ka] or a pharma- ceutically acceptable salt thereof.

[0160] E34.2. The compound according to E34.1 of formula (II-A), or a pharma- ceutically acceptable salt thereof. [ka]

[0161] E34.3 The compound according to E34.2 of formula (II-A1), or a pharma- ceutically acceptable salt thereof. [ka]

[0162] E34.4 The compound according to E34.2 of formula (II-A2), or a pharma- ceutically acceptable salt thereof. [ka]

[0163] E34.5 The compound according to E34.1 of formula (II-B), or a pharma- ceutically acceptable salt thereof. [ka]

[0164] E34.6 The compound according to E34.5 of formula (II-B1), or a pharma- ceutically acceptable salt thereof. [ka]

[0165] E34.7 The compound according to E34.5 of formula (II-B2), or a pharma- ceutically acceptable salt thereof. [ka]

[0166] E34.8. Formula (IV) [ka] or a pharma- ceutically acceptable salt thereof.

[0167] E34.9. The compound according to E34.8 of formula (IV-A), or a pharma- ceutically acceptable salt thereof. [ka]

[0168] E34.10 The compound according to E34.9 of formula (IV-A1), or a pharma- ceutically acceptable salt thereof. [ka]

[0169] E34.11 The compound according to E34.9 of formula (IV-A2), or a pharma- ceutically acceptable salt thereof. [ka]

[0170] E34.12 The compound according to E34.8 of formula (IV-B), or a pharma- ceutically acceptable salt thereof. [ka]

[0171] E34.13 The compound according to E34.12 of formula (IV-B1), or a pharma- ceutically acceptable salt thereof. [ka]

[0172] E34.14 The compound according to E34.12 of formula (IV-B2), or a pharma- ceutically acceptable salt thereof. [ka]

[0173] E35.R 1a and R 1b together with the atoms to which they are attached form a 5- or 6-membered unsaturated or partially unsaturated carbocyclic or heterocyclic ring, which carbocyclic or heterocyclic ring is unsubstituted or is substituted with halogen, cyano, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 2~4 Alkenyl, C 3~6 Cycloalkyl, and -C 1~3 Alkylene-C 3~4 The compound according to any one of E1a to E28, or a pharma- ceutically acceptable salt thereof, substituted with 1 to 4 substituents independently selected from the group consisting of cycloalkyl.

[0174] E36.R 1a and R 1b together with the atom to which they are attached form an unsubstituted or substituted 5-membered unsaturated heterocyclic ring, or a pharma- ceutically acceptable salt thereof.

[0175] E37 The compound according to E36, wherein the unsubstituted or substituted 5-membered unsaturated heterocyclic ring system is thiophene, or a pharma- ceutically acceptable salt thereof.

[0176] E38. G 1 but, [ka] 38. The compound of claim 37, wherein:

[0177] E39.R 1a and R 1b together with the atom to which they are attached form an unsubstituted or substituted 6-membered unsaturated or partially unsaturated carbocyclic ring, or a pharma- ceutically acceptable salt thereof.

[0178] E40. G 1 but, [ka] or a pharma- ceutically acceptable salt thereof.

[0179] E41. G 1a but, [ka] The compound according to any one of E1a to E1.6, E3 to E34, or E35 to E40, or a pharma- ceutically acceptable salt thereof.

[0180] E41.1. G 1a but, [ka] or a pharma- ceutically acceptable salt thereof.

[0181] E42. G 1a but, [ka] The compound according to any one of E1a to E1.6, E3 to E34, or E35 to E40, or a pharma- ceutically acceptable salt thereof.

[0182] E43. The compound according to any one of E1a to E1.6, E3 to E34, or E35 to E42, or a pharma- ceutically acceptable salt thereof, wherein n is 0.

[0183] E43.1. G 1a but, [ka] or a pharma- ceutically acceptable salt thereof.

[0184] E43.2. G 1a but, [ka] or a pharma- ceutically acceptable salt thereof.

[0185] E44. The compound according to any one of E1a to E1.6, E3 to E34, or E35 to E42, wherein n is 1, or a pharma- ceutically acceptable salt thereof.

[0186] E45.R 2a But CF 3 The compound according to any one of E1a to E1.6, E3 to E34, or E35 to E44, or a pharma- ceutically acceptable salt thereof.

[0187] E46.R 2 But CF 3 The compound according to any one of E1a to E45, or a pharma- ceutically acceptable salt thereof.

[0188] E46.1. G 1a but, [ka] or a pharma- ceutically acceptable salt thereof.

[0189] E46.2. G 1a but, [ka] or a pharma- ceutically acceptable salt thereof.

[0190] E46.3. G 1a but, [ka] or a pharma- ceutically acceptable salt thereof.

[0191] E47.R 2 But CHF 2 The compound according to any one of E1a to E45, or a pharma- ceutically acceptable salt thereof.

[0192] E47.1. G 1a but, [ka] or a pharma- ceutically acceptable salt thereof.

[0193] E47.2. G 1a but, [ka] or a pharma- ceutically acceptable salt thereof.

[0194] E48. The compound according to any one of E1a to E47.2, or a pharma- ceutically acceptable salt thereof, wherein R is hydrogen.

[0195] E49.R 4 The compound according to any one of E1a to E1.6 or E3 to E48, or a pharma- ceutically acceptable salt thereof, wherein: is hydrogen.

[0196] E49.1 The compounds according to E49 of formula (V), or a pharma- ceutically acceptable salt thereof. [ka]

[0197] E49.1a. G 1 but, [ka] and G 1a but, [ka] and R is hydrogen, C 1~4 Alkyl, C 3~4 Cycloalkyl or -C 1~3 Alkylene-C 3~4 is cycloalkyl; R 1a But hydrogen, C 1~4 Alkyl, C 1~4 Fluoroalkyl, -OC 1~4 Alkyl, -OC 1~4 Fluoroalkyl, -OC 3~6 Cycloalkyl, -OCH 2 C 3~6 Cycloalkyl, -SO 2 C 1~4 Alkyl, -SO 2 C 3~6 Cycloalkyl, phenyl, or C 3~6 cycloalkyl, where phenyl and each C 3~6 Cycloalkyl is halogen, cyano, C 1~4 Alkyl, C 1~4 Haloalkyl, -OC 1~4Alkyl and -OC 1~4 optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkyl; R 1b But hydrogen, halogen, cyano, C 1~4 Alkyl, C 1~4 Fluoroalkyl or C 3~6 is cycloalkyl; Or alternatively, R 1a and R 1b together with the atoms to which they are attached form a 5- or 6-membered unsaturated or partially unsaturated carbocyclic or heterocyclic ring, which carbocyclic or heterocyclic ring is unsubstituted or is substituted with halogen, cyano, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 2~4 Alkenyl, C 3~6 Cycloalkyl, and -C 1~3 Alkylene-C 3~4 substituted with 1 to 4 substituents independently selected from the group consisting of cycloalkyl; R 2 But CF 3 or CHF 2 and; R 2a Each occurrence independently represents a halogen, C 1~4 Alkyl, C 1~4 Fluoroalkyl, -OC 1~4 Alkyl or -OC 1~4 is a fluoroalkyl; n is 0, 1, or 2; R 3 But -L 1 -G 2 and; L 1 But, CH 2 and; G 2 but, [ka] or a pharma- ceutically acceptable salt thereof.

[0198] E49.1b. Formula (VA): [ka] or a pharma- ceutically acceptable salt thereof.

[0199] E49.1c. L 1 CH in 2 But, CD 2 or a pharma- ceutically acceptable salt thereof.

[0200] E49.1d. G 1 but, [ka] The compound according to any one of E49.1a to E49.1c, or a pharma- ceutically acceptable salt thereof.

[0201] E49.1e. G 1a but, [ka] The compound according to any one of E49.1a to E49.1d, or a pharma- ceutically acceptable salt thereof, wherein:

[0202] E49.1f. G 1a but, [ka] The compound according to any one of E49.1a to E49.1d, or a pharma- ceutically acceptable salt thereof, wherein:

[0203] E49.1g The compound according to any one of E49.1a to E49.1f, or a pharma- ceutically acceptable salt thereof, wherein n is 0.

[0204] E49.1h The compound according to any one of E49.1a to E49.1g, or a pharma- ceutically acceptable salt thereof, wherein R is hydrogen.

[0205] E49.1i. [ka] or a pharma- ceutically acceptable salt thereof.

[0206] E49.1j. [ka] or a pharma- ceutically acceptable salt thereof.

[0207] E49.1k The compound according to any one of E49.1a to E49.1j, or a pharma- ceutically acceptable salt thereof, in a form having an enantiomeric excess at the chiral carbon atom equal to or greater than 90%.

[0208] E49.1m. A compound according to any one of E49.1a to E49.1j, or a pharma- ceutically acceptable salt thereof, in substantially free form of its enantiomer.

[0209] E49.1n. A compound according to any one of E49.1a to E49.1m, or a pharma- ceutically acceptable salt thereof, in a form having at least 50% deuterium incorporation at each deuterium label.

[0210] E49.2 The compound according to E49.1 of formula (VA), or a pharma- ceutically acceptable salt thereof. [ka]

[0211] E49.3 The compound according to E49.1 of formula (VB), or a pharma- ceutically acceptable salt thereof. [ka]

[0212] E49.4. Formula (V) is a compound of formula (VI) [ka] or a pharma- ceutically acceptable salt thereof.

[0213] E49.5. Formula (VA) is a compound represented by the formula (VI-A) [ka] or a pharma- ceutically acceptable salt thereof.

[0214] E49.6. Formula (VB) is a compound of formula (VI-B) [ka] or a pharma- ceutically acceptable salt thereof.

[0215] E50.R 4 The compound according to any one of E1a to E1.6 or E3 to E48, or a pharma- ceutically acceptable salt thereof, wherein is methyl.

[0216] E51. (3aR,5s,6aS)-2-((tetrahydro-2H-pyran-4-yl)methyl)-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-((tetrahydro-2H-pyran-4-yl)methyl-d 2 )-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-((3,3-dimethyltetrahydro-2H-pyran-4-yl)methyl-d 2 )-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-((4-methyltetrahydro-2H-pyran-4-yl)methyl-d 2 )-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-(((S)-1,4-dioxan-2-yl)methyl-d 2 )-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-(((R)-1,4-dioxan-2-yl)methyl-d 2 )-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-(((R)-Tetrahydro-2H-pyran-2-yl)methyl-d 2 )-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-(((S)-Tetrahydro-2H-pyran-2-yl)methyl-d 2 )-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-((tetrahydro-2H-pyran-3-yl)methyl-d 2 )-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-(cyclohexylmethyl-d2 )-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-((4-fluorotetrahydro-2H-pyran-4-yl)methyl-d 2 )-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-((tetrahydro-2H-pyran-4-yl-2,2,6,6-d 4 ) Methyl-d 2 )-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-N-(6-(4-(difluoromethyl)pyridin-3-yl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d 2 ) Octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-N-(4-cyclopropyl-6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d 2 ) Octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-N-(4-Methoxy-6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d 2 ) Octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-N-(4-methyl-6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d 2 ) Octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-N-(6-(4,6-bis(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d 2 ) Octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-N-(4-methyl-6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl-2,2,6,6-d 4 ) Methyl-d 2 ) Octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-N-(4-methyl-6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl-2,2,6,6-d 4 )Methyl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-((3,3-dimethyltetrahydro-2H-pyran-4-yl)methyl-d 2 )-N-(4-methyl-6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-((3,3-dimethyltetrahydro-2H-pyran-4-yl)methyl-d 2 )-N-(4-methoxy-6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-N-(4-methoxy-6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl-2,2,6,6-d 4 ) Methyl-d 2 ) Octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-N-(4-methoxy-6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl-2,2,6,6-d 4 )Methyl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-(((S)-Tetrahydro-2H-pyran-3-yl)methyl-d 2 )-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-(((R)-Tetrahydro-2H-pyran-3-yl)methyl-d 2 )-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-N-(4-(difluoromethyl)-6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d 2 ) Octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5S,6aS)-3a-Methyl-2-((tetrahydro-2H-pyran-4-yl-2,2,6,6-d 4 ) Methyl-d 2 )-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aS,5R,6aR)-3a-Methyl-2-((tetrahydro-2H-pyran-4-yl-2,2,6,6-d 4 ) Methyl-d 2 )-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-(oxepan-4-ylmethyl-d 2)-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-(((3aR,6aR)-Hexahydro-3aH-cyclopenta[b]furan-3a-yl)methyl-d 2 )-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-(((3aS,6aS)-Hexahydro-3aH-cyclopenta[b]furan-3a-yl)methyl-d 2 )-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-(((3aS,8aR)-Octahydro-3aH-cyclohepta[b]furan-3a-yl)methyl-d 2 )-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-(((3aR,8aS)-Octahydro-3aH-cyclohepta[b]furan-3a-yl)methyl-d 2 )-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1,1-d 2 )-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-((2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)methyl-d 2 )-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl-d 2 )-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; N-((3aR,5s,6aS)-2-((tetrahydro-2H-pyran-4-yl)methyl-d 2 ) octahydrocyclopenta[c]pyrrol-5-yl)-7-(4-(trifluoromethyl)pyridin-3-yl)thieno[2,3-d]pyridazin-4-amine; N-((3aR,5s,6aS)-2-((tetrahydro-2H-pyran-4-yl)methyl-d 2 ) octahydrocyclopenta[c]pyrrol-5-yl)-4-(4-(trifluoromethyl)pyridin-3-yl)thieno[2,3-d]pyridazin-7-amine; (3aR,5s,6aS)-2-(2,2-difluoro-2-(tetrahydro-2H-pyran-4-yl)ethyl-1,1-d 2 )-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-(2,2-difluoro-2-(tetrahydro-2H-pyran-4-yl)ethyl-1,1-d 2 )-N-(4-methyl-6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-N-(6-(2-(difluoromethyl)pyridin-3-yl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d 2 ) Octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-((tetrahydro-2H-pyran-4-yl)methyl-d 2 )-N-(6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-((tetrahydro-2H-pyran-4-yl)methyl)-N-(6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-((tetrahydro-2H-pyran-4-yl)methyl-d 2 )-N-(2'-(trifluoromethyl)-[2,3'-bipyridin]-5-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1,1-d 2 )-N-(6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl-d 2 )-N-(6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-((tetrahydro-2H-pyran-4-yl-2,2,6,6-d 4 ) Methyl-d 2 )-N-(6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-((2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)methyl-d 2 )-N-(6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-(((R)-Tetrahydro-2H-pyran-3-yl)methyl-d 2 )-N-(6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-(((S)-Tetrahydro-2H-pyran-3-yl)methyl-d 2 )-N-(6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-(((S)-Tetrahydro-2H-pyran-2-yl)methyl-d 2 )-N-(6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-(((R)-Tetrahydro-2H-pyran-2-yl)methyl-d 2 )-N-(6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-N-(4-methyl-6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d 2 ) Octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-(((S)-1,4-dioxan-2-yl)methyl-d 2 )-N-(6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-(oxepan-4-ylmethyl-d 2 )-N-(6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-((3,3-dimethyltetrahydro-2H-pyran-4-yl)methyl-d 2 )-N-(6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-((5-oxaspiro[2.4]heptan-6-yl)methyl-d 2 )-N-(6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-((1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)methyl-d 2 )-N-(6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5S,6aS)-3a-Methyl-2-((tetrahydro-2H-pyran-4-yl)methyl-d 2 )-N-(6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aS,5R,6aR)-3a-Methyl-2-((tetrahydro-2H-pyran-4-yl)methyl-d 2 )-N-(6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5S,6aS)-3a-Methyl-2-((tetrahydro-2H-pyran-4-yl-2,2,6,6-d 4 ) Methyl-d 2 )-N-(6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aS,5R,6aR)-3a-Methyl-2-((tetrahydro-2H-pyran-4-yl-2,2,6,6-d 4 ) Methyl-d 2 )-N-(6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-(((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl-d 2)-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-(((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl-d 2 )-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-((5-oxaspiro[3.5]nonan-8-yl)methyl-d 2 )-N-(6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-(((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl-d 2 )-N-(6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-(((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl-d 2 )-N-(6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-((tetrahydro-2H-pyran-4-yl)methyl-d)-N-(6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; The compound according to E1a, selected from the group consisting of: (3aR,5s,6aS)-2-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)-N-(6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine, or a pharma- ceutically acceptable salt thereof.

[0217] E52. The compound according to any one of E1a to E51, or a pharma- ceutically acceptable salt thereof, which is isotopically labeled.

[0218] E52.1. The compound according to any one of E1a to E52, or a pharma- ceutically acceptable salt thereof, having at least 50% deuterium incorporation at each deuterium label.

[0219] E52.2. A compound according to E52.1, or a pharma- ceutically acceptable salt thereof, having at least 75% deuterium incorporation at each deuterium label.

[0220] E52.3. A compound according to E52.1, or a pharma- ceutically acceptable salt thereof, having at least 90% deuterium incorporation at each deuterium label.

[0221] E52.4. A compound according to E52.1, or a pharma- ceutically acceptable salt thereof, having at least 99% deuterium incorporation at each deuterium label.

[0222] E52.5. The compound according to E52.1, or a pharma- ceutically acceptable salt thereof, having at least 99.5% deuterium incorporation at each deuterium label.

[0223] E53. The compound according to any one of E1a to E52.5, or a pharma- ceutically acceptable salt thereof, in a form having an enantiomeric excess at the chiral carbon atom equal to or greater than 90%.

[0224] E53.1 The compounds according to E53 in a form having an enantiomeric excess at the chiral carbon atom equal to or greater than 95%, or a pharma- ceutically acceptable salt thereof.

[0225] E53.2. The compound according to E53.1, or a pharma- ceutically acceptable salt thereof, in a form having an enantiomeric excess at the chiral carbon atom equal to or greater than 98%.

[0226] E53.3 The compound according to E53.2, or a pharma- ceutically acceptable salt thereof, in a form having an enantiomeric excess at the chiral carbon atom equal to or greater than 99%.

[0227] E54. A compound according to any one of E1a to E52.5, or a pharma- ceutically acceptable salt thereof, in substantially free form of its enantiomer.

[0228] E55. A pharmaceutical composition comprising a compound according to any one of E1a to E54, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0229] E56. mAChR M in subjects 4 A method for antagonizing the above-mentioned inflammatory bowel disease, comprising administering to a subject a therapeutically effective amount of a compound described in any one of E1a to E54, or a pharma- ceutical acceptable salt thereof, or a pharmaceutical composition described in E55.

[0230] E57. A method of treating a disorder in a subject, the subject being administered mAChR M 4 and a method for treating a disease in a mammal which will benefit from the antagonism of E1a-E54, the method comprising administering to the mammal a therapeutically effective amount of a compound described in any of E1a-E54, or a pharma- ceutical acceptable salt thereof, or a pharmaceutical composition described in E55.

[0231] E58. The method of E57, wherein the disorder is a neurodegenerative disorder, a movement disorder, or a brain disorder.

[0232] E59. The method of E58, wherein the disorder is a movement disorder.

[0233] E60. The method of E58, wherein the disorder is selected from Parkinson's disease, drug-induced parkinsonism, dystonia, Tourette's syndrome, dyskinesia, schizophrenia, cognitive deficits associated with schizophrenia, excessive daytime sleepiness, attention deficit hyperactivity disorder (ADHD), Huntington's disease, chorea, cerebral palsy, and progressive supranuclear palsy.

[0234] E61. A method of treating a motor symptom in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any of E1a-E54, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to E55.

[0235] E62. The method of E61, wherein the subject has a disorder selected from Parkinson's disease, drug-induced parkinsonism, dystonia, Tourette's syndrome, dyskinesia, schizophrenia, cognitive deficits associated with schizophrenia, excessive daytime sleepiness, attention deficit hyperactivity disorder (ADHD), Huntington's disease, chorea, cerebral palsy, and progressive supranuclear palsy.

[0236] E63. A compound according to any one of E1a to E54, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to E55, for use in the treatment of a neurodegenerative disorder, a movement disorder, or a brain disorder.

[0237] E64. Use of a compound according to any of E1a to E54, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to E55, for the preparation of a medicament for the treatment of a neurodegenerative disorder, a movement disorder, or a brain disorder.

[0238] 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).

[0239] Compound names and / or structures can be assigned / determined by using the Struct=Name naming algorithm as part of CHEMDRAW® ULTRA.

[0240] Compounds may exist as stereoisomers where asymmetric or chiral centers exist. Compounds may exist in stereochemically enriched forms, including enantiomerically enriched forms. Enantiomerically enriched forms of a compound may be defined by the percent enantiomeric excess of a particular enantiomer. An enantiomerically enriched compound may be substantially free of its enantiomer. Stereoisomers are "R" or "S", depending on the configuration of the substituents around the chiral carbon atom. As used herein, the terms "R" and "S" refer to the configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, 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, as well as mixtures of enantiomers or diastereomers. Each stereoisomer of the 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 the 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 the mixture of optical enantiomers on a chiral chromatographic column, or (3) fractional recrystallization methods.

[0241] The compounds have a 3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole core structure, which may have a plane of symmetry as shown in the two representative structures below. [ka] These structures are considered meso because A and B are superimposable with their respective mirror images. For A and B type symmetric structures, the stereochemical symbols 3a, 5, and 6a are used herein to indicate the relative stereochemistry between the ring fusion and the 5-position. Thus, when drawn in the orientation shown above, 3aR, 5s, 6aS refers to the trans relative stereochemistry between the 5-position substituent and the ring fusion, and 3aR, 5r, 6aS refers to the cis relative stereochemistry between the 5-position substituent and the ring fusion. The lowercase s and r symbols at the 5-position indicate pseudo-asymmetry as described by GP Moss in "Basic terminology of stereochemistry (IUPAC Recommendations)" in Pure and Applied Chemistry (1996), 68(12) 2193-2222. Those skilled in the art will appreciate that when structures A and B are drawn as mirror images, chemical naming programs may invert the stereochemical designations at positions 3a and 6 from R to S and S to R, respectively, depending on the program, but the pseudochirality at position 5 remains unchanged since R is preferred over S according to the priority rules and inversion of the carbons bearing the R and S designations. Compounds of formula (I) or (III) or any subformulas thereof may have the 5-position substituent in the trans or cis configuration, or may be prepared as a mixture of trans and cis.

[0242] It should be understood that the compounds may have tautomeric forms as well as geometric isomers, which also constitute embodiments of the present disclosure.

[0243] In the compounds of formula (I) or (III), and any subformulas, any "hydrogen" or "H", whether expressly stated or implied in the structure, represents a hydrogen isotope. 1 H (protium) and 2 H (deuterium) is included.

[0244] 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 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 Cl. Deuterium, i.e. 2 Substitution with heavier isotopes such as H may be preferred in some circumstances as it may provide certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. The compounds may incorporate positron-emitting isotopes for medical imaging and positron emission tomography (PET) studies to determine receptor distribution. Suitable positron-emitting isotopes that may be incorporated into compounds of formula (I) or (III) include: 11 C. 13 N, 15 O and 18 It's F.

[0245] Isotopically enriched forms of compounds of formula (I) or (III), 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 the 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 label).

[0246] Pharmaceutically acceptable salts The disclosed compounds can exist as pharmaceutically acceptable salts. The term "pharmaceutically acceptable salts" refers to water or oil soluble or dispersible salts or zwitterions of the compounds suitable for treating disorders without undue toxicity, irritation and 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 compounds or separately by reacting the amino group of the compounds with a suitable acid. For example, the compounds 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 salts 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.

[0247] 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 hydroxides, carbonates, or bicarbonates of metal cations, such as lithium, sodium, potassium, calcium, magnesium, or aluminum, or primary, secondary, or tertiary organic amines. 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.

[0248] b. General synthesis The compounds of formula (I) or (III) or any subformula may be prepared by synthetic processes or by metabolic processes, including those that occur within the human or animal body (in vivo) or in vitro.

[0249] Abbreviations: AcOH is acetic acid; BMS is borane dimethylsulfide complex; Boc is tert-butyloxycarbonyl; BrettPhos-Pd-G3 is [(2-di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (CAS number 1470372-59-8); t-BuXPhos is 2-di- tert-Butylphosphino-2',4',6'-triisopropylbiphenyl; DAST is diethylaminosulfur trifluoride; DCE is 1,2-dichloroethane; DCM is dichloromethane; DIAD is diisopropyl azodicarboxylate; DIBAL is diisobutylaluminum hydride; DIEA and DIPEA both refer to N,N-diisopropylethylamine; DMF is N,N-dimethylformamide; Et 3 SiCl is chlorotriethylsilane; HATU is 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate; LiAlH(OtBu) 3 is lithium tri-tert-butoxyaluminum hydride; m-CPBA is meta-chloroperoxybenzoic acid; MeOH is methanol; MsCl is methanesulfonyl chloride; NaBH(OAc) 3 and STAB both refer to sodium triacetoxyborohydride; rt or rt is room temperature; NMP is N-methyl-2-pyrrolidone; Pd(dppf)Cl 2 is [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); Pd 2 (dba) 3 is tris(dibenzylideneacetone)dipalladium(0); PPh 3is triphenylphosphine; RuPhos-Pd-G3 is (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (CAS number 1445085-77-7); Selectfuor™ is 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate); t-BuOH is tert-butyl alcohol; t-BuOK is potassium tert-butoxide; TBAI is tetrabutylammonium iodide; THF is tetrahydrofuran; and TosMIC is toluenesulfonylmethyl isocyanide.

[0250] Compounds of formula (I) or (III) or any subformula may be synthesized as shown in the following schemes.

[0251] [ka] As shown in Scheme 1, cis-tert-butyl 5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (compound A; CAS#146231-54-1, Synthonix, catalog #B8253) can be reduced (e.g., with lithium tri-t-butoxyaluminum hydride) to form compound B, which can be converted to the corresponding azide compound C. Reduction to an amine gives compound D, which can be reacted with 3,6-dichloropyridazine to produce compound E. Coupling with a suitable boronic acid or ester gives compound F, which can be deprotected (e.g., with hydrochloric acid) to produce compound G. Compound G can be converted to the corresponding azide compound C by reaction with R 3 to give H by reductive amination, where R 3 is G 2’ , -L 1 -G 2 , -C 2~6 Alkylene-R3a , or C 3~7 is alkyl, G 2’ is G 2 is a carbocyclyl or heterocyclyl of the formula:

[0252] Compound A can also be reduced with sodium borodeuteride to introduce deuterium into B at the point of attachment of the hydroxyl group.

[0253] [ka] Scheme 2 illustrates an alternative synthetic route to compounds of formula H, in which the reductive amination and boronic acid coupling steps are reversed. Deprotection of compound E under acid conditions provides compound I, which can be converted to compound R by reductive amination. 3 with an appropriate aldehyde or ketone corresponding to compound J, 3 is G 2’ , -L 1 -G 2 , -C 2~6 Alkylene-R 3a , or C 3~7 Reaction of compound J with an appropriate boronic acid or ester can then provide compound H. Intermediate J can also be prepared using the alkylation process of Scheme 4.

[0254] [ka] As shown in Scheme 3, compound G can be converted to carboxylic acid R under standard amide bond forming conditions. 20 CO 2 H to give amide M. Suitable reaction conditions include reacting G (1 eq.) with a carboxylic acid (1.2 eq.) in the presence of DIPEA (3 eq.) and HATU (1.5 eq.) in DME at room temperature. Amide M can be prepared by the addition of ethyl Grignard and Ti(OiPr) 4This can be reacted with titanacyclopropane generated in situ from the Kulinkovich-de Meijere reaction to provide the cyclopropyl compound of formula N. Suitable reaction conditions include reacting a solution of ethylmagnesium bromide (5 eq, 1.0 M solution) in THF with titanium(IV) isopropoxide (2.1 eq) for 30 min at -78 °C under an inert atmosphere, adding compound M (1 eq in THF), warming to room temperature, and stirring at reflux for 1 h. In Scheme 3, R 20 is G 2 , -L 1 -G 2 , alkyl groups (e.g., C 1~4 alkyl), -C 1~3 Alkylene-OR 13 , or -C 1~3 Alkylene-N(R 13 ) 2 where G 2 , L 1 , and R 13 is as defined herein.

[0255] [ka] As shown in Scheme 4, compounds of formula G can be alkylated to provide tertiary amines H, where R 3 -L 1 -G 2 , -C 2~6 Alkylene-R 3a , or C 3~7 haloalkyl; L 3 is C 2~6 is an alkylene group; LG is a leaving group (e.g., Cl, Br, I, mesylate, tosylate, triflate); R 3a , L 1 , and G 2 is as defined herein. An exemplary set of conditions for alkylation is 2 CO 3In the presence of a base such as DIPEA, the reactants are heated in a solvent such as DMF or DMSO to about 70° C. Another exemplary set of alkylation conditions is to heat the reactants in the presence of a tertiary base such as DIPEA, with a solvent such as acetonitrile, DMF or DMSO to about >100° C. in a closed vessel in a microwave reactor.

[0256] The alkylation process of Scheme 4 may be applied to compound I. Alkylation of I may be followed by a Suzuki reaction to provide compound H. Suitable Suzuki reaction conditions include those generally outlined in Schemes 1 and 2, and described in the Examples herein.

[0257] [ka] As shown in Scheme 5, a secondary amine compound G can be reacted with an epoxide under basic conditions to provide a hydroxy compound P, where R 30 is an alkyl group having a total of 2 to 4 carbon atoms, or two R 30 together with the carbon to which they are attached, G 2 to form a carbocyclyl or heterocyclyl (eg, tetrahydropyranyl, cyclohexyl).

[0258] [ka] As shown in Scheme 6, compound G can be reacted with an appropriate carboxylic acid to form an amide compound R, which can be reduced to produce compound S, where R 4 is G 2 , -C 1~2 Alkylene-G 2 , -C 1~5 Alkylene-R 3a , or C 2~6 alkyl, where G 2 and R 3aare as defined herein. Amide coupling conditions are known in the art and include treating the reactants with a coupling agent such as HATU in the presence of a base (e.g., DIPEA) in a solvent such as DMF or DCM. Amide reduction conditions are known in the art and include DIBAL in DCM or LiAlH in THF. 4 The reaction can be carried out at temperatures ranging from -78°C to room temperature. 4 to introduce a deuterium atom in place of the carbonyl.

[0259] The amide coupling step in Scheme 6 is 2 It can be used for compounds in which the substituted pyridine substituent is substituted with chloro (Compound I). The carbonyl reduction may be carried out either before or after the chloro-substituted intermediate is subjected to the Suzuki reaction. Suitable Suzuki reaction conditions include those outlined in Schemes 1 and 2, as well as those described in the Examples herein.

[0260] [ka] As shown in Scheme 7, 7,3-amino-6-chloropyridazine can be reacted with cis-N-Boc-5-oxo-octahydrocyclopenta[c]pyrrole to produce compound T, which can be coupled with an appropriate boronic acid or ester to form compound U. Deprotection (e.g., with hydrochloric acid) produces compound V, which upon reaction with a suitable aldehyde or ketone produces compound W (R 3 is G 2’ (as defined above), -L 1 -G 2 , -C 2~6 Alkylene-R 3a , or C 3~7 is alkyl, and L 1 , G 2 , and R 3a are as defined herein).

[0261] [ka] Scheme 8 shows the preparation of intermediates X and Y, the conversion of Y to Z by reductive amination, followed by Suzuki coupling. The reductive amination of Y may involve reaction with a suitable aldehyde or ketone (R 3 is G 2’ (as defined above), -L 1 -G 2 , -C 2~6 Alkylene-R 3a , or C 3~7 is alkyl, and L 1 , G 2 , and R 3a are as defined herein). Alternatively, intermediate X can be treated according to Scheme 1 to provide final compound Z. Compound X can also be treated according to Schemes 1 and 3-6 to provide additional compounds of the invention.

[0262] [ka] Scheme 9 shows processes for preparing racemic intermediates AG, AH, and AJ, and the conversion of AJ to AK using the process of Scheme 1. Compound AG may also be processed according to Schemes 2-7 to provide additional compounds of the invention.

[0263] The processes of Schemes 1-9 can be used to obtain additional compounds of formula (III), where G 1a teeth, [ka] For example, (2-(trifluoromethyl)pyridin-3-yl)boronic acid (or the corresponding ester reagent) can be used in the schemes and synthetic processes described herein to prepare compounds of the invention, such as compounds 39-57 in Table 1.

[0264] [ka] A variety of substituted dichloropyridazine intermediates can be prepared using the Minissi reaction outlined in Scheme 10 to afford substituent R 1a where R 1a is C 1~4 Alkyl, C 1~4 difluoroalkyl or optionally substituted C 3~6 cycloalkyl, R 1b is as defined herein.

[0265] [ka] As shown in Scheme 11, compound D can be coupled with 2-chloro-5-iodopyridine to provide compound AL, which is a boronic acid G 1a B(OH) 2 (or the corresponding ester) to give compound AM, 1a Compound AM may be treated by the methods described in Schemes 1 or 3-6 to obtain R 3 Groups can be added to provide compounds of the general formula AN.

[0266] Substituted Pyridazine Reagents That Can Be Used to Prepare Compounds of the Invention [ka] are 3,6-dichloro-4-methylpyridazine, 3,6-dichloro-4-cyclopropylpyridazine, 3,6-dichloro-4-(trifluoromethyl)pyridazine, 3,6-dichloro-4-cyclopropyl-5-(trifluoromethyl)pyridazine, 4-(tert-butyl)-3,6-dichloropyridazine, 3,6-dichloro-4-(1,1-difluoroethyl)pyridazine, 3,6-dichloro-4-(1-(trifluoromethyl)cyclopropyl)pyridazine, 3,6-dichloro-4-(2,2-difluorocyclopropyl)pyridazine, dazine, 3,6-dichloro-4-(difluoromethyl)pyridazine, 3,6-dichloro-4-cyclobutylpyridazine, 3,6-dichloro-4-methyl-5-(trifluoromethyl)pyridazine, 3,6-dichloro-5-methylpyridazine-4-carbonitrile, 3,6-dichloro-4-methoxypyridazine, and 3,6-dichloro-4-(methylsulfonyl)pyridazine, 4,7-dichlorothieno[2,3-d]pyridazine, 1,4-dichlorophthalazine, and 1,4-dichloro-5,6,7,8-tetrahydrophthalazine. Substituted pyridazine reagents are commercially available, known in the literature, or may be prepared using the synthetic processes described herein.

[0267] Suitable reductive amination conditions for use in the processes of Schemes 1-9 are known in the art. Exemplary reaction conditions for aldehyde reductive amination include reacting the reactants with NaBH(OA) in a solvent such as DCM, THF, and MeOH, and mixtures thereof, optionally in the presence of a base (e.g., DIPEA). 3 Aldehyde reductive amination can also be carried out by treating with NaBH in EtOH with heating (e.g., to about 80° C.). 3 The ketone reductive amination may be carried out by treatment with CN. The ketone reductive amination can be facilitated by the addition of an acid such as acetic acid to a solvent mixture (e.g., DCM-THF) and heating to 40° C. for about 1 hour. A typical solvent ratio of DCM:THF:AcOH is (3:3:0.5). The ketone reductive amination can also be carried out by treatment with Ti(OiPr) in EtOH at temperatures ranging from room temperature to 80° C. 4 and NaBH 3CN or NaBH 4 This may be achieved by treatment with NaBH 3 NaBD instead of CN 3 Using CN, deuterium can be incorporated to obtain compounds that are rich in deuterium relative to protium.

[0268] Boronic Acid and Ester Reagents [ka] can be prepared from the corresponding halide (eg, bromide) using known procedures.

[0269] 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 vacuum.

[0270] 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 may be reacted with an acid at room temperature or above room temperature to provide a 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, phosphoric acid of hydrobromic acid, sulfuric acid, citric acid, hydroxybutyric acid, camphorsulfonic acid, malic acid, phenylacetic acid, aspartic acid or glutamic acid.

[0271] 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 generally known in the art, including but not limited to crystallization, distillation, extraction, trituration and chromatography. Unless otherwise stated, starting materials and reagents are either commercially available or can be prepared by one skilled in the art from commercially available materials using methods described in the chemical literature. If not commercially available, the 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 analogous to those described in the schemes or synthetic examples section above.

[0272] 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, are 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). The 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.

[0273] If 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 of 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).

[0274] Similarly, if a pure geometric isomer of this compound is required, this can be obtained by carrying out one of the procedures above using a pure geometric isomer as a starting material, or by resolution of a mixture of geometric isomers of the compound or intermediates using standard procedures such as chromatographic separation.

[0275] It will be understood that the described synthetic schemes and specific examples are illustrative and should not be construed as limiting the scope of the invention as 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.

[0276] Muscarinic acetylcholine receptor M 4 Activity M 4 is the most highly expressed mAChR subtype in the striatum, and its expression is similar in rodents and primates. 4 In the absence of an antagonist, M 4 The mechanism of action is being elucidated through biochemical and genetic studies as well as the use of highly selective M 4 This has been driven by the use of positive allosteric modulators (PAMs). 4 PAM induces a potent reduction in behavioral responses to psychomotor stimulants that act by increasing striatal DA levels. 4 Genetic deletion of M increases exploratory locomotor activity, enhances locomotor responses to amphetamine and other stimulants, and suppresses M on locomotor activity. 4 These effects were also mediated by M signaling from striatal-spinal projection neurons expressing the D1 subtype of DA receptor (D1-SPN). 4 In vivo microdialysis studies have demonstrated that M 4 Administration of PAM reduced amphetamine-induced DA release in the dorsal and ventral striatum, and fMRI studies demonstrated that 4 We show that PAM reverses amphetamine-induced increases in cerebral blood flow (CBV) in the striatum and other basal ganglia. Furthermore, recent fast-scan cyclic voltammetry (FSCV) and genetic studies have demonstrated that M 4 We demonstrate that PAMs act, at least in part, by inhibiting endocannabinoid release from striatal spinal cord projection neurons (SPNs) and DA release from presynaptic DA terminals in the striatum, through activation of CB2 cannabinoid receptors on DA terminals.

[0277] M 4 DA receptors (D 1 D of DR) 1 It is strongly expressed in a subset of SPNs that also express the D subtype, which form a direct pathway (D1-SPNs) that sends inhibitory projections to the substantia nigra pars reticulata (SNr). 1DR activates a specific GTP-binding protein in D1-SPN, which activates D 1 G, which binds R to activate adenylate cyclase, generate cAMP, and activate protein kinase A (PKA) αolf This signaling pathway is important for many of the behaviors that result from DA-mediated activation of locomotor activity. 4 inhibits adenylyl cyclase and D 1 Gα with the ability to directly inhibit receptor signaling and effects on motor function i / o These studies have demonstrated that in addition to inhibiting DA release, 4 PAM inhibits cAMP formation by direct inhibition 1 This raises the possibility of directly inhibiting D1R-mediated signaling in the -SPN, which may result in selective modulation of DA signaling in the basal ganglia. 4 This may also contribute to the strong inhibitory effect of M 4 PAM is a direct acting 1 Moreover, a series of pharmacological, genetic and molecular / cellular studies have demonstrated that this response is mediated by D1-SPNs. 1 This finding indicates that the effect is mediated by inhibition of DR signaling. 1 M against DR signaling 4 The primary effect of PAM is D in the SNr, not in the striatum. 1 - GABAergic terminals of SPNs, where D 1 Activation of the DR induces a strong increase in GABA release. This challenges the widespread view that cholinergic regulation of striatal function is mediated almost exclusively through ACh released from tonically active striatal cholinergic interneurons (ChIs) and raises the possibility that cholinergic innervation of the SNr from cholinergic projections from the pedunculopontine nucleus may also play an important role in regulating motor activity and other functions of the basal ganglia direct pathway. Taken together, these data suggest that in addition to inhibiting DA release, M 4 Activation is D 1 These results suggest that it also acts postsynaptically in expressing SPNs to inhibit motor function.

[0278] M as the major mAChR subtype involved in regulating motor function 4 Consistent with a prominent role for M, the locomotor-activating effects of the mAChR antagonist scopolamine were 4 The activity of the four other mAChR subtypes (M 1 ~ 3、5 ) has been shown in multiple reports to be unaffected by haloperidol. Furthermore, haloperidol-induced catalepsy (a model of Parkinson's movement disorder) was significantly reduced by M compared to wild-type controls. 4 Evaluation of the antiparkinsonian action of scopolamine by assessing the effect of this compound on catalepsy induced by the DA receptor antagonist haloperidol shows a strong catalepsy that is completely reversed by scopolamine in WT mice. The reversal by scopolamine is due to the activation of the metabotropic glutamate (mGlu) receptor mGlu 4 or mGlu 5 , A 2 This was extraordinarily robust and more pronounced than that observed with many other drugs targeting other targets being evaluated for potential antiparkinsonian effects, including A adenosine receptors and NMDA receptors. Importantly, scopolamine inhibited the M 4 The anti-cataleptic effect of scopolamine was not effective in reducing catalepsy in mAChR M 4 These results suggest that the effects of basal ganglia and motor function are required. 4 These studies, together with extensive research on regulation, 4 Our results provide compelling evidence that is the predominant mAChR subtype responsible for the antiparkinsonian effects of nonselective mAChR antagonists and suggest the potential use of selective M for the treatment of neurodegenerative diseases such as PD, dystonia, tardive dyskinesia, and other movement disorders. 4 Provides support for the discovery and development of antagonists.

[0279] Despite advances in mAChR research, 4Compounds that are potent, efficacious and selective antagonists of mAChRs remain lacking. 4 Antagonists represent a novel therapeutic approach for the treatment of neurodegenerative diseases, including PD, dystonia, tardive dyskinesia and other movement disorders, and may provide the clinical benefits of scopolamine without the adverse effects mediated by pan-mAChR inhibition.

[0280] In some embodiments, the disclosed compounds are 4 Such activity can be demonstrated by methodologies known in the art. For example, mAChR M 4 The antagonistic effect of Ca 2+ Antagonist activity can be determined by measuring calcium flux in response to an agonist, such as acetylcholine, in cells loaded with a sensitive fluorescent dye (e.g., Fluo-4) and co-expression of a chimeric or promiscuous G protein. In some embodiments, calcium flux can be measured as an increase in the fluorescence resting ratio. In some embodiments, antagonist activity can be measured by measuring the EC 80 Acetylcholine response (i.e., mAChR M at the acetylcholine concentration that produces 80% of the maximum response) 4 The concentration-dependent increase in the α-terminal region of the cytoplasmic endothelial cell (cC) can be analyzed as a concentration-dependent increase in the α-terminal region of the cytoplasmic endothelial cell (cC) and the α-terminal region of the cytoplasmic endothelial cell (cC).

[0281] In some embodiments, the disclosed compounds reduce the mAChR M activity in the presence of the compound compared to the response of comparable CHO-K1 cells in the absence of the compound. 4 mAChRM as a decrease in calcium fluorescence in transfected CHO-K1 cells 4 In some embodiments, the disclosed compounds have an IC of less than about 10 μM, less than about 5 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, or less than about 50 nM. 50 mAChR M 4 In some embodiments, the mAChR M 4 Transfected CHO-K1 cells express human mAChR M 4In some embodiments, the mAChR M 4 Transfected CHO-K1 cells express the rat mAChR M 4 In some embodiments, the mAChR M 4 Transfected CHO-K1 cells were incubated with mAChR M 4 The plasmid p53 is transfected with .

[0282] The disclosed compounds are mAChR M 1 , M 2 , M 3 Or M 5 IC against one or more of the transfected CHO-K1 cells 50 Less than IC 50 mAChR M 4 mAChRM in transfected CHO-K1 cells 4 That is, the disclosed compounds can antagonize the mAChR M 1 , M 2 , M 3 Or M 5 mAChR M 4 For example, in some embodiments, the disclosed compounds can have selectivity for the mAChR M 1 IC50 that is about 5-fold lower, about 10-fold lower, about 20-fold lower, about 30-fold lower, about 50-fold lower, about 100-fold lower, about 200-fold lower, about 300-fold lower, about 400-fold lower, or more than about 500-fold lower than IC50 50 mAChR M 4 In some embodiments, the disclosed compounds can antagonize the mAChR M 2 IC50 that is about 5-fold lower, about 10-fold lower, about 20-fold lower, about 30-fold lower, about 50-fold lower, about 100-fold lower, about 200-fold lower, about 300-fold lower, about 400-fold lower, or more than about 500-fold lower than IC50 50 mAChR M 4 In some embodiments, the disclosed compounds can antagonize the mAChR M 3IC50 that is about 5-fold lower, about 10-fold lower, about 20-fold lower, about 30-fold lower, about 50-fold lower, about 100-fold lower, about 200-fold lower, about 300-fold lower, about 400-fold lower, or more than about 500-fold lower than IC50 50 mAChR M 4 In some embodiments, the disclosed compounds can antagonize the mAChR M 5 IC50 that is about 5-fold lower, about 10-fold lower, about 20-fold lower, about 30-fold lower, about 50-fold lower, about 100-fold lower, about 200-fold lower, about 300-fold lower, about 400-fold lower, or more than about 500-fold lower than IC50 50 mAChR M 4 In some embodiments, the disclosed compounds can antagonize the M 2 ~M 5 5 times lower, about 10 times lower, about 20 times lower, about 30 times lower than that for the mAChR M receptor 1 , M 2 , M 3 Or M 5 IC50 lower, about 100 lower, about 200 lower, about 300 lower, about 400 lower, or more than about 500 lower than that for the receptor 50 mAChR M 4 The reaction can be antagonized.

[0283] The disclosed compounds have an IC of less than about 10 μM 50 M 4 mAChRM in transfected CHO-K1 cells 4 mAChR M 1 , M 2 , M 3 Or M 5 M for one or more of the receptors 4 For example, in some embodiments, the compounds may exhibit an IC of less than about 10 μM, less than about 5 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, or less than about 50 nM. 50 The compound may have the formula: 1IC50 about 5-fold lower, 10-fold lower, 20-fold lower, 30-fold lower, 50-fold lower, 100-fold lower, 200-fold lower, 300-fold lower, 400-fold lower, or about 500-fold lower than that for 50 mAChR M 4 In some embodiments, the compounds have an IC of less than about 10 μM, less than about 5 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, or less than about 50 nM. 50 The compound may have the formula: 2 IC50 that is about 5-fold lower, about 10-fold lower, about 20-fold lower, about 30-fold lower, about 50-fold lower, about 100-fold lower, about 200-fold lower, about 300-fold lower, about 400-fold lower, or more than about 500-fold lower than IC50 50 mAChR M 4 In some embodiments, the compounds have an IC of less than about 10 μM, less than about 5 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, or less than about 50 nM. 50 The compound may have the formula: 3 IC50 that is about 5-fold lower, about 10-fold lower, about 20-fold lower, about 30-fold lower, about 50-fold lower, about 100-fold lower, about 200-fold lower, about 300-fold lower, about 400-fold lower, or more than about 500-fold lower than IC50 50 mAChR M 4 In some embodiments, the compounds have an IC of less than about 10 μM, less than about 5 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, or less than about 50 nM. 50 The compound may have the formula: 5 IC50 that is about 5-fold lower, about 10-fold lower, about 20-fold lower, about 30-fold lower, about 50-fold lower, about 100-fold lower, about 200-fold lower, about 300-fold lower, about 400-fold lower, or more than about 500-fold lower than IC50 50 mAChR M 4 In some embodiments, the compounds have an IC of less than about 10 μM, less than about 5 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, or less than about 50 nM. 50 The compound may have M 2 ~M5 Approximately 5 times lower, approximately 10 times lower, approximately 20 times lower, approximately 30 times lower than that for the receptor, M 2 , M 3 Or M 5 about 50 times lower, about 100 times lower, about 200 times lower, about 300 times lower, about 400 times lower, or mAChR M 1 , M 2 , M 3 Or M 5 IC approximately 500-fold lower than that for the receptor 50 So, mAChR M 4 It can also antagonize the reaction.

[0284] The in vivo efficacy of the disclosed compounds in predictive models of anti-Parkinson's disease activity can be measured in a number of preclinical rat models.For example, the disclosed compounds can reverse the motor deficits induced by dopamine receptor antagonists in mice or rats.These compounds can also reverse the motor deficits observed with other manipulations that reduce dopaminergic signaling, such as selective lesions of dopamine neurons.Furthermore, it is possible that these compounds have efficacy in animal models of dystonia and can increase measures of attention, cognitive function and motivation in animal models.

[0285] 3. Pharmaceutical Compositions and Formulations The disclosed compounds can be incorporated into pharmaceutical compositions suitable for administration to a subject (such as a patient, which can be a human or non-human). The disclosed compounds can also be provided as a formulation, such as a spray-dried dispersion formulation.

[0286] 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 a desired therapeutic result. The therapeutically effective amount of the composition can be determined by one skilled in the art and may vary depending on factors such as the disease state, age, sex, and weight of the individual, 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., compounds of formula (I) or (III) or any subformula thereof) 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 a 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.

[0287] For example, a therapeutically effective amount of a compound of formula (I) or (III) or any subformula thereof 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 6 The dose may be about 100 mg / kg, about 45 mg / kg to about 550 mg / kg, about 50 mg / kg to about 500 mg / kg, about 55 mg / kg to about 450 mg / kg, about 60 mg / kg to about 400 mg / kg, about 65 mg / kg to about 350 mg / kg, about 70 mg / kg to about 300 mg / kg, about 75 mg / kg to about 250 mg / kg, about 80 mg / kg to about 200 mg / kg, about 85 mg / kg to about 150 mg / kg, and about 90 mg / kg to about 100 mg / kg.

[0288] The pharmaceutical compositions and formulations may include a pharma- ceutically acceptable carrier. The term "pharmaceutically acceptable carrier" as used herein means any kind of non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary. Some examples of materials that can serve as pharma- ceutically 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 glycerin; 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 buffers, as well as 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.

[0289] Thus, the compounds and their physiologically acceptable salts can be formulated, for example, in solid dosages, eye drops, oil-based topical preparations, for 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.

[0290] The route by which the disclosed compounds are administered and the form of the composition will determine the type of carrier used. The composition can be in a variety of forms suitable for, for example, systemic administration (e.g., oral, rectal, nasal, sublingual, buccal, implanted or parenteral) or local administration (e.g., skin, lung, nose, ear, eye, liposome delivery system or iontophoresis).

[0291] 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.

[0292] 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%.

[0293] Suitable lubricants include silica, talc, stearic acid and its magnesium and calcium salts, calcium sulfate; and liquid lubricants such as polyethylene glycols 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%.

[0294] 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 the systemic composition is generally about 5 to about 50%.

[0295] Suitable disintegrants include agar, alginic acid and its sodium salt, effervescent mixtures, croscarmelose, 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%.

[0296] 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%.

[0297] Suitable flavors include menthol, peppermint, and fruit flavors. If used, the amount of flavor in a systemic or topical composition is generally from about 0.1 to about 1.0%.

[0298] 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%.

[0299] Suitable antioxidants include butylated hydroxyanisole ("BHA"), butylated hydroxytoluene ("BHT"), and vitamin E. The amount of antioxidant in a systemic or topical composition is generally from about 0.1 to about 5%.

[0300] 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%.

[0301] Suitable glidants include silicon dioxide. The amount of glidant in a systemic or topical composition is generally about 1 to about 5%.

[0302] 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%.

[0303] 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 from about 1 to about 8%.

[0304] 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%.

[0305] The amounts of components in a systemic composition may vary depending on the type of systemic composition prepared, but generally, a systemic composition contains 0.01%-50% of an active compound (e.g., a compound of formula (I) or (III) or any subformula thereof) and 50%-99.99% of one or more carriers. Compositions for parenteral administration generally contain 0.1%-10% of an active substance and 90%-99.9% of a carrier (including diluents and solvents).

[0306] Compositions for oral administration may have 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 active material, usually 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 carrier.

[0307] Tablets can be compressed, wet tableted, enteric coated, sugar coated, film coated or multiple compressed. Tablets generally contain an active ingredient and a carrier comprising a component 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 colorants are FD&C dyes that can be added for appearance. Chewable tablets preferably contain sweeteners such as aspartame and saccharin or flavors such as menthol, peppermint, fruit flavors or combinations thereof.

[0308] Capsules (including implants, sustained release and sustained release formulations) generally contain an active compound (e.g., a compound of formula (I) or (III) or any subformula thereof) and a carrier comprising one or more diluents disclosed above in a capsule comprising gelatin. Granules generally contain a compound disclosed and preferably a flow agent such as silicon dioxide to improve flow properties. Implants can be of the biodegradable or non-biodegradable type.

[0309] The selection of ingredients in a carrier for an oral composition depends on secondary considerations such as taste, cost, and storage stability which are not critical for the purposes of this invention.

[0310] The solid compositions can be coated by conventional methods, typically with a pH or time dependent coating, so that the disclosed compounds are released in the gastrointestinal tract or near the desired application site, or at various locations and times to continue the desired action. The coating typically includes one or more components selected from the group consisting of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, ethyl cellulose, EUDRAGIT® coating (available from Evonik Industries of Essen, Germany), wax, and shellac.

[0311] 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 orally administered composition generally comprises the disclosed compound and a carrier, i.e. a carrier selected from diluents, colorants, flavorants, sweeteners, preservatives, solvents, suspending agents, and surfactants.Preferably, the oral liquid composition comprises one or more components selected from colorants, flavorants, and sweeteners.

[0312] Other compositions that are useful for achieving systemic delivery of the target compound include sublingual, buccal and nasal dosage forms.These compositions generally include 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 further include lubricants, colorants, flavors, sweeteners, antioxidants and flow agents.

[0313] 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, cleaners, moisturizers, sprays, skin patches, and the like. The topical composition comprises the disclosed compounds (e.g., compounds of formula (I) or (III) or any subformula thereof) and a carrier. The carrier of the topical composition is preferably one that facilitates the penetration of the compound into the skin. The carrier may further comprise one or more optional components.

[0314] 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 method 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).

[0315] 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 alcohol, symmetric alcohol, aloe vera gel, allantoin, glycerin, vitamin A and E oil, mineral oil, propylene glycol, PPG-2 myristyl propionate, dimethyl isosorbide, castor oil, combinations thereof, etc. More specifically, carriers for skin application include propylene glycol, dimethyl isosorbide and water, more specifically phosphate buffered saline, isotonic water, deionized water, monofunctional alcohol and symmetric alcohol.

[0316] 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.

[0317] 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, octadecyl-2-ol, isocetyl alcohol, cetyl palmitate, sebacillus acidophilus, and the like. Examples of emollients 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 the skin include stearyl alcohol and polydimethylsiloxane. The amount of emollient in a topical composition for the skin is generally about 5% to about 95%.

[0318] 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%.

[0319] 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 alcohol. The amount of solvent in the topical composition is generally about 0% to about 95%.

[0320] 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 the topical composition is generally 0% to 95%.

[0321] The amount of thickening agent in a topical composition generally ranges from about 0% to about 95%.

[0322] Suitable powders include beta-cyclodextrin, hydroxypropylcyclodextrin, 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, aluminum silicate hydrate, 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%.

[0323] 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%.

[0324] Suitable pH adjusting additives include HCl or NaOH in an amount sufficient to adjust the pH of the topical pharmaceutical composition.

[0325] The pharmaceutical composition or formulation may have an IC of less than about 10 μM, less than about 5 μM, less than about 1 μM, less than about 500 nM, or less than about 100 nM. 50 mAChR M 4 The pharmaceutical composition or preparation may have an IC of about 10 μM to about 1 nM, about 1 μM to about 1 nM, about 100 nM to about 1 nM, or about 10 nM to about 1 nM. 50 can antagonize mAChR M4.

[0326] A spray-dried dispersion formulation The disclosed compounds can be formulated as spray-dried dispersions (SDDs). SDDs are single-phase amorphous molecular dispersions of drugs in a polymer matrix. It is a solid solution that contains 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 such that the solvent evaporates from the droplets so quickly that the time provided is insufficient for phase separation or crystallization. SDDs exhibit long-term stability and manufacturability. For example, SDDs have demonstrated shelf lives 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), reproducible, controllable and scalable manufacturing processes, and broad applicability to structurally diverse insoluble compounds with a wide range of physical properties.

[0327] Thus, in one embodiment, the present disclosure may provide a spray-dried dispersion formulation comprising a compound of formula (I) or (III) or any subformula.

[0328] 4.How to use The disclosed compounds, pharmaceutical compositions and formulations can be used in methods for the treatment of disorders, such as neurological and / or psychiatric disorders, associated with muscarinic acetylcholine receptor dysfunction.The disclosed compounds and pharmaceutical compositions can also be used in methods for reducing muscarinic acetylcholine receptor activity in mammals.The methods further include co-treatment methods for improving therapeutic outcomes.In the methods of use described herein, additional therapeutic agents can be administered simultaneously or sequentially with the disclosed compounds and compositions.

[0329] Treatment of the disorder The disclosed compounds, pharmaceutical compositions and formulations are intended to provide a method for treating mAChR M 4 The compounds can be used in methods for treating, preventing, ameliorating, controlling, alleviating, or reducing the risk of various disorders or symptoms of disorders that would benefit from antagonism of. In some embodiments, the disorder can be a neurodegenerative disorder, a movement disorder, or a brain disorder. The methods can include administering to a subject in need of such treatment a therapeutically effective amount of a compound of Formula (I) or (III) or any subformula, or a pharmacologic acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) or (III) or any subformula, or a pharmacologic acceptable salt thereof.

[0330] Patients with mAChR M 4 Disorders that would benefit from antagonism of may include neurodegenerative disorders and movement disorders. For example, exemplary disorders may include Parkinson's disease, drug-induced parkinsonism, dystonia, Tourette's syndrome, dyskinesia (e.g., tardive dyskinesia or levodopa-induced dyskinesia), schizophrenia, cognitive impairment associated with schizophrenia, excessive daytime sleepiness (e.g., narcolepsy), attention deficit hyperactivity disorder (ADHD), Huntington's disease, chorea (e.g., chorea associated with Huntington's disease), cerebral palsy, and progressive supranuclear palsy.

[0331] In some embodiments, the disclosure provides a method for treating motor symptoms in a subject with Parkinson's disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) or (III) or any subformula, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) or (III) or any subformula, or a pharma- ceutically acceptable salt thereof. In some embodiments, the motor symptoms are selected from bradykinesia, tremor, rigidity, gait dysfunction, and postural instability. The method can treat, control, and / or reduce the motor symptoms in the subject.

[0332] In some embodiments, the disclosure provides a method for treating a motor symptom in a subject with dystonia, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or (III) or any subformula or a pharma- ceutically acceptable salt thereof or a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) or (III) or any subformula or a pharma- ceutically acceptable salt thereof. The method can treat, control, and / or reduce the motor symptom in the subject. For example, the treatment can reduce muscle contractions or spasms in a subject with dystonia.

[0333] In some embodiments, the disclosure provides a method for treating motor symptoms in a subject with tardive dyskinesia, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or (III) or any subformula or a pharma- ceutically acceptable salt thereof or a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) or (III) or any subformula or a pharma- ceutically acceptable salt thereof. The method can treat, control, and / or reduce the motor symptoms in the subject. For example, the treatment can reduce involuntary movements in a subject with tardive dyskinesia.

[0334] In some embodiments, the disclosure provides a method of preventing or delaying tardive dyskinesia in a subject at risk of developing tardive dyskinesia, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or (III) or any subformula or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) or (III) or any subformula or a pharma- ceutically acceptable salt thereof. For example, the subject may be a subject being treated with a neuroleptic drug (e.g., a typical or atypical antipsychotic), a dopamine antagonist, or an antiemetic drug.

[0335] In some embodiments, the present disclosure provides a method of treating catalepsy in a subject suffering from schizophrenia, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or (III) or any subformula or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or (III) or any subformula or a pharma- ceutically acceptable salt thereof. For example, a subject suffering from schizophrenia may have catalepsy induced by a neuroleptic drug (e.g., a typical antipsychotic or an atypical antipsychotic).

[0336] In some embodiments, the present disclosure provides a mAChR M 4 The present invention provides a method of treating a brain disorder characterized by alterations in dopamine and cholinergic signaling that can benefit from antagonism of dopamine, comprising administering to a subject a therapeutically effective amount of a compound of Formula (I) or (III) or any subformula, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) or (III) or any subformula, or a pharma- ceutically acceptable salt thereof. For example, treatment can increase motivation or goal-directed behavior in patients suffering from disorders characterized by decreased motivation for goal-directed behavior, such as schizophrenia and other brain disorders.

[0337] In some embodiments, the disclosure provides a method for increasing wakefulness and / or reducing excessive daytime sleepiness in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or (III) or any subformula, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) or (III) or any subformula, or a pharma- ceutically acceptable salt thereof. In some embodiments, the subject is a subject suffering from narcolepsy.

[0338] In some embodiments, the disclosure provides a method of increasing attention in a subject in need thereof (e.g., a subject suffering from an attention deficit disorder such as ADHD), comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or (III) or any subformula, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) or (III) or any subformula, or a pharma- ceutically acceptable salt thereof.

[0339] In some embodiments, the disclosure provides a method for treating motor symptoms in a subject with a drug-induced movement disorder, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or (III) or any subformula or a pharma- ceutically acceptable salt thereof or a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) or (III) or any subformula or a pharma- ceutically acceptable salt thereof. In some embodiments, the drug-induced movement disorder is selected from drug-induced parkinsonism, tardive dyskinesia, tardive dystonia, akathisia, myoclonus, and tremor. The method can treat, control, and / or reduce the motor symptoms in the subject.

[0340] The compounds and compositions may further be useful in the prevention, treatment, control, amelioration, or reduction of risk of the diseases, disorders and conditions mentioned herein. The compounds and compositions may further be useful in combination with other agents in methods for the prevention, treatment, control, amelioration, or reduction of risk of the aforementioned diseases, disorders and conditions.

[0341] mAChR M 4 In the treatment of conditions such as those that would benefit from antagonism of, suitable dosage levels may be about 0.01 to 500 mg / kg of patient body weight per day, which may be administered in single or multiple doses. Suitable dosage levels may be about 0.1 to about 250 mg / kg per day, or about 0.5 to about 100 mg / kg per day. Suitable dosage levels may be about 0.01 to 250 mg / kg per day, about 0.05 to 100 mg / kg per day, or about 0.1 to 50 mg / kg per day. Within this range, dosages may be 0.05 to 0.5, 0.5 to 5, or 5 to 50 mg / kg per day. For oral administration, the composition is provided in the form of a tablet containing 1.0 to 1000 milligrams of active ingredient, particularly 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900 or 1000 milligrams of active ingredient, allowing the dosage to be adjusted symptomatically to the patient being treated. The compound may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. This dosage regimen may be adjusted to provide the optimum therapeutic response. However, it will be understood that the specific dose level and frequency of administration for any particular patient may vary and will depend on a variety of factors, including the activity of the particular compound used, the metabolic stability and length of action of that compound, age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, severity of the particular condition and the host being treated.

[0342] Thus, in some embodiments, the present disclosure provides a method for detecting mAChR M in at least one cell. 4 A method for antagonizing a mAChR M receptor in at least one cell.4 In some embodiments, the cell is a mammal, such as a human. In some embodiments, the cell is isolated from a subject prior to the contacting step. In some embodiments, the contacting is via administration to the subject.

[0343] In some embodiments, the present invention provides a method for the detection of mAChR M 4 A method of antagonizing a mAChR M receptor in a subject. 4 The present invention relates to a method comprising administering to a subject at least one disclosed compound or at least one product of the disclosed method in a dosage and amount effective to antagonize the mAChR M receptor. In some embodiments, the subject is a mammal, such as a human. In some embodiments, the mammal is a mammalian animal, such as a human, having a mAChR M receptor prior to the administering step. 4 In some embodiments, the mammal is diagnosed as having a need for antagonism. 4 In some embodiments, the method comprises administering to a patient a therapeutically effective amount of mAChR M 4 The method further includes identifying a subject in need of antagonism.

[0344] Muscarinic acetylcholine receptor antagonism In some embodiments, the present disclosure provides a method for the detection of mAChR M 4 The present invention relates to a method for antagonizing an anti-inflammatory agent comprising administering to a mammal an effective amount of at least one disclosed compound, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising at least one disclosed compound, or a pharma- ceutically acceptable salt thereof.

[0345] In some embodiments, antagonism of a muscarinic acetylcholine receptor decreases muscarinic acetylcholine receptor activity.

[0346] In some embodiments, the compound administered has an IC of less than about 10 μM, less than about 5 μM, less than about 1 μM, less than about 500 nM, or less than about 100 nM. 50 mAChR M 4 In some embodiments, the administered compound has an IC of about 10 μM to about 1 nM, about 1 μM to about 1 nM, about 100 nM to about 1 nM, or about 10 nM to about 1 nM. 50 mAChR M 4 is antagonistic to.

[0347] In some embodiments, the mammal is a human. In some embodiments, the mammal has been diagnosed as being in need of reducing muscarinic acetylcholine receptor activity prior to the administering step. In some embodiments, the method further comprises identifying a mammal in need of reducing muscarinic acetylcholine receptor activity. In some embodiments, antagonism of the muscarinic acetylcholine receptor treats a disorder associated with muscarinic acetylcholine receptor activity in a mammal. In some embodiments, the muscarinic acetylcholine receptor is a mAChR M 4 It is.

[0348] In some embodiments, antagonism of a muscarinic acetylcholine receptor in a mammal is associated with the treatment of a disorder associated with muscarinic receptor dysfunction, such as a disorder disclosed herein. In some embodiments, the muscarinic receptor is a mAChR M 4 It is.

[0349] In some embodiments, the disclosure provides a method for antagonizing a muscarinic acetylcholine receptor in a cell, comprising contacting the cell with an effective amount of at least one disclosed compound or a pharma- ceutically acceptable salt thereof. In some embodiments, the cell is a mammal (e.g., a human). In some embodiments, the cell is isolated from the mammal prior to the contacting step. In some embodiments, the contacting is via administration to the mammal.

[0350] Co-treatment method The present invention provides a selective mAChR M 4 mAChR M such as antagonists 4 That is, in some embodiments, the present disclosure relates to a co-therapeutic method comprising administering to a mammal an effective amount and dosage of at least one disclosed compound, or a pharma- ceutically acceptable salt thereof.

[0351] In some embodiments, 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, 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 a still further 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 compound administered.

[0352] In some embodiments, administration can improve therapeutic outcomes in the context of physical or occupational therapy. Administration associated with physical or occupational 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, physical or occupational therapy can be provided within 1, 2, 3, 4, 5, 6, 7 days before or after administration of the compound. As a further example, physical or occupational therapy can be provided within 1, 2, 3, or 4 weeks before or after administration of the compound. As yet a further example, physical or occupational 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.

[0353] It is understood that the disclosed co-treatment methods can be used in conjunction with the disclosed compounds, compositions, kits and uses.

[0354] Combination therapy In the methods of use described herein, the additional therapeutic agent may be administered simultaneously or sequentially with the disclosed compounds and compositions. Sequential administration includes administration before or after the disclosed compounds and compositions. In some embodiments, the additional therapeutic agent may be administered in the same composition as the disclosed compounds. In other embodiments, there may be a time interval between administration of the additional therapeutic agent and administration of the disclosed compounds. In some embodiments, administration of the additional therapeutic agent with the disclosed compounds may allow for administration of a lower dose of the other therapeutic agent and / or at less frequent intervals. When used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used alone. Thus, pharmaceutical compositions of the present invention include those that contain one or more other active ingredients in addition to a compound of formula (I) or (III) or any subformula. The above combinations include combinations of the compounds of the present invention with not only one other active compound, but also two or more other active compounds.

[0355] The disclosed compounds may be used as a single agent or in combination with one or more other drugs in the treatment, prevention, control, amelioration or risk reduction of the aforementioned diseases, disorders and conditions for which the compounds or other drugs have utility, where the combination of drugs is safer or more effective than either drug alone. The other drugs may 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 drugs and the disclosed compounds may be used. However, the combination therapy may also be administered on an overlapping schedule. It is also envisioned that the combination of one or more active ingredients and the disclosed compounds may be more effective than either as a single agent. Thus, when used in combination with one or more other active ingredients, the disclosed compounds and the other active ingredients may be used in lower doses than when each is used alone.

[0356] The pharmaceutical compositions and methods of the present invention may further comprise other therapeutically active compounds as described herein that are normally applied in the treatment of the above mentioned pathological conditions.

[0357] The above combinations include not only the combination of the disclosed compound with one other active compound, but also the combination of two or more other active compounds.Similarly, the disclosed compound can be used in combination with other drugs used in the prevention, treatment, control, amelioration or risk reduction of diseases or conditions for which the disclosed compound is useful.These other drugs can be administered simultaneously or sequentially with the compound of the present invention by a route and in an amount commonly used therefor.When the compound of the present invention is used simultaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the disclosed compound is preferred.Thus, this pharmaceutical composition includes those containing one or more other active ingredients in addition to the compound of the present invention.

[0358] The weight ratio of the disclosed compound to the second active ingredient may vary and depends on the effective dose of each ingredient. Generally, each effective dose is used. Thus, for example, when the compound of the present invention is combined with another drug, the weight ratio of the disclosed compound to the other drug will generally be in the range of about 1000:1 to about 1:1000, preferably about 200:1 to about 1:200. The combination of the compound of the present invention with the other active ingredient will also generally be within the aforementioned range, but each time an effective dose of each active ingredient should be used.

[0359] 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.

[0360] 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 that increase the efficacy, safety, convenience, or reduce undesirable side effects or toxicity of the disclosed compounds. The subject compounds and other agents can be co-administered in combination therapy or in fixed dose combinations.

[0361] In some embodiments, the compound can be used in combination with any other agent used to treat a disorder described herein, such as a mAChR M 4 The compounds may be used in combination with standard treatment therapies for disorders that would benefit from antagonism. For example, in some embodiments, the compounds may be used in combination with Parkinson's disease medications (e.g., L-DOPA or carbidopa / levodopa), mGlu 4 Positive allosteric modulator, mGlu 5 Negative allosteric modulator, A 2 A inhibitors, T-type calcium channel antagonists, VMAT2 inhibitors, muscle relaxants (e.g., baclofen), anticholinergics, antiemetics, typical or atypical neuroleptics (e.g., risperidone, ziprasidone, haloperidol, pimozide, fluphenazine), antihypertensives (e.g., clonidine or guanfacine), tricyclic antidepressants (e.g., amitriptyline, butriptyline, clomipramine, desipramine, dosulepin, doxepin, imipramine, iprindole, loxacin, valproate ... may be used in combination with drugs that increase extracellular dopamine concentrations (e.g., amphetamine, methylphenidate, or lisdexamfetamine), drugs that treat excessive daytime sleepiness (e.g., sodium oxybate or wakefulness-promoting drugs such as armodafinil or modafinil), and norepinephrine reuptake inhibitors (including selective NRIs, e.g., atomoxetine, and non-selective NRIs, e.g., bupropion).

[0362] Mode of Administration The therapeutic method may include any number of modes of administering the disclosed compositions. Modes of administration may 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. For the preparation of pharmaceutical compositions for oral administration, the agents may 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 agent may also be dispersed in microparticle, eg, nanoparticle, compositions.

[0363] 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. For oil, for example, but not limited to, olive oil, peanut oil, cottonseed oil, soybean oil, castor oil and sesame oil may be used. 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.

[0364] The term "parenteral" as used herein refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.

[0365] 5. Kit In one aspect, the disclosure provides a kit comprising at least one disclosed compound or a pharma- ceutically acceptable salt thereof, or at least one disclosed compound or a pharma- ceutically acceptable salt thereof, and a pharmaceutical composition comprising one or more of the following: (a)mAChR M 4 at least one agent known to increase activity; (b) mAChR M 4 at least one agent known to reduce activity; (c)mAChR M 4 at least one agent known to treat a disorder associated with (e.g., a disorder described herein); and (d) instructions for administering the compound.

[0366] In some embodiments, at least one of the disclosed compounds and at least one of the drugs are co-formulated. In some embodiments, at least one of the disclosed compounds and at least one of the drugs 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 the disclosed compounds and / or products and another component for delivery to a patient.

[0367] The disclosed kits can be used in conjunction with the disclosed methods of use.

[0368] These kits may include information, instructions, or both, that use of the kit provides treatment for a physical disorder in a mammal, particularly a human. The information and instructions may be in the form of words, images, or both, etc. 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.

[0369] 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 to limit, the scope of the invention. EXAMPLES

[0370] 6. Working Example All NMR spectra were recorded on a 400 MHz AMX Bruker NMR spectrometer. 1 H chemical shifts are reported in δ values ​​in ppm (downfield) using deuterated solvents as internal standards. 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 constants, integrals. 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 thermostatted column compartment, a C18 column, a diode array detector (DAD) and an Agilent 6150 MSD with the following parameters: Gradient conditions were 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 and signals used were 220 nm and 254 nm (both with 4 nm wide 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 at 0.13 cycles / sec and a peak width of 0.008 min. The drying gas flow was set at 13 liters / min at 300° C. and the nebulizer pressure was set at 30 psi. The capillary needle voltage was set at 3000 V and the fragmentor voltage was set at 100 V. Data acquisition was performed using Agilent Chemstation and Analytical Studio Reviewer software.

[0371] Abbreviations that may be used in the examples below are: AcOH is acetic acid; BINAP is 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl; Boc is tert-butyloxycarbonyl; BrettPhos-Pd-G3 is [(2-di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (CAS number 1470372-59-8); tBuOH is tert-butyl alcohol; Celite® is diatomaceous earth; DCE is 1,2-dichloroethane; DCM is dichloromethane; DIAD is diisopropyl azodicarboxylate; DIPEA is N,N-diisopropylethylamine; DMF is N,N-dimethylformamide; DMSO is dimethyl sulfoxide; eq, eq., or equiv are equivalents; Et 2 O is diethyl ether; EtOAc is ethyl acetate; EtOH is ethanol; Et 3 N is triethylamine; HATU is 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate; h or h. is hour; hex is hexane; IPA is isopropyl alcohol; LCMS is liquid chromatography mass spectrometry; LiAlD 4 is lithium aluminum deuteride; LiAlH(OtBu) 3is lithium sulfate tri-tert-butoxyaluminum hydride; m-CPBA is metachloroperbenzoic acid; MeCN is acetonitrile; MeMgBr is methylmagnesium bromide; MeOH is methanol; MeOD is deuterated methanol; min or min. is minutes; MTBE is methyl tert-butyl ether; NMP is N-methyl-2-pyrrolidone; Pd(OAc) 2 is palladium(II) acetate; Pd(dppf)Cl 2 is [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); PPh 3 is triphenylphosphine; RP-HPLC is reversed-phase high-performance liquid chromatography; RuPhos-Pd-G3 is (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (CAS number 1445085-77-7); rt, RT, or rt is room temperature; sat. is saturated; SFC is supercritical fluid chromatography; soln., solution; TESCl is chlorotriethylsilane; TFA is trifluoroacetic acid; THF is tetrahydrofuran; tosyl is toluenesulfonyl.

[0372] Example 1. tert-Butyl (3aR,5s,6aS)-5-((6-chloropyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate [ka] tert-Butyl (3aR,5r,6aS)-5-hydroxy-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carboxylate. To a solution of tert-butyl (3aR,6aS)-5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (10.0 g, 44.4 mmol) in THF (300 mL) at -78 °C was added dropwise 1.0 M lithium tri-tert-butoxyaluminum hydride solution (53.3 mL, 53.3 mmol). The resulting solution was stirred at -78 °C for 2 h, after which the reaction mixture was warmed to 0 °C and H was added. 2 O (17.0 mL), 1 M NaOH solution (17.0 mL) and H 2 The mixture was quenched by the slow addition of successive portions of 2×O (51.0 mL). The mixture was stirred at 0° C. for 1 h, after which the solids were removed by filtration with the aid of diethyl ether (3×200 mL). The filtrate was washed with EtOAc (500 mL) and sat. NH 4 The aqueous layer was diluted with Cl solution (300 mL) and extracted with EtOAc (3×500 mL). The combined organic extracts were washed with MgSO 4 Drying at rt, filtration and concentration under reduced pressure gave a crude mixture of the title compounds as a yellow oil which was carried on to the next step without further purification. 1 H-NMR (400MHz, CDCl 3 )δ 4.30(pent,J=6.4Hz,1H),3.54-3.46(m,2H),3.34(dd,J=11.2,3.7Hz,2H),2.65-2.5 6(m,2H),2.20-2.13(m,2H),1.53-1.47(m,2H),1.45(s,9H);dr=97:3;ESI-MS=[M+H] + -t-butyl=172.0. [ka]

[0373] tert-Butyl (3aR,5s,6aS)-5-azido-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carboxylate. To a solution of tert-butyl (3aR,5r,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (10.1 g, 44.4 mmol) in DCM (250 mL) was added mesyl chloride (4.12 mL, 53.3 mmol), 4-dimethylaminopyridine (0.06 mL, 0.44 mmol), and N,N-diisopropylethylamine (11.6 mL, 66.6 mmol). The reaction mixture was stirred at rt overnight. After completion, the reaction mixture was diluted with sat.NaHCO 3 (100 mL) and then extracted with DCM (3×200 mL). The combined organic extracts were washed with Na 2 SO 4 The mixture was dried at 4° C., filtered and concentrated under reduced pressure to give the crude mixture of mesylate intermediates as an oil, which was carried on to the next step without further purification. ES-MS=[M+H] + -t-butyl=250.0.

[0374] A mixture of tert-butyl (3aR,5r,6aS)-5-((methylsulfonyl)oxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (13.6 g, 44.4 mmol), sodium azide (7.2 g, 111.0 mmol), and tetrabutylammonium iodide (16.4 mg, 0.04 mmol) in DMF (200 mL) was stirred at 60° C. After stirring overnight, the reaction was allowed to cool to rt and then diluted with EtOAc (200 mL) and H 2 The organic layer was diluted with H2O (100 mL). 2 O and the aqueous layer was back-extracted 1× with EtOAc (200 mL). The combined organic extracts were washed with Na 2 SO 4The mixture was dried at 40° C., the solvent was filtered and concentrated under reduced pressure, and the crude residue was purified by column chromatography on silica gel (0-100% EtOAc in hexanes) to give the title compound as a clear oil (6.9 g, 62% for three steps). 1 H-NMR (400MHz, CDCl 3 )δ 4.14-4.10(m,1H),3.50-3.48(m,2H),3.22-3.16(m,2H),2.84-2.78(m,2H),2.03-1.97(m,2H),1.76-1.68(m,2H),1.45(s,9H);ES-MS=[M+H] + -t-butyl=197.0. [ka]

[0375] tert-Butyl (3aR,5s,6aS)-5-amino-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carboxylate. tert-Butyl (3aR,5s,6aS)-5-azido-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carboxylate (6.4 g, 25.3 mmol) was dissolved in THF (400 mL) and then diluted with 20% wt Pd(OH). 2 1.8 g, 2.5 mmol) of 1 / C was added. The resulting mixture was heated to 100° C. 2 After stirring at 0 °C under (balloon) for 8 h, followed by slowly warming to rt and stirring overnight, the reaction mixture was filtered through a pad of Celite® with EtOAc and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel (0-100% DCM, MeOH, NH in DCM). 4 OH (89:10:1)) to give the title compound as a solid (5.3 g, 93%). 1 H-NMR(400MHz,MeOD)δ 3.54-3.43(m,3H),3.33-3.32(m,2H),3.17-3.12(m,2H),2.86-2.80(m,2H),1.81-1.75(m,2H),1.70-1.62(m,2H),1.47(s,9H);ES-MS[M+H]+ =227.0. [ka]

[0376] tert-Butyl (3aR,5s,6aS)-5-((6-chloropyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate. 3,6-Dichloropyridazine (3.95 g, 26.5 mmol, 3 eq.), tert-butyl (3aR,5s,6aS)-5-aminohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (2 g, 8.84 mmol, 1 eq.), and DIPEA (4.62 mL, 26.5 mmol, 3 eq.) were suspended in tert-butanol (40 mL) in a microwave vial and heated under microwave irradiation at 150 °C for 2 h. The reaction was concentrated under vacuum and then purified by column chromatography (0-80% EtOAc in hexanes) to give the title compound (967 mg, 32%). 1 H-NMR(400MHz,MeOD)δ 7.27(d,J=9.4Hz,1H),6.87(d,J=9.4Hz,1H),4.41(p,J=6.3Hz,1H),3.55(dd,J=11.4,8.0Hz,2H),3.19(d d,J=11.4,3.9Hz,2H),2.90-2.80(m,2H),1.98-1.92(m,2H),1.89-1.82(m,2H),1.46(s,9H).ES-MS[M+H] + (-t-butyl)=283.4.

[0377] Example 1.1. (3aR,5s,6aS)-N-(6-chloropyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine dihydrochloride [ka] tert-Butyl (3aR,5s,6aS)-5-((6-chloropyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (2.22 g, 6.55 mmol) was dissolved in 1,4-dioxane (22 mL) and MeOH (2 mL) and 4M HCl in dioxane solution (16 mL) was added dropwise. The resulting mixture was stirred at rt overnight, after which time the solvent was concentrated under reduced pressure and the resulting white solid was dried under vacuum and used directly without further purification (2.04 g, 100%). ES-MS [M+H] + =239.4.

[0378] Example 1.2. (3aR,5s,6aS)-N-(6-chloropyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine [ka] (3aR,5s,6aS)-N-(6-chloropyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine dihydrochloride (2.04 g, 6.55 mmol) was dissolved in DCM (30 mL) and THF (30 mL), tetrahydro-2H-pyran-4-carbaldehyde (2.05 mL, 19.7 mmol) was added, and the resulting solution was stirred for 10 min. Sodium triacetoxyborohydride (4.17 g, 19.7 mmol) was then added. The resulting solution was stirred at rt for 2 h, after which time the reaction was diluted with sat.NaHCO 3 The mixture was quenched by slow addition of 0.05 ml of chloroform / IPA and the aqueous layer was extracted with 3:1 chloroform / IPA. The combined organic extracts were washed with MgSO 4 The mixture was dried at rt, the solvent was filtered and concentrated under reduced pressure, and the yellow solid thus obtained was used without further purification (1.75 g, 79%). 1 H-NMR (400MHz, CDCl 3)δ 7.15(d,J=9.3Hz,1H),6.63(d,J=9.3Hz,1H),4.84(d,J=7.0Hz,1H),4.32-4.24(m,1H),3.96(dd,J=10.9,3.7Hz,2H),3.38(td, ES-MS[M+H] + =337.2.

[0379] Example 2. (3aR,5s,6aS)-2-((tetrahydro-2H-pyran-4-yl)methyl-d 2 )-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine [ka] (Tetrahydro-2H-pyran-4-yl)methyl-d 2 4-Methylbenzenesulfonate. Lithium aluminum deuteride (2.0 g, 53 mmol, 2.5 eq) was added to THF (60 mL) at 0° C. The resulting solution was placed under an inert atmosphere, followed by the dropwise addition of methyl sulfate tetrahydro-2H-pyran-4-carboxylate (3.0 g, 21 mmol, 1 eq). The resulting solution was stirred while warming to rt for 2 h, after which time the reaction was cooled to 0° C. and quenched by slow repeated addition of 0.05 mL of water and 0.15 mL of 1N NaOH solution until 2 mL of water and 5 mL of NaOH solution had been added. The mixture was then stirred at rt for 1 h, after which time the aluminum sulfate precipitate was filtered off and washed several times with THF and DCM. The organic layer was then diluted with MgSO 4The mixture was dried over 100 ml and the solvent was removed under reduced pressure (2.46 g, 100%). The alcohol thus obtained was suspended in DCM (30 mL) followed by the addition of triethylamine (6.4 mL, 2.2 eq) and tosyl chloride (5.1 g, 27 mmol, 1.3 eq) and heated to 40° C. overnight. The solvent was removed and the crude residue was purified by column chromatography (3-70% EtOAc in hexanes). The fractions containing the product were concentrated to give the title compound as a white crystalline solid (3.55 g, 63% over two steps). 1 H NMR (400 MHz, CDCl 3 )δ 7.77(d,J=8.2Hz,2H),7.34(d,J=8.2Hz,2H),3.92(dd,J=11.6,3.9Hz,2H),3.32(td,J=11.8,2.1Hz ,2H),2.44(s,3H),1.91(tt,J=11.7,3.9Hz,1H),1.59-1.52(m,2H),1.31-1.19(m,2H).ES-MS[M+H] + =273.2.

[0380] [ka] (3aR,5s,6aS)-N-(6-chloropyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d 2 ) Octahydrocyclopenta[c]pyrrol-5-amine. Tert-Butyl (3aR,5s,6aS)-5-((6-chloropyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (760 mg, 2.2 mmol, 1 eq) was dissolved in MeOH (5 mL) and 4M HCl in dioxane solution (17 mL) was added dropwise. The resulting solution was stirred at rt for 1 h, after which time the solvent was concentrated under reduced pressure to give the HCl salt as a white solid, which was dried under vacuum and used without further purification (620 mg, 100%). The HCl amine was suspended in THF (6 mL) followed by H 2NaOH (650 mg, 16 mmol, 7 eq) in 20O (6 mL) was slowly added. The solution was stirred at rt for 5 min, followed by (tetrahydro-2H-pyran-4-yl)methyl-d 2 4-Methylbenzenesulfonate (1800 mg, 6.7 mmol, 3 eq) was added. The resulting solution was sealed and heated to 80° C. for 18 h. The solvent was removed and the resulting solid was washed multiple times with EtOAc. The organic layer was concentrated and the resulting crude residue was purified by RP-HPLC (0.05% NH over 20 min.). 4 The product was purified by elution with 20-55% MeCN in aqueous OH. The fractions containing the product were extracted with DCM and MgSO 4 The solvent was concentrated under reduced pressure to give the title compound as a white solid (395 mg, 52%). 1 H NMR (400 MHz, CDCl 3 )δ 7.15(d,J=9.3Hz,1H),6.66(d,J=9.3Hz,1H),4.96(d,J=7.3Hz,1H),4.38-4.27(m,1H),3.96(dd,J=11.5,3.6Hz,2H),3.38(td, ES-MS[M+H] + =339.2.

[0381] [ka] (3aR,5s,6aS)-2-((tetrahydro-2H-pyran-4-yl)methyl-d 2 )-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine. (3aR,5s,6aS)-N-(6-chloropyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d 2) Octahydrocyclopenta[c]pyrrol-5-amine (2.50 g, 7.38 mmol, 1 eq), potassium carbonate (3.10 g, 22.1 mmol, 3 eq), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)pyridine (4.03 g, 14.8 mmol, 2 eq), and BrettPhos-Pd-G3 (1.00 g, 1.11 mmol, 0.15 eq) were added to the flask, which was sealed and placed under an inert atmosphere. Then, 5:1 1,4-dioxane / H 2 2H2O solution (40 mL total, degassed under vacuum) was added via syringe. The resulting solution was stirred at 100 °C for 4 h, after which time the reaction mixture was cooled to rt and H 2 The aqueous layer was extracted with DCM and the combined organic extracts were washed with MgSO 4 The solvent was filtered, concentrated under reduced pressure and the crude residue was purified by RP-HPLC (5-35% MeCN in 0.1% TFA aqueous solution over 20 min). The product-containing fractions were purified with sat. NaHCO 3 The solution was basified with DCM and extracted with DCM. The combined organic extracts were washed with MgSO 4 The solvent was filtered and concentrated under reduced pressure to give the title compound as a yellow solid (614 mg, 19%). 1 H NMR(400MHz,MeOD)δ 8.87(d,J=5.2,1H),8.79(s,1H),7.84(d,J=5.2Hz,1H),7.42(d,J=9.4H z,1H),6.94(d,J=9.4Hz,1H),4.57-4.48(m,1H),3.93(dd,J=11.5,5.1H z,2H),3.42(td,J=11.8,2.0Hz,2H),2.86-2.74(m,4H),2.27-2.21(m,2 H),2.00-1.93(m,2H),1.81-1.69(m,5H),1.32-1.20(m,2H).ES-MS[M+H] + =450.4.

[0382] Example 2.1. (3aR,5s,6aS)-N-(6-chloropyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d2)octahydrocyclopenta[c]pyrrol-5-amine (alternate synthesis) [ka] (Tetrahydro-2H-pyran-4-yl)methane-d 2 -ol. To a solution of lithium aluminum deuteride (1.45 g, 38.1 mmol, 1.1 eq) in THF (30 mL) was added a solution of methyl tetrahydro-2H-pyran-4-carboxylate (5.00 g, 34.7 mmol, 1 eq) in THF (70 mL) dropwise at 0° C. under an inert atmosphere. The resulting reaction mixture was allowed to warm to rt and stirred for 1.5 h, after which time the reaction was cooled again to 0° C. and H 2 HO (1 mL), 1 M NaOH (1 mL), and H 2 O (3 mL) was added sequentially. The reaction mixture was warmed to rt and stirred for 5 min, after which time MgSO 4 was added with further stirring. The reaction mixture was filtered through a pad of Celite® with EtOAc. The filtrate was concentrated to give the title compound as a slightly yellow oil which was used directly without further purification (4.10 g, 100%). 1 H NMR (400 MHz, CDCl 3 )δ 4.02-3.92(m,2H),3.39(td,J=11.8,2.2Hz,2H),1.78-1.72(m,1H),1.64(ddd,J=13.3,4.1,2.1Hz,2H),1.39-1.20(m,2H).

[0383] [ka] 4-(bromomethyl-d 2 ) Tetrahydro-2H-pyran. (Tetrahydro-2H-pyran-4-yl)methane-d 24.10 g, 34.7 mmol, 1 eq) and triphenylphosphine (11.8 g, 45.1 mmol, 1.3 eq) were dissolved in DCM (100 mL) and cooled to 0° C. Carbon tetrabromide (15.0 g, 45.1 mmol, 1.3 eq) was then added. The resulting solution was allowed to warm to rt and stirred overnight under an inert atmosphere, after which time H 2 O was added. The aqueous layer was extracted with DCM and the combined organic extracts were washed with brine and MgSO 4 It was dried over ice, filtered and the solvent was removed. The crude residue was purified by column chromatography (3-20% EtOAc in hexanes) to give the title compound as a colorless liquid (4.61 g, 73%). 1 H NMR (400 MHz, CDCl 3 )δ 4.01-3.96(m,2H),3.37(td,J=11.9,2.1Hz,2H),1.91-1.84(m,1H),1.76(ddd,J=13.1,4.0,2.0Hz,2H),1.40-1.30(m,2H).

[0384] [ka] (3aR,5s,6aS)-N-(6-chloropyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d 2 ) octahydrocyclopenta[c]pyrrol-5-amine. (3aR,5s,6aS)-N-(6-chloropyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine (1.00 g, 4.19 mmol, 1 eq) and 4-(bromomethyl-d 2 ) Tetrahydro-2H-pyran (1.02 g, 5.66 mmol, 1.35 eq) was suspended in 1,4-dioxane (3.5 mL) and 2 NaOH (859 mg, 20.9 mmol, 5 eq) in 20O (1.5 mL) was added. The resulting reaction mixture was stirred at 100° C. overnight, after which time the solvent was concentrated and the residue was dissolved in DCM and H 2 The aqueous layer was extracted with DCM and the combined organic extracts were washed with MgSO 4The solvent was filtered and concentrated to give the title compound as a tan solid which was used without further purification (1.04 g, 73%). 1 H NMR (400 MHz, CDCl 3 )δ 7.16(d,J=9.2Hz,1H),6.63(d,J=9.2Hz,1H),4.83(d,J=7.2Hz,1H),4.22-4.32(m,1H),3.94-3.99(m,2H),3.35-3.42(m,2H), 2.65-2.79(m,2H),2.51-2.62(m,2H),2.30-2.37(m,2H),1.89-1.96(m,2H),1.63-1.74(m,5H),1.22-1.34(m,2H).ES-MS[M+H] + =339.2.

[0385] Example 3. (3aR,5s,6aS)-2-((tetrahydro-2H-pyran-4-yl-2,2,6,6-d 4 ) Methyl-d 2 )-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine [ka] tert-Butyl (3aR,5s,6aS)-5-((6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate. Tert-Butyl (3aR,5s,6aS)-5-((6-chloropyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (644 mg, 1.90 mmol, 1 eq), potassium carbonate (800 mg, 5.70 mmol, 3 eq), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)pyridine (2.08 g, 7.60 mmol, 4 eq), and BrettPhos-Pd-G3 (345 mg, 0.38 mmol, 0.2 eq) were added to the flask, which was sealed and placed under an inert atmosphere. Then, 5:1 1,4-dioxane / H 2 2H2O solution (total 10 mL, degassed under vacuum) was added via syringe. The resulting solution was stirred at 100 °C for 2.5 h, after which time the reaction mixture was cooled to rt and H 2 The mixture was diluted with O and DCM. The aqueous layer was extracted with DCM and the combined organic extracts were filtered through a phase separator and concentrated. The crude residue was purified by column chromatography (0-5% MeOH in EtOAc) to give the title compound as a white solid (669 mg, 78%). ES-MS [M+H] + -t-Butyl = 394.2.

[0386] [ka] (Tetrahydro-2H-pyran-4-yl-2,2,6,6-d 4)((3aR,5s,6aS)-5-((6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-yl)methanone. tert-Butyl (3aR,5s,6aS)-5-((6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (669 mg, 1.49 mmol, 1 eq) was dissolved in 1,4-dioxane (6 mL) and MeOH (2 mL) and 4 M HCl in dioxane solution (5 mL) was added dropwise. The resulting cloudy mixture was stirred at rt for 1 h, after which time the solvent was concentrated under reduced pressure and the resulting HCl salt was dried under vacuum and used without further purification (629 mg, 100%). ES-MS[M+H] + = 350.2. HCl amine (350 mg, 0.83 mmol, 1 eq) and tetrahydro-2H-pyran-4-carboxy-2,2,6,6-d 4 To a solution of the acid (133 mg, 0.99 mmol, 1.2 eq) in DMF (5 mL) was added DIPEA (0.43 mL, 2.49 mmol, 3 eq) followed by HATU (473 mg, 1.24 mmol, 1.5 eq). The resulting solution was stirred at rt for 1 h, after which time the reaction mixture was analyzed by RP-HPLC (0.05% NH over 20 min). 4 The product was purified directly by 10-50% MeCN in aqueous OH. The fractions containing the product were concentrated to give the title compound as a colorless oil (274 mg, 71%). ES-MS [M+H] + =466.3.

[0387] [ka] (3aR,5s,6aS)-2-((tetrahydro-2H-pyran-4-yl-2,2,6,6-d 4 ) Methyl-d 2)-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine. (Tetrahydro-2H-pyran-4-yl-2,2,6,6-d 4 )((3aR,5s,6aS)-5-((6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (274 mg, 0.59 mmol, 1 eq) was dissolved in THF (5 mL) and placed under an inert atmosphere. Lithium aluminum deuteride (112 mg, 2.94 mmol, 5 eq) was then added. The resulting yellow reaction mixture was stirred at rt for 15 min, after which time the reaction mixture was cooled to 0° C. and diluted with Et 2 Diluted with O. 2 HO (0.1 mL), 1 M NaOH (0.1 mL), and H 2 O (0.3 mL) was added sequentially. The reaction mixture was warmed to rt and MgSO 4 was added followed by stirring for 15 min. The solids were removed by filtration and the filtrate was concentrated. The crude residue was purified by RP-HPLC (5-25% MeCN in 0.1% aqueous TFA over 20 min). The product-containing fractions were purified by HPLC with sat.NaHCO 3 The mixture was basified with and extracted with DCM. The combined organic extracts were washed with MgSO 4 The mixture was dried at 40° C. The solvent was filtered and concentrated to give the title compound as a slightly yellow solid (123 mg, 46%). 1 H NMR(400MHz,MeOD)δ 8.87(d,J=5.3,Hz,1H),8.79(s,1H),7.84(d,J=5.3Hz,1H),7.42(d,J=9.3,1H),6.94(d,J=9.3Hz,1H),4.57- 4.48(m,1H),2.86-2.73(m,4H),2.27-2.21(m,2H),2.00-1.94(m,2H),1.81-1.68(m,5H),1.30-1.20(m,2H).

[0388] Example 4. Tetrahydro-2H-pyran-4-carboxy-2,2,6,6-d 4 acid [ka] (E)-Diethyl 3-styrylpentanedioate. A mixture of cinnamaldehyde (60 g, 456 mmol, 57.4 mL, 1 eq), 3-ethoxy-3-oxopropanoic acid (301.4 g, 2281 mmol, 5 eq), and DMAP (11.2 g, 91.3 mmol, 0.2 eq) in pyridine (210 mL) was degassed and purified with N 2 The mixture was purged with hexane and stirred at 60° C. for 20 h under an inert atmosphere. The mixture was then stirred at 140° C. for 48 h. The reaction mixture was concentrated under reduced pressure to remove pyridine. The residue was then purified with H 2 The mixture was diluted with O and extracted with MTBE. The combined organic layers were washed with HCl (15%) and 2 SO 4 The mixture was dried over 1000 ml of water, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=1 / 0-10 / 1) to give the title compound as a yellow solid (27 g, 61%). 1 H NMR (400 MHz, CDCl 3 )δ 7.27-7.37(m,4H)7.17-7.25(m,1H)6.48(d,J=15.9Hz,1H)6.12(dd,J=15.8,8.4Hz,1H)4.13(q ,J=7.1Hz,4H)3.23(dq,J=14.6,7.2Hz,1H)2.52(qd,J=15.4,7.1Hz,4H)1.23(t,J=7.1Hz,6H).

[0389] [ka] 1,1,5,5-Tetradeuterio-3-[(E)-styryl]pentane-1,5-diol. To a solution of lithium aluminum deuteride (7.60 g, 180.8 mmol, 1.5 eq) in THF (80 mL) was added (E)-diethyl 3-styrylpentanedioate (35 g, 120.5 mmol, 1 eq) in THF (350 mL) dropwise at 0° C. The resulting mixture was stirred at 20° C. for 1 h. The reaction mixture was diluted with H 2 O (76 mL), 15% NaOH aqueous solution (76 mL) and H 2 O (227 mL) was added gradually with stirring. 4 was added with stirring and the reaction mixture was filtered through a pad of Celite® The filtrate was concentrated under reduced pressure to give the title compound as a white solid (20.4 g, 80%). 1 H NMR (400 MHz, CDCl 3 )δ 7.27-7.37(m,4H)7.17-7.23(m,1H)6.43(d,J=15.8Hz,1H)5.96(dd,J=15.9,9.1H z,1H)2.54(qt,J=9.2,4.8Hz,1H)1.72(dd,J=13.8,4.9Hz,2H)1.52-1.64(m,2H).

[0390] [ka] 2,2,6,6-Tetradeuterio-4-[(E)-styryl]tetrahydropyran. A mixture of 1,1,5,5-tetradeuterio-3-[(E)-styryl]pentane-1,5-diol (14 g, 66.6 mmol, 1 eq) and TsOH (2.29 g, 13.3 mmol, 0.2 eq) in toluene (140 mL) was heated to reflux at 140 °C for 12 h with a Dean-Stark trap. The residue thus obtained was dissolved in sat.NaHCO 3 The aqueous phase was extracted with ethyl acetate and the combined organic phase was washed with brine and anhydrous Na 2 SO 4 The crude residue was purified by column chromatography (SiO 2, petroleum ether / ethyl acetate=20 / 1 to 5 / 1) to give the title compound as a colorless oil (7.23 g, 56%). 1 H NMR (400 MHz, CDCl 3 )δ 7.28-7.41(m,4H)7.20-7.26(m,1H)6.41(d,J=16.0Hz,1H)6.18(dd,J=16.0,6.8Hz,1H)2.34-2.46(m,1H)1.68-1.75(m,2H)1.52-1.63(m,2H).

[0391] [ka] 2,2,6,6-Tetradeuteriotetrahydropyran-4-carbaldehyde. Ozone was bubbled into a solution of 2,2,6,6-tetradeuterio-4-[(E)-styryl]tetrahydropyran (6.0 g, 31.2 mmol, 1 eq) in DCM (90 mL) and MeOH (18 mL) at -78 °C for 30 min. Excess O 3 N 2 After purging with Me 2 S (22 mL) was added at 20° C. for 2 h. The reaction mixture was concentrated to give the crude product. The crude residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=10 / 1 to 1 / 1) to give the title compound as a colorless oil (3.05 g, 83%). 1 H NMR (400 MHz, CDCl 3 )δ 9.64(s,1H)2.43-2.55(m,1H)1.83(dd,J=13.8,4.1Hz,2H)1.63-1.71(m,2H).

[0392] [ka] 2,2,6,6-Tetradeuteriotetrahydropyran-4-carboxylic acid. 2,2,6,6-Tetradeuteriotetrahydropyran-4-carbaldehyde (3.0 g, 25.4 mmol, 1 eq) in t-BuOH (30 mL), H 2In a solution of 200 (10 mL) and THF (15 mL), NaClO 2 (6.89g, 76.2mmol, 3eq), NaH 2 PO 4 (9.14 g, 76.2 mmol, 3 eq) and 2-methylbut-2-ene (14.2 g, 203 mmol, 21.5 mL, 8 eq) were added. The resulting mixture was stirred at 25° C. for 12 h. The reaction mixture was then heated at 20° C. with H 2 The mixture was quenched by adding 2H2O, then adjusted to pH 2 with 1M HCl and extracted. The combined organic layers were washed with brine and diluted with Na 2 SO 4 The solvent was filtered and concentrated under reduced pressure to give the title compound as a white solid (2.1 g, 62%). 1 H NMR (400 MHz, CDCl 3 )δ 9.76-12.28(m,1H)2.58(tt,J=10.8,4.3Hz,1H)1.83-1.91(m,2H)1.73-1.83(m,2H).

[0393] Example 5. Representative synthesis procedure Representative synthesis 1. [ka] (3aR,5s,6aS)-N-(6-chloropyridazin-3-yl)-2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)octahydrocyclopenta[c]pyrrol-5-amine. (3aR,5s,6aS)-N-(6-chloropyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine dihydrochloride (300 mg, 0.96 mmol) was dissolved in DCM (3 mL), THF (3 mL) and AcOH (0.5 mL) and 2,2-dimethyltetrahydro-4H-pyran-4-one (370 mg, 2.89 mmol) was added followed by sodium triacetoxyborohydride (612 mg, 2.89 mmol). The resulting solution was stirred at 40 °C for 1 h, after which the reaction was cooled to 40 °C and cooled to 5 °C. 3The mixture was quenched with 1,000 ml of 1:1 chloroform / IPA (v / v) and extracted with 3:1 chloroform / IPA (v / v). The combined organic extracts were filtered through a phase separator and concentrated. The crude residue was dissolved in DMSO and then directly purified by RP-HPLC (5–35% MeCN in 0.1% TFA in water for 20 min). The product-containing fractions were purified by elution with sat.NaHCO 3 The mixture was basified with 100 mL of chloroform and extracted with 3:1 chloroform / IPA (v / v). The combined organic extracts were washed with MgSO 4 The mixture was dried at 40° C., the solvent was filtered and concentrated under reduced pressure to give the title compound as a white solid (138 mg, 41%). ES-MS [M+H] + =351.3.

[0394] Representative Synthesis 2. (3aR,5s,6aS)-N-(6-(2-chloro-5-fluorophenyl)pyridazin-3-yl)-2-(1-(tetrahydro-2H-pyran-4-yl)cyclopropyl)octahydrocyclopenta[c]pyrrol-5-amine [ka] ((3aR,5s,6aS)-N-((6-(2-chloro-5-fluorophenyl)pyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl(tetrahydro-2H-pyran-4-yl)methanone. (3aR,5s,6aS)-N-(6-(2-chloro-5-fluorophenyl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine hydrochloride (53.4 mg, 0.14 mmol) and 4-oxanoic acid (22.6 mg, 0.17 mmol) were dissolved in DMF (1 mL) and DIPEA (0.076 mL, 0.43 mmol) was added followed by HATU (82.5 mg, 0.22 mmol). The resulting solution was stirred at rt for 1 h, after which the reaction mixture was analyzed by RP-HPLC (0.05% NH 4 The product was purified directly by 25-65% MeCN in aqueous OH (10 min). The product-containing fractions were concentrated to give the title compound as a colorless oil (39 mg, 61%). ES-MS [M+H] + =445.0.

[0395] [ka] (3aR,5s,6aS)-N-(6-(2-chloro-5-fluorophenyl)pyridazin-3-yl)-2-(1-tetrahydro-2H-pyran-4-yl)cyclopropyl)octahydrocyclopenta[c]pyrrol-5-amine. To a solution of ethylmagnesium bromide (0.062 mL, 0.062 mmol, 1.0 M solution) in THF (0.2 mL) at -78 °C was added titanium(IV) isopropoxide (0.008 mL, 0.026 mmol) in 0.1 mL of THF. The resulting solution was stirred at -78 °C under inert atmosphere for 30 min, after which ((3aR,5s,6aS)-5-((6-(2-chloro-5-fluorophenyl)pyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl(tetrahydro-2H-pyran-4-yl)methanone (11 mg, 0.025 mmol (0.3 mL in THF)) was added dropwise. The resulting solution was warmed to rt and stirred at reflux for 1 h, after which the reaction mixture was cooled to 0 °C before the dropwise addition of an additional 2.5 eq of ethylmagnesium bromide (1.0 M solution, 5 eq total) and 1.05 eq of titanium(IV) isopropoxide (0.1 mL in THF, 2.1 eq total). The resulting brown solution was warmed to rt and stirred for 1 h, after which the reaction was cooled to 0 °C before the dropwise addition of ... 2 The mixture was quenched with 0 and diluted with 3:1 chloroform / IPA (v / v). The aqueous layer was extracted with 3:1 chloroform / IPA (v / v) and the combined organic extracts were filtered through a phase separator and concentrated. The crude residue was purified by RP-HPLC (0.05% NH 4 Purification by 65-95% MeCN in aqueous OH (5 min) and concentration of fractions containing product afforded the title compound as a tan solid (1.1 mg, 10%). 1H-NMR(400MHz,MeOD)δ 7.58(d,J=9.4Hz,1H),7.56(dd,J=8.8,5.0Hz,1H),7.37(dd,J=9.0,3.1Hz,1H),7 .24-7.19(m,1H),6.94(d,J=9.4Hz,1H),4.54-4.48(m,1H),3.99-3.95(m,2H),3. 45-3.39(m,2H),2.67-2.64(m,4H),2.46-2.42(m,2H),1.94-1.83(m,4H),1.63-1 .49(m,5H),0.70(dd,J=6.5,5.0Hz,2H),0.44(dd,J=6.2,4.8Hz,2H).ES-MS[M+H] + =457.4.

[0396] Representative Synthesis 3. (3aR,5s,6aS)-N-(6-(2-chloro-5-fluorophenyl)pyridazin-3-yl)-2-(3-methoxypropyl)octahydrocyclopenta[c]pyrrol-5-amine [ka] (3aR,5s,6aS)-N-(6-(2-chloro-5-fluorophenyl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine hydrochloride (20.3 mg, 0.050 mmol) was dissolved in DMF (1 mL) and then cesium carbonate (49 mg, 0.15 mmol) was added followed by 1-bromo-3-methoxypropane (38 mg, 0.25 mmol). The resulting solution was stirred at 70 °C overnight, after which the solids were removed by syringe filtration and the crude residue was purified by RP-HPLC (5 min with 5–35% MeCN in 0.1% TFA aqueous solution). The fractions containing the product were purified by HPLC with sat.NaHCO 3 The mixture was basified with 50 ml of chloroform / IPA and extracted with 3:1 chloroform / IPA (v / v). The combined organic extracts were filtered through a phase separator and concentrated to give the title compound as a white solid (3.2 mg, 16%). 1H-NMR(400MHz,MeOD)δ 7.46(d,J=9.3Hz,1H),7.44(dd,J=8.8,5.0Hz,1H),7.25(dd,J=9.0,3.1Hz, 1H),7.12-7.07(m,1H),6.82(d,J=9.4Hz,1H),4.45-4.38(m,1H),3.35(t,J= 6.2Hz,2H),3.23(s,3H),2.92-2.87(m,2H),2.74-2.69(m,2H),2.49-2.45( m,2H),2.17-2.14(m,2H),1.91-1.85(m,2H),1.74-1.61(m,4H).ES-MS[M+H] + =405.4.

[0397] Representative Synthesis 4. 1-((3aR,5s,6aS)-5-((6-(2-chloro-5-fluorophenyl)pyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-2-methylpropan-2-ol [ka] (3aR,5s,6aS)-N-(6-(2-chloro-5-fluorophenyl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine hydrochloride (19.7 mg, 0.053 mmol) was dissolved in EtOH (1 mL) and then DIPEA (0.028 mg, 0.16 mmol) was added followed by isobutylene oxide (0.014 mL, 0.16 mmol). The resulting solution was stirred at 70 °C for 4 h, after which the reaction mixture was allowed to cool to rt and the solvent was concentrated. The crude residue was purified by RP-HPLC (5–35% MeCN in 0.1% TFA aqueous solution for 5 min). The product-containing fractions were purified by HPLC with sat.NaHCO 3 The mixture was basified with 50 ml of chloroform / IPA and extracted with 3:1 chloroform / IPA (v / v). The combined organic extracts were filtered through a phase separator and concentrated to give the title compound as a white solid (11 mg, 51%). 1 H-NMR (400MHz, CDCl 3)δ 7.62(d,J=9.3Hz,1H),7.47(dd,J=9.2,3.1Hz,1H),7.41(dd,J=8.8,5.0Hz,1H),7.07-7.02(m,1H),6.71(d,J=9.3Hz,1H),5.03(d,J=4.8Hz, 1H),4.41(br,1H),2.96(br,2H),2.85(br,2H),2.67(br,2H),2.55(br,2H),2.04-1.96(m,2H),1.86-1.79(m,2H),1.24(m,6H);ES-MS[M+H] + =405.4.

[0398] Representative Synthesis 5. N-[4-[6-[[(3aR,5r,6aS)-2-(3,3-dimethylbutyl)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]amino]pyridazin-3-yl]phenyl]acetamide [ka] tert-Butyl (3aR,5r,6aS)-5-((6-chloropyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate. cis-N-Boc-5-oxo-octahydrocyclopenta[c]pyrrole (100 mg, 0.44 mmol) was dissolved in THF (1 mL) and DCE (1 mL), followed by the addition of 3-amino-6-chloropyridazine (288 mg, 2.22 mmol) and the resulting solution was stirred for 10 min. Sodium triacetoxyborohydride (376 mg, 1.78 mmol) was then added and the resulting solution was heated to 60° C. and stirred overnight, after which the reaction was diluted with DCM and 3:1 chloroform / IPA solution and the aqueous layer was extracted with 3:1 chloroform / IPA solution. The combined organic extracts were filtered through a phase separator and concentrated, after which the crude residue was purified by RP-HPLC. The product-containing fractions were purified with sat.NaHCO 3 After basifying with 50 ml of 1000 ml of 3:1 chloroform / iPA, the combined organic extracts were filtered through a phase separator and concentrated to give the title compound as a brown oil (15.1 mg, 10%). ES-MS [M+H]+ =339.3.

[0399] [ka] tert-Butyl (3aR,5r,6aS)-5-((6-(4-acetamidophenyl)pyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate. tert-Butyl (3aR,5r,6aS)-5-((6-chloropyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (15.1 mg, 0.045 mmol), K 2 CO 3 (18.7 mg, 0.13 mmol), 4-acetylaminophenylboronic acid (9.6 mg, 0.053 mmol) and RuPhos-Pd-G3 (3.7 mg, 0.004 mmol) were combined in a sealed vial and placed under an inert atmosphere. Then, 5:1 1,4-dioxane / H 2 A solution of NaHCO (0.6 mL, degassed) was added. The resulting mixture was heated to 120 °C for 30 min under microwave irradiation, after which the reaction was cooled to rt and then saturated with sat.NaHCO 3 and diluted with DCM. The aqueous layer was extracted with DCM and the combined extracts were filtered through a phase separator and concentrated. The crude residue was purified by column chromatography (hex / EtOAc) to give the title compound as a brown oil (3.9 mg, 20%). ES-MS [M+H] + =438.4.

[0400] [ka] N-(4-(6-(((3aR,5r,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)amino)pyridazin-3-yl)phenyl)acetamide dihydrochloride. tert-Butyl (3aR,5r,6aS)-5-((6-(4-acetamidophenyl)pyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (3.9 mg, 0.009 mmol) was dissolved in 1,4-dioxane (0.5 mL) followed by dropwise addition of 4 M HCl in dioxane (0.5 mL). The resulting solution was stirred at rt for 30 min, after which the solvent was concentrated under reduced pressure and the resulting white solid was used directly without further purification (3.9 mg, 100%). ES-MS [M+H] + =338.4.

[0401] [ka] N-(4-(6-(((3aR,5r,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)amino)pyridazin-3-yl)phenyl)acetamide dihydrochloride (3.3 mg, 0.009 mmol) was dissolved in THF (0.25 mL) and DCE (0.25 mL) before adding 3,3-dimethylbutyraldehyde (4.3 mg, 0.004 mmol). The resulting mixture was stirred at rt for 6 h, after which sodium triacetoxyborohydride (9.2 mg, 0.044 mmol) was added and the resulting solution was stirred at rt overnight, after which the solvent was concentrated and the crude residue was directly purified by RP-HPLC. The product-containing fractions were purified by HPLC with sat.NaHCO 3 The mixture was basified with and then extracted with 3:1 chloroform / iPA. The combined organic extracts were filtered through a phase separator and concentrated to give the title compound as a white solid (1.8 mg, 49%). 1 H-NMR (400MHz, CDCl 3)δ 7.95(d,J=8.6Hz,2H),7.58(d,J=8.6Hz,2H),7.51(d,J=9.3Hz,1H),6.54(d,J=9.3Hz,1H),4.67-4.62(m,1H),2.81(d ,J=9.6Hz,2H),2.75-2.67(m,2H),2.47-2.43(m,2H),2.22-2.15(m,7H),1.74-1.44(m,4H),0.94(s,9H).ES-MS[M+H] + =422.4.

[0402] Representative Synthesis 6. (3aR,5s,6aS)-2-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-N-(6-(2,3,5-trifluorophenyl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine [ka] (3aR,5s,6aS)-N-(6-(2,3,5-trifluorophenyl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine hydrochloride (10 mg, 0.027 mmol, 1 eq) and 1-(tetrahydro-2H-pyran-4-yl)ethan-1-one (17 mg, 0.13 mmol, 5 eq) were suspended in EtOH (0.5 mL) and titanium(IV) isopropoxide (40 μL, 0.13 mmol, 5 eq) was added. The resulting solution was stirred at 45 °C for 2 h, after which time NaBH 4 (5.1 mg, 0.13 mmol, 5 eq) was added. The resulting solution was stirred at rt for 1 h, after which time the reaction mixture was diluted with sat.NaHCO 3 The mixture was quenched with 100 mL of ethyl acetate and extracted with DCM. The combined organic extracts were filtered through a phase separator, concentrated, and the crude residue was purified by RP-HPLC (5-35% MeCN in 0.1% aqueous TFA over 5 min). The product-containing fractions were purified with sat.NaHCO 3The mixture was basified with 50 ml of 1:1 chloroform / IPA and extracted with 3:1 chloroform / IPA. The combined organic extracts were filtered through a phase separator and concentrated to give the title compound as a white solid (1.9 mg, 16%). ES-MS [M+H] + =447.4.

[0403] Example 6. 3,6-Dichloro-4-cyclopropylpyridazine and 3,6-dichloro-4,5-dicyclopropylpyridazine [ka] 3,6-Dichloropyridazine (3000 mg, 20.1 mmol, 1 eq), cyclopropanecarboxylic acid (2770 mg, 32.2 mmol, 1.6 eq), silver nitrate (342 mg, 2.0 mmol, 0.1 eq), and sulfuric acid (1.6 mL, 1.5 eq) in water (90 mL) were heated to 72 °C, followed by the addition of ammonium persulfate (6890 mg, 30.2 mmol, 1.5 eq). After 20 min, the reaction was cooled and quenched with 1 M NaOH solution (20 mL), followed by extraction with DCM and concentration. The residue was purified by RP-HPLC (0.05 N for 20 min). 4 The product was purified by 20-60% MeCN in aqueous OH). The fractions containing the product were concentrated under reduced pressure to give the title compound. Major product: (1665.4 mg, 44%) 1 H-NMR (400MHz, CDCl 3 )δ 6.94(s,1H),2.24-2.16(m,1H),1.34-1.27(m,2H),0.90-0.84(m,2H).ES-MS[M+H] + = 189.4, minor product: (355.1 mg, 8%) 1 H-NMR (400MHz, CDCl 3 )δ 1.90-1.81(m,2H),1.29-1.23(m,4H),0.83-0.77(m,4H).ES-MS[M+H] + =230.4.

[0404] Example 7. 3,6-Dichloro-4-cyclopropyl-5-(trifluoromethyl)pyridazine [ka] 3,6-Dichloro-4-(trifluoromethyl)pyridazine (1000 mg, 4.61 mmol, 1 eq), cyclopropanecarboxylic acid (600 mg, 6.91 mmol, 1.5 eq), ammonium persulfate (1100 mg, 4.82 mmol, 1.1 eq), and silver nitrate (235 mg, 1.38 mmol, 0.3 eq) were heated to 72 °C, followed by the addition of sulfuric acid (0.37 mL, 1.2 eq). After 1 h, the reaction was cooled, neutralized with 1 M NaOH (10 mL), extracted with DCM, and concentrated. The residue was purified by RP-HPLC (50-80% MeCN in 0.1% TFA solution over 20 min). The fractions containing the product were purified by elution with sat.NaHCO 3 The solution was basified, extracted with DCM and concentrated to give the title compound as an off-white oil (639.2 mg, 54%). 1 H-NMR (400MHz, CDCl 3 )δ 2.07-1.98(m,1H),1.40-1.32(m,2H),0.81-0.74(m,2H).ES-MS[M+H] + =257.0.

[0405] Example 8. 4-(tert-butyl)-3,6-dichloropyridazine [ka] To a solution of 3,6-dichloropyridazine (1000 mg, 6.7 mmol, 1 eq), pivalic acid (1370 mg, 13.4 mmol, 2 eq), ammonium persulfate (2300 mg, 10.1 mmol, 1.5 eq), and silver nitrate (285 mg, 1.7 mmol, 0.25 eq) in water (30 mL) was added sulfuric acid (0.54 mL, 1.5 eq) at 72 °C. After 1 h, the reaction was cooled, neutralized with 1 M NaOH (10 mL), extracted with DCM and concentrated. The residue was purified by RP-HPLC (0.05% NH over 20 min). 4The product was purified by elution with 30-70% MeCN in OH solution. The product-containing fractions were extracted with DCM and concentrated to give the title compound as a white solid (753.7 mg, 55%). 1 H-NMR (400MHz, CDCl 3 )δ 7.46(s,1H),1.48(s,9H).ES-MS[M+H] + =205.2.

[0406] Example 9. 3,6-Dichloro-4-(1,1-difluoroethyl)pyridazine and 3,6-dichloro-4,5-bis(1,1-difluoroethyl)pyridazine [ka] To a mixture of 3,6-dichloropyridazine (1000 mg, 6.7 mmol, 1 eq), 2,2-difluoropropanoic acid (1293 mg, 11.7 mmol, 1.75 eq), ammonium persulfate (2300 mg, 10.1 mmol, 1.5 eq), and silver nitrate (400 mg, 2.3 mmol, 0.35 eq) in water (40 mL) was added sulfuric acid (0.54 mL, 1.5 eq) at 72 °C. After 30 min, the reaction was cooled, neutralized with 1 M NaOH (5 mL), extracted with DCM and concentrated. The residue was purified by RP-HPLC (0.05% NH over 20 min). 4 The product was purified by elution with 30-70% MeCN in OH solution. The product-containing fractions were extracted with DCM and concentrated to give both title compounds as white solids. Major product: (767.2 mg, 54%) 1 H-NMR (400MHz, CDCl 3 )δ 7.71(s,1H),2.13-2.04(m,3H).ES-MS[M+H] + = 213.0., minor product: (153.3 mg, 8%) ES-MS [M+H] + =277.0.

[0407] Example 10. 3,6-Dichloro-4-(1-(trifluoromethyl)cyclopropyl)pyridazine [ka] To a mixture of 3,6-dichloropyridazine (1000 mg, 6.7 mmol, 1 eq), 1-(trifluoromethyl)cyclopropane-1-carboxylic acid (2070 mg, 13.4 mmol, 2 eq), ammonium persulfate (2300 mg, 10.1 mmol, 1.5 eq), and silver nitrate (285 mg, 1.7 mmol, 0.25 eq) in water (30 mL) was added sulfuric acid (0.54 mL, 1.5 eq) at 72 °C. After 1 h, the reaction was cooled, neutralized with 1 M NaOH (10 mL), extracted with DCM and concentrated. The residue was purified by RP-HPLC (0.05% NH over 20 min). 4 The product was purified by elution with 30-70% MeCN in OH. The product-containing fractions were extracted with DCM and concentrated to give the title compound as a white solid (474.1 mg, 28%). 1 H-NMR (400MHz, CDCl 3 )δ 7.64(s,1H),1.67-1.62(m,2H),1.22-1.16(m,2H).ES-MS[M+H] + =257.0.

[0408] Example 11. 3,6-Dichloro-4-(2,2-difluorocyclopropyl)pyridazine [ka] To 3,6-dichloropyridazine (600 mg, 4.0 mmol, 1 eq), 2,2-difluorocyclopropane-1-carboxylic acid (790 mg, 6.4 mmol, 1.6 eq), and silver nitrate (170 mg, 1.0 mmol, 0.25 eq) in water (18 mL) was added sulfuric acid (0.53 mL, 1.5 eq). The reaction was heated to 72 °C, followed by the addition of ammonium persulfate (1380 mg, 6.0 mmol, 1.5 eq) in water (6 mL). After 30 min, the reaction was cooled, neutralized with 1 M NaOH (5 mL), extracted with DCM, and concentrated. The residue was purified by RP-HPLC (25-65% MeCN in 0.1% TFA solution over 20 min). The fractions containing the product were extracted with DCM and concentrated to give the title compound (261.2 mg, 29%). ES-MS[M+H]+ =225.0.

[0409] Example 12. 3,6-Dichloro-4-(difluoromethyl)pyridazine and 3,6-dichloro-4,5-bis(difluoromethyl)pyridazine [ka] 3,6-Dichloropyridazine (3000 mg, 20.1 mmol, 1 eq) was dissolved in water (120 mL) and sulfuric acid (1.6 mL), followed by addition of ammonium persulfate (6900 mg, 30.2 mmol, 1.5 eq), silver nitrate (2000 mg, 11.7 mmol, 0.58 eq), and difluoroacetic acid (2.4 mL, 40.3 mmol, 2 eq). The resulting grey solution was stirred at 72 °C for 45 min, cooled to rt, neutralized with 1 M NaOH (10 mL) and extracted with DCM. The organics were concentrated and the residue was purified by RP-HPLC (0.05 NHCl over 20 min). 4 The product was purified by elution with 30-70% MeCN in aqueous OH. The product-containing fractions were extracted with DCM and concentrated to give the title compound. Major product (russet-green oil): (848.4 mg, 21%) 1 H-NMR (400MHz, CDCl 3 )δ 7.80(s,1H),6.97-6.7(t,J=53.8Hz,1H),ES-MS[M+H] + =199.2. Trace product (brown solid): (331.8 mg, 7%) 1 H-NMR (400MHz, CDCl 3 )δ 7.38-7.07(m,2H).ES-MS[M+H] + =249.0.

[0410] Example 13. 3,6-Dichloro-4-cyclobutylpyridazine and 3,6-dichloro-4,5-dicyclobutylpyridazine [ka] 3,6-Dichloropyridazine (2000 mg, 13.4 mmol, 1 eq), cyclobutanecarboxylic acid (1613 mg, 16.1 mmol, 1.2 eq), silver nitrate (228 mg, 1.34 mmol, 0.1 eq), and sulfuric acid (1.6 mL, 1.5 eq) in water (90 mL) were heated to 72 °C, followed by the addition of ammonium persulfate (4595 mg, 20.1 mmol, 1.5 eq). After 30 min, the reaction was cooled and quenched with 1 M NaOH solution (10 mL), followed by extraction with DCM and concentration. The residue was purified by RP-HPLC (0.05 N for 20 min). 4 Purification by 25-75% MeCN in aqueous OH). The product-containing fractions were concentrated under reduced pressure to give the title compound. Major product: (1583.5 mg, 58%). 1 H-NMR (400MHz, CDCl 3 )δ 7.38(s,1H),3.74-3.63(m,1H),2.53-2.43(m,2H),2.19-2.07(m,3H),1.97-1.88(m,1H).ES-MS[M+H] + =203.2.Minor product: (377.8 mg, 11%), 1 H-NMR (400MHz, CDCl 3 )δ 3.85-3.74(m,2H),2.56-2.37(m,8H),2.09-1.85(m,4H).ES-MS[M+H] + =257.2.

[0411] Example 14. 3,6-Dichloro-4-methyl-5-(trifluoromethyl)pyridazine [ka] 3,6-Dichloro-4-(trifluoromethyl)pyridazine (1500 mg, 6.9 mmol, 1 eq), acetic acid (1245 mg, 20.7 mmol, 3 eq), silver nitrate (352.3 mg, 2.07 mmol, 0.3 eq), and ammonium persulfate (2366 mg, 10.4 mmol, 1.5 eq) in water (40 mL) were heated to 72 °C, followed by the addition of sulfuric acid (0.55 mL, 1.5 eq). After 1 h, the reaction was cooled, neutralized with 1 M NaOH (10 mL), extracted with DCM, and concentrated. The residue was purified by RP-HPLC (25-65% MeCN in 0.1% TFA solution over 20 min). The fractions containing the product were purified by elution with sat.NaHCO 3 The solution was basified with DCM, extracted with DCM and concentrated to give the title compound (807.2 mg, 51%). 1 H-NMR (400MHz, CDCl 3 )δ 2.67-2.64(m,3H).ES-MS[M+H] + =231.0.

[0412] Example 15. 3,6-Dichloro-5-methylpyridazine-4-carbonitrile [ka] 3,6-Dichloro-5-methylpyridazine-4-carboxylic acid. Methyl 3,6-dichloro-5-methylpyridazine-4-carboxylate (1.0 g, 4.52 mmol, 1 eq) and LiOH (135 mg, 5.66 mmol, 1.25 eq) were dissolved in THF (15 mL) and H 2 2H 2 O (15 mL) and the resulting mixture was heated to 45° C. for 2 h, after which time the reaction mixture was cooled to rt and diluted with EtOAc and H 2 The aqueous layer was acidified to pH 2 with 1M HCl solution and extracted with EtOAc. The combined organic extracts were washed with MgSO 4 Drying at 40° C., filtering the solvent and concentrating under reduced pressure gave the title compound as a tan solid (691 mg, 74%). ES-MS [M+H] + =207.4.

[0413] 3,6-Dichloro-5-methylpyridazine-4-carbonitrile. To a stirred solution of 3,6-dichloro-5-methylpyridazine-4-carboxylic acid (691 mg, 3.34 mmol, 1 eq) and ammonium chloride (357 mg, 6.68 mmol, 2 eq) in DMF (11 mL) was added dropwise DIPEA (2.91 mL, 16.70 mmol, 5 eq) followed by HATU (3.81 g, 10.02 mmol, 3 eq). The resulting solution was stirred at rt for 72 h, after which time the reaction mixture was diluted with H 2 The aqueous layer was diluted with O and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine and MgSO 4 The solvent was filtered and concentrated under reduced pressure to give the title compound as a yellow oil, which was used directly without further purification (688 mg, 100%). ES-MS [M+H] + = 206.2. To a stirred solution of 3,6-dichloro-5-methylpyridazine-4-carboxamide (688 mg, 3.34 mmol, 1 eq) in DCM (22 mL) was added trifluoroacetic anhydride (1.62 mL, 11.69 mmol, 3.5 eq). The resulting solution was stirred at rt for 15 min, after which time the reaction mixture was diluted with H 2 The mixture was slowly diluted with O and the aqueous layer was extracted with DCM. The combined organic extracts were washed with sat.NaHCO 3 Wash with solution of MgSO 4 The solvent was filtered and concentrated under reduced pressure, and the crude residue was purified by column chromatography (0-50% EtOAc in hexanes) to give the title compound as a white solid (251 mg, 40% over two steps). ES-MS [M+H] + =188.2.

[0414] Example 16. (3aR,5s,6aS)-N-(4-cyclopropyl-6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d2)octahydrocyclopenta[c]pyrrol-5-amine [ka] tert-Butyl (3aR,5s,6aS)-5-((6-chloro-4-cyclopropylpyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate and tert-butyl (3aR,5s,6aS)-5-((6-chloro-5-cyclopropylpyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate. Tert-Butyl (3aR,5s,6aS)-5-aminohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (650 mg, 2.9 mmol, 1 eq), 3,6-dichloro-4-cyclopropylpyridazine (814 mg, 4.3 mmol, 1.5 eq), cesium carbonate (2044 mg, 6.2 mmol, 2.2 eq), palladium(II) acetate (32.5 mg, 0.14 mmol, 0.05 eq.), and racemic BINAP (268.3 mg, 0.43 mmol, 0.15 eq) were sealed in a vial and placed under an inert atmosphere, followed by the addition of toluene (14 mL). The reaction was heated at 110° C. overnight, removed from the heat, and filtered through a Celite® plug with DCM and EtOAc. The solvent was removed and the residue was purified by column chromatography (3-80% EtOAc in hexanes) to give the title compound. Major product: (542.8 mg, 50%) 1 H-NMR (400MHz, CDCl 3 )δ 6.87(s,1H),4.95-4.85(m,1H),4.74-4.65(m,1H),3.62-3.52(m,2H),3.23-3.12(m,2H),2.88-2.77(m,2H),2.15- 2.06(m,2H),1.87-1.79(m,2H),1.59-1.52(m,1H),1.45(s,9H),1.08-1.02(m,2H),0.68-0.63(m,2H).ES-MS[M+H] + -t-Butyl = 323.4. Minor products: (75 mg, 7%) 1 H-NMR (400MHz, CDCl 3)δ 6.15(s,1H),5.10-5.04(m,1H),4.33-4.26(m,1H),3.59-3.50(m,2H),3.23-3.13(m,2H),2.85-2.76(m,2H),2.10- 2.04(m,1H),2.01-1.93(m,2H),1.84-1.74(m,2H),1.46(s,9H),1.16-1.10(m,2H),0.75-0.69(m,2H).ES-MS[M+H] + -t-Butyl = 323.4.

[0415] [ka] ((3aR,5s,6aS)-5-((6-chloro-4-cyclopropylpyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-yl)(tetrahydro-2H-pyran-4-yl)methanone. To a solution of tert-butyl (3aR,5s,6aS)-5-((6-chloro-4-cyclopropylpyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (542.8 mg, 1.43 mmol, 1 eq) in methanol (2 mL) and 1,4-dioxane (6 mL) was added dropwise 4M HCl in dioxane (7.2 mL, 20 eq). After 1.5 h at rt the reaction was concentrated under reduced pressure and used without further purification (452 ​​mg, 100%). To the hydrochloride salt (452 ​​mg, 1.43 mmol, 1 eq) in DMF (8 mL) was added tetrahydro-2H-pyran-4-carboxylic acid (233 mg, 1.79 mmol, 1.25 eq) and DIPEA (1.25 mL, 5 eq), followed by HATU (816 mg, 2.15 mmol, 1.5 eq). After 2 h, the reaction was purified by RP-HPLC (0.05% NH over 20 min). 4 The product was purified by elution with 5-60% MeCN in OH solution. The product-containing fractions were concentrated to give the title compound as a white solid. 1 H NMR (400 MHz, CDCl 3)δ 6.87(s,1H),5.10-4.92(m,1H),4.74-4.61(m,1H),4.06-3.95(m,2H),3. 78-3.67(m,2H),3.48-3.30(m,4H),3.01-2.89(m,1H),2.89-2.79(m,1H) 2.63-2.53(m,1H),2.24-2.14(m,1H),2.13-2.03(m,1H),1.95-1.80(m,4 H),1.68-1.53(m,3H),1.10-1.01(m,2H),0.69-0.62(m,2H).ES-MS[M+H] += 391.5.

[0416] [ka] ((3aR,5s,6aS)-5-((4-cyclopropyl-6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)(tetrahydro-2H-pyran-4-yl)methanone. ((3aR,5s,6aS)-5-((6-chloro-4-cyclopropylpyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)(tetrahydro-2H-pyran-4-yl)methanone (111 mg, 0.28 mmol, 1 eq), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)pyridine (116 mg, 0.43 mmol, 1.5 eq), potassium carbonate (119 mg, 0.85 mmol, 3 eq), and BrettPhos-Pd-G3 (38.7 mg, 0.043 mmol, 0.15 eq) were sealed in a vial and placed under inert atmosphere. 2 O (3 mL total, degassed under vacuum) was added via syringe. After 3 h at 100 °C, the reaction was cooled and 2 The mixture was diluted with O, extracted with DCM and passed through a phase separator. The concentrated crude was purified by normal phase chromatography (0-10% MeOH in DCM) to give the title compound as a pale yellow solid (42 mg, 30%). 1H NMR(400MHz,MeOD)δ 8.86(d,J=5.3Hz,1H),8.76(s,1H),7.83(d,J=5.2Hz,1H),7.14(s,1H),4.82-4.73(m,1H),4.00-3.94(m,2H) ),3.87(dd,J=10.9,8.5Hz,2H),3.70(dd,J=12.4,8.6Hz,1H),3.56-3.45(m,3H),3.40(dd,J=12.6,4.7Hz,1 H),3.09-2.99(m,1H),2.99-2.89(m,1H),2.83(tt,J=11.3,3.9Hz,1H),2.19(ddd,J=13.4,6.8,4.0Hz,1H), 2.10-1.95(m,3H),1.87-1.71(m,3H),1.71-1.61(m,1H),1.14-1.08(m,2H),0.74-0.69(m,2H).ES-MS[M+H] += 502.2.

[0417] [ka] (3aR,5s,6aS)-N-(4-cyclopropyl-6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d 2 ) Octahydrocyclopenta[c]pyrrol-5-amine. To a solution of ((3aR,5s,6aS)-5-((4-cyclopropyl-6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)(tetrahydro-2H-pyran-4-yl)methanone (42 mg, 0.084 mmol, 1 eq) in THF (3 mL) was added lithium aluminum deuteride (16 mg, 0.42 mmol, 5 eq) at 0° C. The resulting yellow-orange solution was stirred for 1 h while warming to rt and then diluted with H 2 After 15 min, the aqueous mixture was quenched with MgSO 4The concentrate was purified by RP-HPLC (10-40% MeCN in 0.1% TFA solution over 4 min). The product-containing fractions were purified with sat.NaHCO 3 It was basified with soln. and extracted with DCM. The organics were filtered through a phase separator and concentrated to give the title compound as an off-white solid. 1 H NMR(400MHz,MeOD)δ 8.86(d,J=5.3,1H),8.77(s,1H),7.84(d,J=5.3Hz,1H),7.14(s,1H),4.82-4.73(m ,1H),3.93(dd,J=11.5,4.9Hz,2H),3.42(td,J=11.9,2.0Hz,2H),2.98-2.91(m,2H) ,2.83-2.76(m,2H),2.18(dd,J=9.2,5.7Hz,1H),2.04(dd,J=12.5,6.1Hz,2H),1.86 -1.70(m,6H),1.33-1.21(m,2H),1.13-1.07(m,2H),0.73-0.68(m,2H).ES-MS[M+H] + =490.2.

[0418] Example 17. (3aR,5s,6aS)-N-(4-methyl-6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d 2 ) Octahydrocyclopenta[c]pyrrol-5-amine [ka] tert-Butyl (3aR,5s,6aS)-5-((6-chloro-4-methylpyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate and tert-butyl (3aR,5s,6aS)-5-((6-chloro-5-methylpyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate. tert-Butyl (3aR,5s,6aS)-5-aminohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (2500 mg, 11 mmol, 1 eq), 3,6-dichloro-4-methylpyridazine (2520 mg, 15 mmol, 1.4 eq), cesium carbonate (7200 mg, 22 mmol, 2 eq), palladium(II) acetate (125 mg, 0.55 mmol, 0.05 eq), and racemic BINAP (1000 mg, 1.7 mmol, 0.15 eq) were sealed in a vial and placed under an inert atmosphere. Toluene (40 mL) was added via syringe. After heating at 110° C. overnight, the reaction was cooled and filtered through Celite® with EtOAc. The solvent was removed and the residue was purified by column chromatography (3-80% EtOAc in hexanes) to give the title compound as a tan solid. Major product: (259.7 mg, 22%) 1 H-NMR (400MHz, CDCl 3 )δ 7.0(s,1H),4.73-4.64(m,1H),4.12(d,J=5.7Hz,1H),3.64-3.53(m,2H),3.48(d,J=5.3Hz),3.18 -3.13(m,2H),2.86-2.76(m,2H),2.19-2.06(m,5H),1.83-1.71(m,2H),1.45(s,9H).ES-MS[M+H-] + -t-Butyl = 297.4. Minor product: (43.5 mg, 4%) 1 H-NMR (400MHz, CDCl 3)δ 6.49(s,1H),4.80-4.71(m,1H),4.31-4.21(m,1H),3.61-3.50(m,2H),3.25-3.13(m,2H),2. 86-2.76(m,2H),2.28(s,3H),2.03-1.95(m,2H),1.85-1.76(m,2H),1.45(s,9H).ES-MS[M+H] + -t-Butyl = 297.4.

[0419] [ka] tert-Butyl (3aR,5s,6aS)-5-((4-methyl-6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate. tert-Butyl (3aR,5s,6aS)-5-((6-chloro-4-methylpyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (1200 mg, 3.4 mmol, 1 eq), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)pyridine (2800 mg, 10 mmol, 3 eq), potassium carbonate (1400 mg, 10 mmol, 3 eq), and BrettPhos-Pd-G3 (620 mg, 0.68 mmol, 0.2 eq) were placed in a sealed vial under inert atmosphere in a 5:1 mixture of 1,4-dioxane / H 2 O (15 mL total, degassed under vacuum) was added via syringe. After 4 h at 100 °C, the reaction was cooled and 2 The crude residue was purified by normal phase chromatography (3-100% EtOAc in hexanes, then 0-10% MeOH in DCM) to give the title compound as a tan solid (1087 mg, 69%). 1 H NMR (400 MHz, CDCl 3)δ 8.84(s,1H),8.78(d,J=5.2Hz,1H),7.59(d,J=5.1Hz,1H),7.14(s,1H),4.87-4.78(m,1H),4.62-4.55(m,1H),3.62-3.51(m,2H) ),3.20-3.13(d,J=11.3Hz,2H),2.85-2.78(m,2H),2.17-2.08(m,2H),2.15(s,3H),1.88-1.79(m,2H),1.42(s,9H).ES-MS[M+H] + =464.1.

[0420] [ka] (3aR,5s,6aS)-N-(4-methyl-6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d 2 ) Octahydrocyclopenta[c]pyrrol-5-amine. To tert-butyl (3aR,5s,6aS)-5-((4-methyl-6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (900 mg, 1.9 mmol, 1 eq) in MeOH (2 mL) was added dropwise 4M HCl (10 mL, 21 eq). After 30 min. at rt, the solvent was concentrated under reduced pressure and the white solid thus obtained was used without further purification (776 mg, 100%). To the hydrochloride salt (776 mg, 1.9 mmol, 1 eq) in 1,4-dioxane (8 mL) was added 4-(bromomethyl-d2)tetrahydro-2H-pyran (530 mg, 2.9 mmol, 1.5 eq) followed by H 2 NaOH (640 mg, 16 mmol, 8 eq) suspended in 2 mL of O was added dropwise. After 18 h at 100 °C, the reaction was cooled and 2 The crude residue was purified by RP-HPLC (3-33% MeCN in 0.1% TFA over 20 min.). The product-containing fractions were purified with sat. NaHCO 3Basification with soln. and extraction with DCM afforded the title compound as a white solid (570 mg, 63%). 1 H NMR(400MHz,MeOD)δ 8.86(d,J=5.2,1H),8.77(s,1H),7.83(d,J=5.2Hz,1H),7.32(s,1H),4 .80-4.72(m,1H),3.93(dd,J=11.6,4.7,2H),3.42(td,J=11.8,2.0Hz,2 H),3.00-2.93(m,2H),2.83-2.75(m,2H),2.22(s,3H),2.19-2.14(m,2H ),2.07-2.00(m,2H),1.83-1.70(m,5H),1.31-1.20(m,2H).ES-MS[M+H] + =464.2.

[0421] Example 18. N-((3aR,5s,6aS)-2-((tetrahydro-2H-pyran-4-yl)methyl-d 2 )octahydrocyclopenta[c]pyrrol-5-yl)-7-(4-(trifluoromethyl)pyridin-3-yl)thieno[2,3-d]pyridazin-4-amine and N-((3aR,5s,6aS)-2-((tetrahydro-2H-pyran-4-yl)methyl-d 2 ) Octahydrocyclopenta[c]pyrrol-5-yl)-4-(4-(trifluoromethyl)pyridin-3-yl)thieno[2,3-d]pyridazin-7-amine [ka] tert-Butyl (3aR,5s,6aS)-5-((7-chlorothieno[2,3-d]pyridazin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate and tert-butyl (3aR,5s,6aS)-5-((4-chlorothieno[2,3-d]pyridazin-7-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate. To a solution of tert-butyl (3aR,5s,6aS)-5-aminohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (250 mg, 1.10 mmol, 1 eq) and 4,7-dichlorothieno[2,3-d]pyridazine (453 mg, 2.21 mmol, 2 eq) in t-butanol (2 mL) was added DIPEA (0.58 mL, 3.31 mmol, 3 eq). The resulting solution was heated under microwave irradiation at 150° C. for 2 h, after which time the solvent was concentrated and the crude residue purified by column chromatography (3-80% EtOAc in hexanes) to give a mixture of chlorothienopyridazine regioisomers which were further separated by supercritical fluid chromatography (4.6×250 mm Lux Cellulose-4 column; 25% isocratic gradient with ethanol co-solvent, 80 mL / min at 40° C.) to give both title compounds as off-white solids. Major product: (183 mg, 42%). 1 H-NMR (400MHz, CDCl 3 )δ 7.74(d,J=5.4Hz,1H),7.34(d,J=5.4Hz,1H),4.86-4.77(m,2H),3.65-3.55(m,2H),3.27-3. 15(m,2H),2.89-2.80(m,2H),2.24-2.09(m,2H),1.94-1.81(m,2H),1.46(s,9H).ES-MS[M+H] + = 395.4.Minor product: (92 mg, 21%). 1 H-NMR (400MHz, CDCl 3)δ 7.72(d,J=5.3Hz,1H),7.50(d,J=5.3Hz,1H),4.87-4.78(m,1H),4.53(d,J=6.5Hz,1H),3.65-3.55(m,2H) ),3.28-3.16(m,2H),2.90-2.81(m,2H),2.23-2.09(m,2H),1.95-1.83(m,2H),1.47(s,9H).ES-MS[M+H] + =395.4.

[0422] [ka] tert-Butyl (3aR,5s,6aS)-5-((7-(4-(trifluoromethyl)pyridin-3-yl)thieno[2,3-d]pyridazin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate. Tert-Butyl (3aR,5s,6aS)-5-((7-chlorothieno[2,3-d]pyridazin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (250 mg, 0.63 mmol, 1 eq), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)pyridine (520 mg, 1.9 mmol, 3 eq), potassium carbonate (270 mg, 1.9 mmol, 3 eq), and BrettPhos-Pd-G3 (110 mg, 0.13 mmol, 0.2 eq) were placed in a sealed vial under inert atmosphere in a 5:1 mixture of 1,4-dioxane / H 2 O (4 mL total, degassed under vacuum) was added via syringe. After 4 h at 100 °C, the reaction was cooled and 2 The crude residue was purified by RP-HPLC (20-70% MeCN in 0.1% aqueous TFA over 12 min.). The product-containing fractions were purified with sat. NaHCO 3 and extracted with DCM to give the title compound as a white solid (22.3 mg, 7%). 1H NMR(400MHz,MeOD)δ 8.98(d,J=5.3,1H),8.87(s,1H),7.98(d,J=5.4Hz,1H),7.93(d,J=5.2Hz,1H),7.88(d,J=5.4Hz,1H),4.89-4.81(m,1H),3.61(dd,J=11.2, 8.1Hz,2H),3.25(dd,J=11.4,4.1Hz,2H),2.97-2.90(dq,J=8.1,4.4Hz,2H),2.16-2.07(m,2H),2.07-1.98(m,2H),1.47(s,9H).ES-MS[M+H] + =506.2.

[0423] [ka] N-((3aR,5s,6aS)-2-((tetrahydro-2H-pyran-4-yl)methyl-d 2 ) octahydrocyclopenta[c]pyrrol-5-yl)-7-(4-(trifluoromethyl)pyridin-3-yl)thieno[2,3-d]pyridazin-4-amine. To tert-butyl (3aR,5s,6aS)-5-((7-(4-(trifluoromethyl)pyridin-3-yl)thieno[2,3-d]pyridazin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (22.3 mg, 0.044 mmol, 1 eq) was added 4 M HCl in dioxane soln. (0.33 mL, 30 eq). After stirring at rt for 1 h, the solvent was removed and used without further purification (19.5 mg, 100%). To the hydrochloride salt (19.5 mg, 0.044 mmol, 1 eq) in 1,4-dioxane (1 mL) was added 4-(bromomethyl-d2)tetrahydro-2H-pyran (12 mg, 0.066 mmol, 1.5 eq), followed by H 2 NaOH (14 mg, 0.35 mmol, 8 eq) in O (0.2 mL) was added dropwise. After stirring at 100 °C overnight, the reaction was cooled and 2The crude residue was purified by RP-HPLC (3-35% MeCN in 0.1% TFA over 5 min). The product-containing fractions were purified with sat. NaHCO 3 and extraction with DCM to give the title compound as a white solid (10 mg, 45%). 1 H NMR(400MHz,MeOD)δ 8.98(d,J=5.3Hz,1H),8.87(s,1H),7.96(d,J=5.3Hz,1H),7.93(d,J=5.2Hz,1H),7 .87(d,J=5.4Hz,1H),4.89-4.80(m,1H),3.93(dd,J=11.5,5.0Hz,2H),3.42(td,J= 11.9,2.0Hz,2H),2.96-2.90(m,2H),2.84-2.78(m,2H),2.21(dd,J=9.3,5.7Hz,2H ),2.07(dd,J=13.0,6.0Hz,2H),1.88-1.71(m,5H),1.32-1.21(m,2H).ES-MS[M+H] + =506.2.

[0424] [ka] tert-Butyl (3aR,5s,6aS)-5-((4-(4-(trifluoromethyl)pyridin-3-yl)thieno[2,3-d]pyridazin-7-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate. tert-Butyl (3aR,5s,6aS)-5-((4-chlorothieno[2,3-d]pyridazin-7-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (100 mg, 0.25 mmol, 1 eq), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)pyridine (210 mg, 0.76 mmol, 3 eq), potassium carbonate (110 mg, 0.76 mmol, 3 eq), and BrettPhos-Pd-G3 (46 mg, 0.051 mmol, 0.2 eq) were placed in a sealed vial under inert atmosphere in a 5:1 mixture of 1,4-dioxane / H 2O (4 mL total, degassed under vacuum) was added via syringe. After 4 h at 100 °C, the reaction was cooled and 2 The crude residue was purified by RP-HPLC (20-70% MeCN in 0.1% aqueous TFA over 12 min.). The product-containing fractions were purified with sat. NaHCO 3 and extracted with DCM to give the title compound as a white solid (28.9 mg, 23%). 1 H NMR(400MHz,MeOD)δ 8.96(d,J=5.3Hz,1H),8.78(s,1H),7.98(d,J=5.3Hz,1H),7.92(d,J=5.2Hz,1H),7.08(d,J=5.3Hz,1H),4.93-4.85(s,1H), 3.60(dd,J=11.3,8.2Hz,2H),3.25(dd,J=11.4,4.0Hz,2H),2.98-2.90(m,2H),2.15-1.99(m,4H),1.47(s,9H).ES-MS[M+H] + =506.1.

[0425] [ka] N-((3aR,5s,6aS)-2-((tetrahydro-2H-pyran-4-yl)methyl-d 2) octahydrocyclopenta[c]pyrrol-5-yl)-4-(4-(trifluoromethyl)pyridin-3-yl)thieno[2,3-d]pyridazin-7-amine. To tert-butyl (3aR,5s,6aS)-5-((4-(4-(trifluoromethyl)pyridin-3-yl)thieno[2,3-d]pyridazin-7-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (28.9 mg, 0.057 mmol, 1 eq) was added 4 M HCl in dioxane solution (0.43 mL, 30 eq). After stirring at rt for 1 h, the solvent was removed and used without further purification (25.3 mg, 100%). To the hydrochloride salt (19.5 mg, 0.044 mmol, 1 eq) in 1,4-dioxane (1 mL) was added 4-(bromomethyl-d2)tetrahydro-2H-pyran (16 mg, 0.086 mmol, 1.5 eq), followed by H 2 NaOH (19 mg, 0.46 mmol, 8 eq) in O (0.2 mL) was added dropwise. After stirring at 100 °C overnight, the reaction was cooled and 2 The crude residue was purified by RP-HPLC (5-35% MeCN in 0.1% TFA over 5 min). The product-containing fractions were purified with sat. NaHCO 3 and extracted with DCM to give the title compound as a white solid (10.9 mg, 38%). 1 H NMR(400MHz,MeOD)δ 8.96(d,J=5.3Hz,1H),8.79(s,1H),7.97(d,J=5.2Hz 1H),7.92(d,J=5.3Hz,1H),7.08(d,J=5.3Hz,1H),4.92-4.84(m,1H),3.93(dd,J=11.2,3.9Hz,2H),3.43(td,J=11.8,2.0Hz,2H),2.96-2. 90(m,2H),2.85-2.77(s,2H),2.21(dd,J=8.6,5.0Hz,2H),2.07(dd,J=12.5,6.0Hz,2H),1.90-1.70(m,5H),1.33-1.21(m,2H).ES-MS[M+H] + =506.2.

[0426] Example 19. (3aR,5s,6aS)-N-(4-Methoxy-6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d 2 ) Octahydrocyclopenta[c]pyrrol-5-amine [ka] tert-Butyl (3aR,5s,6aS)-5-((6-chloro-4-methoxypyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate. Tert-Butyl (3aR,5s,6aS)-5-aminohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (350 mg, 1.55 mol., 1 eq), 3,6-dichloro-4-methoxypyridazine (291 mg, 1.62 mmol, 1.05 eq), Pd(OAc) 2 (17.5 mg, 0.077 mmol, 0.05 eq), racemic-BINAP (144 mg, 0.23 mmol, 0.15 eq) and cesium carbonate (1.01 g, 3.09 mmol, 2 eq) were combined in a sealed vial and placed under inert atmosphere. Toluene (7 mL) was then added via syringe and the resulting mixture was stirred under vacuum for 5 min, after which time the reaction mixture was placed under inert atmosphere and stirred at 110° C. overnight. The reaction mixture was cooled to rt and filtered through a plug of Celite® with DCM. The solvent was concentrated under reduced pressure and the crude residue was purified by column chromatography (3-100% EtOAc in hexanes) to give the title compound as a white solid (260 mg, 46%). 1 H-NMR(400MHz,CDCl3)δ 6.53(s,1H),4.81(d,J=6.6Hz,1H),4.67-4.59(m,1H),3.90(s,3H),3.57(br s,2H),3.18(br s,2H),2.86-2.76(m,2H),2.05(br s,2H),1.81(br s,2H),1.45(s,9H).ES-MS[M+H] + -t-Butyl = 313.4.

[0427] [ka] ((3aR,5s,6aS)-5-((6-chloro-4-methoxypyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-yl)(tetrahydro-2H-pyran-4-yl)methanone. To tert-butyl (3aR,5s,6aS)-5-((6-chloro-4-methoxypyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (375 mg, 1.0 mmol, 1 eq) was added 4 M HCl in dioxane solution (7.6 mL, 30 eq). After 30 min, the solvent was removed and the white solid thus obtained was used without further purification (309 mg, 100%). To the hydrochloride salt in DMF (5 mL) was added tetrahydro-2H-pyran-4-carboxylic acid (200 mg, 1.5 mmol, 1.5 eq) and DIPEA (0.88 mL, 5 eq) followed by HATU (580 mg, 1.5 mmol, 1.5 eq). After 1 h at rt, the crude was purified by RP-HPLC (0.05% NH over 20 min). 4 The product was purified by 5-60% MeCN in aqueous OH. The product-containing fractions were concentrated to give the title compound as a white solid (319.1 mg, 82%). 1 H NMR (400 MHz, CDCl 3 )δ 6.58(s,1H),5.26-5.05(m,1H),4.71-4.62(m,1H),4.05-3.99(m,2H) ,3.93(s,3H),3.77-3.69(m,2H),3.49-3.35(m,4H),2.99-2.89(m,1H ),2.89-2.79(m,1H),2.60(tt,J=11.4,3.8Hz,1H),2.22-2.15(m,1H),2.09-2.02(m,1H),1.96-1.80(m,4H),1.70-1.55(m,2H).ES-MS[M+H] + =381.2.

[0428] [ka] ((3aR,5s,6aS)-5-((4-methoxy-6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)(tetrahydro-2H-pyran-4-yl)methanone. ((3aR,5s,6aS)-5-((6-chloro-4-methoxypyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)(tetrahydro-2H-pyran-4-yl)methanone (200 mg, 0.53 mmol, 1 eq), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)pyridine (430 mg, 1.6 mmol, 3 eq), potassium carbonate (220 mg, 1.6 mmol, 3 eq), and BrettPhos-Pd-G3 (95 mg, 0.11 mmol, 0.2 eq) were sealed in a vial and placed under inert atmosphere. 2 O (4 mL total, degassed under vacuum) was added via syringe. After 4 h at 100 °C, the reaction was cooled and 2 The crude residue was purified by normal phase chromatography (0-10% MeOH in DCM) to give the title compound as an off-white solid (173.8 mg, 67%). 1 H NMR(400MHz,MeOD)δ 8.88(d,J=5.2Hz,1H),8.79(s,1H),7.84(d,J=5.2Hz,1H),7.01(s,1H),4.72-4.63(m,1H),3.98( s,3H),4.01-3.94(m,2H),3.85(dd,J=11.1,8.4Hz,1H),3.68(dd,J=12.5,8.7Hz,1H),3.54-3.45 (m,3H),3.38(dd,J=12.7,4.7Hz,1H),3.06-2.96(m,1H),2.96-2.86(m,1H),2.82(tt,J=11.3,3. 9Hz,1H),2.16-2.09(m,1H),2.04-1.90(m,3H),1.85-1.70(m,3H),1.70-1.60(m,1H).ES-MS[M+H] + =492.2.

[0429] [ka] (3aR,5s,6aS)-N-(4-Methoxy-6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d 2 ) Octahydrocyclopenta[c]pyrrol-5-amine. ((3aR,5s,6aS)-5-((4-Methoxy-6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)(tetrahydro-2H-pyran-4-yl)methanone (170 mg, 0.35 mmol, 1 eq) was suspended in THF (3 mL) and cooled to 0° C. Lithium aluminum deuteride (45 mg, 1.2 mmol, 3.4 eq) was added. After 1 h the reaction was diluted with H while warming to rt. 2 The reaction mixture was quenched with O (50 μL) followed by stirring for 15 min. 4 The mixture was dried over 1000 ml of ethyl acetate, rinsed with DCM and concentrated. The crude residue was purified by RP-HPLC (5-35% MeCN in 0.1% aqueous TFA over 12 min). The product-containing fractions were purified with sat. NaHCO 3 Basification with soln. and extraction with DCM afforded the title compound as a pale yellow solid (25.4 mg, 15%). 1 H NMR (400MHz, MeOD) δ 8.88(d,J=5.3,1H),8.80(s,1H),7.85(d,J=5.2Hz,1H),7.01(s,1H),4.71-4 .63(m,1H),3.97(s,3H),3.93(d,J=11.3,4.0Hz,2H),3.42(td,J=11.9,1.9Hz ,2H),2.94-2.88(m,2H),2.80-2.73(m,2H),2.16(dd,J=9.1,5.6Hz,2H),1.9 9(dd,J=13.0,6.0,Hz,2H),1.81-1.69(m,5H),1.32-1.20(m,2H).ES-MS[M+H] + =480.2

[0430] Example 20. (3aR,5s,6aS)-N-(4-(difluoromethyl)-6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d 2 ) Octahydrocyclopenta[c]pyrrol-5-amine [ka] tert-Butyl (3aR,5s,6aS)-5-((6-chloro-4-(difluoromethyl)pyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate and tert-butyl (3aR,5s,6aS)-5-((6-chloro-5-(difluoromethyl)pyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate. To a solution of tert-butyl (3aR,5s,6aS)-5-aminohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (700 mg, 3.1 mmol, 1 eq) and 3,6-dichloro-4-(difluoromethyl)pyridazine (770 mg, 3.9 mmol, 1.25 eq) in t-butanol (8 mL) was added DIPEA (1.6 mL, 9.28 mmol, 3 eq). The resulting solution was heated under microwave irradiation at 150° C. for 4 h, after which time the solvent was removed and the residue was purified by column chromatography to give both title compounds as red-brown oils. Major products: 1 H-NMR (400MHz, CDCl 3 )δ 7.26(s,1H),6.68-6.4(t,J=51.0Hz 1H),4.92-4.82(m,1H),4.81-4.71(m,1H),3.66-3.56(m,2H),3.25-3.17(m,2H), 2.90-2.71(m,2H),2.19-2.09(m,2H),1.90-1.79(m,2H),1.48(s,9H),ES-MS[M+H] + -t-Butyl = 333.2. Minor product: (383.8 mg, 32%) 1 H-NMR (400MHz, CDCl 3)δ 6.99(s,1H),6.87-6.6(t,J=52.5Hz,1H),5.87-5.76(m,1H),4.43-4.34(m,2H),3.62-3.53(m,2H), 3.27-3.18(m,2H),2.92-2.82(m,2H),2.09-2.01(m,2H),1.93-1.84(m,2H),1.47(s,9H)ES-MS[M+H] + -t-Butyl = 333.2.

[0431] [ka] tert-Butyl (3aR,5s,6aS)-5-((4-(difluoromethyl)-6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate. Tert-butyl (3aR,5s,6aS)-5-((6-chloro-4-(difluoromethyl)pyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (145 mg, 0.37 mmol, 1 eq), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)pyridine (305 mg, 1.1 mmol, 3 eq), potassium carbonate (160 mg, 1.1 mmol, 3 eq), and BrettPhos-Pd-G3 (68 mg, 0.075 mmol, 0.2 eq) were sealed in a vial and placed under inert atmosphere. 2 O (4 mL total, degassed under vacuum) was added via syringe. After 4 h at 100 °C, the reaction was cooled and 2 The crude residue was purified by normal phase chromatography (3-100% EtOAc in hexanes, then 0-10% MeOH in DCM) to give the title compound as a pale yellow-green solid (153.2 mg, 78%). 1 H NMR (400 MHz, CDCl 3)δ 8.91(s,1H),8.89(d,J=5.1Hz,1H),7.68(d,J=5.2Hz,1H),7.41(s,1H),6.68(t,J=53.8Hz,1H),5.34-5.20(m,1H),4.97-4.88(m,1H),3 .60(dd,J=11.4,7.8Hz,2H),3.22(d,J=11.2Hz,2H),2.91-2.84(m,2H),2.21-2.14(m,2H),1.95-1.87(m,2H),1.46(s,9H).ES-MS[M+H] + =444.2.

[0432] [ka] (3aR,5s,6aS)-N-(4-(difluoromethyl)-6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d 2 ) Octahydrocyclopenta[c]pyrrol-5-amine. To tert-butyl (3aR,5s,6aS)-5-((4-(difluoromethyl)-6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (138 mg, 0.28 mmol, 1 eq) in MeOH (1 mL) was added 4 M HCl in dioxane (1.4 mL, 21 eq). After 30 min at rt, the solvent was removed and the off-white solid thus obtained was used without further purification (120 mg, 100%). To the hydrochloride salt (30 mg, 0.069 mmol, 1 eq) in DMF (1 mL) was added 4-(bromomethyl-d2)tetrahydro-2H-pyran (25 mg, 0.14 mmol, 2 eq) and cesium carbonate (45 mg, 0.14 mmol, 2 eq). After stirring at 100 °C overnight, the crude was purified by RP-HPLC (5-45% MeCN in 0.1% TFA aqueous solution over 6 min). The fractions containing the product were purified with sat.NaHCO 3 Basification with soln. and extraction with DCM afforded the title compound as an off-white solid (5.7 mg, 17%).1 H NMR (400MHz, MeOD) δ 8.90(d,J=5.2Hz,1H),8.83(s,1H),7.87(d,J=5.2Hz,1H),7.64(s,1H),6.97(t, J=53.8Hz,1H),4.87-4.80(m,1H),3.93(dd,J=11.4,3.9Hz,2H),3.42(td,J=11. 9,2.0Hz,2H),2.95-2.87(m,2H),2.84-2.75(m,2H),2.25(dd,J=8.8,4.7Hz,2H) ,2.04(dd,J=12.7,6.0Hz,2H),1.84-1.70(m,5H),1.33-1.21(m,2H).ES-MS[M+H] + =500.2.

[0433] Example 21. 2,2-Difluoro-2-(tetrahydro-2H-pyran-4-yl)ethyl-1,1-d 2 4-Methylbenzenesulfonate [ka] 2,2-Difluoro-2-(tetrahydro-2H-pyran-4-yl)ethyl-1,1-d 2 4-Methylbenzenesulfonate. A solution of lithium aluminum deuteride (208 mg, 5.48 mmol, 2.1 eq) in THF (20 mL) was cooled to 0° C. and 2,2-difluoro-2-(tetrahydro-2H-pyran-4-yl)acetic acid (470 mg, 2.61 mmol, 1 eq) was added. The reaction mixture was stirred at 0° C. for 15 min and then warmed to rt. After 2 h, the reaction mixture was diluted with H 2The reaction mixture was quenched by slow addition of 2H2O (0.05 mL) and 1M NaOH (0.15 mL). After stirring for an additional 30 min, the precipitate was removed by filtration and rinsed with THF. The solvent was concentrated to near dryness until approximately 10 mL of solution remained. To this solution was added DCM (30 mL) and trimethylamine (0.8 mL, 5.74 mmol, 2.2 eq) with stirring. Tosyl chloride (597 mg, 3.13 mmol, 1.2 eq) was then added and the reaction mixture was stirred overnight. The solvent was concentrated and the crude residue was purified by column chromatography (3-80% EtOAc in hexanes) to give the title compound as a white solid (362 mg, 43% over two steps). 1 H NMR (400 MHz, CDCl 3 )δ 7.81(d,J=8.3Hz,2H),7.38(d,J=8.0Hz,2H),4.01(dt,J=11.4,3.3Hz,2H),3.35(ddd,J =11.6,8.7,5.6Hz,2H),2.47(s,3H),2.27-2.12(m,1H),1.64-1.52(m,4H).ES-MS[M+H] + =323.0.

[0434] Example 22. (3aR,5s,6aS)-2-((tetrahydro-2H-pyran-4-yl)methyl)-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine [ka] (3aR,5s,6aS)-N-(6-chloropyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine (65 mg, 0.19 mmol, 1 eq), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)pyridine (63 mg, 0.23 mmol, 1.2 eq), potassium carbonate (81 mg, 0.58 mmol, 3 eq) and BrettPhos-Pd-G3 (18 mg, 0.019 mmol, 0.1 eq) were combined in a vial, which was sealed and placed under inert atmosphere. Then, 5:1 1,4-dioxane / H 2 2H2O solution (1 mL total, degassed under vacuum) was added via syringe. The resulting reaction mixture was stirred at 100 °C for 1 h, after which time the reaction was cooled to rt and diluted with DCM and H 2 The aqueous layer was extracted with DCM and the combined organic extracts were filtered through a phase separator and concentrated. The crude residue was purified by RP-HPLC (2-32% MeCN in 0.1% aqueous TFA over 10 min). The product-containing fractions were purified with sat.NaHCO 3 and extracted with DCM. The combined organic extracts were filtered through a phase separator and concentrated to give the title compound as a white solid (11 mg, 13%). 1 H NMR(400MHz,MeOD)δ 8.77(dd,J=5.3,0.8Hz,1H),8.69(s,1H),7.74(d,J=5.2Hz,1H),7.32(dd,J=9.3,0.7 Hz,1H),6.84(d,J=9.3Hz,1H),4.47-4.39(m,1H),3.83(dd,J=11.7,4.2Hz,2H),3.32 (td,J=11.9,2.0Hz,2H),2.78-2.63(m,4H),2.23(d,J=6.8Hz,2H),2.16(d,J=7.6Hz, 2H),1.88(dd,J=12.6,5.9Hz,2H),1.73-1.59(m,5H),1.25-1.08(m,2H).ES-MS[M+H] + =448.2.

[0435] Example 23 (3aR,5s,6aS)-2-((tetrahydro-2H-pyran-4-yl)methyl-d 2 )-N-(6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine [ka] (3aR,5s,6aS)-N-(6-chloropyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d 2 ) Octahydrocyclopenta[c]pyrrol-5-amine (500 mg, 1.48 mmol, 1 eq), (2-(trifluoromethyl)pyridin-3-yl)boronic acid (423 mg, 2.21 mmol, 1.5 eq), potassium carbonate (620 mg, 4.43 mmol, 3 eq) and BrettPhos-Pd-G3 (134 mg, 0.148 mmol, 0.1 eq) were combined in a vial, which was sealed and placed under an inert atmosphere. Then, 5:1 1,4-dioxane / H 2 The resulting reaction mixture was stirred at 100° C. for 22 h, after which time the reaction mixture was cooled to rt and H 2 The mixture was diluted with 0 and extracted with DCM. The solvent was removed and the crude residue was purified by RP-HPLC (2-35% MeCN in 0.1% aqueous TFA over 20 min). The fractions containing the product were basified with sat.NaHCO3 solution, extracted with DCM and the organic solvent was concentrated. The compound was subjected to further purification by RP-HPLC (20-50% MeCN in 0.05% aqueous NH4OH over 10 min). The fractions containing the product were extracted with DCM and the organic solvent was concentrated to give the title compound as a white solid (165.6 mg, 25%). 1H NMR (400MHz, MeOD) δ 8.76(dd,J=4.7,0.9Hz,1H),8.03(dd,J=7.9,0.9Hz,1H),7.76(dd,J=8.0,4.8H z,1H),7.39(d,J=9.3Hz,1H),6.93(d,J=9.3Hz,1H),4.57-4.47(m,1H),3.93(dd ,J=11.1,3.3Hz,2H),3.42(td,J=11.9,2.0Hz,2H),2.86-2.72(m,4H),2.28-2. 20(m,2H),2.01-1.93(m,2H),1.81-1.67(m,5H),1.36-1.19(m,2H).ES-MS[M+H] + =450.2.

[0436] Example 24 (3aR,5S,6aS)-2-(((R)-1,4-dioxane-2-yl)methyl-d 2 )-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine [ka] ((3aR,5s,6aS)-5-((6-chloropyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)((S)-1,4-dioxane-2-yl)methanone. (3aR,5s,6aS)-N-(6-chloropyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine (310 mg, 1.30 mmol, 1 eq) and (S)-1,4-dioxane-2-carboxylic acid (223 mg, 1.69 mmol, 1.3 eq) were dissolved in DMF (10 mL). DIPEA (0.68 mL, 3.90 mmol, 3 eq) was added to the reaction mixture followed by HATU (741 mg, 1.95 mmol, 1.5 eq) and stirred at rt for 2 h. The reaction mixture was stirred for 2 h at rt. 2The mixture was diluted with 0 and extracted with DCM. The solvent was concentrated and the crude residue was purified by RP-HPLC (2-22% MeCN in 0.1% aqueous TFA over 20 min). The fractions containing the product were basified with sat. NaHCO3 solution, extracted with DCM and the organic solvent was concentrated to give the title compound as a white solid (458.2 mg, 38%). ES-MS [M+H] += 353.1.

[0437] [ka] (3aR,5s,6aS)-2-(((R)-1,4-dioxan-2-yl)methyl-d 2 )-N-(6-chloropyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine. ((3aR,5s,6aS)-5-((6-chloropyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)((S)-1,4-dioxan-2-yl)methanone (172 mg, 0.49 mmol, 1 eq) was dissolved in THF (4 mL). Lithium aluminum deuteride (93 mg, 2.44 mmol, 5 eq) was added slowly and the reaction mixture was stirred at rt for 1 h. Sequentially, H 2 O (92 μL), 1M NaOH (92 μL), H 2 HO (92 μL) followed by MgSO 4 was added to the mixture, which was stirred for an additional 5 min. The solid was dissolved in Et 2 After multiple washes with O, the solvent was filtered and concentrated to give the title compound as a white solid (166.1 mg, 100%). ES-MS [M+H] + =341.2.

[0438] [ka] (3aR,5s,6aS)-2-(((R)-1,4-dioxan-2-yl)methyl-d 2)-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine. (3aR,5s,6aS)-2-(((R)-1,4-dioxan-2-yl)methyl-d 2 )-N-(6-chloropyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine (166 mg, 0.49 mmol, 1 eq), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)pyridine (0.17 mL, 0.73 mmol, 1.5 eq), potassium carbonate (205 mg, 1.46 mmol, 3 eq) and BrettPhos-Pd-G3 (44 mg, 0.049 mmol, 0.1 eq) were combined in a vial, which was sealed and placed under an inert atmosphere. Then, 5:1 1,4-dioxane / H 2 The resulting reaction mixture was stirred at 100° C. for 5 days, after which time the reaction mixture was cooled to rt and H 2 The mixture was diluted with 0 and extracted with DCM. The solvent was removed and the crude residue was purified by RP-HPLC (2-27% MeCN in 0.1% aqueous TFA over 10 min). The fractions containing the product were basified with sat. NaHCO3 solution, extracted with DCM and the organic solvent was concentrated to give the title compound as a white solid (23.6 mg, 11%). 1 H NMR(400MHz,MeOD)δ 8.87(d,J=5.2Hz,1H),8.79(s,1H),7.84(d,J=5.2Hz,1H),7.43(d,J=9.3Hz,1H),6.95 (d,J=9.3Hz,1H),4.56-4.47(m,1H),3.80-3.65(m,5H),3.58(dd,J=11.5,2.7Hz,1H), 3.29(d,J=1.5Hz,1H),2.93(dt,J=16.0,8.3Hz,2H),2.84-2.72(m,2H),2.26(dt,J=9. 4,6.2Hz,2H),1.97(dd,J=13.2,5.8Hz,2H),1.75(dt,J=12.8,8.2Hz,2H),ES-MS[M+H] + =452.1.

[0439] Example 25 (3aR,5S,6aS)-3a-methyl-2-((tetrahydro-2H-pyran-4-yl-2,2,6,6-d 4 ) Methyl-d 2 )-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine and (3aS,5R,6aR)-3a-methyl-2-((tetrahydro-2H-pyran-4-yl-2,2,6,6-d 4 ) Methyl-d 2 )-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine [ka] tert-Butyl 5-((triethylsilyl)oxy)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate. To a solution of tert-butyl (3aR,6aS)-5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (1.0 g, 4.4 mmol, 1.0 eq) in DMF (17.8 mL) was added dropwise chlorotriethylsilane (0.89 mL, 5.3 mmol, 1.2 eq). Triethylamine (1.48 mL, 10.7 mmol, 2.4 eq) was then added dropwise under inert atmosphere. The reaction was allowed to proceed overnight at 80° C., after which time the reaction was cooled to rt and diluted with DCM (50 mL) and sat. NaHCO. 3 (50 mL). The aqueous layer was extracted with DCM (3×50 mL). The combined organic extracts were washed with MgSO 4 The mixture was dried at 40° C., filtered and concentrated. The crude residue was purified by column chromatography (1-10% EtOAc in hexanes) to give the title compound as a colorless oil (723.6 mg, 48%). ES-MS [M+H] + -t-Butyl = 284.4.

[0440] [ka] tert-Butyl 5-oxo-3,3a,4,5-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate. To a stirred solution of tert-butyl 5-((triethylsilyl)oxy)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (724 mg, 2.1 mmol, 1.0 eq) in MeCN (15 mL) was added palladium(II) acetate (531 mg, 2.3 mmol, 1.1 eq). The reaction was stirred in open air for 2 h, after which time excess catalyst was removed by syringe filtration and the solvent was evaporated under reduced pressure to give a crude residue. The crude residue was purified by column chromatography (0-60% EtOAc in hexanes) to give the title compound as a brown crystalline solid (422 mg, 89%). 1 H NMR (400 MHz, CDCl 3 )δ 6.07(d,J=10.5Hz,1H),4.25(t,J=10.3Hz,2H),4.06(dt,J=34.8,8.4Hz,1H),3.22(d,J=35.8Hz,2H),2.87( dd,J=10.9,7.0Hz,1H),2.66(dd,J=17.6,8.3Hz,1H),2.18(dt,J=19.4,6.7Hz,1H),1.48(s,9H).ES-MS[M+H] + -t-Butyl = 168.4.

[0441] [ka] tert-Butyl (3aR,6aS)-3a-methyl-5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate and tert-Butyl (3aS,6aR)-3a-methyl-5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate. A stirred suspension of CuI (719 mg, 3.78 mmol, 2.0 eq) in THF (2.5 mL) was added at -78 °C with Et 2A 3.0 M solution of MeMgBr in 2O (1.9 mL, 5.7 mmol, 3.0 eq) was added dropwise under an inert atmosphere. The resulting solution was stirred at -78 °C for 30 min., after which time a solution of tert-butyl 5-oxo-3,3a,4,5-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (422 mg, 1.88 mmol, 1.0 eq) in THF (2.5 mL) was added dropwise. After stirring for 30 min, the reaction mixture was warmed to rt and the sat. NH 4 The reaction was quenched with EtOAc (50 mL) and H 2 The aqueous layer was extracted with EtOAc (3×50 mL). The combined organic extracts were washed with MgSO 4 The mixture was dried at 40° C., the solvent was filtered and then concentrated. The crude residue was purified by column chromatography (0-50% EtOAc in hexanes) to give the title compound as a white solid (310 mg, 69%). 1 H NMR (400 MHz, CDCl 3 )δ 3.73(d,J=7.2Hz,1H),3.45-3.10(m,3H),2.59-2.43(m,2H),2.39-2.12(m,3H),1.45(s,9H),1.23(s,3H).ES-MS[M+H] +- t-Butyl=184.4.

[0442] [ka] tert-Butyl (3aR,5R,6aS)-5-hydroxy-3a-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate and tert-butyl (3aS,5S,6aR)-5-hydroxy-3a-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate. A stirred mixture of the stereoisomeric tert-butyl (3aR,6aS)-3a-methyl-5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate / tert-butyl (3aS,6aR)-3a-methyl-5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (310 mg, 1.3 mmol, 1.0 eq) in THF (6.4 mL, 0.2 M) was added at -78 °C with LiAlH(OtBu) 3 (1.9 mL, 1.9 mmol, 1.3 eq) was added dropwise via syringe. The resulting solution was stirred at -78 °C for 1 h, after which the reaction was diluted with H 2 The reaction was quenched by slow addition of 0.5 mL of 2H2O followed by 0.5 mL of 1M NaOH at -78 °C. The reaction was warmed to rt and stirred for 15 min. MgSO 4 was added to give a slurry. After stirring for an additional 15 min, the slurry was diluted with DCM (20 mL) and the solids were removed by filtration. The filtrate was then diluted with DCM and sat. NH 4 The aqueous layer was extracted with EtOAc (3×50 mL). The combined organic extracts were washed with MgSO 4 The mixture was dried at 4° C., the solvent was filtered and concentrated to give a crude colorless liquid which did not require further purification. ES-MS [M+H] + -t-Butyl = 184.4.

[0443] [ka] tert-Butyl (3aR,5S,6aS)-5-(1,3-dioxoisoindolin-2-yl)-3a-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate and tert-Butyl (3aS,5R,6aR)-5-(1,3-dioxoisoindolin-2-yl)-3a-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate. To a mixture of stereoisomeric tert-butyl (3aR,5R,6aS)-5-hydroxy-3a-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate / tert-butyl (3aS,5S,6aR)-5-hydroxy-3a-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (433 mg, 2.9 mmol, 1.0 eq.) and triphenylphosphine (772 mg, 2.9 mmol, 1.0 eq) in THF (5.0 mL, 0.45 M) was added dropwise a solution of diisopropyl azodicarboxylate (0.58 mL, 2.94 mmol) in THF (1 mL) at 0° C. The flask was removed from the ice bath and stirred at rt for 1 h, after which time the reaction was quenched with MeOH (0.25 mL) and the organics were evaporated under reduced pressure. The crude residue was purified by column chromatography (5-30% EtOAc in hexanes) to give the title compound as a white solid (422 mg, 50%). ES-MS [M+H] + -t-Butyl = 315.2.

[0444] [ka] tert-Butyl (3aR,5S,6aS)-5-amino-3a-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate and tert-butyl (3aS,5R,6aR)-5-amino-3a-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate. To a stirred mixture of stereoisomeric tert-butyl (3aR,5S,6aS)-5-(1,3-dioxoisoindolin-2-yl)-3a-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate / tert-butyl (3aS,5R,6aR)-5-(1,3-dioxoisoindolin-2-yl)-3a-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (423 mg, 1.1 mmol, 1.0 eq) in EtOH (6 mL, 0.19 M) was added hydrazine (0.18 mL, 5.7 mmol, 5.0 eq) at rt. The reaction was then refluxed at 80° C. for 1 h, after which time the reaction mixture was cooled to rt. The solids were removed by filtration and the mixture was dissolved in Et 2 0 (10 mL) and then DCM (10 mL). The organic solvent was evaporated under reduced pressure to give the title compound as a crude liquid which was used without further purification (228 mg, 83%). ES-MS [M+H] + =241.4.

[0445] [ka] tert-Butyl (3aR,5S,6aS)-5-((6-chloropyridazin-3-yl)amino)-3a-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate and tert-butyl (3aS,5R,6aR)-5-((6-chloropyridazin-3-yl)amino)-3a-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate. To a solution of the mixture of stereoisomeric tert-butyl (3aR,5S,6aS)-5-amino-3a-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate / tert-butyl (3aS,5R,6aR)-5-amino-3a-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (490 mg, 3.8 mmol, 1.0 eq) in tBuOH (3.2 mL) was added solid 3,6-dichloropyridazine (239 mg, 1.6 mmol, 1.7 eq) and DIPEA (0.66 mL, 3.79 mmol, 4 eq). The reaction vessel was subjected to microwave irradiation at 150 °C for 4 h. The solvent was evaporated under reduced pressure and the crude residue was purified by column chromatography (0-80% EtOAc in hexanes) to give the title compound as a white solid (153 mg, 46%). ES-MS[M+H] + -t-Butyl = 297.4

[0446] [ka] tert-Butyl (3aR,5S,6aS)-3a-methyl-5-((6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate and tert-butyl (3aS,5R,6aR)-3a-methyl-5-((6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate. In a round bottom flask equipped with a stir bar, the stereoisomers tert-butyl (3aR,5S,6aS)-5-((6-chloropyridazin-3-yl)amino)-3a-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate / tert-butyl (3aS,5R,6aR)-5-((6-chloropyridazin-3-yl)amino)-3a-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate / A mixture of pyrrole-2(1H)-carboxylate (153.3 mg, 0.43 mmol, 1.0 eq), BrettPhos-Pd-G3 (98.6 mg, 0.11 mmol, 0.25 eq), 4-(trifluoromethyl)pyridine-3-boronic acid pinacol ester (355 mg, 1.3 mmol, 3.0 eq), and potassium carbonate (0.08 mL, 1.3 mmol, 3.0 eq) was added. The flask was sealed and the solids were then dissolved in degassed 1,4-dioxane / H 2 The reaction was then stirred at 100° C. for 2 h. After this time, the reaction mixture was cooled to rt and diluted with DCM (5.0 mL) and H 2 The organic layer was filtered through a phase separator and the organic extract was diluted with Na 2 SO 4 It was dried at 75° C., filtered and the solvent was evaporated under reduced pressure. The crude residue was purified by column chromatography (0-90% EtOAc in DCM) to give the title compound as a yellow / brown solid (94.5 mg, 47%). ES-MS [M+H] + =464.4.

[0447] [ka] (3aR,5S,6aS)-3a-Methyl-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine hydrochloride and (3aS,5R,6aR)-3a-Methyl-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine hydrochloride. To a stirred mixture of stereoisomeric tert-butyl (3aR,5S,6aS)-3a-methyl-5-((6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate / tert-butyl (3aS,5R,6aR)-3a-methyl-5-((6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (94.5 mg, 0.20 mmol, 1.0 eq) in MeOH (0.5 mL) was added 4 M HCl in dioxane (0.68 mL). The resulting cloudy mixture was stirred at rt for 1 h. After this time, the organic solvent was evaporated under reduced pressure and the resulting HCl salt was dried under vacuum to give the title compound as a white solid (88.0 mg, 100% yield). ES-MS [M+H] + =364.0.

[0448] [ka] ((3aR,5S,6aS)-3a-Methyl-5-((6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)(tetrahydro-2H-pyran-4-yl-2,2,6,6-d 4)methanone and ((3aS,5R,6aR)-3a-methyl-5-((6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)(tetrahydro-2H-pyran-4-yl-2,2,6,6-d 4 )methanone. The stirred stereoisomers (3aR,5S,6aS)-3a-methyl-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine hydrochloride / (3aS,5R,6aR)-3a-methyl-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol To a mixture of diol-5-amine hydrochloride (112 mg, 0.26 mmol, 1.0 eq) and 2,2,6,6-tetradeuteriotetrahydropyran-4-carboxylic acid (41.3 mg, 0.31 mmol, 1.2 eq) in DMF (5.0 mL) was added DIPEA (0.13 mL, 0.77 mmol, 3 eq) followed by HATU (146 mg, 0.38 mmol, 1.5 eq) at rt. The reaction was stirred at rt for 1 h. After this time, the reaction mixture was directly purified by RP-HPLC (5-40% MeCN in 0.1% TFA aqueous solution over 10 min). The fractions containing the product were purified by sat. NaHCO 3 The mixture was basified with and extracted with DCM. The combined organic extracts were washed with MgSO 4 Drying at 40° C., filtering and concentrating under reduced pressure gave the title compound as a white solid (55.2 mg, 45% yield). 1 H NMR (400 MHz, CDCl 3)δ 8.88(s,1H),8.84(d,J=5.2Hz,1H),7.64(d,J=5.2Hz,1H),7.35(dd,J=9.1,2.1Hz,1H),6.71(d d,J=9.4,3.1Hz,1H),5.40(s,1H),4.49(dq,J=18.8,7.2Hz,1H),3.83-3.71(m,1H),3.60-3.26( m,3H),2.58(qt,J=11.6,3.9Hz,1H),2.52-2.35(m,2H),2.17(dddd,J=16.5,12.6,7.4,5.0Hz,1 ES-MS[M+H] + =480.0.

[0449] [ka] (3aR,5S,6aS)-3a-Methyl-2-((tetrahydro-2H-pyran-4-yl-2,2,6,6-d 4 ) Methyl-d 2 )-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine and (3aS,5R,6aR)-3a-methyl-2-((tetrahydro-2H-pyran-4-yl-2,2,6,6-d 4 ) Methyl-d 2 )-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine. The stereoisomer ((3aR,5S,6aS)-3a-methyl-5-((6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)(tetrahydro-2H-pyran-4-yl-2,2,6,6-d 4)methanone / ((3aS,5R,6aR)-3a-methyl-5-((6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)(tetrahydro-2H-pyran-4-yl-2,2,6,6-d 4 To a stirred solution of a mixture of 1,2-dimethylbutane (55.2 mg, 0.12 mmol, 1.0 eq) and 1,2-dimethylbutane (55.2 mg, 0.12 mmol, 1.0 eq) at rt was added lithium aluminum deuteride (21.9 mg, 0.58 mmol, 5.0 eq) in one portion. The reaction was continued to stir at rt for 20 min. after this time the reaction was diluted with Et 2 The mixture was diluted with 100 mL of O, quenched with 1 M NaOH (0.5 mL) and stirred for 30 min. Then, MgSO 4 After stirring for an additional 15 min, the slurry was diluted with Et 2 The mixture was diluted with 20 mL of HO (20 mL) and the solids were removed by filtration. The solvent was evaporated under reduced pressure and the crude residue thus obtained was purified by RP-HPLC (5-40% MeCN in 0.1% aqueous TFA over 10 min). The fractions containing the product were purified with sat. NaHCO 3 The mixture was basified with and extracted with DCM. The combined organic extracts were washed with MgSO 4 Drying at 40° C., filtering and concentrating under reduced pressure gave the title compound as a white solid (19.2 mg, 36% yield). 1 H NMR (400 MHz, CDCl 3 )δ 8.89(s,1H),8.83(d,J=5.2Hz,1H),7.63(d,J=5.2Hz,1H),7.34(d,J=9.2Hz,1H),6.75(d,J=9.3Hz,1H),5.16(s,1H),4.50(s,1H),3 .11-2.18(m,8H),2.08(dd,J=13.0,5.8Hz,1H),1.86-1.60(m,4H),1.44(dd,J=12.6,9.8Hz,1H),1.29(d,J=7.9Hz,3H).ES-MS[M+H] + =468.1.

[0450] Example 26 (3aR,5s,6aS)-2-(2,2-difluoro-2-(tetrahydro-2H-pyran-4-yl)ethyl-1,1-d 2 )-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine [ka] tert-Butyl (3aR,5s,6aS)-5-((6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate. tert-Butyl (3aR,5s,6aS)-5-((6-chloropyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (660 mg, 1.95 mmol, 1 eq), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)pyridine (1.60 g, 5.84 mmol, 3 eq), potassium carbonate (819 mg, 5.84 mmol, 3 eq) and BrettPhos-Pd-G3 (354 mg, 0.39 mmol, 0.2 eq) were combined in a vial, which was sealed and placed under an inert atmosphere. Then, 5:1 1,4-dioxane / H 2 The resulting reaction mixture was stirred at 100° C. for 4 h, after which time the reaction mixture was cooled to rt and H 2 O and extracted with DCM. The combined organic extracts were removed and the crude residue was purified by column chromatography (3-100% EtOAc in hexanes, then 0-10% MeOH in DCM) to give the title compound as a pale yellow solid (620 mg, 71%). ES-MS [M+H] + =450.3.

[0451] [ka] (3aR,5s,6aS)-2-(2,2-difluoro-2-(tetrahydro-2H-pyran-4-yl)ethyl-1,1-d 2 )-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine. tert-Butyl (3aR,5s,6aS)-5-((6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (400 mg, 0.89 mmol, 1 eq) was dissolved in MeOH (1 mL) and 4M HCl in dioxane solution (4.6 mL) was added dropwise. The resulting yellow solution was stirred at rt for 30 min, after which time the solvent was concentrated to give the HCl salt as a yellow solid which was dried and used without further purification (343 mg, 100%). ES-MS [M+H] + = 350.1. HCl amine (20 mg, 0.052 mmol, 1 eq) and 2,2-difluoro-2-(tetrahydro-2H-pyran-4-yl)ethyl-1,1-d2 4-methylbenzenesulfonate (25 mg, 0.078 mmol, 1.5 eq) were suspended in 1,4-dioxane (1 mL) followed by H 2 NaOH (17 mg, 0.41 mmol, 8 eq) in 2H2O (0.2 mL) was added dropwise. The reaction mixture was stirred at 100 °C for 18 h and then at 180 °C for 4 h under microwave irradiation, after which time the solvent was removed and the crude residue was purified by RP-HPLC (5-35% MeCN in 0.1% aqueous TFA over 5 min). The fractions containing the product were purified with sat.NaHCO 3 and extracted with DCM. The combined organic extracts were filtered through a phase separator and concentrated to give the title compound (1.3 mg, 5%). 1H NMR(400MHz,MeOD)δ 8.87(dd,J=5.2,0.8Hz,1H),8.79(s,1H),7.84(d,J=5.2Hz,1H),7.42(d,J=9.3Hz,1H ),6.93(d,J=9.3Hz,1H),4.64-4.47(m,1H),3.97(dd,J=11.5,4.5Hz,2H),3.44(td,J= 12.0,2.1Hz,2H),2.78-2.67(m,4H),2.55(dd,J=9.1,2.8Hz,2H),2.45-2.26(m,1H), 1.97(ddd,J=12.3,5.8,2.2Hz,2H),1.86-1.69(m,4H),1.63-1.53(m,2H).ES-MS[M+H] + =500.0.

[0452] Example 27. (3aR,5s,6aS)-N-(6-(4,6-bis(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d 2 ) Octahydrocyclopenta[c]pyrrol-5-amine [ka] 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,4-bis(trifluoromethyl)pyridine. 5-Bromo-2,4-bis(trifluoromethyl)pyridine (50 mg, 0.17 mmol, 1 eq), potassium acetate (50 mg, 0.51 mmol, 3 eq), bis(pinacolato)diboron (65 mg, 0.26 mmol, 1.5 eq) and Pd(dppf)Cl 2.DCM (14 mg, 0.017 mmol, 0.1 eq) were combined in a vial which was sealed and placed under an inert atmosphere. 1,4-dioxane (1.7 mL) was then added via syringe. The resulting reaction mixture was stirred at 150° C. under microwave irradiation for 1 h, after which time the reaction mixture was filtered through a plug of Celite® with DCM and the solvent was concentrated. The crude residue was purified by column chromatography (0-10% MeOH in DCM) to give the title compound as an orange oil (50 mg, 86%). ES-MS [M+H] + = 260.6 (observed mass of boronic acid).

[0453] [ka] (3aR,5s,6aS)-N-(6-(4,6-bis(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d 2 ) Octahydrocyclopenta[c]pyrrol-5-amine. (3aR,5s,6aS)-N-(6-chloropyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d 2 ) Octahydrocyclopenta[c]pyrrol-5-amine (25 mg, 0.074 mmol, 1 eq), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,4-bis(trifluoromethyl)pyridine (75 mg, 0.22 mmol, 3 eq), potassium carbonate (31 mg, 0.22 mmol, 3 eq) and BrettPhos-Pd-G3 (17 mg, 0.018 mmol, 0.25 eq) were combined in a flask, which was sealed and placed under an inert atmosphere. Then, 5:1 1,4-dioxane / H 22H2O (total 1 mL, degassed under vacuum) was added. The resulting reaction mixture was stirred at 100 °C for 4 h, after which time the reaction was cooled to rt and the aqueous layer was extracted with DCM. The combined organic extracts were concentrated and the crude residue was purified by RP-HPLC (5-35% MeCN in 0.1% aqueous TFA over 5 min). The product-containing fractions were purified with sat.NaHCO 3 The mixture was basified with and extracted with DCM. The combined organic extracts were washed with MgSO 4 Dry at 40° C., filter and remove the solvent to give the title compound (4.9 mg, 13%). 1 H NMR (400 MHz, CDCl 3 )δ 9.05(s,1H),8.01(s,1H),7.39(d,J=9.3Hz,1H),6.73(d,J=9.3Hz,1H),5. 10(d,J=9.9Hz,1H),4.45-4.35(m,1H),3.97(dd,J=10.8,3.6Hz,2H),3.39( td,J=11.9,1.9Hz,2H),2.85-2.71(m,2H),2.65-2.52(m,2H),2.44-2.32(m ,2H),2.05-1.94(m,2H),1.81-1.69(m,5H),1.36-1.20(m,2H).ES-MS[M+H] + =518.3.

[0454] Example 28. (3aR,5s,6aS)-2-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl-d 2 )-N-(6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine [ka] ((3aR,5s,6aS)-5-((6-chloropyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)(2,2-dimethyltetrahydro-2H-pyran-4-yl)methanone. (3aR,5s,6aS)-N-(6-chloropyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine hydrochloride (50 mg, 0.18 mmol, 1 eq) and 2,2-dimethyltetrahydro-2H-pyran-4-carboxylic acid (32 mg, 0.20 mmol, 1.1 eq) were dissolved in DMF (2 mL) and DIPEA (0.095 mL, 0.55 mmol, 3 eq) and HATU (104 mg, 0.27 mmol, 1.5 eq) were added. The resulting reaction mixture was stirred at rt for 1 h, after which time the reaction was diluted with H 2 The mixture was diluted with 0 and DCM. The aqueous layer was extracted with DCM and the combined organic extracts were filtered through a phase separator and concentrated to give a residue which was dried under vacuum and used without further purification (69 mg, 100%). ES-MS [M+H] + =379.2.

[0455] [ka] (3aR,5s,6aS)-N-(6-chloropyridazin-3-yl)-2-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl-d 2 ) Octahydrocyclopenta[c]pyrrol-5-amine. ((3aR,5s,6aS)-5-((6-chloropyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)(2,2-dimethyltetrahydro-2H-pyran-4-yl)methanone (69 mg, 0.18 mmol, 1 eq) was dissolved in THF (1 mL) and cooled to 0° C. Then lithium aluminum deuteride (34 mg, 0.91 mmol, 5 eq) was added and the resulting reaction mixture was allowed to warm to rt and stirred for 2 h, after which time H 2 HO (34 μL), 1 M NaOH (34 μL), and H 2 O (34 μL) was added sequentially. 2SO 4 was added and the resulting mixture was stirred for 5 min. The solids were removed by filtration with diethyl ether and the filtrate was concentrated under reduced pressure to give a residue which was dried under vacuum and used without further purification (67 mg, 100%). ES-MS [M+H] + =367.2.

[0456] [ka] (3aR,5s,6aS)-2-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl-d 2 )-N-(6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine. (3aR,5s,6aS)-N-(6-chloropyridazin-3-yl)-2-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl-d 2 ) Octahydrocyclopenta[c]pyrrol-5-amine (67 mg, 0.18 mmol, 1 eq), potassium carbonate (76 mg, 0.55 mmol, 3 eq), (2-(trifluoromethyl)pyridin-3-yl)boronic acid (52 mg, 0.27 mmol, 1.5 eq) and BrettPhos-Pd-G3 (16 mg, 0.018 mmol, 0.1 eq) were combined in a vial and placed under inert atmosphere. Then, 5:1 1,4-dioxane / H 2 2H2O solution (total 1 mL, degassed under vacuum) was added via syringe and the resulting reaction mixture was stirred at 100 °C for 15 h. The reaction mixture was then cooled to rt and diluted with DCM and H 2 The aqueous layer was extracted with DCM and the combined organic extracts were filtered through a phase separator and concentrated. The crude residue was purified by RP-HPLC (0.05% NH over 10 min). 4 The residue was purified by elution with 34-69% MeCN in aqueous OH (34-69% MeCN). The product-containing fractions were extracted with a 3:1 chloroform / IPA solution (v / v). The combined organic extracts were filtered through a phase separator and concentrated to give the title compound (5.5 mg, 6% over three steps). 1H NMR (400MHz, MeOD) δ 8.76(dd,J=4.7,0.9Hz,1H),8.03(dd,J=8.1,1.2Hz,1H),7.76(dd,J=7.9,4.7Hz ,1H),7.39(d,J=9.3Hz,1H),6.93(d,J=9.3Hz,1H),4.56-4.49(m,1H),3.72-3.69 (m,2H),2.90-2.83(m,2H),2.82-2.75(m,2H),2.28-2.21(m,2H),2.00-1.91(m, 3H),1.78-1.66(m,4H),1.24(s,3H),1.20(s,3H),1.18-1.02(m,2H).ES-MS[M+H] + =478.2.

[0457] Example 29. (3aR,5s,6aS)-2-((tetrahydro-2H-pyran-4-yl)methyl-d 2 )-N-(2'-(trifluoromethyl)-[2,3'-bipyridin]-5-yl)octahydrocyclopenta[c]pyrrol-5-amine [ka] tert-Butyl (3aR,5s,6aS)-5-((6-chloropyridin-3-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate. 2-Chloro-5-iodopyridine (200 mg, 0.84 mmol, 1 eq), tert-butyl (3aR,5s,6aS)-5-aminohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (246 mg, 1.09 mmol, 1.3 eq), copper(I) iodide (8.0 mg, 0.042 mmol, 0.05 eq), and cesium carbonate (548 mg, 1.67 mmol, 2 eq) were sealed under inert atmosphere. DMF (0.5 mL) was added followed by 2-isobutyrylcyclohexanone (28.1 mg, 0.17 mmol, 0.2 eq). After 80 h at rt, the reaction mixture was filtered and the organic phase was washed with sat.NaHCO 3The concentrated crude was purified by column chromatography (3-100% EtOAc in hexanes) to give the title compound as a colorless oil (194.3 mg, 69%). 1 H NMR (400 MHz, CDCl 3 )δ 7.72(d,J=2.9Hz,1H),7.07(d,J=8.6Hz,1H),6.83(dd,J=8.6,3.1Hz,1H),3.96-3.87(m,1H),3.76(d,J=6.2Hz,1H),3.60-3 .48(m,2H),3.25-3.12(s,2H),2.85-2.75(m,2H),1.98-1.90(m,2H),1.81-1.73(m,2H),1.45(s,9H).ES-MS[M+H-tert-butyl] + =282.0.

[0458] [ka] tert-Butyl (3aR,5s,6aS)-5-((2'-(trifluoromethyl)-[2,3'-bipyridin]-5-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate. tert-Butyl (3aR,5s,6aS)-5-((6-chloropyridin-3-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (180 mg, 0.53 mmol, 1 eq), (2-(trifluoromethyl)pyridin-3-yl)boronic acid (295 mg, 1.55 mmol, 2.9 eq), potassium carbonate (224 mg, 1.60 mmol, 3 eq), and BrettPhos-Pd-G3 (73 mg, 0.08 mmol, 0.15 eq) were combined in a vial and sealed under inert atmosphere. 5:1 1,4-dioxane / H 2 O (4 mL total, degassed under vacuum) was added via syringe and the resulting mixture was heated to 100° C. After 2 h, the reaction mixture was cooled and 2The mixture was diluted with 0 and extracted with DCM. After concentration, the resulting residue was purified by column chromatography (3-100% EtOAc in hexanes) to give the title compound as a pale yellow oil (206 mg, 86%). 1 H NMR (400 MHz, CDCl 3 )δ 8.68(d,J=4.8Hz,1H),8.07(d,J=2.8Hz,1H),7.91(d,J=8.0Hz,1H),7.52(dd,J= 8.0,4.6Hz,1H),7.26(d,J=8.5Hz,1H),6.91(dd,J=8.5,2.9Hz,1H),4.05-3.97( m,1H),3.94(d,J=6.2Hz,1H),3.60-3.51(d,J=9.1Hz,2H),3.28-3.15(m,2H),2. 89-2.78(m,2H),2.02-1.95(m,2H),1.87-1.80(m,2H),1.46(s,9H).ES-MS[M+H] + =449.1.

[0459] [ka] (3aR,5s,6aS)-2-((tetrahydro-2H-pyran-4-yl)methyl-d 2 )-N-(2'-(trifluoromethyl)-[2,3'-bipyridin]-5-yl)octahydrocyclopenta[c]pyrrol-5-amine. tert-Butyl (3aR,5s,6aS)-5-((2'-(trifluoromethyl)-[2,3'-bipyridin]-5-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (100 mg, 0.22 mmol, 1 eq) was suspended in 4 M HCl in dioxane solution (1.67 mL). The resulting mixture was stirred at rt for 30 min, after which time the solvent was concentrated to give the hydrochloride salt as a white solid (85.8 mg, 100%). A solution of the hydrochloride (85.8 mg, 0.22 mmol, 1 eq) in NMP (3 mL) was added to cesium carbonate (292 mg, 0.89 mmol, 4 eq) and 4-(bromomethyl-d 2) tetrahydro-2H-pyran (60.6 mg, 0.33 mmol, 1.5 eq) was added. The resulting reaction mixture was stirred at 100 °C for 16 h, after which time the reaction was cooled to rt and directly purified by RP-HPLC (3-33% MeCN in 0.1% aqueous TFA over 11 min). The fractions containing the product were purified with sat.NaHCO 3 Basification with soln. and extraction with DCM afforded the title compound as a white solid (5.2 mg, 5%). 1 H NMR(400MHz,MeOD)δ 8.68(dd,J=4.8,1.2Hz,1H),7.99(d,J=2.9,1H),7.96(dd,J=7.8,1.2Hz,1H),7.70(dd,J=7.9,4. 7Hz,1H),7.26(d,J=8.7Hz,1H),7.09(dd,J=8.5,2.8Hz,1H),4.04-3.97(m,1H),3.94(dd,J=11.4, 4.3Hz,2H),3.43(td,J=11.8,2.1Hz,2H),2.80-2.72(m,2H),2.73-2.66(m,2H),2.32(dd,J=8.9, ES-MS[M+H] + =449.1.

[0460] Example 30. (3aR,5s,6aS)-2-(((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl-d 2 )-N-(6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine and (3aR,5s,6aS)-2-(((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl-d 2 )-N-(6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine [ka] tert-Butyl (3aR,5s,6aS)-5-((6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate. tert-Butyl (3aR,5s,6aS)-5-((6-chloropyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (38.0 g, 112 mmol, 1 eq), potassium carbonate (47.2 g, 336 mmol, 3 eq), (2-(trifluoromethyl)pyridin-3-yl)boronic acid (42.8 g, 224 mmol, 2 eq) and BrettPhos-Pd-G3 (15.3 g, 16.8 mmol, 0.15 eq) were combined in a flask and treated with 1,4-dioxane (300 mL) and H 2 O (60 mL) was added. The resulting reaction mixture was stirred under vacuum and N 2 The reaction mixture was heated to 100° C. and stirred for 5 h, after which time it was cooled to rt and the solids were removed by filtration along with DCM. The filtrate was concentrated and diluted with DCM and H 2 The aqueous layer was extracted with DCM and the combined organic extracts were washed with MgSO 4 The solvent was filtered and removed under reduced pressure, and the crude residue was purified by column chromatography (3-100% EtOAc in hexanes) to give the title compound as a light brown solid (25.8 g, 51%). 1 H NMR (400 MHz, CDCl 3 )δ 8.76(dd,J=4.7,1.1Hz,1H),8.04(dd,J=7.7,1.0Hz,1H),7.60(dd,J=7.9,4.7Hz,1H),7.37(d,J=9.2Hz,1H),6.70(d,J=9.3Hz,1H),5.07(d,J=6.8H) z,1H),4.45-4.37(m,1H),3.63-3.52(m,2H),3.27-3.16(m,2H),2.91-2. 82(m,2H),2.10-2.04(m,2H),1.92-1.85(m,2H),1.46(s,9H).ES-MS[M+H] + =394.2(-t-butyl).

[0461] [ka] (2,2-Dimethyltetrahydro-2H-pyran-4-yl)((3aR,5s,6aS)-5-((6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-yl)methanone. tert-Butyl (3aR,5s,6aS)-5-((6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate was dissolved in 1,4-dioxane (300 mL) and 4M HCl in 1,4-dioxane solution (200 mL) was added at 0°C. The resulting reaction mixture was warmed to rt and stirred for 2 h, after which time the solid was collected by filtration followed by washing with diethyl ether to give the HCl salt of (3aR,5s,6aS)-N-(6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine as a tan solid which was dried under vacuum and used without further purification (29.1 g, 99%; ES-MS [M+H]). + =350.2). To a suspension of HCl salt (3.46 g, 8.19 mmol, 1 eq) and 2,2-dimethyltetrahydro-2H-pyran-4-carboxylic acid (1.56 g, 9.83 mmol, 1.2 eq) in DCM (45 mL) was added DIPEA (4.28 mL, 24.6 mmol, 3 eq) followed by HATU (4.67 g, 12.3 mmol, 1.5 eq). The reaction mixture thus obtained was stirred at rt overnight, after which time it was dissolved in sat.NaHCO 3 The solution was diluted with DCM and the aqueous layer was extracted with MgSO. 4 The solvent was filtered and concentrated under reduced pressure and the crude residue was purified by column chromatography (0-7% MeOH in DCM) to give the title compound as a white spongy solid (3.02 g, 75%). 1 H NMR (400 MHz, CDCl 3)δ 8.79(dd,J=4.7,1.1Hz,1H),8.03(dd,J=8.2,1.1Hz,1H),7.62(dd,J=7.9,4.7Hz,1H),7.43(d ,J=9.3Hz,1H),6.80(dd,J=9.4,3.3Hz,1H),5.58(d,J=26.4Hz,1H),4.50-4.44(m,1H),3.84- 3.64(m,4H),3.43-3.34(m,2H),3.06-2.97(m,1H),2.95-2.86(m,1H),2.79-2.70(m,1H),2.1 6-2.05(m,2H),2.01-1.91(m,2H),1.88-1.51(m,4H),1.25(dd,J=5.1,2.3Hz,6H).ES-MS[M+H] + =490.1.

[0462] [ka] (3aR,5s,6aS)-2-(((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl-d 2 )-N-(6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine and (3aR,5s,6aS)-2-(((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl-d 2 )-N-(6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine. To a solution of (2,2-dimethyltetrahydro-2H-pyran-4-yl)((3aR,5s,6aS)-5-((6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (3.02 g, 6.17 mmol, 1 eq) in THF (35 mL) was added lithium aluminum deuteride (702 mg, 18.5 mmol, 3 eq). The resulting solution was stirred at rt for 20 min, after which time the reaction mixture was cooled to 0° C. and diluted with diethyl ether. H 2O (0.7 mL), 10% NaOH solution (0.7 mL) and H 2 2.1 mL of O was added dropwise in succession. The resulting mixture was warmed to rt and MgSO 4 was added followed by stirring for 10 min. The solids were removed by filtration along with DCM and diethyl ether, and the filtrate was concentrated under reduced pressure to give the racemic title compound as a yellow solid. ES-MS [M+H] + =478.1.

[0463] The racemic material was purified using preparative supercritical fluid (SFC) chiral chromatography (4.6 x 250 mm Chiralpak® IA column, MeOH co-solvent with 0.1% diethylamine modifier; 20% isocratic at 40°C) to give each enantiomer as a white solid in >98% ee. Crystals grown in MeOH / EtOAc of the early eluting peak were identified by X-ray crystallography as (3aR,5s,6aS)-2-(((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl-d 2 )-N-(6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine (Figure 1).

[0464] (3aR,5s,6aS)-2-(((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl-d 2 )-N-(6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine (937 mg, 32%). 1 H NMR (400 MHz, CDCl 3)δ 8.76(dd,J=4.7,1.6Hz,1H),8.05(dd,J=7.8,1.6Hz,1H),7.60(dd,J=7.9,4.7Hz,1H),7.37(d,J=9.2Hz,1H) ,6.70(d,J=9.3Hz,1H),4.96(d,J=7.3Hz,1H),4.41-4.32(m,1H),3.75(ddd,J=11.8,5.2,1.6Hz,1H),3.66( td,J=12.2,2.3Hz,1H),2.79-2.70(m,2H),2.67-2.54(m,2H),2.31(d,J=9.0Hz,2H),2.00-1.96(m,2H),1.8 9-1.80(m,1H),1.78-1.70(m,2H),1.69-1.59(m,2H),1.21(d,J=2.1Hz,6H),1.21-1.03(m,2H).ES-MS[M+H] + =478.1.

[0465] (3aR,5s,6aS)-2-(((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl-d 2 )-N-(6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine (906 mg, 31%). ES-MS [M+H] + =478.1.

[0466] Example 31. (3aR,5s,6aS)-2-((tetrahydro-2H-pyran-4-yl)methyl-d)-N-(6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine [ka] A solution of (3aR,5s,6aS)-N-(6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine hydrochloride (100 mg, 0.26 mmol, 1 eq) and tetrahydro-2H-pyran-4-carbaldehyde (89 mg, 0.78 mmol, 3 eq) in DCM (2 mL) was added with THF and D until the reaction mixture became homogenous. 2 Sodium cyanoborodeuteride (51 mg, 0.78 mmol, 3 eq) was then added and the resulting reaction mixture was stirred at rt for 1 h, after which time the reaction mixture was diluted with sat.NaHCO 3 The solution was made basic and the aqueous layer was extracted with DCM. The combined organic extracts were filtered through a phase separator, concentrated and the residue thus obtained was purified by RP-HPLC (0.05% NH over 20 min). 4 The mixture was purified by 15-55% MeCN in aqueous OH) and the fractions were concentrated to give the title compound as a white solid (29 mg, 25%). 1 H NMR(400MHz,MeOD)δ 8.76(dd,J=4.9,1.6Hz,1H),8.04-8.01(m,1H),7.76(dd,J=7.9,4.7Hz,1H),7.39( d,J=9.3Hz,1H),6.93(d,J=9.3Hz,1H),4.56-4.49(m,1H),3.93(ddd,J=11.3,4.9, 1.8Hz,2H),3.42(td,J=11.8,2.0Hz,2H),2.86-2.75(m,4H),2.31-2.23(m,3H),1. 97(ddd,J=13.0,5.8,2.0Hz,2H),1.82-1.70(m,5H),1.32-1.21(m,2H);ES-MS[M+H] + =449.3.

[0467] Example 32. (3aR,5s,6aS)-2-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)-N-(6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine [ka] (3aR,5s,6aS)-N-(6-chloropyridazin-3-yl)-2-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine. To a solution of (3aR,5s,6aS)-N-(6-chloropyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine hydrochloride (200 mg, 0.73 mmol, 1 eq) and 2,2-dimethyltetrahydro-2H-pyran-4-carbaldehyde (114 mg, 0.80 mmol, 1.1 eq) in DCM (1 mL) and THF (1 mL) was added sodium triacetoxyborohydride (462 mg, 2.18 mmol, 3 eq). The reaction mixture thus obtained was stirred at rt for 1.5 h, after which time sat.NaHCO 3 The aqueous layer was extracted with DCM and the combined organic extracts were filtered through a phase separator and concentrated. The crude residue was purified by RP-HPLC (2-25% MeCN in 0.1% TFA aqueous solution over 10 min). The fractions containing the product were purified with sat.NaHCO 3 The mixture was basified with hexanes and extracted with DCM. The combined organic extracts were filtered through a phase separator and concentrated to give the title compound (144 mg, 54%). ES-MS [M+H] + =365.4.

[0468] [ka] (3aR,5s,6aS)-2-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)-N-(6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine. (3aR,5s,6aS)-N-(6-chloropyridazin-3-yl)-2-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-amine (93 mg, 0.25 mmol., 1 eq), (2-(trifluoromethyl)pyridin-3-yl)boronic acid (73 mg, 0.38 mmol., 1.5 eq), potassium carbonate (107 mg, 0.76 mmol., 3 eq), and BrettPhos-Pd-G3 (23 mg, 0.025 mmol., 0.1 eq) were combined in a vial, which was sealed and placed under an inert atmosphere. Then, 5:1 1,4-dioxane / H 2 O solution (1 mL total, degassed under vacuum) was added via syringe and the resulting reaction mixture was stirred at 100 °C for 2 h, after which time the reaction was cooled to rt and diluted with DCM and H 2 The aqueous layer was extracted with DCM and the combined organic extracts were filtered through a phase separator and concentrated. The crude residue was purified by RP-HPLC (0.05% NH over 10 min). 4 The product was purified by elution with 30-65% MeCN in aqueous OH. The product-containing fractions were extracted with a 3:1 chloroform / IPA solution (v / v) and the combined organic extracts were filtered through a phase separator and concentrated to give the title compound as a white solid (2.6 mg, 2%). ES-MS [M+H] + =476.3.

[0469] The compounds shown in Table 1 can be prepared similarly to the compounds described above with the appropriate starting materials. Additional starting materials that can be used to prepare the compounds of the present invention include 3-bromo-4-(difluoromethyl)pyridine, tetrahydro-2H-pyran-4-carbaldehyde, (S)-(1,4-dioxane-2-yl)methanol), (R)-(1,4-dioxane-2-yl)methanol), (S)-1,4-dioxane-2-carboxylic acid, (R)-1,4-dioxane-2-carboxylic acid, (S)-tetrahydro-2H-pyran-2-carboxylic acid, (R ... S)-Tetrahydro-2H-pyran-3-carboxylic acid, (R)-Tetrahydro-2H-pyran-3-carboxylic acid, 4-fluorotetrahydro-2H-pyran-4-carboxylic acid, 4-methoxytetrahydro-2H-pyran-4-carboxylic acid, 3-methyltetrahydro-2H-pyran-3-carboxylic acid, 2-methyltetrahydro-2H-pyran-2-carboxylic acid, 4-ethyltetrahydro-2H-pyran-4-carboxylic acid, 2,2-dimethyltetrahydro-2H-pyran-4-carboxylic acid, 3,3-dimethyltetrahydro Hydro-2H-pyran-4-carboxylic acid, 2,2,6,6-tetramethyltetrahydro-2H-pyran-4-carboxylic acid, (S)-tetrahydrofuran-3-carboxylic acid, (R)-tetrahydrofuran-3-carboxylic acid, (R)-(tetrahydrofuran-3-yl)methanol, 2-(tetrahydro-2H-pyran-4-yl)acetaldehyde, 4-methyltetrahydro-2H-pyran-4-carbaldehyde, 4-methyltetrahydro-2H-pyran-4-carboxylic acid, rac-(1R,2S,4S)-2 -(Bromomethyl)-7-oxabicyclo[2.2.1]heptane, rac-(1R,2R,4S)-2-(Bromomethyl)-7-oxabicyclo[2.2.1]heptane, rac-(3aR,6aS)-Hexahydro-2H-cyclopenta[b]furan-3a-carboxylic acid, Octahydro-3aH-cyclohepta[b]furan-3a-carboxylic acid, 5-oxaspiro[2.4]heptane-6-carboxylic acid, 1-methyl-2-oxabicyclo[2.1.1]hexane-4-carboxylic acid, 5-oxaspiro[3.5]nonane-8-carboxylic acid, 2,2,6,6-tetramethyltetrahydro-4H-pyran-4-one, 2-oxaspiro[3.3]heptan-6-one, 1,6-dioxaspiro[2.5]octane, cyclohexanecarbaldehyde, cycloheptanecarbaldehyde, cyclohexanone, picolinaldehyde, 6-methylpicolinaldehyde, 6-methoxypicolinaldehyde, 4-chloropicolinaldehyde, 6-chloropicolinaldehyde, 5-fluoropicolinaldehyde, 6-fluoropicolinaldehyde, 3-methylpicolinaldehyde aldehyde, 1-(pyridin-2-yl)ethan-1-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-carbaldehyde, 2,2-difluorobenzo[d][1,3]dioxole-5-carbaldehyde, pyridazine-4-carbaldehyde, 1-fluorocyclohexane-1-carboxylic acid, 2-fluorobenzaldehyde, 2,3-difluorobenzaldehyde, 2,4-difluorobenzaldehyde, 2,6-difluorobenzoic acid and 3,3-difluorotetrahydro-2H-pyran-4-carboxylic acid.

[0470] [Table 1-1]

[0471] [Table 1-2]

[0472] [Table 1-3]

[0473] [Table 1-4]

[0474] [Table 1-5]

[0475] [Table 1-6]

[0476] [Table 1-7]

[0477] [Table 1-8]

[0478] [Table 1-9]

[0479] biological activity A. Cell lines expressing muscarinic acetylcholine receptor M4 Human or rat M 4 The cDNA was transformed with the chimeric G protein G qi5 Chinese hamster ovary (CHO-K1) cells purchased from the American Type Culture Collection were transfected with Lipofectamine 2000. 4 / G qi5 / CHO cells were grown in Ham's F-12 medium containing 10% heat-inactivated fetal bovine serum (FBS), 20 mM HEPES, 500 μg / mL G418 sulfate and 200 μg / mL hygromycin B.

[0480] B. Cell-Based Functional Assay of Muscarinic Acetylcholine Receptor M4 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 Greiner 384-well black-walled tissue culture (TC)-treated clear-bottom plates (VWR) in growth medium lacking G418 and hygromycin. Cells were incubated at 37° C. and 5% CO. 2The cells were incubated at 37°C and 5% CO overnight. The next day, the cells were washed with assay buffer using an ELX405 (BioTek) and then the final volume was aspirated to 20 μL. Next, 20 μL of a 2.3 μM stock of 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 at 37°C and 5% CO 2 The plates were incubated at 4°C for 50 min. Dye was removed by washing with ELX405 and the final volume was aspirated to 20 μL. Compound master plates were formatted in 10-point concentration-response curve (CRC) format (1:3 dilution) in 100% DMSO with starting concentrations of 10 or 1 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 2× stocks in assay buffer (40 μL) using a Thermo Fisher Combi (Thermo Fisher Scientific, Waltham, MA).

[0481] Calcium influx was measured as an increase in static fluorescence ratio using a Functional Drug Screening System (FDSS) 6000 or 7000 (Hamamatsu Corporation, Tokyo, Japan). Compounds were applied to cells (20 μL, 2×) at 2 seconds of the protocol using the automated system of the FDSS, and data were collected at 1 Hz. An EC of 10 μL at 143 seconds was obtained. 20 A concentration of the muscarinic receptor agonist acetylcholine was added (5×), followed by 12 μL of EC 80 A concentration of acetylcholine was added (5x). Agonist activity was assayed as a concentration-dependent increase in calcium mobilization upon compound addition. Positive allosteric modulator activity was assayed as a concentration-dependent increase in calcium mobilization upon compound addition above EC 20Antagonist activity was analyzed as a concentration-dependent increase in the acetylcholine response. 80 The IC was analyzed as a concentration-dependent decrease in the acetylcholine response. For the purposes of the tables herein, 50 (inhibitory concentration 50) is the EC 80 The 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) or the Dotmatics software platform (Dotmatics, Bishop's Stortford, UK).

[0482] The above assay was also operated in a second mode in which an appropriate fixed concentration of a compound of the invention was added to the cells for approximately 3 seconds after establishment of a fluorescence baseline, and the response in the cells was measured. After 140 seconds, the full concentration-response range consisting of increasing concentrations of agonist was added and the calcium response (maximum-minimal response) was measured. The EC of the agonist in the presence or absence of test compound was 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. The EC 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 the compound of the invention. The second mode also indicates whether the compound of the invention affects the maximum response of a muscarinic receptor to an agonist.

[0483] C.mAChR M 4 Compound activity in cell-based assays Compounds were synthesized as described above. Activity (IC 50 and E min) is the mAChR M 4 This was measured in a cell-based functional assay, and the data are shown in Table 2.

[0484] [Table 2-1]

[0485] [Table 2-2]

[0486] D. Cell lines expressing the muscarinic acetylcholine receptor M1 hM 1 cDNA was purchased from Missouri S&T cDNA Resource and used to stably transfect CHO-K1 cells purchased from the American Type Culture Collection using Lipofectamine 2000. hM was cultured in Ham's F-1 medium containing 10% heat-inactivated fetal bovine serum (FBS), 20 mM HEPES, and 50 μg / mL G418 sulfate. 1 The cells were grown.

[0487] E. Cell-Based Functional Assay of Muscarinic Acetylcholine Receptor M1 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-walled tissue culture (TC)-treated clear bottom plates (VWR). Cells were incubated at 37° C. and 5% CO. 2The cells were incubated at 37° C. overnight. The next day, the 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, diluted in ...

Claims

1. A compound of formula (III): 【Chemical 1】 or a pharmaceutically acceptable salt thereof (wherein: G １ is 【Chemical Formula 2】 is G １ａ is [Chemical 3] is R is hydrogen, C １～４ alkyl, C ３～４ cycloalkyl, or -C １～３ alkylene-C ３～４ cycloalkyl; R １ａ is hydrogen, C １～４ alkyl, C １～４ fluoroalkyl, -OC １～４ alkyl, -OC １～４ fluoroalkyl, -OC ３～６ cycloalkyl, -OCH ２ C ３～６ cycloalkyl, -SO ２ C １～４ alkyl, -SO ２ C ３～６ cycloalkyl, phenyl, or C ３～６ cycloalkyl, where the phenyl and each C ３～６ cycloalkyl are optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, cyano, C １～４ alkyl, C １～４ haloalkyl, -OC １～４ alkyl, and -OC １～４ haloalkyl; R １ｂ is hydrogen, halogen, cyano, C １～４ alkyl, C １～４ fluoroalkyl, or C ３～６ cycloalkyl; Alternatively, instead of R １ａ and R １ｂ together with the atoms to which they are attached form a 5- or 6-membered unsaturated or partially unsaturated carbocyclic or heterocyclic ring, and the carbocyclic or heterocyclic ring is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of halogen, cyano, C １～４ alkyl, C １～４ fluoroalkyl, C ２～４ alkenyl, C ３～６ cycloalkyl, and -C １～３ alkylene-C ３～４ cycloalkyl; R ２ is CF ３ or CHF ２ and; R ２ａ is, each time it appears, independently, halogen, C １～４ alkyl, C １～４ fluoroalkyl, -OC １～４ alkyl, or -OC １～４ fluoroalkyl; n is 0, 1, or 2, R ３ is -L １ -G ２ , G ２ , -L ２ -G ２ , -L ２ -L １ -G ２ , -C ２～６ alkylene -R ３ａ , C ３～７ alkyl, or C ３～７ is haloalkyl; R ４ is hydrogen or methyl; L １ is C １～５ alkylene or C １～５ fluoroalkylene; L ２ is 1,1-cyclopropylene; G ２ is a C optionally condensed with a 4- to 12-membered heterocyclyl, 6- to 12-membered aryl, 5- to 12-membered heteroaryl, or 6-membered aromatic hydrocarbon ３～１２ carbocyclyl, where G ２ is independently selected from the group consisting of C １～４ alkyl, halogen, cyano, oxo, C １～４ haloalkyl, -OR １３ , -N(R １３ ), -C ２ alkylene-OR １～３ , and -C １３ alkylene-N(R １～３ ), and is optionally substituted with 1 to 5 substituents independently selected from the group consisting of １３ ; ２ ​ R ３ａ is -OR １４ or -N(R １４ ) ２ and; R １３ is, each time it appears, independently, hydrogen, C １～４ alkyl, C １～４ haloalkyl, C ３～４ cycloalkyl, or -C １～３ alkylene-C ３～４ cycloalkyl, wherein, alternatively, two R １３ together with the nitrogen to which said two R １３ are attached, form a 4- to 6-membered heterocyclic ring optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen and C １～４ alkyl; R １４ is, each time it appears, independently, hydrogen, C １～４ alkyl, C １～４ haloalkyl, G ３ , or -C １～３ alkylene-G ３ ; alternatively, two Rs １４ together with the nitrogen to which said two Rs １４ are attached, form a 4- to 6-membered heterocyclic ring optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen and C １～４ alkyl; G ３ is phenyl, monocyclic 5- to 6-membered heteroaryl, monocyclic 4- to 8-membered heterocyclyl, or monocyclic C ３～８ cycloalkyl, where G ３ is optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, cyano, C １～４ alkyl, C １～４ haloalkyl, oxo, -OR １５ , and -N(R １５ ) ２ ; R １５ is, each time it appears independently, hydrogen, C １～４ alkyl, C １～４ haloalkyl, C ３～４ cycloalkyl, or -C １～３ alkylene-C ３～４ cycloalkyl, where, alternatively, two R １５ together with the nitrogen to which the two R １５ are attached, form a 4- to 6-membered heterocyclic ring optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen and C １～４ alkyl).

2. R ３ is -L １ -G ２ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein

3. G ２ The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein G is an optionally substituted 4- to 12-membered heterocyclyl.

4. G ２ In the formula, the optionally substituted 4- to 12-membered heterocyclyl ring system is a 4- to 8-membered monocyclic heterocyclyl ring system, a 6- to 10-membered bridged bicyclic heterocyclyl ring system, a 7- to 12-membered fused bicyclic heterocyclyl ring system, or a 7- to 12-membered spiro heterocyclyl ring system, wherein the heterocyclyl ring system contains 1 to 2 heteroatoms independently selected from O, N, and S. The compound according to claim 3, or a pharmaceutically acceptable salt thereof.

5. G ２ In the case of the optionally substituted 4- to 12-membered heterocyclyl ring system, it is tetrahydropyranyl, oxetanyl, tetrahydrofuranyl, oxepanyl, tetrahydrothiopyranyl, 7-oxabicyclo[2.2.1]heptanyl, 1,4-dioxanyl, hexahydro-2H-cyclopenta[b]furanyl, octahydro-3aH-cyclohepta[b]furanyl, 3-oxabicyclo[3.1.0]hexanyl, 2-oxaspiro[3.3]heptanyl, 3-oxaspiro[5.5]undecanyl, 6-oxaspiro[2.5]octanyl, 5-oxaspiro[2.4]heptanyl, 2-oxabicyclo[2.1.1]hexanyl, or 5-oxaspiro[3.5]nonanyl. The compound according to claim 3 or 4, or a pharmaceutically acceptable salt thereof.

6. G ２ is optionally substituted with 1 to 4 substituents independently selected from the group consisting of C １～４ alkyl, halogen, hydroxy, oxo, and -OC １～４ alkyl, or a pharmaceutically acceptable salt thereof, the compound according to any one of claims 1 to 5.

7. G ２ is 【Chemical 4】 The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein

8. G ２ is 【Chemical 55】 The compound according to claim 1 or 7, or a pharmaceutically acceptable salt thereof, wherein

9. L １ is C １～５ an alkylene, a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof.

10. L １ is CH ２ The compound according to claim 9, or a pharmaceutically acceptable salt thereof.

11. L １ wherein said CH in ２ is CD ２ The compound according to claim 10, or a pharmaceutically acceptable salt thereof.

12. R ３ is -L １ -G ２ and L １ is CH ２ and G ２ is 【Chemical 55】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein

13. R １ａ is hydrogen, C １～４ alkyl, C １～４ difluoroalkyl, -OC １～４ alkyl, -OC １～４ fluoroalkyl, -OC ３～６ cycloalkyl, -OCH ２ C ３～６ cycloalkyl, -SO ２ C １～４ alkyl, -SO ２ C ３～６ cycloalkyl, phenyl, or C ３～６ cycloalkyl, where the phenyl and each C ３～６ cycloalkyl are optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, cyano, C １～４ alkyl, C １～４ haloalkyl, -OC １～４ alkyl, and -OC １～４ haloalkyl; R １ｂ is hydrogen, halogen, cyano, C １～４ alkyl, C １～４ fluoroalkyl, or C ３～６ cycloalkyl, a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof.

14. G １ is [Chemical Formula 5] The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein

15. G １ is ​ The compound according to claim 1 or 14, or a pharmaceutically acceptable salt thereof, wherein

16. R １ａ and R １ｂ together with the atoms to which they are attached form a 5- or 6-membered unsaturated or partially unsaturated carbocyclic or heterocyclic ring, and the carbocyclic or heterocyclic ring is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of halogen, cyano, C １～４ alkyl, C １～４ fluoroalkyl, C ２～４ alkenyl, C ３～６ cycloalkyl, and -C １～３ alkylene-C ３～４ cycloalkyl, a compound according to any of claims 1 to 12, or a pharmaceutically acceptable salt thereof.

17. G １ is 【Chemical Formula 6】 The compound according to claim 16, or a pharmaceutically acceptable salt thereof, wherein

18. G １ａ is 【Chemical Formula 7】 The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein

19. G １ａ is 【Chemical Formula 8】 The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein

20. The compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein n is 0

21. R ２ is CF ３ the compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof.

22. n is 0 and R ２ is CF ３ The compound according to any one of claims 1 or 18 to 19, or a pharmaceutically acceptable salt thereof.

23. The compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein R is hydrogen

24. R ４ is hydrogen, the compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof.

25. (3aR,5s,6aS)-2-((tetrahydro-2H-pyran-4-yl)methyl)-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-((Tetrahydro-2H-pyran-4-yl)methyl-d ２ )-N-(6-(4-(Trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-((3,3-dimethyltetrahydro-2H-pyran-4-yl)methyl-d ２ )-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-((4-methyltetrahydro-2H-pyran-4-yl)methyl-d ２ )-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-(((S)-1,4-dioxan-2-yl)methyl-d ２ )-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-(((R)-1,4-dioxan-2-yl)methyl-d ２ )-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-(((R)-Tetrahydro-2H-pyran-2-yl)methyl)-d ２ )-N-(6-(4-(Trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-(((S)-tetrahydro-2H-pyran-2-yl)methyl)-d ２ )-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-((tetrahydro-2H-pyran-3-yl)methyl-d ２ )-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-(Cyclohexylmethyl-d ２ )-N-(6-(4-(Trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)-d ２ )-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-((Tetrahydro-2H-pyran-4-yl-2,2,6,6-d ４ )methyl-d ２ )-N-(6-(4-(Trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-N-(6-(4-(difluoromethyl)pyridin-3-yl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d ２ )octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-N-(4-cyclopropyl-6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d ２ )octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-N-(4-methoxy-6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d ２ )octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-N-(4-methyl-6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d ２ ) octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-N-(6-(4,6-bis(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d ２ ) octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-N-(4-Methyl-6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl-2,2,6,6-d ４ )methyl-d ２ )octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-N-(4-Methyl-6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl-2,2,6,6-d ４ )methyl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-(((3,3-dimethyltetrahydro-2H-pyran-4-yl)methyl-d ２ )-N-(4-methyl-6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-((3,3-dimethyltetrahydro-2H-pyran-4-yl)methyl-d ２ )-N-(4-methoxy-6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-N-(4-methoxy-6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl-2,2,6,6-d ４ )methyl-d ２ )octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-N-(4-methoxy-6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl-2,2,6,6-d ４ )methyl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-(((S)-tetrahydro-2H-pyran-3-yl)methyl)-d ２ )-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-(((R)-tetrahydro-2H-pyran-3-yl)methyl)-d ２ )-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-N-(4-(difluoromethyl)-6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d ２ )octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5S,6aS)-3a-Methyl-2-((tetrahydro-2H-pyran-4-yl-2,2,6,6-d ４ )methyl-d ２ )-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aS,5R,6aR)-3a-Methyl-2-((tetrahydro-2H-pyran-4-yl-2,2,6,6-d ４ )methyl-d ２ )-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-(oxepan-4-ylmethyl-d ２ )-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-(((3aR,6aR)-Hexahydro-3aH-cyclopenta[b]furan-3a-yl)methyl-d ２ )-N-(6-(4-(Trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-(((3aS,6aS)-hexahydro-3aH-cyclopenta[b]furan-3a-yl)methyl-d ２ )-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; ((3aR,5s,6aS)-2-(((3aS,8aR)-octahydro-3aH-cyclohepta[b]furan-3a-yl)methyl-d ２ )-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; ((3aR,5s,6aS)-2-(((3aR,8aS)-octahydro-3aH-cyclohepta[b]furan-3a-yl)methyl-d ２ )-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1,1-d ２ )-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-(((2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)methyl-d ２ )-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl-d ２ )-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; N-((3aR,5s,6aS)-2-((tetrahydro-2H-pyran-4-yl)methyl-d ２ )octahydrocyclopenta[c]pyrrol-5-yl)-7-(4-(trifluoromethyl)pyridin-3-yl)thieno[2,3-d]pyridazin-4-amine; N-((3aR,5s,6aS)-2-((tetrahydro-2H-pyran-4-yl)methyl-d ２ )octahydrocyclopenta[c]pyrrol-5-yl)-4-(4-(trifluoromethyl)pyridin-3-yl)thieno[2,3-d]pyridazin-7-amine; (3aR,5s,6aS)-2-(2,2-difluoro-2-(tetrahydro-2H-pyran-4-yl)ethyl)-1,1-d ２ )-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-(2,2-difluoro-2-(tetrahydro-2H-pyran-4-yl)ethyl)-1,1-d ２ )-N-(4-methyl-6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-N-(6-(2-(difluoromethyl)pyridin-3-yl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d ２ )octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-((Tetrahydro-2H-pyran-4-yl)methyl-d ２ )-N-(6-(2-(Trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-((tetrahydro-2H-pyran-4-yl)methyl)-N-(6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-((tetrahydro-2H-pyran-4-yl)methyl-d ２ )-N-(2'-(trifluoromethyl)-[2,3'-bipyridin]-5-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-(2-(tetrahydro-2H-pyran-4-yl)ethyl-1,1-d ２ )-N-(6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl-d ２ )-N-(6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-((Tetrahydro-2H-pyran-4-yl-2,2,6,6-d ４ )methyl-d ２ )-N-(6-(2-(Trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-((2,2,6,6-Tetramethyltetrahydro-2H-pyran-4-yl)methyl-d ２ )-N-(6-(2-(Trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-(((R)-Tetrahydro-2H-pyran-3-yl)methyl-d ２ )-N-(6-(2-(Trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-(((S)-tetrahydro-2H-pyran-3-yl)methyl)-d ２ )-N-(6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-(((S)-tetrahydro-2H-pyran-2-yl)methyl)-d ２ )-N-(6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-(((R)-Tetrahydro-2H-pyran-2-yl)methyl-d ２ )-N-(6-(2-(Trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-N-(4-methyl-6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl-d ２ ) octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-(((S)-1,4-dioxan-2-yl)methyl-d ２ )-N-(6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-(oxepan-4-ylmethyl-d ２ )-N-(6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-((3,3-dimethyltetrahydro-2H-pyran-4-yl)methyl-d ２ )-N-(6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-((5-oxaspiro[2.4]heptan-6-yl)methyl-d ２ )-N-(6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-((1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)methyl-d ２ )-N-(6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5S,6aS)-3a-methyl-2-((tetrahydro-2H-pyran-4-yl)methyl-d ２ )-N-(6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aS,5R,6aR)-3a-Methyl-2-(((tetrahydro-2H-pyran-4-yl)methyl)-d ２ )-N-(6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5S,6aS)-3a-Methyl-2-((tetrahydro-2H-pyran-4-yl-2,2,6,6-d ４ )methyl-d ２ )-N-(6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aS,5R,6aR)-3a-Methyl-2-((tetrahydro-2H-pyran-4-yl-2,2,6,6-d ４ )methyl-d ２ )-N-(6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-(((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)-d ２ )-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-(((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl-d ２ )-N-(6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5S,6aS)-2-(((5-oxaspiro[3.5]nonan-8-yl)methyl)-d ２ )-N-(6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; (3aR,5s,6aS)-2-((tetrahydro-2H-pyran-4-yl)methyl-d)-N-(6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine; The compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of

26. The compound, wherein The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein

27. The compound is the compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein

28. The compound is the compound according to claim 25, or a pharmaceutically acceptable salt thereof, wherein

29. The compound is the compound according to claim 25, or a pharmaceutically acceptable salt thereof, wherein

30. The compound is the compound according to claim 25, or a pharmaceutically acceptable salt thereof, wherein

31. The compound is the compound according to claim 25, or a pharmaceutically acceptable salt thereof, wherein

32. The compound is the compound according to claim 25, or a pharmaceutically acceptable salt thereof, wherein

33. The compound is the compound according to claim 25, or a pharmaceutically acceptable salt thereof, wherein

34. The compound according to any one of claims 1 or 25 to 33, or a pharmaceutically acceptable salt thereof, wherein the compound is isotopically labeled with deuterium.

35. The compound according to claim 34, or a pharmaceutically acceptable salt thereof, having at least 90% deuterium incorporation in each deuterium label.

36. A pharmaceutical composition comprising the compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

37. The compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 36, for use in the treatment of a neurodegenerative disorder, a movement disorder, or a brain disorder.

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